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Zalutsky, Michael Rod

Overview:

The overall objective of our laboratory is the development of novel radioactive compounds for improving the diagnosis and treatment of cancer. This work primarily involves radiohalo-genation of biomolecules via site-specific approaches, generally via demetallation reactions. Radionuclides utilized for imaging include I-123, I-124 and F-18, the later two being of particular interest because they can be used for the quantification of biochemical and physiological processes in the living human through positron emission tomography. For therapy, astatine-211 decays by the emission of alpha-particles, a type of radiation considerably more cytotoxic that the beta-particles used in conventional endoradiotherapy. The range of At-211 alpha particles is only a few cell diameters, offering the possibility of extremely focal irradiation of malignant cells while leaving neighboring cells intact. Highlights of recent work include: a)
development of reagents for protein and peptide radioiodination that decrease deiodination in vivo by up to 100-fold, b) demonstration that At-211 labeled monoclonal antibodies are effective in the treatment of a rat model of neoplastic meningitis, c) synthesis of a thymidine analogue labeled with At-211 and the demonstration that this molecule is taken up in cellular DNA with highly cytotoxicity even at levels of only one atom bound per cell and d) development of
radiohalobenzylguanidines which are specifically cytotoxic for human neuroblastoma cells.

Positions:

Jonathan Spicehandler, M.D. Professor of Neuro Oncology, in the School of Medicine

Radiology
School of Medicine

Professor of Radiology

Radiology
School of Medicine

Professor of Radiation Oncology

Radiation Oncology
School of Medicine

Professor in Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.A. 1972

M.A. — Washington University

Ph.D. 1974

Ph.D. — Washington University

Grants:

Astatine And Iodine Radiolabeled Monoclonal Antibodies

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 01, 1985
End Date
December 31, 2020

Labeling nanobodies with 18F residualizing labels for HER2 specific PET imaging

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
May 01, 2015
End Date
April 30, 2020

Image-guided Dosimetry for Injectable Brachytherapy based on Elastin-like Polypeptide Nanoparticles

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
August 01, 2017
End Date
July 31, 2019

Systemic EGFRvIII-targeted bispecific antibody as immunotherapy for glioblastoma

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
March 01, 2015
End Date
February 28, 2019

Novel Radiohalogenation Strategies for Enhancing Imaging and Targeted Radiotherapy

Administered By
Radiology
AwardedBy
Memorial Sloan Kettering Cancer Center
Role
Principal Investigator
Start Date
August 01, 2016
End Date
July 31, 2018

Treating Melanoma with a Molecularly Engineered, Long Circulating Immunotoxin

Administered By
Biomedical Engineering
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 15, 2015
End Date
June 30, 2018

Development of Tethered Hsp90 Inhibitors Carrying Radiolabelled Probes to Specifically Descriminate and Kill Malignant

Administered By
Pharmacology & Cancer Biology
AwardedBy
Department of Defense
Role
Partnering PI
Start Date
May 01, 2015
End Date
April 30, 2018

Development of Tethered Hsp90 Inhibitors Carrying Radioiodinated Probes to Specifically Discriminate and Kill Malignant

Administered By
Radiology
AwardedBy
Department of Defense
Role
Principal Investigator
Start Date
May 01, 2015
End Date
April 30, 2018

Small Molecule PSMA-Targeted Alpha Therapy

Administered By
Radiology
AwardedBy
Johns Hopkins University
Role
Principal Investigator
Start Date
May 01, 2014
End Date
April 30, 2018

University Training Program in Biomolecular and Tissue Engineering

Administered By
Biomedical Engineering
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1994
End Date
June 30, 2017

Development of a Targeted Radionuclide Therapy for Triple Negative Breast Cancer

Administered By
Radiology
AwardedBy
OncoTAb, Inc.
Role
Co Investigator
Start Date
September 19, 2016
End Date
June 18, 2017

Pediatric Brain Tumor Consortium

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
St. Jude Children's Research Hospital
Role
Collaborator
Start Date
April 01, 2014
End Date
March 31, 2017

Imaging IDH1 Mutations in Glioma and Other Malignancies

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
January 01, 2014
End Date
December 31, 2016

Research Training In Neuro-Oncology

Administered By
Neurosurgery, Neuro-Oncology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1998
End Date
August 31, 2016

Thermally Triggered Multivalent Targeting of Tumors

Administered By
Biomedical Engineering
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
April 01, 2007
End Date
June 30, 2016

Thermally Targeted Drug Delivery by Elastin Biopolymers

Administered By
Pratt School of Engineering
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
August 01, 2002
End Date
April 30, 2016

Local Radionuclide Delivery to Solid Tumors by Injectible Biopolymer

Administered By
Biomedical Engineering
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
May 17, 2009
End Date
January 31, 2016

Production of Astatine-211 at the Duke University Medical Center for its Regional Distribution

Administered By
Radiology, Nuclear Medicine
AwardedBy
Department of Energy
Role
Co Investigator
Start Date
August 01, 2012
End Date
November 30, 2014

Modulation of the blood-tumor barrier through targeted suppression of claudin 5

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
August 16, 2011
End Date
August 02, 2013

Cross-disciplinary Training in Medical Physics

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 2007
End Date
June 30, 2013

Brain Tumors - Immunological and Biological Studies

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
April 20, 2001
End Date
March 31, 2013

Small Animal PET / CT Molecular Imaging

Administered By
Radiology, Nuclear Medicine
AwardedBy
National Institutes of Health
Role
Major User
Start Date
April 01, 2011
End Date
March 31, 2012

Radionuclide-based Molecular Imaging of the DNA Repair Protein AGT

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
March 01, 2009
End Date
February 28, 2011

Astatine-211 Radiochemistry: The Development of Methodologies for High Activity Level Radio-Synthesis

Administered By
Radiology
AwardedBy
Department of Energy
Role
Principal Investigator
Start Date
September 15, 2008
End Date
December 14, 2010

Research Training In Neuro-Oncology

Administered By
Neurosurgery, Neuro-Oncology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 15, 2005
End Date
August 31, 2010

Thermally-Induced Intra-Articular Drug Delivery System

Administered By
Orthopaedics
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 01, 2006
End Date
June 30, 2009

Imaging of O6-Alkylguianine-DNA Alkyltransferase

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
September 30, 2002
End Date
August 31, 2007

Targeted Radiotherapeutics: Chemical and Biological Aspects

Administered By
Radiology
AwardedBy
Department of Energy
Role
Principal Investigator
Start Date
December 01, 2004
End Date
November 30, 2006

Astatine-211 & Radioiodine Labeled Octreotide Conjugates

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 2001
End Date
June 30, 2006

Anti-Tenascin Antibody Constructs

Administered By
Radiology
AwardedBy
Department of Energy
Role
Principal Investigator
Start Date
May 01, 1995
End Date
November 30, 2005

GCRC CAP

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 01, 2000
End Date
August 31, 2005

Higher Oxidation State Astatine-211 Radiopharmaceuticals

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 30, 2003
End Date
August 10, 2005

Molecular Imaging Center Planning Grant

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
August 01, 2000
End Date
July 31, 2004

Astatine And Iodine Radiolabeled Monoclonal Antibodies

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 1999
End Date
January 31, 2004

Development of Novel Tumor Imaging Agents

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
March 07, 2000
End Date
February 28, 2003

Radiolabeled Monoclonal Antibodies And Hyperthermia

Administered By
Radiology
AwardedBy
Department of Energy
Role
Principal Investigator
Start Date
November 01, 1998
End Date
October 31, 2001

Brain Tumors--Immunological and Biological Studies

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
December 01, 1976
End Date
March 31, 2001

Brain Tumors - Immunological And Biological Studies

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
April 01, 1997
End Date
March 31, 1999

Src On Primary And Matastatic Tumors Of The Cns

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
May 01, 1994
End Date
March 31, 1999

Astatine And Iodine Radiolabeled Monoclonal Antibodies

Administered By
Radiology, Nuclear Medicine
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 1994
End Date
March 31, 1999

Src On Primary And Metastatic Tumors Of The Cns

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
March 01, 1997
End Date
February 28, 1999

Astatine And Iodine Radiolabeled Monoclonal Antibodies

Administered By
Radiology, Nuclear Medicine
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 01, 1993
End Date
January 31, 1999

Astatine And Iodine Radiolabeled Monoclonal Antibodies

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 01, 1985
End Date
January 31, 1999

Cancer Center Core Support Grant

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 01, 1976
End Date
December 31, 1998

Comprehensive Cancer Center Core Support Grant

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 01, 1976
End Date
December 31, 1998

Comprehensive Cancer Center Core Support Grant

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 01, 1976
End Date
December 31, 1998

Positron Emission Imaging Of Tumors Using Monoclonal Antib

Administered By
Radiology, Nuclear Medicine
AwardedBy
Department of Energy
Role
Principal Investigator
Start Date
November 01, 1995
End Date
October 31, 1998

Mibg And Analogs For Diagnosis And Therapy

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
April 01, 1993
End Date
March 31, 1998

Recombinant Anti-Tenascin Antibody Constructs

Administered By
Radiology, Nuclear Medicine
AwardedBy
Department of Energy
Role
Principal Investigator
Start Date
May 01, 1995
End Date
February 28, 1998

Positron Tomographic Imaging Of Tumors Using Monoclonal An

Administered By
Radiology, Nuclear Medicine
AwardedBy
Department of Energy
Role
Principal Investigator
Start Date
November 01, 1993
End Date
October 31, 1995

Positron Emission Tomography Imaging Of Tumors Using Monoc

Administered By
Radiology, Nuclear Medicine
AwardedBy
Department of Energy
Role
Principal Investigator
Start Date
November 01, 1992
End Date
October 31, 1995

Intrathecal Therapy Of Melanoma Neoplastic Meningitis

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
May 01, 1993
End Date
April 30, 1995

Positron Emission Tom0graphic Imaging Of Tumors Using Mono

Administered By
Radiology, Nuclear Medicine
AwardedBy
Department of Energy
Role
Principal Investigator
Start Date
June 01, 1992
End Date
April 14, 1995

Positron Emission Tomographic Imaging Of Tumors Using Mono

Administered By
Radiology, Nuclear Medicine
AwardedBy
Department of Energy
Role
Principal Investigator
Start Date
April 15, 1989
End Date
April 14, 1995

Specific Applications Of Pet And Mrs In Brain Tumors

Administered By
Radiology, Nuclear Medicine
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
April 01, 1994
End Date
March 31, 1995

Scor In Coronary And Vascular Diseases

Administered By
Medicine, Cardiology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
January 01, 1992
End Date
December 31, 1994

Src On Malignant Human Gliomas And Medulloblastomas

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
April 01, 1993
End Date
March 31, 1994

Cancer And Leukemia Group B Statistical Center

Administered By
Duke Cancer Institute
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
April 01, 1992
End Date
March 31, 1993

Positron Emission Tomagraphic Imaging Of Tumors Using Mono

Administered By
Radiology, Nuclear Medicine
AwardedBy
Department of Energy
Role
Principal Investigator
Start Date
April 15, 1991
End Date
May 31, 1992

Positron Emission Tomagraphic Imaging Of Tumors Using ...

Administered By
Radiology, Nuclear Medicine
AwardedBy
Department of Education
Role
Principal Investigator
Start Date
April 15, 1990
End Date
April 14, 1992

Positron Emission Tomogrphic Imaging Of Tumors Using Monoc

Administered By
Radiology, Nuclear Medicine
AwardedBy
Department of Energy
Role
Principal Investigator
Start Date
April 01, 1989
End Date
April 01, 1992

Radiotherapy Using Monoclonal Antibodies And Astatine

Administered By
Radiology, Nuclear Medicine
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 01, 1987
End Date
June 01, 1989
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Publications:

131I-labeled Anti-HER2 Camelid sdAb as a Theranostic Tool in Cancer Treatment.

Purpose: Camelid single-domain antibody-fragments (sdAb) have beneficial pharmacokinetic properties, and those targeted to HER2 can be used for imaging of HER2-overexpressing cancer. Labeled with a therapeutic radionuclide, they may be used for HER2-targeted therapy. Here, we describe the generation of a 131I-labeled sdAb as a theranostic drug to treat HER2-overexpressing cancer.Experimental Design: Anti-HER2 sdAb 2Rs15d was labeled with 131I using [131I]SGMIB and evaluated in vitro Biodistribution was evaluated in two HER2+ murine xenograft models by micro-SPECT/CT imaging and at necropsy, and under challenge with trastuzumab and pertuzumab. The therapeutic potential of [131I]SGMIB-2Rs15d was investigated in two HER2+ tumor mouse models. A single-dose toxicity study was performed in mice using unlabeled [127I]SGMIB-sdAb at 1.4 mg/kg. The structure of the 2Rs15d-HER2 complex was determined by X-ray crystallography.Results: [131I]SGMIB-2Rs15d bound specifically to HER2+ cells (Kd = 4.74 ± 0.39 nmol/L). High and specific tumor uptake was observed in both BT474/M1 and SKOV-3 tumor xenografted mice and surpassed kidney levels by 3 hours. Extremely low uptake values were observed in other normal tissues at all time points. The crystal structure revealed that 2Rs15d recognizes HER2 Domain 1, consistent with the lack of competition with trastuzumab and pertuzumab observed in vivo [131I]SGMIB-2Rs15d alone, or in combination with trastuzumab, extended median survival significantly. No toxicity was observed after injecting [127I]SGMIB-2Rs15d.Conclusions: These findings demonstrate the theranostic potential of [131I]SGMIB-2Rs15d. An initial scan using low radioactive [*I]SGMIB-2Rs15d allows patient selection and dosimetry calculations for subsequent therapeutic [131I]SGMIB-2Rs15d and could thereby impact therapy outcome on HER2+ breast cancer patients. Clin Cancer Res; 23(21); 6616-28. ©2017 AACR.

Authors
D'Huyvetter, M; De Vos, J; Xavier, C; Pruszynski, M; Sterckx, YGJ; Massa, S; Raes, G; Caveliers, V; Zalutsky, MR; Lahoutte, T; Devoogdt, N
MLA Citation
D'Huyvetter, M, De Vos, J, Xavier, C, Pruszynski, M, Sterckx, YGJ, Massa, S, Raes, G, Caveliers, V, Zalutsky, MR, Lahoutte, T, and Devoogdt, N. "131I-labeled Anti-HER2 Camelid sdAb as a Theranostic Tool in Cancer Treatment." Clinical cancer research : an official journal of the American Association for Cancer Research 23.21 (November 2017): 6616-6628.
PMID
28751451
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
23
Issue
21
Publish Date
2017
Start Page
6616
End Page
6628
DOI
10.1158/1078-0432.ccr-17-0310

Astatine-211 labeled anti-HER2 5F7 single domain antibody fragment conjugates: radiolabeling and preliminary evaluation.

Derived from heavy chain only camelid antibodies, ~15-kDa single-domain antibody fragments (sdAbs) are an attractive platform for developing molecularly specific imaging probes and targeted radiotherapeutics. The rapid tumor accumulation and normal tissue clearance of sdAbs might be ideal for use with (211)At, a 7.2-h half-life α-emitter, if appropriate labeling chemistry can be devised to trap (211)At in cancer cells after sdAb binding. This study evaluated two reagents, [(211)At]SAGMB and iso-[(211)At]SAGMB, for this purpose.[(211)At]SAGMB and iso-[(211)At]SAGMB, and their radioiodinated analogues [(131)I]SGMIB and iso-[(131)I]SGMIB, were synthesized by halodestannylation and reacted with the anti-HER2 sdAb 5F7. Radiochemical purity, immunoreactivity and binding affinity were determined. Paired-label internalization assays on HER2-expressing BT474M1 breast carcinoma cells directly compared [(131)I]SGMIB-5F7/[(211)At]SAGMB-5F7 and iso-[(131)I]SGMIB-5F7/iso-[(211)At]SAGMB-5F7 tandems. The biodistribution of the two tandems was evaluated in SCID mice with subcutaneous BT474M1 xenografts.Radiochemical yields for Boc2-iso-[(211)At]SAGMB and Boc2-[(211)At]SAGMB synthesis, and efficiencies for coupling of iso-[(211)At]SAGMB and [(211)At]SAGMB to 5F7 were similar, with radiochemical purities of [(211)At]SAGMB-5F7 and iso-[(211)At]SAGMB-5F7 >98%. iso-[(211)At]SAGMB-5F7 and [(211)At]SAGMB-5F7 had immunoreactive fractions >80% and HER2 binding affinities of less than 5 nM. Internalization assays demonstrated high intracellular trapping of radioactivity, with little difference observed between corresponding (211)At- and (131)I-labeled 5F7 conjugates. Higher BT474M1 intracellular retention was observed from 1-6 h for the iso-conjugates (iso-[(211)At]SAGMB-5F7, 74.3 ± 2.8%, vs. [(211)At]SAGMB-5F7, 63.7 ± 0.4% at 2 h) with the opposite behavior observed at 24 h. Peak tumor uptake for iso-[(211)At]SAGMB-5F7 was 23.4 ± 2.2% ID/g at 4 h, slightly lower than its radioiodinated counterpart, but significantly higher than observed with [(211)At]SAGMB-5F7. Except in kidneys and lungs, tumor-to-normal organ ratios for iso-[(211)At]SAGMB-5F7 were greater than 10:1 by 2 h, and significantly higher than those for [(211)At]SAGMB-5F7.These (211)At-labeled sdAb conjugates, particularly iso-[(211)At]SAGMB-5F7, warrant further evaluation for targeted α-particle radiotherapy of HER2-expressing cancers.

Authors
Choi, J; Vaidyanathan, G; Koumarianou, E; Kang, CM; Zalutsky, MR
MLA Citation
Choi, J, Vaidyanathan, G, Koumarianou, E, Kang, CM, and Zalutsky, MR. "Astatine-211 labeled anti-HER2 5F7 single domain antibody fragment conjugates: radiolabeling and preliminary evaluation." Nuclear medicine and biology 56 (September 19, 2017): 10-20.
Website
http://hdl.handle.net/10161/15690
PMID
29031230
Source
epmc
Published In
Nuclear Medicine and Biology
Volume
56
Publish Date
2017
Start Page
10
End Page
20
DOI
10.1016/j.nucmedbio.2017.09.003

Fluorine-18 Labeling of the HER2-Targeting Single-Domain Antibody 2Rs15d Using a Residualizing Label and Preclinical Evaluation.

Our previous studies with F-18-labeled anti-HER2 single-domain antibodies (sdAbs) utilized 5F7, which binds to the same epitope on HER2 as trastuzumab, complicating its use for positron emission tomography (PET) imaging of patients undergoing trastuzumab therapy. On the other hand, sdAb 2Rs15d binds to a different epitope on HER2 and thus might be a preferable vector for imaging in these patients. The aim of this study was to evaluate the tumor targeting of F-18 -labeled 2Rs15d in HER2-expressing breast carcinoma cells and xenografts.sdAb 2Rs15d was labeled with the residualizing labels N-succinimidyl 3-((4-(4-[18F]fluorobutyl)-1H-1,2,3-triazol-1-yl)methyl)-5-(guanidinomethyl)benzoate ([18F]RL-I) and N-succinimidyl 4-guanidinomethyl-3-[125I]iodobenzoate ([125I]SGMIB), and the purity and HER2-specific binding affinity and immunoreactivity were assessed after labeling. The biodistribution of I-125- and F-18-labeled 2Rs15d was determined in SCID mice bearing subcutaneous BT474M1 xenografts. MicroPET/x-ray computed tomograph (CT) imaging of [18F]RL-I-2Rs15d was performed in this model and compared to that of nonspecific sdAb [18F]RL-I-R3B23. MicroPET/CT imaging was also done in an intracranial HER2-positive breast cancer brain metastasis model after administration of 2Rs15d-, 5F7-, and R3B23-[18F]RL-I conjugates.[18F]RL-I was conjugated to 2Rs15d in 40.8 ± 9.1 % yield and with a radiochemical purity of 97-100 %. Its immunoreactive fraction (IRF) and affinity for HER2-specific binding were 79.2 ± 5.4 % and 7.1 ± 0.4 nM, respectively. [125I]SGMIB was conjugated to 2Rs15d in 58.4 ± 8.2 % yield and with a radiochemical purity of 95-99 %; its IRF and affinity for HER2-specific binding were 79.0 ± 12.9 % and 4.5 ± 0.8 nM, respectively. Internalized radioactivity in BT474M1 cells in vitro for [18F]RL-I-2Rs15d was 43.7 ± 3.6, 36.5 ± 2.6, and 21.7 ± 1.2 % of initially bound radioactivity at 1, 2, and 4 h, respectively, and was similar to that seen for [125I]SGMIB-2Rs15d. Uptake of [18F]RL-I-2Rs15d in subcutaneous xenografts was 16-20 %ID/g over 1-3 h. Subcutaneous tumor could be clearly delineated by microPET/CT imaging with [18F]RL-I-2Rs15d but not with [18F]RL-I-R3B23. Intracranial breast cancer brain metastases could be visualized after intravenous administration of both [18F]RL-I-2Rs15d and [18F]RL-I-5F7.Although radiolabeled 2Rs15d conjugates exhibited lower tumor cell retention both in vitro and in vivo than that observed previously for 5F7, given that it binds to a different epitope on HER2 from those targeted by the clinically utilized HER2-targeted therapeutic antibodies trastuzumab and pertuzumab, F-18-labeled 2Rs15d has potential for assessing HER2 status by PET imaging after trastuzumab and/or pertuzumab therapy.

Authors
Zhou, Z; Vaidyanathan, G; McDougald, D; Kang, CM; Balyasnikova, I; Devoogdt, N; Ta, AN; McNaughton, BR; Zalutsky, MR
MLA Citation
Zhou, Z, Vaidyanathan, G, McDougald, D, Kang, CM, Balyasnikova, I, Devoogdt, N, Ta, AN, McNaughton, BR, and Zalutsky, MR. "Fluorine-18 Labeling of the HER2-Targeting Single-Domain Antibody 2Rs15d Using a Residualizing Label and Preclinical Evaluation." Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging (April 13, 2017).
PMID
28409338
Source
epmc
Published In
Molecular Imaging and Biology
Publish Date
2017
DOI
10.1007/s11307-017-1082-x

Radiopharmaceutical chemistry of targeted radiotherapeutics, part 4: Strategies for 211At labeling at high activities and radiation doses of 211At α-particles.

Alpha particles are radiation of high energy and short range, properties that can lead to radiolysis-mediated complications in labeling chemistry at the high radioactivity levels required for clinical application. In previous papers in this series, we have shown that radiation dose has a profound effect on the astatine species that are present in the labeling reaction and their suitability for the synthesis of N-succinimidyl 3-[211At]astatobenzoate. The purpose of this study was to evaluate the effects of adding N-chlorosuccinimide (NCS) to the methanol solution used for initial isolation of 211At after distillation, a process referred to as 211At stabilization, on 211At chemistry after exposure to high radiation doses.High performance liquid chromatography was used to evaluate the distribution of 211At species present in methanol in the 500-65,000Gy radiation dose range and the synthesis of SAB from N-succinimidyl 3-(tri-n-butylstannyl)benzoate in the 500-120,000Gy radiation dose range using different 211At timeactivity combinations under conditions with/without 211At stabilization.In the absence of NCS stabilization, a reduced form of astatine, At(2), increased with increasing radiation dose, accounting for about half the total activity by about 15,000Gy, while with stabilization, At(2) accounted for <10% of 211At activity even at doses >60,000Gy. SAB yields without stabilization rapidly declined with increasing dose, falling to ~20% at about 5000Gy while with stabilization, yields >80% were obtained with 211At solutions stored for more than 23h and receiving radiation doses >100,000Gy.Adding NCS to the methanol solution used for initial isolation of 211At is a promising strategy for countering the deleterious effects of radiolysis on 211At chemistry.This strategy could facilitate the ability to perform 211At labeling at sites remote from its production and at the high activity levels required for clinical applications.

Authors
Pozzi, OR; Zalutsky, MR
MLA Citation
Pozzi, OR, and Zalutsky, MR. "Radiopharmaceutical chemistry of targeted radiotherapeutics, part 4: Strategies for 211At labeling at high activities and radiation doses of 211At α-particles." Nuclear medicine and biology 46 (March 2017): 43-49.
PMID
28013121
Source
epmc
Published In
Nuclear Medicine and Biology
Volume
46
Publish Date
2017
Start Page
43
End Page
49
DOI
10.1016/j.nucmedbio.2016.11.009

Preparation, cytotoxicity, and in vivo antitumor efficacy of 111In-labeled modular nanotransporters.

Modular nanotransporters (MNTs) are a polyfunctional platform designed to achieve receptor-specific delivery of short-range therapeutics into the cell nucleus by receptor-mediated endocytosis, endosome escape, and targeted nuclear transport. This study evaluated the potential utility of the MNT platform in tandem with Auger electron emitting 111In for cancer therapy.Three MNTs developed to target either melanocortin receptor-1 (MC1R), folate receptor (FR), or epidermal growth factor receptor (EGFR) that are overexpressed on cancer cells were modified with p-SCN-Bn-NOTA and then labeled with 111In in high specific activity. Cytotoxicity of the 111In-labeled MNTs was evaluated on cancer cell lines bearing the appropriate receptor target (FR: HeLa, SK-OV-3; EGFR: A431, U87MG.wtEGFR; and MC1R: B16-F1). In vivo micro-single-photon emission computed tomography/computed tomography imaging and antitumor efficacy studies were performed with intratumoral injection of MC1R-targeted 111In-labeled MNT in B16-F1 melanoma tumor-bearing mice.The three NOTA-MNT conjugates were labeled with a specific activity of 2.7 GBq/mg with nearly 100% yield, allowing use without subsequent purification. The cytotoxicity of 111In delivered by these MNTs was greatly enhanced on receptor-expressing cancer cells compared with 111In nontargeted control. In mice with B16-F1 tumors, prolonged retention of 111In by serial imaging and significant tumor growth delay (82% growth inhibition) were found.The specific in vitro cytotoxicity, prolonged tumor retention, and therapeutic efficacy of MC1R-targeted 111In-NOTA-MNT suggest that this Auger electron emitting conjugate warrants further evaluation as a locally delivered radiotherapeutic, such as for ocular melanoma brachytherapy. Moreover, the high cytotoxicity observed with FR- and EGFR-targeted 111In-NOTA-MNT suggests further applications of the MNT delivery strategy should be explored.

Authors
Slastnikova, TA; Rosenkranz, AA; Morozova, NB; Vorontsova, MS; Petriev, VM; Lupanova, TN; Ulasov, AV; Zalutsky, MR; Yakubovskaya, RI; Sobolev, AS
MLA Citation
Slastnikova, TA, Rosenkranz, AA, Morozova, NB, Vorontsova, MS, Petriev, VM, Lupanova, TN, Ulasov, AV, Zalutsky, MR, Yakubovskaya, RI, and Sobolev, AS. "Preparation, cytotoxicity, and in vivo antitumor efficacy of 111In-labeled modular nanotransporters." International Journal of Nanomedicine 12 (January 10, 2017): 395-410.
PMID
28138237
Source
epmc
Published In
International journal of nanomedicine
Volume
12
Publish Date
2017
Start Page
395
End Page
410
DOI
10.2147/ijn.s125359

Synthesis and Preliminary Evaluation of 5-[18F]fluoroleucine.

Amino acid transporters, such as LAT1, are overexpressed in aggressive prostate and breast carcinomas, directly influencing pathways of growth and proliferation.The purpose of this study was to synthesize and characterize a novel 18F labeled leucine analog, 5-[18F]fluoroleucine, as a potential imaging agent for aggressive tumors which may not be amenable to imaging by FDG PET.5-fluoroleucine was synthesized and characterized, and its 18F-labeled analog was synthesized from a mesylate precursor. First, breast cancer cell line assays were performed to evaluate uptake of 3H- or 14C-labeled L-leucine and other essential amino acids. Both L-leucine and 5- [18F]fluoroleucine were tested for uptake and accumulation over time, and for uptake via LAT1. Biodistribution studies were performed to estimate radiation dosimetry for human studies. Small animal PET / CT studies of a breast cancer were performed to evaluate in vivo 5-[18F]fluoroleucine tumor uptake.Breast cancer cell lines showed increasing high net accumulation of L-[14C]leucine. Both L-leucine and 5-[18F]fluoroleucine showed increasing uptake over time in in vitro tumor cell assays, and uptake was also shown to occur via LAT1. The biodistribution study of 5-[18F]fluoroleucine showed rapid renal excretion, no significant in vivo metabolism, and acceptable dosimetry for use in humans. In vivo small animal PET / CT imaging of a breast cancer xenograft showed uptake of 5- [18F]fluoroleucine in the tumor, which progressively increased over time.5-[18F]fluoroleucine is a leucine analog which may be useful in identifying tumors with high or upregulated expression of amino acid transporters, providing additional information that may not be provided by FDG PET.

Authors
Chin, BB; McDougald, D; Weitzel, DH; Hawk, T; Reiman, RE; Zalutsky, MR; Vaidyanathan, G
MLA Citation
Chin, BB, McDougald, D, Weitzel, DH, Hawk, T, Reiman, RE, Zalutsky, MR, and Vaidyanathan, G. "Synthesis and Preliminary Evaluation of 5-[18F]fluoroleucine." Current radiopharmaceuticals 10.1 (January 2017): 41-50.
Website
http://hdl.handle.net/10161/13590
PMID
28034351
Source
epmc
Published In
Current Radiopharmaceuticals
Volume
10
Issue
1
Publish Date
2017
Start Page
41
End Page
50
DOI
10.2174/1874471009666161230114954

(2S)-2-(3-(1-Carboxy-5-(4-211At-Astatobenzamido)Pentyl)Ureido)-Pentanedioic Acid for PSMA-Targeted α-Particle Radiopharmaceutical Therapy.

Alpha-particle emitters have a high linear energy transfer and short range, offering the potential for treating micrometastases while sparing normal tissues. We developed a urea-based, 211At-labeled small molecule targeting prostate-specific membrane antigen (PSMA) for the treatment of micrometastases due to prostate cancer (PC).PSMA-targeted (2S)-2-(3-(1-carboxy-5-(4-211At-astatobenzamido)pentyl)ureido)-pentanedioic acid (211At- 6: ) was synthesized. Cellular uptake and clonogenic survival were tested in PSMA-positive (PSMA+) PC3 PIP and PSMA-negative (PSMA-) PC3 flu human PC cells after 211At- 6: treatment. The antitumor efficacy of 211At- 6: was evaluated in mice bearing PSMA+ PC3 PIP and PSMA- PC3 flu flank xenografts at a 740-kBq dose and in mice bearing PSMA+, luciferase-expressing PC3-ML micrometastases. Biodistribution was determined in mice bearing PSMA+ PC3 PIP and PSMA- PC3 flu flank xenografts. Suborgan distribution was evaluated using α-camera images, and microscale dosimetry was modeled. Long-term toxicity was assessed in mice for 12 mo.211At- 6: treatment resulted in PSMA-specific cellular uptake and decreased clonogenic survival in PSMA+ PC3 PIP cells and caused significant tumor growth delay in PSMA+ PC3 PIP flank tumors. Significantly improved survival was achieved in the newly developed PSMA+ micrometastatic PC model. Biodistribution showed uptake of 211At- 6: in PSMA+ PC3 PIP tumors and in kidneys. Microscale kidney dosimetry based on α-camera images and a nephron model revealed hot spots in the proximal renal tubules. Long-term toxicity studies confirmed that the dose-limiting toxicity was late radiation nephropathy.PSMA-targeted 211At- 6: α-particle radiotherapy yielded significantly improved survival in mice bearing PC micrometastases after systemic administration. 211At- 6: also showed uptake in renal proximal tubules resulting in late nephrotoxicity, highlighting the importance of long-term toxicity studies and microscale dosimetry.

Authors
Kiess, AP; Minn, I; Vaidyanathan, G; Hobbs, RF; Josefsson, A; Shen, C; Brummet, M; Chen, Y; Choi, J; Koumarianou, E; Baidoo, K; Brechbiel, MW; Mease, RC; Sgouros, G; Zalutsky, MR; Pomper, MG
MLA Citation
Kiess, AP, Minn, I, Vaidyanathan, G, Hobbs, RF, Josefsson, A, Shen, C, Brummet, M, Chen, Y, Choi, J, Koumarianou, E, Baidoo, K, Brechbiel, MW, Mease, RC, Sgouros, G, Zalutsky, MR, and Pomper, MG. "(2S)-2-(3-(1-Carboxy-5-(4-211At-Astatobenzamido)Pentyl)Ureido)-Pentanedioic Acid for PSMA-Targeted α-Particle Radiopharmaceutical Therapy." Journal of nuclear medicine : official publication, Society of Nuclear Medicine 57.10 (October 2016): 1569-1575.
PMID
27230930
Source
epmc
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
57
Issue
10
Publish Date
2016
Start Page
1569
End Page
1575
DOI
10.2967/jnumed.116.174300

Prostate-Specific Membrane Antigen-Targeted Radiohalogenated PET and Therapeutic Agents for Prostate Cancer.

Radiohalogenated agents are often the first line of pursuit in the development of new radiopharmaceuticals-whether antibodies, peptides, or small molecules-because of their ease of synthesis, lack of substantial steric perturbation of the original affinity agent (in some cases, providing enhanced affinity), and capacity to be transformed into therapeutics (in some cases, with a mere switch of an isotope). They often provide proof of a principle before optimization for pharmacokinetics or generation of radiometallated agents, when the latter are necessary. In particular, 18F has been well integrated into normal clinical work flow in the form of 18F-FDG for oncologic imaging, with reliable daily production and distribution to sites for immediate use, without the need for on-site preparation. Here we discuss radiohalogenated versions of imaging and therapeutic agents targeting the prostate-specific membrane antigen (PSMA); these were among the first such agents to be synthesized and used clinically. PSMA is highly expressed on prostate cancer epithelial cells and is currently being extensively investigated around the world as a target for imaging and therapy of prostate cancer. Additionally, the presence of PSMA on nonprostate tumor neovasculature has opened the possibility of PSMA-targeted molecules as generalizable cancer imaging and therapy agents. We focus on 18F-labeled agents for PET, as they begin to redefine-along with the corresponding 68Ga-labeled agents discussed elsewhere in this supplement to The Journal of Nuclear Medicine-the management of prostate cancer across a variety of clinical contexts.

Authors
Rowe, SP; Drzezga, A; Neumaier, B; Dietlein, M; Gorin, MA; Zalutsky, MR; Pomper, MG
MLA Citation
Rowe, SP, Drzezga, A, Neumaier, B, Dietlein, M, Gorin, MA, Zalutsky, MR, and Pomper, MG. "Prostate-Specific Membrane Antigen-Targeted Radiohalogenated PET and Therapeutic Agents for Prostate Cancer." Journal of nuclear medicine : official publication, Society of Nuclear Medicine 57.Suppl 3 (October 2016): 90S-96S. (Review)
PMID
27694179
Source
epmc
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
57
Issue
Suppl 3
Publish Date
2016
Start Page
90S
End Page
96S
DOI
10.2967/jnumed.115.170175

Anti-HER2 Single Domain Antibody 2Rs15d Labeled with F-18 Using a Residualizing Label: Preliminary Evaluation

Authors
Vaidyanathan, GV; Zhou, Z; McDougald, D; Lahoutte, T; Zalutsky, MR
MLA Citation
Vaidyanathan, GV, Zhou, Z, McDougald, D, Lahoutte, T, and Zalutsky, MR. "Anti-HER2 Single Domain Antibody 2Rs15d Labeled with F-18 Using a Residualizing Label: Preliminary Evaluation." October 2016.
Source
wos-lite
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
43
Publish Date
2016
Start Page
S179
End Page
S179

Radiolabeled inhibitors as probes for imaging mutant IDH1 expression in gliomas: Synthesis and preliminary evaluation of labeled butyl-phenyl sulfonamide analogs.

Malignant gliomas frequently harbor mutations in the isocitrate dehydrogenase 1 (IDH1) gene. Studies suggest that IDH mutation contributes to tumor pathogenesis through mechanisms that are mediated by the neomorphic metabolite of the mutant IDH1 enzyme, 2-hydroxyglutarate (2-HG). The aim of this work was to synthesize and evaluate radiolabeled compounds that bind to the mutant IDH1 enzyme with the goal of enabling noninvasive imaging of mutant IDH1 expression in gliomas by positron emission tomography (PET).A small library of nonradioactive analogs were designed and synthesized based on the chemical structure of reported butyl-phenyl sulfonamide inhibitors of mutant IDH1. Enzyme inhibition assays were conducted using purified mutant IDH1 enzyme, IDH1-R132H, to determine the IC50 and the maximal inhibitory efficiency of the synthesized compounds. Selected compounds, 1 and 4, were labeled with radioiodine ((125)I) and/or (18)F using bromo- and phenol precursors, respectively. In vivo behavior of the labeled inhibitors was studied by conducting tissue distribution studies with [(125)I]1 in normal mice. Cell uptake studies were conducted using an isogenic astrocytoma cell line that carried a native IDH1-R132H mutation to evaluate the potential uptake of the labeled inhibitors in IDH1-mutated tumor cells.Enzyme inhibition assays showed good inhibitory potency for compounds that have iodine or a fluoroethoxy substituent at the ortho position of the phenyl ring in compounds 1 and 4 with IC50 values of 1.7 μM and 2.3 μM, respectively. Compounds 1 and 4 inhibited mutant IDH1 activity and decreased the production of 2-HG in an IDH1-mutated astrocytoma cell line. Radiolabeling of 1 and 4 was achieved with an average radiochemical yield of 56.6 ± 20.1% for [(125)I]1 (n = 4) and 67.5 ± 6.6% for [(18)F]4 (n = 3). [(125)I]1 exhibited favorable biodistribution characteristics in normal mice, with rapid clearance from the blood and elimination via the hepatobiliary system by 4 h after injection. The uptake of [(125)I]1 in tumor cells positive for IDH1-R132H was significantly higher compared to isogenic WT-IDH1 controls, with a maximal uptake ratio of 1.67 at 3 h post injection. Co-incubation of the labeled inhibitors with the corresponding nonradioactive analogs, and decreasing the normal concentrations of FBS (10%) in the incubation media substantially increased the uptake of the labeled inhibitors in both the IDH1-mutant and WT-IDH1 tumor cell lines, suggesting significant non-specific binding of the synthesized labeled butyl-phenyl sulfonamide inhibitors.These data demonstrate the feasibility of developing radiolabeled probes for the mutant IDH1 enzyme based on enzyme inhibitors. Further optimization of the labeled inhibitors by modifying the chemical structure to decrease the lipophilicity and to increase potency may yield compounds with improved characteristics as probes for imaging mutant IDH1 expression in tumors.

Authors
Chitneni, SK; Reitman, ZJ; Gooden, DM; Yan, H; Zalutsky, MR
MLA Citation
Chitneni, SK, Reitman, ZJ, Gooden, DM, Yan, H, and Zalutsky, MR. "Radiolabeled inhibitors as probes for imaging mutant IDH1 expression in gliomas: Synthesis and preliminary evaluation of labeled butyl-phenyl sulfonamide analogs." European journal of medicinal chemistry 119 (August 2016): 218-230.
Website
http://hdl.handle.net/10161/12001
PMID
27163884
Source
epmc
Published In
European Journal of Medicinal Chemistry
Volume
119
Publish Date
2016
Start Page
218
End Page
230
DOI
10.1016/j.ejmech.2016.04.066

Preclinical Evaluation of 18F-Labeled Anti-HER2 Nanobody Conjugates for Imaging HER2 Receptor Expression by Immuno-PET.

The human growth factor receptor type 2 (HER2) is overexpressed in breast as well as other types of cancer. Immuno-PET, a noninvasive imaging procedure that could assess HER2 status in both primary and metastatic lesions simultaneously, could be a valuable tool for optimizing application of HER2-targeted therapies in individual patients. Herein, we have evaluated the tumor-targeting potential of the 5F7 anti-HER2 Nanobody (single-domain antibody fragment; ∼13 kDa) after (18)F labeling by 2 methods.The 5F7 Nanobody was labeled with (18)F using the novel residualizing label N-succinimidyl 3-((4-(4-(18)F-fluorobutyl)-1H-1,2,3-triazol-1-yl)methyl)-5-(guanidinomethyl)benzoate ((18)F-SFBTMGMB; (18)F-RL-I) and also via the most commonly used (18)F protein-labeling prosthetic agent N-succinimidyl 3-(18)F-fluorobenzoate ((18)F-SFB). For comparison, 5F7 Nanobody was also labeled using the residualizing radioiodination agent N-succinimidyl 4-guanidinomethyl-3-(125)I-iodobenzoate ((125)I-SGMIB). Paired-label ((18)F/(125)I) internalization assays and biodistribution studies were performed on HER2-expressing BT474M1 breast carcinoma cells and in mice with BT474M1 subcutaneous xenografts, respectively. Small-animal PET/CT imaging of 5F7 Nanobody labeled using (18)F-RL-I also was performed.Internalization assays indicated that intracellularly retained radioactivity for (18)F-RL-I-5F7 was similar to that for coincubated (125)I-SGMIB-5F7, whereas that for (18)F-SFB-5F7 was lower than coincubated (125)I-SGMIB-5F7 and decreased with time. BT474M1 tumor uptake of (18)F-RL-I-5F7 was 28.97 ± 3.88 percentage injected dose per gram of tissue (%ID/g) at 1 h and 36.28 ± 14.10 %ID/g at 2 h, reduced by more than 90% on blocking with trastuzumab, indicating HER2 specificity of uptake, and was also 26%-28% higher (P < 0.05) than that of (18)F-SFB-5F7. At 2 h, the tumor-to-blood ratio for (18)F-RL-I-5F7 (47.4 ± 13.1) was significantly higher (P < 0.05) than for (18)F-SFB-5F7 (25.4 ± 10.3); however, kidney uptake was 28-36-fold higher for (18)F-RL-I-5F7.(18)F-RL-I-5F7 is a promising tracer for evaluating HER2 status by immuno-PET; however, in settings in which renal background is problematic, strategies for reducing its kidney uptake may be needed.

Authors
Vaidyanathan, G; McDougald, D; Choi, J; Koumarianou, E; Weitzel, D; Osada, T; Lyerly, HK; Zalutsky, MR
MLA Citation
Vaidyanathan, G, McDougald, D, Choi, J, Koumarianou, E, Weitzel, D, Osada, T, Lyerly, HK, and Zalutsky, MR. "Preclinical Evaluation of 18F-Labeled Anti-HER2 Nanobody Conjugates for Imaging HER2 Receptor Expression by Immuno-PET." Journal of nuclear medicine : official publication, Society of Nuclear Medicine 57.6 (June 2016): 967-973.
PMID
26912425
Source
epmc
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
57
Issue
6
Publish Date
2016
Start Page
967
End Page
973
DOI
10.2967/jnumed.115.171306

Preclinical toxicity evaluation of a novel immunotoxin, D2C7-(scdsFv)-PE38KDEL, administered via intracerebral convection-enhanced delivery in rats.

D2C7-(scdsFv)-PE38KDEL (D2C7-IT) is a novel immunotoxin that reacts with wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFRvIII proteins overexpressed in glioblastomas. This study assessed the toxicity of intracerebral administration of D2C7-IT to support an initial Food and Drug Administration Investigational New Drug application. After the optimization of the formulation and administration, two cohorts (an acute and chronic cohort necropsied on study days 5 and 34) of Sprague-Dawley (SD) rats (four groups of 5 males and 5 females) were infused with the D2C7-IT formulation at total doses of 0, 0.05, 0.1, 0.4 μg (the acute cohort) and 0, 0.05, 0.1, 0.35 μg (the chronic cohort) for approximately 72 h by intracerebral convection-enhanced delivery using osmotic pumps. Mortality was observed in the 0.40 μg (5/10 rats) and 0.35 μg (4/10 rats) high-dose groups of each cohort. Body weight loss and abnormal behavior were only revealed in the rats treated with high doses of D2C7-IT. No dose-related effects were observed in clinical laboratory tests in either cohort. A gross pathologic examination of systemic tissues from the high-dose and control groups in both cohorts exhibited no dose-related or drug-related pathologic findings. Brain histopathology revealed the frequent occurrence of dose-related encephalomalacia, edema, and demyelination in the high-dose groups of both cohorts. In this study, the maximum tolerated dose of D2C7-IT was determined to be between 0.10 and 0.35 μg, and the no-observed-adverse-effect-level was 0.05 μg in SD rats. Both parameters were utilized to design the Phase I/II D2C7-IT clinical trial.

Authors
Bao, X; Chandramohan, V; Reynolds, RP; Norton, JN; Wetsel, WC; Rodriguiz, RM; Aryal, DK; McLendon, RE; Levin, ED; Petry, NA; Zalutsky, MR; Burnett, BK; Kuan, C-T; Pastan, IH; Bigner, DD
MLA Citation
Bao, X, Chandramohan, V, Reynolds, RP, Norton, JN, Wetsel, WC, Rodriguiz, RM, Aryal, DK, McLendon, RE, Levin, ED, Petry, NA, Zalutsky, MR, Burnett, BK, Kuan, C-T, Pastan, IH, and Bigner, DD. "Preclinical toxicity evaluation of a novel immunotoxin, D2C7-(scdsFv)-PE38KDEL, administered via intracerebral convection-enhanced delivery in rats." Investigational new drugs 34.2 (April 2016): 149-158.
PMID
26728879
Source
epmc
Published In
Investigational New Drugs
Volume
34
Issue
2
Publish Date
2016
Start Page
149
End Page
158
DOI
10.1007/s10637-015-0318-3

Injectable polypeptide micelles that form radiation crosslinked hydrogels in situ for intratumoral radiotherapy.

Intratumoral radiation therapy - 'brachytherapy' - is a highly effective treatment for solid tumors, particularly prostate cancer. Current titanium seed implants, however, are permanent and are limited in clinical application to indolent malignancies of low- to intermediate-risk. Attempts to develop polymeric alternatives, however, have been plagued by poor retention and off-target toxicity due to degradation. Herein, we report on a new approach whereby thermally sensitive micelles composed of an elastin-like polypeptide (ELP) are labeled with the radionuclide (131)I to form an in situ hydrogel that is stabilized by two independent mechanisms: first, body heat triggers the radioactive ELP micelles to rapidly phase transition into an insoluble, viscous coacervate in under 2 min; second, the high energy β-emissions of (131)I further stabilize the depot by introducing crosslinks within the ELP depot over 24h. These injectable brachytherapy hydrogels were used to treat two aggressive orthotopic tumor models in athymic nude mice: a human PC-3 M-luc-C6 prostate tumor and a human BxPc3-luc2 pancreatic tumor model. The ELP depots retained greater than 52% and 70% of their radioactivity through 60 days in the prostate and pancreatic tumors with no appreciable radioactive accumulation (≤ 0.1% ID) in off-target tissues after 72h. The (131)I-ELP depots achieved >95% tumor regression in the prostate tumors (n=8); with a median survival of more than 60 days compared to 12 days for control mice. For the pancreatic tumors, ELP brachytherapy (n=6) induced significant growth inhibition (p=0.001, ANOVA) and enhanced median survival to 27 days over controls.

Authors
Schaal, JL; Li, X; Mastria, E; Bhattacharyya, J; Zalutsky, MR; Chilkoti, A; Liu, W
MLA Citation
Schaal, JL, Li, X, Mastria, E, Bhattacharyya, J, Zalutsky, MR, Chilkoti, A, and Liu, W. "Injectable polypeptide micelles that form radiation crosslinked hydrogels in situ for intratumoral radiotherapy." Journal of controlled release : official journal of the Controlled Release Society 228 (April 2016): 58-66.
PMID
26928529
Source
epmc
Published In
Journal of Controlled Release
Volume
228
Publish Date
2016
Start Page
58
End Page
66
DOI
10.1016/j.jconrel.2016.02.040

Spatiotemporally photoradiation-controlled intratumoral depot for combination of brachytherapy and photodynamic therapy for solid tumor.

In an attempt to spatiotemporally control both tumor retention and the coverage of anticancer agents, we developed a photoradiation-controlled intratumoral depot (PRCITD) driven by convection enhanced delivery (CED). This intratumoral depot consists of recombinant elastin-like polypeptide (ELP) containing periodic cysteine residues and is conjugated with a photosensitizer, chlorin-e6 (Ce6) at the N-terminus of the ELP. We hypothesized that this cysteine-containing ELP (cELP) can be readily crosslinked through disulfide bonds upon exposure to oxidative agents, specifically the singlet oxygen produced during photodynamic stimulation. Upon intratumoral injection, CED drives the distribution of the soluble polypeptide freely throughout the tumor interstitium. Formation and retention of the depot was monitored using fluorescence molecular tomography imaging. When imaging shows that the polypeptide has distributed throughout the entire tumor, 660-nm light is applied externally at the tumor site. This photo-radiation wavelength excites Ce6 and generates reactive oxygen species (ROS) in the presence of oxygen. The ROS induce in situ disulfide crosslinking of the cysteine thiols, stabilizing the ELP biopolymer into a stable therapeutic depot. Our results demonstrate that this ELP design effectively forms a hydrogel both in vitro and in vivo. These depots exhibit high stability in subcutaneous tumor xenografts in nude mice and significantly improved intratumoral retention compared to controls without crosslinking, as seen by fluorescent imaging and iodine-125 radiotracer studies. The photodynamic therapy provided by the PRCITD was found to cause significant tumor inhibition in a Ce6 dose dependent manner. Additionally, the combination of PDT and intratumoral radionuclide therapy co-delivered by PRCITD provided a greater antitumor effect than either monotherapy alone. These results suggest that the PRCITD could provide a stable platform for delivering synergistic, anti-cancer drug depots.

Authors
Mukerji, R; Schaal, J; Li, X; Bhattacharyya, J; Asai, D; Zalutsky, MR; Chilkoti, A; Liu, W
MLA Citation
Mukerji, R, Schaal, J, Li, X, Bhattacharyya, J, Asai, D, Zalutsky, MR, Chilkoti, A, and Liu, W. "Spatiotemporally photoradiation-controlled intratumoral depot for combination of brachytherapy and photodynamic therapy for solid tumor." Biomaterials 79 (February 2016): 79-87.
PMID
26702586
Source
epmc
Published In
Biomaterials
Volume
79
Publish Date
2016
Start Page
79
End Page
87
DOI
10.1016/j.biomaterials.2015.11.064

N-Succinimidyl 3-((4-(4-[(18)F]fluorobutyl)-1H-1,2,3-triazol-1-yl)methyl)-5-(guanidinomethyl)benzoate ([(18)F]SFBTMGMB): a residualizing label for (18)F-labeling of internalizing biomolecules.

Residualizing labeling methods for internalizing peptides and proteins are designed to trap the radionuclide inside the cell after intracellular degradation of the biomolecule. The goal of this work was to develop a residualizing label for the (18)F-labeling of internalizing biomolecules based on a template used successfully for radioiodination. N-Succinimidyl 3-((4-(4-[(18)F]fluorobutyl)-1H-1,2,3-triazol-1-yl)methyl)-5-(bis-Boc-guanidinomethyl)benzoate ([(18)F]SFBTMGMB-Boc2) was synthesized by a click reaction of an azide precursor and [(18)F]fluorohexyne in 8.5 ± 2.8% average decay-corrected radiochemical yield (n = 15). An anti-HER2 nanobody 5F7 was labeled with (18)F using [(18)F]SFBTMGMB ([(18)F]RL-I), obtained by the deprotection of [(18)F]SFBTMGMB-Boc2, in 31.2 ± 6.7% (n = 5) conjugation efficiency. The labeled nanobody had a radiochemical purity of >95%, bound to HER2-expressing BT474M1 breast cancer cells with an affinity of 4.7 ± 0.9 nM, and had an immunoreactive fraction of 62-80%. In summary, a novel residualizing prosthetic agent for labeling biomolecules with (18)F has been developed. An anti-HER2 nanobody was labeled using this prosthetic group with retention of affinity and immunoreactivity to HER2.

Authors
Vaidyanathan, G; McDougald, D; Choi, J; Pruszynski, M; Koumarianou, E; Zhou, Z; Zalutsky, MR
MLA Citation
Vaidyanathan, G, McDougald, D, Choi, J, Pruszynski, M, Koumarianou, E, Zhou, Z, and Zalutsky, MR. "N-Succinimidyl 3-((4-(4-[(18)F]fluorobutyl)-1H-1,2,3-triazol-1-yl)methyl)-5-(guanidinomethyl)benzoate ([(18)F]SFBTMGMB): a residualizing label for (18)F-labeling of internalizing biomolecules." Organic & biomolecular chemistry 14.4 (January 2016): 1261-1271.
PMID
26645790
Source
epmc
Published In
Organic & Biomolecular Chemistry
Volume
14
Issue
4
Publish Date
2016
Start Page
1261
End Page
1271
DOI
10.1039/c5ob02258d

An Anti-HER2 Nanobody Labeled with 18F Using a Residualizing Label for Assessing HER2 Status

Authors
Vaidyanathan, G; McDougald, D; Choi, J; Koumarianou, E; Pruszynski, M; Osada, T; Lyerly, H; Lahoutte, T; Zalutsky, MR
MLA Citation
Vaidyanathan, G, McDougald, D, Choi, J, Koumarianou, E, Pruszynski, M, Osada, T, Lyerly, H, Lahoutte, T, and Zalutsky, MR. "An Anti-HER2 Nanobody Labeled with 18F Using a Residualizing Label for Assessing HER2 Status." October 2015.
Source
wos-lite
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
42
Publish Date
2015
Start Page
S102
End Page
S102

Abstract 1809: Next-generation brachytherapy: a preclinical study of a thermally stabilized biopolymer gel for delivering intratumoral radionuclide therapy in a pancreatic tumor mouse model

Authors
Schaal, JL; Liu, W; Chilkoti, A; Li, X; Mastria, E; Zalutsky, MR
MLA Citation
Schaal, JL, Liu, W, Chilkoti, A, Li, X, Mastria, E, and Zalutsky, MR. "Abstract 1809: Next-generation brachytherapy: a preclinical study of a thermally stabilized biopolymer gel for delivering intratumoral radionuclide therapy in a pancreatic tumor mouse model." August 1, 2015.
Source
crossref
Published In
Cancer Research
Volume
75
Issue
15 Supplement
Publish Date
2015
Start Page
1809
End Page
1809
DOI
10.1158/1538-7445.AM2015-1809

Synthesis and evaluation of 4-[18F]fluoropropoxy-3-iodobenzylguanidine ([18F]FPOIBG): A novel 18F-labeled analogue of MIBG.

Radioiodinated meta-iodobenzylguanidine (MIBG), a norepinephrine transporter (NET) substrate, has been extensively used as an imaging agent to study the pathophysiology of the heart and for the diagnosis and treatment of neuroendocrine tumors. The goal of this study was to develop an (18)F-labeled analogue of MIBG that like MIBG itself could be synthesized in a single radiochemical step. Towards this end, we designed 4-fluoropropoxy-3-iodobenzylguanidine (FPOIBG).Standards of FPOIBG and 4-fluoropropoxy-3-bromobenzylguanidine (FPOBBG) as well as their tosylate precursors for labeling with (18)F, and a tin precursor for the preparation of radioiodinated FPOIBG were synthesized. Radiolabeled derivatives were synthesized by nucleophilic substitution and electrophilic iododestannylation from the corresponding precursors. Labeled compounds were evaluated for NET transporter recognition in in vitro assays using three NET-expressing cell lines and in biodistribution experiments in normal mice, with all studies performed in a paired-label format. Competitive inhibition of [(125)I]MIBG uptake by unlabeled benzylguanidine compounds was performed in UVW-NAT cell line to determine IC50 values.[(18)F]FPOIBG was synthesized from the corresponding tosylate precursor in 5.2 ± 0.5% (n = 6) overall radiochemical yields starting with aqueous fluoride in about 105 min. In a paired-label in vitro assay, the uptake of [(18)F]FPOIBG at 2h was 10.2 ± 1.5%, 39.6 ± 13.4%, and 13.3 ± 2.5%, in NET-expressing SK-N-SH, UVW-NAT, and SK-N-BE(2c) cells, respectively, while these values for [(125)I]MIBG were 57.3 ± 8.1%, 82.7 ± 8.9%, and 66.3 ± 3.6%. The specificity of uptake of both tracers was demonstrated by blocking with desipramine. The (125)I-labeled congener of FPOIBG gave similar results. On the other hand, [(18)F]FPOBBG, a compound recently reported in the literature, demonstrated much higher uptake, albeit less than that of co-incubated [(125)I]MIBG. IC50 values for FPOIBG were higher than those obtained for MIBG and FPOBBG. Unlike the case with [(18)F]FPOBBG, the heart uptake [(18)F]FPOIBG in normal mice was significantly lower than that of MIBG.Although [(18)F]FPOIBG does not appear to warrant further consideration as an (18)F-labeled MIBG analogue, analogues wherein the iodine in it is replaced with a chlorine, fluorine or hydrogen might be worth pursuing.An (18)F-labeled analogue of the well-known radiopharmaceutical MIBG could have significant impact, potentially improving imaging of NET related disease in cardiology and in the imaging of neuroendocrine tumors. Although (18)F-labeled analogues of MIBG have been reported including LMI1195, we undertook this work hypothesizing that based on its greater structural similarity to MIBG, FPOIBG might be a better analogue than LMI1195.

Authors
Vaidyanathan, G; McDougald, D; Koumarianou, E; Choi, J; Hens, M; Zalutsky, MR
MLA Citation
Vaidyanathan, G, McDougald, D, Koumarianou, E, Choi, J, Hens, M, and Zalutsky, MR. "Synthesis and evaluation of 4-[18F]fluoropropoxy-3-iodobenzylguanidine ([18F]FPOIBG): A novel 18F-labeled analogue of MIBG." Nuclear medicine and biology 42.8 (August 2015): 673-684.
PMID
25956997
Source
epmc
Published In
Nuclear Medicine and Biology
Volume
42
Issue
8
Publish Date
2015
Start Page
673
End Page
684
DOI
10.1016/j.nucmedbio.2015.04.005

Stability and in vivo behavior of Rh[16aneS4-diol]211 at complex: a potential precursor for astatine radiopharmaceuticals.

The heavy halogen (211)At is of great interest for targeted radiotherapy because it decays by the emission of short-range, high-energy α-particles. However, many astatine compounds that have been synthesized are unstable in vivo, providing motivation for seeking other (211)At labeling strategies. One relatively unexplored approach is to utilize prosthetic groups based on astatinated rhodium (III) complex stabilized with a tetrathioether macrocyclic ligand - Rh[16aneS(4)-diol](211)At. The purpose of the current study was to evaluate the in vitro and in vivo stability of this complex in comparison to its iodine analog - Rh[16aneS(4)-diol](131)I.Rh[16aneS(4)-diol](211)At and Rh[16aneS(4)-diol](131)I complexes were synthesized and purified by HPLC. The stability of both complexes was evaluated in vitro by incubation in phosphate-buffered saline (PBS) and human serum at different temperatures. The in vivo behavior of the two radiohalogenated complexes was assessed by a paired-label biodistribution study in normal Balb/c mice.Both complexes were synthesized in high yield and purity. Almost no degradation was observed for Rh[16aneS(4)-diol](131)I in PBS over a 72 h incubation. The astatinated analog exhibited good stability in PBS over 14 h. A slow decline in the percentage of intact complex was observed for both tracers in human serum. In the biodistribution study, retention of (211)At in most tissues was higher than that of (131)I at all time points, especially in spleen and lungs. Renal clearance of Rh[16aneS(4)-diol](211)At and Rh[16aneS(4)-diol](131)I predominated, with 84.1 ± 2.3% and 94.6 ± 0.9% of injected dose excreted via the urine at 4 h.The Rh[16aneS(4)-diol](211)At complex might be useful for constructing prosthetic groups for the astatination of biomolecules and further studies are planned to evaluate this possibility.

Authors
Pruszyński, M; Łyczko, M; Bilewicz, A; Zalutsky, MR
MLA Citation
Pruszyński, M, Łyczko, M, Bilewicz, A, and Zalutsky, MR. "Stability and in vivo behavior of Rh[16aneS4-diol]211 at complex: a potential precursor for astatine radiopharmaceuticals." Nuclear medicine and biology 42.5 (May 2015): 439-445.
PMID
25687450
Source
epmc
Published In
Nuclear Medicine and Biology
Volume
42
Issue
5
Publish Date
2015
Start Page
439
End Page
445
DOI
10.1016/j.nucmedbio.2014.12.011

Reply: Pharmacokinetic and Pharmacodynamic Modifiers of EF5 Uptake and Binding.

Authors
Chitneni, SK; Bida, GT; Zalutsky, MR; Dewhirst, MW
MLA Citation
Chitneni, SK, Bida, GT, Zalutsky, MR, and Dewhirst, MW. "Reply: Pharmacokinetic and Pharmacodynamic Modifiers of EF5 Uptake and Binding." Journal of nuclear medicine : official publication, Society of Nuclear Medicine 56.4 (April 2015): 653-654. (Letter)
PMID
25745087
Source
epmc
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
56
Issue
4
Publish Date
2015
Start Page
653
End Page
654
DOI
10.2967/jnumed.115.154054

Stability and in vivo behavior of Rh[16aneS<inf>4</inf>-diol]<sup>211</sup>At complex: A potential precursor for astatine radiopharmaceuticals

© 2014 Elsevier Inc. Introduction: The heavy halogen < sup > 211 < /sup > At is of great interest for targeted radiotherapy because it decays by the emission of short-range, high-energy α-particles. However, many astatine compounds that have been synthesized are unstable in vivo, providing motivation for seeking other < sup > 211 < /sup > At labeling strategies. One relatively unexplored approach is to utilize prosthetic groups based on astatinated rhodium (III) complex stabilized with a tetrathioether macrocyclic ligand - Rh[16aneS < inf > 4 < /inf > -diol] < sup > 211 < /sup > At. The purpose of the current study was to evaluate the in vitro and in vivo stability of this complex in comparison to its iodine analog - Rh[16aneS < inf > 4 < /inf > -diol] < sup > 131 < /sup > I. Methods: Rh[16aneS < inf > 4 < /inf > -diol] < sup > 211 < /sup > At and Rh[16aneS < inf > 4 < /inf > -diol] < sup > 131 < /sup > I complexes were synthesized and purified by HPLC. The stability of both complexes was evaluated in vitro by incubation in phosphate-buffered saline (PBS) and human serum at different temperatures. The in vivo behavior of the two radiohalogenated complexes was assessed by a paired-label biodistribution study in normal Balb/c mice. Results: Both complexes were synthesized in high yield and purity. Almost no degradation was observed for Rh[16aneS < inf > 4 < /inf > -diol] < sup > 131 < /sup > I in PBS over a 72h incubation. The astatinated analog exhibited good stability in PBS over 14h. A slow decline in the percentage of intact complex was observed for both tracers in human serum. In the biodistribution study, retention of < sup > 211 < /sup > At in most tissues was higher than that of < sup > 131 < /sup > I at all time points, especially in spleen and lungs. Renal clearance of Rh[16aneS < inf > 4 < /inf > -diol] < sup > 211 < /sup > At and Rh[16aneS < inf > 4 < /inf > -diol] < sup > 131 < /sup > I predominated, with 84.1±2.3% and 94.6±0.9% of injected dose excreted via the urine at 4h. Conclusions: The Rh[16aneS < inf > 4 < /inf > -diol] < sup > 211 < /sup > At complex might be useful for constructing prosthetic groups for the astatination of biomolecules and further studies are planned to evaluate this possibility.

Authors
Pruszyński, M; Łyczko, M; Bilewicz, A; Zalutsky, MR
MLA Citation
Pruszyński, M, Łyczko, M, Bilewicz, A, and Zalutsky, MR. "Stability and in vivo behavior of Rh[16aneS<inf>4</inf>-diol]<sup>211</sup>At complex: A potential precursor for astatine radiopharmaceuticals." Nuclear Medicine and Biology 42.5 (January 1, 2015): 439-445.
Source
scopus
Published In
Nuclear Medicine and Biology
Volume
42
Issue
5
Publish Date
2015
Start Page
439
End Page
445
DOI
10.1016/j.nucmedbio.2014.12.011

D-Amino acid peptide residualizing agents bearing N-hydroxysuccinimido- and maleimido-functional groups and their application for trastuzumab radioiodination.

Proteins that undergo receptor-mediated endocytosis are subject to lysosomal degradation, requiring radioiodination methods that minimize loss of radioactivity from tumor cells after this process occurs. To accomplish this, we developed the residualizing radioiodination agent N(ϵ)-(3-[(*)I]iodobenzoyl)-Lys(5)-N(α)-maleimido-Gly(1)-D-GEEEK (Mal-D-GEEEK-[(*)I]IB), which enhanced tumor uptake but also increased kidney activity and necessitates generation of sulfhydryl moieties on the protein. The purpose of the current study was to synthesize and evaluate a new D-amino acid based agent that might avoid these potential problems.N(α)-(3-iodobenzoyl)-(5-succinimidyloxycarbonyl)-D-EEEG (NHS-IB-D-EEEG), which contains 3 D-glutamates to provide negative charge and a N-hydroxysuccinimide function to permit conjugation to unmodified proteins, and the corresponding tin precursor were produced by solid phase peptide synthesis and subsequent conjugation with appropriate reagents. Radioiodination of the anti-HER2 antibody trastuzumab using NHS-IB-D-EEEG and Mal-D-GEEEK-IB was compared. Paired-label internalization assays on BT474 breast carcinoma cells and biodistribution studies in athymic mice bearing BT474M1 xenografts were performed to evaluate the two radioiodinated D-peptide trastuzumab conjugates.NHS-[(131)I]IB-D-EEEG was produced in 53.8%±13.4% and conjugated to trastuzumab in 39.5%±7.6% yield. Paired-label internalization assays with trastuzumab-NHS-[(131)I]IB-D-EEEG and trastuzumab-Mal-D-GEEEK-[(125)I]IB demonstrated similar intracellular trapping for both conjugates at 1h ((131)I, 84.4%±6.1%; (125)I, 88.6%±5.2%) through 24h ((131)I, 60.7%±6.8%; (125)I, 64.9%±6.9%). In the biodistribution experiment, tumor uptake peaked at 48 h (trastuzumab-NHS-[(131)I]IB-D-EEEG, 29.8%±3.6%ID/g; trastuzumab-Mal-D-GEEEK-[(125)I]IB, 45.3%±5.3%ID/g) and was significantly higher for (125)I at all time points. In general, normal tissue levels were lower for trastuzumab-NHS-[(131)I]IB-D-EEEG, with the differences being greatest in kidneys ((131)I, 2.2%±0.4%ID/g; (125)I, 16.9%±2.8%ID/g at 144 h).NHS-[(131)I]IB-D-EEEG warrants further evaluation as a residualizing radioiodination agent for labeling internalizing antibodies/fragments, particularly for applications where excessive renal accumulation could be problematic.

Authors
Pruszynski, M; Koumarianou, E; Vaidyanathan, G; Chitneni, S; Zalutsky, MR
MLA Citation
Pruszynski, M, Koumarianou, E, Vaidyanathan, G, Chitneni, S, and Zalutsky, MR. "D-Amino acid peptide residualizing agents bearing N-hydroxysuccinimido- and maleimido-functional groups and their application for trastuzumab radioiodination." Nuclear medicine and biology 42.1 (January 2015): 19-27.
Website
http://hdl.handle.net/10161/10679
PMID
25240914
Source
epmc
Published In
Nuclear Medicine and Biology
Volume
42
Issue
1
Publish Date
2015
Start Page
19
End Page
27
DOI
10.1016/j.nucmedbio.2014.08.007

Modular nanotransporters for targeted intracellular delivery of drugs: folate receptors as potential targets.

The review is devoted to a subcellular drug delivery system, modular nanotransporters (MNT) that can penetrate into target cells and deliver a therapeutic into their subcellular compartments, particularly into the nucleus. The therapeutics which need such type of delivery belong to two groups: (i) those that exert their effect only when delivered into a certain cell compartment (like DNA delivered into the nucleus); and (ii) those drugs that are capable of exerting their effect in different parts of the cells, however there can be found a cell compartment that is the most sensitive to their effect. A particular interest attract such cytotoxic agents as Auger electron emitters which are known to be ineffective outside the cell nucleus, whereas they possess high cytotoxicity in the vicinity of nuclear DNA through the induction of non-reparable double-strand DNA breaks. The review discusses main approaches permitting to choose internalizable receptors permitting both recognition of target cells and penetration into them. Special interest attract folate receptors which become accessible to blood circulating therapeutics after malignant transformation or on activated macrophages which makes them an attractive target for both several oncological and inflammatory diseases, like atherosclerosis. In vitro and in vivo experiments demonstrated that MNT is a promising platform for targeted delivery of different therapeutics into the nuclei of target cells.

Authors
Slastnikova, TA; Rosenkranz, AA; Zalutsky, MR; Sobolev, AS
MLA Citation
Slastnikova, TA, Rosenkranz, AA, Zalutsky, MR, and Sobolev, AS. "Modular nanotransporters for targeted intracellular delivery of drugs: folate receptors as potential targets." Current pharmaceutical design 21.9 (January 2015): 1227-1238. (Review)
PMID
25312738
Source
epmc
Published In
Current Pharmaceutical Design
Volume
21
Issue
9
Publish Date
2015
Start Page
1227
End Page
1238
DOI
10.2174/1381612820666141013121032

A Plasmonic Gold Nanostar Theranostic Probe for In Vivo Tumor Imaging and Photothermal Therapy.

Nanomedicine has attracted increasing attention in recent years, because it offers great promise to provide personalized diagnostics and therapy with improved treatment efficacy and specificity. In this study, we developed a gold nanostar (GNS) probe for multi-modality theranostics including surface-enhanced Raman scattering (SERS) detection, x-ray computed tomography (CT), two-photon luminescence (TPL) imaging, and photothermal therapy (PTT). We performed radiolabeling, as well as CT and optical imaging, to investigate the GNS probe's biodistribution and intratumoral uptake at both macroscopic and microscopic scales. We also characterized the performance of the GNS nanoprobe for in vitro photothermal heating and in vivo photothermal ablation of primary sarcomas in mice. The results showed that 30-nm GNS have higher tumor uptake, as well as deeper penetration into tumor interstitial space compared to 60-nm GNS. In addition, we found that a higher injection dose of GNS can increase the percentage of tumor uptake. We also demonstrated the GNS probe's superior photothermal conversion efficiency with a highly concentrated heating effect due to a tip-enhanced plasmonic effect. In vivo photothermal therapy with a near-infrared (NIR) laser under the maximum permissible exposure (MPE) led to ablation of aggressive tumors containing GNS, but had no effect in the absence of GNS. This multifunctional GNS probe has the potential to be used for in vivo biosensing, preoperative CT imaging, intraoperative detection with optical methods (SERS and TPL), as well as image-guided photothermal therapy.

Authors
Liu, Y; Ashton, JR; Moding, EJ; Yuan, H; Register, JK; Fales, AM; Choi, J; Whitley, MJ; Zhao, X; Qi, Y; Ma, Y; Vaidyanathan, G; Zalutsky, MR; Kirsch, DG; Badea, CT; Vo-Dinh, T
MLA Citation
Liu, Y, Ashton, JR, Moding, EJ, Yuan, H, Register, JK, Fales, AM, Choi, J, Whitley, MJ, Zhao, X, Qi, Y, Ma, Y, Vaidyanathan, G, Zalutsky, MR, Kirsch, DG, Badea, CT, and Vo-Dinh, T. "A Plasmonic Gold Nanostar Theranostic Probe for In Vivo Tumor Imaging and Photothermal Therapy." Theranostics 5.9 (January 2015): 946-960.
Website
http://hdl.handle.net/10161/11045
PMID
26155311
Source
epmc
Published In
Theranostics
Volume
5
Issue
9
Publish Date
2015
Start Page
946
End Page
960
DOI
10.7150/thno.11974

Modular nanotransporters for targeted intracellular delivery of drugs: Folate receptors as potential targets

© 2015 Bentham Science Publishers.The review is devoted to a subcellular drug delivery system, modular nanotransporters (MNT) that can penetrate into target cells and deliver a therapeutic into their subcellular compartments, particularly into the nucleus. The therapeutics which need such type of delivery belong to two groups: (i) those that exert their effect only when delivered into a certain cell compartment (like DNA delivered into the nucleus); and (ii) those drugs that are capable of exerting their effect in different parts of the cells, however there can be found a cell compartment that is the most sensitive to their effect. A particular interest attract such cytotoxic agents as Auger electron emitters which are known to be ineffective outside the cell nucleus, whereas they possess high cytotoxicity in the vicinity of nuclear DNA through the induction of non-reparable double-strand DNA breaks. The review discusses main approaches permitting to choose internalizable receptors permitting both recognition of target cells and penetration into them. Special interest attract folate receptors which become accessible to blood circulating therapeutics after malignant transformation or on activated macrophages which makes them an attractive target for both several oncological and inflammatory diseases, like atherosclerosis. In vitro and in vivo experiments demonstrated that MNT is a promising platform for targeted delivery of different therapeutics into the nuclei of target cells.

Authors
Slastnikova, TA; Rosenkranz, AA; Zalutsky, MR; Sobolev, AS
MLA Citation
Slastnikova, TA, Rosenkranz, AA, Zalutsky, MR, and Sobolev, AS. "Modular nanotransporters for targeted intracellular delivery of drugs: Folate receptors as potential targets." Current Pharmaceutical Design 21.9 (2015): 1227-1238.
Source
scival
Published In
Current Pharmaceutical Design
Volume
21
Issue
9
Publish Date
2015
Start Page
1227
End Page
1238

N-Succinimidyl guanidinomethyl iodobenzoate protein radiohalogenation agents: Influence of isomeric substitution on radiolabeling and target cell residualization

© 2014 Elsevier Inc. Introduction: N-succinimidyl 4-guanidinomethyl-3-[ * I]iodobenzoate ([ * I]SGMIB) has shown promise for the radioiodination of monoclonal antibodies (mAbs) and other proteins that undergo extensive internalization after receptor binding, enhancing tumor targeting compared to direct electrophilic radioiodination. However, radiochemical yields for [ 131 I]SGMIB synthesis are low, which we hypothesize is due to steric hindrance from the Boc-protected guanidinomethyl group ortho to the tin moiety. To overcome this, we developed the isomeric compound, N-succinimidyl 3-guanidinomethyl-5-[ 131 I]iodobenzoate (iso-[ 131 I]SGMIB) wherein this bulky group was moved from ortho to meta position. Methods: Boc 2 -iso-SGMIB standard and its tin precursor, N-succinimidyl 3-((1,2-bis(tert-butoxycarbonyl)guanidino)methyl)-5-(trimethylstannyl)benzoate (Boc 2 -iso-SGMTB), were synthesized using two disparate routes, and iso-[*I]SGMIB synthesized from the tin precursor. Two HER2-targeted vectors - trastuzumab (Tras) and a nanobody 5F7 (Nb) - were labeled using iso-[ * I]SGMIB and [ * I]SGMIB. Paired-label internalization assays in vitro with both proteins, and biodistribution in vivo with trastuzumab, labeled using the two isomeri c prosthetic agents were performed. Results: When the reactions were performed under identical conditions, radioiodination yields for the synthesis of Boc 2 -iso-[ 131 I]SGMIB were significantly higher than those for Boc 2 -[ 131 I]SGMIB (70.7±2.0% vs 56.5±5.5%). With both Nb and trastuzumab, conjugation efficiency also was higher with iso-[ 131 I]SGMIB than with [ 131 I]SGMIB (Nb, 33.1±7.1% vs 28.9±13.0%; Tras, 45.1±4.5% vs 34.8±10.3%); however, the differences were not statistically significant. Internalization assays performed on BT474 cells with 5F7 Nb indicated similar residualizing capacity over 6h; however, at 24h, radioactivity retained intracellularly for iso-[ 131 I]SGMIB-Nb was lower than for [ 125 I]SGMIB-Nb (46.4±1.3% vs 56.5±2.5%); similar results were obtained using Tras. Likewise, a paired-label biodistribution of Tras labeled using iso-[ 125 I]SGMIB and [ 131 I]SGMIB indicated an up to 22% tumor uptake advantage at later time points for [ 131 I]SGMIB-Tras. Conclusion: Given the higher labeling efficiency obtained with iso-SGMIB, this residualizing agent might be of value for use with shorter half-life radiohalogens.

Authors
Choi, J; Vaidyanathan, G; Koumarianou, E; McDougald, D; Pruszynski, M; Osada, T; Lahoutte, T; Lyerly, HK; Zalutsky, MR
MLA Citation
Choi, J, Vaidyanathan, G, Koumarianou, E, McDougald, D, Pruszynski, M, Osada, T, Lahoutte, T, Lyerly, HK, and Zalutsky, MR. "N-Succinimidyl guanidinomethyl iodobenzoate protein radiohalogenation agents: Influence of isomeric substitution on radiolabeling and target cell residualization." Nuclear Medicine and Biology 41.10 (November 1, 2014): 802-812.
Source
scopus
Published In
Nuclear Medicine and Biology
Volume
41
Issue
10
Publish Date
2014
Start Page
802
End Page
812
DOI
10.1016/j.nucmedbio.2014.07.005

N-Succinimidyl guanidinomethyl iodobenzoate protein radiohalogenation agents: influence of isomeric substitution on radiolabeling and target cell residualization.

N-succinimidyl 4-guanidinomethyl-3-[(*)I]iodobenzoate ([(*)I]SGMIB) has shown promise for the radioiodination of monoclonal antibodies (mAbs) and other proteins that undergo extensive internalization after receptor binding, enhancing tumor targeting compared to direct electrophilic radioiodination. However, radiochemical yields for [(131)I]SGMIB synthesis are low, which we hypothesize is due to steric hindrance from the Boc-protected guanidinomethyl group ortho to the tin moiety. To overcome this, we developed the isomeric compound, N-succinimidyl 3-guanidinomethyl-5-[(131)I]iodobenzoate (iso-[(131)I]SGMIB) wherein this bulky group was moved from ortho to meta position.Boc2-iso-SGMIB standard and its tin precursor, N-succinimidyl 3-((1,2-bis(tert-butoxycarbonyl)guanidino)methyl)-5-(trimethylstannyl)benzoate (Boc2-iso-SGMTB), were synthesized using two disparate routes, and iso-[*I]SGMIB synthesized from the tin precursor. Two HER2-targeted vectors - trastuzumab (Tras) and a nanobody 5F7 (Nb) - were labeled using iso-[(*)I]SGMIB and [(*)I]SGMIB. Paired-label internalization assays in vitro with both proteins, and biodistribution in vivo with trastuzumab, labeled using the two isomeric prosthetic agents were performed.When the reactions were performed under identical conditions, radioiodination yields for the synthesis of Boc2-iso-[(131)I]SGMIB were significantly higher than those for Boc2-[(131)I]SGMIB (70.7±2.0% vs 56.5±5.5%). With both Nb and trastuzumab, conjugation efficiency also was higher with iso-[(131)I]SGMIB than with [(131)I]SGMIB (Nb, 33.1±7.1% vs 28.9±13.0%; Tras, 45.1±4.5% vs 34.8±10.3%); however, the differences were not statistically significant. Internalization assays performed on BT474 cells with 5F7 Nb indicated similar residualizing capacity over 6h; however, at 24h, radioactivity retained intracellularly for iso-[(131)I]SGMIB-Nb was lower than for [(125)I]SGMIB-Nb (46.4±1.3% vs 56.5±2.5%); similar results were obtained using Tras. Likewise, a paired-label biodistribution of Tras labeled using iso-[(125)I]SGMIB and [(131)I]SGMIB indicated an up to 22% tumor uptake advantage at later time points for [(131)I]SGMIB-Tras.Given the higher labeling efficiency obtained with iso-SGMIB, this residualizing agent might be of value for use with shorter half-life radiohalogens.

Authors
Choi, J; Vaidyanathan, G; Koumarianou, E; McDougald, D; Pruszynski, M; Osada, T; Lahoutte, T; Lyerly, HK; Zalutsky, MR
MLA Citation
Choi, J, Vaidyanathan, G, Koumarianou, E, McDougald, D, Pruszynski, M, Osada, T, Lahoutte, T, Lyerly, HK, and Zalutsky, MR. "N-Succinimidyl guanidinomethyl iodobenzoate protein radiohalogenation agents: influence of isomeric substitution on radiolabeling and target cell residualization." Nuclear medicine and biology 41.10 (November 2014): 802-812.
PMID
25156548
Source
epmc
Published In
Nuclear Medicine and Biology
Volume
41
Issue
10
Publish Date
2014
Start Page
802
End Page
812
DOI
10.1016/j.nucmedbio.2014.07.005

Copper signaling axis as a target for prostate cancer therapeutics.

Previously published reports indicate that serum copper levels are elevated in patients with prostate cancer and that increased copper uptake can be used as a means to image prostate tumors. It is unclear, however, to what extent copper is required for prostate cancer cell function as we observed only modest effects of chelation strategies on the growth of these cells in vitro. With the goal of exploiting prostate cancer cell proclivity for copper uptake, we developed a "conditional lethal" screen to identify compounds whose cytotoxic actions were manifested in a copper-dependent manner. Emerging from this screen was a series of dithiocarbamates, which, when complexed with copper, induced reactive oxygen species-dependent apoptosis of malignant, but not normal, prostate cells. One of the dithiocarbamates identified, disulfiram (DSF), is an FDA-approved drug that has previously yielded disappointing results in clinical trials in patients with recurrent prostate cancer. Similarly, in our studies, DSF alone had a minimal effect on the growth of prostate cancer tumors when propagated as xenografts. However, when DSF was coadministered with copper, a very dramatic inhibition of tumor growth in models of hormone-sensitive and of castrate-resistant disease was observed. Furthermore, we determined that prostate cancer cells express high levels of CTR1, the primary copper transporter, and additional chaperones that are required to maintain intracellular copper homeostasis. The expression levels of most of these proteins are increased further upon treatment of androgen receptor (AR)-positive prostate cancer cell lines with androgens. Not surprisingly, robust CTR1-dependent uptake of copper into prostate cancer cells was observed, an activity that was accentuated by activation of AR. Given these data linking AR to intracellular copper uptake, we believe that dithiocarbamate/copper complexes are likely to be effective for the treatment of patients with prostate cancer whose disease is resistant to classical androgen ablation therapies.

Authors
Safi, R; Nelson, ER; Chitneni, SK; Franz, KJ; George, DJ; Zalutsky, MR; McDonnell, DP
MLA Citation
Safi, R, Nelson, ER, Chitneni, SK, Franz, KJ, George, DJ, Zalutsky, MR, and McDonnell, DP. "Copper signaling axis as a target for prostate cancer therapeutics." Cancer research 74.20 (October 2014): 5819-5831.
Website
http://hdl.handle.net/10161/9192
PMID
25320179
Source
epmc
Published In
Cancer Research
Volume
74
Issue
20
Publish Date
2014
Start Page
5819
End Page
5831
DOI
10.1158/0008-5472.can-13-3527

Radiolabeling and in vitro evaluation of (67)Ga-NOTA-modular nanotransporter--a potential Auger electron emitting EGFR-targeted radiotherapeutic.

Modular nanotransporters (MNTs) are vehicles designed to transport drugs from the cell surface via receptor-mediated endocytosis and endosomal escape to nucleus. Hence their conjugation to Auger electron emitters, can cause severe cell killing, by nuclear localization. Herein we evaluate the use of MNT as a platform for targeted radiotherapy with (67)Ga.EGF was the targeting ligand on the MNT, and NOTA was selected for its radiolabeling with (67)Ga. In the radiolabeling study we dealt with the precipitation of MNT (pI 5.7) at the labeling pH (4.5-5.5) of (67)Ga. Cellular and nuclei uptake of (67)Ga-NOTA-MNT by the A431 cell line was determined. Its specific cytotoxicity was compared to that of (67)Ga-EDTA, (67)Ga-NOTA-BSA and (67)Ga-NOTA-hEGF, in A431 and U87MGWTT, cell lines, by clonogenic assay. Dosimetry studies were also performed.(67)Ga-NOTA-MNT was produced with 90% yield and specific activity of 25.6mCi/mg. The in vitro kinetics revealed an increased uptake over 24h. 55% of the internalized radioactivity was detected in the nuclei at 1h. The cytotoxicity of (67)Ga-NOTA-MNT on A431 cell line was 17 and 385-fold higher when compared to non-specific (67)Ga-NOTA-BSA and (67)Ga-EDTA. While its cytotoxic potency was 13 and 72-fold higher when compared to (67)Ga-NOTA-hEGF in the A431 and the U87MGWTT cell lines, respectively, validating its nuclear localization. The absorbed dose, for 63% cell killing, was 8Gy, confirming the high specific index of (67)Ga.These results demonstrate the feasibility of using MNT as a platform for single cell kill targeted radiotherapy by Auger electron emitters.

Authors
Koumarianou, E; Slastnikova, TA; Pruszynski, M; Rosenkranz, AA; Vaidyanathan, G; Sobolev, AS; Zalutsky, MR
MLA Citation
Koumarianou, E, Slastnikova, TA, Pruszynski, M, Rosenkranz, AA, Vaidyanathan, G, Sobolev, AS, and Zalutsky, MR. "Radiolabeling and in vitro evaluation of (67)Ga-NOTA-modular nanotransporter--a potential Auger electron emitting EGFR-targeted radiotherapeutic." Nuclear medicine and biology 41.6 (July 2014): 441-449.
PMID
24776093
Source
epmc
Published In
Nuclear Medicine and Biology
Volume
41
Issue
6
Publish Date
2014
Start Page
441
End Page
449
DOI
10.1016/j.nucmedbio.2014.03.026

Comparison of the Hypoxia PET Tracer (18)F-EF5 to Immunohistochemical Marker EF5 in 3 Different Human Tumor Xenograft Models.

The availability of (18)F-labeled and unlabeled 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide (EF5) allows for a comparative assessment of tumor hypoxia by PET and immunohistochemistry; however, the combined use of these 2 approaches has not been fully assessed in vivo. The aim of this study was to evaluate (18)F-EF5 tumor uptake versus EF5 binding and hypoxia as determined from immunohistochemistry at both macroscopic and microregional levels.Three tumor models-PC3, HCT116, and H460-were evaluated. Tumor-bearing animals were coinjected with (18)F-EF5 and EF5 (30 mg/kg), and PET imaging was performed at 2.5 h after injection. After PET imaging and 2 min after Hoechst 33342 injection, the tumors were excised and evaluated for (18)F-EF5 distribution by autoradiography and EF5 binding by immunohistochemistry. Additionally, the effects of nonradioactive EF5 (30 mg/kg) on the hypoxia-imaging characteristics of (18)F-EF5 were evaluated by comparing the PET data for H460 tumors with those from animals injected with (18)F-EF5 alone.The uptake of (18)F-EF5 in hypoxic tumor regions and the spatial relationship between (18)F-EF5 uptake and EF5 binding varied among tumors. H460 tumors showed higher tumor-to-muscle contrast in PET imaging; however, the distribution and uptake of the tracer was less specific for hypoxia in H460 than in HCT116 and PC3 tumors. Correlation analyses revealed that the highest spatial correlation between (18)F-EF5 uptake and EF5 binding was in PC3 tumors (r = 0.73 ± 0.02) followed by HCT116 (r = 0.60 ± 0.06) and H460 (r = 0.53 ± 0.10). Uptake and binding of (18)F-EF5 and EF5 correlated negatively with Hoechst 33342 perfusion marker distribution in the 3 tumor models. Image contrast and heterogeneous uptake of (18)F-EF5 in H460 tumors was significantly higher when the radiotracer was used alone versus in combination with unlabeled EF5 (tumor-to-muscle ratio of 2.51 ± 0.33 vs. 1.71 ± 0.17, P < 0.001).The uptake and hypoxia selectivity of (18)F-EF5 varied among tumor models when animals also received nonradioactive EF5. Combined use of radioactive and nonradioactive EF5 for independent assessment of tumor hypoxia by PET and immunohistochemistry methods is promising; however, the EF5 drug concentrations that are required for immunohistochemistry assays may affect the uptake of (18)F-EF5 in hypoxic cells in certain tumor types as observed in H460 in this study.

Authors
Chitneni, SK; Bida, GT; Zalutsky, MR; Dewhirst, MW
MLA Citation
Chitneni, SK, Bida, GT, Zalutsky, MR, and Dewhirst, MW. "Comparison of the Hypoxia PET Tracer (18)F-EF5 to Immunohistochemical Marker EF5 in 3 Different Human Tumor Xenograft Models." Journal of nuclear medicine : official publication, Society of Nuclear Medicine 55.7 (July 2014): 1192-1197.
PMID
24854792
Source
epmc
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
55
Issue
7
Publish Date
2014
Start Page
1192
End Page
1197
DOI
10.2967/jnumed.114.137448

Improved tumor targeting of anti-HER2 nanobody through N-succinimidyl 4-guanidinomethyl-3-iodobenzoate radiolabeling.

Nanobodies are approximately 15-kDa proteins based on the smallest functional fragments of naturally occurring heavy chain-only antibodies and represent an attractive platform for the development of molecularly targeted agents for cancer diagnosis and therapy. Because the human epidermal growth factor receptor type 2 (HER2) is overexpressed in breast and ovarian carcinoma, as well as in other malignancies, HER2-specific Nanobodies may be valuable radiodiagnostics and therapeutics for these diseases. The aim of the present study was to evaluate the tumor-targeting potential of anti-HER2 5F7GGC Nanobody after radioiodination with the residualizing agent N-succinimidyl 4-guanidinomethyl 3-(125/131)I-iodobenzoate (*I-SGMIB).The 5F7GGC Nanobody was radiolabeled using *I-SGMIB and, for comparison, with N(ε)-(3-*I-iodobenzoyl)-Lys(5)-N(α)-maleimido-Gly(1)-GEEEK (*I-IB-Mal-d-GEEEK), another residualizing agent, and by direct radioiodination using IODO-GEN ((125)I-Nanobody). The 3 labeled Nanobodies were evaluated in affinity measurements, and paired-label internalization assays were performed on HER2-expressing BT474M1 breast carcinoma cells and in paired-label tissue distribution measurements in mice bearing subcutaneous BT474M1 xenografts.*I-SGMIB-Nanobody was produced in 50.4% ± 3.6% radiochemical yield and exhibited a dissociation constant of 1.5 ± 0.5 nM. Internalization assays demonstrated that intracellular retention of radioactivity was up to 1.5-fold higher for *I-SGMIB-Nanobody than for coincubated (125)I-Nanobody or *I-IB-Mal-d-GEEEK-Nanobody. Peak tumor uptake for *I-SGMIB-Nanobody was 24.50% ± 9.89% injected dose/g at 2 h, 2- to 4-fold higher than observed with other labeling methods, and was reduced by 90% with trastuzumab blocking, confirming the HER2 specificity of localization. Moreover, normal-organ clearance was fastest for *I-SGMIB-Nanobody, such that tumor-to-normal-organ ratios greater than 50:1 were reached by 24 h in all tissues except lungs and kidneys, for which the values were 10.4 ± 4.5 and 5.2 ± 1.5, respectively.Labeling anti-HER2 Nanobody 5F7GGC with *I-SGMIB yields a promising new conjugate for targeting HER2-expressing malignancies. Further research is needed to determine the potential utility of *I-SGMIB-5F7GGC labeled with (124)I, (123)I, and (131)I for PET and SPECT imaging and for targeted radiotherapy, respectively.

Authors
Pruszynski, M; Koumarianou, E; Vaidyanathan, G; Revets, H; Devoogdt, N; Lahoutte, T; Lyerly, HK; Zalutsky, MR
MLA Citation
Pruszynski, M, Koumarianou, E, Vaidyanathan, G, Revets, H, Devoogdt, N, Lahoutte, T, Lyerly, HK, and Zalutsky, MR. "Improved tumor targeting of anti-HER2 nanobody through N-succinimidyl 4-guanidinomethyl-3-iodobenzoate radiolabeling." Journal of nuclear medicine : official publication, Society of Nuclear Medicine 55.4 (April 2014): 650-656.
PMID
24578241
Source
epmc
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
55
Issue
4
Publish Date
2014
Start Page
650
End Page
656
DOI
10.2967/jnumed.113.127100

Radiolabeling and in vitro evaluation of 67Ga-NOTA-modular nanotransporter - A potential Auger electron emitting EGFR-targeted radiotherapeutic

Introduction: Modular nanotransporters (MNTs) are vehicles designed to transport drugs from the cell surface via receptor-mediated endocytosis and endosomal escape to nucleus. Hence their conjugation to Auger electron emitters, can cause severe cell killing, by nuclear localization. Herein we evaluate the use of MNT as a platform for targeted radiotherapy with 67 Ga. Methods: EGF was the targeting ligand on the MNT, and NOTA was selected for its radiolabeling with 67 Ga. In the radiolabeling study we dealt with the precipitation of MNT (pI 5.7) at the labeling pH (4.5-5.5) of 67 Ga. Cellular and nuclei uptake of 67 Ga-NOTA-MNT by the A431 cell line was determined. Its specific cytotoxicity was compared to that of 67 Ga-EDTA, 67 Ga-NOTA-BSA and 67 Ga-NOTA-hEGF, in A431 and U87MGWTT, cell lines, by clonogenic assay. Dosimetry studies were also performed. Results: 67 Ga-NOTA-MNT was produced with 90% yield and specific activity of 25.6mCi/mg. The in vitro kinetics revealed an increased uptake over 24h. 55% of the internalized radioactivity was detected in the nuclei at 1h. The cytotoxicity of 67 Ga-NOTA-MNT on A431 cell line was 17 and 385-fold higher when compared to non-specific 67 Ga-NOTA-BSA and 67 Ga-EDTA. While its cytotoxic potency was 13 and 72-fold higher when compared to 67 Ga-NOTA-hEGF in the A431 and the U87MGWTT cell lines, respectively, validating its nuclear localization. The absorbed dose, for 63% cell killing, was 8Gy, confirming the high specific index of 67 Ga. Conclusion: These results demonstrate the feasibility of using MNT as a platform for single cell kill targeted radiotherapy by Auger electron emitters. © 2014 Elsevier Inc.

Authors
Koumarianou, E; Slastnikova, TA; Pruszynski, M; Rosenkranz, AA; Vaidyanathan, G; Sobolev, AS; Zalutsky, MR
MLA Citation
Koumarianou, E, Slastnikova, TA, Pruszynski, M, Rosenkranz, AA, Vaidyanathan, G, Sobolev, AS, and Zalutsky, MR. "Radiolabeling and in vitro evaluation of 67Ga-NOTA-modular nanotransporter - A potential Auger electron emitting EGFR-targeted radiotherapeutic." Nuclear Medicine and Biology 41.6 (January 1, 2014): 441-449.
Source
scopus
Published In
Nuclear Medicine and Biology
Volume
41
Issue
6
Publish Date
2014
Start Page
441
End Page
449
DOI
10.1016/j.nucmedbio.2014.03.026

Abstract C86: Tethered Hsp90 inhibitors carrying optical or radioiodinated probes reveal selective internalization of ectopic Hsp90 in malignant breast tumor cells.

Authors
Barrott, JJ; Smith, AP; Osada, T; Ramanujam, N; Zalutsky, MR; Lyerly, K; Haystead, TAJ
MLA Citation
Barrott, JJ, Smith, AP, Osada, T, Ramanujam, N, Zalutsky, MR, Lyerly, K, and Haystead, TAJ. "Abstract C86: Tethered Hsp90 inhibitors carrying optical or radioiodinated probes reveal selective internalization of ectopic Hsp90 in malignant breast tumor cells." November 1, 2013.
Source
crossref
Published In
Molecular cancer therapeutics
Volume
12
Issue
11_Supplement
Publish Date
2013
Start Page
C86
End Page
C86
DOI
10.1158/1535-7163.TARG-13-C86

Optical and radioiodinated tethered Hsp90 inhibitors reveal selective internalization of ectopic Hsp90 in malignant breast tumor cells.

Inhibitors of heat-shock protein 90 (Hsp90) have demonstrated an unusual selectivity for tumor cells despite its ubiquitous expression. This phenomenon has remained unexplained, but could be influenced by ectopically expressed Hsp90 in tumors. In this work, we synthesized Hsp90 inhibitors that can carry optical or radioiodinated probes via a polyethyleneglycol tether. We show that these tethered inhibitors selectively recognize cells expressing ectopic Hsp90 and become internalized. The internalization process is blocked by Hsp90 antibodies, suggesting that active cycling of the protein occurs at the plasma membrane. In mice, we observed exquisite accumulation of the fluor-tethered versions within breast tumors at very sensitive levels. Cell-based assays with the radiolabeled version showed picomolar detection in cells that express ectopic Hsp90. Our findings show that fluor-tethered or radiolabeled inhibitors that target ectopic Hsp90 can be used to detect breast cancer malignancies through noninvasive imaging.

Authors
Barrott, JJ; Hughes, PF; Osada, T; Yang, X-Y; Hartman, ZC; Loiselle, DR; Spector, NL; Neckers, L; Rajaram, N; Hu, F; Ramanujam, N; Vaidyanathan, G; Zalutsky, MR; Lyerly, HK; Haystead, TA
MLA Citation
Barrott, JJ, Hughes, PF, Osada, T, Yang, X-Y, Hartman, ZC, Loiselle, DR, Spector, NL, Neckers, L, Rajaram, N, Hu, F, Ramanujam, N, Vaidyanathan, G, Zalutsky, MR, Lyerly, HK, and Haystead, TA. "Optical and radioiodinated tethered Hsp90 inhibitors reveal selective internalization of ectopic Hsp90 in malignant breast tumor cells." Chem Biol 20.9 (September 19, 2013): 1187-1197.
PMID
24035283
Source
pubmed
Published In
Chemistry and Biology
Volume
20
Issue
9
Publish Date
2013
Start Page
1187
End Page
1197
DOI
10.1016/j.chembiol.2013.08.004

18F-EF5 PET imaging as an early response biomarker for the hypoxia-activated prodrug SN30000 combined with radiation treatment in a non-small cell lung cancer xenograft model.

UNLABELLED: Hypoxia is a significant therapeutic problem for solid tumors because hypoxic cells are treatment-resistant and more aggressive. Hypoxia-activated prodrugs such as SN30000 use a mechanism of activation in hypoxic cells similar to that of 2-nitroimidazole hypoxia PET tracers. Therefore, we have evaluated the usefulness of 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-(18)F-pentafluoropropyl)-acetamide ((18)F-EF5) PET to monitor and predict tumor response to SN30000 plus radiation treatment (RT). METHODS: Human non-small cell lung cancer xenografts (H460) in athymic rats were imaged with (18)F-EF5 PET before and after treatment with SN30000 (90 mg/kg), with or without 15-Gy RT. The feasibility of imaging early changes in hypoxia in response to SN30000 was examined 24 h after treatment, followed by ex vivo γ-counting and immunohistochemical examination to study drug-induced apoptosis. Subsequently, the therapeutic effects of SN30000 with or without RT were evaluated in tumor growth delay studies and compared with early treatment-induced changes observed by (18)F-EF5 PET. Changes in tumor hemoglobin oxygen saturation as a function of time after treatment measured by optical spectroscopy were compared with PET data. RESULTS: The uptake of (18)F-EF5 was significantly lower in SN30000-treated tumors than in saline controls 24 h after treatment (mean standardized uptake value, 0.44 ± 0.08 vs. 0.56 ± 0.08 for control group; P < 0.05). Apoptosis was significantly higher in SN30000-treated tumors than in controls. Early treatment-induced changes in (18)F-EF5 uptake were indicative of tumor response in growth delay studies at the group level. SN30000 plus RT significantly decreased (18)F-EF5 uptake relative to baseline and resulted in complete tumor remission in 5 of 7 animals. SN30000 alone decreased (18)F-EF5 uptake, generally in tumors with high initial standardized uptake values, and showed a minor tumor growth delay effect. The changes induced by SN30000 with or without RT in (18)F-EF5 uptake correlated with baseline hypoxia levels. RT caused significant increases in tumor oxygen concentration and hemoglobin oxygen saturation. CONCLUSION: A hypoxia PET imaging agent can measure changes in tumor hypoxic fraction in response to SN30000. These results suggest the utility of (18)F-EF5 PET for monitoring early response to tumor treatment with SN30000 plus RT in the clinical development of this novel hypoxia-activated prodrug.

Authors
Chitneni, SK; Bida, GT; Yuan, H; Palmer, GM; Hay, MP; Melcher, T; Wilson, WR; Zalutsky, MR; Dewhirst, MW
MLA Citation
Chitneni, SK, Bida, GT, Yuan, H, Palmer, GM, Hay, MP, Melcher, T, Wilson, WR, Zalutsky, MR, and Dewhirst, MW. "18F-EF5 PET imaging as an early response biomarker for the hypoxia-activated prodrug SN30000 combined with radiation treatment in a non-small cell lung cancer xenograft model." J Nucl Med 54.8 (August 2013): 1339-1346.
PMID
23740105
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
54
Issue
8
Publish Date
2013
Start Page
1339
End Page
1346
DOI
10.2967/jnumed.112.116293

Modular nanotransporters: a versatile platform for nuclear delivery of anti-cancer pharmaceuticals

Authors
Sobolev, AS; Rosenkranz, AA; Zalutsky, MR
MLA Citation
Sobolev, AS, Rosenkranz, AA, and Zalutsky, MR. "Modular nanotransporters: a versatile platform for nuclear delivery of anti-cancer pharmaceuticals." July 2013.
Source
wos-lite
Published In
FEBS Journal
Volume
280
Publish Date
2013
Start Page
376
End Page
376

Isomeric N-succinimidyl 3-guanidinomethyl-5-[I-131]iodobenzoate (iso-[I-131]SGMIB): A guanidine-containing residualizing agent for radiohalogenation of internalizing biomolecules

Authors
Choi, J; Vaidyanathan, G; Koumarianou, E; Pruszynski, M; Lahoutte, T; Zalutsky, MR
MLA Citation
Choi, J, Vaidyanathan, G, Koumarianou, E, Pruszynski, M, Lahoutte, T, and Zalutsky, MR. "Isomeric N-succinimidyl 3-guanidinomethyl-5-[I-131]iodobenzoate (iso-[I-131]SGMIB): A guanidine-containing residualizing agent for radiohalogenation of internalizing biomolecules." JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS 56 (May 2013): S39-S39.
Source
wos-lite
Published In
Journal of Labelled Compounds and Radiopharmaceuticals
Volume
56
Publish Date
2013
Start Page
S39
End Page
S39

SFBTMGMB (N-succinimidyl 3-((4-(4-fluorobutyl)-1H-1,2,3-triazol-1-yl)methyl)-5-(guanidinomethyl)benzoate): An SGMIB analogue for labeling internalizing biomolecules with F-18

Authors
Vaidyanathan, G; McDougald, D; Pruszynski, M; Koumarianou, E; Hens, MA; Lahoutte, T; Zalutsky, MR
MLA Citation
Vaidyanathan, G, McDougald, D, Pruszynski, M, Koumarianou, E, Hens, MA, Lahoutte, T, and Zalutsky, MR. "SFBTMGMB (N-succinimidyl 3-((4-(4-fluorobutyl)-1H-1,2,3-triazol-1-yl)methyl)-5-(guanidinomethyl)benzoate): An SGMIB analogue for labeling internalizing biomolecules with F-18." JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS 56 (May 2013): S127-S127.
Source
wos-lite
Published In
Journal of Labelled Compounds and Radiopharmaceuticals
Volume
56
Publish Date
2013
Start Page
S127
End Page
S127

Abstract 4341: A novel injectable polymer liquid that self-assembles into radioactive “seeds” for brachytherapy.

Authors
Liu, W; McDaniel, JR; Li, X; Schaal, J; Bhattacharyya, J; Zalutsky, MR; Chilkoti, A
MLA Citation
Liu, W, McDaniel, JR, Li, X, Schaal, J, Bhattacharyya, J, Zalutsky, MR, and Chilkoti, A. "Abstract 4341: A novel injectable polymer liquid that self-assembles into radioactive “seeds” for brachytherapy." April 15, 2013.
Source
crossref
Published In
Cancer Research
Volume
73
Issue
8 Supplement
Publish Date
2013
Start Page
4341
End Page
4341
DOI
10.1158/1538-7445.AM2013-4341

Targeting breast carcinoma with radioiodinated anti-HER2 Nanobody.

INTRODUCTION: With a molecular weight an order of magnitude lower than antibodies but possessing comparable affinities, Nanobodies (Nbs) are attractive as targeting agents for cancer diagnosis and therapy. An anti-HER2 Nb could be utilized to determine HER2 status in breast cancer patients prior to trastuzumab treatment. This provided motivation for the generation of HER2-specific 5F7GGC Nb, its radioiodination and evaluation for targeting HER2 expressing tumors. METHODS: 5F7GGC Nb was radioiodinated with ¹²⁵I using Iodogen and with ¹³¹I using the residualizing agent N(ɛ)-(3-[¹³¹I]iodobenzoyl)-Lys⁵-N(α)-maleimido-Gly¹-GEEEK ([¹³¹I]IB-Mal-D-GEEEK) used previously successfully with intact antibodies. Paired-label internalization assays using BT474M1 cells and tissue distribution experiments in athymic mice bearing BT474M1 xenografts were performed to compare the two labeled Nb preparations. RESULTS: The radiochemical yields for Iodogen and [¹³¹I]IB-Mal-D-GEEEK labeling were 83.6±5.0% (n=10) and 59.6±9.4% (n=15), respectively. The immunoreactivity of labeled proteins was preserved as confirmed by in vitro and in vivo binding to tumor cells. Biodistribution studies showed that Nb radiolabeled using [¹³¹I]IB-Mal-D-GEEEK, compared with the directly labeled Nb, had a higher tumor uptake (4.65±0.61% ID/g vs. 2.92±0.24% ID/g at 8h), faster blood clearance, lower accumulation in non-target organs except kidneys, and as a result, higher concomitant tumor-to-blood and tumor-to-tissue ratios. CONCLUSIONS: Taken together, these results demonstrate that 5F7GGC anti-HER2 Nb labeled with residualizing [¹³¹I]IB-Mal-D-GEEEK had better tumor targeting properties compared to the directly labeled Nb suggesting the potential utility of this Nb conjugate for SPECT (¹²⁹I) and PET imaging (¹²⁴I) of patients with HER2-expressing tumors.

Authors
Pruszynski, M; Koumarianou, E; Vaidyanathan, G; Revets, H; Devoogdt, N; Lahoutte, T; Zalutsky, MR
MLA Citation
Pruszynski, M, Koumarianou, E, Vaidyanathan, G, Revets, H, Devoogdt, N, Lahoutte, T, and Zalutsky, MR. "Targeting breast carcinoma with radioiodinated anti-HER2 Nanobody." Nucl Med Biol 40.1 (January 2013): 52-59.
PMID
23159171
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
40
Issue
1
Publish Date
2013
Start Page
52
End Page
59
DOI
10.1016/j.nucmedbio.2012.08.008

Targeting breast carcinoma with radioiodinated anti-HER2 Nanobody

Introduction: With a molecular weight an order of magnitude lower than antibodies but possessing comparable affinities, Nanobodies (Nbs) are attractive as targeting agents for cancer diagnosis and therapy. An anti-HER2 Nb could be utilized to determine HER2 status in breast cancer patients prior to trastuzumab treatment. This provided motivation for the generation of HER2-specific 5F7GGC Nb, its radioiodination and evaluation for targeting HER2 expressing tumors. Methods: 5F7GGC Nb was radioiodinated with 125I using Iodogen and with 131I using the residualizing agent Ne-(3-[131I]iodobenzoyl)-Lys5-Nα -maleimido-Gly1-GEEEK ([131I]IB-Mal-d-GEEEK) used previously successfully with intact antibodies. Paired-label internalization assays using BT474M1 cells and tissue distribution experiments in athymic mice bearing BT474M1 xenografts were performed to compare the two labeled Nb preparations. Results: The radiochemical yields for Iodogen and [131I]IB-Mal-d-GEEEK labeling were 83.6±5.0% (n=10) and 59.6±9.4% (n=15), respectively. The immunoreactivity of labeled proteins was preserved as confirmed by in vitro and in vivo binding to tumor cells. Biodistribution studies showed that Nb radiolabeled using [131I]IB-Mal-d-GEEEK, compared with the directly labeled Nb, had a higher tumor uptake (4.65±0.61% ID/g vs. 2.92±0.24% ID/g at 8h), faster blood clearance, lower accumulation in non-target organs except kidneys, and as a result, higher concomitant tumor-to-blood and tumor-to-tissue ratios. Conclusions: Taken together, these results demonstrate that 5F7GGC anti-HER2 Nb labeled with residualizing [131I]IB-Mal-d-GEEEK had better tumor targeting properties compared to the directly labeled Nb suggesting the potential utility of this Nb conjugate for SPECT (129I) and PET imaging (124I) of patients with HER2-expressing tumors. © 2013 Elsevier Inc.

Authors
Pruszynski, M; Koumarianou, E; Vaidyanathan, G; Revets, H; Devoogdt, N; Lahoutte, T; Zalutsky, MR
MLA Citation
Pruszynski, M, Koumarianou, E, Vaidyanathan, G, Revets, H, Devoogdt, N, Lahoutte, T, and Zalutsky, MR. "Targeting breast carcinoma with radioiodinated anti-HER2 Nanobody." Nuclear Medicine and Biology 40.1 (2013): 52-59.
Source
scival
Published In
Nuclear Medicine and Biology
Volume
40
Issue
1
Publish Date
2013
Start Page
52
End Page
59
DOI
10.1016/j.nucmedbio.2012.08.008

SIB-DOTA: a trifunctional prosthetic group potentially amenable for multi-modal labeling that enhances tumor uptake of internalizing monoclonal antibodies.

A major drawback of internalizing monoclonal antibodies (mAbs) radioiodinated with direct electrophilic approaches is that tumor retention of radioactivity is compromised by the rapid washout of iodo-tyrosine, the primary labeled catabolite for mAbs labeled via this strategy. In our continuing efforts to develop more versatile residualizing labels that could overcome this problem, we have designed SIB-DOTA, a prosthetic labeling template that combines the features of the prototypical, dehalogenation-resistant N-succinimidyl 3-iodobenzoate (SIB) with DOTA, a useful macrocyclic chelator for labeling with radiometals. Herein we describe the synthesis of the unlabeled standard of this prosthetic moiety, its protected tin precursor, and radioiodinated SIB-DOTA. An anti-EGFRvIII-reactive mAb, L8A4 was radiolabeled with [(131)I]SIB-DOTA in 27.1±6.2% (n=2) conjugation yields and its targeting properties to the same mAb labeled with [(125)I]SGMIB both in vitro and in vivo using U87MG·ΔEGFR cells and xenografts were compared. In vitro paired-label internalization assays showed that the intracellular radioactivity from [(131)I]SIB-DOTA-L8A4 was 21.4±0.5% and 26.2±1.1% of initially bound radioactivity at 16 and 24h, respectively. In comparison, these values for [(125)I]SGMIB-L8A4 were 16.7±0.5% and 14.9±1.1%. Similarly, the SIB-DOTA prosthetic group provided better tumor targeting in vivo than SGMIB over 8 d period. These results suggest that SIB-DOTA warrants further evaluation as a residualizing agent for labeling internalizing mAbs including those targeted to EGFRvIII.

Authors
Vaidyanathan, G; White, BJ; Affleck, DJ; Zhao, XG; Welsh, PC; McDougald, D; Choi, J; Zalutsky, MR
MLA Citation
Vaidyanathan, G, White, BJ, Affleck, DJ, Zhao, XG, Welsh, PC, McDougald, D, Choi, J, and Zalutsky, MR. "SIB-DOTA: a trifunctional prosthetic group potentially amenable for multi-modal labeling that enhances tumor uptake of internalizing monoclonal antibodies." Bioorg Med Chem 20.24 (December 15, 2012): 6929-6939.
PMID
23159039
Source
pubmed
Published In
Bioorganic & Medicinal Chemistry
Volume
20
Issue
24
Publish Date
2012
Start Page
6929
End Page
6939
DOI
10.1016/j.bmc.2012.10.025

Brachytherapy using injectable seeds that are self-assembled from genetically encoded polypeptides in situ.

Brachytherapy is a common clinical technique involving implantation of sealed radioactive "seeds" within a tumor to selectively irradiate the tumor mass while minimizing systemic toxicity. To mitigate the disadvantages associated with complex surgical implantation and subsequent device removal procedures, we have developed an alternative approach using a genetically encoded peptide polymer solution composed of a thermally responsive elastin-like polypeptide (ELP) radiolabeled with (131)I that self-assembles into radionuclide seeds upon intratumoral injection. The formation of these nontoxic and biodegradable polymer seeds led to prolonged intratumoral retention (~85% ID/tumor 7 days postinjection) of the radionuclide, elicited a tumor growth delay in 100% of the tumors in two human xenografts (FaDu and PC-3), and cured more than 67% of tumor-bearing animals after a single administration of labeled ELP. These results suggest that in situ self-assembly of biodegradable and injectable radionuclide-containing polypeptide seeds could be a promising therapeutic alternative to conventional brachytherapy.

Authors
Liu, W; McDaniel, J; Li, X; Asai, D; Quiroz, FG; Schaal, J; Park, JS; Zalutsky, M; Chilkoti, A
MLA Citation
Liu, W, McDaniel, J, Li, X, Asai, D, Quiroz, FG, Schaal, J, Park, JS, Zalutsky, M, and Chilkoti, A. "Brachytherapy using injectable seeds that are self-assembled from genetically encoded polypeptides in situ." Cancer Res 72.22 (November 15, 2012): 5956-5965.
PMID
23155121
Source
pubmed
Published In
Cancer Research
Volume
72
Issue
22
Publish Date
2012
Start Page
5956
End Page
5965
DOI
10.1158/0008-5472.CAN-12-2127

Modular nanotransporters: a versatile approach for enhancing nuclear delivery and cytotoxicity of Auger electron-emitting 125I.

UNLABELLED: BACKGROUND: This study evaluates the potential utility of a modular nanotransporter (MNT) for enhancing the nuclear delivery and cytotoxicity of the Auger electron emitter 125I in cancer cells that overexpress the epidermal growth factor receptor (EGFR). METHODS: MNTs are recombinant multifunctional polypeptides that we have developed for achieving selective delivery of short-range therapeutics into cancer cells. MNTs contain functional modules for receptor binding, internalization, endosomal escape and nuclear translocation, thereby facilitating the transport of drugs from the cell surface to the nucleus. The MNT described herein utilized EGF as the targeting ligand and was labeled with 125I using N-succinimidyl-4-guanidinomethyl-3-[125I]iodobenzoate (SGMIB). Membrane binding, intracellular and nuclear accumulation kinetics, and clonogenic survival assays were performed using the EGFR-expressing A431 epidermoid carcinoma and D247 MG glioma cell lines. RESULTS: [125I]SGMIB-MNT bound to A431 and D247 MG cells with an affinity comparable to that of native EGF. More than 60% of internalized [125I]SGMIB-MNT radioactivity accumulated in the cell nuclei after a 1-h incubation. The cytotoxic effectiveness of [125I]SGMIB-MNT compared with 125I-labeled bovine serum albumin control was enhanced by a factor of 60 for D247 MG cells and more than 1,000-fold for A431 cells, which express higher levels of EGFR. CONCLUSIONS: MNT can be utilized to deliver 125I into the nuclei of cancer cells overexpressing EGFR, significantly enhancing cytotoxicity. Further evaluation of [125I]SGMIB-MNT as a targeted radiotherapeutic for EGFR-expressing cancer cells appears warranted.

Authors
Slastnikova, TA; Koumarianou, E; Rosenkranz, AA; Vaidyanathan, G; Lupanova, TN; Sobolev, AS; Zalutsky, MR
MLA Citation
Slastnikova, TA, Koumarianou, E, Rosenkranz, AA, Vaidyanathan, G, Lupanova, TN, Sobolev, AS, and Zalutsky, MR. "Modular nanotransporters: a versatile approach for enhancing nuclear delivery and cytotoxicity of Auger electron-emitting 125I. (Published online)" EJNMMI Res 2.1 (October 29, 2012): 59-.
Website
http://hdl.handle.net/10161/11046
PMID
23107475
Source
pubmed
Published In
EJNMMI Research
Volume
2
Issue
1
Publish Date
2012
Start Page
59
DOI
10.1186/2191-219X-2-59

A simplified synthesis of the hypoxia imaging agent 2-(2-Nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-[(18)F]pentafluoropropyl)-acetamide ([18F]EF5).

INTRODUCTION: [(18)F]EF5 is a validated marker for PET imaging of tumor hypoxia. It is prepared by reacting a trifluoroallyl precursor with carrier-added [(18)F]F(2) gas in trifluoroacetic acid (TFA) solvent. We report here an improved radiosynthesis and purification of [(18)F]EF5 by utilizing an electroformed nickel (Ni) target for [(18)F]F(2) production, and Oasis® HLB cartridges for on-line solid phase extraction of [(18)F]EF5 prior to HPLC purification. METHODS: [(18)F]F(2) was produced by deuteron bombardment of neon plus F(2) in an Ni target, and bubbled through the radiolabelling precursor solution. Purification was achieved by extracting the contents of the crude reaction mixture onto Oasis HLB cartridges, and subsequently eluted onto a semi-preparative HPLC column for further separation. Purified [(18)F]EF5 was evaluated in small animal PET studies using HCT116 tumor xenografts in nude mice. RESULTS: The electroformed Ni target enabled recovery of >75% of the radioactivity from the cyclotron target, resulting in 16.2 ± 2.2 GBq (438 ± 58 mCi) of [(18)F]F(2) available for the synthesis. Use of Oasis cartridges yielded a less complex mixture for purification. On average, 1140 ± 200 MBq (30.8 ± 5.4 mCi) of [(18)F]EF5 were collected at EOS. Small animal PET imaging studies showed specific retention of [(18)F]EF5 in tumors, with tumor-to-muscle ratios of 2.7 ± 0.3 at about 160 min after injection. CONCLUSION: A simple procedure has been developed for the routine synthesis of [(18)F]EF5 in amounts and purity required for clinical studies. This new method avoids the need for TFA evaporation and also enables facile automation of the synthesis using commercially available radiosynthesis modules.

Authors
Chitneni, SK; Bida, GT; Dewhirst, MW; Zalutsky, MR
MLA Citation
Chitneni, SK, Bida, GT, Dewhirst, MW, and Zalutsky, MR. "A simplified synthesis of the hypoxia imaging agent 2-(2-Nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-[(18)F]pentafluoropropyl)-acetamide ([18F]EF5)." Nucl Med Biol 39.7 (October 2012): 1012-1018.
PMID
22727821
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
39
Issue
7
Publish Date
2012
Start Page
1012
End Page
1018
DOI
10.1016/j.nucmedbio.2012.05.006

Protein polymer hydrogels by in situ, rapid and reversible self-gelation.

Protein-based biomaterials are an important class of materials for applications in biotechnology and medicine. The exquisite control of their composition, stereochemistry, and chain length offers unique opportunities to engineer biofunctionality, biocompatibility, and biodegradability into these materials. Here, we report the synthesis of a thermally responsive peptide polymer-based hydrogel composed of a recombinant elastin-like polypeptide (ELP) that rapidly forms a reversibly cross-linked hydrogel by the formation of intermolecular disulfide cross-links. To do so, we designed and synthesized ELPs that incorporate periodic cysteine residues (cELPs), and show that cELPs are thermally responsive protein polymers that display rapid gelation under physiologically relevant, mild oxidative conditions. Gelation of cELPs, at concentrations as low as 2.5 wt%, occurs in ≈ 2.5 min upon addition a low concentration of hydrogen peroxide (0.3 wt%). We show the utility of these hydrogels for the sustained release of a model protein in vitro, and demonstrate the ability of this injectable biomaterial to pervade tumors to maximize tumor coverage and retention time upon intratumoral injection. cELPs represent a new class of injectable reversibly cross-linked hydrogels with properties intermediate between ELP coacervates and chemically cross-linked ELP hydrogels that will find useful applications in drug delivery and tissue engineering.

Authors
Asai, D; Xu, D; Liu, W; Garcia Quiroz, F; Callahan, DJ; Zalutsky, MR; Craig, SL; Chilkoti, A
MLA Citation
Asai, D, Xu, D, Liu, W, Garcia Quiroz, F, Callahan, DJ, Zalutsky, MR, Craig, SL, and Chilkoti, A. "Protein polymer hydrogels by in situ, rapid and reversible self-gelation." Biomaterials 33.21 (July 2012): 5451-5458.
PMID
22538198
Source
pubmed
Published In
Biomaterials
Volume
33
Issue
21
Publish Date
2012
Start Page
5451
End Page
5458
DOI
10.1016/j.biomaterials.2012.03.083

Abstract 2884: Preclinical studies on tumor retention, antitumor efficacy and toxicity of thermally responsive polypeptide-based radionuclide intratumoral depot in nude mice

Authors
Liu, W; McDaniel, JR; Li, X; Asai, D; Zalutsky, MR; Chilkoti, A
MLA Citation
Liu, W, McDaniel, JR, Li, X, Asai, D, Zalutsky, MR, and Chilkoti, A. "Abstract 2884: Preclinical studies on tumor retention, antitumor efficacy and toxicity of thermally responsive polypeptide-based radionuclide intratumoral depot in nude mice." Cancer Research 72.8 Supplement (April 15, 2012): 2884-2884.
Source
crossref
Published In
Cancer Research
Volume
72
Issue
8 Supplement
Publish Date
2012
Start Page
2884
End Page
2884
DOI
10.1158/1538-7445.AM2012-2884

Radioimmunotargeting of malignant glioma by monoclonal antibody D2C7 reactive against both wild-type and variant III mutant epidermal growth factor receptors.

INTRODUCTION: Malignant glioma remains a significant therapeutic challenge, and immunotherapeutics might be a beneficial approach for these patients. A monoclonal antibody (MAb) specific for multiple molecular targets could expand the treatable patient population and the fraction of tumor cells targeted, with potentially increased efficacy. This motivated the generation of MAb D2C7, which recognizes both wild-type epidermal growth factor receptor (EGFRwt) and a tumor-specific mutant, EGFRvIII. METHODS: D2C7 binding affinity was determined by surface plasmon resonance and its specificity characterized through comparison to EGFRwt-specific EGFR.1 and EGFRvIII-specific L8A4 MAbs by flow cytometry and immunohistochemical analysis. The three MAbs were labeled with (125)I or (131)I using Iodogen, and paired-label internalization assays and biodistribution experiments in athymic mice with human tumor xenografts were performed. RESULTS: The affinity of D2C7 for EGFRwt and EGFRvIII was 5.2×10(9) M(-1) and 3.6×10(9) M(-1), and cell-surface reactivity with both receptors was documented by flow cytometry. Immunohistochemical analyses revealed D2C7 reactivity with malignant glioma tissue from 90 of 101 patients. Internalization assays performed on EGFRwt-expressing WTT cells and EGFRvIII-expressing NR6M cells indicated a threefold lower degradation of (125)I-labeled D2C7 compared with (131)I-labeled EGFR.1. Uptake of (125)I-labeled D2C7 in NR6M xenografts (52.45±13.97 %ID g(-1) on Day 3) was more than twice that of (131)I-labeled L8A4; a threefold to fivefold tumor delivery advantage was seen when compared to (131)I-labeled EGFR.1 in mice with WTT xenografts. CONCLUSIONS: These results suggest that D2C7 warrants further evaluation for the development of MAb-based therapeutics against cancers expressing EGFRwt and EGFRvIII.

Authors
Zalutsky, MR; Boskovitz, A; Kuan, C-T; Pegram, CN; Ayriss, J; Wikstrand, CJ; Buckley, AF; Lipp, ES; Herndon, JE; McLendon, RE; Bigner, DD
MLA Citation
Zalutsky, MR, Boskovitz, A, Kuan, C-T, Pegram, CN, Ayriss, J, Wikstrand, CJ, Buckley, AF, Lipp, ES, Herndon, JE, McLendon, RE, and Bigner, DD. "Radioimmunotargeting of malignant glioma by monoclonal antibody D2C7 reactive against both wild-type and variant III mutant epidermal growth factor receptors." Nucl Med Biol 39.1 (January 2012): 23-34.
PMID
21958852
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
39
Issue
1
Publish Date
2012
Start Page
23
End Page
34
DOI
10.1016/j.nucmedbio.2011.06.005

Modular nanotransporters: a multipurpose in vivo working platform for targeted drug delivery.

BACKGROUND: Modular nanotransporters (MNT) are recombinant multifunctional polypeptides created to exploit a cascade of cellular processes, initiated with membrane receptor recognition to deliver selective short-range and highly cytotoxic therapeutics to the cell nucleus. This research was designed for in vivo concept testing for this drug delivery platform using two modular nanotransporters, one targeted to the α-melanocyte-stimulating hormone (αMSH) receptor overexpressed on melanoma cells and the other to the epidermal growth factor (EGF) receptor overexpressed on several cancers, including glioblastoma, and head-and-neck and breast carcinoma cells. METHODS: In vivo targeting of the modular nanotransporter was determined by immuno-fluorescence confocal laser scanning microscopy and by accumulation of (125)I-labeled modular nanotransporters. The in vivo therapeutic effects of the modular nanotransporters were assessed by photodynamic therapy studies, given that the cytotoxicity of photosensitizers is critically dependent on their delivery to the cell nucleus. RESULTS: Immunohistochemical analyses of tumor and neighboring normal tissues of mice injected with multifunctional nanotransporters demonstrated preferential uptake in tumor tissue, particularly in cell nuclei. With (125)I-labeled MNT{αMSH}, optimal tumor:muscle and tumor:skin ratios of 8:1 and 9.8:1, respectively, were observed 3 hours after injection in B16-F1 melanoma-bearing mice. Treatment with bacteriochlorin p-MNT{αMSH} yielded 89%-98% tumor growth inhibition and a two-fold increase in survival for mice with B16-F1 and Cloudman S91 melanomas. Likewise, treatment of A431 human epidermoid carcinoma-bearing mice with chlorin e(6)- MNT{EGF} resulted in 94% tumor growth inhibition compared with free chlorin e(6), with 75% of animals surviving at 3 months compared with 0% and 20% for untreated and free chlorin e(6)-treated groups, respectively. CONCLUSION: The multifunctional nanotransporter approach provides a new in vivo functional platform for drug development that could, in principle, be applicable to any combination of cell surface receptor and agent (photosensitizers, oligonucleotides, radionuclides) requiring nuclear delivery to achieve maximum effectiveness.

Authors
Slastnikova, TA; Rosenkranz, AA; Gulak, PV; Schiffelers, RM; Lupanova, TN; Khramtsov, YV; Zalutsky, MR; Sobolev, AS
MLA Citation
Slastnikova, TA, Rosenkranz, AA, Gulak, PV, Schiffelers, RM, Lupanova, TN, Khramtsov, YV, Zalutsky, MR, and Sobolev, AS. "Modular nanotransporters: a multipurpose in vivo working platform for targeted drug delivery." Int J Nanomedicine 7 (2012): 467-482.
Website
http://hdl.handle.net/10161/11049
PMID
22346349
Source
pubmed
Published In
International journal of nanomedicine
Volume
7
Publish Date
2012
Start Page
467
End Page
482
DOI
10.2147/IJN.S28249

Applications of 211At and 223Ra in targeted alpha-particle radiotherapy.

Targeted radiotherapy using agents tagged with α-emitting radionuclides is gaining traction with several clinical trials already undertaken or ongoing, and others in the advanced planning stage. The most commonly used α-emitting radionuclides are 213Bi, 211At, 223Ra and 225Ac. While each one of these has pros and cons, it can be argued that 211At probably is the most versatile based on its half life, decay scheme and chemistry. On the other hand, for targeting bone metastases, 223Ra is the ideal radionuclide because simple cationic radium can be used for this purpose. In this review, we will discuss the recent developments taken place in the application of 211At-labeled radiopharmaceuticals and give an overview of the current status of 223Ra for targeted α-particle radiotherapy.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Applications of 211At and 223Ra in targeted alpha-particle radiotherapy." Curr Radiopharm 4.4 (October 2011): 283-294. (Review)
PMID
22202151
Source
pubmed
Published In
Current Radiopharmaceuticals
Volume
4
Issue
4
Publish Date
2011
Start Page
283
End Page
294

An alternative and expedient synthesis of radioiodinated 4-iodophenylalanine.

Radiolabeled amino acids have been used extensively in oncology both as diagnostic and therapeutic agents. In our pursuit to develop radiopharmaceuticals to target breast cancer, we were interested in determining the uptake of radioiodinated 4-iodophenylalanine, among other labeled amino acids, in breast cancer cells. In this work, we have developed an alternative method for the synthesis of this agent. The novel tin precursor, (S)-tert-butyl 2-(tert-butoxycarbonylamino)-3-(4-(tributylstannyl)phenyl)propanoate (3) was synthesized from the known, corresponding iodo derivative. Initially, the labeled 4-iodophenylalanine was synthesized from the above tin precursor in two steps with radiochemical yields of 91.6 ± 2.7% and 83.7 ± 1.7% (n=5), for the radioiodination (first) and deprotection (second) step, respectively. Subsequently, it was synthesized in a single step with an average radiochemical yield of 94.8 ± 3.4% (n=5). After incubation with MCF-7 breast cancer cells for 60 min, an uptake of up to 49.0 ± 0.7% of the input dose was seen; in comparison, the uptake of [¹⁴C]phenylalanine under the same conditions was 55.9 ± 0.5%. Furthermore, the uptake of both tracers was inhibited to a similar degree in a concentration-dependent manner by both unlabeled phenylalanine and 4-iodophenylalanine. With [¹⁴C]phenylalanine as the tracer, IC₅₀ values of 1.45 and 2.50 mM were obtained for Phe and I-Phe, respectively, and these values for [¹²⁵I]I-Phe inhibition were 1.3 and 1.0 mM. In conclusion, an improved and convenient method for the synthesis of no-carrier-added 4-[(⁎)I]phenylalanine was developed and the radiotracer prepared by this route demonstrated an amino acid transporter-mediated uptake in MCF-7 breast cancer cells in vitro that was comparable to that of [¹⁴C]phenylalanine.

Authors
Vaidyanathan, G; McDougald, D; Grasfeder, L; Zalutsky, MR; Chin, B
MLA Citation
Vaidyanathan, G, McDougald, D, Grasfeder, L, Zalutsky, MR, and Chin, B. "An alternative and expedient synthesis of radioiodinated 4-iodophenylalanine." Appl Radiat Isot 69.10 (October 2011): 1401-1406.
PMID
21621415
Source
pubmed
Published In
Applied Radiation and Isotopes
Volume
69
Issue
10
Publish Date
2011
Start Page
1401
End Page
1406
DOI
10.1016/j.apradiso.2011.05.004

Colocalization of gadolinium-diethylene triamine pentaacetic acid with high-molecular-weight molecules after intracerebral convection-enhanced delivery in humans.

BACKGROUND: Convection-enhanced delivery (CED) permits site-specific therapeutic drug delivery within interstitial spaces at increased dosages through circumvention of the blood-brain barrier. CED is currently limited by suboptimal methodologies for monitoring the delivery of therapeutic agents that would permit technical optimization and enhanced therapeutic efficacy. OBJECTIVE: To determine whether a readily available small-molecule MRI contrast agent, gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA), could effectively track the distribution of larger therapeutic agents. METHODS: Gd-DTPA was coinfused with the larger molecular tracer, I-labeled human serum albumin (I-HSA), during CED of an EGFRvIII-specific immunotoxin as part of treatment for a patient with glioblastoma. RESULTS: Infusion of both tracers was safe in this patient. Analysis of both Gd-DTPA and I-HSA during and after infusion revealed a high degree of anatomical and volumetric overlap. CONCLUSION: Gd-DTPA may be able to accurately demonstrate the anatomic and volumetric distribution of large molecules used for antitumor therapy with high resolution and in combination with fluid-attenuated inversion recovery (FLAIR) imaging, and provide additional information about leaks into cerebrospinal fluid spaces and resection cavities. Similar studies should be performed in additional patients to validate our findings and help refine the methodologies we used.

Authors
Sampson, JH; Brady, M; Raghavan, R; Mehta, AI; Friedman, AH; Reardon, DA; Petry, NA; Barboriak, DP; Wong, TZ; Zalutsky, MR; Lally-Goss, D; Bigner, DD
MLA Citation
Sampson, JH, Brady, M, Raghavan, R, Mehta, AI, Friedman, AH, Reardon, DA, Petry, NA, Barboriak, DP, Wong, TZ, Zalutsky, MR, Lally-Goss, D, and Bigner, DD. "Colocalization of gadolinium-diethylene triamine pentaacetic acid with high-molecular-weight molecules after intracerebral convection-enhanced delivery in humans." Neurosurgery 69.3 (September 2011): 668-676.
PMID
21430586
Source
pubmed
Published In
Neurosurgery
Volume
69
Issue
3
Publish Date
2011
Start Page
668
End Page
676
DOI
10.1227/NEU.0b013e3182181ba8

Astatine-211: production and availability.

The 7.2-h half life radiohalogen (211)At offers many potential advantages for targeted α-particle therapy; however, its use for this purpose is constrained by its limited availability. Astatine-211 can be produced in reasonable yield from natural bismuth targets via the (209)Bi(α,2n)(211)At nuclear reaction utilizing straightforward methods. There is some debate as to the best incident α-particle energy for maximizing 211At production while minimizing production of (210)At, which is problematic because of its 138.4-day half life α-particle emitting daughter, (210)Po. The intrinsic cost for producing (211)At is reasonably modest and comparable to that of commercially available (123)I. The major impediment to (211)At availability is attributed to the need for a medium energy α-particle beam for its production. On the other hand, there are about 30 cyclotrons in the world that have the beam characteristics required for (211)At production.

Authors
Zalutsky, MR; Pruszynski, M
MLA Citation
Zalutsky, MR, and Pruszynski, M. "Astatine-211: production and availability." Curr Radiopharm 4.3 (July 2011): 177-185. (Review)
PMID
22201707
Source
pubmed
Published In
Current Radiopharmaceuticals
Volume
4
Issue
3
Publish Date
2011
Start Page
177
End Page
185

TARGETED RADIOTHERAPY OF MEDULLOBLASTOMA USING SOMATOSTATIN RECEPTOR AVID RADIOLABELED PEPTIDES

Authors
Vaidyanathan, G; Li, J; Bigner, DD; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Li, J, Bigner, DD, and Zalutsky, MR. "TARGETED RADIOTHERAPY OF MEDULLOBLASTOMA USING SOMATOSTATIN RECEPTOR AVID RADIOLABELED PEPTIDES." May 2011.
Source
wos-lite
Published In
Neuro-Oncology
Volume
13
Publish Date
2011
Start Page
I27
End Page
I27

Abstract 5306: 18 F-EF5 microPET imaging of treatment response from a novel, hypoxia-selective cytotoxin SN30000 in a human lung cancer xenograft model

Authors
Chitneni, SK; Bida, GT; Hay, MP; Zalutsky, MR; Melcher, T; Wilson, WR; Dewhirst, MW
MLA Citation
Chitneni, SK, Bida, GT, Hay, MP, Zalutsky, MR, Melcher, T, Wilson, WR, and Dewhirst, MW. "Abstract 5306: 18 F-EF5 microPET imaging of treatment response from a novel, hypoxia-selective cytotoxin SN30000 in a human lung cancer xenograft model." Cancer Research 71.8 Supplement (April 15, 2011): 5306-5306.
Source
crossref
Published In
Cancer Research
Volume
71
Issue
8 Supplement
Publish Date
2011
Start Page
5306
End Page
5306
DOI
10.1158/1538-7445.AM2011-5306

Molecular imaging of hypoxia.

A wide variety of imaging approaches have been developed in the past few decades for monitoring tumor oxygenation and hypoxia in vivo. In particular, nuclear medicine has seen the development of several radiolabeled hypoxia markers and is the preferred method for imaging of tumor hypoxia. Hypoxia imaging is increasingly being used in the clinical setting and is progressing from a mere detection method to application in individualization of chemoradiotherapy.

Authors
Chitneni, SK; Palmer, GM; Zalutsky, MR; Dewhirst, MW
MLA Citation
Chitneni, SK, Palmer, GM, Zalutsky, MR, and Dewhirst, MW. "Molecular imaging of hypoxia." J Nucl Med 52.2 (February 2011): 165-168. (Review)
PMID
21233176
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
52
Issue
2
Publish Date
2011
Start Page
165
End Page
168
DOI
10.2967/jnumed.110.075663

Radioiodinated O(6)-Benzylguanine derivatives containing an azido function.

INTRODUCTION: Drug resistance to alkylator chemotherapy has been primarily attributed to the DNA repair protein alkylguanine-DNA alkyltransferase (AGT); thus, personalizing chemotherapy could be facilitated if tumor AGT content could be quantified prior to administering chemotherapy. We have been investigating the use of radiolabeled O(6)-benzylguanine (BG) analogues to label and quantify AGT in vivo. BG derivatives containing an azido function were sought to potentially enhance the targeting of these analogues to AGT, which is primarily present in the cell nucleus, either by conjugating them to nuclear localization sequence (NLS) peptides or by pretargeting via bio-orthogonal approaches. METHODS: Two O(6)-(3-iodobenzyl)guanine (IBG) derivatives containing an azido moiety-O(6)-(4-azidohexyloxymethyl-3-iodobenzyl)guanine (AHOMIBG) and O(6)-(4-azido-3-iodobenzyl)guanine (AIBG)--and their tin precursors were synthesized in multiple steps and the tin precursors were converted to radioiodinated AHOMIBG and AIBG, respectively. Both unlabeled and radioiodinated AHOMIBG analogues were conjugated to alkyne-derivatized NLS peptide heptynoyl-PK(3)RKV. The ability of these radioiodinated compounds to bind to AGT was determined by a trichloroacetic acid precipitation assay and gel electrophoresis/phosphor imaging. Labeling of an AGT-AIBG conjugate via Staudinger ligation using the (131)I-labeled phosphine ligand, 2-(diphenylphosphino)phenyl 4-[(131)I]iodobenzoate, also was investigated. RESULTS: [(131)I]AHOMIBG was synthesized in two steps from its tin precursor in 52.2 ± 7.5% (n = 5) radiochemical yield and conjugated to the NLS peptide via click reaction in 50.7 ± 4.9% (n = 6) yield. The protected tin precursor of AIBG was radioiodinated in an average radiochemical yield of 69.6 ± 4.5% (n = 7); deprotection of the intermediate gave [(131)I]AIBG in 17.8 ± 4.2% (n = 9) yield. While both [(131)I]AHOMIBG and its NLS conjugate bound to AGT pure protein, their potency as a substrate for AGT was substantially lower than that of [(125)I]IBG. Uptake of [(131)I]AHOMIBG-NLS conjugate in DAOY medulloblastoma cells was up to eightfold higher than that of [(125)I]IBG; however, the uptake was not changed when the cellular AGT content was first depleted with BG treatment. [(131)I]AIBG was almost equipotent as [(125)I]IBG with respect to binding to pure AGT; however, attempts to radiolabel AGT by treatment with unlabeled AIBG followed by Staudinger ligation using the radiolabeled phosphine ligand, 2-(diphenylphosphino)phenyl 4-[(131)I]iodobenzoate were not successful. CONCLUSION: Although AHOMIBG, and AIBG were synthesized successfully in both unlabeled and radioiodinated forms, the radioiodinated compounds failed to label AGT either after NLS peptide conjugation or via Staundiger ligation. Currently, other bio-orthogonal approaches are being evaluated for labeling AGT by pretargeting.

Authors
Vaidyanathan, G; White, B; Affleck, DJ; McDougald, D; Zalutsky, MR
MLA Citation
Vaidyanathan, G, White, B, Affleck, DJ, McDougald, D, and Zalutsky, MR. "Radioiodinated O(6)-Benzylguanine derivatives containing an azido function." Nucl Med Biol 38.1 (January 2011): 77-92.
PMID
21220131
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
38
Issue
1
Publish Date
2011
Start Page
77
End Page
92
DOI
10.1016/j.nucmedbio.2010.07.006

Applications of 211AT and 223RA in targeted alpha-particle radiotherapy

Targeted radiotherapy using agents tagged with α-emitting radionuclides is gaining traction with several clinical trials already undertaken or ongoing, and others in the advanced planning stage. The most commonly used α-emitting radionuclides are 213Bi, 211At, 223Ra and 225Ac. While each one of these has pros and cons, it can be argued that 211At probably is the most versatile based on its half life, decay scheme and chemistry. On the other hand, for targeting bone metastases, 223Ra is the ideal radionuclide because simple cationic radium can be used for this purpose. In this review, we will discuss the recent developments taken place in the application of 211At-labeled radiopharmaceuticals and give an overview of the current status of 223Ra for targeted α-particle radiotherapy. © 2011 Bentham Science Publishers Ltd.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Applications of 211AT and 223RA in targeted alpha-particle radiotherapy." Current Radiopharmaceuticals 4.4 (2011): 283-294.
Source
scival
Published In
Current Radiopharmaceuticals
Volume
4
Issue
4
Publish Date
2011
Start Page
283
End Page
294

A tin precursor of SGMIB potentially useful in the direct modification of peptides and proteins before radiohalogenation

Authors
Vaidyanathan, G; McDougald, D; Affleck, DJ; Zalutsky, MR
MLA Citation
Vaidyanathan, G, McDougald, D, Affleck, DJ, and Zalutsky, MR. "A tin precursor of SGMIB potentially useful in the direct modification of peptides and proteins before radiohalogenation." JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS 54 (2011): S64-S64.
Source
wos-lite
Published In
Journal of Labelled Compounds and Radiopharmaceuticals
Volume
54
Publish Date
2011
Start Page
S64
End Page
S64

Anti-EGFRvIII monoclonal antibody armed with 177Lu: in vivo comparison of macrocyclic and acyclic ligands.

INTRODUCTION: Monoclonal antibody (mAb) L8A4 binds specifically to the epidermal growth factor receptor variant III (EGFRvIII) that is present on gliomas but not on normal tissues, and is internalized rapidly after receptor binding. Because of the short range of its β-emissions, labeling this mAb with (177)Lu would be an attractive approach for the treatment of residual tumor margins remaining after surgical debulking of brain tumors. MATERIALS AND METHODS: L8A4 mAb was labeled with (177)Lu using the acyclic ligands [(R)-2-amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-pentaacetic acid (CHX-A″-DTPA) and 2-(4-isothiocyanatobenzyl)-6-methyldiethylene-triaminepentaacetic acid (1B4M-DTPA), and the macrocyclic ligands S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-tetraacetic acid (C-DOTA) and α-(5-isothiocyanato-2-methoxyphenyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (MeO-DOTA). Paired-label tissue distribution experiments were performed in athymic mice bearing subcutaneous EGFRvIII-expressing U87.ΔEGFR glioma xenografts over a period of 1 to 8 days to directly compare (177)Lu-labeled L8A4 to L8A4 labeled with (125)I using N-succinimidyl 4-guanidinomethyl-3-[(125)I]iodobenzoate ([(125)I]SGMIB). RESULTS: Except with C-DOTA, tumor uptake for the (177)Lu-labeled mAb was significantly higher than the co-administered radioiodinated preparation; however, this was also the case for spleen, liver, bone and kidneys. Tumor/normal tissue ratios for (177)Lu-1B4M-DTPA-L8A4 and, to an even greater extent, (177)Lu-MeO-DOTA-L8A4 were higher than those for [(125)I]SGMIB-L8A4 in most other tissues. CONCLUSIONS: Tumor and normal tissue distribution patterns for this anti-EGFRvIII mAb were dependent on the nature of the bifunctional chelate used for (177)Lu labeling. Optimal results were obtained with 1B4M-DTPA and MeO-DOTA, suggesting no clear advantage for acyclic vs. macrocyclic ligands for this application.

Authors
Hens, M; Vaidyanathan, G; Zhao, X-G; Bigner, DD; Zalutsky, MR
MLA Citation
Hens, M, Vaidyanathan, G, Zhao, X-G, Bigner, DD, and Zalutsky, MR. "Anti-EGFRvIII monoclonal antibody armed with 177Lu: in vivo comparison of macrocyclic and acyclic ligands." Nucl Med Biol 37.7 (October 2010): 741-750.
PMID
20870149
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
37
Issue
7
Publish Date
2010
Start Page
741
End Page
750
DOI
10.1016/j.nucmedbio.2010.04.020

Evaluation of anti-podoplanin rat monoclonal antibody NZ-1 for targeting malignant gliomas.

INTRODUCTION: Podoplanin/aggrus is a mucin-like sialoglycoprotein that is highly expressed in malignant gliomas. Podoplanin has been reported to be a novel marker to enrich tumor-initiating cells, which are thought to resist conventional therapies and to be responsible for cancer relapse. The purpose of this study was to determine whether an anti-podoplanin antibody is suitable to target radionuclides to malignant gliomas. METHODS: The binding affinity of an anti-podoplanin antibody, NZ-1 (rat IgG(2a)), was determined by surface plasmon resonance and Scatchard analysis. NZ-1 was radioiodinated with (125)I using Iodogen [(125)I-NZ-1(Iodogen)] or N-succinimidyl 4-guanidinomethyl 3-[(131)I]iodobenzoate ([(131)I]SGMIB-NZ-1), and paired-label internalization assays of NZ-1 were performed. The tissue distribution of (125)I-NZ-1(Iodogen) and that of [(131)I]SGMIB-NZ-1 were then compared in athymic mice bearing glioblastoma xenografts. RESULTS: The dissociation constant (K(D)) of NZ-1 was determined to be 1.2 × 10(-10) M by surface plasmon resonance and 9.8 × 10(-10) M for D397MG glioblastoma cells by Scatchard analysis. Paired-label internalization assays in LN319 glioblastoma cells indicated that [(131)I]SGMIB-NZ-1 resulted in higher intracellular retention of radioactivity (26.3 ± 0.8% of initially bound radioactivity at 8 h) compared to that from the (125)I-NZ-1(Iodogen) (10.0 ± 0.1% of initially bound radioactivity at 8 h). Likewise, tumor uptake of [(131)I]SGMIB-NZ-1 (39.9 ± 8.8 %ID/g at 24 h) in athymic mice bearing D2159MG xenografts in vivo was significantly higher than that of (125)I-NZ-1(Iodogen) (29.7 ± 6.1 %ID/g at 24 h). CONCLUSIONS: The overall results suggest that an anti-podoplanin antibody NZ-1 warrants further evaluation for antibody-based therapy against glioblastoma.

Authors
Kato, Y; Vaidyanathan, G; Kaneko, MK; Mishima, K; Srivastava, N; Chandramohan, V; Pegram, C; Keir, ST; Kuan, C-T; Bigner, DD; Zalutsky, MR
MLA Citation
Kato, Y, Vaidyanathan, G, Kaneko, MK, Mishima, K, Srivastava, N, Chandramohan, V, Pegram, C, Keir, ST, Kuan, C-T, Bigner, DD, and Zalutsky, MR. "Evaluation of anti-podoplanin rat monoclonal antibody NZ-1 for targeting malignant gliomas." Nucl Med Biol 37.7 (October 2010): 785-794.
PMID
20870153
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
37
Issue
7
Publish Date
2010
Start Page
785
End Page
794
DOI
10.1016/j.nucmedbio.2010.03.010

Radioiodinated O6-Benzylguanine Analogues Containing an Azido Function

Authors
Vaidyanathan, G; White, B; Affleck, DJ; McDougald, D; Zalutsky, MR
MLA Citation
Vaidyanathan, G, White, B, Affleck, DJ, McDougald, D, and Zalutsky, MR. "Radioiodinated O6-Benzylguanine Analogues Containing an Azido Function." October 2010.
Source
wos-lite
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
37
Publish Date
2010
Start Page
S265
End Page
S265

In situ growth of a PEG-like polymer from the C terminus of an intein fusion protein improves pharmacokinetics and tumor accumulation.

This paper reports a general in situ method to grow a polymer conjugate solely from the C terminus of a recombinant protein. GFP was fused at its C terminus with an intein; cleavage of the intein provided a unique thioester moiety at the C terminus of GFP that was used to install an atom transfer radical polymerization (ATRP) initiator. Subsequent in situ ATRP of oligo(ethylene glycol) methyl ether methacrylate (OEGMA) yielded a site-specific (C-terminal) and stoichiometric conjugate with high yield and good retention of protein activity. A GFP-C-poly(OEGMA) conjugate (hydrodynamic radius (R(h)): 21 nm) showed a 15-fold increase in its blood exposure compared to the protein (R(h): 3.0 nm) after intravenous administration to mice. This conjugate also showed a 50-fold increase in tumor accumulation, 24 h after intravenous administration to tumor-bearing mice, compared to the unmodified protein. This approach for in situ C-terminal polymer modification of a recombinant protein is applicable to a large subset of recombinant protein and peptide drugs and provides a general methodology for improvement of their pharmacological profiles.

Authors
Gao, W; Liu, W; Christensen, T; Zalutsky, MR; Chilkoti, A
MLA Citation
Gao, W, Liu, W, Christensen, T, Zalutsky, MR, and Chilkoti, A. "In situ growth of a PEG-like polymer from the C terminus of an intein fusion protein improves pharmacokinetics and tumor accumulation." Proc Natl Acad Sci U S A 107.38 (September 21, 2010): 16432-16437.
PMID
20810920
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
107
Issue
38
Publish Date
2010
Start Page
16432
End Page
16437
DOI
10.1073/pnas.1006044107

Recombinant single-chain variable fragment antibodies against extracellular epitopes of human multidrug resistance protein MRP3 for targeting malignant gliomas.

Multidrug resistance protein 3 (MRP3), a multidrug resistance protein identified by serial analysis of gene expression as a glioblastoma multiforme (GBM)-associated molecule, is highly expressed in GBM, but not in normal brain cells. Thus, MRP3 is a candidate for GBM immunotargeting, but to date, no monoclonal antibody has been isolated that can target an extracellular MRP3 epitope. By phage display, we have isolated 3 recombinant, fully human, single-chain Fv (scFv) antibodies, M25, M58 and M89, which specifically react with the extracellular N-terminus of human MRP3. In ELISA, these scFvs reacted only with the peptide used for screening and not with other MRP3-derived peptides. Flow cytometric analysis revealed that these scFv fragments bind specifically to viable human GBM cells displaying different MRP3 expression levels, but not to MRP3-null cells. Furthermore, these scFv antibodies failed to react with tumor cells overexpressing other MRP proteins, including MRP1, MRP2, MRP4 and MRP5. M25 and M58 also bound to viable neurospheres. Iodogen-labeled scFvs demonstrated a yield of 56-76%. The immunoreactive fractions of the radiolabeled M25, M58 and M89 scFvs were 32, 52 and 69%, respectively. M25 exhibited 20% internalization into D2159MG neurospheres, M58, 33% into D54MG cells and M89, 26% into D247MG. Immunohistochemical evaluation of human gliomas to determine the localization of MRP3 antigen using scFvs M25 and M58 showed a dense cytoplasmic and membranous staining pattern. These Fv-based recombinant antibodies, which possess superior tumor penetration capabilities and selectively target tumor cells that express MRP3, may potentially be used in immunotherapy and diagnosis for brain tumors and other cancers.

Authors
Kuan, C-T; Srivastava, N; McLendon, RE; Marasco, WA; Zalutsky, MR; Bigner, DD
MLA Citation
Kuan, C-T, Srivastava, N, McLendon, RE, Marasco, WA, Zalutsky, MR, and Bigner, DD. "Recombinant single-chain variable fragment antibodies against extracellular epitopes of human multidrug resistance protein MRP3 for targeting malignant gliomas." Int J Cancer 127.3 (August 1, 2010): 598-611.
PMID
19937796
Source
pubmed
Published In
International Journal of Cancer
Volume
127
Issue
3
Publish Date
2010
Start Page
598
End Page
611
DOI
10.1002/ijc.25062

Targeted Radiotherapy of Central Nervous System Malignancies

Authors
Zalutsky, MR; Reardon, DA; Bigner, DD
MLA Citation
Zalutsky, MR, Reardon, DA, and Bigner, DD. "Targeted Radiotherapy of Central Nervous System Malignancies." (July 15, 2010): 139-167. (Chapter)
Source
scopus
Publish Date
2010
Start Page
139
End Page
167
DOI
10.1002/9780470613214.ch5

[177Lu]-DOTA0-Tyr3-octreotate: A potential targeted radiotherapeutic for the treatment of Medulloblastoma

Medulloblastoma, the most common pediatric brain tumor, is difficult to treat because conventional therapeutic approaches result in significant toxicity to normal central nervous system tissues, compromising quality of life. Given the fact that medulloblastomas express the somatostatin subtype 2 receptor, [ 177 Lu-DOTA 0 ,Tyr 3 ]octreotate ([ 177 Lu]DOTA- TATE) could be a potentially useful targeted radiotherapeutic for the treatment of this malignancy. The current study was undertaken to evaluate this possibility in preclinical models of D341 MED human medulloblastoma by comparing the properties of [ 177 Lu]DOTA-TATE to those of glucose-[ 125 I-Tyr 3 ]-octreotate ([ 125 I]Gluc-TOCA), a radiopeptide previously shown to target this cell line. In vitro assays indicated that both labeled peptides exhibited similar cell-associated and in- ternalized radioactivity after a 30-min incubation at 37 o C; however, at the end of the 4 h incubation period, the internal- ized radioactivity for [ 177 Lu]DOTA-TATE (6.22 ± 0.75%) was nearly twice that for [ 125 I]Gluc-TOCA (3.16 ± 0.27%), with similar differences seen in total cell-associated radioactivity levels. Consistent with the results from the internaliza- tion assays, results from paired-label tissue distribution studies in athymic mice with subcutaneous D341 MED medul- loblastoma xenografts showed a similar degree of tumor accumulation for [ 177 Lu]DOTA-TATE and [ 125 I]Gluc-TOCA at early time points but by 24 h, a more than 5-fold advantage was observed for the 177 Lu-labeled peptide. Tumor-to-normal tissue ratios generally were more favorable for [ 177 Lu]DOTA-TATE at all time points, due in part to its lower accumula- tion in normal tissues except kidneys. Taken together, these results suggest that [ 177 Lu]DOTA-TATE warrants further in- vestigation as a targeted radiotherapeutic for medulloblastoma treatment. ©2010 Bentham Science Publishers Ltd.

Authors
Vaidyanathan, G; Affleck, DJ; Zhao, XG; Keir, ST; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, Zhao, XG, Keir, ST, and Zalutsky, MR. "[177Lu]-DOTA0-Tyr3-octreotate: A potential targeted radiotherapeutic for the treatment of Medulloblastoma." Current Radiopharmaceuticals 3.1 (July 12, 2010): 29-36.
Source
scopus
Published In
Current Radiopharmaceuticals
Volume
3
Issue
1
Publish Date
2010
Start Page
29
End Page
36
DOI
10.2174/1874471011003010029

Injectable intratumoral depot of thermally responsive polypeptide-radionuclide conjugates delays tumor progression in a mouse model.

This study evaluated a biodegradable drug delivery system for local cancer radiotherapy consisting of a thermally sensitive elastin-like polypeptide (ELP) conjugated to a therapeutic radionuclide. Two ELPs (49 kDa) were synthesized using genetic engineering to test the hypothesis that injectable biopolymeric depots can retain radionuclides locally and reduce the growth of tumors. A thermally sensitive polypeptide, ELP(1), was designed to spontaneously undergo a soluble-insoluble phase transition (forming viscous microparticles) between room temperature and body temperature upon intratumoral injection, while ELP(2) was designed to remain soluble upon injection and to serve as a negative control for the effect of aggregate assembly. After intratumoral administration of radionuclide conjugates of ELPs into implanted tumor xenografts in nude mice, their retention within the tumor, spatio-temporal distribution, and therapeutic effect were quantified. The residence time of the radionuclide-ELP(1) in the tumor was significantly longer than the thermally insensitive ELP(2) conjugate. In addition, the thermal transition of ELP(1) significantly protected the conjugated radionuclide from dehalogenation, whereas the conjugated radionuclide on ELP(2) was quickly eliminated from the tumor and cleaved from the biopolymer. These attributes of the thermally sensitive ELP(1) depot improved the antitumor efficacy of iodine-131 compared to the soluble ELP(2) control. This novel injectable and biodegradable depot has the potential to control advanced-stage cancers by reducing the bulk of inoperable tumors, enabling surgical removal of de-bulked tumors, and preserving healthy tissues.

Authors
Liu, W; MacKay, JA; Dreher, MR; Chen, M; McDaniel, JR; Simnick, AJ; Callahan, DJ; Zalutsky, MR; Chilkoti, A
MLA Citation
Liu, W, MacKay, JA, Dreher, MR, Chen, M, McDaniel, JR, Simnick, AJ, Callahan, DJ, Zalutsky, MR, and Chilkoti, A. "Injectable intratumoral depot of thermally responsive polypeptide-radionuclide conjugates delays tumor progression in a mouse model." J Control Release 144.1 (May 21, 2010): 2-9.
PMID
20117157
Source
pubmed
Published In
Journal of Controlled Release
Volume
144
Issue
1
Publish Date
2010
Start Page
2
End Page
9
DOI
10.1016/j.jconrel.2010.01.032

[Lu]-DOTA-Tyr-octreotate: A Potential Targeted Radiotherapeutic for the Treatment of Medulloblastoma.

Medulloblastoma, the most common pediatric brain tumor, is difficult to treat because conventional therapeutic approaches result in significant toxicity to normal central nervous system tissues, compromising quality of life. Given the fact that medulloblastomas express the somatostatin subtype 2 receptor, [(177)Lu-DOTA(0),Tyr(3)]octreotate ([(177)Lu]DOTA-TATE) could be a potentially useful targeted radiotherapeutic for the treatment of this malignancy. The current study was undertaken to evaluate this possibility in preclinical models of D341 MED human medulloblastoma by comparing the properties of [(177)Lu]DOTA-TATE to those of glucose-[(125)I-Tyr(3)]-octreotate ([(125)I]Gluc-TOCA), a radiopeptide previously shown to target this cell line. In vitro assays indicated that both labeled peptides exhibited similar cell-associated and internalized radioactivity after a 30-min incubation at 37°C; however, at the end of the 4 h incubation period, the internalized radioactivity for [(177)Lu]DOTA-TATE (6.22 " 0.75%) was nearly twice that for [(125)I]Gluc-TOCA (3.16 " 0.27%), with similar differences seen in total cell-associated radioactivity levels. Consistent with the results from the internalization assays, results from paired-label tissue distribution studies in athymic mice with subcutaneous D341 MED medulloblastoma xenografts showed a similar degree of tumor accumulation for [(177)Lu]DOTA-TATE and [(125)I]Gluc-TOCA at early time points but by 24 h, a more than 5-fold advantage was observed for the (177)Lu-labeled peptide. Tumor-to-normal tissue ratios generally were more favorable for [(177)Lu]DOTA-TATE at all time points, due in part to its lower accumulation in normal tissues except kidneys. Taken together, these results suggest that [(177)Lu]DOTA-TATE warrants further investigation as a targeted radiotherapeutic for medulloblastoma treatment.

Authors
Vaidyanathan, G; Affleck, DJ; Zhao, X-G; Keir, ST; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, Zhao, X-G, Keir, ST, and Zalutsky, MR. "[Lu]-DOTA-Tyr-octreotate: A Potential Targeted Radiotherapeutic for the Treatment of Medulloblastoma." Curr Radiopharm 3.1 (2010): 29-36.
PMID
21243098
Source
pubmed
Published In
Current Radiopharmaceuticals
Volume
3
Issue
1
Publish Date
2010
Start Page
29
End Page
36
DOI
10.2174/1874471011003010029

Detection of amino-terminal extracellular domain of somatostatin receptor 2 by specific monoclonal antibodies and quantification of receptor density in medulloblastoma.

Somatostatin receptor 2 (SSTR2) is expressed by most medulloblastomas (MEDs). We isolated monoclonal antibodies (MAbs) to the 12-mer (33)QTEPYYDLTSNA(44), which resides in the extracellular domain of the SSTR2 amino terminus, screened the peptide-bound MAbs by fluorescence microassay on D341 and D283 MED cells, and demonstrated homogeneous cell-surface binding, indicating that all cells expressed cell surface-detectable epitopes. Five radiolabeled MAbs were tested for immunoreactive fraction (IRF), affinity (KA) (Scatchard analysis vs. D341 MED cells), and internalization by MED cells. One IgG(3) MAb exhibited a 50-100% IRF, but low KA. Four IgG(2a) MAbs had 46-94% IRFs and modest KAs versus intact cells (0.21-1.2 x 10(8) M(-1)). Following binding of radiolabeled MAbs to D341 MED at 4 degrees C, no significant internalization was observed, which is consistent with results obtained in the absence of ligand. However, all MAbs exhibited long-term association with the cells; binding at 37 degrees C after 2 h was 65-66%, and after 24 h, 52-64%. In tests with MAbs C10 and H5, the number of cell surface receptors per cell, estimated by Scatchard and quantitative FACS analyses, was 3.9 x 10(4) for the "glial" phenotype DAOY MED cell line and 0.6-8.8 x 10(5) for four neuronal phenotype MED cell lines. Our results indicate a potential immunotherapeutic application for these MAbs.

Authors
Kuan, C-T; Wikstrand, CJ; McLendon, RE; Zalutsky, MR; Kumar, U; Bigner, DD
MLA Citation
Kuan, C-T, Wikstrand, CJ, McLendon, RE, Zalutsky, MR, Kumar, U, and Bigner, DD. "Detection of amino-terminal extracellular domain of somatostatin receptor 2 by specific monoclonal antibodies and quantification of receptor density in medulloblastoma." Hybridoma (Larchmt) 28.6 (December 2009): 389-403.
Website
http://hdl.handle.net/10161/3241
PMID
20025498
Source
pubmed
Published In
Hybridoma
Volume
28
Issue
6
Publish Date
2009
Start Page
389
End Page
403
DOI
10.1089/hyb.2009.0049

Targeting aldehyde dehydrogenase: a potential approach for cell labeling.

INTRODUCTION: To advance the science and clinical application of stem cell therapy, the availability of a highly sensitive, quantitative and translational method for tracking stem cells would be invaluable. Because hematopoetic stem cells express high levels of the cytosolic enzyme aldehyde dehydrogenase-1A1 (ALDH1), we sought to develop an agent that is specific to ALDH1 and thus to cells expressing the enzyme. Such an agent might be also helpful in identifying tumors that are resistant to cyclophosphomide chemotherapy because ALDH1 is known to be responsible for this resistance. METHODS: We developed schemes for the synthesis of two radioiodinated aldehdyes - N-formylmethyl-5-[*I]iodopyridine-3-carboxamide ([*I]FMIC) and 4-diethylamino-3-[*I]iodobenzaldehyde ([*I]DEIBA)-at no-carrier-added levels from their respective tin precursors. These agents were evaluated using pure ALDH1 and tumor cells that expressed the enzyme. RESULTS: The average radiochemical yields for the synthesis of [(125)I]FMIC and [(125)I]DEIBA were 70+/-5% and 47+/-14%, respectively. ALDH1 converted both compounds to respective acids suggesting their suitability as ALDH1 imaging agents. Although ability of ALDH1 within the cells to oxidize one of these substrates was shown, specific uptake in ALDH-expressing tumor cells could not be demonstrated. CONCLUSION: To pursue this approach for ALDH1 imaging, radiolabeled aldehydes need to be designed such that, in addition to being good substrates for ALDH1, the cognate products should be sufficiently polar so as to be retained within the cells.

Authors
Vaidyanathan, G; Song, H; Affleck, D; McDougald, DL; Storms, RW; Zalutsky, MR; Chin, BB
MLA Citation
Vaidyanathan, G, Song, H, Affleck, D, McDougald, DL, Storms, RW, Zalutsky, MR, and Chin, BB. "Targeting aldehyde dehydrogenase: a potential approach for cell labeling." Nucl Med Biol 36.8 (November 2009): 919-929.
PMID
19875048
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
36
Issue
8
Publish Date
2009
Start Page
919
End Page
929
DOI
10.1016/j.nucmedbio.2009.08.001

In situ growth of a stoichiometric PEG-like conjugate at a protein's N-terminus with significantly improved pharmacokinetics.

The challenge in the synthesis of protein-polymer conjugates for biological applications is to synthesize a stoichiometric (typically 1:1) conjugate of the protein with a monodisperse polymer, with good retention of protein activity, significantly improved pharmacokinetics and increased bioavailability, and hence improved in vivo efficacy. Here we demonstrate, using myoglobin as an example, a general route to grow a PEG-like polymer, poly(oligo(ethylene glycol) methyl ether methacrylate) [poly(OEGMA)], with low polydispersity and high yield, solely from the N-terminus of the protein by in situ atom transfer radical polymerization (ATRP) under aqueous conditions, to yield a site-specific (N-terminal) and stoichiometric conjugate (1:1). Notably, the myoglobin-poly(OEGMA) conjugate [hydrodynamic radius (R(h)): 13 nm] showed a 41-fold increase in its blood exposure compared to the protein (R(h): 1.7 nm) after IV administration to mice, thereby demonstrating that comb polymers that present short oligo(ethylene glycol) side chains are a class of PEG-like polymers that can significantly improve the pharmacological properties of proteins. We believe that this approach to the synthesis of N-terminal protein conjugates of poly(OEGMA) may be applicable to a large subset of protein and peptide drugs, and thereby provide a general methodology for improvement of their pharmacological profiles.

Authors
Gao, W; Liu, W; Mackay, JA; Zalutsky, MR; Toone, EJ; Chilkoti, A
MLA Citation
Gao, W, Liu, W, Mackay, JA, Zalutsky, MR, Toone, EJ, and Chilkoti, A. "In situ growth of a stoichiometric PEG-like conjugate at a protein's N-terminus with significantly improved pharmacokinetics." Proc Natl Acad Sci U S A 106.36 (September 8, 2009): 15231-15236.
PMID
19706892
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
106
Issue
36
Publish Date
2009
Start Page
15231
End Page
15236
DOI
10.1073/pnas.0904378106

Treatment of HER2-positive breast carcinomatous meningitis with intrathecal administration of alpha-particle-emitting (211)At-labeled trastuzumab.

INTRODUCTION: Carcinomatous meningitis (CM) is a devastating disease characterized by the dissemination of malignant tumor cells into the subarachnoid space along the brain and spine. Systemic treatment with monoclonal antibody (mAb) trastuzumab can be effective against HER2-positive systemic breast carcinoma but, like other therapies, is ineffective against CM. The goal of this study was to evaluate the therapeutic effect of alpha-particle emitting (211)At-labeled trastuzumab following intrathecal administration in a rat model of breast carcinoma CM. METHODS: Athymic rats were injected intrathecally with MCF-7/HER2-18 breast carcinoma cells through a surgically implanted indwelling intrathecal catheter. In Experiment 1, animals received 33 or 66 muCi (211)At-labeled trastuzumab, cold trastuzumab or saline. In Experiment 2, animals were inoculated with a lower tumor burden and received 46 or 92 muCi (211)At-labeled trastuzumab or saline. In Experiment 3, animals received 28 muCi (211)At-labeled trastuzumab, 30 muCi (211)At-labeled TPS3.2 control mAb or saline. Histopathological analysis of the neuroaxis was performed at the end of the study. RESULTS: In Experiment 1, median survival increased from 21 days for the saline and cold trastuzumab groups to 45 and 48 days for 33 and 66 muCi (211)At-labeled trastuzumab, respectively. In Experiment 2, median survival increased from 23 days for saline controls to 68 and 92 days for 46 and 92 muCi (211)At-labeled trastuzumab, respectively. In Experiment 3, median survival increased from 20 days to 29 and 36 days for animals treated with (211)At-labeled TPS3.2 and (211)At-labeled trastuzumab, respectively. Long-term survivors were observed exclusively in the (211)At-trastuzumab-treated groups. CONCLUSION: Intrathecal (211)At-labeled trastuzumab shows promise as a treatment for patients with HER2-positive breast CM.

Authors
Boskovitz, A; McLendon, RE; Okamura, T; Sampson, JH; Bigner, DD; Zalutsky, MR
MLA Citation
Boskovitz, A, McLendon, RE, Okamura, T, Sampson, JH, Bigner, DD, and Zalutsky, MR. "Treatment of HER2-positive breast carcinomatous meningitis with intrathecal administration of alpha-particle-emitting (211)At-labeled trastuzumab." Nucl Med Biol 36.6 (August 2009): 659-669.
PMID
19647172
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
36
Issue
6
Publish Date
2009
Start Page
659
End Page
669
DOI
10.1016/j.nucmedbio.2009.04.003

Evaluation of an anti-p185(HER2) (scFv-C(H)2-C(H)3)2 fragment following radioiodination using two different residualizing labels: SGMIB and IB-Mal-D-GEEEK.

INTRODUCTION: A 105-kDa double mutant single-chain Fv-Fc fragment (scFv-Fc DM) derived from the anti-p185(HER2) hu4D5v8 antibody (trastuzumab; Herceptin) has been described recently. The goal of this study was to investigate whether improved tumor targeting could be achieved with this fragment through the use of residualizing radioiodination methods. METHODS: The scFv-Fc DM fragment was radioiodinated using N-succinimidyl 4-guanidinomethyl 3-[(131)I]iodobenzoate ([(131)I]SGMIB) and N(epsilon)-(3-[(131)I]iodobenzoyl)-Lys(5)-N(alpha)- maleimido-Gly(1)-GEEEK ([(131)I]IB-Mal-D-GEEEK), two residualizing radioiodination agents that have been used successfully with intact antibodies. Paired-label internalization assays of the labeled fragments were performed in vitro using MCF7 human breast cancer cells transfected to express HER2 (MCF7-HER2); comparisons were made to scFv-Fc DM directly radioiodinated using Iodogen. The tissue distribution of the scFv-Fc DM labeled with [(125)I]IB-Mal-d-GEEEK and [(131)I]SGMIB was compared in athymic mice bearing MCF7-HER2 xenografts. RESULTS: The scFv-Fc DM fragment was labeled with [(131)I]SGMIB and [(131)I]IB-Mal-d-GEEEK in conjugation yields of 53% and 25%, respectively, with preservation of immunoreactivity for HER2. Internalization assays indicated that labeling via SGMIB resulted in a 1.6- to 3.5-fold higher (P<.05) retention of radioactivity, compared to that from the directly labeled fragment, in HER2-expressing cells during a 24-h observation period. Likewise, the amount of radioactivity retained in cells from the IB-Mal-d-GEEEK-labeled fragment was 1.4- to 3.3-fold higher (P<.05). Tumor uptake of radioiodine activity in athymic mice bearing MCF7-HER2 xenografts in vivo was significantly higher for the [(125)I]IB-Mal-d-GEEEK-labeled scFv-Fc DM fragment compared with that of the [(131)I]SGMIB-labeled fragment, particularly at later time points. The uptake of (125)I was threefold (3.6+/-1.1 %ID/g vs. 1.2+/-0.4 %ID/g) and fourfold (3.1+/-1.7 %ID/g vs. 0.8+/-0.4 %ID/g) higher than that for (131)I at 24 and 48 h, respectively. However, the [(125)I]IB-Mal-d-GEEEK-labeled scFv-Fc DM fragment also exhibited considerably higher levels of radioiodine activity in liver, spleen and kidney. CONCLUSIONS: The overall results further demonstrate the potential utility of these two prosthetic groups for the radiohalogenation of internalizing monoclonal antibodies and their fragments. Specifically, the trastuzumab-derived double mutant fragment in combination with these residualizing agents warrants further evaluation for imaging and possibly treatment of HER2 expressing malignancies.

Authors
Vaidyanathan, G; Jestin, E; Olafsen, T; Wu, AM; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Jestin, E, Olafsen, T, Wu, AM, and Zalutsky, MR. "Evaluation of an anti-p185(HER2) (scFv-C(H)2-C(H)3)2 fragment following radioiodination using two different residualizing labels: SGMIB and IB-Mal-D-GEEEK." Nucl Med Biol 36.6 (August 2009): 671-680.
PMID
19647173
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
36
Issue
6
Publish Date
2009
Start Page
671
End Page
680
DOI
10.1016/j.nucmedbio.2009.04.002

RECOMBINANT ANTIBODY-BASED MOLECULAR THERAPEUTICS FOR BRAIN TUMOR IMMUNOTHERAPY

Authors
Kuan, C-T; Wakiya, K; II, HJE; Wikstrand, CJ; McLendon, RE; Zalutsky, MR; Pastan, IH; Bigner, DD
MLA Citation
Kuan, C-T, Wakiya, K, II, HJE, Wikstrand, CJ, McLendon, RE, Zalutsky, MR, Pastan, IH, and Bigner, DD. "RECOMBINANT ANTIBODY-BASED MOLECULAR THERAPEUTICS FOR BRAIN TUMOR IMMUNOTHERAPY." NEURO-ONCOLOGY 11.2 (April 2009): 224-224.
Source
wos-lite
Published In
Neuro-Oncology
Volume
11
Issue
2
Publish Date
2009
Start Page
224
End Page
224

Labeling internalizing anti-epidermal growth factor receptor variant III monoclonal antibody with (177)Lu: in vitro comparison of acyclic and macrocyclic ligands.

INTRODUCTION: The monoclonal antibody (mAb) L8A4, reactive with the epidermal growth factor receptor variant III (EGFRvIII), internalizes rapidly in glioma cells after receptor binding. Combining this tumor-specific mAb with the low-energy beta-emitter (177)Lu would be an attractive approach for brain tumor radioimmunotherapy, provided that trapping of the radionuclide in tumor cells after mAb intracellular processing could be maximized. MATERIALS AND METHODS: L8A4 mAb was labeled with (177)Lu using the acyclic ligands [(R)-2-amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-pentaacetic acid (CHX-A''-DTPA), 2-(4-isothiocyanatobenzyl)-diethylenetriaminepenta-acetic acid (pSCN-Bz-DTPA) and 2-(4-isothiocyanatobenzyl)-6-methyldiethylenetriaminepentaacetic acid (1B4M-DTPA), and the macrocyclic ligands S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-tetraacetic acid (C-DOTA) and alpha-(5-isothiocyanato-2-methoxyphenyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (MeO-DOTA). Paired-label internalization and cellular processing assays were performed on EGFRvIII-expressing U87.DeltaEGFR glioma cells over 24 h to directly compare (177)Lu-labeled L8A4 to L8A4 labeled with (125)I using either iodogen or N-succinimidyl 4-guanidinomethyl-3-[(125)I]iodobenzoate ([(125)I]SGMIB). In order to facilitate comparison of labeling methods, the primary parameter evaluated was the ratio of (177)Lu to (125)I activity retained in U87.DeltaEGFR cells. RESULTS: All chelates demonstrated higher retention of internalized activity compared with mAb labeled using iodogen, with (177)Lu/(125)I ratios of >20 observed for the three DTPA chelates at 24 h. When compared to L8A4 labeled using SGMIB, except for MeO-DOTA, internalized activity for (125)I was higher than (177)Lu from 1-8 h with the opposite behavior observed thereafter. At 24 h, (177)Lu/(125)I ratios were between 1.5 and 3, with higher values observed for the three DTPA chelates. CONCLUSIONS: The nature of the chelate used to label this internalizing mAb with (177)Lu influenced intracellular retention in vitro, although at early time points, only MeO-DOTA provided more favorable results than radioiodination of the mAb via SGMIB.

Authors
Hens, M; Vaidyanathan, G; Welsh, P; Zalutsky, MR
MLA Citation
Hens, M, Vaidyanathan, G, Welsh, P, and Zalutsky, MR. "Labeling internalizing anti-epidermal growth factor receptor variant III monoclonal antibody with (177)Lu: in vitro comparison of acyclic and macrocyclic ligands." Nucl Med Biol 36.2 (February 2009): 117-128.
PMID
19217523
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
36
Issue
2
Publish Date
2009
Start Page
117
End Page
128
DOI
10.1016/j.nucmedbio.2008.11.001

Propargyl 4-[F]fluorobenzoate: A Putatively More Stable Prosthetic group for the Fluorine-18 Labeling of Biomolecules via Click Chemistry.

Faster and more efficient approaches for radiolabeling biomolecules with short-lived (18)F are in dire need. Herein we report a new (18)F-labeled prosthetic group containing an acetylene function that permits the labeling of biomolecules via click chemistry. This template, propargyl 4-[(18)F]fluorobenzoate ([(18)F]PFB) was synthesized from a quaternary salt precursor in decay-corrected radiochemical yields of 58 +/- 31%. Several model compounds containing an azide moiety-benzyl azide, two lysine derivatives and a transglutaminase-reactive peptide-were labeled using [(18)F]PFB via a click reaction in decay-corrected radiochemical yields of 88 +/- 4%, 79 +/- 33%, 75 +/- 5%, and 37 +/- 31%, respectively. Our results suggest that the novel agent [(18)F]PFB is a potentially useful template for the (18)F-labeling of biomolecules via click chemistry.

Authors
Vaidyanathan, G; White, BJ; Zalutsky, MR
MLA Citation
Vaidyanathan, G, White, BJ, and Zalutsky, MR. "Propargyl 4-[F]fluorobenzoate: A Putatively More Stable Prosthetic group for the Fluorine-18 Labeling of Biomolecules via Click Chemistry." Curr Radiopharm 2.1 (January 1, 2009): 63-74.
PMID
20414475
Source
pubmed
Published In
Current Radiopharmaceuticals
Volume
2
Issue
1
Publish Date
2009
Start Page
63
End Page
74

Engineered modular recombinant transporters: application of new platform for targeted radiotherapeutic agents to alpha-particle emitting 211 At.

PURPOSE: To generate and evaluate a modular recombinant transporter (MRT) for targeting 211 At to cancer cells overexpressing the epidermal growth factor receptor (EGFR). METHODS AND MATERIALS: The MRT was produced with four functional modules: (1) human epidermal growth factor as the internalizable ligand, (2) the optimized nuclear localization sequence of simian vacuolating virus 40 (SV40) large T-antigen, (3) a translocation domain of diphtheria toxin as an endosomolytic module, and (4) the Escherichia coli hemoglobin-like protein (HMP) as a carrier module. MRT was labeled using N-succinimidyl 3-[211 At]astato-5-guanidinomethylbenzoate (SAGMB), its 125 I analogue SGMIB, or with 131 I using Iodogen. Binding, internalization, and clonogenic assays were performed with EGFR-expressing A431, D247 MG, and U87MG.wtEGFR human cancer cell lines. RESULTS: The affinity of SGMIB-MRT binding to A431 cells, determined by Scatchard analysis, was 22 nM, comparable to that measured before labeling. The binding of SGMIB-MRT and its internalization by A431 cancer cells was 96% and 99% EGFR specific, respectively. Paired label assays demonstrated that compared with Iodogen-labeled MRT, SGMIB-MRT and SAGMB-MRT exhibited more than threefold greater peak levels and durations of intracellular retention of activity. SAGMB-MRT was 10-20 times more cytotoxic than [211 At]astatide for all three cell lines. CONCLUSION: The results of this study have demonstrated the initial proof of principle for the MRT approach for designing targeted alpha-particle emitting radiotherapeutic agents. The high cytotoxicity of SAGMB-MRT for cancer cells overexpressing EGFR suggests that this 211 At-labeled conjugate has promise for the treatment of malignancies, such as glioma, which overexpress this receptor.

Authors
Rosenkranz, AA; Vaidyanathan, G; Pozzi, OR; Lunin, VG; Zalutsky, MR; Sobolev, AS
MLA Citation
Rosenkranz, AA, Vaidyanathan, G, Pozzi, OR, Lunin, VG, Zalutsky, MR, and Sobolev, AS. "Engineered modular recombinant transporters: application of new platform for targeted radiotherapeutic agents to alpha-particle emitting 211 At." Int J Radiat Oncol Biol Phys 72.1 (September 1, 2008): 193-200.
PMID
18722270
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
72
Issue
1
Publish Date
2008
Start Page
193
End Page
200
DOI
10.1016/j.ijrobp.2008.05.055

Astatine Radiopharmaceuticals: Prospects and Problems.

For the treatment of minimum residual diseases such micrometastases and residual tumor margins that remain after debulking of the primary tumor, targeted radiotherapy using radiopharmaceuticals tagged with alpha-particle-emitting radionuclides is very attractive. In addition to the their short range in tissue, which helps minimize harmful effects on adjacent normal tissues, alpha-particles, being high LET radiation, have several radiobiological advantages. The heavy halogen, astatine-211 is one of the prominent alpha-particle-emitting radionuclides in practice. Being a halogen, it can often be incorporated into biomolecules of interest by adapting radioiodination chemistry. A wide spectrum of compounds from the simple [(211)At]astatide ion to small organic molecules, peptides, and large proteins labeled with (211)At have been investigated with at least two reaching the stage of clinical evaluation. The chemistry, cytotoxic advantages, biodistribution studies, and microdosimetry/pharmacokinetic modeling of some of these agents will be reviewed. In addition, potential problems such as the harmful effect of radiolysis on the synthesis, lack of sufficient in vivo stability of astatinated compounds, and possible adverse effects when they are systemically administered will be discussed.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Astatine Radiopharmaceuticals: Prospects and Problems." Curr Radiopharm 1.3 (September 1, 2008): 177-.
PMID
20150978
Source
pubmed
Published In
Current Radiopharmaceuticals
Volume
1
Issue
3
Publish Date
2008
Start Page
177

Intracerebral infusion of an EGFR-targeted toxin in recurrent malignant brain tumors.

The purpose of this study is to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and intracerebral distribution of a recombinant toxin (TP-38) targeting the epidermal growth factor receptor in patients with recurrent malignant brain tumors using the intracerebral infusion technique of convection-enhanced delivery (CED). Twenty patients were enrolled and stratified for dose escalation by the presence of residual tumor from 25 to 100 ng/ml in a 40-ml infusion volume. In the last eight patients, coinfusion of (123)I-albumin was performed to monitor distribution within the brain. The MTD was not reached in this study. Dose escalation was stopped at 100 ng/ml due to inconsistent drug delivery as evidenced by imaging the coinfused (123)I-albumin. Two DLTs were seen, and both were neurologic. Median survival after TP-38 was 28 weeks (95% confidence interval, 26.5-102.8). Of 15 patients treated with residual disease, two (13.3%) demonstrated radiographic responses, including one patient with glioblastoma multiforme who had a nearly complete response and remains alive >260 weeks after therapy. Coinfusion of (123)I-albumin demonstrated that high concentrations of the infusate could be delivered >4 cm from the catheter tip. However, only 3 of 16 (19%) catheters produced intraparenchymal infusate distribution, while the majority leaked infusate into the cerebrospinal fluid spaces. Intracerebral CED of TP-38 was well tolerated and produced some durable radiographic responses at doses

Authors
Sampson, JH; Akabani, G; Archer, GE; Berger, MS; Coleman, RE; Friedman, AH; Friedman, HS; Greer, K; Herndon, JE; Kunwar, S; McLendon, RE; Paolino, A; Petry, NA; Provenzale, JM; Reardon, DA; Wong, TZ; Zalutsky, MR; Pastan, I; Bigner, DD
MLA Citation
Sampson, JH, Akabani, G, Archer, GE, Berger, MS, Coleman, RE, Friedman, AH, Friedman, HS, Greer, K, Herndon, JE, Kunwar, S, McLendon, RE, Paolino, A, Petry, NA, Provenzale, JM, Reardon, DA, Wong, TZ, Zalutsky, MR, Pastan, I, and Bigner, DD. "Intracerebral infusion of an EGFR-targeted toxin in recurrent malignant brain tumors." Neuro Oncol 10.3 (June 2008): 320-329.
PMID
18403491
Source
pubmed
Published In
Neuro-Oncology
Volume
10
Issue
3
Publish Date
2008
Start Page
320
End Page
329
DOI
10.1215/15228517-2008-012

A pilot study: 131I-antitenascin monoclonal antibody 81c6 to deliver a 44-Gy resection cavity boost.

The purpose of this study was to determine the feasibility and assess the efficacy and toxicity, among newly diagnosed malignant glioma patients, of administering (131)I-labeled murine antitenascin monoclonal antibody 81C6 ((131)I-81C6) into a surgically created resection cavity (SCRC) to achieve a patient-specific, 44-Gy boost to the 2-cm SCRC margin. A radioactivity dose of (131)I-81C6 calculated to achieve a 44-Gy boost to the SCRC was administered, followed by conventional external beam radiotherapy (XRT) and chemotherapy. Twenty-one patients were enrolled in the study: 16 with glioblastoma multiforme (GBM) and 5 with anaplastic astrocytoma. Twenty patients received the targeted 44-Gy boost (+/-10%) to the SCRC. Attributable toxicity was mild and limited to reversible grade 3 neutropenia or thrombocytopenia (n = 3; 14%), CNS wound infections (n = 3; 14%), and headache (n = 2; 10%). With a median follow-up of 151 weeks, median overall survival times for all patients and those with GBM are 96.6 and 90.6 weeks, respectively; 87% of GBM patients are alive at 1 year. It is feasible to consistently achieve a 44-Gy boost dose to the SCRC margin with patient-specific dosing of (131)I-81C6. Our study regimen ((131)I-81C6 + XRT + temozolomide) was well tolerated and had encouraging survival. To determine if selection of good-prognosis patients affects outcome associated with this approach, the U.S. Food and Drug Administration has approved a trial randomizing newly diagnosed GBM patients to either our study regimen or standard XRT plus temozolomide.

Authors
Reardon, DA; Zalutsky, MR; Akabani, G; Coleman, RE; Friedman, AH; Herndon, JE; McLendon, RE; Pegram, CN; Quinn, JA; Rich, JN; Vredenburgh, JJ; Desjardins, A; Guruangan, S; Boulton, S; Raynor, RH; Dowell, JM; Wong, TZ; Zhao, X-G; Friedman, HS; Bigner, DD
MLA Citation
Reardon, DA, Zalutsky, MR, Akabani, G, Coleman, RE, Friedman, AH, Herndon, JE, McLendon, RE, Pegram, CN, Quinn, JA, Rich, JN, Vredenburgh, JJ, Desjardins, A, Guruangan, S, Boulton, S, Raynor, RH, Dowell, JM, Wong, TZ, Zhao, X-G, Friedman, HS, and Bigner, DD. "A pilot study: 131I-antitenascin monoclonal antibody 81c6 to deliver a 44-Gy resection cavity boost." Neuro Oncol 10.2 (April 2008): 182-189.
PMID
18287339
Source
pubmed
Published In
Neuro-Oncology
Volume
10
Issue
2
Publish Date
2008
Start Page
182
End Page
189
DOI
10.1215/15228517-2007-053

Preparation of Rh[16aneS4-diol](211)At and Ir[16aneS4-diol](211)At complexes as potential precursors for astatine radiopharmaceuticals. Part I: Synthesis.

The goal of this study was to evaluate a new approach that can be applied for labeling biomolecules with (211)At. Many astatine compounds that have been synthesized are unstable in vivo, providing motivation for seeking different (211)At labeling strategies. The approach evaluated in this study was to attach astatide anions to soft metal cations, which are also complexed by a bifunctional ligand. Ultimately, this complex could in principle be subsequently conjugated to a biomolecule with the proper selection of ligand functionality. We report here the attachment of (211)At(-) and *I(-) (*I = (131)I or (125)I) anions to the soft metal cations Rh(III) and Ir(III), which are complexed by the 1,5,9,13-tetrathiacyclohexadecane-3,11-diol (16aneS4-diol) ligand. Radioactive *I(-) anions were used for preliminary studies directed at the optimization of reaction conditions and to provide a baseline for comparison of results with (211)At. Four complexes Rh[16aneS4-diol]*I/(211)At and Ir[16aneS4-diol]*I/(211)At were synthesized in high yield in a one-step procedure, and the products were characterized mainly by paper electrophoresis and reversed-phase HPLC. The influences of time and temperature of heating and concentrations of metal cations and sulfur ligand 16aneS4-diol, as well as pH on the reaction yields were determined. Yields of about 80% were obtained when the quantities of Rh(III) or Ir(III) cations and 16aneS4-diol ligand in the solutions were 62.5 nmol and 250 nmol, respectively, and the pH ranged 3.0-4.0. Syntheses required heating for 1-1.5 h at 75-80 degrees C. The influence of microwave heating on the time and completeness of the complexation reaction was evaluated and compared with the conventional method of heating in an oil bath. Microwave synthesis accelerates reactions significantly. With microwave heating, yields of about 75% for Rh[16aneS4-diol](131)I and Ir[16aneS4-diol](131)I complexes were obtained after only 20 min exposure of the reaction mixtures to microwave radiation. In conclusion, this study has shown that it is possible to attach an astatide anion to soft metal cations in a simple and fast one-step procedure, with high yields. These complexes will be evaluated as reagents for labeling biomolecules.

Authors
Pruszyński, M; Bilewicz, A; Zalutsky, MR
MLA Citation
Pruszyński, M, Bilewicz, A, and Zalutsky, MR. "Preparation of Rh[16aneS4-diol](211)At and Ir[16aneS4-diol](211)At complexes as potential precursors for astatine radiopharmaceuticals. Part I: Synthesis." Bioconjug Chem 19.4 (April 2008): 958-965.
PMID
18338858
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
19
Issue
4
Publish Date
2008
Start Page
958
End Page
965
DOI
10.1021/bc700413r

Clinical experience with alpha-particle emitting 211At: treatment of recurrent brain tumor patients with 211At-labeled chimeric antitenascin monoclonal antibody 81C6.

UNLABELLED: alpha-Particle-emitting radionuclides, such as (211)At, with a 7.2-h half-life, may be optimally suited for the molecularly targeted radiotherapy of strategically sensitive tumor sites, such as those in the central nervous system. Because of the much shorter range and more potent cytotoxicity of alpha-particles than of beta-particles, (211)At-labeled agents may be ideal for the eradication of tumor cells remaining after surgical debulking of malignant brain tumors. The main goal of this study was to investigate the feasibility and safety of this approach in patients with recurrent malignant brain tumors. METHODS: Chimeric antitenascin monoclonal antibody 81C6 (ch81C6) (10 mg) was labeled with 71-347 MBq of (211)At by use of N-succinimidyl 3-[(211)At]astatobenzoate. Eighteen patients were treated with (211)At-labeled ch81C6 ((211)At-ch81C6) administered into a surgically created resection cavity (SCRC) and then with salvage chemotherapy. Serial gamma-camera imaging and blood sampling over 24 h were performed. RESULTS: A total of 96.7% +/- 3.6% (mean +/- SD) of (211)At decays occurred in the SCRC, and the mean blood-pool percentage injected dose was < or = 0.3. No patient experienced dose-limiting toxicity, and the maximum tolerated dose was not identified. Six patients experienced grade 2 neurotoxicity within 6 wk of (211)At-ch81C6 administration; this neurotoxicity resolved fully in all but 1 patient. No toxicities of grade 3 or higher were attributable to the treatment. No patient required repeat surgery for radionecrosis. The median survival times for all patients, those with glioblastoma multiforme, and those with anaplastic astrocytoma or oligodendroglioma were 54, 52, and 116 wk, respectively. CONCLUSION: This study provides proof of concept for regional targeted radiotherapy with (211)At-labeled molecules in oncology. Specifically, the regional administration of (211)At-ch81C6 is feasible, safe, and associated with a promising antitumor benefit in patients with malignant central nervous system tumors.

Authors
Zalutsky, MR; Reardon, DA; Akabani, G; Coleman, RE; Friedman, AH; Friedman, HS; McLendon, RE; Wong, TZ; Bigner, DD
MLA Citation
Zalutsky, MR, Reardon, DA, Akabani, G, Coleman, RE, Friedman, AH, Friedman, HS, McLendon, RE, Wong, TZ, and Bigner, DD. "Clinical experience with alpha-particle emitting 211At: treatment of recurrent brain tumor patients with 211At-labeled chimeric antitenascin monoclonal antibody 81C6." J Nucl Med 49.1 (January 2008): 30-38.
PMID
18077533
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
49
Issue
1
Publish Date
2008
Start Page
30
End Page
38
DOI
10.2967/jnumed.107.046938

Radiolabelling of glucose-Tyr3-octreotate with 125I and analysis of its metabolism in rats: comparison with radiolabelled DOTA-Tyr3-octreotate.

Somatostatin analogues labelled with radiometals or radiohalogens are useful for the imaging and treatment of somatostatin receptor-containing tumours. In this study, the procedures for the radioiodination of glucose-Tyr3-octreotate (gluc-Tyr3-tate) and radiolabelling of DOTA-Tyr3-octreotate (DOTA-Tyr3-tate) with 111In, 177Lu and 125I were compared and their metabolism in rats was analyzed. The usefulness of high performance liquid chromatography (HPLC) analysis and instant thin-layer chromatography on silica gel (ITLC-SG) for both radiochemical purity determination and analysis of metabolism in urine was investigated.For labelling with radiometals, the formation of a complex with the 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) functionality of the peptide was employed. Radioiodination was performed by the chloramime-T method. The radiochemical purity of radiolabelled peptides and the analyses of rat urine were determined by HPLC and/or ITLC-SG methods. Male Wistar rats were used in the elimination studies.DOTA-Tyr3-tate was simply radiolabelled with radiometals with high yield and high radiochemical purity. Stopping of the reaction was a critical step for radioiodination, therefore labelling of gluc-Tyr3-tate and DOTA-Tyr3-tate with 125I was not so simple and the reaction product had to be purified by preparative HPLC analysis. Whereas 111In-DOTA-Tyr3-tate and 177Lu-DOTA-Tyr3-tate were eliminated in rat urine in a practically unchanged form, a significant proportion of metabolites was observed with radioiodinated peptides, particularly at longer time intervals.Labelling of DOTA-Tyr3-tate with radiometals is simple and the radiochemical purity of prepared compounds is very high, while iodination of the peptides demands purification of the product by preparative HPLC. The analysis of rat urine showed that excretion of radioiodinated peptides included a significant proportion of metabolites.

Authors
Petrik, M; Laznickova, A; Laznicek, M; Zalutsky, MR
MLA Citation
Petrik, M, Laznickova, A, Laznicek, M, and Zalutsky, MR. "Radiolabelling of glucose-Tyr3-octreotate with 125I and analysis of its metabolism in rats: comparison with radiolabelled DOTA-Tyr3-octreotate." Anticancer research 27.6B (November 2007): 3941-3946.
PMID
18225554
Source
epmc
Published In
Anticancer research
Volume
27
Issue
6B
Publish Date
2007
Start Page
3941
End Page
3946

A radioiodinated MIBG-octreotate conjugate exhibiting enhanced uptake and retention in SSTR2-expressing tumor cells.

Several neuroendocrine tumors are known to express both the somatostatin receptor subtype 2 (SSTR2) and the norepinephrine transporter (NET), and radiopharmaceuticals directed toward both these targets such as MIBG and octreotide derivatives are routinely used in the clinic. To investigate the possibility of targeting both NET and SSTR2 conjointly, a conjugate of radioiodinated MIBG and octreotate was synthesized. Attempts to synthesize the radioiodinated target compound (MIBG-octreotate; [ (131)I] 12a) from a tin precursor were futile; however, it could be accomplished from a bromo precursor by exchange radioiodination in 3-36% ( n = 10) radiochemical yields. The total uptake of [ (131)I] 12a in SK-N-SH human neuroblastoma cells transfected to express SSTR2 (SK-N-SHsst2) was similar to that for [ (125)I]MIBG at all time points (34.9 +/- 2.4% vs 43.8 +/- 1.2% at 4 h; p < 0.05), while it was substantially lower (5.4 +/- 0.3% vs 35.9 +/- 1.2%) in the SH-SY5Y cell line, a subclone of SK-N-SH line that is known to express SSTR2. The NET blocker desipramine reduced the uptake of [ (131)I] 12a only to a small extent, further suggesting a limited role of NET in its binding and accumulation. Uptake of [ (131)I] 12a in SK-N-SHsst2 cells was 8-10-fold higher ( p < 0.05) than that of [ (125)I]I-Gluc-TOCA, an octreotide analogue, at all time points over a 4 h period and was reduced to about 20% by 10 muM octreotide demonstrating that the uptake of [ (131)I] 12a in this cell line is predominantly mediated by SSTR2. The intracellularly trapped radioactivity in SK-N-SHsst2 cells was substantially higher for [ (131)I] 12a compared to that for [ (125)I]OIBG-octreotate, an isomeric congener of 12a. Because MIBG has more specific NET-mediated uptake than OIBG, this suggests at least a partial role for NET-mediated uptake of [ (131)I] 12a in this cell line. While further refinement in the structure of the conjugate-probably interposition of a flexible and/or cleavable linker between the MIBG and octreotate moieties-may be necessary to make it a substrate/ligand for both NET and SSTR2, this conjugate is demonstrated to be much superior than I-Gluc-TOCA with respect to the uptake in SSTR2-expressing cells.

Authors
Vaidyanathan, G; Affleck, DJ; Norman, J; O'Dorisio, S; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, Norman, J, O'Dorisio, S, and Zalutsky, MR. "A radioiodinated MIBG-octreotate conjugate exhibiting enhanced uptake and retention in SSTR2-expressing tumor cells." Bioconjug Chem 18.6 (November 2007): 2122-2130.
PMID
17979223
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
18
Issue
6
Publish Date
2007
Start Page
2122
End Page
2130
DOI
10.1021/bc700240r

Targeted alpha-particle radiotherapy with 211At-labeled monoclonal antibodies.

An attractive feature of targeted radionuclide therapy is the ability to select radionuclides and targeting vehicles with characteristics that are best suited for a particular clinical application. One combination that has been receiving increasing attention is the use of monoclonal antibodies (mAbs) specifically reactive to receptors and antigens that are expressed in tumor cells to selectively deliver the alpha-particle-emitting radiohalogen astatine-211 (211At) to malignant cell populations. Promising results have been obtained in preclinical models with multiple 211At-labeled mAbs; however, translation of the concept to the clinic has been slow. Impediments to this process include limited radionuclide availability, the need for suitable radiochemistry methods operant at high activity levels and lack of data concerning the toxicity of alpha-particle emitters in humans. Nonetheless, two clinical trials have been initiated to date with 211At-labeled mAbs, and others are planned for the near future.

Authors
Zalutsky, MR; Reardon, DA; Pozzi, OR; Vaidyanathan, G; Bigner, DD
MLA Citation
Zalutsky, MR, Reardon, DA, Pozzi, OR, Vaidyanathan, G, and Bigner, DD. "Targeted alpha-particle radiotherapy with 211At-labeled monoclonal antibodies." Nucl Med Biol 34.7 (October 2007): 779-785. (Review)
PMID
17921029
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
34
Issue
7
Publish Date
2007
Start Page
779
End Page
785
DOI
10.1016/j.nucmedbio.2007.03.007

Targeted alpha-particle radiotherapy with At-211-labeled monoclonal antibodies

Authors
Zalutsky, MR; Reardon, DA; Pozzi, OR; Vaidyanathan, G; Bigner, DD
MLA Citation
Zalutsky, MR, Reardon, DA, Pozzi, OR, Vaidyanathan, G, and Bigner, DD. "Targeted alpha-particle radiotherapy with At-211-labeled monoclonal antibodies." October 2007.
Source
wos-lite
Published In
Nuclear Medicine and Biology
Volume
34
Issue
7
Publish Date
2007
Start Page
779
End Page
785
DOI
10.1016/j.nuemedbio.2007.03.007

[I-125] iodoquine uptake in tumor cell lines with high ALDH expression

Authors
Chin, BB; Storms, RW; Base, K; Lascola, C; Haystead, T; Zalutsky, MR; Vaidyanathan, G
MLA Citation
Chin, BB, Storms, RW, Base, K, Lascola, C, Haystead, T, Zalutsky, MR, and Vaidyanathan, G. "[I-125] iodoquine uptake in tumor cell lines with high ALDH expression." October 2007.
Source
wos-lite
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
34
Publish Date
2007
Start Page
S222
End Page
S222

Synthesis of Rh[16aneS4] At-211 and Ir[16aneS4] At-211 complexes - new prosthetic groups for labelling with astatine.

Authors
Pruszynski, M; Bilewicz, A; Zalutsky, MR
MLA Citation
Pruszynski, M, Bilewicz, A, and Zalutsky, MR. "Synthesis of Rh[16aneS4] At-211 and Ir[16aneS4] At-211 complexes - new prosthetic groups for labelling with astatine." October 2007.
Source
wos-lite
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
34
Publish Date
2007
Start Page
S210
End Page
S210

Radiopharmaceutical chemistry of targeted radiotherapeutics, Part 3: alpha-particle-induced radiolytic effects on the chemical behavior of (211)At.

UNLABELLED: Two characteristics of alpha-particles that enhance their potential for targeted radiotherapy are their high energy and approximately cellular range. Unfortunately, these properties also can have negative consequences, confounding the production of clinically relevant levels of radiopharmaceutical because of radiolytic effects. The purpose of this study was to evaluate the effect of radiation dose on the astatine species present before initiation of a labeling reaction and the potential role of these molecules in the efficiency of N-succinimidyl 3-(211)At-astatobenzoate (SAB) synthesis. The ranges of radiation dose evaluated were selected to reflect those that might be encountered in SAB synthesis for the preparation of clinical doses of (211)At-labeled radiopharmaceuticals. METHODS: The distribution of astatine species present in methanol, and the yields for the synthesis of SAB from N-succinimidyl 3-(tri-n-butylstannyl)benzoate as a function of radiation dose, were determined by high-performance liquid chromatography. Radiation doses in the range of 500-12,000 Gy were evaluated using different (211)At time-activity combinations, and the effect of acetic acid, a normal component of astatodestannylation reactions, also was studied. Finally, the effect of the reducing agent sodium sulfite also was evaluated to characterize the nature of the species produced by radiolysis. RESULTS: At radiation doses below 1,000 Gy, high-performance liquid chromatography analysis indicated that more than 90% of the (211)At was present in methanol as a single species, At(1), whereas at higher doses, a second peak, At(2), emerged. At(1) decreased and At(2) increased in a radiation dose-dependent fashion, with At(2) becoming the predominant species at about 3,000 Gy. At(2) was identified as a reduced form of astatine, presumably astatide, which could not be efficiently oxidized to a species suitable for electrophilic astatination. In methanol/acetic acid, more than 95% of the astatine was present as At(2) even at doses below 1,400 Gy. CONCLUSION: The emergence of a reduced form of astatine, At(2), at higher radiation doses is consistent with the decline in SAB yields observed under these conditions. Alteration of the chemical form of the astatine by radiolysis could account for the declining yields noted in the preparation of clinical-level (211)At-labeled radiopharmaceuticals and when the labeling chemistry is initiated hours after (211)At production.

Authors
Pozzi, OR; Zalutsky, MR
MLA Citation
Pozzi, OR, and Zalutsky, MR. "Radiopharmaceutical chemistry of targeted radiotherapeutics, Part 3: alpha-particle-induced radiolytic effects on the chemical behavior of (211)At." J Nucl Med 48.7 (July 2007): 1190-1196.
PMID
17574991
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
48
Issue
7
Publish Date
2007
Start Page
1190
End Page
1196
DOI
10.2967/jnumed.106.038505

A kit method for the high level synthesis of [211At]MABG.

meta-[(211)At]Astatobenzylguanidine ([(211)At]MABG), an analogue of meta-iodobenzylguanidine (MIBG) labeled with the alpha-emitter (211)At, targets the norepinephrine transporter. Because MABG has been shown to have excellent characteristics in preclinical studies, it has been considered to be a promising targeted radiotherapeutic for the treatment of tumors such as micrometastatic neuroblastoma that overexpress the norepinephrine transporter. To facilitate clinical evaluation of this agent, a convenient method for the high level synthesis of [(211)At]MABG that is adaptable for kit formulation has been developed. A tin precursor anchored to a solid-support was treated with a methanolic solution of (211)At in the presence of a mixture of H(2)O(2)/HOAc as the oxidant; [(211)At]MABG was isolated by simple solid-phase extraction. By using C-18 solid-phase extraction, the radiochemical yield from 25 batches was 63+/-13%; however, loss of radioactivity during evaporation of the methanolic solution was a problem. This difficulty was avoided by use of a cation exchange resin cartridge for isolation of [(211)At]MABG, which resulted in radiochemical yields of 63+/-9% in a shorter duration of synthesis. The radiochemical purity was more than 90% and no chemical impurity has been detected. The final doses were sterile and apyrogenic. These results demonstrate that [(211)At]MABG can be prepared via a kit method at radioactivity levels anticipated for initiation of clinical studies.

Authors
Vaidyanathan, G; Affleck, DJ; Alston, KL; Zhao, X-G; Hens, M; Hunter, DH; Babich, J; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, Alston, KL, Zhao, X-G, Hens, M, Hunter, DH, Babich, J, and Zalutsky, MR. "A kit method for the high level synthesis of [211At]MABG." Bioorg Med Chem 15.10 (May 15, 2007): 3430-3436.
PMID
17387017
Source
pubmed
Published In
Bioorganic & Medicinal Chemistry
Volume
15
Issue
10
Publish Date
2007
Start Page
3430
End Page
3436
DOI
10.1016/j.bmc.2007.03.016

Tumor resection cavity administered iodine-131-labeled antitenascin 81C6 radioimmunotherapy in patients with malignant glioma: neuropathology aspects.

INTRODUCTION: The neurohistological findings in patients treated with targeted beta emitters such as (131)I are poorly described. We report a histopathologic analysis from patients treated with combined external beam therapy and a brachytherapy consisting of a (131)I-labeled monoclonal antibody (mAb) injected into surgically created resection cavities during brain tumor resections. METHODS: Directed tissue samples of the cavity walls were obtained because of suspected tumor recurrence from 28 patients. Samples and clinical follow-up were evaluated on all patients (Group A) based on total radiation dose received and a subset of these (n=18; Group B, proximal therapy subset) who had received external beam therapy within

Authors
McLendon, RE; Akabani, G; Friedman, HS; Reardon, DA; Cleveland, L; Cokgor, I; Herndon, JE; Wikstrand, C; Boulton, ST; Friedman, AH; Bigner, DD; Zalutsky, MR
MLA Citation
McLendon, RE, Akabani, G, Friedman, HS, Reardon, DA, Cleveland, L, Cokgor, I, Herndon, JE, Wikstrand, C, Boulton, ST, Friedman, AH, Bigner, DD, and Zalutsky, MR. "Tumor resection cavity administered iodine-131-labeled antitenascin 81C6 radioimmunotherapy in patients with malignant glioma: neuropathology aspects." Nucl Med Biol 34.4 (May 2007): 405-413.
PMID
17499730
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
34
Issue
4
Publish Date
2007
Start Page
405
End Page
413
DOI
10.1016/j.nucmedbio.2007.01.009

Antitenascin-C monoclonal antibody radioimmunotherapy for malignant glioma patients.

Adults with primary malignant glioma have an unacceptably poor outcome. Most of these tumors recur at or adjacent to the site of origin, which indicates that failure to eradicate local tumor growth is a major factor contributing to poor outcome. Therefore, locoregional therapies may improve local control and overall outcome for malignant glioma patients. Malignant gliomas selectively express several factors that are not present on normal CNS tissue. Regional administration of radiolabeled monoclonal antibodies targeting tumor-specific antigens expressed by malignant gliomas offers an innovative therapeutic strategy that has recently demonstrated encouraging antitumor activity and acceptable toxicity in clinical trials at a number of centers. Most studies have utilized monoclonal antibodies against tenascin-C, an extracellular matrix glycoprotein ubiquitously expressed by malignant gliomas. This review summarizes clinical trials performed using radiolabeled antitenascin-C monoclonal antibodies for malignant glioma patients to date and highlights future plans to further develop this therapeutic strategy.

Authors
Reardon, DA; Zalutsky, MR; Bigner, DD
MLA Citation
Reardon, DA, Zalutsky, MR, and Bigner, DD. "Antitenascin-C monoclonal antibody radioimmunotherapy for malignant glioma patients." Expert Rev Anticancer Ther 7.5 (May 2007): 675-687. (Review)
PMID
17492931
Source
pubmed
Published In
Expert Review of Anticancer Therapy
Volume
7
Issue
5
Publish Date
2007
Start Page
675
End Page
687
DOI
10.1586/14737140.7.5.675

Antitenascin antibody 81C6 armed with 177Lu: in vivo comparison of macrocyclic and acyclic ligands.

INTRODUCTION: When labeled with iodine-131, the antitenascin monoclonal antibody (mAb) 81C6 has shown promise as a targeted radiotherapeutic in patients with brain tumors. Because of its more favorable gamma-ray properties, lutetium-177 might be a better low-energy beta-emitter for this type of therapy. MATERIALS AND METHODS: Chimeric 81C6 (ch81C6) was labeled with (177)Lu using the acyclic 1B4M ligand and the macrocyclic ligands NHS-DOTA and MeO-DOTA and evaluated for binding to tenascin. Three paired-label tissue distribution experiments were performed in normal mice receiving one of the (177)Lu-labeled immunoconjugates plus (125)I-labeled ch81C6 labeled using Iodogen. Paired-label experiments in athymic mice bearing subcutaneous D54 MG human glioma xenografts were done to directly compare the biodistribution of ch81C6-1B4M-(177)Lu and (125)I-labeled ch81C6, and ch81C6-MeO-DOTA-(177)Lu and (125)I-labeled ch81C6. Similar comparisons were done using murine (mu) instead of ch81C6. The primary parameter utilized for evaluation was the (177)Lu/(125)I uptake ratio in each tissue. RESULTS: In the studies performed in normal mice, the NHS-DOTA ligand yielded the highest (177)Lu/(125)I uptake ratios in tissues indicative of loss of label from the chelate; for this reason, only 1B4M and MeO-DOTA were evaluated further. The (177)Lu/(125)I ratio in bone increased gradually with time for the chimeric conjugates; however, there were no significant differences between ch81C6-1B4M-DTPA-(177)Lu and ch81C6-MeO-DOTA-(177)Lu. In contrast, mu81C6-1B4M-DTPA-(177)Lu and mu81C6-MeO-DOTA-(177)Lu showed a more dramatic increase in the (177)Lu/(125)I ratio in bone - from 2.4+/-0.3 and 1.7+/-0.2 at Day 1 to 8.5+/-1.1 and 4.2+/-0.5 at Day 7, respectively. CONCLUSION: With these antitenascin constructs, the nature of the mAb had a profound influence on the relative degree of loss of (177)Lu from these immunoconjugates. MeO-DOTA shows promise as a bifunctional chelate for labeling 81C6 mAbs with (177)Lu.

Authors
Yordanov, AT; Hens, M; Pegram, C; Bigner, DD; Zalutsky, MR
MLA Citation
Yordanov, AT, Hens, M, Pegram, C, Bigner, DD, and Zalutsky, MR. "Antitenascin antibody 81C6 armed with 177Lu: in vivo comparison of macrocyclic and acyclic ligands." Nucl Med Biol 34.2 (February 2007): 173-183.
PMID
17307125
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
34
Issue
2
Publish Date
2007
Start Page
173
End Page
183
DOI
10.1016/j.nucmedbio.2006.11.003

Synthesis of N-succinimidyl 4-guanidinomethyl-3-[*I]iodobenzoate: a radio-iodination agent for labeling internalizing proteins and peptides.

This protocol describes a detailed procedure for the synthesis of N-succinimidyl 4-guanidinomethyl-3-[*I]iodobenzoate ([*I]SGMIB), an agent useful in the radio-iodination of proteins, including monoclonal Abs, and peptides that undergo internalization after receptor or antigen binding. In this procedure, the tin precursor N-succinimidyl 4-[N1,N2-bis(tert-butyloxycarbonyl)guanidinomethyl]-3-(trimethylstannyl)benzoate (Boc-SGMTB, 3) was first radio-iodinated to [*I]Boc-SGMIB, a derivative of [*I]SGMIB with the guanidine function protected with Boc groups. Treatment of [*I]Boc-SGMIB with trifluoroacetic acid delivered the final product. The total time for the synthesis and purification of [*I]Boc-SGMIB and its subsequent de-protection is approximately 140 min.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Synthesis of N-succinimidyl 4-guanidinomethyl-3-[*I]iodobenzoate: a radio-iodination agent for labeling internalizing proteins and peptides." Nat Protoc 2.2 (2007): 282-286.
PMID
17406587
Source
pubmed
Published In
Nature Protocols
Volume
2
Issue
2
Publish Date
2007
Start Page
282
End Page
286
DOI
10.1038/nprot.2007.20

A tin precursor for the synthesis of no-carrier-added [*I]MIBG and [211At]MABG

Radioiodinated MIBG has shown considerable promise as an imaging agent for cardiac and oncologic applications, and also as a targeted radio therapeutic for treating patients with neuroendocrine tumors. This radiolabeled agent, synthesized at a no-carrier-added level, has demonstrated advantages over the carrier-added preparation in preliminary clinical studies. Earlier we developed a silicon precursor from which both radioiodinated MIBG and the α-particle-emitting 211At analog [211At]MABG could be synthesized at a no-carrier-added level. In order to increase the practicality of this approach, we have developed a synthesis of a tin precursor in two steps from a readily available starting material. This tin precursor, N, N′-bis(tert-butyloxycarbonyl)-3-(trimethylstannyl)benzylguanidine (Bis-Boc MTMSBG) was evaluated for the synthesis of n.c.a. [*I]MIBG and [ 211At]MABG via halodestannylation. The radiochemical yields were 83 ± 9% (n = 7), 30 ± 21% (n = 2), 77 ± 2% (n = 2), and 66 ± 7% (n = 4) for labeling with 131I, 124I, 125I, and 211At, respectively. Copyright © 2007 John Wiley & Sons, Ltd.

Authors
Vaidyanathan, G; Affleck, DJ; Alston, KL; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, Alston, KL, and Zalutsky, MR. "A tin precursor for the synthesis of no-carrier-added [*I]MIBG and [211At]MABG." Journal of Labelled Compounds and Radiopharmaceuticals 50.3 (2007): 177-182.
Source
scival
Published In
Journal of Labelled Compounds and Radiopharmaceuticals
Volume
50
Issue
3
Publish Date
2007
Start Page
177
End Page
182
DOI
10.1002/jlcr.1243

Radiolabelling of glucose-Tyr3-octreotate with 125I and analysis of its metabolism in rats: Comparison with radiolabelled DOTA-Tyr3-octreotate

Background: Somatostatin analogues labelled with radiometals or radiohalogens are useful for the imaging and treatment of somatostatin receptor-containing tumours. In this study, the procedures for the radioiodination of glucose-Tyr3-octreotate (gluc-Tyr 3-tate) and radiolabelling of DOTA-Tyr3-octreotate (DOTA-Tyr3-tate) with 111In, 177Lu and 125I were compared and their metabolism in rats was analyzed. The usefulness of high performance liquid chromatography (HPLC) analysis and instant thin-layer chromatography on silica gel (ITLC-SG) for both radiochemical purity determination and analysis of metabolism in urine was investigated. Materials and Methods: For labelling with radiometals, the formation of a complex with the 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) functionality of the peptide was employed. Radioiodination was performed by the chloramime-T method. The radiochemical purity of radiolabelled peptides and the analyses of rat urine were determined by HPLC and/or ITLC-SG methods. Male Wistar rats were used in the elimination studies. Results: DOTA-Tyr3-tate was simply radiolabelled with radiometals with high yield and high radiochemical purity. Stopping of the reaction was a critical step for radioiodination, therefore labelling of gluc-Tyr3-tate and DOTA-Tyr3-tate with 125I was not so simple and the reaction product had to be purified by preparative HPLC analysis. Whereas 111In-DOTA-Tyr3-tate and 177Lu-DOTA-Tyr3-tate were eliminated in rat urine in a practically unchanged form, a significant proportion of metabolites was observed with radioiodinated peptides, particularly at longer time intervals. Conclusion: Labelling of DOTA-Tyr3-tate with radiometals is simple and the radiochemical purity of prepared compounds is very high, while iodination of the peptides demands purification of the product by preparative HPLC. The analysis of rat urine showed that excretion of radioiodinated peptides included a significant proportion of metabolites.

Authors
Petrik, M; Laznickova, A; Laznicek, M; Zalutsky, MR
MLA Citation
Petrik, M, Laznickova, A, Laznicek, M, and Zalutsky, MR. "Radiolabelling of glucose-Tyr3-octreotate with 125I and analysis of its metabolism in rats: Comparison with radiolabelled DOTA-Tyr3-octreotate." Anticancer Research 27.6 B (2007): 3941-3946.
Source
scival
Published In
Anticancer research
Volume
27
Issue
6 B
Publish Date
2007
Start Page
3941
End Page
3946

Tumor accumulation, degradation and pharmacokinetics of elastin-like polypeptides in nude mice.

ELPs are genetically engineered, thermally responsive polypeptides that preferentially accumulate in solid tumors subjected to focused, mild hyperthermia. In this paper, we report the biodegradation, pharmacokinetics, tumor localization, and tumor spatial distribution of (14)C-labeled ELPs that were radiolabeled during their biosynthesis in Escheriehia coli. The in vitro degradation rate of a thermally responsive (14)C-labeled ELP1 ([(14)C] ELP1) with a molecular weight of 59.4 kDa, upon exposure to murine serum, was 2.49 wt.%/day. The apparent in vivo degradation rate of ELP1 after intravenous injection of nude mice was 2.46 wt.%/day and its terminal half-life was 8.7 h. The tumor accumulation and spatial distribution of intravenously administered ELP1 and a control ELP that was designed to remain soluble in heated tumors (ELP2) were examined in both heated (41.5 degrees C) and unheated tumors. ELP1 accumulated at a significantly higher concentration in heated tumors than ELP1 in unheated tumors and ELP2 in heated tumors. Quantitative autoradiography of tumor sections provided similar tumor accumulation results as the whole tumor analysis but, in addition, showed that ELP1 had a more homogeneous distribution in heated tumors and a greater concentration in the tumor center than either control treatment.

Authors
Liu, W; Dreher, MR; Furgeson, DY; Peixoto, KV; Yuan, H; Zalutsky, MR; Chilkoti, A
MLA Citation
Liu, W, Dreher, MR, Furgeson, DY, Peixoto, KV, Yuan, H, Zalutsky, MR, and Chilkoti, A. "Tumor accumulation, degradation and pharmacokinetics of elastin-like polypeptides in nude mice." J Control Release 116.2 (November 28, 2006): 170-178.
PMID
16919353
Source
pubmed
Published In
Journal of Controlled Release
Volume
116
Issue
2
Publish Date
2006
Start Page
170
End Page
178
DOI
10.1016/j.jconrel.2006.06.026

A thermally responsive biopolymer for intra-articular drug delivery.

Intra-articular drug delivery is the preferred standard for targeting pharmacologic treatment directly to joints to reduce undesirable side effects associated with systemic drug delivery. In this study, a biologically based drug delivery vehicle was designed for intra-articular drug delivery using elastin-like polypeptides (ELPs), a biopolymer composed of repeating pentapeptides that undergo a phase transition to form aggregates above their transition temperature. The ELP drug delivery vehicle was designed to aggregate upon intra-articular injection at 37 degrees C, and form a drug 'depot' that could slowly disaggregate and be cleared from the joint space over time. We evaluated the in vivo biodistribution and joint half-life of radiolabeled ELPs, with and without the ability to aggregate, at physiological temperatures encountered after intra-articular injection in a rat knee. Biodistribution studies revealed that the aggregating ELP had a 25-fold longer half-life in the injected joint than a similar molecular weight protein that remained soluble and did not aggregate. These results suggest that the intra-articular joint delivery of ELP-based fusion proteins may be a viable strategy for the prolonged release of disease-modifying protein drugs for osteoarthritis and other arthritides.

Authors
Betre, H; Liu, W; Zalutsky, MR; Chilkoti, A; Kraus, VB; Setton, LA
MLA Citation
Betre, H, Liu, W, Zalutsky, MR, Chilkoti, A, Kraus, VB, and Setton, LA. "A thermally responsive biopolymer for intra-articular drug delivery." J Control Release 115.2 (October 10, 2006): 175-182.
PMID
16959360
Source
pubmed
Published In
Journal of Controlled Release
Volume
115
Issue
2
Publish Date
2006
Start Page
175
End Page
182
DOI
10.1016/j.jconrel.2006.07.022

At-211-labeled trastuzumab: Evaluation of an alpha-particle emitting targeted radiotherapeutic for the treatment of breast carcinoma carcinomatous meningitis

Authors
Boskovitz, A; Ochiai, H; Okamura, T; Akabani, G; Carlin, S; Bigner, DD; Zalutsky, MR
MLA Citation
Boskovitz, A, Ochiai, H, Okamura, T, Akabani, G, Carlin, S, Bigner, DD, and Zalutsky, MR. "At-211-labeled trastuzumab: Evaluation of an alpha-particle emitting targeted radiotherapeutic for the treatment of breast carcinoma carcinomatous meningitis." EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 33 (September 2006): S184-S184.
Source
wos-lite
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
33
Publish Date
2006
Start Page
S184
End Page
S184

Chimeric murine/human IgG(2) anti-tenascin 81C6 monoclonal antibody: phase I trial in patients with malignant glioma of a construct with improved stability

Authors
Zalutsky, MR; Reardon, DA; Quinn, JA; Coleman, RE; Akabani, G; Friedman, AH; Friedman, HS; II, HJE; McLendon, RE; Wong, TZ; Bigner, DD
MLA Citation
Zalutsky, MR, Reardon, DA, Quinn, JA, Coleman, RE, Akabani, G, Friedman, AH, Friedman, HS, II, HJE, McLendon, RE, Wong, TZ, and Bigner, DD. "Chimeric murine/human IgG(2) anti-tenascin 81C6 monoclonal antibody: phase I trial in patients with malignant glioma of a construct with improved stability." EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 33 (September 2006): S194-S194.
Source
wos-lite
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
33
Publish Date
2006
Start Page
S194
End Page
S194

At-211-labeled trastuzumab: Evaluation of an alpha-particle emitting targeted radiotherapeutic for the treatment of breast carcinoma carcinomatous meningitis

Authors
Boskovitz, A; Ochiai, H; Okamura, T; Akabani, G; Carlin, S; Bigner, DD; Zalutsky, MR
MLA Citation
Boskovitz, A, Ochiai, H, Okamura, T, Akabani, G, Carlin, S, Bigner, DD, and Zalutsky, MR. "At-211-labeled trastuzumab: Evaluation of an alpha-particle emitting targeted radiotherapeutic for the treatment of breast carcinoma carcinomatous meningitis." EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 33 (September 2006): S378-S378.
Source
wos-lite
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
33
Publish Date
2006
Start Page
S378
End Page
S378

Radioimmunotherapy of patients with malignant brain tumors: patient-specific dosing of I-131-labeled anti-tenacin antibody to achieve 44 Gy boost dose to resection cavity margins

Authors
Reardon, DA; Zalutsky, MR; Akabani, G; Coleman, RE; Friedman, AH; McLendon, RE; Friedman, HS; II, HJE; Kirkpatrick, J; Bigner, DD
MLA Citation
Reardon, DA, Zalutsky, MR, Akabani, G, Coleman, RE, Friedman, AH, McLendon, RE, Friedman, HS, II, HJE, Kirkpatrick, J, and Bigner, DD. "Radioimmunotherapy of patients with malignant brain tumors: patient-specific dosing of I-131-labeled anti-tenacin antibody to achieve 44 Gy boost dose to resection cavity margins." EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 33 (September 2006): S194-S194.
Source
wos-lite
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
33
Publish Date
2006
Start Page
S194
End Page
S194

Preclinical pharmacokinetic comparison of glucose-125I-Tyr3-octreotate with DOTA-125I-Tyr3-octreotate

Authors
Laznickova, A; Petrik, M; Melicharova, L; Laznicek, M; Zalutsky, MR
MLA Citation
Laznickova, A, Petrik, M, Melicharova, L, Laznicek, M, and Zalutsky, MR. "Preclinical pharmacokinetic comparison of glucose-125I-Tyr3-octreotate with DOTA-125I-Tyr3-octreotate." EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 33 (September 2006): S307-S308.
Source
wos-lite
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
33
Publish Date
2006
Start Page
S307
End Page
S308

Tracking the in vivo fate of recombinant polypeptides by isotopic labeling.

We report a method to incorporate a stable isotope (13C) and a radioactive isotope (14C) into a recombinant polypeptide during Escherichia coli culture in M9 minimal medium supplemented with universally labeled 13C- or 14C-labeled glucose. We chose a thermally responsive elastin-like polypeptide (ELP) as a model polypeptide for this study because of its utility in various biotechnology applications such as drug delivery and tissue engineering. High cell densities were obtained by step-wise adaptation of E. coli to M9 medium in addition to supplementing the medium with trace elements that facilitated growth of E. coli. Furthermore, an optimal concentration of isopropyl-beta-d-thiogalactopyranoside was determined for induction of ELP expression to achieve high yield (mg/L culture) of the ELP. The incorporation of carbon isotopes was stoichiometrically related to the ratio of labeled glucose to unlabeled glucose in the culture medium. The isotope-labeled variants retained the physicochemical properties of the unlabeled ELP, specifically its temperature dependent aggregation behavior. As an example of the utility of this method, the in vitro stability of 14C-labeled ELP in PBS and mouse serum was conveniently quantified by SDS-PAGE and autoradiography. In addition, the in vivo stability of the 14C-labeled ELP in plasma was determined along with its plasma pharmacokinetics.

Authors
Liu, W; Dreher, MR; Chow, DC; Zalutsky, MR; Chilkoti, A
MLA Citation
Liu, W, Dreher, MR, Chow, DC, Zalutsky, MR, and Chilkoti, A. "Tracking the in vivo fate of recombinant polypeptides by isotopic labeling." J Control Release 114.2 (August 28, 2006): 184-192.
PMID
16904221
Source
pubmed
Published In
Journal of Controlled Release
Volume
114
Issue
2
Publish Date
2006
Start Page
184
End Page
192
DOI
10.1016/j.jconrel.2006.06.001

Tracking the in vivo fate of recombinant polypeptides by isotopic labeling

Authors
Liu, W; Dreher, MR; Chow, DC; Zalutsky, MR; Chilkoti, A
MLA Citation
Liu, W, Dreher, MR, Chow, DC, Zalutsky, MR, and Chilkoti, A. "Tracking the in vivo fate of recombinant polypeptides by isotopic labeling." August 28, 2006.
Source
wos-lite
Published In
Journal of Controlled Release
Volume
114
Issue
2
Publish Date
2006
Start Page
184
End Page
192
DOI
10.1016/j.jcornel.2006.06.001

Targeted alpha-particle therapy of microscopic disease: Providing a further rationale for clinical investigation.

Authors
Zalutsky, MR
MLA Citation
Zalutsky, MR. "Targeted alpha-particle therapy of microscopic disease: Providing a further rationale for clinical investigation." J Nucl Med 47.8 (August 2006): 1238-1240.
PMID
16882999
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
47
Issue
8
Publish Date
2006
Start Page
1238
End Page
1240

Nε-(3[*I]iodobenzoyl)-Lys5-N α-maleimido-Gly1-GEEEK([*I]IB-Mal-D-GEEEK): A radioiodinated prosthetic group containing negatively charged D-glutamates for labeling internalizing monoclonal antibodies

Novel methods are needed for the radiohalogenation of cell-internalizing proteins and peptides because rapid loss of label occurs after lysosomal processing when these molecules are labeled using conventional radioiodination methodologies. We have developed a radiolabeled prosthetic group that contains multiple negatively charged D-amino acids to facilitate trapping of the radioactivity in the cell after proteolysis of the labeled protein. N ε -(3-[ 125 I]iodobenzoyl-Lys 5 -N α -maleimido-Gly 1 -GEEEK ([ 125 I]IB-Mal-D- GEEEK) was synthesized via iododestannylation in 90.3 ± 3.9% radiochemical yields. This radioiodinated agent was conjugated to iminothiolane-treated L8A4, an anti-epidermal growth factor receptor variant III (EGFRvIII) specific monoclonal antibody (mAb) in 54.3 ± 17.7% conjugation yields. In vitro assays with the EGFRvIII-expressing U87MGΔEGFR glioma cell line demonstrated that the internalized radioactivity for the [ 125 I]IB-Mal-D-GEEEK-L8A4 conjugate increased from 14.1% at 1 h to 44.7% at 24 h and was about 15-fold higher than that of directly radioiodinated L8A4 at 24 h. A commensurately increased tumor uptake in vivo in athymic mice bearing subcutaneous U87MGΔEGFR xenografts (52.6 ± 14.3% injected dose per gram versus 17.4 ± 3.5% ID/g at 72 h) also was observed. These results suggest that [ 125 I]IB-Mal-D-GEEEK is a promising reagent for the radioiodination of internalizing mAbs. © 2006 American Chemical Society.

Authors
Vaidyanathan, G; Alston, KL; Bigner, DD; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Alston, KL, Bigner, DD, and Zalutsky, MR. "Nε-(3[*I]iodobenzoyl)-Lys5-N α-maleimido-Gly1-GEEEK([*I]IB-Mal-D-GEEEK): A radioiodinated prosthetic group containing negatively charged D-glutamates for labeling internalizing monoclonal antibodies." Bioconjugate Chemistry 17.4 (July 1, 2006): 1085-1092.
Source
scopus
Published In
Bioconjugate Chemistry
Volume
17
Issue
4
Publish Date
2006
Start Page
1085
End Page
1092
DOI
10.1021/bc0600766

Nepsilon-(3-[*I]Iodobenzoyl)-Lys5-Nalpha-maleimido-Gly1-GEEEK ([*I]IB-Mal-D-GEEEK): a radioiodinated prosthetic group containing negatively charged D-glutamates for labeling internalizing monoclonal antibodies.

Novel methods are needed for the radiohalogenation of cell-internalizing proteins and peptides because rapid loss of label occurs after lysosomal processing when these molecules are labeled using conventional radioiodination methodologies. We have developed a radiolabeled prosthetic group that contains multiple negatively charged D-amino acids to facilitate trapping of the radioactivity in the cell after proteolysis of the labeled protein. N(epsilon)-(3-[(125)I]iodobenzoyl)-Lys(5)-N(alpha)-maleimido-Gly(1)-GEEEK ([(125)I]IB-Mal-D-GEEEK) was synthesized via iododestannylation in 90.3 +/- 3.9% radiochemical yields. This radioiodinated agent was conjugated to iminothiolane-treated L8A4, an anti-epidermal growth factor receptor variant III (EGFRvIII) specific monoclonal antibody (mAb) in 54.3 +/- 17.7% conjugation yields. In vitro assays with the EGFRvIII-expressing U87MGDeltaEGFR glioma cell line demonstrated that the internalized radioactivity for the [(125)I]IB-Mal-D-GEEEK-L8A4 conjugate increased from 14.1% at 1 h to 44.7% at 24 h and was about 15-fold higher than that of directly radioiodinated L8A4 at 24 h. A commensurately increased tumor uptake in vivo in athymic mice bearing subcutaneous U87MGDeltaEGFR xenografts (52.6 +/- 14.3% injected dose per gram versus 17.4 +/- 3.5% ID/g at 72 h) also was observed. These results suggest that [(125)I]IB-Mal-d-GEEEK is a promising reagent for the radioiodination of internalizing mAbs.

Authors
Vaidyanathan, G; Alston, KL; Bigner, DD; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Alston, KL, Bigner, DD, and Zalutsky, MR. "Nepsilon-(3-[*I]Iodobenzoyl)-Lys5-Nalpha-maleimido-Gly1-GEEEK ([*I]IB-Mal-D-GEEEK): a radioiodinated prosthetic group containing negatively charged D-glutamates for labeling internalizing monoclonal antibodies." Bioconjug Chem 17.4 (July 2006): 1085-1092.
PMID
16848419
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
17
Issue
4
Publish Date
2006
Start Page
1085
End Page
1092
DOI
10.1021/bc0600766

Radiation-induced biologic bystander effect elicited in vitro by targeted radiopharmaceuticals labeled with alpha-, beta-, and auger electron-emitting radionuclides.

UNLABELLED: Recent studies have shown that indirect effects of ionizing radiation may contribute significantly to the effectiveness of radiotherapy by sterilizing malignant cells that are not directly hit by the radiation. However, there have been few investigations of the importance of indirect effects in targeted radionuclide treatment. Our purpose was to compare the induction of bystander effects by external beam gamma-radiation with those resultant from exposure to 3 radiohaloanalogs of metaiodobenzylguanidine (MIBG): (131)I-MIBG (low-linear-energy-transfer [LET] beta-emitter), (123)I-MIBG (potentially high-LET Auger electron emitter), and meta-(211)At-astatobenzylguanidine ((211)At-MABG) (high-LET alpha-emitter). METHODS: Two human tumor cell lines-UVW (glioma) and EJ138 (transitional cell carcinoma of bladder)-were transfected with the noradrenaline transporter (NAT) gene to enable active uptake of MIBG. Medium from cells that accumulated the radiopharmaceuticals or were treated with external beam radiation was transferred to cells that had not been exposed to radioactivity, and clonogenic survival was determined in donor and recipient cultures. RESULTS: Over the dose range 0-9 Gy of external beam radiation of donor cells, 2 Gy caused 30%-40% clonogenic cell kill in recipient cultures. This potency was maintained but not increased by higher dosage. In contrast, no corresponding saturation of bystander cell kill was observed after treatment with a range of activity concentrations of (131)I-MIBG, which resulted in up to 97% death of donor cells. Cellular uptake of (123)I-MIBG and (211)At-MABG induced increasing recipient cell kill up to levels that resulted in direct kill of 35%-70% of clonogens. Thereafter, the administration of higher activity concentrations of these high-LET emitters was inversely related to the kill of recipient cells. Over the range of activity concentrations examined, neither direct nor indirect kill was observed in cultures of cells not expressing the NAT and, thus, incapable of active uptake of MIBG. CONCLUSION: Potent toxins are generated specifically by cells that concentrate radiohalogenated MIBG. These may be LET dependent and distinct from those elicited by conventional radiotherapy.

Authors
Boyd, M; Ross, SC; Dorrens, J; Fullerton, NE; Tan, KW; Zalutsky, MR; Mairs, RJ
MLA Citation
Boyd, M, Ross, SC, Dorrens, J, Fullerton, NE, Tan, KW, Zalutsky, MR, and Mairs, RJ. "Radiation-induced biologic bystander effect elicited in vitro by targeted radiopharmaceuticals labeled with alpha-, beta-, and auger electron-emitting radionuclides." J Nucl Med 47.6 (June 2006): 1007-1015.
PMID
16741311
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
47
Issue
6
Publish Date
2006
Start Page
1007
End Page
1015

Novel human IgG2b/murine chimeric antitenascin monoclonal antibody construct radiolabeled with 131I and administered into the surgically created resection cavity of patients with malignant glioma: phase I trial results.

UNLABELLED: Results from animal experiments have shown that human IgG2/mouse chimeric antitenascin 81C6 (ch81C6) monoclonal antibody exhibited higher tumor accumulation and enhanced stability compared with its murine parent. Our objective was to determine the effect of these differences on the maximum tolerated dose (MTD), pharmacokinetics, dosimetry, and antitumor activity of (131)I-ch81C6 administered into the surgically created resection cavity (SCRC) of malignant glioma patients. METHODS: In this phase I trial, eligible patients received a single injection of (131)I-ch81C6 administered through a Rickham catheter into the SCRC. Patients were stratified as newly diagnosed and untreated (stratum A), newly diagnosed after external beam radiotherapy (XRT) (stratum B), and recurrent (stratum C). (131)I-ch81C6 was administered either before (stratum A) or after (stratum B) conventional XRT for newly diagnosed patients. In addition, chemotherapy was prescribed for all patients after (131)I-ch81C6 administration. Dose escalation was performed independently for each stratum. Patients were observed for toxicity and response until death or progressive disease. RESULTS: We treated 47 patients with (131)I-ch81C6 doses up to 4.44 GBq (120 mCi), including 35 with newly diagnosed tumors (strata A and B) and 12 with recurrent disease (stratum C). Dose-limiting hematologic toxicity defined the MTD to be 2.96 GBq (80 mCi) for all patients, regardless of treatment strata. Neurologic dose-limiting toxicity developed in 3 patients; however, none required further surgery to debulk radiation necrosis. Median survival was 88.6 wk and 65.0 wk for newly diagnosed and recurrent patients, respectively. CONCLUSION: The MTD of (131)I-ch81C6 is 2.96 GBq (80 mCi) because of dose-limiting hematologic toxicity. Although encouraging survival was observed, (131)I-ch81C6 was associated with greater hematologic toxicity, probably due to the enhanced stability of the IgG2 construct, than previously observed with (131)I-murine 81C6.

Authors
Reardon, DA; Quinn, JA; Akabani, G; Coleman, RE; Friedman, AH; Friedman, HS; Herndon, JE; McLendon, RE; Pegram, CN; Provenzale, JM; Dowell, JM; Rich, JN; Vredenburgh, JJ; Desjardins, A; Sampson, JH; Gururangan, S; Wong, TZ; Badruddoja, MA; Zhao, X-G; Bigner, DD; Zalutsky, MR
MLA Citation
Reardon, DA, Quinn, JA, Akabani, G, Coleman, RE, Friedman, AH, Friedman, HS, Herndon, JE, McLendon, RE, Pegram, CN, Provenzale, JM, Dowell, JM, Rich, JN, Vredenburgh, JJ, Desjardins, A, Sampson, JH, Gururangan, S, Wong, TZ, Badruddoja, MA, Zhao, X-G, Bigner, DD, and Zalutsky, MR. "Novel human IgG2b/murine chimeric antitenascin monoclonal antibody construct radiolabeled with 131I and administered into the surgically created resection cavity of patients with malignant glioma: phase I trial results." J Nucl Med 47.6 (June 2006): 912-918.
PMID
16741299
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
47
Issue
6
Publish Date
2006
Start Page
912
End Page
918

Potential of immuno-positron emission tomography for tumor imaging and immunotherapy planning.

Authors
Zalutsky, MR
MLA Citation
Zalutsky, MR. "Potential of immuno-positron emission tomography for tumor imaging and immunotherapy planning." Clin Cancer Res 12.7 Pt 1 (April 1, 2006): 1958-1960.
PMID
16609003
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
12
Issue
7 Pt 1
Publish Date
2006
Start Page
1958
End Page
1960
DOI
10.1158/1078-0432.CCR-06-0405

Molecular imaging of alkylguanine-DNA alkyltransferase: further evaluation of radioiodinated derivatives of O6-benzylguanine.

PURPOSE: An inverse correlation has been established between tumor levels of the DNA repair protein alkylguanine-DNA alkyltransferase (AGT) and a positive outcome after alkylator chemotherapy. Quantitative imaging of AGT could provide important information for patient-specific cancer treatment. Several radiolabeled analogues of O6-benzylguanine (BG), a potent AGT inactivator, have been developed and shown to be capable of labeling pure AGT protein. Herein, two of these analogues--O6-3-[*I]iodobenzylguanine ([*I]IBG) and O6-3-[*I]iodobenzyl-2'-deoxyguanosine ([*I]IBdG)--were further evaluated in two murine xenograft models. (AcO)2-[131I]IBdG, a peracetylated derivative of IBdG, also was investigated as an alternative agent. METHODS: Several biodistribution studies of radioiodinated IBG and IBdG were performed in TE-671 human rhabdomyosarcoma and DAOY human medulloblastoma murine xenograft models. Mice were treated with BG or its nucleoside analogue dBG to deplete the tumor AGT content. The effect of unlabeled IBG and that of 7,8-benzoflavone (BF), an inhibitor of the cytochrome P-450 isozyme CYP1A2, on the tumor uptake of the tracers was determined. The uptake of (AcO)2-[131I]IBdG along with that of [125I]IBdG in DAOY cells in vitro was determined in the presence and absence of a nucleoside transporter inhibitor, dipyridamole. RESULTS: Pretreatment of mice either with BG or dBG failed to reduce tumor levels of [*I]IBG or [*I]IBdG even though such treatments completely depleted tumor AGT content. Treatment of mice with BF increased tumor uptake of [125I]IBG by 56%; however, differentiation of tumors with and without AGT still was not possible. (AcO)2-[131I]IBdG, a peracetylated derivative of IBdG, had a higher uptake in vitro in DAOY tumor cells. However, its uptake, like that of [125I]IBdG, was blocked by dipyridamole. CONCLUSIONS: Taken together, these results suggest that labeled agents that are more specific for cellular AGT and that are more metabolically stable are needed.

Authors
Shankar, S; Zalutsky, MR; Friedman, H; Vaidyanathan, G
MLA Citation
Shankar, S, Zalutsky, MR, Friedman, H, and Vaidyanathan, G. "Molecular imaging of alkylguanine-DNA alkyltransferase: further evaluation of radioiodinated derivatives of O6-benzylguanine." Nucl Med Biol 33.3 (April 2006): 399-407.
PMID
16631089
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
33
Issue
3
Publish Date
2006
Start Page
399
End Page
407
DOI
10.1016/j.nucmedbio.2005.12.015

In vitro cytotoxicity of 211At-labeled trastuzumab in human breast cancer cell lines: effect of specific activity and HER2 receptor heterogeneity on survival fraction.

INTRODUCTION: Radioimmunotherapy with anti-HER2 monoclonal antibodies (mAbs) such as trastuzumab is a promising strategy for treating HER2-positive breast and ovarian carcinoma patients. The objective of this study was to determine the cytotoxic effectiveness of trastuzumab labeled with the 7.2-h half-life alpha-particle emitter 211At. METHODS: Experiments were performed on SKBr-3, BT-474 and the transfected MCF7/HER2-18 human breast carcinoma cell lines. Intrinsic radiosensitivity was determined after exposure to external beam irradiation. The cytotoxicity of 211At-labeled trastuzumab was measured by clonogenic assays. The distribution of HER2 receptor expression on the cell lines was measured using fluorescence-activated cell sorting. A pharmacokinetic (PK)/microdosimetric model was established to assess the effects of specific activity (SA), HER2 receptor expression and absorbed dose on survival fraction (SF). RESULTS: With external beam irradiation, the 2-Gy SF for BT-474, SKBr-3 and MCF7/HER2-18 cells was 0.78, 0.53 and 0.64 Gy, respectively. Heterogeneous HER2 expression was observed, with a subpopulation of cells lacking measurable receptor (14.5%, SKBr-3; 0.34%, MCF-7/HER2; 1.73%, BT-474). When plotted as a function of activity concentration, SF curves were biphasic and inversely proportional to SA; however, when the model was applied and absorbed doses calculated, the SF curve was monoexponential independent of SA. Thus, the PK model was able to demonstrate the effects of competition between cold and labeled mAb. These studies showed that the relative biological effectiveness of 211At-labeled trastuzaumab was about 10 times higher than that of external beam therapy. CONCLUSION: These in vitro studies showed that 211At-labeled trastuzumab mAb is an effective cytotoxic agent for the treatment of HER2-positive tumor cells. The SA of the labeled mAb and the homogeneity of HER2 receptor expression are important variables influencing the efficiency of cell killing.

Authors
Akabani, G; Carlin, S; Welsh, P; Zalutsky, MR
MLA Citation
Akabani, G, Carlin, S, Welsh, P, and Zalutsky, MR. "In vitro cytotoxicity of 211At-labeled trastuzumab in human breast cancer cell lines: effect of specific activity and HER2 receptor heterogeneity on survival fraction." Nucl Med Biol 33.3 (April 2006): 333-347.
PMID
16631082
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
33
Issue
3
Publish Date
2006
Start Page
333
End Page
347
DOI
10.1016/j.nucmedbio.2005.12.006

Salvage radioimmunotherapy with murine iodine-131-labeled antitenascin monoclonal antibody 81C6 for patients with recurrent primary and metastatic malignant brain tumors: phase II study results.

PURPOSE: To assess the efficacy and toxicity of intraresection cavity iodine-131-labeled murine antitenascin monoclonal antibody 81C6 (131I-m81C6) among recurrent malignant brain tumor patients. PATIENTS AND METHODS: In this phase II trial, 100 mCi of 131I-m81C6 was injected directly into the surgically created resection cavity (SCRC) of 43 patients with recurrent malignant glioma (glioblastoma multiforme [GBM], n = 33; anaplastic astrocytoma [AA], n = 6; anaplastic oligodendroglioma [AO], n = 2; gliosarcoma [GS], n = 1; and metastatic adenocarcinoma, n = 1) followed by chemotherapy. RESULTS: With a median follow-up of 172 weeks, 63% and 59% of patients with GBM/GS and AA/AO tumors were alive at 1 year. Median overall survival for patients with GBM/GS and AA/AO tumors was 64 and 99 weeks, respectively. Ten patients (23%) developed acute hematologic toxicity. Five patients (12%) developed acute reversible neurotoxicity. One patient (2%) developed irreversible neurotoxicity. No patients required reoperation for radionecrosis. CONCLUSION: In this single-institution phase II study, administration of 100 mCi of 131I-m81C6 to recurrent malignant glioma patients followed by chemotherapy is associated with a median survival that is greater than that of historical controls treated with surgery plus iodine-125 brachytherapy. Furthermore, toxicity was acceptable. Administration of a fixed millicurie dose resulted in a wide range of absorbed radiation doses to the SCRC. We are now conducting a phase II trial, approved by the US Food and Drug Administration, using patient-specific 131I-m81C6 dosing, to deliver 44 Gy to the SCRC followed by standardized chemotherapy. A phase III multicenter trial with patient-specific dosing is planned.

Authors
Reardon, DA; Akabani, G; Coleman, RE; Friedman, AH; Friedman, HS; Herndon, JE; McLendon, RE; Pegram, CN; Provenzale, JM; Quinn, JA; Rich, JN; Vredenburgh, JJ; Desjardins, A; Gururangan, S; Badruddoja, M; Dowell, JM; Wong, TZ; Zhao, X-G; Zalutsky, MR; Bigner, DD
MLA Citation
Reardon, DA, Akabani, G, Coleman, RE, Friedman, AH, Friedman, HS, Herndon, JE, McLendon, RE, Pegram, CN, Provenzale, JM, Quinn, JA, Rich, JN, Vredenburgh, JJ, Desjardins, A, Gururangan, S, Badruddoja, M, Dowell, JM, Wong, TZ, Zhao, X-G, Zalutsky, MR, and Bigner, DD. "Salvage radioimmunotherapy with murine iodine-131-labeled antitenascin monoclonal antibody 81C6 for patients with recurrent primary and metastatic malignant brain tumors: phase II study results." J Clin Oncol 24.1 (January 1, 2006): 115-122.
PMID
16382120
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
1
Publish Date
2006
Start Page
115
End Page
122
DOI
10.1200/JCO.2005.03.4082

Antiepidermal growth factor variant III scFv fragment: effect of radioiodination method on tumor targeting and normal tissue clearance.

INTRODUCTION: MR1-1 is a single-chain Fv (scFv) fragment that binds with high affinity to epidermal growth factor receptor variant III, which is overexpressed on gliomas and other tumors but is not present on normal tissues. The objective of this study was to evaluate four different methods for labeling MR1-1 scFv that had been previously investigated for the radioiodinating of an intact anti-epidermal growth factor receptor variant III (anti-EGFRvIII) monoclonal antibody (mAb) L8A4. METHODS: The MR1-1 scFv was labeled with (125)I/(131)I using the Iodogen method, and was also radiohalogenated with acylation agents bearing substituents that were positively charged--N-succinimidyl-3-[*I]iodo-5-pyridine carboxylate and N-succinimidyl-4-guanidinomethyl-3-[*I]iodobenzoate ([*I]SGMIB)--and negatively charged--N-succinimidyl-3-[*I]iodo-4-phosphonomethylbenzoate ([*I]SIPMB). In vitro internalization assays were performed with the U87MGDeltaEGFR cell line, and the tissue distribution of the radioiodinated scFv fragments was evaluated in athymic mice bearing subcutaneous U87MGDeltaEGFR xenografts. RESULTS AND CONCLUSION: As seen previously with the anti-EGFRvIII IgG mAb, retention of radioiodine activity in U87MGDeltaEGFR cells in the internalization assay was labeling method dependent, with SGMIB and SIPMB yielding the most prolonged retention. However, unlike the case with the intact mAb, the results of the internalization assays were not predictive of in vivo tumor localization capacity of the labeled scFv. Renal activity was dependent on the nature of the labeling method. With MR1-1 labeled using SIPMB, kidney uptake was highest and most prolonged; catabolism studies indicated that this uptake primarily was in the form of epsilon-N-3-[*I]iodo-4-phosphonomethylbenzoyl lysine.

Authors
Shankar, S; Vaidyanathan, G; Kuan, C-T; Bigner, DD; Zalutsky, MR
MLA Citation
Shankar, S, Vaidyanathan, G, Kuan, C-T, Bigner, DD, and Zalutsky, MR. "Antiepidermal growth factor variant III scFv fragment: effect of radioiodination method on tumor targeting and normal tissue clearance." Nucl Med Biol 33.1 (January 2006): 101-110.
PMID
16459265
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
33
Issue
1
Publish Date
2006
Start Page
101
End Page
110
DOI
10.1016/j.nucmedbio.2005.08.004

Synthesis and evaluation of glycosylated octreotate analogues labeled with radioiodine and 211At via a tin precursor.

Carbohydration of N-terminus and substitution of a threonine for the threoninol residue at the C-terminus of Tyr3-octreotide (TOC) has resulted in improved pharmacokinetics and tumor targeting of its radioiodinated derivatives. Yet, these peptides are very susceptible to in vivo deiodination due to the similarity of monoiodotyrosine (MIT) to thyroid hormone. The goal of this work was to develop octreotate analogues containing both a sugar moiety and a nontyrosine prosthetic group on which a radioiodine or 211At can be introduced. Solid-phase synthesis and subsequent modifications delivered an iodo standard of the target peptide N(alpha)-(1-deoxy-D-fructosyl)-N(epsilon)-(3-iodobenzoyl)-Lys0-octreotate (GIBLO) and the corresponding tin precursor N(alpha)-(1-deoxy-D-fructosyl)-N(epsilon)-[(3-tri-n-butylstannyl)benzoyl]-Lys0-octreotate (GTBLO). GIBLO displaced [125I]TOC from somatostatin receptor subtype 2 (SSTR2)-positive AR42J rat pancreatic tumor cell membranes with an IC50 of 0.46 +/- 0.05 nM suggesting that GIBLO retained affinity to SSTR2. GTBLO was radiohalogenated to [131I]GIBLO and N(alpha)-(1-deoxy-D-fructosyl)-N(epsilon)-(3-[211At]astatobenzoyl)-Lys0-octreotate ([211At]GABLO) in 21.2 +/- 4.9% and 46.8 +/- 9.5% radiochemical yields, respectively. From a paired-label internalization assay using D341 Med medulloblastoma cells, the maximum specific internalized radioactivity from [131I]GIBLO was 1.78 +/- 0.8% of input dose compared to 9.67 +/- 0.43% for N(alpha)-(1-deoxy-D-fructosyl)-[125I]iodo-Tyr3-octreotate ([125I]I-Gluc-TOCA). Over a 4 h period, the extent of internalization of [131I]GIBLO and [211At]GABLO was similar in this cell line. In D341 Med murine subcutaneous xenografts, the uptake of [125I]I-Gluc-TOCA at 0.5, 1 and 4 h was 21.5 +/- 4.0% ID/g, 18.8 +/- 7.7% ID/g, and 0.9 +/- 0.4% ID/g, respectively. In comparison, these values for [131I]GIBLO were 6.9 +/- 1.2% ID/g, 4.7 +/- 1.4% ID/g, and 0.8 +/- 0.5% ID/g. Both in vitro and in vivo catabolism studies did not suggest the severance of the lys0 along with its appendages from the peptide. Taken together, although GIBLO maintained affinity to SSTR2, its tumor uptake both in vitro and in vivo was substantially lower than that of I-Gluc-TOCA suggesting other factors such as net charge and overall geometry of the peptide may be important.

Authors
Vaidyanathan, G; Affleck, DJ; Schottelius, M; Wester, H; Friedman, HS; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, Schottelius, M, Wester, H, Friedman, HS, and Zalutsky, MR. "Synthesis and evaluation of glycosylated octreotate analogues labeled with radioiodine and 211At via a tin precursor." Bioconjug Chem 17.1 (January 2006): 195-203.
PMID
16417269
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
17
Issue
1
Publish Date
2006
Start Page
195
End Page
203
DOI
10.1021/bc0502560

Preparation of N-succinimidyl 3-[*I]iodobenzoate: an agent for the indirect radioiodination of proteins.

A procedure for the synthesis of N-succinimidyl 3-iodobenzoate labeled with any iodine isotope ([*I]SIB), which is an agent used in the radioiodination of proteins and peptides, from its tin precursor N-succinimidyl 3-(tri-n-butylstannyl)benzoate (STB) is described. Also included are protocols for the synthesis of an unlabeled standard of SIB and the tin precursor. Radioiododestannylation of STB using tert-butylhydroperoxide as the oxidant gives [*I]SIB in 80% radiochemical yields. The total time for the synthesis of [*I]SIB from STB is approximately 95 min. Use of [*I]SIB yields radioiodinated proteins that are considerably more stable in vivo than those radioiodinated by the direct electrophilic method.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Preparation of N-succinimidyl 3-[*I]iodobenzoate: an agent for the indirect radioiodination of proteins." Nat Protoc 1.2 (2006): 707-713.
PMID
17406300
Source
pubmed
Published In
Nature Protocols
Volume
1
Issue
2
Publish Date
2006
Start Page
707
End Page
713
DOI
10.1038/nprot.2006.99

Synthesis of N-succinimidyl 4-[18F]fluorobenzoate, an agent for labeling proteins and peptides with 18F.

This protocol describes the step-by-step procedure for the synthesis of N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB), an agent widely used for labeling proteins and peptides with the positron-emitting radionuclide 18F. The protocols for the synthesis of unlabeled SFB and the quaternary salt precursor 4-formyl-N,N,N-trimethyl benzenaminium trifluoromethane sulfonate also are described. For the [18F]SFB synthesis, the quaternary salt is first converted to 4-[18F]fluorobenzaldehyde. Oxidation of the latter provides 4-[18F]fluorobenzoic acid, which is converted to [18F]SFB by treatment with N,N-disuccinimidyl carbonate. Using this method, [18F]SFB can be synthesized in decay-corrected radiochemical yields of 30%-35% and a specific radioactivity of 11-12 GBq micromol(-1). The total synthesis and purification time required is about 80 min, starting from delivery of the [18F]fluoride. [18F]SFB remains an optimal reagent for labeling proteins and peptides with 18F because of good conjugation yields and metabolic stability.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Synthesis of N-succinimidyl 4-[18F]fluorobenzoate, an agent for labeling proteins and peptides with 18F." Nat Protoc 1.4 (2006): 1655-1661.
PMID
17487148
Source
pubmed
Published In
Nature Protocols
Volume
1
Issue
4
Publish Date
2006
Start Page
1655
End Page
1661
DOI
10.1038/nprot.2006.264

Comparison of radiohaloanalogues of meta-iodobenzylguanidine (MIBG) for a combined gene- and targeted radiotherapy approach to bladder carcinoma.

Targeted radiotherapy using radiolabelled meta-iodobenzylguanidine (MIBG) is a promising treatment option for bladder cancer, restricting the effects of radiotherapy to malignant cells thereby increasing efficacy and decreasing morbidity of radiotherapy. We investigated the efficacy of a combined gene therapy and targeted radiotherapy approach for bladder cancer using radiolabelled MIBG. The effectiveness of alternative radiohalogens and alternative preparations of radiolabelled MIBG for this therapeutic strategy were compared. Bladder cancer cells, EJ138, were transfected with a gene encoding the noradrenaline transporter (NAT) under the control of a tumour specific telomerase promoter, enabling them to actively take up radiolabelled MIBG. This resulted in tumour-specific cell kill. Uptake and retention of radioactivity in cells transfected with the NAT gene were compared with that obtained in cells transfected with the sodium iodide symporter (NIS) gene. Substantially greater uptake and longer retention of radioactivity in NAT-transfected cells was observed. Carrier-added (c.a.) [131I]MIBG, no-carrier added (n.c.a.) [131I]MIBG, and [211At]-labelled benzylguanidine (i.e. [211At] meta-astatobenzylguanidine (MABG)) were compared with respect to efficiency of induction of cell kill. N.c.a[(131)I]MIBG was more cytotoxic than c.a.[131I]MIBG. However, the alpha-emitter [211At]MABG was, by three orders of magnitude, more effective in causing tumour cell kill than the beta-emitter [131I]MIBG. We conclude that NAT gene transfer combined with the administration of n.c.a.[131I]MIBG or [211At]MABG, is a promising novel treatment approach for bladder cancer therapy.

Authors
Fullerton, NE; Boyd, M; Ross, SC; Pimlott, SL; Babich, J; Kirk, D; Zalutsky, MR; Mairs, RJ
MLA Citation
Fullerton, NE, Boyd, M, Ross, SC, Pimlott, SL, Babich, J, Kirk, D, Zalutsky, MR, and Mairs, RJ. "Comparison of radiohaloanalogues of meta-iodobenzylguanidine (MIBG) for a combined gene- and targeted radiotherapy approach to bladder carcinoma." Med Chem 1.6 (November 2005): 611-618.
PMID
16787344
Source
pubmed
Published In
Medicinal chemistry (Shariqah (United Arab Emirates))
Volume
1
Issue
6
Publish Date
2005
Start Page
611
End Page
618

Radiopharmaceutical chemistry of targeted radiotherapeutics, Part 2: radiolytic effects of 211At alpha-particles influence N-succinimidyl 3-211AT-astatobenzoate synthesis.

UNLABELLED: A variety of promising targeted radiotherapeutics labeled with alpha-emitters have been developed. Clinical investigation of these radiopharmaceuticals requires the production of high activity levels, which can be hindered by alpha-particle-mediated radiolytic effects on labeling chemistry. The purpose of this study was to investigate the effects of radiation dose on the synthesis of N-succinimidyl 3-(211)At-astatobenzoate (SAB), a compound used in our clinical trials for labeling antibodies with alpha-particle-emitting (211)At. METHODS: Yields for the synthesis of SAB as a function of the radiation dose received by the reaction medium were determined. The variables studied included the radiohalogenation precursors N-succinimidyl 3-(tri-n-butylstannyl)benzoate (BuSTB) and N-succinimidyl 3-(trimethylstannyl)benzoate (MeSTB); the solvents chloroform, benzene, and methanol; and the addition of acetic acid and the oxidant N-chlorosuccinimide. The (211)At product spectra were determined from high-performance liquid chromatograms and then plotted against radiation dose. RESULTS: SAB production declined rapidly with increasing dose, consistent with the documented radiolytic decomposition of BuSTB and MeSTB in chloroform. Even though these tin precursors were not appreciably degraded in benzene, SAB could not be produced in this solvent; instead, highly lipophilic (211)At-labeled species were generated in nearly quantitative yields. Although a dose-dependent decline in SAB yield also was observed in methanol, both in the presence and in the absence of an oxidant, the results were better than those obtained with the other solvents. An unexpected observation was that SAB could be obtained at a yield of greater than 30% when the reaction was run in methanol without the addition of acetic acid or an oxidant; these 2 components previously were considered essential for astatodestannylation. CONCLUSION: Radiolytic factors can play an important role in the synthesis of clinical-level activities of (211)At-labeled radiopharmaceuticals, necessitating the development of reaction conditions different from those that are used successfully at lower activity levels.

Authors
Pozzi, OR; Zalutsky, MR
MLA Citation
Pozzi, OR, and Zalutsky, MR. "Radiopharmaceutical chemistry of targeted radiotherapeutics, Part 2: radiolytic effects of 211At alpha-particles influence N-succinimidyl 3-211AT-astatobenzoate synthesis." J Nucl Med 46.8 (August 2005): 1393-1400.
PMID
16085599
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
46
Issue
8
Publish Date
2005
Start Page
1393
End Page
1400

Pre-clinical evaluation of D2C7, a monoclonal antibody reactive for both the wild type and variant III mutant epidermal growth factor receptor, for radioimmunotherapy of malignant gliomas

Authors
Boskovitz, A; Pegram, C; Peixoto, K; Zalutsky, MR; Bigner, DD
MLA Citation
Boskovitz, A, Pegram, C, Peixoto, K, Zalutsky, MR, and Bigner, DD. "Pre-clinical evaluation of D2C7, a monoclonal antibody reactive for both the wild type and variant III mutant epidermal growth factor receptor, for radioimmunotherapy of malignant gliomas." July 2005.
Source
wos-lite
Published In
Neuro-Oncology
Volume
7
Issue
3
Publish Date
2005
Start Page
370
End Page
370

Enhanced cellular retention of an internalizing anti-EGFRvIII monoclonal antibody radioiodinated using LYS5-[*I]iodobenzoyl Gly(1)-maleimido GEEEK ([*I]IB-Mal-D-GEEEK), a prosthetic group containing negatively charged D-glutamates

Authors
Vaidyanathan, G; Alston, KL; Welsh, PC; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Alston, KL, Welsh, PC, and Zalutsky, MR. "Enhanced cellular retention of an internalizing anti-EGFRvIII monoclonal antibody radioiodinated using LYS5-[*I]iodobenzoyl Gly(1)-maleimido GEEEK ([*I]IB-Mal-D-GEEEK), a prosthetic group containing negatively charged D-glutamates." July 2005.
Source
wos-lite
Published In
Neuro-Oncology
Volume
7
Issue
3
Publish Date
2005
Start Page
386
End Page
386

O6-3-[125I]iodobenzyl-2'-deoxyguanosine ([125I]IBdG): synthesis and evaluation of its usefulness as an agent for quantification of alkylguanine-DNA alkyltransferase (AGT).

The development of O(6)-(3-[(125)I]iodobenzyl)-2'-deoxyguanosine ([(125)I]IBdG), the glycosylated analogue of the O(6)-3-iodobenzylguanine (IBG), as an agent for the in vivo mapping of the DNA repair protein alkylguanine-DNA alkyltransferase (AGT) is described. Synthesis of its tin precursor, O(6)-3-trimethylstannylbenzyl-2'-deoxyguanosine (TBdG) was achieved in four steps from deoxyguanosine. Radioiodination of TBdG in a single step gave [(125)I]IBdG in 70-85% isolated radiochemical yield. [(125)I]IBdG bound specifically to pure AGT with an IC(50) of 7.1 microM. From paired-label assays, [(125)I]IBdG showed a 2- to 3-fold higher cellular uptake than [(131)I]IBG in DAOY medulloblastoma, TE-671 rhabdomyosarcoma, SK-Mel-28 melanoma, and HT-29 colon carcinoma human cell lines. Uptake of both labeled compounds in these cell lines decreased with increasing concentrations of unlabeled O(6)-benzylguanine (BG) when BG was present in the medium during incubation with the labeled compounds. Compared to BG, unlabeled IBdG diminished the uptake of [(125)I]IBdG and [(131)I]IBG in DAOY cells more efficiently (IC(50)<1 microM vs >10 microM for BG). There was no significant change in cell-bound activity of [(125)I]IBdG and [(131)I]IBG when BG was removed from the incubation medium before incubating cells with the tracers, suggesting that only a very small portion of radioactivity taken up by the cells is AGT bound. This was corroborated by gel-electrophoresis performed on extracts from cells treated with varying amounts of BG and then incubated with [(125)I]IBdG in the presence of BG. No radiolabeled AGT band was discernable by phosphor-imaging, signifying low cellular AGT binding of the radiotracer. In contrast, when cell extracts were prepared from BG pre-treated cells and aliquots were incubated with [(125)I]IBdG subsequently, the intensity of radiolabeled AGT band decreased linearly as a function of BG concentration. This suggests that the low level of [(125)I]IBdG that binds to AGT does so in a concentration dependent manner. These data suggest that IBdG is transported across the cell membrane to a higher degree than IBG. However, to be a practical tracer for quantifying cellular AGT, considerable localization of such derivatives need to occur within the cell nucleus where AGT is present predominantly.

Authors
Shankar, S; Zalutsky, MR; Vaidyanathan, G
MLA Citation
Shankar, S, Zalutsky, MR, and Vaidyanathan, G. "O6-3-[125I]iodobenzyl-2'-deoxyguanosine ([125I]IBdG): synthesis and evaluation of its usefulness as an agent for quantification of alkylguanine-DNA alkyltransferase (AGT)." Bioorg Med Chem 13.12 (June 2, 2005): 3889-3898.
PMID
15911305
Source
pubmed
Published In
Bioorganic & Medicinal Chemistry
Volume
13
Issue
12
Publish Date
2005
Start Page
3889
End Page
3898
DOI
10.1016/j.bmc.2005.04.014

Dosimetry and radiographic analysis of 131I-labeled anti-tenascin 81C6 murine monoclonal antibody in newly diagnosed patients with malignant gliomas: a phase II study.

UNLABELLED: The objective was to perform dosimetry and evaluate dose-response relationships in newly diagnosed patients with malignant brain tumors treated with direct injections of (131)I-labeled anti-tenascin murine 81C6 monoclonal antibody (mAb) into surgically created resection cavities (SCRCs) followed by conventional external-beam radiotherapy and chemotherapy. METHODS: Absorbed doses to the 2-cm-thick shell, measured from the margins of the resection cavity interface, were estimated for 33 patients with primary brain tumors. MRI/SPECT registrations were used to assess the distribution of the radiolabeled mAb in brain parenchyma. Results from biopsies obtained from 15 patients were classified as tumor, radionecrosis, or tumor and radionecrosis, and these were correlated with absorbed dose and dose rate. Also, MRI/PET registrations were used to assess radiographic progression among patients. RESULTS: This therapeutic strategy yielded a median survival of 86 and 79 wk for all patients and glioblastoma multiforme (GBM) patients, respectively. The average SCRC residence time of (131)I-mu81C6 mAb was 76 h (range, 34-169 h). The average absorbed dose to the 2-cm cavity margins was 48 Gy (range, 25-116 Gy) for all patients and 51 Gy (range, 27-116 Gy) for GBM patients. In MRI/SPECT registrations, we observed a preferential distribution of (131)I-mu81C6 mAb through regions of vasogenic edema. An analysis of the relationship between the absorbed dose and dose rate and the first biopsy results yielded a most favorable absorbed dose of 44 Gy. A correlation between decreased survival and irreversible neurotoxicity was noted. A comparative analysis, in terms of median survival, was performed with previous brachytherapy clinical studies, which showed a proportional relationship between the average boost absorbed dose and the median survival. CONCLUSION: This study shows that (131)I-mu81C6 mAb increases the median survival of GBM patients. An optimal absorbed dose of 44 Gy to the 2-cm cavity margins is suggested to reduce the incidence of neurologic toxicity. Further clinical studies are warranted to determine the effectiveness of (131)I-mu81C6 mAb based on a target dose of 44 Gy rather than a fixed administered activity.

Authors
Akabani, G; Reardon, DA; Coleman, RE; Wong, TZ; Metzler, SD; Bowsher, JE; Barboriak, DP; Provenzale, JM; Greer, KL; DeLong, D; Friedman, HS; Friedman, AH; Zhao, X-G; Pegram, CN; McLendon, RE; Bigner, DD; Zalutsky, MR
MLA Citation
Akabani, G, Reardon, DA, Coleman, RE, Wong, TZ, Metzler, SD, Bowsher, JE, Barboriak, DP, Provenzale, JM, Greer, KL, DeLong, D, Friedman, HS, Friedman, AH, Zhao, X-G, Pegram, CN, McLendon, RE, Bigner, DD, and Zalutsky, MR. "Dosimetry and radiographic analysis of 131I-labeled anti-tenascin 81C6 murine monoclonal antibody in newly diagnosed patients with malignant gliomas: a phase II study." J Nucl Med 46.6 (June 2005): 1042-1051.
PMID
15937318
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
46
Issue
6
Publish Date
2005
Start Page
1042
End Page
1051

Radiopharmaceutical chemistry of targeted radiotherapeutics, part 1: effects of solvent on the degradation of radiohalogenation precursors by 211At alpha-particles.

UNLABELLED: The high energy and short range of alpha-particles make them attractive for targeted radiotherapy. However, these properties can be problematic when the production of high activity levels of alpha-particle-emitting radiotherapeutics is required. For example, difficulties were encountered in the production of N-succinimidyl 3-[211At]-astatobenzoate (SAB), when 370-MBq doses of 211At-labeled antibody were required. The purpose of this study was to investigate a potential cause of this behavior--radiolytic degradation of the radiohalogenation precursor. METHODS: Both N-succinimidyl 3-(tri-n-butylstannyl)benzoate (BuSTB) and N-succinimidyl 3-trimethylstannylbenzoate (MeSTB) were incubated with various 211At time-activity combinations such that the radiation dose received by the reaction medium ranged from about 0 to 20,000 Gy. Studies were performed using chloroform, methanol, and benzene as the solvent, and both at neutral pH and at a pH of approximately 5.5, as used in SAB synthesis. The fraction of tin precursor remaining and the generation of unlabeled byproducts were determined from high-performance liquid chromatograms and then plotted against radiation dose. RESULTS: Extensive radiolytic decomposition of BuSTB and MeSTB was observed in chloroform, with 50% degradation taking place even at doses below 500 Gy. Formation of a byproduct, most likely N-succinimidyl 3-chlorobenzoate, increased with radiation dose. A greater degree of stability was seen in both methanol and benzene, with more than 85% of the precursor remaining at 3,500 Gy. No cold byproducts were observed with either solvent. CONCLUSION: The nature of the solvent profoundly influences the ability to synthesize high activity levels of SAB and possibly other 211At-labeled radiopharmaceuticals.

Authors
Pozzi, OR; Zalutsky, MR
MLA Citation
Pozzi, OR, and Zalutsky, MR. "Radiopharmaceutical chemistry of targeted radiotherapeutics, part 1: effects of solvent on the degradation of radiohalogenation precursors by 211At alpha-particles." J Nucl Med 46.4 (April 2005): 700-706.
PMID
15809494
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
46
Issue
4
Publish Date
2005
Start Page
700
End Page
706

0(6)-{4-(3-[F-18]fluoropropyl)-benzyl}-2 '-deoxyguanosine ([F-18]FPBdG) - Synthesis and evaluation of a potential DNA repair protein 0(6)-alkyguanine-DNA alkyltransferase (AGT) imaging agent.

Authors
Vaidyanathan, G; Base, K; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Base, K, and Zalutsky, MR. "0(6)-{4-(3-[F-18]fluoropropyl)-benzyl}-2 '-deoxyguanosine ([F-18]FPBdG) - Synthesis and evaluation of a potential DNA repair protein 0(6)-alkyguanine-DNA alkyltransferase (AGT) imaging agent." March 13, 2005.
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
229
Publish Date
2005
Start Page
U182
End Page
U182

No-carrier-added synthesis of a 4-methyl-substituted meta-iodobenzylguanidine analogue.

Radioiodinated meta-iodobenzylguanidine (MIBG) is used in the diagnosis and therapy of various neuroendocrine tumors. As a part of our efforts to develop an MIBG analogue with improved characteristics for these applications, a synthesis of 3-[131I]iodo-4-methylbenzylguanidine ([131I]MeIBG) was developed. Unlabeled MeIBG and the tin precursor, N, N'-(bis-tert-butyloxycarbonyl)-N-(4-methyl-3-trimethylstannylbenzyl) guanidine were synthesized in two steps from 3-iodo-4-methylbenzylalcohol. Radioiodinated MeIBG was synthesized at a no-carrier-added level by the iododestannylation of the tin precursor in about 85% radiochemical yield. The accumulation of [131I]MeIBG (38.9+/-3.0% of input counts) by human neuroblastoma SK-N-SH cells in vitro was 87% that of [125I]MIBG (44.5+/-3.0%) and a number of Uptake-1 inhibiting conditions reduced the uptake of both tracers in this cell line to a similar degree suggesting that introduction of a methyl substituent at the 4-position of MIBG did not adversely affect its biological characteristics.

Authors
Vaidyanathan, G; Affleck, DJ; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, and Zalutsky, MR. "No-carrier-added synthesis of a 4-methyl-substituted meta-iodobenzylguanidine analogue." Appl Radiat Isot 62.3 (March 2005): 435-440.
PMID
15607920
Source
pubmed
Published In
Applied Radiation and Isotopes
Volume
62
Issue
3
Publish Date
2005
Start Page
435
End Page
440
DOI
10.1016/j.apradiso.2004.07.001

Enhanced tumour uptake of radiolabelled antibodies by hyperthermia. Part II: Application of the thermal equivalency equation.

Clinical application of local hyperthermia as a means for modulating drug and macro-molecular tumour uptake have been slow to develop, due in part to the difficulty in designing and comparing heating protocols. The thermal isodose formula developed by Sapareto and Dewey is used in cytotoxicity and radiosensitization hyperthermia protocols to compare different time/temperature combinations; however, its relevance to other end-points has not been evaluated. The current study was undertaken to determine whether heating protocols of different time and temperature, but predicted to be thermally equivalent by this formula, had similar effects on the tumour and normal tissue distribution of radiolabelled tumour-specific (anti-tenascin 81C6) and non-specific (anti-dansyl TPS3.2) monoclonal antibodies (mAbs). Two thermally equivalent heating protocols, 4 h at 41.8 degrees C and 45 min at 43 degrees C, were compared in mice with subcutaneous D54 MG human glioma xenografts. A 4-fold increase in xenograft localization of 81C6 mAb was achieved relative to that in non-heated control groups with both heating protocols. Both hyperthermia protocols also resulted in improved tumour:normal tissue ratios. However, differences in absolute tumour and normal tissue uptake were seen, suggesting that the thermal isodose formula has limited usefulness in the design and comparison of hyperthermia protocols for enhancing the tumour uptake of radiolabelled mAbs.

Authors
Hauck, ML; Zalutsky, MR
MLA Citation
Hauck, ML, and Zalutsky, MR. "Enhanced tumour uptake of radiolabelled antibodies by hyperthermia. Part II: Application of the thermal equivalency equation." Int J Hyperthermia 21.1 (February 2005): 13-27.
PMID
15764348
Source
pubmed
Published In
International Journal of Hyperthermia (Informa)
Volume
21
Issue
1
Publish Date
2005
Start Page
13
End Page
27
DOI
10.1080/02656730400011032

Enhanced tumour uptake of radiolabelled antibodies by hyperthermia: Part I: Timing of injection relative to hyperthermia.

Improving drug and macromolecular delivery of anti-cancer agents to tumours results in greater efficacy without increased toxicity. The current study was undertaken to assess the effects of the timing of injection of tumour specific and non-specific monoclonal antibodies (mAbs) relative to a hyperthermia treatment on tumour and normal tissue uptake. Using a local hyperthermia protocol of 45 min at 43 degrees C, uptake in tumour and normal tissues was measured at 1, 4, 12, 24, 48 and 72 h after injection. An anti-tenascin chimeric mAb, ch81C6, served as the specific mAb in a D-54 MG glioma xenograft mouse model. The chimeric mAb chTPS3.2 served as the control. A five-to-eight-fold increase in uptake of the tumour-targeted mAb was achieved in the heated tumours when compared with the non-heated tumours at 1 h. Differences in absolute tumour uptake of the specific mAb between the mice injected prior to hyperthermia and mice injected post-hyperthermia were seen only at 1 and 12 h. The median uptakes in the tumours of mice injected pre-heat were 25%ID/g at 1 h and 43.5%ID/g at 12 h, while in the animals injected post-hyperthermia the median uptakes were 45.5%ID/g and 80.2%ID/g, respectively. Blood levels of both the specific and non-specific mAbs were consistently higher over the initial 12 h period in the mice injected post-hyperthermia. Normal tissue uptake was also increased at most time points in the mice injected post-hyperthermia. The clinical importance of the differences in specific mAb uptake in tumour detected statistically at 1 and 12 h is questionable, given the highly variable nature of mAb uptake in vivo. Tumour targeting mAbs administered in combination with heat may be injected either prior to or immediately following hyperthermia treatment, with the expectation that levels of uptake in tumour will be relatively equivalent. Absolute normal tissue levels will be higher in patients receiving the mAb post-hyperthermia.

Authors
Hauck, ML; Zalutsky, MR
MLA Citation
Hauck, ML, and Zalutsky, MR. "Enhanced tumour uptake of radiolabelled antibodies by hyperthermia: Part I: Timing of injection relative to hyperthermia." Int J Hyperthermia 21.1 (February 2005): 1-11.
PMID
15764347
Source
pubmed
Published In
International Journal of Hyperthermia (Informa)
Volume
21
Issue
1
Publish Date
2005
Start Page
1
End Page
11
DOI
10.1080/02656730410001695906

Current status of therapy of solid tumors: brain tumor therapy.

Treatment of malignant brain tumors with conventional approaches is largely unsuccessful because curative doses generally cannot be delivered without excessive toxicity to normal brain. Radioimmunotherapy is emerging as an attractive alternative for glioma therapy because of the potential for more selectively irradiating tumor cells while sparing normal tissues. Several institutions are engaged in phase I and phase II trials investigating the therapeutic potential of monoclonal antibodies (mAbs) labeled with the beta-emitters (131)I and (90)Y and the alpha-emitter (211)At in patients with recurrent and newly diagnosed brain tumors. The current status of these trials will be discussed with regard to efficacy, toxicity, and future directions.

Authors
Zalutsky, MR
MLA Citation
Zalutsky, MR. "Current status of therapy of solid tumors: brain tumor therapy." J Nucl Med 46 Suppl 1 (January 2005): 151S-156S. (Review)
PMID
15653663
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
46 Suppl 1
Publish Date
2005
Start Page
151S
End Page
156S

Radioiodine and 211At-labeled guanidinomethyl halobenzoyl octreotate conjugates: potential peptide radiotherapeutics for somatostatin receptor-positive cancers.

Derivatives of the somatostatin analogues octreotide and octreotate labeled with radioiosotopes are used in the diagnosis and therapy of somatostatin receptor (SSTR)-positive tumors. A method has been devised to synthesize {N-(4-guanidinomethyl-3-iodobenzoyl)-Phe1-octreotate (GMIBO). Receptor binding assay and scatchard analysis yielded a Kd of 4.83 +/- 0.19 nM for this peptide. Derivatives of this peptide labeled with radioiodine ([*I]GMIBO) and the alpha-particle-emitting radiohalogen 211At N-(3-[211At]astato-4-guanidinomethylbenzoyl)-Phe1-octreotate; [211At]AGMBO} were prepared in a single step from a tin precursor in radiochemical yields of 30-35% and 15-20%, respectively. Paired-label internalization assays performed with the SSTR-positive D341 Med human medulloblastoma cell line demonstrated that [125I]GMIBO and [211At]AGMBO were specifically internalized 20-40% more than Nalpha-(1-deoxy-D-fructosyl)-[131I]I-Tyr3-octreotate ([131I]I-Glu-TOCA), the radioiodinated octreotide derivative previously shown to exhibit maximum internalization in this cell line. Uptake of [131I]GMIBO in D341 Med subcutaneous xenografts in a murine model (8.34 +/- 1.82 versus 8.10 +/- 2.23% ID/g at 1h) and SSTR-expressing normal tissues was comparable to that of [125I]I-Glu-TOCA and was shown to be specific. However, the uptake of [131I]GMIBO also was substantially higher in liver (16.9 +/- 3.15 versus 1.39 +/- 0.45% ID/g at 1 h) and in kidneys (44.33 +/- 6.47 versus 3.44 +/- 0.68% ID/g at 1h) compared to that of [125I]I-Glu-TOCA. These data suggest that these novel peptide conjugates retain their specificity for SSTR both in vitro and in vivo; however, because of their higher accumulation in normal tissues they would be best applied in settings amenable to loco-regional administration such as medulloblastoma neoplastic meningitis.

Authors
Vaidyanathan, G; Boskovitz, A; Shankar, S; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Boskovitz, A, Shankar, S, and Zalutsky, MR. "Radioiodine and 211At-labeled guanidinomethyl halobenzoyl octreotate conjugates: potential peptide radiotherapeutics for somatostatin receptor-positive cancers." Peptides 25.12 (December 2004): 2087-2097.
PMID
15572196
Source
pubmed
Published In
Peptides
Volume
25
Issue
12
Publish Date
2004
Start Page
2087
End Page
2097
DOI
10.1016/j.peptides.2004.08.018

Radioimmunotherapy with alpha-particle emitting radionuclides.

An important consideration in the development of effective strategies for radioimmunotherapy is the nature of the radiation emitted by the radionuclide. Radionuclides decaying by the emission of alpha-particles offer the possibility of matching the cell specific reactivity of monoclonal antibodies with radiation with a range of only a few cell diameters. Furthermore, alpha-particles have important biological advantages compared with external beam radiation and beta-particles including a higher biological effectiveness, which is nearly independent of oxygen concentration, dose rate and cell cycle position. In this review, the clinical settings most likely to benefit from alpha-particle radioimmunotherapy will be discussed. The current status of preclinical and clinical research with antibodies labeled with 3 promising alpha-particle emitting radionuclides - (213)Bi, (225)Ac, and (211)At - also will be summarized.

Authors
Zalutsky, MR; Pozzi, OR
MLA Citation
Zalutsky, MR, and Pozzi, OR. "Radioimmunotherapy with alpha-particle emitting radionuclides." Q J Nucl Med Mol Imaging 48.4 (December 2004): 289-296. (Review)
PMID
15640792
Source
pubmed
Published In
The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of...
Volume
48
Issue
4
Publish Date
2004
Start Page
289
End Page
296

A 4-methyl-substituted meta-iodobenzylguanidine analogue with prolonged retention in human neuroblastoma cells.

PURPOSE: As a part of our efforts to develop a meta-iodobenzylguanidine (MIBG) analogue with improved characteristics for the diagnosis and treatment of neuroendocrine tumours, 3-[131I]iodo-4-methyl-benzylguanidine ([131I]MeIBG) has been developed. The purpose of this study was to evaluate [131I]MeIBG in vitro using the uptake-1 positive SK-N-SH neuroblastoma cell line and in vivo in normal mice and mice bearing human neuroblastoma xenografts. METHODS: The ability of SK-N-SH human neuroblastoma cells to retain [131I]MeIBG in vitro over a period of 4 days, in comparison to [125I]MIBG, was determined by a paired-label assay. Paired-label biodistributions of [131I]MeIBG and [125I]MIBG were performed in normal mice as well as in athymic mice bearing SK-N-SH and IMR-32 human neuroblastoma xenografts. RESULTS: Retention of [131I]MeIBG by SK-N-SH cells in vitro was increased by factors of 1.2, 1.5, 2.0, 2.5 and 3.1 compared with [125I]MIBG at 8, 24, 48, 72 and 96 h, respectively. In normal mice, the uptake of [131I]MeIBG in the heart was similar to that of [125I]MIBG at 1 and 4 h; in contrast, myocardial uptake of [131I]MeIBG was 1.6-fold higher than that of [125I]MIBG (p<0.05) at 24 h. When mice were pre-treated with the uptake-1 inhibitor desipramine (DMI), the heart uptake of both tracers was reduced to about half that in untreated controls at 1 h post injection (p<0.05). The hepatic uptake of [131I]MeIBG was two- to threefold lower than that of [125I]MIBG. On the other hand, blood levels of [131I]MeIBG were substantially higher (up to sixfold), especially at early time points. Uptake of [131I]MeIBG in heart and tumour at 1 h in the murine SK-N-SH model was specific and comparable to that of [125I]MIBG. However, [131I]MeIBG uptake was 1.6- to 1.7-fold lower than that of [125I]MIBG over 4-48 h. While the uptake of both tracers in IMR32 xenografts was similar, it was not uptake-1 mediated. CONCLUSION: Introduction of a methyl group at the 4-position of MIBG seems to be advantageous in terms of higher tumour retention in vitro and lower hepatic uptake in vivo. However, the slower blood clearance of MeIBG may be problematic for some applications.

Authors
Vaidyanathan, G; Welsh, PC; Vitorello, KC; Snyder, S; Friedman, HS; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Welsh, PC, Vitorello, KC, Snyder, S, Friedman, HS, and Zalutsky, MR. "A 4-methyl-substituted meta-iodobenzylguanidine analogue with prolonged retention in human neuroblastoma cells." Eur J Nucl Med Mol Imaging 31.10 (October 2004): 1362-1370.
PMID
15205923
Source
pubmed
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
31
Issue
10
Publish Date
2004
Start Page
1362
End Page
1370
DOI
10.1007/s00259-004-1596-8

Evaluation of an internalizing monoclonal antibody labeled using N-succinimidyl 3-[131I]iodo-4-phosphonomethylbenzoate ([131I]SIPMB), a negatively charged substituent bearing acylation agent.

Monoclonal antibodies such as L8A4, reactive with the epidermal growth factor receptor variant III, internalize after receptor binding resulting in proteolytic degradation by lysosomes. Labeling internalizing mAbs requires the use of methodologies that result in the trapping of labeled catabolites in tumor cells after intracellular processing. Herein we have investigated the potential utility of N-succinimidyl-3-[131I]iodo-4-phosphonomethylbenzoate ([131I]SIPMB), an acylation agent that couples the corresponding negatively charged acid [131I]IPMBA to the protein, for this purpose. Biodistribution studies demonstrated that [131I]IPMBA cleared rapidly from normal tissues and exhibited thyroid levels < or =0.1% injected dose, consistent with a low degree of dehalogenation. Biodistribution experiments in athymic mice bearing subcutaneous D-256 human glioma xenografts were performed to compare L8A4 labeled using [131I]SIPMB to L8A4 labeled with 125I using both the analogous positively charged acylation agent N-succinimidyl-4-guanidinomethyl-3-[125I]iodobenzoate ([125I]SGMIB) and Iodogen. Tumor uptake of [131I]SIPMB-L8A4 (41.9+/-3.5% ID/g) was nearly threefold that of L8A4 labeled using Iodogen (14.0+/-1.1% ID/g) after 2 days, and tumor to tissue ratios remained uniformly high throughout with [131I]SIPMB-L8A4. Thyroid uptake increased for the Iodogen labeled mAb (3.55+/-0.36 %ID at 5 days) whereas that of [131I]SIPMB labeled mAb remained low (0.21+/-0.04% ID at 5 days). In the second biodistribution, L8A4 labeled using [131I]SIPMB and [125I]SGMIB showed no difference in normal tissue uptake and had nearly identical tumor uptake ([131I]SIPMB, 41.8+/-14.2% ID/g; [125I]SGMIB, 41.6+/-15.8% ID/g, at 4 days). These results suggest that [131I]SIPMB may be a viable acylation agent for the radioiodination of internalizing mAbs.

Authors
Shankar, S; Vaidyanathan, G; Affleck, DJ; Peixoto, K; Bigner, DD; Zalutsky, MR
MLA Citation
Shankar, S, Vaidyanathan, G, Affleck, DJ, Peixoto, K, Bigner, DD, and Zalutsky, MR. "Evaluation of an internalizing monoclonal antibody labeled using N-succinimidyl 3-[131I]iodo-4-phosphonomethylbenzoate ([131I]SIPMB), a negatively charged substituent bearing acylation agent." Nucl Med Biol 31.7 (October 2004): 909-919.
PMID
15464393
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
31
Issue
7
Publish Date
2004
Start Page
909
End Page
919
DOI
10.1016/j.nucmedbio.2004.04.007

Medulloblastoma neoplastic meningitis targeted radiotherapy with intrathecal alpha-emitter At-211-labeled thymidine analogue

Authors
Boskovitz, A; Vaidyanathan, G; Archer, GE; Ochiai, H; Okamura, T; Sampson, JH; Bigner, DD; Zalutsky, MR
MLA Citation
Boskovitz, A, Vaidyanathan, G, Archer, GE, Ochiai, H, Okamura, T, Sampson, JH, Bigner, DD, and Zalutsky, MR. "Medulloblastoma neoplastic meningitis targeted radiotherapy with intrathecal alpha-emitter At-211-labeled thymidine analogue." October 2004.
Source
wos-lite
Published In
Neuro-Oncology
Volume
6
Issue
4
Publish Date
2004
Start Page
403
End Page
403

Monoclonal antibodies (MABS) against somatostatin receptor 2A (SSTR2A) as potential medulloblastoma therapeutic reagents

Authors
Kuan, CT; Wikstrand, CJ; Davis, TS; Zalutsky, MR; Bigner, DD
MLA Citation
Kuan, CT, Wikstrand, CJ, Davis, TS, Zalutsky, MR, and Bigner, DD. "Monoclonal antibodies (MABS) against somatostatin receptor 2A (SSTR2A) as potential medulloblastoma therapeutic reagents." October 2004.
Source
wos-lite
Published In
Neuro-Oncology
Volume
6
Issue
4
Publish Date
2004
Start Page
409
End Page
409

Somatostatin targeted radiotherapeuiccs for medulloblastoma

Authors
Vaidyanathan, G; Boskovitz, A; Friedman, HS; Affleck, DJ; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Boskovitz, A, Friedman, HS, Affleck, DJ, and Zalutsky, MR. "Somatostatin targeted radiotherapeuiccs for medulloblastoma." October 2004.
Source
wos-lite
Published In
Neuro-Oncology
Volume
6
Issue
4
Publish Date
2004
Start Page
416
End Page
416

Monoclonal antibodies for brain tumour treatment.

Conventional treatment of brain tumours includes surgical, radiotherapeutic and chemotherapeutic modalities. Nonetheless, the outcome of patients with brain tumours, in particular glioblastoma, remains poor. Immunotherapy with armed or unarmed monoclonal antibodies targeting tumour-specific antigens has emerged in the last two decades as a novel potential adjuvant treatment for all types of neoplasia. Many challenges to its implementation as a safe and viable therapy for brain tumours still need to be addressed; nevertheless, results from ongoing Phase I/II clinical trials are encouraging, as disease stabilisation and patient survival prolongation have been observed. Advances in preclinical and clinical research indicate that treatment of brain tumours with monoclonal antibodies can be increasingly adjusted to the characteristics of the targeted tumour and its environment. This aspect relies on the careful selection of the target antigen and corresponding specific monoclonal antibody, and antibody format (size, class, affinity), conjugation to the appropriate toxin or radioactive isotope (half-life, range), and proper compartmental administration.

Authors
Boskovitz, A; Wikstrand, CJ; Kuan, C-T; Zalutsky, MR; Reardon, DA; Bigner, DD
MLA Citation
Boskovitz, A, Wikstrand, CJ, Kuan, C-T, Zalutsky, MR, Reardon, DA, and Bigner, DD. "Monoclonal antibodies for brain tumour treatment." Expert Opin Biol Ther 4.9 (September 2004): 1453-1471. (Review)
PMID
15335313
Source
pubmed
Published In
Expert Opinion on Biological Therapy
Volume
4
Issue
9
Publish Date
2004
Start Page
1453
End Page
1471
DOI
10.1517/14712598.4.9.1453

Catabolism of 4-fluoro-3-iodobenzylguanidine and meta-iodobenzylguanidine by SK-N-SH neuroblastoma cells.

BACKGROUND: A fluorine substituted derivative of meta-iodobenzylguanidine (MIBG), 4-fluoro-3-iodobenzylguanidine (FIBG), is retained in SK-N-SH human neuroblastoma cells in vitro to a higher degree than the MIBG. METHOD: To investigate whether the higher retention of FIBG is due to differences in the catabolic degradation of the two tracers, in vitro paired-label studies were performed using SK-N-SH cells. RESULTS: No detectable amount of benzyl amines, benzoic acids or hippuran derivatives, potential catabolites of these tracers, were seen in either case. Even after 48 h, the cell culture supernatants contained exclusively intact I-MIBG and I-FIBG. In contrast, in some cases, HPLC analysis of cell lysates indicated the presence of a very polar compound(s) as the predominant species with smaller quantities of intact tracers. The per cent total radioactivity in the lysate at each time point that was associated with intact I-FIBG was (average [range]) 25.4% [20.3-30.5], 22.5% [19.3-25.6], and 18.8% [14.3-23.3], at 0 h, 24 h and 48 h, respectively. The corresponding values for I-MIBG were 24.3% [21.0-27.5], 19.1% [11.7-26.5] and 17.4% [14.6-20.1]. No significant amount of activity was associated with high molecular weight species for either halobenzylguanidine, indicating that protein binding was not a major factor.

Authors
Vaidyanathan, G; Affleck, DJ; Alston, KL; Welsh, P; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, Alston, KL, Welsh, P, and Zalutsky, MR. "Catabolism of 4-fluoro-3-iodobenzylguanidine and meta-iodobenzylguanidine by SK-N-SH neuroblastoma cells." Nucl Med Commun 25.9 (September 2004): 947-955.
PMID
15319601
Source
pubmed
Published In
Nuclear Medicine Communications
Volume
25
Issue
9
Publish Date
2004
Start Page
947
End Page
955

Investigation of cell kill in a targeted radiotherapy/gene therapy strategy utilising radiation induced biological bystander effects

Authors
Boyd, M; Tan, KW; Ross, SC; Dorrens, J; Zalutsky, MR; Mairs, RJ
MLA Citation
Boyd, M, Tan, KW, Ross, SC, Dorrens, J, Zalutsky, MR, and Mairs, RJ. "Investigation of cell kill in a targeted radiotherapy/gene therapy strategy utilising radiation induced biological bystander effects." September 2004.
Source
wos-lite
Published In
The Journal of Gene Medicine
Volume
6
Issue
9
Publish Date
2004
Start Page
S30
End Page
S30

Enhancement of targeted radiotherapy in neuroblastoma: a novel gene therapy approach

Authors
Cosimo, E; Boyd, M; McCluskey, A; Robson, T; Zalutsky, MR; Mairs, RJ; Grp, TT
MLA Citation
Cosimo, E, Boyd, M, McCluskey, A, Robson, T, Zalutsky, MR, Mairs, RJ, and Grp, TT. "Enhancement of targeted radiotherapy in neuroblastoma: a novel gene therapy approach." September 2004.
Source
wos-lite
Published In
The Journal of Gene Medicine
Volume
6
Issue
9
Publish Date
2004
Start Page
S27
End Page
S27

A tumour specific targeted radiotherapy/gene therapy for the treatment of malignant disease

Authors
Boyd, M; Mairs, RJ; Ross, S; Dorrens, J; Zalutsky, MR
MLA Citation
Boyd, M, Mairs, RJ, Ross, S, Dorrens, J, and Zalutsky, MR. "A tumour specific targeted radiotherapy/gene therapy for the treatment of malignant disease." September 2004.
Source
wos-lite
Published In
The Journal of Gene Medicine
Volume
6
Issue
9
Publish Date
2004
Start Page
S33
End Page
S34

Phase 1 trial study of 131I-labeled chimeric 81C6 monoclonal antibody for the treatment of patients with non-Hodgkin lymphoma.

We report a phase 1 study of pharmacokinetics, dosimetry, toxicity, and response of (131)I anti-tenascin chimeric 81C6 for the treatment of lymphoma. Nine patients received a dosimetric dose of 370 MBq (10 mCi). Three patients received an administered activity of 1480 MBq (40 mCi), and 2 developed hematologic toxicity that required stem cell infusion. Six patients received an administered activity of 1110 MBq (30 mCi), and 2 developed toxicity that required stem cell infusion. The clearance of whole-body activity was monoexponential with a mean effective half-life of 110 hours (range, 90-136 hours) and a mean effective whole-body residence time of 159 hours (range, 130-196 hours). There was rapid uptake within the viscera; however, tumor uptake was slower. Activity in normal viscera decreased proportional to the whole body; however, tumor sites presented a slow clearance (T(1/2), 86-191 hours). The mean absorbed dose to whole-body was 67 cGy (range, 51-89 hours), whereas the dose to tumor sites was 963 cGy (range, 363-1517 cGy). Despite lack of a "blocking" antibody, 1 of 9 patients attained a complete remission and 1 a partial remission. These data demonstrate this radiopharmaceutical to be an encouraging agent for the treatment of lymphoma particularly if methods to protect the normal viscera are developed.

Authors
Rizzieri, DA; Akabani, G; Zalutsky, MR; Coleman, RE; Metzler, SD; Bowsher, JE; Toaso, B; Anderson, E; Lagoo, A; Clayton, S; Pegram, CN; Moore, JO; Gockerman, JP; DeCastro, C; Gasparetto, C; Chao, NJ; Bigner, DD
MLA Citation
Rizzieri, DA, Akabani, G, Zalutsky, MR, Coleman, RE, Metzler, SD, Bowsher, JE, Toaso, B, Anderson, E, Lagoo, A, Clayton, S, Pegram, CN, Moore, JO, Gockerman, JP, DeCastro, C, Gasparetto, C, Chao, NJ, and Bigner, DD. "Phase 1 trial study of 131I-labeled chimeric 81C6 monoclonal antibody for the treatment of patients with non-Hodgkin lymphoma." Blood 104.3 (August 1, 2004): 642-648.
PMID
15100153
Source
pubmed
Published In
Blood
Volume
104
Issue
3
Publish Date
2004
Start Page
642
End Page
648
DOI
10.1182/blood-2003-12-4264

An efficient targeted radiotherapy/gene therapy strategy utilising human telomerase promoters and radioastatine and harnessing radiation-mediated bystander effects.

BACKGROUND: Targeted radiotherapy achieves malignant cell-specific concentration of radiation dosage by tumour-affinic molecules conjugated to radioactive atoms. Combining gene therapy with targeted radiotherapy is attractive because the associated cross-fire irradiation of the latter induces biological bystander effects upon neighbouring cells overcoming low gene transfer efficiency. METHODS: We sought to maximise the tumour specificity and efficacy of noradrenaline transporter (NAT) gene transfer combined with treatment using the radiopharmaceutical meta-[(131)I]iodobenzylguanidine ([(131)I]MIBG). Cell-kill was achieved by treatment with the beta-decay particle emitter [(131)I]MIBG or the alpha-particle emitter [(211)At]MABG. We utilised our novel transfected mosaic spheroid model (TMS) to determine whether this treatment strategy could result in sterilisation of spheroids containing only a small proportion of NAT-expressing cells. RESULTS: The concentrations of [(131)I]MIBG and [(211)At]MABG required to reduce to 0.1% the survival of clonogens derived from the TMS composed of 100% of NAT gene-transfected cells were 1.5 and 0.004 MBq/ml (RSV promoter), 8.5 and 0.0075 MBq/ml (hTR promoter), and 9.0 and 0.008 MBq/ml (hTERT promoter), respectively. The concentrations of radiopharmaceutical required to reduce to 0.1% the survival of clonogens derived from 5% RSV/NAT and 5% hTERT/NAT TMS were 14 and 23 MBq/ml, respectively, for treatment with [(131)I]MIBG and 0.018 and 0.028 MBq/ml, respectively, for treatment with [(211)At]MABG. CONCLUSIONS: These results indicate that the telomerase promoters have the capacity to drive the expression of the NAT. The potency of [(211)At]MABG is approximately three orders of magnitude greater than that of [(131)I]MIBG. Spheroids composed of only 5% of cells expressing NAT under the control of the RSV or hTERT promoter were sterilised by radiopharmaceutical treatment. This observation is indicative of bystander cell-kill.

Authors
Boyd, M; Mairs, RJ; Keith, WN; Ross, SC; Welsh, P; Akabani, G; Owens, J; Vaidyanathan, G; Carruthers, R; Dorrens, J; Zalutsky, MR
MLA Citation
Boyd, M, Mairs, RJ, Keith, WN, Ross, SC, Welsh, P, Akabani, G, Owens, J, Vaidyanathan, G, Carruthers, R, Dorrens, J, and Zalutsky, MR. "An efficient targeted radiotherapy/gene therapy strategy utilising human telomerase promoters and radioastatine and harnessing radiation-mediated bystander effects." J Gene Med 6.8 (August 2004): 937-947.
PMID
15293352
Source
pubmed
Published In
The Journal of Gene Medicine
Volume
6
Issue
8
Publish Date
2004
Start Page
937
End Page
947
DOI
10.1002/jgm.578

Phase I trial study of [131]I-labeled chimeric 81C6 mAb for the treatment of patients with non-Hodgkin's lymphoma

Authors
Akabani, G; Rizzieri, DA; Zalutsky, MR; Coleman, RE; Metzler, SD; Bowsher, JE; Toaso, B; Lagoo, A; Moore, JO; Gockerman, JP; DeCastro, C; Gasparetto, C; Chao, NJ; Bigner, DD
MLA Citation
Akabani, G, Rizzieri, DA, Zalutsky, MR, Coleman, RE, Metzler, SD, Bowsher, JE, Toaso, B, Lagoo, A, Moore, JO, Gockerman, JP, DeCastro, C, Gasparetto, C, Chao, NJ, and Bigner, DD. "Phase I trial study of [131]I-labeled chimeric 81C6 mAb for the treatment of patients with non-Hodgkin's lymphoma." August 2004.
Source
wos-lite
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
31
Publish Date
2004
Start Page
S222
End Page
S222

Enhancement of targeted radiotehrapy in neuroblastoma: A novel gene therapy approach

Authors
Boyd, M; Cosimo, E; McCluskey, AG; Clark, AM; Robson, T; McCarthy, HO; Zalutsky, MR; Maits, RJ
MLA Citation
Boyd, M, Cosimo, E, McCluskey, AG, Clark, AM, Robson, T, McCarthy, HO, Zalutsky, MR, and Maits, RJ. "Enhancement of targeted radiotehrapy in neuroblastoma: A novel gene therapy approach." July 2004.
Source
wos-lite
Published In
British Journal of Cancer
Volume
91
Publish Date
2004
Start Page
S19
End Page
S19

Targeted radiotherapy of brain tumours.

The utility of external beam radiotherapy for the treatment of malignant brain tumours is compromised by the need to avoid excessive radiation damage to normal CNS tissues. This review describes the current status of targeted radiotherapy, an alternative strategy for brain tumour treatment that offers the exciting prospect of increasing the specificity of tumour cell irradiation.

Authors
Zalutsky, MR
MLA Citation
Zalutsky, MR. "Targeted radiotherapy of brain tumours." Br J Cancer 90.8 (April 19, 2004): 1469-1473. (Review)
Website
http://hdl.handle.net/10161/11048
PMID
15083170
Source
pubmed
Published In
British Journal of Cancer
Volume
90
Issue
8
Publish Date
2004
Start Page
1469
End Page
1473
DOI
10.1038/sj.bjc.6601771

Meta-iodobenzylguanidine derivatives containing a second guanidine moiety.

Radioiodinated meta-iodobenzylguanidine (MIBG) is used in the diagnosis and therapy of various neuroendocrine tumors. To investigate whether an additional guanidine function in the structure of MIBG will yield analogues that may potentially enhance tumor-to-target ratios, two derivatives-one with a guanidine moiety and another with a guanidinomethyl group at the 4-position of MIBG-were prepared. In the absence of any uptake-1 inhibiting conditions, the uptake of 4-guanidinomethyl-3-[(131)I]iodobenzylguanidine ([(131)I]GMIBG) by SK-N-SH cells in vitro was 1.7+/-0.1% of input counts, compared to a value of 40.3+/-1.4% for [(125)I[MIBG suggesting that guanidinomethyl group at the 4-position negated the biological properties of MIBG. On the other hand, 4-guanidino-3-[(131)I]iodobenzylguanidine ([(131)I]GIBG) had an uptake (5.6+/-0.3%) that was 12-13% that of [(125)I]MIBG (46.1+/-2.7%), and the ratio of uptake by control over DMI-treated (nonspecific) cultures was higher for [(131)I]GIBG (20.9+/-0.3) than [(125)I]MIBG itself (15.0+/-2.7). The exocytosis of [(131)I]GIBG and [(125)I]MIBG from SK-N-SH cells was similar. The uptake of [(131)I]GIBG in the mouse target tissues, heart and adrenals, as well as in a number of other tissues was about half that of [(125)I]MIBG. These results suggest that substitution of guanidine functions, especially a guanidinomethyl group, in MIBG structure may not be advantageous.

Authors
Vaidyanathan, G; Shankar, S; Affleck, DJ; Alston, K; Norman, J; Welsh, P; LeGrand, H; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Shankar, S, Affleck, DJ, Alston, K, Norman, J, Welsh, P, LeGrand, H, and Zalutsky, MR. "Meta-iodobenzylguanidine derivatives containing a second guanidine moiety." Bioorg Med Chem 12.7 (April 1, 2004): 1649-1656.
PMID
15028258
Source
pubmed
Published In
Bioorganic & Medicinal Chemistry
Volume
12
Issue
7
Publish Date
2004
Start Page
1649
End Page
1656
DOI
10.1016/j.bmc.2004.01.026

Human/murine chimeric 81C6 F(ab')(2) fragment: preclinical evaluation of a potential construct for the targeted radiotherapy of malignant glioma.

We have obtained encouraging responses in recent Phase I studies evaluating (131)I-labeled human/murine chimeric 81C6 anti-tenascin monoclonal antibody (ch81C6) administered into surgically-created tumor resection cavities in brain tumor patients. However, because the blood clearance is slow, hematologic toxicity has been higher than seen with murine 81C6 (mu81C6). In the current study, a series of paired-label experiments were performed in athymic mice bearing subcutaneous D-245 MG human glioma xenografts to compare the biodistribution of the fragment ch81C6 F(ab')(2) labeled using Iodogen to a) intact ch81C6, b) mu81C6, and c) ch81C6 F(ab')(2) labeled using N-succinimidyl 3-[(131)I]iodobenzoate. Tumor retention of radioiodine activity for the F(ab')(2) fragment was comparable to that for intact ch81C6 for the first 24 h and to that for mu81C6 for the first 48 h; as expected, blood and other normal tissue levels declined faster for ch81C6 F(ab')(2.) Radiation dosimetry calculations suggest that (131)I-labeled ch81C6 F(ab')(2) may warrant further evaluation as a targeted radiotherapeutic for the treatment of brain tumors.

Authors
Boskovitz, A; Akabani, GH; Pegram, CN; Bigner, DD; Zalutsky, MR
MLA Citation
Boskovitz, A, Akabani, GH, Pegram, CN, Bigner, DD, and Zalutsky, MR. "Human/murine chimeric 81C6 F(ab')(2) fragment: preclinical evaluation of a potential construct for the targeted radiotherapy of malignant glioma." Nucl Med Biol 31.3 (April 2004): 345-355.
PMID
15028247
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
31
Issue
3
Publish Date
2004
Start Page
345
End Page
355
DOI
10.1016/j.nucmedbio.2003.10.008

O6-3-[131I]iodobenzylguanine: improved synthesis and further evaluation of a potential agent for imaging of alkylguanine-DNA alkyltransferase.

O(6)-Benzylguanine derivatives with suitable radionuclides attached to the benzyl ring are potentially useful in the noninvasive imaging of the DNA repair protein, alkylguanine-DNA alkyltransferase (AGT). Previously, O(6)-3-[(131)I]iodobenzylguanine ([(131)I]IBG) was prepared using a two-step approach; we now report its synthesis in a single step by the radioiododestannylation of O(6)-3-(trimethylstannyl)benzylguanine in 85-95% radiochemical yield. The in vitro specific uptake of [(131)I]IBG in DAOY human medulloblastoma cells, in TE-671 human rhabdomyosarcoma cells and a CHO cell line transfected to express AGT was linear (r(2) = 0.9-1.0) as a function of cell density. After intravenous injection of [(131)I]IBG in athymic mice bearing TE-671 xenografts, tumor uptake was 1.38 +/- 0.34% ID/g at 0.5 h and declined at 2 and 4 h. Preadministration of O(6)-(3-iodobenzyl)guanine (IBG) at 0.5 h increased uptake not only in tumor but also in several normal tissues. Notable exceptions were thyroid (p < 0.05), lung (p <0.05) and stomach. After intratumoral injection of [(131)I]IBG in the same xenograft model, the uptake in tumors that were depleted of AGT by BG treatment (165.8 +/- 27.5% ID/g) was about 60% of that in control mice (272.4 +/- 48.2% ID/g; p < 0.05).

Authors
Vaidyanathan, G; Affleck, DJ; Norman, J; Welsh, P; Liu, W; Johnson, SP; Friedman, HS; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, Norman, J, Welsh, P, Liu, W, Johnson, SP, Friedman, HS, and Zalutsky, MR. "O6-3-[131I]iodobenzylguanine: improved synthesis and further evaluation of a potential agent for imaging of alkylguanine-DNA alkyltransferase." Bioconjug Chem 15.2 (March 2004): 402-408.
PMID
15025538
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
15
Issue
2
Publish Date
2004
Start Page
402
End Page
408
DOI
10.1021/bc0341977

Imaging drug resistance with radiolabeled molecules.

A major obstacle to successful cancer chemotherapy is drug resistance. Multidrug resistance (MDR) is often seen with chemotherapeutic agents such as anthracycline derivatives, vinca alkaloids and taxanes. Multiple aspects of cellular biochemistry have been implicated in the MDR process. Cellular mechanisms of resistance are due to the presence of efflux pumps, P-glycoprotein (P-gp) and multiple resistance-associated protein (MRP), which belong to the ATP-binding cassette (ABC) family of transporters. Another form of drug resistance is involved in the chemotherapy of cancers with alkylating agents such as nitrosourea derivatives and nitrogen mustards. The cytotoxicity of these agents is primarily due to alkylation of the DNA guanine residues at their O6-position, which leads, via a cascade of events, to DNA strand breaks. The DNA repair protein, alkylguanine-DNA alkyl transferase (AGT) removes the alkyl groups from the lesions stoichiometrically to a cysteine in its active site. This process is irreversible and results in the degradation of the protein and its recovery is entirely from de novo synthesis. Noninvasive methodologies for monitoring the transport activity of these efflux pumps and determining tumor content of AGT could serve as critical tools for optimizing chemotherapeutic protocols on a patient-specific basis and gaining an understanding of the dynamics of resistance in living patients. In this review, we will describe the efforts made to date to synthesize radioactive probes of chemotherapy resistance and their use to quantitate these transporters and DNA repair protein by radionuclide imaging.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Imaging drug resistance with radiolabeled molecules." Curr Pharm Des 10.24 (2004): 2965-2979. (Review)
PMID
15379662
Source
pubmed
Published In
Current Pharmaceutical Design
Volume
10
Issue
24
Publish Date
2004
Start Page
2965
End Page
2979

Targeted Radiotherapy with Alpha-Particle Emitting Radionuclides Seminar, November 18, 2004, Cracow, Poland.

Authors
Zalutsky, MR; Petelenz, B
MLA Citation
Zalutsky, MR, and Petelenz, B. "Targeted Radiotherapy with Alpha-Particle Emitting Radionuclides Seminar, November 18, 2004, Cracow, Poland." Nucl Med Rev Cent East Eur 7.2 (2004): 195-.
PMID
15968616
Source
pubmed
Published In
Nuclear medicine review. Central & Eastern Europe : journal of Bulgarian, Czech, Macedonian, Polish, Romanian, Russian, Slovak, Yugoslav societies of nuclear medicine and Ukrainian Society of Radiology
Volume
7
Issue
2
Publish Date
2004
Start Page
195

Wet harvesting of no-carrier-added 211At from an irradiated 209Bi target for radiopharmaceutical applications

Astatine-211 is one of the most promising α-emitters for targeted cancer radiotherapy. However, research and clinical trials involving 211At-labeled radiopharmaceuticals have often been impeded due to the irregular and sometimes inconveniently low recovery yields obtained by the currently used dry distillation procedure. Therefore, a wet harvesting procedure isolating 211At from an irradiated 209Bi target was explored. The procedure involves target dissolution in concentrated HNO 3 and extraction of the high oxidation state 211At activity with butyl or isopropyl ether. This method resulted in consistent and nearly quantitative yields. The activity was re-extracted in aqueous phase and applied to NIS6 UVW human glioma cells transfected with cDNA encoding the human sodium/iodide symporter (NIS). The significant and specific uptake of 211At activity by these cells suggests that in the ether phase, high oxidation state 211At is reduced to [ 211At]astatide anion. The synthesis of the first astatinated organic compound derived from wet harvested 211At, 3-astatobenzoic acid (ABA), was achieved.

Authors
Yordanov, AT; Pozzi, O; Carlin, S; Akabani, G; Wieland, B; Zalutsky, MR
MLA Citation
Yordanov, AT, Pozzi, O, Carlin, S, Akabani, G, Wieland, B, and Zalutsky, MR. "Wet harvesting of no-carrier-added 211At from an irradiated 209Bi target for radiopharmaceutical applications." Journal of Radioanalytical and Nuclear Chemistry 262.3 (2004): 593-599.
Source
scival
Published In
Journal of Radioanalytical and Nuclear Chemistry
Volume
262
Issue
3
Publish Date
2004
Start Page
593
End Page
599
DOI
10.1007/s10967-004-0481-z

Reagents for Astatination of Biomolecules: Comparison of the in Vivo Distribution and Stability of Some Radioiodinated/Astatinated Benzamidyl and nido-Carboranyl Compounds

An investigation has been conducted to assess the in vivo stability of a series of astatinated benzamides and astatinated nido-carborane compounds in mice. It was hypothesized that the higher bond strength of boron-astatine bonds in the nido-carboranes might provide increased stability toward in vivo deastatination. Four tri-n-butylstannylbenzamides were prepared for radiohalogenation and evaluation in vivo. Those compounds were N-propyl-4-(tri-n-butylstannyl)benzamide la, N-propyl-3-(tri-n-butylstannyl)benzamide 2a, ethyl 4-tri-n-butylstannylhippurate 3a, and 4-tri-n-butylstannyl-hippuric acid 4a. Seven mono-nido-carboranyl derivatives were prepared for radiohalogenation and in vivo evaluation. Four of the seven mono-carboranyl derivatives (5a, 6a, 7a, 13a) contained a 3-(nido-carboranyl)propionamide functionality, and the remaining compounds (8a, 8g, 10a) contained a 4-(nido-carboranyl)aniline functionality. Two additional derivatives (11a, 12a) were prepared that contained bis-(nido-carboranylmethyl)benzene moieties (also referred to as Venus flytrap complexes (VFCs). All benzamide and nido-carborane compounds underwent facile iodination and radiohalogenation, except a 4-(nido-carboranyl)aniline derivative, 8a. Iodination of 8a resulted in a mixture, of which the desired iodinated product was a minor component. Therefore, radiohalogenation was not attempted. It is believed that the mixture of products is due to the presence of a thiourea bond. Previous studies have shown that thiourea bonds can interfere with halogenation reactions. In vivo comparisons of the compounds were conducted by co-injection of dual labeled (125/131I and 211At) compounds. Tissue distribution data were obtained at 1 and 4 h postinjection of the radiolabeled compounds, as that was sufficient to determine if astatine was being released. Stability of the astatinated compound was assessed by the difference in concentration of radioiodine and astatine in lung and spleen. All of the benzamides were found to undergo rapid deastatination in vivo. The nido-carborane derivatives appeared to be slightly more stable to in vivo deastatination; however, they had long blood residence times. The surprising finding was that the VFC derivatives did not release 211At in vivo, even though they rapidly localized to liver. This finding provides encouragement that stable conjugates of 211At may be attained if appropriate modifications of the VFC can be made to redirect their excretion through the renal system.

Authors
Wilbur, DS; Chyan, M-K; Hamlin, DK; Kegley, BB; Risler, R; Pathare, PM; Quinn, J; Vessella, RL; Foulon, C; Zalutsky, M; Wedge, TJ; Hawthorne, MF
MLA Citation
Wilbur, DS, Chyan, M-K, Hamlin, DK, Kegley, BB, Risler, R, Pathare, PM, Quinn, J, Vessella, RL, Foulon, C, Zalutsky, M, Wedge, TJ, and Hawthorne, MF. "Reagents for Astatination of Biomolecules: Comparison of the in Vivo Distribution and Stability of Some Radioiodinated/Astatinated Benzamidyl and nido-Carboranyl Compounds." Bioconjugate Chemistry 15.1 (2004): 203-223.
PMID
14733601
Source
scival
Published In
Bioconjugate Chemistry
Volume
15
Issue
1
Publish Date
2004
Start Page
203
End Page
223
DOI
10.1021/bc034175k

Astatine-211 labeled Herceptin: An alpha-particle emitting radiotherapeutic.

Authors
Boskovitz, A; Akabani, G; Zhao, XG; Alston, K; Zalutsky, MR
MLA Citation
Boskovitz, A, Akabani, G, Zhao, XG, Alston, K, and Zalutsky, MR. "Astatine-211 labeled Herceptin: An alpha-particle emitting radiotherapeutic." December 1, 2003.
Source
wos-lite
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
9
Issue
16
Publish Date
2003
Start Page
6189S
End Page
6189S

Efficacy of intracerebral microinfusion of trastuzumab in an athymic rat model of intracerebral metastatic breast cancer.

PURPOSE: The monoclonal antibody (MAb) trastuzumab (Herceptin) effectively treats HER2-overexpressing extracerebral breast neoplasms. Delivery of such macromolecule therapeutic agents to intracerebral metastases, however, is limited by the tight junctions characteristic of the cerebral vasculature. Direct intracerebral microinfusion (ICM) is a technique that bypasses this blood-brain barrier and allows for a greater delivery of drugs directly into intracerebral tumors. EXPERIMENTAL DESIGN: A human breast cancer cell line transfected to overexpress HER2, MCF-7/HER2-18, was transplanted into the cerebrum of athymic rats. Saline, trastuzumab, or an isotype-matched control MAb was delivered systemically or by ICM to assess toxicity and efficacy. RESULTS: No clinical or histological toxicity related to trastuzumab was evident under any of the conditions studied. Delivery of trastuzumab (2 mg/kg) i.p. led to a median survival of 26.5 days, whereas treatment with trastuzumab (2 mg/kg) by ICM increased the median survival by 96% to 52 days, with two of nine rats surviving >120 days (P = 0.009). Treatment with an isotype-matched control MAb (16 mg/kg) resulted in a median survival of 21 days, which did not differ significantly from the survival of rats treated by ICM with saline (16 days; P = 0.42). Treatment by ICM with trastuzumab (16 mg/kg) led to a median survival of 45 days, with 2 of 10 rats surviving >120 days. These results represent 181% and 114% increases in median survival over the saline and MAb controls, respectively (P < 0.001). CONCLUSION: ICM of trastuzumab is safe and superior to systemic delivery as therapy for HER2-overexpressing intracerebral neoplasms in an athymic rat model.

Authors
Grossi, PM; Ochiai, H; Archer, GE; McLendon, RE; Zalutsky, MR; Friedman, AH; Friedman, HS; Bigner, DD; Sampson, JH
MLA Citation
Grossi, PM, Ochiai, H, Archer, GE, McLendon, RE, Zalutsky, MR, Friedman, AH, Friedman, HS, Bigner, DD, and Sampson, JH. "Efficacy of intracerebral microinfusion of trastuzumab in an athymic rat model of intracerebral metastatic breast cancer." Clin Cancer Res 9.15 (November 15, 2003): 5514-5520.
PMID
14654531
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
9
Issue
15
Publish Date
2003
Start Page
5514
End Page
5520

In vitro cytotoxicity of (211)at-astatide and (131)I-iodide to glioma tumor cells expressing the sodium/iodide symporter.

UNLABELLED: The sodium/iodide symporter (NIS) has been identified as an attractive target for cancer therapy. The efficacy of (131)I-iodide for NIS-expressing tumor therapy may be limited by a combination of poor cellular retention and unfavorable physical characteristics (long physical half-life and low linear-energy-transfer [LET] radiative emissions). On the other hand, (211)At-astatide is also transported by NIS and offers several therapeutic advantages over (131)I-iodide due to its physical characteristics (short half-life, high LET alpha-particle emissions). The objective of this study was to directly compare the radiotoxicity of both radionuclides using a NIS-transfected cultured cell model. METHODS: Cytotoxicity was determined by colony-forming assays. Also, a first-order pharmacokinetic model was used to simulate the closed compartmental system between the medium and cells. Experimental data were then fitted to this model and used to estimate the transfer coefficients between medium and cells, k(m)(c), and between cells and medium, k(c)(m). Using the pharmacokinetic model, the cumulated activity concentrations in the medium and cells were calculated. Monte Carlo transport methods were then used to assess absorbed doses from (131)I and (211)At. RESULTS: (211)At-Astatide was significantly more cytotoxic than (131)I-iodide in this closed compartmental system. For (211)At-astatide, absorbed doses per unit administered activity were 54- to 65-fold higher than for (131)I-iodide. Both NIS-expressing and control cells showed increased sensitivity to (211)At over (131)I, with significantly lower D(0) (absorbed dose required to reduce the survival fraction to e(-1)) and SF(2) (2-Gy survival fraction) values, highlighting the higher intrinsic cytotoxicity of alpha-particles. However, NIS-independent (nonspecific) binding of (211)At-astatide was higher than that of (131)I-iodide, therefore, yielding a lower absorbed dose ratio between NIS-transfected and -nontransfected cells. CONCLUSION: Treatment of NIS-expressing cells with (211)At-astatide resulted in higher absorbed doses and increased cytotoxicity per unit administered activity than that observed with (131)I-iodide. These results suggest that (211)At-astatide may be a promising treatment strategy for the therapy of NIS-expressing tumors.

Authors
Carlin, S; Akabani, G; Zalutsky, MR
MLA Citation
Carlin, S, Akabani, G, and Zalutsky, MR. "In vitro cytotoxicity of (211)at-astatide and (131)I-iodide to glioma tumor cells expressing the sodium/iodide symporter." J Nucl Med 44.11 (November 2003): 1827-1838.
PMID
14602867
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
44
Issue
11
Publish Date
2003
Start Page
1827
End Page
1838

Progress report of a Phase I study of the intracerebral microinfusion of a recombinant chimeric protein composed of transforming growth factor (TGF)-alpha and a mutated form of the Pseudomonas exotoxin termed PE-38 (TP-38) for the treatment of malignant brain tumors.

TP-38 is a recombinant chimeric targeted toxin composed of the EGFR binding ligand TGF-alpha and a genetically engineered form of the Pseudomonas exotoxin, PE-38. After in vitro and in vivo animal studies that showed specific activity and defined the maximum tolerated dose (MTD), we investigated this agent in a Phase I trial. The primary objective of this study was to define the MTD and dose limiting toxicity of TP-38 delivered by convection-enhanced delivery in patients with recurrent malignant brain tumors. Twenty patients were enrolled in the study and doses were escalated from 25 ng/mL to 100 with a 40 mL infusion volume delivered by two catheters. One patient developed Grade IV fatigue at the 100 ng/mL dose, but the MTD has not been established. The overall median survival after TP-38 for all patients was 23 weeks whereas for those without radiographic evidence of residual disease at the time of therapy, the median survival was 31.9 weeks. Overall, 3 of 15 patients, with residual disease at the time of therapy, have demonstrated radiographic responses and one patient with a complete response and has survived greater than 83 weeks.

Authors
Sampson, JH; Akabani, G; Archer, GE; Bigner, DD; Berger, MS; Friedman, AH; Friedman, HS; Herndon, JE; Kunwar, S; Marcus, S; McLendon, RE; Paolino, A; Penne, K; Provenzale, J; Quinn, J; Reardon, DA; Rich, J; Stenzel, T; Tourt-Uhlig, S; Wikstrand, C; Wong, T; Williams, R; Yuan, F; Zalutsky, MR; Pastan, I
MLA Citation
Sampson, JH, Akabani, G, Archer, GE, Bigner, DD, Berger, MS, Friedman, AH, Friedman, HS, Herndon, JE, Kunwar, S, Marcus, S, McLendon, RE, Paolino, A, Penne, K, Provenzale, J, Quinn, J, Reardon, DA, Rich, J, Stenzel, T, Tourt-Uhlig, S, Wikstrand, C, Wong, T, Williams, R, Yuan, F, Zalutsky, MR, and Pastan, I. "Progress report of a Phase I study of the intracerebral microinfusion of a recombinant chimeric protein composed of transforming growth factor (TGF)-alpha and a mutated form of the Pseudomonas exotoxin termed PE-38 (TP-38) for the treatment of malignant brain tumors." J Neurooncol 65.1 (October 2003): 27-35.
PMID
14649883
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
65
Issue
1
Publish Date
2003
Start Page
27
End Page
35

Targeted radiotherapy of brain tumours

Authors
Zalutsky, MR
MLA Citation
Zalutsky, MR. "Targeted radiotherapy of brain tumours." July 2003.
Source
wos-lite
Published In
British Journal of Cancer
Volume
88
Publish Date
2003
Start Page
S6
End Page
S6

Specific and high-level targeting of radiolabeled octreotide analogues to human medulloblastoma xenografts.

PURPOSE: The objective of this study was to determine the feasibility of exploiting the overexpression of somatostatin subtype-2 receptors (sstr(2)) on human medulloblastoma cells to develop targeted radiodiagnostics and radiotherapeutics for this disease. EXPERIMENTAL DESIGN: The following radioiodinated peptides were prepared using chloramine-T and evaluated: [(131)I-Tyr(3)]octreotide ([(131)I]TOC), [(131)I-Tyr(3)]octreotate ([(131)I]TOCA), involving substitution of Thr(ol)(8) in TOC with Thr(8), and glucose-[(131)I-Tyr(3)]octreotide ([(131)I]Gluc-TOC) and glucose-[(131)I-Tyr(3)]octreotate ([(131)I]Gluc-TOCA), prepared by conjugation of glucose to the peptide NH(2) terminus. Specific internalization of the peptides by sstr(2)-expressing AR42J rat pancreatic carcinoma cells in vitro was evaluated in paired-label assays. The tissue distribution of i.v. administered [(131)I]TOC, [(131)I]TOCA, [(131)I]Gluc-TOC, and [(131)I]Gluc-TOCA was evaluated in athymic mice bearing s.c. D341 Med human medulloblastoma xenografts. RESULTS: Compared with [(125)I]TOC, internalized radioiodine levels were higher for the other three peptides. For example, internalized counts were 1.9 +/- 0.2, 2.0 +/- 0.3, and 5.7 +/- 1.9 times higher for [(131)I]Gluc-TOC, [(131)I]TOCA, and [(131)I]Gluc-TOCA after a 3-h incubation, respectively, demonstrating that carbohydration and COOH-terminus modification significantly improved the retention of radioiodine activity in sstr(2)-expressing tumor cells. COOH-terminus modification significantly increased (131)I localization in D341 Med medulloblastoma xenografts [[(131)I]TOCA, 8.1 +/- 2.2% of injected dose/g (% ID/g); [(131)I]TOC, 3.9 +/- 0.5% ID/g at 1 h], whereas carbohydration of the NH(2) terminus resulted in even higher gains in tumor accumulation ([(131)I]Gluc-TOC, 11.1 +/- 1.8% ID/g; [(131)I]Gluc-TOCA, 21.4 +/- 7.3% ID/g). In addition, the three modified peptides exhibited liver activity levels that were less than half those of [(131)I]TOC. Uptake of the two glucose-peptide conjugates in this human medulloblastoma xenograft was blocked by coinjection of 100 micro g of octreotide, demonstrating that it was receptor-specific. Tumor:normal tissue uptake ratios for [(131)I]Gluc-TOCA generally were higher that those for [(131)I]Gluc-TOC. At 1 h, tumor:normal tissue ratios for [(131)I]Gluc-TOCA were 29:1, 15:1, 8:1, 8:1, 240:1, and 82:1 for blood, liver, kidney, spleen, brain, and muscle, respectively. CONCLUSIONS: Our findings suggest that additional investigation of radiolabeled Gluc-TOCA analogues for the imaging and targeted radiotherapy of medulloblastoma is warranted.

Authors
Vaidyanathan, G; Friedman, HS; Affleck, DJ; Schottelius, M; Wester, H-J; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Friedman, HS, Affleck, DJ, Schottelius, M, Wester, H-J, and Zalutsky, MR. "Specific and high-level targeting of radiolabeled octreotide analogues to human medulloblastoma xenografts." Clin Cancer Res 9.5 (May 2003): 1868-1876.
PMID
12738745
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
9
Issue
5
Publish Date
2003
Start Page
1868
End Page
1876

N-succinimidyl 3-[211At]astato-4-guanidinomethylbenzoate: an acylation agent for labeling internalizing antibodies with alpha-particle emitting 211At.

The objective of this study was to develop a method for labeling internalizing monoclonal antibodies (mAbs) such as those reactive to the anti-epidermal growth factor receptor variant III (EGFRvIII) with the alpha-particle emitting radionuclide (211)At. Based on previous work utilizing the guanidine-containing acylation agent, N-succinimidyl 4-guanidinomethyl-3-[(131)I]iodobenzoate ([(131)I]SGMIB), we have now investigated the potential utility of its astato analogue for labeling the anti-EGFRvIII mAb L8A4. N-succinimidyl 3-[(211)At]astato-4-guanidinomethylbenzoate ([(211)At]SAGMB) in its Boc-protected form was prepared from a tin precursor in 61.7 +/- 13.1% radiochemical yield, in situ deprotected to [(211)At]SAGMB, which was coupled to L8A4 in 36.1 +/- 1.9% yield. Paired-label internalization assays demonstrated that tumor cell retention of radioactivity for L8A4 labeled using [(211)At]SAGMB was almost identical to L8A4 labeled using [(131)I]SGMIB, and 3-4-fold higher than for mAb radioiodinated using Iodogen. Paired-label biodistribution of L8A4 labeled using [(211)At]SAGMB and [(131)I]SGMIB in athymic mice hosting U87MGdeltaEGFR xenografts resulted in identical uptake of both (211)At and (131)I in tumor tissues over 24 h. Although higher levels of (211)At compared with (131)I were sometimes seen in tissues known to sequester free astatide, these (211)At/(131)I uptake ratios were considerably lower than those seen with other labeling methods. These results suggest that [(211)At]SAGMB may be a useful acylation agent for labeling internalizing mAbs with (211)At.

Authors
Vaidyanathan, G; Affleck, DJ; Bigner, DD; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, Bigner, DD, and Zalutsky, MR. "N-succinimidyl 3-[211At]astato-4-guanidinomethylbenzoate: an acylation agent for labeling internalizing antibodies with alpha-particle emitting 211At." Nucl Med Biol 30.4 (May 2003): 351-359.
PMID
12767391
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
30
Issue
4
Publish Date
2003
Start Page
351
End Page
359

Microdosimetric analysis of alpha-particle-emitting targeted radiotherapeutics using histological images.

UNLABELLED: The purpose of this study was to evaluate the therapeutic efficacy and limitations of alpha-particle-emitting radiolabeled compounds by means of 2-dimensional histological images and distribution of activity on a microscopic level. METHODS: A microdosimetric approach based on histological images is used to analyze the therapeutic effectiveness of alpha-particle-emitting (211)At and (213)Bi conjugated to 201B monoclonal antibody (mAb), which is reactive with murine lung blood vessels for the treatment of EMT-6 lung tumor colonies in nude mice. Autoradiography images were used to define the tissue morphology and activity distribution within lung tissues. Two animal groups were studied: Group A consisted of animals bearing small tumors (<130 micro m) and group B consisted of larger tumors (<600 micro m). Probability density functions (pdf) described the variability in average absorbed dose and survival probability among normal and tumor target cells and, in turn, were used to assess the survival fraction of tumor and normal tissue. RESULTS: The average absorbed dose to tumor cells per unit cumulated activity concentration for animals in group A was 1.10 x 10(-3) and 1.37 x 10(-3) Gy g MBq(-1) s(-1) for (211)At and (213)Bi, respectively, and for animals in group B was 3.8 x 10(-4) and 5.6 x 10(-4) Gy g MBq(-1) s(-1) for (211)At and (213)Bi, respectively. The fraction of tumor cells that received a zero absorbed dose for animals in group A was 0.04% for (213)Bi and 0.2% for (211)At and for animals in group B was 25% for (213)Bi and 31% for (211)At. Both (213)Bi- and (211)At-labeled 201B mAb were effective therapies for animals with small tumors, where predicted therapeutic effectiveness was consistent with experimental findings; however, they were ineffective for animals with larger tumors. CONCLUSION: Microdosimetric methods based on knowledge of tissue morphology and activity distribution on a small-scale level can be a useful tool for evaluating a priori the therapeutic efficacy and limitations of targeted alpha-particle endoradiotherapeutic strategies.

Authors
Akabani, G; Kennel, SJ; Zalutsky, MR
MLA Citation
Akabani, G, Kennel, SJ, and Zalutsky, MR. "Microdosimetric analysis of alpha-particle-emitting targeted radiotherapeutics using histological images." J Nucl Med 44.5 (May 2003): 792-805.
PMID
12732682
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
44
Issue
5
Publish Date
2003
Start Page
792
End Page
805

N-succinimidyl 3-[(131)I]iodo-4-phosphonomethylbenzoate ([(131)I]SIPMB), a negatively charged substituent-bearing acylation agent for the radioiodination of peptides and mAbs.

An important criterion in design of acylation agents for the radioiodination of internalizing monoclonal antibodies (mAbs) is to maximize the retention of radioiodine in the tumor following mAb intracellular processing. We have previously shown that labeling methods that generate positively charged catabolites have enhanced tumor retention. Herein we have extended this strategy to investigate the potential utility of labeling internalizing mAbs with an acylation agent that yielded labeled catabolites that would be negatively charged at lysosomal pH. The negatively charged acylation agent, N-succinimidyl 3-[(131)I]iodo-4-phosphonomethylbenzoate ([(131)I]SIPMB), was prepared from its tin precursor, N-succinimidyl 4-di-tert-butylphosphonomethyl-3-trimethylstannylbenzoate (tBu-SPMTB), in 40% radiochemical yield. The free acid, 3-[(131)I]iodo-4-phosphonomethylbenzoic acid ([(131)I]IPMBA), was also prepared from the corresponding precursor, 4-di-tert-butylphosphonomethyl-3-trimethylstannylbenzoic acid (tBu-PMTBA), in 80% radiochemical yield. The rapidly internalizing mAb L8A4 was conjugated to [(131)I]SIPMB in 25-40% yield with preservation of its immunoreactivity. Internalization and processing in the U87DeltaEGFR glioma cell line was studied in a paired label format with L8A4 labeled with (125)I using the Iodogen method. Retention of initially bound radioactivity in these cells at 24 h from [(131)I]SIPMB-labeled mAb was approximately 6-fold higher than that for directly labeled mAb. Catabolite analysis demonstrated that this difference reflected an order of magnitude higher retention of low molecular weight species in these cells. The [(131)I]SIPMB-L8A4 conjugate was intact over the first 2 h; thereafter, lysine-[(131)I]SIPMB was the predominant catabolite. In contrast, L8A4 labeled using Iodogen rapidly gave rise to mono-[(125)I]iodotyrosine within 2 h, which then cleared rapidly from the cells. These results suggest that SIPMB could be a potent candidate for labeling internalizing mAbs and warrant further study.

Authors
Shankar, S; Vaidyanathan, G; Affleck, D; Welsh, PC; Zalutsky, MR
MLA Citation
Shankar, S, Vaidyanathan, G, Affleck, D, Welsh, PC, and Zalutsky, MR. "N-succinimidyl 3-[(131)I]iodo-4-phosphonomethylbenzoate ([(131)I]SIPMB), a negatively charged substituent-bearing acylation agent for the radioiodination of peptides and mAbs." Bioconjug Chem 14.2 (March 2003): 331-341.
PMID
12643743
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
14
Issue
2
Publish Date
2003
Start Page
331
End Page
341
DOI
10.1021/bc025636p

N-succinimidyl 3-[211AT]astato-4-guanidinomethylbenzoate: An acylation agent for labeling internalizing antibodies with alpha-particle emitting (211)AT.

Authors
Vaidyanathan, G; Affleck, DJ; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, and Zalutsky, MR. "N-succinimidyl 3-[211AT]astato-4-guanidinomethylbenzoate: An acylation agent for labeling internalizing antibodies with alpha-particle emitting (211)AT." March 2003.
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
225
Publish Date
2003
Start Page
U265
End Page
U265

Optimizing methods for labeling biomolecules with astatine-211.

Authors
Wilbur, DS; Hamlin, DK; Chyan, MK; Foulon, C; Zalutsky, MR; Wedge, T; Hawthorne, MF
MLA Citation
Wilbur, DS, Hamlin, DK, Chyan, MK, Foulon, C, Zalutsky, MR, Wedge, T, and Hawthorne, MF. "Optimizing methods for labeling biomolecules with astatine-211." March 2003.
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
225
Publish Date
2003
Start Page
U264
End Page
U265

Evaluation of astatine-211 labeled targeted radiotherapeutics.

Authors
Zalutsky, MR; Pozzi, O; Zhao, XG; Alston, KL
MLA Citation
Zalutsky, MR, Pozzi, O, Zhao, XG, and Alston, KL. "Evaluation of astatine-211 labeled targeted radiotherapeutics." March 2003.
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
225
Publish Date
2003
Start Page
U264
End Page
U264

Vascular targeted endoradiotherapy of tumors using alpha-particle-emitting compounds: theoretical analysis.

PURPOSE: To establish the theoretical framework and study the feasibility of (211)At-labeled anti-tenascin chimeric 81C6 monoclonal antibody (mAb) as anti-vascular endoradiotherapy for the treatment of glioblastoma multiforme (GBM) tumors. METHODS AND MATERIALS: The morphology of blood vessels from histologic images was analyzed and used along with reaction-diffusion equations to assess the activity concentration of (211)At-labeled chimeric 81C6 mAb in GBM tumor and normal-brain tissue. Alpha particle microdosimetry was then used to assess the survival probability and average absorbed dose for tumor and normal tissue endothelial cells (ECs) per unit vascular cumulated activity concentration q(source) (MBq-s g(-1)). In turn, these survival probabilities were used to assess the probability of failure Phi for a single vessel. Furthermore, using the vessel density, the specific tumor control probability per unit mass of tumor tissue (tcp) and the specific normal-tissue complication probability per unit mass of normal-brain tissue (ntcp) were estimated. The specific tumor control probability, tcp, was used to assess the overall tumor control probability (TCP) as a function of tumor mass. RESULTS: The levels of (211)At-labeled ch81C6 mAb cumulated activity concentration in GBM tumor tissue were approximately five times higher than that in normal-brain tissue. Thus, the average absorbed dose to tumor ECs was higher than that of normal tissue ECs, and the survival probability for GBM ECs was lower than for normal-brain tissue ECs. Consequently, the resulting vessel-failure probability, Phi, for GBM tumor and for normal-brain tissue differ considerably, yielding a q(source) range between 10(3) and 10(4) MBq-s g(-1). CONCLUSIONS: This theoretical analysis demonstrated that (211)At-labeled chimeric 81C6 is an effective anti-vascular therapy for the treatment of GBM tumors, yielding a tcp higher than 0.999 for vascular cumulated activity concentrations q(source) higher than 1 x 10(4) MBq-s g(-1), while yielding a low probability for normal-brain tissue damage.

Authors
Akabani, G; McLendon, RE; Bigner, DD; Zalutsky, MR
MLA Citation
Akabani, G, McLendon, RE, Bigner, DD, and Zalutsky, MR. "Vascular targeted endoradiotherapy of tumors using alpha-particle-emitting compounds: theoretical analysis." Int J Radiat Oncol Biol Phys 54.4 (November 15, 2002): 1259-1275.
PMID
12419456
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
54
Issue
4
Publish Date
2002
Start Page
1259
End Page
1275

Sodium-iodide symporter (NIS)-mediated accumulation of [(211)At]astatide in NIS-transfected human cancer cells.

The cellular expression of the sodium iodide symporter (NIS) has been shown to confer iodide-concentrating capacity in non-thyroid cell types. We examined the role of NIS in the uptake of the alpha-particle emitting radiohalide [(211)At]astatide in the UVW human glioma cell line transfected to express NIS. [(211)At]Astatide uptake is shown to be NIS-dependent, with characteristics similar to [(131)I]iodide uptake. These studies suggest [(211)At]astatide as a possible alternative radionuclide to [(131)I]iodide for NIS-based endoradiotherapy, and provide a model for the study of [(211)At]astatide behavior at a cellular level.

Authors
Carlin, S; Mairs, RJ; Welsh, P; Zalutsky, MR
MLA Citation
Carlin, S, Mairs, RJ, Welsh, P, and Zalutsky, MR. "Sodium-iodide symporter (NIS)-mediated accumulation of [(211)At]astatide in NIS-transfected human cancer cells." Nucl Med Biol 29.7 (October 2002): 729-739.
PMID
12381453
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
29
Issue
7
Publish Date
2002
Start Page
729
End Page
739

Radioimmunotherapy of refractory non-Hodgkin's lymphoma with I-131-labeled chimeric 81C6 anti-tenascin monoclonal antibody: Dosimetry study.

Authors
Akabani, G; Rizzieri, D; Coleman, RE; Metzler, SD; Zalutsky, MR; Bigner, DD
MLA Citation
Akabani, G, Rizzieri, D, Coleman, RE, Metzler, SD, Zalutsky, MR, and Bigner, DD. "Radioimmunotherapy of refractory non-Hodgkin's lymphoma with I-131-labeled chimeric 81C6 anti-tenascin monoclonal antibody: Dosimetry study." JOURNAL OF NUCLEAR MEDICINE 43.5 (May 2002): 313P-313P.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
43
Issue
5
Publish Date
2002
Start Page
313P
End Page
313P

Synthesis and in vitro evaluation of glycated octreotate conjugates labeled with radioiodine and At-211 via a tin precursor.

Authors
Vaidyanathan, G; Affleck, DJ; Welsh, P; Schottelius, M; Wester, H; Norman, JA; Alston, KL; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, Welsh, P, Schottelius, M, Wester, H, Norman, JA, Alston, KL, and Zalutsky, MR. "Synthesis and in vitro evaluation of glycated octreotate conjugates labeled with radioiodine and At-211 via a tin precursor." JOURNAL OF NUCLEAR MEDICINE 43.5 (May 2002): 92P-92P.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
43
Issue
5
Publish Date
2002
Start Page
92P
End Page
92P

Negatively charged substituent-bearing acylation agent for the radiohalogenation of mAbs.

Authors
Shankar, S; Vaidyanathan, G; Affleck, DJ; Welsh, P; LeGrand, H; Zalutsky, MR
MLA Citation
Shankar, S, Vaidyanathan, G, Affleck, DJ, Welsh, P, LeGrand, H, and Zalutsky, MR. "Negatively charged substituent-bearing acylation agent for the radiohalogenation of mAbs." JOURNAL OF NUCLEAR MEDICINE 43.5 (May 2002): 366P-366P.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
43
Issue
5
Publish Date
2002
Start Page
366P
End Page
366P

Phase II trial of murine (131)I-labeled antitenascin monoclonal antibody 81C6 administered into surgically created resection cavities of patients with newly diagnosed malignant gliomas.

PURPOSE: To assess the efficacy and toxicity of intraresection cavity (131)I-labeled murine antitenascin monoclonal antibody 81C6 and determine its true response rate among patients with newly diagnosed malignant glioma. PATIENTS AND METHODS: In this phase II trial, 120 mCi of (131)I-labeled murine 81C6 was injected directly into the surgically created resection cavity of 33 patients with previously untreated malignant glioma (glioblastoma multiforme [GBM], n = 27; anaplastic astrocytoma, n = 4; anaplastic oligodendroglioma, n = 2). Patients then received conventional external-beam radiotherapy followed by a year of alkylator-based chemotherapy. RESULTS: Median survival for all patients and those with GBM was 86.7 and 79.4 weeks, respectively. Eleven patients remain alive at a median follow-up of 93 weeks (range, 49 to 220 weeks). Nine patients (27%) developed reversible hematologic toxicity, and histologically confirmed, treatment-related neurologic toxicity occurred in five patients (15%). One patient (3%) required reoperation for radionecrosis. CONCLUSION: Median survival achieved with (131)I-labeled 81C6 exceeds that of historical controls treated with conventional radiotherapy and chemotherapy, even after accounting for established prognostic factors including age and Karnofsky performance status. The median survival achieved with (131)I-labeled 81C6 compares favorably with either (125)I interstitial brachy-therapy or stereotactic radiosurgery and is associated with a significantly lower rate of reoperation for radionecrosis. Our results confirm the efficacy of (131)I-labeled 81C6 for patients with newly diagnosed malignant glioma and suggest that a randomized phase III study is indicated.

Authors
Reardon, DA; Akabani, G; Coleman, RE; Friedman, AH; Friedman, HS; Herndon, JE; Cokgor, I; McLendon, RE; Pegram, CN; Provenzale, JM; Quinn, JA; Rich, JN; Regalado, LV; Sampson, JH; Shafman, TD; Wikstrand, CJ; Wong, TZ; Zhao, X-G; Zalutsky, MR; Bigner, DD
MLA Citation
Reardon, DA, Akabani, G, Coleman, RE, Friedman, AH, Friedman, HS, Herndon, JE, Cokgor, I, McLendon, RE, Pegram, CN, Provenzale, JM, Quinn, JA, Rich, JN, Regalado, LV, Sampson, JH, Shafman, TD, Wikstrand, CJ, Wong, TZ, Zhao, X-G, Zalutsky, MR, and Bigner, DD. "Phase II trial of murine (131)I-labeled antitenascin monoclonal antibody 81C6 administered into surgically created resection cavities of patients with newly diagnosed malignant gliomas." J Clin Oncol 20.5 (March 1, 2002): 1389-1397.
PMID
11870184
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
20
Issue
5
Publish Date
2002
Start Page
1389
End Page
1397
DOI
10.1200/JCO.2002.20.5.1389

Imaging of pheochromocytoma in 2 dogs using p-[18F] fluorobenzylguanidine.

p-[18F]Fluorobenzylguanidine ([18F]PFBG) is a norepinephrine analog that has been developed as a positron emission tomography (PET) imaging radiopharmaceutical. Myocardial sympathetic innervation, neuroendocrine structures, and tumors can be noninvasively imaged with [18F]PFBG. In this study, the uptake characteristics of [18F]PFBG were investigated in 2 dogs with a spontaneous pheochromocytoma. The extent of the pheochromocytoma was well documented in both dogs on the PET study. The standardized uptake values within the pheochromocytomas were greater than 25 by 10 min, and were 37 and 50 by 45 min in each dog. A third dog that was suspected to have an adrenal mass was also studied. In this dog, the [18F]PFBG study was normal. Surgical exploration and adrenal biopsy confirmed the [15F]PFBG imaging findings in both dogs. In each dog, there was rapid blood-pool clearance (within 10 min after intravenous administration of the [18F]PFBG), with high uptake specific within the myocardium and adrenal medulla. The results indicate that [18F]PFBG may be useful for imaging canine pheochromocytomas and aid in differentiating adrenal masses.

Authors
Berry, CR; DeGrado, TR; Nutter, F; Garg, PK; Breitschwerdt, EB; Spaulding, K; Concannon, KD; Zalutsky, MR; Coleman, RE
MLA Citation
Berry, CR, DeGrado, TR, Nutter, F, Garg, PK, Breitschwerdt, EB, Spaulding, K, Concannon, KD, Zalutsky, MR, and Coleman, RE. "Imaging of pheochromocytoma in 2 dogs using p-[18F] fluorobenzylguanidine." Vet Radiol Ultrasound 43.2 (March 2002): 183-186.
PMID
11954815
Source
pubmed
Published In
Veterinary Radiology & Ultrasound
Volume
43
Issue
2
Publish Date
2002
Start Page
183
End Page
186

Improved xenograft targeting of tumor-specific anti-epidermal growth factor receptor variant III antibody labeled using N-succinimidyl 4-guanidinomethyl-3-iodobenzoate.

Monoclonal antibodies (mAbs) such as the tumor-specific anti-epidermal growth factor receptor variant III (EGFRvIII) that are internalized and degraded after cell binding necessitate the use of radioiodination methods that minimize the loss of radioactivity from the tumor cell after intracellular processing. The purpose of the current study was to determine the suitability of N-succinimidyl 4-guanidinomethyl-3-iodobenzoate (SGMIB) for labeling this internalizing mAb. A series of paired-label biodistribution experiments were performed in athymic mice bearing subcutaneous, EGFRvIII-expressing, D-256 human glioma and U87 Delta EGFR xenografts. The tissue distribution of radioiodine activity following injection of anti-EGFRvIII mAb L8A4 labeled using N-succinimidyl 4-guanidinomethyl-3-iodobenzoate (SGMIB) were compared to those for mAb labeled using Iodogen, N-succinimidyl 3-iodo-5-pyridinecarboxylate (SIPC) as well as the Boc-protected precursor of SGMIB. Tumor uptake of radioiodine activity for mAb labeled via SGMIB was significantly higher than co-administered L8A4 radioiodinated by other methods. For example, 3 days after injection, D-256 tumor uptake of L8A4 labeled via SGMIB was 20.4 +/- 4.6% ID/g compared with 11.7 +/- 5.5% ID/g when the SIPC method was used. Thyroid uptake for L8A4 (SGMIB) was up to 36 times lower than L8A4 (Iodogen) and less than 0.35% in all experiments, indicating a low degree of deiodination in vivo. These results suggest that SGMIB may be a useful reagent for the radioiodination of this internalizing anti-EGFRvIII mAb.

Authors
Vaidyanathan, G; Affleck, DJ; Bigner, DD; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, Bigner, DD, and Zalutsky, MR. "Improved xenograft targeting of tumor-specific anti-epidermal growth factor receptor variant III antibody labeled using N-succinimidyl 4-guanidinomethyl-3-iodobenzoate." Nucl Med Biol 29.1 (January 2002): 1-11.
PMID
11786270
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
29
Issue
1
Publish Date
2002
Start Page
1
End Page
11

Radiolabeled anti-tenascin antibody for refractory non-Hodgkins lymphoma (NHL).

Authors
Rizzieri, DA; Akabani, G; Coleman, RE; Zalutsky, MR; Niedzwiecki, D; Payne, N; Wikstrand, C; Bigner, DD
MLA Citation
Rizzieri, DA, Akabani, G, Coleman, RE, Zalutsky, MR, Niedzwiecki, D, Payne, N, Wikstrand, C, and Bigner, DD. "Radiolabeled anti-tenascin antibody for refractory non-Hodgkins lymphoma (NHL)." BLOOD 98.11 (November 16, 2001): 247B-247B.
Source
wos-lite
Published In
Blood
Volume
98
Issue
11
Publish Date
2001
Start Page
247B
End Page
247B

Positively charged templates for labeling internalizing antibodies: comparison of N-succinimidyl 5-iodo-3-pyridinecarboxylate and the D-amino acid peptide KRYRR.

Receptor-mediated internalization of monoclonal antibodies (mAbs), such as those specific for the epidermal growth factor receptor variant III (EGFRvIII), can lead to rapid loss of radioactivity from the target cell. In the current study, the anti-EGFRvIII mAb L8A4 was radioiodinated using two methods -N-succinimidyl 5-iodo-3-pyridinecarboxylate (SIPC) and via a D-amino acid peptide LysArgTyrArgArg (D-KRYRR). Paired-label internalization assays performed on EGFRvIII-expressing U87DeltaEGFR cells in vitro demonstrated that labeling L8A4 using D-KRYRR resulted in significantly higher retention of radioiodine in the intracellular compartment. In athymic mice with D256 human glioma xenografts, tumor uptake was similar for both labeling methods through 24 hr. However, an up to fourfold higher tumor retention was observed for mAb labeled with the D-amino acid peptide at later time points. Radiation absorbed dose calculations based on these biodistribution data indicated that L8A4 labeled using D-KRYRR exhibited better tumor-to-normal-organ radiation dose ratios, suggesting that this labeling method may be of particular value for labeling internalizing mAbs.

Authors
Foulon, CF; Welsh, PC; Bigner, DD; Zalutsky, MR
MLA Citation
Foulon, CF, Welsh, PC, Bigner, DD, and Zalutsky, MR. "Positively charged templates for labeling internalizing antibodies: comparison of N-succinimidyl 5-iodo-3-pyridinecarboxylate and the D-amino acid peptide KRYRR." Nucl Med Biol 28.7 (October 2001): 769-777.
PMID
11578897
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
28
Issue
7
Publish Date
2001
Start Page
769
End Page
777

High-level production of alpha-particle-emitting (211)At and preparation of (211)At-labeled antibodies for clinical use.

UNLABELLED: In vitro and in vivo studies in human glioma models suggest that the antitenascin monoclonal antibody 81C6 labeled with the 7.2-h-half-life alpha-particle emitter (211)At might be a valuable endoradiotherapeutic agent for the treatment of brain tumors. The purpose of this study was to develop methods for the production of high levels of (211)At and the radiosynthesis of clinically useful amounts of (211)At-labeled human/mouse chimeric 81C6 antibody. METHODS: (211)At was produced through the (209)Bi(alpha, 2n)(211)At reaction using an internal target system and purified by a dry distillation process. Antibody labeling was accomplished by first synthesizing N-succinimidyl 3-[(211)At]astatobenzoate from the corresponding tri-n-butyl tin precursor and reacting it with the antibody in pH 8.5 borate buffer. Quality control procedures consisted of methanol precipitation, size-exclusion high-performance liquid chromatography (HPLC), and pyrogen and sterility assays, as well as determination of the immunoreactive fraction by a rapid procedure using a recombinant tenascin fragment coupled to magnetic beads. RESULTS: A total of 16 antibody labeling runs were performed. Using beam currents of 50-60 microA alpha-particles and irradiation times of 1.5-4.5 h, the mean (211)At production yield was 27.75 +/- 2.59 MBq/microA.h, and the maximum level of (211)At produced was 6.59 GBq after a 4-h irradiation at 55 microA. The decay-corrected distillation yield was 67% +/- 16%. The yield for the coupling of the (211)At-labeled active ester to the antibody was 76% +/- 8%. The fraction of (211)At activity that eluted with a retention time corresponding to intact IgG on HPLC was 96.0% +/- 2.5%. All preparations had a pyrogen level of <0.125 EU/mL and were determined to be sterile. The mean immunoreactive fraction for these 16 preparations was 83.3% +/- 5.3%. Radiolysis did not interfere with labeling chemistry or the quality of the labeled antibody product. CONCLUSION: These results show that it is feasible to produce clinically relevant activities of (211)At-labeled antibodies and have permitted the initiation of a phase I trial of (211)At-labeled chimeric 81C6 administered directly into the tumor resection cavities of brain tumor patients.

Authors
Zalutsky, MR; Zhao, XG; Alston, KL; Bigner, D
MLA Citation
Zalutsky, MR, Zhao, XG, Alston, KL, and Bigner, D. "High-level production of alpha-particle-emitting (211)At and preparation of (211)At-labeled antibodies for clinical use." J Nucl Med 42.10 (October 2001): 1508-1515.
PMID
11585865
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
42
Issue
10
Publish Date
2001
Start Page
1508
End Page
1515

Biological evaluation of ring- and side-chain-substituted m-iodobenzylguanidine analogues.

A number of ring- and side-chain-substituted m-iodobenzylguanidine analogues were evaluated for their lipophilicity, in vitro stability, uptake by SK-N-SH human neuroblastoma cells in vitro, and biodistribution in normal mice. As expected, the lipophilicity of m-iodobenzylguanidine increased when a halogen was introduced onto the ring and decreased with the addition of polar hydroxyl, amino, and nitro substitutents. Most of the derivatives showed reasonable stability up to 24 h in PBS at 37 degrees C. While N(1)-hydroxy-N(3)-3-[(131)I]iodobenzylguanidine and 3,4-dihydroxy-5-[(131)I]iodobenzylguanidine generated a more nonpolar product in addition to the free iodide, 3-[(131)I]iodo-4-nitrobenzylguanidine decomposed to a product more polar than the parent compound. The specific uptake of 4-chloro-3-[(131)I]iodobenzylguanidine, 3-[(131)I]iodo-4-nitrobenzylguanidine, and N(1)-hydroxy-N(3)-3-[(131)I]iodobenzylguanidine by SK-N-SH human neuroblastoma cells in vitro, relative to that of m-[(125)I]iodobenzylguanidine, was 117 +/- 10%, 50 +/- 4%, and 12 +/- 2%, respectively. The specific uptake of the known m-iodobenzylguanidine analogues 4-hydroxy-3-[(131)I]iodobenzylguanidine and 4-amino-3-[(131)I]iodobenzylguanidine was 80 +/- 4% and 66 +/- 4%, respectively. None of the other m-iodobenzylguanidine derivatives showed any significant specific uptake by SK-N-SH cells. Heart uptake of 4-chloro-3-[(131)I]iodobenzylguanidine in normal mice was higher than that of m-[(125)I]iodobenzylguanidine at later time points (11 +/- 1% ID/g versus 3 +/- 1% ID/g at 24 h; p < 0.05) while uptake of 3-[(131)I]iodo-4-nitrobenzylguanidine and of N(1)-hydroxy-N(3)-3-[(131)I]iodobenzylguanidine in the heart was lower than that of m-iodobenzylguanidine at all time points. In accordance with the in vitro results, none of the other novel m-iodobenzylguanidine derivatives showed any significant myocardial or adrenal uptake in vivo.

Authors
Vaidyanathan, G; Shankar, S; Affleck, DJ; Welsh, PC; Slade, SK; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Shankar, S, Affleck, DJ, Welsh, PC, Slade, SK, and Zalutsky, MR. "Biological evaluation of ring- and side-chain-substituted m-iodobenzylguanidine analogues." Bioconjug Chem 12.5 (September 2001): 798-806.
PMID
11562198
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
12
Issue
5
Publish Date
2001
Start Page
798
End Page
806

Synthesis of ring- and side-chain-substituted m-iodobenzylguanidine analogues.

With the goal of developing MIBG analogues with improved targeting properties especially for oncologic applications, several radioiodinated ring- and side-chain-substituted MIBG analogues were synthesized. Except for 3-[(131)I]iodo-4-nitrobenzylguanidine and N-hydroxy-3-[(131)I]iodobenzylguanidine, the radioiodinated analogues were prepared at no-carrier-added levels from their respective tin precursors. The radiochemical yields generally were in the range of 70-90% except for 3-amino-5-[(131)I]iodobenzylguanidine for which a radiochemical yield of about 40% was obtained. While the silicon precursor N(1),N(2)-bis(tert-butyloxycarbonyl)-N(1)-(4-nitro-3-trimethylsilylbenzyl)guanidine did not yield 3-[(131)I]iodo-4-nitrobenzylguanidine, its deprotected derivative, N(1)-(4-nitro-3-trimethylsilylbenzyl)guanidine was radioiodinated in a modest yield of 20% providing 3-[(131)I]iodo-4-nitrobenzylguanidine. Exchange radioiodination of 3-iodo-4-nitrobenzylguanidine gave 3-[(131)I]iodo-4-nitrobenzylguanidine in 80% radiochemical yield. No-carrier-added [(131)I]NHIBG was prepared from its silicon precursor N(1)-hydroxy-N(3)-(3-trimethylsilylbenzyl)guanidine in 85% radiochemical yield.

Authors
Vaidyanathan, G; Shankar, S; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Shankar, S, and Zalutsky, MR. "Synthesis of ring- and side-chain-substituted m-iodobenzylguanidine analogues." Bioconjug Chem 12.5 (September 2001): 786-797.
PMID
11562197
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
12
Issue
5
Publish Date
2001
Start Page
786
End Page
797

Transfection of the sodium iodide symporter gene for tumour targeting with radioiodine and [At-211]radioastatine

Authors
Mairs, RJ; Carlin, S; Boyd, M; Cunningham, SH; Welsh, P; Zalutsky, MR
MLA Citation
Mairs, RJ, Carlin, S, Boyd, M, Cunningham, SH, Welsh, P, and Zalutsky, MR. "Transfection of the sodium iodide symporter gene for tumour targeting with radioiodine and [At-211]radioastatine." BRITISH JOURNAL OF CANCER 85 (July 2001): 24-24.
Source
wos-lite
Published In
British Journal of Cancer
Volume
85
Publish Date
2001
Start Page
24
End Page
24

Long term response in a patient with neoplastic meningitis secondary to melanoma treated with (131)I-radiolabeled antichondroitin proteoglycan sulfate Mel-14 F(ab')(2): a case study.

Even with novel chemotherapeutic agents and external beam radiation therapy, the prognosis of neoplastic meningitis secondary to malignant melanoma is still dismal. The authors report a case study of a 46-year-old white female who presented with progressive hearing loss, severe headaches, nausea, vomiting, and a rapid decline in neurologic status. She was referred to Duke University Medical Center after conventional chemotherapy for malignant melanoma failed. She was enrolled in a Phase I trial of (131)I-labeled monoclonal antibody Mel-14 F(ab')(2) fragment administered intrathecally. Within a year after her treatment, she recovered, having a normal neurologic exam except for residual bilateral hearing loss. The authors discuss dosimetry, preclinical, and clinical studies conducted with Mel-14 F(ab')(2) and introduce a potentially promising therapy option in the treatment of neoplastic meningitis in patients with malignant melanoma. Currently, the patient remains neurologically normal except for a mild bilateral hearing loss more than 4 years after treatment and has no radiographic evidence of neoplastic meningitis.

Authors
Cokgor, I; Akabani, G; Friedman, HS; Friedman, AH; Zalutsky, MR; Zehngebot, LM; Provenzale, JM; Guy, CD; Wikstrand, CJ; Bigner, DD
MLA Citation
Cokgor, I, Akabani, G, Friedman, HS, Friedman, AH, Zalutsky, MR, Zehngebot, LM, Provenzale, JM, Guy, CD, Wikstrand, CJ, and Bigner, DD. "Long term response in a patient with neoplastic meningitis secondary to melanoma treated with (131)I-radiolabeled antichondroitin proteoglycan sulfate Mel-14 F(ab')(2): a case study." Cancer 91.9 (May 1, 2001): 1809-1813.
PMID
11335907
Source
pubmed
Published In
Cancer
Volume
91
Issue
9
Publish Date
2001
Start Page
1809
End Page
1813

A polar substituent-containing acylation agent for the radioiodination of internalizing monoclonal antibodies: N-succinimidyl 4-guanidinomethyl-3-[131I]iodobenzoate ([131I]SGMIB).

The objective of this study was to develop an acylation agent for the radioiodination of monoclonal antibodies that would maximize retention of the label in tumor cells following receptor- or antigen-mediated internalization. The strategy taken was to add a polar substituent to the labeled aromatic ring to impede transport of labeled catabolites across lysosomal and cell membranes after antibody degradation. Preparation of unlabeled N-succinimidyl 4-guanidinomethyl-3-iodobenzoate (SGMIB) was achieved in six steps from 3-iodo-4-methylbenzoic acid. Preparation of 4-guanidinomethyl-3-[131I]iodobenzoic acid from the silicon precursor, 4-(N1,N2-bis-tert-butyloxycarbonyl)guanidinomethyl-3-trimethylsilylbenzoic acid proceeded in less than 5% radiochemical yield. A more successful approach was to prepare [131I]SGMIB directly from the tin precursor, N-succinimidyl 4-(N1,N2-bis-tert-butyloxycarbonyl)guanidinomethyl-3-trimethylstannylbenzoate, which was achieved in 60-65% radiochemical yield. A rapidly internalizing anti-epidermal growth factor receptor variant III antibody L8A4 was labeled using [131I]SGMIB in 65% conjugation efficiency and with preservation of immunoreactivity. Paired-label in vitro internalization assays demonstrated that the amount of radioactivity retained in cells after internalization for L8A4 labeled with [131I]SGMIB was 3-4-fold higher than that for L8A4 labeled with 125I using either Iodogen or [125I]SIPC. Catabolite assays documented that the increased retention of radioiodine in tumor cells for antibody labeled using [131I]SGMIB was due to positively charged, low molecular weight species. These results suggest that [131I]SGMIB warrants further evaluation as a reagent for labeling internalizing antibodies.

Authors
Vaidyanathan, G; Affleck, DJ; Li, J; Welsh, P; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, Li, J, Welsh, P, and Zalutsky, MR. "A polar substituent-containing acylation agent for the radioiodination of internalizing monoclonal antibodies: N-succinimidyl 4-guanidinomethyl-3-[131I]iodobenzoate ([131I]SGMIB)." Bioconjug Chem 12.3 (May 2001): 428-438.
PMID
11353542
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
12
Issue
3
Publish Date
2001
Start Page
428
End Page
438

Radioimmunotherapy of recurrent glioma patients using alpha-particle emitting astatine-211 labeled chimeric anti-tenascin monoclonal antibody.

Authors
Zalutsky, MR; Akabani, G; Friedman, HS; Cokgor, I; Coleman, RE; Friedman, AH; McLendon, RE; Zhao, XG; Alston, KL; Bigner, DD
MLA Citation
Zalutsky, MR, Akabani, G, Friedman, HS, Cokgor, I, Coleman, RE, Friedman, AH, McLendon, RE, Zhao, XG, Alston, KL, and Bigner, DD. "Radioimmunotherapy of recurrent glioma patients using alpha-particle emitting astatine-211 labeled chimeric anti-tenascin monoclonal antibody." JOURNAL OF NUCLEAR MEDICINE 42.5 (May 2001): 121P-122P.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
42
Issue
5
Publish Date
2001
Start Page
121P
End Page
122P

Targeting a genetically engineered elastin-like polypeptide to solid tumors by local hyperthermia.

Elastin-like polypeptides (ELPs) are biopolymers of the pentapeptide repeat Val-Pro-Gly-Xaa-Gly that undergo an inverse temperature phase transition. They are soluble in aqueous solutions below their transition temperature (T1) but hydrophobically collapse and aggregate at temperatures greater than T1. We hypothesized that ELPs conjugated to drugs would enable thermally targeted drug delivery to solid tumors if their T1 were between body temperature and the temperature in a locally heated region. To test this hypothesis, we synthesized a thermally responsive ELP with a T1 of 41 degrees C and a thermally unresponsive control ELP in Escherichia coli using recombinant DNA techniques. In vivo fluorescence videomicroscopy and radiolabel distribution studies of ELP delivery to human tumors (SKOV-3 ovarian carcinoma and D-54MG glioma) implanted in nude mice demonstrated that hyperthermic targeting of the thermally responsive ELP for 1 h provides a approximately 2-fold increase in tumor localization compared to the same polypeptide without hyperthermia. We observed aggregates of the thermally responsive ELP by fluorescence videomicroscopy within the heated tumor microvasculature but not in control experiments, which demonstrates that the phase transition of the thermally responsive ELP carrier can be engineered to occur in vivo at a specified temperature. By exploiting the phase transition-induced aggregation of these polypeptides, this method provides a new way to thermally target polymer-drug conjugates to solid tumors.

Authors
Meyer, DE; Kong, GA; Dewhirst, MW; Zalutsky, MR; Chilkoti, A
MLA Citation
Meyer, DE, Kong, GA, Dewhirst, MW, Zalutsky, MR, and Chilkoti, A. "Targeting a genetically engineered elastin-like polypeptide to solid tumors by local hyperthermia." Cancer Res 61.4 (February 15, 2001): 1548-1554.
PMID
11245464
Source
pubmed
Published In
Cancer Research
Volume
61
Issue
4
Publish Date
2001
Start Page
1548
End Page
1554

Increased binding affinity enhances targeting of glioma xenografts by EGFRvIII-specific scFv.

Combinatorial variation of CDR3 of V(H) and V(L), followed by phage display, was used to select affinity mutants of the parental anti-epidermal growth factor receptor-vIII (EGFRvIII) scFv MR1. One mutant, MR1-1(scFv), had increased specific binding affinity for EGFRvIII. It was produced and radiolabeled, and its biodistribution was evaluated in human glioma-bearing athymic mice. MR1-1 targeted the same EGFRvIII epitope as MR1 with an approximately 15-fold higher affinity (K(d) = 1.5 x 10(-9) M) measured by surface resonance analysis. Labeling with (131)I or (125)I was performed, and the immunoreactive fraction of the labeled MR1-1(scFv) was 50% to 55%. After incubation at 37 degrees C for 4 days, the binding affinity was maintained at 60% of initial levels. The specificity of MR1-1 for EGFRvIII was demonstrated in vitro by flow cytometry and incubation of FITC-labeled scFv with the EGFRvIII-expressing U87MG. DeltaEGFR cell line or with the EGFRvIII-negative U87MG cell line in the presence or absence of competing unlabeled MR1-1(scFv). We also investigated the internalization and processing of MR1-1 compared with MR1; MR1-1 exhibited levels of both cell surface retention and internalization up to 5 times higher than those by MR1. In biodistribution studies performed in athymic mice bearing s.c. U87MG. DeltaEGFR tumor xenografts, animals received paired-label intratumoral infusions of (131)I-labeled MR1-1(scFv) and (125)I-labeled MR1(scFv). Our results showed an up to 244% +/- 77% increase in tumor uptake for MR1-1 compared with that for MR1. The improved tumor retention of MR1-1(scFv) combined with its rapid clearance from normal tissues also resulted in sustained higher tumor:normal organ ratios. These results suggest that the improved affinity of MR1-1 can significantly impact in vivo glioma-specific targeting and immunotherapy.

Authors
Kuan, CT; Wikstrand, CJ; Archer, G; Beers, R; Pastan, I; Zalutsky, MR; Bigner, DD
MLA Citation
Kuan, CT, Wikstrand, CJ, Archer, G, Beers, R, Pastan, I, Zalutsky, MR, and Bigner, DD. "Increased binding affinity enhances targeting of glioma xenografts by EGFRvIII-specific scFv." Int J Cancer 88.6 (December 15, 2000): 962-969.
PMID
11093822
Source
pubmed
Published In
International Journal of Cancer
Volume
88
Issue
6
Publish Date
2000
Start Page
962
End Page
969

Phase I trial results of iodine-131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with newly diagnosed malignant gliomas.

PURPOSE: To determine the maximum-tolerated dose (MTD) of iodine-131 ((131)I)-labeled 81C6 antitenascin monoclonal antibody (mAb) administered clinically into surgically created resection cavities (SCRCs) in malignant glioma patients and to identify any objective responses with this treatment. PATIENTS AND METHODS: In this phase I trial, newly diagnosed patients with malignant gliomas with no prior external-beam therapy or chemotherapy were treated with a single injection of (131)I-labeled 81C6 through a Rickham reservoir into the resection cavity. The initial dose was 20 mCi and escalation was in 20-mCi increments. Patients were observed for toxicity and response until death or for a minimum of 1 year after treatment. RESULTS: We treated 42 patients with (131)I-labeled 81C6 mAb in administered doses up to 180 mCi. Dose-limiting toxicity was observed at doses greater than 120 mCi and consisted of delayed neurotoxicity. None of the patients developed major hematologic toxicity. Median survival for patients with glioblastoma multiforme and for all patients was 69 and 79 weeks, respectively. CONCLUSION: The MTD for administration of (131)I-labeled 81C6 into the SCRC of newly diagnosed patients with no prior radiation therapy or chemotherapy was 120 mCi. Dose-limiting toxicity was delayed neurologic toxicity. We are encouraged by the survival and toxicity and by the low 2.5% prevalence of debulking surgery for symptomatic radiation necrosis.

Authors
Cokgor, I; Akabani, G; Kuan, CT; Friedman, HS; Friedman, AH; Coleman, RE; McLendon, RE; Bigner, SH; Zhao, XG; Garcia-Turner, AM; Pegram, CN; Wikstrand, CJ; Shafman, TD; Herndon, JE; Provenzale, JM; Zalutsky, MR; Bigner, DD
MLA Citation
Cokgor, I, Akabani, G, Kuan, CT, Friedman, HS, Friedman, AH, Coleman, RE, McLendon, RE, Bigner, SH, Zhao, XG, Garcia-Turner, AM, Pegram, CN, Wikstrand, CJ, Shafman, TD, Herndon, JE, Provenzale, JM, Zalutsky, MR, and Bigner, DD. "Phase I trial results of iodine-131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with newly diagnosed malignant gliomas." J Clin Oncol 18.22 (November 15, 2000): 3862-3872.
PMID
11078500
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
18
Issue
22
Publish Date
2000
Start Page
3862
End Page
3872
DOI
10.1200/JCO.2000.18.22.3862

Radiolabeled guanine derivatives for the in vivo mapping of O(6)-alkylguanine-DNA alkyltransferase: 6-(4-[(18)F]Fluoro-benzyloxy)-9H-purin-2-ylamine and 6-(3-[(131)I]Iodo-benzyloxy)-9H-purin-2-ylamine.

Two radiolabeled analogues of 6-benzyloxy-9H-purin-2-ylamine (O(6)-benzylguanine; BG) potentially useful in the in vivo mapping of O(6)-alkylguanine-DNA alkyltransferase (AGT) were synthesized. Fluorine-18 labeling of the known 6-(4-fluoro-benzyloxy)-9H-purin-2-ylamine (FBG; 6) was accomplished by the condensation of 4-[(18)F]fluorobenzyl alcohol with 2-aminopurin-6-yltrimethylammonium chloride (4) or 2-amino-6-chloropurine in average decay-corrected radiochemical yields of 40 and 25%, respectively. Unlabeled 6-(3-iodo-benzyloxy)-9H-purin-2-ylamine (IBG; 7) was prepared from 4 and 3-iodobenzyl alcohol. Radioiodination of 9, prepared from 7 in two steps, and subsequent deprotection gave [(131)I]7 in about 70% overall radiochemical yield. The IC(50) values for the inactivation of AGT from CHO cells transfected with pCMV-AGT were 15 nM for IBG and 50 nM for FBG. The binding of [(18)F]6 and [(131)I]7 to purified AGT was specific and saturable with both exhibiting similar IC(50) values (5-6 microM).

Authors
Vaidyanathan, G; Affleck, DJ; Cavazos, CM; Johnson, SP; Shankar, S; Friedman, HS; Colvin, MO; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, Cavazos, CM, Johnson, SP, Shankar, S, Friedman, HS, Colvin, MO, and Zalutsky, MR. "Radiolabeled guanine derivatives for the in vivo mapping of O(6)-alkylguanine-DNA alkyltransferase: 6-(4-[(18)F]Fluoro-benzyloxy)-9H-purin-2-ylamine and 6-(3-[(131)I]Iodo-benzyloxy)-9H-purin-2-ylamine." Bioconjug Chem 11.6 (November 2000): 868-875.
PMID
11087336
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
11
Issue
6
Publish Date
2000
Start Page
868
End Page
875

Astatine-211-labeled radiotherapeutics: an emerging approach to targeted alpha-particle radiotherapy.

Targeted radiotherapy or endoradiotherapy is an appealing approach to cancer treatment because of the potential for delivering curative doses of radiation to tumor while sparing normal tissues. Radionuclides that decay by the emission of alpha-particles such as the heavy halogen astatine-211 (211At) offer the exciting prospect of combining cell-specific molecular targets with radiation having a range in tissue of only a few cell diameters. Herein, the radiobiological advantages of alpha-particle targeted radiotherapy will be reviewed, and the rationale for using 211At for this purpose will be described. The chemistry of astatine is similar to that of iodine; however, there are important differences which make the synthesis and evaluation of 211At-labeled compounds more challenging. Perhaps the most successful approach that has been developed involves the astatodemetallation of tin, silicon or mercury precursors. Astatine-211 labeled agents that have been investigated for targeted radiotherapy include [211At]astatide, 211At- labeled particulates, 211At-labeled naphthoquinone derivatives, 211At-labeled methylene blue, 211At-labeled DNA precursors, meta-[211At]astatobenzylguanidine, 211At-labeled biotin conjugates, 211At-labeled bisphosphonates, and 211At-labeled antibodies and antibody fragments. The status of these 211At-labeled compounds will be discussed in terms of their labeling chemistry, cytotoxicity in cell culture, as well as their tissue distribution and therapeutic efficacy in animal models of human cancers. Finally, an update on the status of the first clinical trial with an 211At-labeled targeted therapeutic, 211At-labeled chimeric anti-tenascin antibody 81C6, will be provided.

Authors
Zalutsky, MR; Vaidyanathan, G
MLA Citation
Zalutsky, MR, and Vaidyanathan, G. "Astatine-211-labeled radiotherapeutics: an emerging approach to targeted alpha-particle radiotherapy." Curr Pharm Des 6.14 (September 2000): 1433-1455. (Review)
PMID
10903402
Source
pubmed
Published In
Current Pharmaceutical Design
Volume
6
Issue
14
Publish Date
2000
Start Page
1433
End Page
1455

Radioiodination via D-amino acid peptide enhances cellular retention and tumor xenograft targeting of an internalizing anti-epidermal growth factor receptor variant III monoclonal antibody.

The mutant epidermal growth factor receptor variant III (EGFRvIII) has been found on gliomas and other tumors but not on normal tissues, including those that express the wild-type receptor. Monoclonal antibodies (mAbs) specific for EGFRvIII are rapidly internalized and degraded after binding to EGFRvIII-expressing cells. If anti-EGFRvIII mAbs are to be useful for radioimmunotherapy, then methods for trapping radionuclides in target cells after mAb processing are required. Because lysosomes are known to retain positively charged molecules, we have evaluated a new reagent for this purpose that uses a polycationinc peptide composed of D-amino acids (D-Lys-D-Arg-D-Tyr-D-Arg-D-Arg; D-KRYRR). D-KRYRR was first labeled using lodogen and then coupled to the murine anti-EGFRvIII mAb L8A4 via maleimido bond formation in 60% yield. In vitro assays with the U87deltaEGFR cell line indicated that internalized and total cell-associated activity for the 125I-labeled D-KRYRR-L8A4 conjugate were up to 4 and 5 times higher, respectively, than for L8A4 labeled with 131I using Iodogen. Paired-label comparisons in athymic mice with s.c. U87deltaEGFR xenografts demonstrated up to 5-fold higher tumor uptake for mAb labeled using D-KRYRR. Higher levels of radioiodine activity also were observed in kidney when L8A4 was labeled using D-KRYRR. Another paired-label study directly compared L8A4 labeled using radioiodinated D-KRYRR and L-KRYRR, and confirmed the role of D-amino acids in enhancing tumor uptake. These results suggest that D-KRYRR is a promising reagent for the radioiodination of internalizing mAbs, such as the anti-EGFRvIII mAb L8A4.

Authors
Foulon, CF; Reist, CJ; Bigner, DD; Zalutsky, MR
MLA Citation
Foulon, CF, Reist, CJ, Bigner, DD, and Zalutsky, MR. "Radioiodination via D-amino acid peptide enhances cellular retention and tumor xenograft targeting of an internalizing anti-epidermal growth factor receptor variant III monoclonal antibody." Cancer Res 60.16 (August 15, 2000): 4453-4460.
PMID
10969792
Source
pubmed
Published In
Cancer Research
Volume
60
Issue
16
Publish Date
2000
Start Page
4453
End Page
4460

Exposure of human osteosarcoma and bone marrow cells to tumour-targeted alpha-particles and gamma-irradiation: analysis of cell survival and microdosimetry.

PURPOSE: This study was designed to compare the cytotoxic effects of an alpha-emitting radioimmunoconjugate, which binds to osteosarcoma but not to bone marrow cells, with those of external gamma-irradiation. MATERIALS AND METHODS: The human osteosarcoma cell line, OHS-s1, and mononuclear cells from bone marrow (BM) harvested from healthy donors, were used for these experiments. Cells in suspension were added to various activity concentrations of the anti-osteosarcoma monoclonal antibody TP-3 radiolabelled with 211At. Following incubation for 1 h, unbound radioactivity was washed off and cell survival was determined from clonogenic assays. Microdosimetry was calculated based on binding and retention kinetics of 211At to the cells, as well as cellular and nuclear diameters. For comparison, cell suspensions were irradiated with a single dose of 60Co gamma-rays. RESULTS: 211At-labelled TP-3 showed heterogeneous binding to OHS-s1 cells, with a considerable variation among experiments. About 78% of the initially bound 211At decayed while associated with the OHS-s1 cells. D0 values estimated by microdosimetry were 0.33 (0.22-0.48, range) Gy and 1.18 (0.89-1.89) Gy for OHS-s1 and BM cells, respectively, whereas D0 values after external beam irradiation were 0.86+/-0.07Gy and 1.71+/-0.22Gy. The relative biological effectiveness (RBE) of 211At-labelled TP-3 at 37% survival was 3.43 for OHS-s1 and 1.55 for BM. CONCLUSIONS: High-LET targeted alpha-particle exposure killed osteosarcoma cells more effectively than bone marrow cells, although heterogeneous antigen expression among these tumour cells limited the magnitude of this effect.

Authors
Aurlien, E; Larsen, RH; Akabani, G; Olsen, DR; Zalutsky, MR; Bruland, OS
MLA Citation
Aurlien, E, Larsen, RH, Akabani, G, Olsen, DR, Zalutsky, MR, and Bruland, OS. "Exposure of human osteosarcoma and bone marrow cells to tumour-targeted alpha-particles and gamma-irradiation: analysis of cell survival and microdosimetry." Int J Radiat Biol 76.8 (August 2000): 1129-1141.
PMID
10947126
Source
pubmed
Published In
International Journal of Radiation Biology (Informa)
Volume
76
Issue
8
Publish Date
2000
Start Page
1129
End Page
1141

Synergistic interaction between anti-p185HER-2 ricin A chain immunotoxins and radionuclide conjugates for inhibiting growth of ovarian and breast cancer cells that overexpress HER-2.

Radionuclide conjugates or ricin A chain (RTA) immunotoxins that target pl85HER-2 have partially inhibited the growth of human ovarian cancer xenografts in athymic mice but generally have not cured mice bearing human tumor transplants. The present study was undertaken to explore whether a combination of ionizing radiation and an immunotoxin could exert additive or synergistic cytotoxicity in culture and in vivo against cancer cells that overexpress p185HER-2. In cell culture, treatment with 200-2000 cGy external beam irradiation followed by incubation with TA1-anti-pl85mHER2-RTA immunotoxin (TA1-RTA) produced synergistic inhibition of clonogenic growth of ovarian and breast cancer cells that expressed > 10(6) pl85HER-2 receptors/cell. The effect on cell survival correlated with an inhibition of DNA repair. A prior study (F. J. Xu et al, Nucl. Med. Biol., 24: 451-460, 1997) compared the biodistribution of radionuclide conjugates prepared with monoclonal antibodies that bind to different epitopes on the extracellular domain of pl85HER-2 and found optimal tumor uptake with the 520C9 antibody, which did not compete with TA1 for binding to the receptor. In this report, the TA1-RTA immunotoxin and the 131I-labeled 520C9 radionuclide conjugate could each inhibit the growth of clone-9002-18 xenografts in athymic mice but did not yield long-term survivors using maximally tolerated doses of each agent. When TA1-RTA and 131I-labeled 520C9 were used in combination, a greater inhibition of tumor growth was obtained than with either single agent. Similarly, survival with the combined treatment was significantly prolonged (P = 0.004) relative to treatment with immunotoxin or radionuclide conjugate alone. After treatment with an optimal combination of immunotoxin and radionuclide conjugate, 50% of mice survived >300 days, whereas controls succumbed with a median survival of 36 days. These results suggest that combinations of immunotoxins and radionuclide conjugates deserve further evaluation for the treatment of cancers that overexpress pl85HER-2.

Authors
Xu, F; Leadon, SA; Yu, Y; Boyer, CM; O'Briant, K; Ward, K; McWatters, A; Zhao, X; Bae, DS; DeSombre, K; Zalutsky, MR; Bast, RC
MLA Citation
Xu, F, Leadon, SA, Yu, Y, Boyer, CM, O'Briant, K, Ward, K, McWatters, A, Zhao, X, Bae, DS, DeSombre, K, Zalutsky, MR, and Bast, RC. "Synergistic interaction between anti-p185HER-2 ricin A chain immunotoxins and radionuclide conjugates for inhibiting growth of ovarian and breast cancer cells that overexpress HER-2." Clin Cancer Res 6.8 (August 2000): 3334-3341.
PMID
10955821
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
6
Issue
8
Publish Date
2000
Start Page
3334
End Page
3341

Radioiodination and astatination of octreotide by conjugation labeling.

Octreotide was coupled to 3-iodobenzoyl and 3-iodonicotinoyl moieties to obtain [N-(3-iodobenzoyl)-D-Phe(1)]octreotide (IBO) and [N-(3-iodonicotinoyl)-D-Phe(1)]octreotide (INO), respectively. The IC(50) values for the binding of IBO and INO to CA20948 rat pancreatic tumor membranes were 0.90 and 0.13 nM, respectively, compared with 0.35 nM for octreotide itself. Starting from N-succinimidyl 3-[(131)I]iodobenzoate and N-succinimidyl 5-[(131)I]iodopyridine-3- carboxylate, [(131)I]IBO and [(131)I]INO were prepared in overall radiochemical yields of 35%-50%. Likewise, ¿N-(3-[(211)At]astatobenzoyl)-D-Phe(1)¿octreotide ([(211)At]ABO) was prepared in similar yield from N-succinimidyl 3-[(211)At]astatobenzoate. In vitro assays with AR42J rat pancreatic tumor cells demonstrated a higher retention of cell-internalized radioiodine activity for [(131)I]INO compared with [(125)I]IBO. Tissue distribution studies with both conjugates revealed low levels of activity in the thyroid suggesting that dehalogenation of these peptides was minimal.

Authors
Vaidyanathan, G; Affleck, D; Welsh, P; Srinivasan, A; Schmidt, M; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, D, Welsh, P, Srinivasan, A, Schmidt, M, and Zalutsky, MR. "Radioiodination and astatination of octreotide by conjugation labeling." Nucl Med Biol 27.4 (May 2000): 329-337.
PMID
10938466
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
27
Issue
4
Publish Date
2000
Start Page
329
End Page
337

Microdosimetry of alpha-particle-emitting At-211-labelled monoclonal antibody (MAb) using histological images of malignant brain tumors.

Authors
Akabani, G; McLendon, RE; Bigner, DD; Zalutsky, MR
MLA Citation
Akabani, G, McLendon, RE, Bigner, DD, and Zalutsky, MR. "Microdosimetry of alpha-particle-emitting At-211-labelled monoclonal antibody (MAb) using histological images of malignant brain tumors." JOURNAL OF NUCLEAR MEDICINE 41.5 (May 2000): 84P-84P.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
41
Issue
5
Publish Date
2000
Start Page
84P
End Page
84P

Genetically engineered biopolymer conjugate for thermal targeting of anticancer therapeutics.

Authors
Chilkoti, A; Meyer, DE; Kong, GH; Dewhirst, MW; Foulon, C; Zalutsky, MR
MLA Citation
Chilkoti, A, Meyer, DE, Kong, GH, Dewhirst, MW, Foulon, C, and Zalutsky, MR. "Genetically engineered biopolymer conjugate for thermal targeting of anticancer therapeutics." ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 219 (March 26, 2000): U453-U453.
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
219
Publish Date
2000
Start Page
U453
End Page
U453

Dosimetry and dose-response relationships in newly diagnosed patients with malignant gliomas treated with iodine-131-labeled anti-tenascin monoclonal antibody 81C6 therapy.

PURPOSE: The objective of this study was to perform the dosimetry and evaluate the dose-response relationships in newly diagnosed patients with malignant brain tumors treated by direct injections of (131)I-labeled 81C6 monoclonal antibody (MAb) into surgically created resection cavities (SCRCs). METHODS AND MATERIALS: Absorbed doses to the 2-cm-thick shell as measured from the margins of the resection cavity interface were estimated for 42 patients with primary brain tumors. MR images were used to assess the enhanced-rim volume as a function of time after radiolabeled MAb therapy. Biopsy samples were obtained from 15 patients and 1 autopsy. RESULTS: The average absorbed dose [range] to the 2-cm shell region was 32 [3-59] Gy. For the endpoint of minimal time to MR contrast enhancement, the optimal absorbed dose and initial dose-rate were 43 +/- 16 Gy and 0. 41 +/- 0.10 Gy/h, respectively. There was a correlation between the absorbed dose and dose rate to the shell region and biopsy outcome (tumor recurrence, radionecrosis, and tumor recurrence and/or radionecrosis). In this Phase I study, the maximum tolerated dose (MTD) was 120 mCi. At this MTD, the estimated average absorbed dose and initial dose rate to the 2-cm shell were 41 [9-89] Gy and 0.51 [0.24-1.13] Gy/h, respectively. These values are in agreement with the optimal values based on the time to MR lesion rim enhancement. CONCLUSIONS: The average absorbed dose to the 2-cm shell region varied considerably and mainly depended on cavity volume. In future clinical trials, the administered activity of (131)I-labeled 81C6 MAb may be adjusted based on cavity volume in order to deliver the optimal absorbed dose of 43 Gy rather than giving a fixed administered activity.

Authors
Akabani, G; Cokgor, I; Coleman, RE; González Trotter, D; Wong, TZ; Friedman, HS; Friedman, AH; Garcia-Turner, A; Herndon, JE; DeLong, D; McLendon, RE; Zhao, XG; Pegram, CN; Provenzale, JM; Bigner, DD; Zalutsky, MR
MLA Citation
Akabani, G, Cokgor, I, Coleman, RE, González Trotter, D, Wong, TZ, Friedman, HS, Friedman, AH, Garcia-Turner, A, Herndon, JE, DeLong, D, McLendon, RE, Zhao, XG, Pegram, CN, Provenzale, JM, Bigner, DD, and Zalutsky, MR. "Dosimetry and dose-response relationships in newly diagnosed patients with malignant gliomas treated with iodine-131-labeled anti-tenascin monoclonal antibody 81C6 therapy." Int J Radiat Oncol Biol Phys 46.4 (March 1, 2000): 947-958.
PMID
10705017
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
46
Issue
4
Publish Date
2000
Start Page
947
End Page
958

Genetically engineered polypeptide carrier for thermal targeting of anticancer therapeutics

The thermally-responsive carrier, an elastin-like polypeptide (ELP), is an oligomer of a Val-Pro-Gly-Xaa-Gly pentapeptide repeat. Below a specific, inverse phase transition temperature (Tt), ELPs are highly soluble in aqueous solution. However, upon raising the Tt, they undergo a reversible transition resulting in desolvation and aggregation. Control of the amino acid sequence and the molecular weight of the carrier by genetically encodable synthesis enables precise molecular design of ELPs with an inverse transition of -40 °C. ELP was studied whether it will remain soluble systematically but will accumulate at sites of externally-induced local hyperthermia where the temperature is raised above Tt.

Authors
Meyer, DE; Kong, GA; Dewhirst, MW; Foulon, C; Zalutsky, MR; Chilkoti, A
MLA Citation
Meyer, DE, Kong, GA, Dewhirst, MW, Foulon, C, Zalutsky, MR, and Chilkoti, A. "Genetically engineered polypeptide carrier for thermal targeting of anticancer therapeutics." American Chemical Society, Polymer Preprints, Division of Polymer Chemistry 41.1 (2000): 1020-1021.
Source
scival
Published In
American Chemical Society, Polymer Preprints, Division of Polymer Chemistry
Volume
41
Issue
1
Publish Date
2000
Start Page
1020
End Page
1021

Radioiodination and astatination of octreotide by conjugation labeling

Octreotide was coupled to 3-iodobenzoyl and 3-iodonicotinoyl moieties to obtain [N-(3-iodobenzoyl)-D-Phe1]octreotide (IBO) and [N-(3-iodonicotinoyl)-D-Phe1]octreotide (INO), respectively. The IC50 values for the binding of IBO and INO to CA20948 rat pancreatic tumor membranes were 0.90 and 0.13 nM, respectively, compared with 0.35 nM for octreotide itself. Starting from N-succinimidyl 3-[131I]iodobenzoate and N-succinimidyl 5-[131I]iodopyridine-3-carboxylate, [131I]IBO and [131I]INO were prepared in overall radiochemical yields of 35%-50%. Likewise, {N-(3-[11At]astatobenzoyl)-D-Phe1}octreotide ([211At]ABO) was prepared in similar yield from N-succinimidyl 3-[211At]astatobenzoate. In vitro assays with AR42J rat pancreatic tumor cells demonstrated a higher retention of cell-internalized radioiodine activity for [131I]INO compared with [125I]IBO. Tissue distribution studies with both conjugates revealed low levels of activity in the thyroid suggesting that dehalogenation of these peptides was minimal. (C) 2000 Elsevier Science Inc.

Authors
Vaidyanathan, G; Affleck, D; Welsh, P; Srinivasan, A; Schmidt, M; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, D, Welsh, P, Srinivasan, A, Schmidt, M, and Zalutsky, MR. "Radioiodination and astatination of octreotide by conjugation labeling." Journal of Inorganic Biochemistry 78.3 (2000): 329-337.
Source
scival
Published In
Journal of Inorganic Biochemistry
Volume
78
Issue
3
Publish Date
2000
Start Page
329
End Page
337

Dosimetry and microdosimetry of targeted radiotherapy

Dosimetry in targeted radiotherapy (TR) uses different calculation methods, whose degree of refinement is closely conditioned by the particular objective sought. It is more generally performed to establish a correlation between the quantity of radiation delivered to a target and the biological damage observed or that can be reliably predicted. It can thus be used to optimise treatments and allow comparison of different therapeutic approaches, as well as to study the basic methods of irradiation of biological matter. Two broad types of investigations can be found in the literature: microdosimetric ones (stochastic approaches used to study energy deposits) and macrodosimetric ones (non-stochastic or deterministic approaches). The mathematical formalism is consistent between these two types, and the calculation methods currently used are often similar. This review presents different approaches to the dosimetry of radionuclides used in TR. The introduction defines the general problem, the role of dosimetry in TR and the specific problems raised by targeting (non-uniformity of source distributions). The first part considers the types of calculation methods found in TR in relation to the basic quantities used to represent stochastic energy deposit on a cellular scale. In particular, it compares the formalism and the methods used in microdosimetric or conventional macrodosimetric approches. Although microdosimetry, or even track structure calculations, can provide the basic elements for modelling the absorbed dose process, a simplified dosimetric approach may be adequate to describe the phenomena observed. The scheme proposed by the MIRD committee relates to such an approach and is presented together with other methods allowing the calculation of the mean dose delivered (analytic methods, dose point kernels, Monte-Carlo, etc.). The second part shows the application range for the various methods, providing selected examples of dosimetric approaches in TR on different scales, from the organ (or tissues) to the cell or even DNA, and a brief presentation of bone marrow dosimetry.

Authors
Zalutsky, MR; Vaidyanathan, G
MLA Citation
Zalutsky, MR, and Vaidyanathan, G. "Dosimetry and microdosimetry of targeted radiotherapy." Current Pharmaceutical Design 6.14 (2000): 1469-1502.
PMID
10903404
Source
scival
Published In
Current Pharmaceutical Design
Volume
6
Issue
14
Publish Date
2000
Start Page
1469
End Page
1502

Radioiodinated antibody targeting of the HER-2/neu oncoprotein: effects of labeling method on cellular processing and tissue distribution.

Monoclonal antibody (MAb) internalization can have a major effect on tumor retention of radiolabel. Two anti-HER-2/neu MAbs (TA1 and 520C9) were radioiodinated using the iodogen, N-succinimidyl 5-iodo-3-pyridinecarboxylate (SIPC), and tyramine-cellobiose (TCB) methods. Paired-label studies compared internalization and cellular processing of the labeled MAbs by SKOv3 9002-18 ovarian cancer cells in vitro. Intracellular radioiodine activity for 520C9 was up to 2.6 and 3.0 times higher for SIPC and TCB labeling, respectively, compared with iodogen. Likewise, intracellular activity for TA1 was up to 2.3 and 2.9 times higher with the SIPC and TCB methods compared with iodogen labeling. Unfortunately, similar advantages in tumor accumulation were not achieved in athymic mice bearing SKOv3 9008-18 ovarian cancer xenografts.

Authors
Zalutsky, MR; Xu, FJ; Yu, Y; Foulon, CF; Zhao, XG; Slade, SK; Affleck, DJ; Bast, RC
MLA Citation
Zalutsky, MR, Xu, FJ, Yu, Y, Foulon, CF, Zhao, XG, Slade, SK, Affleck, DJ, and Bast, RC. "Radioiodinated antibody targeting of the HER-2/neu oncoprotein: effects of labeling method on cellular processing and tissue distribution." Nucl Med Biol 26.7 (October 1999): 781-790.
PMID
10628557
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
26
Issue
7
Publish Date
1999
Start Page
781
End Page
790

Radiotoxicity of systemically administered 211At-labeled human/mouse chimeric monoclonal antibody: a long-term survival study with histologic analysis.

PURPOSE: The antitenascin human/mouse chimeric monoclonal antibody labeled with the alpha-particle-emitting radionuclide 211At is of interest as an endoradiotherapeutic agent for the treatment of brain tumors. To facilitate the investigation of 211At-labeled chimeric 81C6 in patients, the long-term radiotoxicity of this radiopharmaceutical has been evaluated. METHODS AND MATERIALS: Antibody labeling was performed using N-succinimidyl 3-[211At]astato-benzoate. After an initial dose-finding experiment, a second toxicity study was carried out at 4 dose levels in groups of 30 nonthyroid blocked B6C3F1 mice per group (15 males, 15 females). Male mice received either saline or 15-81 kBq/g and females received either saline or 16-83 kBq/g of 211At-labeled antibody. Ten animals (5 males, 5 females) were followed for 6 months and the remainder for 1 year. RESULTS: The lethal dose in 10% of animals (LD10) for 211At-labeled chimeric 81C6 was 46 kBq/g in females and 102 kBq/g in males. Toxic effects--perivascular fibrosis of the intraventricular septum of the heart, bone marrow suppression, splenic white pulp atrophy, and spermatic maturational delay--generally were confined to a few animals receiving the highest doses of labeled antibody. CONCLUSIONS: The LD10 of 211At-labeled chimeric 81C6 in this mouse strain was about half that of [211At]astatide. These results establish the preclinical maximum tolerated dose of 211At-labeled chimeric 81C6 and define in the mouse the target organs for toxicity. These studies will be useful for determining starting doses for clinical studies with 211At-labeled chimeric 81C6.

Authors
McLendon, RE; Archer, GE; Larsen, RH; Akabani, G; Bigner, DD; Zalutsky, MR
MLA Citation
McLendon, RE, Archer, GE, Larsen, RH, Akabani, G, Bigner, DD, and Zalutsky, MR. "Radiotoxicity of systemically administered 211At-labeled human/mouse chimeric monoclonal antibody: a long-term survival study with histologic analysis." Int J Radiat Oncol Biol Phys 45.2 (September 1, 1999): 491-499.
PMID
10487576
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
45
Issue
2
Publish Date
1999
Start Page
491
End Page
499

Preparation and characterization of anti-tenascin monoclonal antibody-streptavidin conjugates for pretargeting applications.

Radioimmunopretargeting is based on the separate injection of a modified mAb and the radionuclide and most frequently exploits the very high avidity of biotin for streptavidin (SA). Currently, we are evaluating the therapeutic potential of directly labeled monoclonal antibody (mAb) 81C6, reactive with the extracellular matrix protein tenascin, in surgically created glioma resection cavity patients. To be able to investigate pretargeting in this setting, the synthesis of 81C6 mAb-SA conjugates was required. In the current study, we have evaluated five methods for preparing both murine 81C6 (m81C6) and human/mouse chimeric 81C6 (c81C6) SA conjugates with regard to yield, biotin-binding capacity, immunoreactivity, and molecular weight. The 81C6 mAb and SA were coupled by covalent interaction between sulfhydryl groups generated on the mAb via N-succinimidyl-S-acetylthioacetate, dithiothreitol or 2-iminothiolane (2IT), and maleimido-derivatized SA, prepared via sulfosuccinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) or N-succinimidyl-3-(2-pyridyldithio)-propionate. A noncovalent approach involving reaction of a biotinylated mAb, prepared using biotin caproate, and SA also was studied. The evaluation criteria were yield of mAb-SA 215 kDa monomer, as well as conjugate biotin-binding capacity and immunoreactive fraction. The optimal procedure involved activation of m81C6 or c81C6 with 30 equiv of 2IT and reaction of SA with 10 equiv of SMCC and yielded a conjugate with excellent biotin-binding capacity and immunoreactivity. The ((125)I-labeled m81C6)-2IT-SMCC-SA was stable and did not lose biotin-binding capacity after a 72 h incubation in human glioma cyst fluid in vitro. Although the conjugate was stable in murine serum in vivo, its biotin-binding capacity declined rapidly, consistent with high endogenous biotin levels in the mouse. After injection of the radioiodinated conjugate into athymic mice with subcutaneous D-54 MG human glioma xenografts, high tumor uptake (36.0 +/- 10.7% ID/g at 3 days) and excellent tumor:normal tissue ratios were observed.

Authors
Foulon, CF; Bigner, DD; Zalutsky, MR
MLA Citation
Foulon, CF, Bigner, DD, and Zalutsky, MR. "Preparation and characterization of anti-tenascin monoclonal antibody-streptavidin conjugates for pretargeting applications." Bioconjug Chem 10.5 (September 1999): 867-876.
PMID
10502355
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
10
Issue
5
Publish Date
1999
Start Page
867
End Page
876

Astatine-211 labeled chimeric anti-tenascin antibody: Phase I trial in brain tumor resection cavity patients

Authors
Zalutsky, MR; Akabani, G; Cokgor, I; Friedman, HS; Coleman, RE; Friedman, AH; McLendon, RE; Bigner, DD
MLA Citation
Zalutsky, MR, Akabani, G, Cokgor, I, Friedman, HS, Coleman, RE, Friedman, AH, McLendon, RE, and Bigner, DD. "Astatine-211 labeled chimeric anti-tenascin antibody: Phase I trial in brain tumor resection cavity patients." EUROPEAN JOURNAL OF NUCLEAR MEDICINE 26.9 (September 1999): 1215-1215.
Source
wos-lite
Published In
European journal of nuclear medicine
Volume
26
Issue
9
Publish Date
1999
Start Page
1215
End Page
1215

At-211- and I-131-labeled bisphosphonates with high in vivo stability and bone accumulation

Authors
Larsen, RH; Murad, KM; Akabani, G; Hoff, P; Bruland, OS; Zalutsky, MR
MLA Citation
Larsen, RH, Murad, KM, Akabani, G, Hoff, P, Bruland, OS, and Zalutsky, MR. "At-211- and I-131-labeled bisphosphonates with high in vivo stability and bone accumulation." JOURNAL OF NUCLEAR MEDICINE 40.7 (July 1999): 1197-1203.
PMID
10405142
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
40
Issue
7
Publish Date
1999
Start Page
1197
End Page
1203

125I-labeled anti-epidermal growth factor receptor-vIII single-chain Fv exhibits specific and high-level targeting of glioma xenografts.

A single-chain antibody fragment, MR1(scFv), with specific binding to epidermal growth factor receptor-vIII (EGFRvIII), was produced, radiolabeled, and evaluated for biodistribution in human glioma-bearing athymic mice. The mutant receptor EGFRvIII has a deletion in its extracellular domain that results in the formation of a new, tumor-specific antigen found in glioblastomas, breast carcinomas, and other tumors. The scFv molecule, designed as V(H)-(Gly4-Ser)3-V(L), was expressed in Escherichia coli in inclusion body form; recovered scFv fragments were properly refolded in redox-shuffling buffer. Size-exclusion chromatography of purified scFv demonstrated a protein monomer of Mr 26,000. Labeling was performed using N-succinimidyl 5-[125I]iodo-3-pyridinecarboxylate (SIPC) or Iodogen to specific activities of 0.5-2.0 mCi/mg, with yields of 35-50% and 45-70%, respectively. The immunoreactive fraction (IRF) of the labeled MR1(scFv) was 65-80% when SIPC was used and 50-55% when Iodogen was used. The affinity (K(A)) of MRI(scFv) for EGFRvIII was 4.3 x 10(7) +/- 0.1 x 10(7) M(-1) by BIAcore analysis, and it was 1.0 x 10(8) +/- 0.1 x 10(8) M(-1) and by Scatchard analysis versus EGFRvIII-expressing cells. After incubation at 37 degrees C for 24 h, the binding affinity was maintained, and the IRF was maintained at 60-70%. The specificity of MR1(scFv) for EGFRvIII was demonstrated in vitro by incubation of radiolabeled MR1(scFv) with the EGFRvIII-expressing U87MG.deltaEGFR cell line in the presence or absence of competing unlabeled MR1(scFv) or anti-EGFRvIII MAbs L8A4 and H10. In biodistribution studies using athymic mice bearing s.c. U87MG.deltaEGFR tumor xenografts, animals received intratumoral or i.v. infusions of paired-label [125I]SIPC-MR1(scFv) and [131I]SIPC-anti-Tac(scFv) as a control. When given by the intratumoral route, MR1(scFv) retained high tumor uptakes of 85% injected dose per gram of tissue at 1 h and 16% injected dose per gram of tissue at 24 h following administration. Specific: control scFv tumor uptake ratios of more than 20:1 at 24 h demonstrated specific localization of MR1(scFv). The excellent tumor retention of MR1(scFv), combined with its rapid clearance from normal tissues, resulted in high tumor:normal organ ratios.

Authors
Kuan, CT; Reist, CJ; Foulon, CF; Lorimer, IA; Archer, G; Pegram, CN; Pastan, I; Zalutsky, MR; Bigner, DD
MLA Citation
Kuan, CT, Reist, CJ, Foulon, CF, Lorimer, IA, Archer, G, Pegram, CN, Pastan, I, Zalutsky, MR, and Bigner, DD. "125I-labeled anti-epidermal growth factor receptor-vIII single-chain Fv exhibits specific and high-level targeting of glioma xenografts." Clin Cancer Res 5.6 (June 1999): 1539-1549.
PMID
10389943
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
5
Issue
6
Publish Date
1999
Start Page
1539
End Page
1549

I-125-labeled anti-epidermal growth factor receptor-vIII single-chain Fv exhibits specific and high-level targeting of glioma xenografts

Authors
Kuan, CT; Reist, CJ; Foulon, CF; Lorimer, IAJ; Archer, G; Pegram, CN; Pastan, I; Zalutsky, MR; Bigner, DD
MLA Citation
Kuan, CT, Reist, CJ, Foulon, CF, Lorimer, IAJ, Archer, G, Pegram, CN, Pastan, I, Zalutsky, MR, and Bigner, DD. "I-125-labeled anti-epidermal growth factor receptor-vIII single-chain Fv exhibits specific and high-level targeting of glioma xenografts." CLINICAL CANCER RESEARCH 5.6 (June 1999): 1539-1549.
Source
wos-lite
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
5
Issue
6
Publish Date
1999
Start Page
1539
End Page
1549

Astatine-211 labeling of internalizing anti-EGFRvIII monoclonal antibody using N-succinimidyl 5-[211At]astato-3-pyridinecarboxylate.

Monoclonal antibodies (MAbs) such as the anti-epidermal growth factor variant III (EGFRvIII) MAb L8A4 are rapidly internalized, which can lead to rapid loss of radioactivity from the tumor cell. The aim of this study was to evaluate the potential utility of N-succinimidyl 5-[211At]astato-3-pyridinecarboxylate ([211At]SAPC) for labeling murine L8A4 with 211At. SAPC was synthesized by astatodestannylation of N-succinimidyl 5-tri-n-butylstannyl 3-pyridinecarboxylate and then coupled to L8A4 in approximately 50% yield. The affinity and immunoreactive fraction for 211At-labeled L8A4 were comparable to those obtained when the MAb was labeled with 131I via N-succinimidyl 5-[131I]iodo-3-pyridinecarboxylate (SIPC). Paired-label comparisons of the 211At- and 131I-labeled MAbs demonstrated similar internalization and catabolism by EGFRvIII-positive cells in vitro, and with the exception of the stomach, similar tissue distribution in athymic mice with EGFRvIII-expressing U87MGdeltaEGFR xenografts. These results suggest that SAPC may be a useful reagent for labeling L8A4, and possibly other internalizing proteins, with 211At.

Authors
Reist, CJ; Foulon, CF; Alston, K; Bigner, DD; Zalutsky, MR
MLA Citation
Reist, CJ, Foulon, CF, Alston, K, Bigner, DD, and Zalutsky, MR. "Astatine-211 labeling of internalizing anti-EGFRvIII monoclonal antibody using N-succinimidyl 5-[211At]astato-3-pyridinecarboxylate." Nucl Med Biol 26.4 (May 1999): 405-411.
PMID
10382844
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
26
Issue
4
Publish Date
1999
Start Page
405
End Page
411

Synthesis, purification, and in vitro stability of 211At- and 125I-labeled amidobisphosphonates.

A method is described for preparing 211At- and radioiodinated amidobisphosphonates. The active esters N-succinimidyl 3-(tri-methylstannyl) benzoate (ATE) and N-succinimidyl 5-(tri-methylstannyl)-3-pyridinecarboxylate (SPC) were used as precursors. The isolated and purified radiolabeled intermediates were coupled to 3-amino-1-hydroxypropylidene-1,1-bisphosphonate (APB) in high yields ranging from 60% to 97%. The lipophilicity of the compounds was found to depend on the nature of the labeled template and the halogen. High in vitro stability in mouse, fetal calf, and human serum was documented by high performance liquid chromatography.

Authors
Murud, KM; Larsen, RH; Hoff, P; Zalutsky, MR
MLA Citation
Murud, KM, Larsen, RH, Hoff, P, and Zalutsky, MR. "Synthesis, purification, and in vitro stability of 211At- and 125I-labeled amidobisphosphonates." Nucl Med Biol 26.4 (May 1999): 397-403.
PMID
10382843
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
26
Issue
4
Publish Date
1999
Start Page
397
End Page
403

Dosimetry of 131I-labeled 81C6 monoclonal antibody administered into surgically created resection cavities in patients with malignant brain tumors.

UNLABELLED: The objective of this study was to perform the dosimetry of 131I-labeled 81C6 monoclonal antibody (MAb) in patients with recurrent malignant brain tumors, treated by direct injections of MAb into surgically created resection cavities (SCRCs). METHODS: Absorbed dose estimates were performed for nine patients. Dosimetry was performed retrospectively using probe counts (during patient isolation) and whole-body and SPECT images thereafter. Absorbed doses were calculated for the SCRC interface and for regions of interest (ROIs) 1 and 2 cm thick, measured from the margins of cavity interface. Also, mean absorbed doses were calculated for normal brain, liver, spleen, thyroid gland, stomach, bone marrow and whole body. The average residence time for the SCRC was 111 h (65-200h). RESULTS: The average absorbed dose per unit injected activity (range) to the SCRC interface and ROIs 1 and 2 cm thick from the cavity interface were 31.9 (7.8-84.2), 1.9 (0.7-3.6) and 1.0 (0.4-1.8) cGy/MBq, respectively. Average absorbed doses per unit administered activity to brain, liver, spleen, thyroid, stomach, bone marrow and whole body were 0.18, 0.03, 0.08, 0.05, 0.02, 0.02 and 0.01 cGy/MBq, respectively. The high absorbed dose delivered to the SCRC interface may have produced an increase in cavity volume independent of tumor progression. CONCLUSION: At the maximum tolerated dose of 3700 MBq 131I-labeled 81C6 MAb, the absorbed doses to the SCRC interface and ROIs of 1 and 2 cm thickness were estimated to be 1180, 71 and 39 Gy, respectively. The estimated average absorbed dose to the brain was 6.5 Gy. There was no neurological toxicity and minimal hematologic toxicity at this maximum tolerated administration level.

Authors
Akabani, G; Reist, CJ; Cokgor, I; Friedman, AH; Friedman, HS; Coleman, RE; Zhao, XG; Bigner, DD; Zalutsky, MR
MLA Citation
Akabani, G, Reist, CJ, Cokgor, I, Friedman, AH, Friedman, HS, Coleman, RE, Zhao, XG, Bigner, DD, and Zalutsky, MR. "Dosimetry of 131I-labeled 81C6 monoclonal antibody administered into surgically created resection cavities in patients with malignant brain tumors." J Nucl Med 40.4 (April 1999): 631-638.
PMID
10210222
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
40
Issue
4
Publish Date
1999
Start Page
631
End Page
638

Low molecular weight radiopharmaceuticals: Radiohalogenated MIBG and IUdR analogues.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Low molecular weight radiopharmaceuticals: Radiohalogenated MIBG and IUdR analogues." ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 217 (March 21, 1999): U41-U41.
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
217
Publish Date
1999
Start Page
U41
End Page
U41

Radioiodinated D-peptides as prosthetic groups for radiolabeling internalizing antibodies

Authors
Foulon, CF; Reist, CJ; Bigner, DD; Zalutsky, MR
MLA Citation
Foulon, CF, Reist, CJ, Bigner, DD, and Zalutsky, MR. "Radioiodinated D-peptides as prosthetic groups for radiolabeling internalizing antibodies." Journal of Labelled Compounds and Radiopharmaceuticals 42.SUPPL. 1 (1999): S291-S293.
Source
scival
Published In
Journal of Labelled Compounds and Radiopharmaceuticals
Volume
42
Issue
SUPPL. 1
Publish Date
1999
Start Page
S291
End Page
S293

211At- and 131I-labeled bisphosphonates with high in vivo stability and bone accumulation

Bisphosphonates were synthesized for use as carriers for astatine and iodine radioisotopes to target bone neoplasms. Methods: Radiohalogenated activated esters were coupled to the amino group in the side chain of the bisphosphonate. The bisphosphonate 3-amino-1-hydroxypropylidene bisphosphonate was combined with four different acylation agents: N- succinimidyl 3-[211At]astatobenzoate, N-succinimidyl 3- [131I]iodobenzoate, N-succinimidyl-5-[211At]astato-3-pyddinecarboxylate and N-succinimidyl-5-[131I]iodo-5-pyridinecarboxylate. The products, 3- [131I]iodobenzamide-N-3-hydroxypropylidene-3,3-bisphosphonate (IBPB), 3- [211At]astato-benzamide-N-3-hydroxypropylidene-3,3-bisphosphonate (ABPB), 5-[131I]iodopyridine-3-amide-N-3-hydroxypropylidene-3,3-bisphosphonate (IPPB) and 5-[211At]astatopyridine-3-amide-N-3-hydroxypropylidene-3,3- bisphosphonate (APPB), were injected intravenously into Balb/c mice. MIRD and Monte Carlo methods were used on the basis of cumulated activity calculated from biodistribution data to estimate dose to organs and bone segments. Results: All 131I- and 211At-labeled analogs were strongly incorporated into osseous tissue and retained there at stable levels, while a rapid clearance from blood was observed. The bone uptake was found to be similar for 211At- and 131I-labeled bisphosphonate when compared in paired label experiments, Bone uptake and bone-to-tissue ratios were better for IBPB compared with IPPB, and ABPB compared with APPB. All four compounds appeared to be highly resistant to in vivo dehalogenation as indicated by low uptake of 131I/211At in the thyroid gland and stomach. According to dosimetric estimates, the bone surface-to-bone marrow ratio was three times higher with 211At than with 131I. Conclusion: Both the β-particle- and α- particle-emitting compounds showed high in vivo stability and excellent affinity for osseous tissue. Further preclinical evaluation is therefore warranted.

Authors
Larsen, RH; Murud, KM; Akabani, G; Hoff, P; Bruland, ØS; Zalutsky, MR
MLA Citation
Larsen, RH, Murud, KM, Akabani, G, Hoff, P, Bruland, ØS, and Zalutsky, MR. "211At- and 131I-labeled bisphosphonates with high in vivo stability and bone accumulation." Journal of Nuclear Medicine 40.7 (1999): 1197-1203.
Source
scival
Published In
Journal of Nuclear Medicine
Volume
40
Issue
7
Publish Date
1999
Start Page
1197
End Page
1203

Erratum: Cloning and sequencing of V genes from anti-osteosarcoma monoclonal antibodies TP-1 and TP-3: Location of lysine residues and implications for radiolabeling (Nuclear Medicine and Biology (1995) 22 (765- 771))

Authors
Olafsen, T; Bruland, O; Zalutsky, M; Sandlie, I
MLA Citation
Olafsen, T, Bruland, O, Zalutsky, M, and Sandlie, I. "Erratum: Cloning and sequencing of V genes from anti-osteosarcoma monoclonal antibodies TP-1 and TP-3: Location of lysine residues and implications for radiolabeling (Nuclear Medicine and Biology (1995) 22 (765- 771))." Nuclear Medicine and Biology 26.5 (1999): 599--.
Source
scival
Published In
Nuclear Medicine and Biology
Volume
26
Issue
5
Publish Date
1999
Start Page
599-
DOI
10.1016/S0969-8051(99)00025-6

125I-labeled anti-epidermal growth factor receptor-vIII single-chain Fv exhibits specific and high-level targeting of glioma xenografts

A single-chain antibody fragment, MR1(scFv), with specific binding to epidermal growth factor receptor-vIII (EGFRvIII), was produced, radiolabeled, and evaluated for biodistribution in human glioma-bearing athymic mice. The mutant receptor EGFRvIII has a deletion in its extracellular domain that results in the formation of a new, tumor-specific antigen found in glioblastomas, breast carcinomas, and other tumors. The scFv molecule, designed as V(H)-(Gly4-Ser)3-V(L), was expressed in Escherichia coli in inclusion body form; recovered scFv fragments were properly refolded in redox-shuffling buffer. Size-exclusion chromatography of purified scFv demonstrated a protein monomer of M(r) 26,000. Labeling was performed using N-succinimidyl 5-[125I]iodo-3-pyridinecarboxylate (SIPC) or Iodogen to specific activities of 0.5-2.0 mCi/mg, with yields of 35-50% and 45-70%, respectively. The immunoreactive fraction (IRF) of the labeled MR1(scFv) was 65-80% when SIPC was used and 50-55% when Iodogen was used. The affinity (K(A)) of MR1(scFv) for EGFRvIII was 4.3 x 107 ± 0.1 x 107 M-1 by BIAcore analysis, and it was 1.0 x 108 ± 0.1 x 108 M-1 and by Scatchard analysis versus EGFRvIII-expressing cells. After incubation at 37°C for 24 h, the binding affinity was maintained, and the IRF was maintained at 60- 70%. The specificity of MR1(scFv) for EGFRvIII was demonstrated in vitro by incubation of radiolabeled MR1(scFv) with the EGFRvIII-expressing U87MG.ΔEGFR cell line in the presence or absence of competing unlabeled MR1(SCFv) or anti-EGFRvIII MAbs L8A4 and H10. In biodistribution studies using athymic mice bearing s.c. U87MG.ΔEGFR tumor xenografts, animals received intratumoral or i.v. infusions of paired-label [125I]SIPC- MRI(scFv) and [131I]SIPC-anti-Tac(scFv) as a control. When given by the intratumoral route, MR1(scFv) retained high tumor uptakes of 85% injected dose per gram of tissue at 1 h and 16% injected dose per gram of tissue at 24 h following administration. Specific: control scFv tumor uptake ratios of more than 20:1 at 24 h demonstrated specific localization of MR1(scFv). The excellent tumor retention of MR1(scFv), combined with its rapid clearance from normal tissues, resulted in high tumor:normal organ ratios.

Authors
Kuan, C-T; Reist, CJ; Foulon, CF; Lorimer, IAJ; Archer, G; Pegram, CN; Pastan, I; Zalutsky, MR; Bigner, DD
MLA Citation
Kuan, C-T, Reist, CJ, Foulon, CF, Lorimer, IAJ, Archer, G, Pegram, CN, Pastan, I, Zalutsky, MR, and Bigner, DD. "125I-labeled anti-epidermal growth factor receptor-vIII single-chain Fv exhibits specific and high-level targeting of glioma xenografts." Clinical Cancer Research 5.6 (1999): 1539-1549.
Source
scival
Published In
Clinical Cancer Research
Volume
5
Issue
6
Publish Date
1999
Start Page
1539
End Page
1549

Octreotide analogues labeled with radioiodine and astatine-211

Authors
Vaidyanathan, G; Srinivasan, A; Affleck, DJ; Welsh, PC; Slade, SK; Schmidt, MA; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Srinivasan, A, Affleck, DJ, Welsh, PC, Slade, SK, Schmidt, MA, and Zalutsky, MR. "Octreotide analogues labeled with radioiodine and astatine-211." Journal of Labelled Compounds and Radiopharmaceuticals 42.SUPPL. 1 (1999): S33-S35.
Source
scival
Published In
Journal of Labelled Compounds and Radiopharmaceuticals
Volume
42
Issue
SUPPL. 1
Publish Date
1999
Start Page
S33
End Page
S35

Iodopyridine-for-iodobenzene substitution for use with low molecular weight radiopharmaceuticals: application to m-iodobenzylguanidine.

Substituting a pyridine ring for a benzene ring in the acylation agent N-succinimidyl 3-iodobenzoate has resulted in a useful approach for the radiohalogenation of monoclonal antibodies, peptides, and labeled biotin conjugates. It was hypothesized that such a substitution in m-iodobenzylguanidine (MIBG), a radiotracer used in the detection and treatment of neuroendocrine tumors, might result in an analogue with more rapid normal tissue clearance, thereby facilitating its use for tumor therapy. For the preparation of this analogue, 3-guanidinomethyl-5-iodopyridine (GMIP; 9b), the silicon precursor 4 was synthesized starting from 5-bromonicotinic acid. Attempts to convert 4 to 9b under various conditions were not successful. Radioiodinated 9b could be prepared by the iododestannylation of the tin precursor 8 in 65-70% radiochemical yield. A number of in vitro, in vivo, and ex vivo studies showed that pyridine-for-benzene substitution in MIBG yielded a compound that no longer was taken up by the uptake-1 pathway.

Authors
Vaidyanathan, G; Zalutsky, MR; DeGrado, TR
MLA Citation
Vaidyanathan, G, Zalutsky, MR, and DeGrado, TR. "Iodopyridine-for-iodobenzene substitution for use with low molecular weight radiopharmaceuticals: application to m-iodobenzylguanidine." Bioconjug Chem 9.6 (November 1998): 758-764.
PMID
9815170
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
9
Issue
6
Publish Date
1998
Start Page
758
End Page
764
DOI
10.1021/bc980037x

Human IgG2 constant region enhances in vivo stability of anti-tenascin antibody 81C6 compared with its murine parent.

The in vivo properties of radiolabeled chimeric monoclonal antibodies (mAbs) with human IgG1 and IgG3 constant regions generally are similar to those of their corresponding murine construct. In contrast, we have observed that chimeric anti-tenascin mAb 81C6, which contains IgG2 constant regions, exhibits significantly higher localization in s.c. D-54 MG xenografts and prolonged retention in most normal tissues compared with its IgG2b murine parent. The purpose of the present study was to determine whether substitution of the murine IgG2b constant region domains in mAb 81C6 with those from human IgG2 enhanced the in vivo stability of the 81C6 mAb. Both mAbs were radioiodinated using Iodogen and administered to athymic mice bearing s.c. D-54 MG human glioma xenografts. The nature of the labeled species present in tumor and normal tissues over a 144-h period was investigated by trichloroacetic acid precipitation and SDS PAGE. In tumor and most normal tissues, a greater fraction of chimeric compared with murine 81C6 was present as intact IgG. For example, in tumor at 144 h, the fraction of radioactivity present as intact IgG was twice as high for chimeric compared with murine 81C6. A substantial fraction of murine but not chimeric 81C6 was present as a Mr 70,000-90,000 molecule, which could represent the generation of Fab/Fc monomers through the reduction of the interchain disulfide bonds in the murine IgG2b molecule. These results suggest that the higher tumor and normal tissue levels of chimeric compared with murine 81C6 can be attributed in part to the enhanced in vivo stability of the IgG2 chimeric mAb. The chimeric construct also was demonstrated to be more stable than murine after incubation with cyst fluid obtained from glioma resection cavity patients. Chimeric mAbs containing human IgG2 constant region domains could be of particular value for certain radioimmunotherapeutic applications.

Authors
Reist, CJ; Bigner, DD; Zalutsky, MR
MLA Citation
Reist, CJ, Bigner, DD, and Zalutsky, MR. "Human IgG2 constant region enhances in vivo stability of anti-tenascin antibody 81C6 compared with its murine parent." Clin Cancer Res 4.10 (October 1998): 2495-2502.
PMID
9796983
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
4
Issue
10
Publish Date
1998
Start Page
2495
End Page
2502

Survival and DNA damage in Chinese hamster V79 cells exposed to alpha particles emitted by DNA-incorporated astatine-211.

Asynchronous Chinese hamster V79 lung fibroblasts were incubated at 37 degrees C for 30 min with the thymidine analog 5-[211At]astato-2'-deoxyuridine (211AtdU, exposure from DNA-incorporated activity) or with [211At]astatide (211At-, exposure from extracellular activity), and DNA-incorporated activity was determined. The 211AtdU content in cellular DNA increased as a function of extracellular concentration. Incorporation of 211At- was less than 1% of that of 211AtdU. After exposure, cells were frozen in the presence of 10% DMSO. One month later, survival was determined by the colony-forming assay, and DNA double-strand breaks (DSBs) were measured by the neutral elution method (pH 9.6). The survival curve for 211AtdU was biphasic (D37 = 2.8 decays per cell), reflecting killing of 211At-DNA-labeled cells and of unlabeled cells irradiated by 211At in neighboring labeled cells. The toxicity of 211At- decaying outside the cell (30-min exposure) was negligible. Analysis of the survival curve produced a D0 of 1.3 decays/cell for 211At-labeled cells. The yield of DSBs from the decay of DNA-incorporated 211At was compared with that from DNA-incorporated 125I. Each decay of 211At produced at least 10 times the number of DSBs as that obtained per 125I decay. The extreme radiotoxicity of DNA-incorporated 211AtdU seems to be associated with considerable damage to the mammalian cell genome.

Authors
Walicka, MA; Vaidyanathan, G; Zalutsky, MR; Adelstein, SJ; Kassis, AI
MLA Citation
Walicka, MA, Vaidyanathan, G, Zalutsky, MR, Adelstein, SJ, and Kassis, AI. "Survival and DNA damage in Chinese hamster V79 cells exposed to alpha particles emitted by DNA-incorporated astatine-211." Radiat Res 150.3 (September 1998): 263-268.
PMID
9728654
Source
pubmed
Published In
Radiation Research
Volume
150
Issue
3
Publish Date
1998
Start Page
263
End Page
268

The effects of local hyperthermia on the catabolism of a radioiodinated chimeric monoclonal antibody.

Local hyperthermia has been shown to increase the tumor uptake and tumor:normal tissue ratios of radiolabeled monoclonal antibodies (mAbs) in athymic mouse xenograft models. The current study was undertaken to determine whether this behavior was related in part to alterations in mAb catabolism by local hyperthermia. Human/mouse chimeric 81C6 mAb reactive with tenascin and a nonspecific control mAb were labeled with 125I using Iodo-Gen and given to separate groups of athymic mice bearing s.c. D-54 MG human glioma xenografts. Half of the animals were then subjected to 4-h tumor-localized hyperthermia at 41.8 degrees C, a protocol previously shown to enhance the specific tumor uptake of the mAb in this xenograft model. The tumor, serum, liver, kidney, and urine were collected from heated as well as control animals 4 and 24 h after injection of the mAb and analyzed by SDS-PAGE and trichloroacetic acid precipitation. At 24 h, a significantly higher percentage of 81C6 was present as intact mAb in the tumors harvested from heated animals compared with those from controls. Unexpectedly, intact mAb was found in the urine of mice immediately after hyperthermia, but not in unheated control animals. We conclude that local hyperthermia decreases the catabolism of the mAb in the tumor and increases the urinary excretion of the mAb through a transient increase in glomerular permeability.

Authors
Hauck, ML; Zalutsky, MR
MLA Citation
Hauck, ML, and Zalutsky, MR. "The effects of local hyperthermia on the catabolism of a radioiodinated chimeric monoclonal antibody." Clin Cancer Res 4.9 (September 1998): 2071-2077.
PMID
9748121
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
4
Issue
9
Publish Date
1998
Start Page
2071
End Page
2077

Preparation of 5-[131I]iodo- and 5-[211At]astato-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) uracil by a halodestannylation reaction.

To circumvent the in vivo instability of 5-iodo-2'-deoxyuridine (IUdR), a 2'-fluorine-substituted analogue, 5-iodo-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)uracil (FIAU) recently has been introduced. To facilitate the preparation of radioiodinated FIAU as well as its astatinated analogue, a tin precursor, 5-trimethylstannyl-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)ura cil (FTAU) was synthesized. Both [125/131I]FIAU and 5-[211At]astato-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)uracil (FAAU) were prepared from FTAU in more than 85% radiochemical yield under mild conditions. The in vitro serum stability of both fluorine-substituted derivatives was higher than that of the corresponding unsubstituted parents. The enhanced stability of fluorinated derivatives was even more apparent in whole blood. The uptake of [125I]FIAU in D-247 MG human glioma cells in vitro was 20-fold higher than that of [125I]IUdR over an activity concentration range of 5-100 kBq/mL; the uptake of FAAU was not significantly different from that of 5-[211At]astato-2'-deoxyuridine (AUdR). Accumulation of radioiodine in mouse thyroid in vivo with [131I]FIAU was fivefold lower than [125I]IUdR, indicating that the former was less susceptible to deiodination. The tissue uptake of FAAU was similar to that reported for AUdR.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Preparation of 5-[131I]iodo- and 5-[211At]astato-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) uracil by a halodestannylation reaction." Nucl Med Biol 25.5 (July 1998): 487-496.
PMID
9720667
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
25
Issue
5
Publish Date
1998
Start Page
487
End Page
496

Toxicity to neuroblastoma cells and spheroids of benzylguanidine conjugated to radionuclides with short-range emissions.

Radiolabelled meta-iodobenzylguanidine (MIBG) is selectively taken up by tumours of neuroendocrine origin, where its cellular localization is believed to be cytoplasmic. The radiopharmaceutical [131I]MIBG is now widely used in the treatment of neuroblastoma, but other radioconjugates of benzylguanidine have been little studied. We have investigated the cytotoxic efficacy of beta, alpha and Auger electron-emitting radioconjugates in treating neuroblastoma cells grown in monolayer or spheroid culture. Using a no-carrier-added synthesis route, we produced 123I-, 125I-, 131I- and 211At-labelled benzylguanidines and compared their in vitro toxicity to the neuroblastoma cell line SK-N-BE(2c) grown in monolayer and spheroid culture. The Auger electron-emitting conjugates ([123I]MIBG and [125I]MIBG) and the alpha-emitting conjugate ([211At]MABG) were highly toxic to monolayers and small spheroids, whereas the beta-emitting conjugate [131I]MIBG was relatively ineffective. The Auger emitters were more effective than expected if the cellular localization of MIBG is cytoplasmic. As dosimetrically predicted however, [211At]MABG was found to be extremely potent in terms of both concentration of radioactivity and number of atoms ml(-1) administered. In contrast, the Auger electron emitters were ineffective in the treatment of larger spheroids, while the beta emitter showed greater efficacy. These findings suggest that short-range emitters would be well suited to the treatment of circulating tumour cells or small clumps, whereas beta emitters would be superior in the treatment of subclinical metastases or macroscopic tumours. These experimental results provide support for a clinical strategy of combinations ('cocktails') of radioconjugates in targeted radiotherapy.

Authors
Cunningham, SH; Mairs, RJ; Wheldon, TE; Welsh, PC; Vaidyanathan, G; Zalutsky, MR
MLA Citation
Cunningham, SH, Mairs, RJ, Wheldon, TE, Welsh, PC, Vaidyanathan, G, and Zalutsky, MR. "Toxicity to neuroblastoma cells and spheroids of benzylguanidine conjugated to radionuclides with short-range emissions." Br J Cancer 77.12 (June 1998): 2061-2068.
Website
http://hdl.handle.net/10161/11051
PMID
9649115
Source
pubmed
Published In
British Journal of Cancer
Volume
77
Issue
12
Publish Date
1998
Start Page
2061
End Page
2068

Iodine-131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with recurrent malignant gliomas: phase I trial results.

PURPOSE: To determine the maximum-tolerated dose (MTD) of iodine 131 (131I)-labeled 81C6 monoclonal antibody (mAb) in brain tumor patients with surgically created resection cavities (SCRCs) and to identify any objective responses to this treatment. METHODS: In this phase I trial, eligible patients were treated with a single injection of 131I-labeled 81C6. Cohorts of three to six patients were treated with escalating dosages of 131I (starting dose of 20 mCi with a 20-mCi escalation in subsequent cohorts) administered through an Ommaya reservoir in the SCRC. Patients were followed up for toxicity and response until death or for a minimum of 1 year after treatment. The SCRC patients, who were previously irradiated, were followed up without additional treatment unless progressive disease was identified. RESULTS: We administered 36 treatments of 131I doses up to 120 mCi to 34 previously irradiated patients with recurrent or metastatic brain tumors. Dose-limiting toxicity was reached at 120 mCi and was limited to neurologic or hematologic toxicity. None of the patients treated with less than 120 mCi developed significant neurologic toxicity; one patient developed major hematologic toxicity (MHT). The estimated median survival for patients with glioblastoma multiforme (GBM) and for all patients was 56 and 60 weeks, respectively. CONCLUSION: The MTD for administration of 131I-labeled 81C6 into the SCRCs of previously irradiated patients with recurrent primary or metastatic brain tumors was 100 mCi. The dose-limiting toxicity was neurologic toxicity. We are encouraged by the minimal toxicity and survival in this phase I trial. Radiolabeled mAbs may improve the current therapy for brain tumor patients.

Authors
Bigner, DD; Brown, MT; Friedman, AH; Coleman, RE; Akabani, G; Friedman, HS; Thorstad, WL; McLendon, RE; Bigner, SH; Zhao, XG; Pegram, CN; Wikstrand, CJ; Herndon, JE; Vick, NA; Paleologos, N; Cokgor, I; Provenzale, JM; Zalutsky, MR
MLA Citation
Bigner, DD, Brown, MT, Friedman, AH, Coleman, RE, Akabani, G, Friedman, HS, Thorstad, WL, McLendon, RE, Bigner, SH, Zhao, XG, Pegram, CN, Wikstrand, CJ, Herndon, JE, Vick, NA, Paleologos, N, Cokgor, I, Provenzale, JM, and Zalutsky, MR. "Iodine-131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with recurrent malignant gliomas: phase I trial results." J Clin Oncol 16.6 (June 1998): 2202-2212.
PMID
9626222
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
16
Issue
6
Publish Date
1998
Start Page
2202
End Page
2212
DOI
10.1200/JCO.1998.16.6.2202

Blocking [211At]astatide accumulation in normal tissues: preliminary evaluation of seven potential compounds.

Normal tissue accumulation of 211At must be minimized during targeted radiotherapy with 211At-labeled compounds. Therefore, we investigated the ability of seven compounds to block normal organ uptake of [211At]astatide in mice: potassium iodide, sodium thiocyanate, sodium perchlorate, sodium periodate, cysteine, 2,3-dimercapto-1-propanesulfonic acid, and meso-2,3-dimercaptosuccinic acid. The monovalent anions I-, SCN-, and ClO4- reduced 211At uptake in stomach and thyroid, while thiocyanate and cysteine were the only compounds to significantly reduce activity levels in lungs and spleen. This study suggests that blocking agents may help reduce normal organ radiation doses in endoradiotherapeutic procedures with 211At-labeled radiopharmaceuticals.

Authors
Larsen, RH; Slade, S; Zalutsky, MR
MLA Citation
Larsen, RH, Slade, S, and Zalutsky, MR. "Blocking [211At]astatide accumulation in normal tissues: preliminary evaluation of seven potential compounds." Nucl Med Biol 25.4 (May 1998): 351-357.
PMID
9639296
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
25
Issue
4
Publish Date
1998
Start Page
351
End Page
357

Human IgG(2) constant region enhances the in vivo stability of monoclonal antibody 81C6 compared to its murine parent.

Authors
Reist, CJ; Bigner, DD; Zalutsky, MR
MLA Citation
Reist, CJ, Bigner, DD, and Zalutsky, MR. "Human IgG(2) constant region enhances the in vivo stability of monoclonal antibody 81C6 compared to its murine parent." JOURNAL OF NUCLEAR MEDICINE 39.5 (May 1998): 77P-77P.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
39
Issue
5
Publish Date
1998
Start Page
77P
End Page
77P

Pretargeted radioimmunotherapy using anti-tenascin 81C6-streptavidin conjugates and radiolabeled biotin: Preparation of reagents.

Authors
Foulon, CF; Bigner, DD; Zalutsky, MR
MLA Citation
Foulon, CF, Bigner, DD, and Zalutsky, MR. "Pretargeted radioimmunotherapy using anti-tenascin 81C6-streptavidin conjugates and radiolabeled biotin: Preparation of reagents." JOURNAL OF NUCLEAR MEDICINE 39.5 (May 1998): 105P-106P.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
39
Issue
5
Publish Date
1998
Start Page
105P
End Page
106P

Myocardial kinetics of meta-[I-131]iodobenzylguanidine in an adriamycin cardiomyopathy rat model.

Authors
Berry, CR; Vaidyanathan, G; Fisher, PE; Zalutsky, MR; Coleman, RE; DeGrado, TR
MLA Citation
Berry, CR, Vaidyanathan, G, Fisher, PE, Zalutsky, MR, Coleman, RE, and DeGrado, TR. "Myocardial kinetics of meta-[I-131]iodobenzylguanidine in an adriamycin cardiomyopathy rat model." JOURNAL OF NUCLEAR MEDICINE 39.5 (May 1998): 47P-47P.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
39
Issue
5
Publish Date
1998
Start Page
47P
End Page
47P

N.C.A. 5-Iodo-1(2-deoxy,2-fluoro-beta-D-arabinofuranosyl)uracil (FIAU): Tissue uptake in D-54 glioma xenograft mouse model and cytotoxicity to D-247 glioma cells in vitro.

Authors
Valdyanathan, G; Friedman, HS; Zalutsky, MR
MLA Citation
Valdyanathan, G, Friedman, HS, and Zalutsky, MR. "N.C.A. 5-Iodo-1(2-deoxy,2-fluoro-beta-D-arabinofuranosyl)uracil (FIAU): Tissue uptake in D-54 glioma xenograft mouse model and cytotoxicity to D-247 glioma cells in vitro." JOURNAL OF NUCLEAR MEDICINE 39.5 (May 1998): 104P-105P.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
39
Issue
5
Publish Date
1998
Start Page
104P
End Page
105P

Targeted therapy using astatinated radiopharmaceuticals.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Targeted therapy using astatinated radiopharmaceuticals." ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 215 (April 2, 1998): U946-U946.
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
215
Publish Date
1998
Start Page
U946
End Page
U946

The class III variant of the epidermal growth factor receptor (EGFRvIII): characterization and utilization as an immunotherapeutic target.

Any immunotherapeutic approach to cancer cell eradication is based upon the specific recognition of neoplastic cells and the sparing of surrounding normal tissue; perhaps nowhere is this distinction more important than within the central nervous system, due to the diffuse infiltrative nature of primary glial tumor cell growth. Whether ultimate effect moieties are immunoglobulins, fragments and/or their constructs with drugs, toxins, radionuclides, or immune cells, the specificity of effector: cell surface marker is crucial. This review describes the identification, immunologic characterization, and biologic behavior of a transmembrane tumor-specific altered growth factor receptor molecule which may well serve as a mediator of multiple immunotherapeutic approaches: the class III variant of the epidermal growth factor receptor, EGFRvIII.

Authors
Wikstrand, CJ; Reist, CJ; Archer, GE; Zalutsky, MR; Bigner, DD
MLA Citation
Wikstrand, CJ, Reist, CJ, Archer, GE, Zalutsky, MR, and Bigner, DD. "The class III variant of the epidermal growth factor receptor (EGFRvIII): characterization and utilization as an immunotherapeutic target." J Neurovirol 4.2 (April 1998): 148-158. (Review)
PMID
9584952
Source
pubmed
Published In
Journal of NeuroVirology
Volume
4
Issue
2
Publish Date
1998
Start Page
148
End Page
158
DOI
10.3109/13550289809114515

Cytotoxicity of alpha-particle-emitting astatine-211-labelled antibody in tumour spheroids: no effect of hyperthermia.

The high linear energy transfer, alpha-particle-emitting radionuclide astatine-211 (211At) is of interest for certain therapeutic applications; however, because of the 55- to 70-microm path length of its alpha-particles, achieving homogeneous tracer distribution is critical. Hyperthermia may enhance the therapeutic efficacy of alpha-particle endoradiotherapy if it can improve tracer distribution. In this study, we have investigated whether hyperthermia increased the cytotoxicity of an 211At-labelled monoclonal antibody (MAb) in tumour spheroids with a radius (approximately 100 microm) greater than the range of 211At alpha-particles. Hyperthermia for 1 h at 42 degrees C was used because this treatment itself resulted in no regrowth delay. Radiolabelled chimeric MAb 81C6 reactive with the extracellular matrix antigen tenascin was added to spheroids grown from the D-247 MG human glioma cell line at activity concentrations ranging from 0.125 to 250 kBq ml(-1). A significant regrowth delay was observed at 125 and 250 kBq ml(-1) in both hyperthermia-treated and untreated spheroids. For groups receiving hyperthermia, no increase in cytotoxicity was seen compared with normothermic controls at any activity concentration. These results and those from autoradiographs indicate that hyperthermia at 42 degrees C for 1 h had no significant effect on the uptake or distribution of this antitenascin MAb in D-247 MG spheroids.

Authors
Hauck, ML; Larsen, RH; Welsh, PC; Zalutsky, MR
MLA Citation
Hauck, ML, Larsen, RH, Welsh, PC, and Zalutsky, MR. "Cytotoxicity of alpha-particle-emitting astatine-211-labelled antibody in tumour spheroids: no effect of hyperthermia." Br J Cancer 77.5 (March 1998): 753-759.
Website
http://hdl.handle.net/10161/11043
PMID
9514054
Source
pubmed
Published In
British Journal of Cancer
Volume
77
Issue
5
Publish Date
1998
Start Page
753
End Page
759

The cytotoxicity and microdosimetry of astatine-211-labeled chimeric monoclonal antibodies in human glioma and melanoma cells in vitro.

The cytotoxicity of alpha-particle-emitting endoradiotherapeutic compounds is of increasing interest because clinical evaluation of these potential therapeutic agents is commencing. Astatine-211 is a radionuclide with a 7.2-h half-life that emits 5.87 and 7.45 MeV alpha particles. In the present work, we have investigated the in vitro cytotoxicity of 211At-labeled chimeric monoclonal antibodies (mAbs) in monolayers of D-247 MG human glioma cells and SK-MEL-28 human melanoma cells. The mAbs studied were 81C6, reactive with the extracellular matrix antigen tenascin, Mel-14, directed against the cell membrane antigen proteoglycan chondroitin sulfate, and a nonspecific control mAb, TPS3.2. Cell uptake increased as a function of activity concentration after a 1-h exposure to the 211At-labeled mAbs. The retention of activity was also measured to calculate cumulative activity associated with the cells and the medium. The clonogenic survival as a function of activity concentration was linear in all cases with no detectable shoulder. Microdosimetric analyses were performed based on measured cell geometry, cumulative activity and Monte Carlo transport of alpha particles. Using 18 kBq/ml activity concentration and 1 h of incubation, a two to five times higher activity bound to the microcolonies was found for the specific mAbs compared to the nonspecific mAb. These calculations indicated that a survival fraction of 0.37 was achieved with 0.24-0.28 Gy for D-247 MG cells and 0.27-0.29 Gy for SK-MEL-28 cells. The microdosimetric cell sensitivity, z0, for D-247 MG cells was significantly lower than for SK-MEL-28 cells (0.08 compared to 0.15 Gy). For both cell lines, reduction in survival to 0.37 required an average of only 1-2 alpha-particle hits to the cell nucleus.

Authors
Larsen, RH; Akabani, G; Welsh, P; Zalutsky, MR
MLA Citation
Larsen, RH, Akabani, G, Welsh, P, and Zalutsky, MR. "The cytotoxicity and microdosimetry of astatine-211-labeled chimeric monoclonal antibodies in human glioma and melanoma cells in vitro." Radiat Res 149.2 (February 1998): 155-162.
PMID
9457895
Source
pubmed
Published In
Radiation Research
Volume
149
Issue
2
Publish Date
1998
Start Page
155
End Page
162

Astatine-211-labeled biotin conjugates resistant to biotinidase for use in pretargeted radioimmunotherapy.

We report herein the preparation and biological evaluation of two radioastatinated biotin conjugates, (3-[211At]astatobenzoyl)norbiotinamide and ((5-[211At]astato-3-pyridinyl)carbonyl)norbiotinamide. Both conjugates were stable in the presence of human serum and cerebrospinal fluid as well as murine serum, indicating a resistance to degradation to biotinidase. The normal tissue clearance of (3-[211At]astatobenzoyl)norbiotinamide and ((5-[211At]astato-3-pyridinyl)carbonyl)norbiotinamide was rapid, as observed previously with their iodo analogues. Also reported are the first syntheses of N-succinimidyl 5-[211At]astato-3-pyridinecarboxylate and 3-[211At]astatoaniline, two reagents of potential utility for labeling proteins and peptides with 211At.

Authors
Foulon, CF; Alston, KL; Zalutsky, MR
MLA Citation
Foulon, CF, Alston, KL, and Zalutsky, MR. "Astatine-211-labeled biotin conjugates resistant to biotinidase for use in pretargeted radioimmunotherapy." Nucl Med Biol 25.2 (February 1998): 81-88.
PMID
9468020
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
25
Issue
2
Publish Date
1998
Start Page
81
End Page
88

Effects of specific activity on meta-[(131)I]iodobenzylguanidine kinetics in isolated rat heart.

The effects of specific activity of meta-[(131)I]iodobenzylguanidine (MIBG) were studied in uptake-2 blocked isolated perfused rat heart. [(131)I]MIBG was administered in the perfusate as an 8-min pulse, followed by an 80-min washout period. Kinetic analysis of the externally monitored time-activity curves gave estimates of uptake rate and multiexponential clearance. Uptake rate showed an MIBG concentration dependence that is sigmoidal, yielding Michaelis-Menten constants KM = 52 nM and Vmax = 0.23 nmol/min/g. Clearance rate was also dependent on loading MIBG concentrations; the primary effect of increasing loading concentration was an increase in the rate of the slowest clearance component, possibly reflecting nonspecific turnover. No effect of specific activity was observed on tissue uptake and retention of [(131)I]MIBG for loading concentrations of MIBG in the heart tissue under 0.5 nmol/g. Extrapolation of these results to human studies indicates that isotope-exchange-labeled [123I]MIBG has a specific activity sufficiently high to avoid mass effects on its heart retention.

Authors
DeGrado, TR; Zalutsky, MR; Coleman, RE; Vaidyanathan, G
MLA Citation
DeGrado, TR, Zalutsky, MR, Coleman, RE, and Vaidyanathan, G. "Effects of specific activity on meta-[(131)I]iodobenzylguanidine kinetics in isolated rat heart." Nucl Med Biol 25.1 (January 1998): 59-64.
PMID
9466363
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
25
Issue
1
Publish Date
1998
Start Page
59
End Page
64

Microdosimetry of astatine-211 using histological images: application to bone marrow.

A method is presented for calculating the small-scale dosimetry of 211At in red bone marrow using chord-length distributions obtained from digitized histological images. This study used histological samples of bone marrow from beagle dogs to convey morphological information about cell conglomerations within bone marrow. Two 211At activity distributions were considered within the extracellular fluid and the surface of red bone marrow cells. Results confirmed the influence of cell conglomeration and activity distribution in determining the microdosimetry of red bone marrow. Average S* values of 1.6 x 10(-9) and 1.90 x 10(-9) Gy g Bq(-1) s(-1) were calculated for activity distributions located within the extracellular fluid and the surface of red bone marrow cells, respectively. The cumulated activity required to reduce survival probability to 0.37 also was calculated as a function of cell sensitivity for both activity distributions. The activity distribution on the cell surface resulted in a higher cell-killing efficiency, requiring a lower activity concentration of approximately 25% when compared with activity located in the extracellular fluid. Of relevance to potential clinical studies with 211At, the probability for zero hits for red bone marrow cells was > 10% for cumulated activities of less than 5.5 x 10(8) Bq s g(-1) in bone marrow.

Authors
Akabani, G; Zalutsky, MR
MLA Citation
Akabani, G, and Zalutsky, MR. "Microdosimetry of astatine-211 using histological images: application to bone marrow." Radiat Res 148.6 (December 1997): 599-607.
PMID
9399706
Source
pubmed
Published In
Radiation Research
Volume
148
Issue
6
Publish Date
1997
Start Page
599
End Page
607

In vitro and in vivo behavior of radiolabeled chimeric anti-EGFRvIII monoclonal antibody: comparison with its murine parent.

The mutant version of the epidermal growth factor receptor EGFRvIII has been found on gliomas and other tumors, but not on normal tissues. Radioiodinated murine (mu) L8A4 monoclonal antibody (MAb) specifically targets EGFRvIII xenografts in vivo when labeled using N-succinimidyl 5-iodo-3-pyridinecarboxylate (SIPC). A chimeric (ch) MAb consisting of the variable region of muL8A4 and the constant domains of human IgG2 has been developed that has an affinity and radioiodinated immunoreactive fraction comparable to muL8A4. In vitro, both MAbs were internalized and processed by EGFRvIII expressing cell lines (U87MG delta EGFR or NR6M) at similar rates (maximum intracellular retention, 35-40%). In paired-label tissue distribution studies in athymic mice bearing U87MG delta EGFR tumor xenografts, the ch:mu L8A4 uptake ratio in normal tissues rose to greater than 2:1, whereas in tumor, the ratio remained 1:1 throughout the experiment. These results indicate that chL8A4 exhibits similar binding and internalization properties as its murine parent, but suggest different intracellular processing and/or deposition of catabolites in normal tissues for chL8A4.

Authors
Reist, CJ; Batra, SK; Pegram, CN; Bigner, DD; Zalutsky, MR
MLA Citation
Reist, CJ, Batra, SK, Pegram, CN, Bigner, DD, and Zalutsky, MR. "In vitro and in vivo behavior of radiolabeled chimeric anti-EGFRvIII monoclonal antibody: comparison with its murine parent." Nucl Med Biol 24.7 (October 1997): 639-647.
PMID
9352535
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
24
Issue
7
Publish Date
1997
Start Page
639
End Page
647

Method for radioiodination of proteins using N-succinimidyl 3-hydroxy-4-iodobenzoate.

A conjugation method has been developed for the radioiodination of proteins which should be adaptable to kit formulation. m-Hydroxybenzoic acid was converted to 3-hydroxy-4-[131I]iodobenzoic acid in 65% radiochemical yield using Chloramine-T as the oxidant. This intermediate was then converted to N-succinimidyl 3-hydroxy-4-[131I]iodobenzoate ([131I]mSHIB) in 75% yield by reaction with N-hydroxysuccinimide and dicyclohexylcarbodiimide in a reaction time of only 10 min. Monoclonal antibody (mAb) 81C6 was labeled in 40-60% yield by reaction with [131I]mSHIB. Performing purifications of radioiodinated compounds using cartridges instead of HPLC did not alter conjugation efficiency, mAb immunoreactivity, or tissue distribution. Thyroid uptake of labeled mAb was low but up to 2.4 times higher than that seen when the mAb was labeled with N-succinimidyl 3-[125I]-iodobenzoate. These results suggest that [131I]mSHIB may be a useful reagent for the radioiodination of proteins, particularly in contexts when less complicated purification methods would be advantageous.

Authors
Vaidyanathan, G; Affleck, DJ; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, and Zalutsky, MR. "Method for radioiodination of proteins using N-succinimidyl 3-hydroxy-4-iodobenzoate." Bioconjug Chem 8.5 (September 1997): 724-729.
PMID
9327137
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
8
Issue
5
Publish Date
1997
Start Page
724
End Page
729
DOI
10.1021/bc9700502

A new route to guanidines from bromoalkanes

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "A new route to guanidines from bromoalkanes." JOURNAL OF ORGANIC CHEMISTRY 62.14 (July 11, 1997): 4867-4869.
Source
wos-lite
Published In
The Journal of Organic Chemistry
Volume
62
Issue
14
Publish Date
1997
Start Page
4867
End Page
4869
DOI
10.1021/jo9704164

Cytotoxicity of alpha-particle-emitting 5-[211At]astato-2'-deoxyuridine in human cancer cells.

This study was performed to determine the cytotoxicity of alpha-particle-emitting 5-[211At]astato-2-deoxyuridine (i.e. [211At]AUdR) for monolayers of D-247 MG human glioma cells and SK-MEL-28 human melanoma cells. Cells in exponential growth were exposed to varying activity concentrations of [211At]AUdR and for comparison [211At]astatide and the Auger electron-emitting analogue, 5-[125I]iodo-2'-deoxyuridine (i.e. [125I]IUdR). Cell uptake, DNA binding and clonogenic survival as a function of activity concentration in the medium were determined following 2 and 20-h incubations. None of the survival curves had detectable shoulders, an observation consistent with high-LET effects. The A37 (initial activity concentration yielding 37% cell survival) were significantly lower for both cell lines following 20-h exposure of [211At]AUdR than [211At]astatide. After correcting for effects from non-cell-associated activity in the medium, the specific cytotoxicity of cell-associated and DNA-bound [211At]AUdR was estimated. In the 20-h incubation experiments, the A37 for DNA-associated [211At]AUdR corresponded to about one 211At atom bound per cell for both cell lines. Unlike [211At]AUdR, there was a biphasic survival response to [125I]IUdR, consistent with the lower fractional uptake of [125I]IUdR at higher activity concentrations. These studies suggest that [211At]AUdR warrants further evaluation as an endoradiotherapeutic agent for the treatment of rapidly proliferating cancers.

Authors
Larsen, RH; Vaidyanathan, G; Zalutsky, MR
MLA Citation
Larsen, RH, Vaidyanathan, G, and Zalutsky, MR. "Cytotoxicity of alpha-particle-emitting 5-[211At]astato-2'-deoxyuridine in human cancer cells." Int J Radiat Biol 72.1 (July 1997): 79-90.
PMID
9246197
Source
pubmed
Published In
International Journal of Radiation Biology (Informa)
Volume
72
Issue
1
Publish Date
1997
Start Page
79
End Page
90

Radioiodinated antibody targeting of the HER-2/neu oncoprotein.

The HER-2/neu oncogene encodes a 185 kDa phosphoglycoprotein that is overexpressed in breast, ovarian and other cancers. Seven monoclonal antibodies reactive with oncoprotein were labeled with 131I. In vitro experiments with SKOv3 9002-18 cells determined binding affinity, internalization and degradation. The biodistribution of these antibodies in comparison to 125I-labeled nonspecific antibody was measured in athymic mice with SKOv3 9002-18 ovarian carcinoma xenografts. Antibody 520C9 exhibited the highest and most specific retention in tumor, peaking at 17.4 +/- 5.6% ID/g at 24 h.

Authors
Xu, FJ; Yu, YH; Bae, DS; Zhao, XG; Slade, SK; Boyer, CM; Bast, RC; Zalutsky, MR
MLA Citation
Xu, FJ, Yu, YH, Bae, DS, Zhao, XG, Slade, SK, Boyer, CM, Bast, RC, and Zalutsky, MR. "Radioiodinated antibody targeting of the HER-2/neu oncoprotein." Nucl Med Biol 24.5 (July 1997): 451-459.
PMID
9290082
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
24
Issue
5
Publish Date
1997
Start Page
451
End Page
459

3-[At-211]astato-4-fluorobenzylguanidine: a potential therapeutic agent with prolonged retention by neuroblastoma cells

Authors
Vaidyanathan, G; Zhao, XG; Larsen, RH; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Zhao, XG, Larsen, RH, and Zalutsky, MR. "3-[At-211]astato-4-fluorobenzylguanidine: a potential therapeutic agent with prolonged retention by neuroblastoma cells." BRITISH JOURNAL OF CANCER 76.2 (July 1997): 226-233.
Source
wos-lite
Published In
British Journal of Cancer
Volume
76
Issue
2
Publish Date
1997
Start Page
226
End Page
233
DOI
10.1038/bjc.1997.366

Growth factor receptors as molecular targets for cancer diagnosis and therapy.

Growth factor receptors are of great interest as molecular targets for the diagnosis and treatment of cancer. Growth factor receptors are frequently over expressed on malignant cell populations since many cellular oncogenes encode either growth factors or their receptors. The wild-type epidermal growth factor receptor has a molecular weight of 170 kD and is over expressed on gliomas, bladder tumors, squamous cells carcinomas and breast carcinomas. Another growth factor oncogene, c-erbB-2, encodes a 185-kD glycoprotein found on the surface of gliomas, breast and ovarian cancers as well as other carcinomas of epithelial origin. In addition to causing over expression, oncogenic transformation also can result in genomic re-arrangements. An important example from the perspective of targeting is EGFRvIII, a deletion mutant which lacks amino acids 6-273 in the extracellular domain of the epidermal growth factor receptor. The EGFRvIII molecule (145 kD) may be of great value for targeting because it appears to be tumor-specific. Antibodies have been developed with specific reactivity with these growth factor receptors. Since these antibodies are internalized into the cell after receptor binding, it is necessary to use radiolabeling methods which residualize the radioactivity in the tumor cell after intracellular catabolism. To investigate this problem, we have evaluated the effect of radioiodination method on the in vitro and in vivo properties of an anti-EGFRvIII antibody. Methods studied were Iodogen, tyramine-cellobiose, and N-succinimidyl 5-iodo-3-pyridine-carboxylate with the last offering optimal localization in a human xenograft model.

Authors
Zalutsky, MR
MLA Citation
Zalutsky, MR. "Growth factor receptors as molecular targets for cancer diagnosis and therapy." Q J Nucl Med 41.2 (June 1997): 71-77.
PMID
9203846
Source
pubmed
Published In
The Quarterly Journal of Nuclear Medicine and Molecular Imaging
Volume
41
Issue
2
Publish Date
1997
Start Page
71
End Page
77

A local hyperthermia treatment which enhances antibody uptake in a glioma xenograft model does not affect tumour interstitial fluid pressure.

Solid tumours have an elevated interstitial fluid pressure (IFP) due to the lack of normal lymphatics, increased permeability of tumour vasculature and an expanding cell population within a potentially limited space. This elevated IFP has been proposed to be an important barrier to the delivery of drugs and marcromolecules. We have demonstrated that local hyperthermia (4 h, 41.8 degrees C) is capable of significantly enhancing the uptake of radiolabelled monoclonal antibodies (mAbs) in D-54 MG glioma xenografts grown subcutaneously in athymic mice. To determine if this increased uptake was attributable to alterations in the tumour IFP, pressure measurements using the wick-in-needle technique were made in tumours after hyperthermia treatment. These pressure measurements were taken at various time points from 4 to 90 h following the initiation of the hyperthermia and compared with pressures taken concurrently in untreated tumours. In addition, pressures were measured following a 2 h, 41.8 degrees C hyperthermia treatment, a protocol which does not result in elevated uptake of radiolabeled mAbs. No significant differences were seen at any time point in IFP measured in the tumours receiving either hyperthermia treatment when compared with untreated tumours. Thus, we conclude that the mechanism by which this hyperthermia regimen enhances mAb uptake in this human glioma xenograft model is not due to alternations in tumour IFP.

Authors
Hauck, ML; Coffin, DO; Dodge, RK; Dewhirst, MW; Mitchell, JB; Zalutsky, MR
MLA Citation
Hauck, ML, Coffin, DO, Dodge, RK, Dewhirst, MW, Mitchell, JB, and Zalutsky, MR. "A local hyperthermia treatment which enhances antibody uptake in a glioma xenograft model does not affect tumour interstitial fluid pressure." Int J Hyperthermia 13.3 (May 1997): 307-316.
PMID
9222813
Source
pubmed
Published In
International Journal of Hyperthermia (Informa)
Volume
13
Issue
3
Publish Date
1997
Start Page
307
End Page
316

Dosimetry methods for patients with malignant CNS tumors treated with I-131 81C6 via surgically created cystic resection cavity.

Authors
Akabani, G; Thorstad, WL; Brown, MT; Coleman, RE; Zalutsky, MR; Bigner, DD
MLA Citation
Akabani, G, Thorstad, WL, Brown, MT, Coleman, RE, Zalutsky, MR, and Bigner, DD. "Dosimetry methods for patients with malignant CNS tumors treated with I-131 81C6 via surgically created cystic resection cavity." JOURNAL OF NUCLEAR MEDICINE 38.5 (May 1997): 395-395.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
38
Issue
5
Publish Date
1997
Start Page
395
End Page
395

A method for labeling internalizing antibodies with astatine-211.

Authors
Reist, CJ; Foulon, CF; Bigner, DD; Zalutsky, MR
MLA Citation
Reist, CJ, Foulon, CF, Bigner, DD, and Zalutsky, MR. "A method for labeling internalizing antibodies with astatine-211." JOURNAL OF NUCLEAR MEDICINE 38.5 (May 1997): 15-15.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
38
Issue
5
Publish Date
1997
Start Page
15
End Page
15

Survival and DNA damage in V79 cells exposed to the alpha emitters 5-[At-211]astato-2'-deoxy-uridine and [At-211]astatide.

Authors
Kassis, AI; Walicka, MA; Vaidyanathan, G; Zalutsky, MR; Adelstein, SJ
MLA Citation
Kassis, AI, Walicka, MA, Vaidyanathan, G, Zalutsky, MR, and Adelstein, SJ. "Survival and DNA damage in V79 cells exposed to the alpha emitters 5-[At-211]astato-2'-deoxy-uridine and [At-211]astatide." JOURNAL OF NUCLEAR MEDICINE 38.5 (May 1997): 964-964.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
38
Issue
5
Publish Date
1997
Start Page
964
End Page
964

Mechanisms of uptake in isolated rat heart of potential radiotherapeutic agent [At-211]meta-astatobenzylguanidine (MABG).

Authors
DeGrado, TR; Zalutsky, MR; Vaidyanathan, G
MLA Citation
DeGrado, TR, Zalutsky, MR, and Vaidyanathan, G. "Mechanisms of uptake in isolated rat heart of potential radiotherapeutic agent [At-211]meta-astatobenzylguanidine (MABG)." JOURNAL OF NUCLEAR MEDICINE 38.5 (May 1997): 106-106.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
38
Issue
5
Publish Date
1997
Start Page
106
End Page
106

Microdosimetry and small-scale dosimetry of At-211 in bone marrow: An analysis based on histological imaging.

Authors
Akabani, G; Zalutsky, MR
MLA Citation
Akabani, G, and Zalutsky, MR. "Microdosimetry and small-scale dosimetry of At-211 in bone marrow: An analysis based on histological imaging." JOURNAL OF NUCLEAR MEDICINE 38.5 (May 1997): 963-963.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
38
Issue
5
Publish Date
1997
Start Page
963
End Page
963

Improved targeting of an anti-epidermal growth factor receptor variant III monoclonal antibody in tumor xenografts after labeling using N-succinimidyl 5-iodo-3-pyridinecarboxylate.

Monoclonal antibody (mAb) L8A4, specific for the tumor-associated mutant epidermal growth factor receptor variant III (EGFRvII), is internalized and degraded after cell binding. Four paired-label experiments were performed in athymic mice bearing EGFRvIII-positive xenografts to determine the suitability of N-succinimidyl 3-iodo-5-pyridinecarboxylate (SIPC) for labeling this internalizing mAb. In mice with HC2 20 d2 xenografts, tumor uptake reached a maximum of 32.7 +/- 2.0% injected dose/g when labeled using SIPC, a value significantly higher (P < 0.05, paired t test) than that observed when L8A4 was labeled using lodogen (24.4 +/- 2.2% injected dose/g). The specificity of mAb uptake in HC2 20 d2 and U87MG(delta)EGFR xenografts was measured in separate experiments by coadministration of L8A4 and nonspecific, isotype-matched P3X63Ag8 mAb, both radioiodinated using SIPC. Tumor localization indices were approximately 10 or more by 72 h, a degree of specificity 3-4 times higher than that reported previously when labeling was performed using the tyramine cellobiose (TCB) method. In a final study directly comparing L8A4 labeled using SIPC and TCB, similar tumor levels were obtained (SIPC, 33.7 +/- 6.1% injected dose/g at 24 h; TCB, 37.8 +/- 6.7% injected dose/g at 24 h); however, tumor-to-tissue ratios for the liver, spleen, and kidneys were 3 times higher with SIPC at later time points. These results suggest that SIPC is a promising method for labeling this anti-EGFRvIII mAb and possibly other mAbs that internalize after binding.

Authors
Reist, CJ; Archer, GE; Wikstrand, CJ; Bigner, DD; Zalutsky, MR
MLA Citation
Reist, CJ, Archer, GE, Wikstrand, CJ, Bigner, DD, and Zalutsky, MR. "Improved targeting of an anti-epidermal growth factor receptor variant III monoclonal antibody in tumor xenografts after labeling using N-succinimidyl 5-iodo-3-pyridinecarboxylate." Cancer Res 57.8 (April 15, 1997): 1510-1515.
PMID
9108453
Source
pubmed
Published In
Cancer Research
Volume
57
Issue
8
Publish Date
1997
Start Page
1510
End Page
1515

Tissue distribution and radiation dosimetry of astatine-211-labeled chimeric 81C6, an alpha-particle-emitting immunoconjugate.

A paired-label study was performed in athymic mice bearing subcutaneous D-54 MG human glioma xenografts to compare the localization of human/mouse anti-tenascin chimeric antibody 81C6 labeled by reaction with N-succinimidyl 3-[211At]astatobenzoate and N-succinimidyl 3-[131I]iodobenzoate. Over the 48-h observation period, the distribution of 211At- and 131I-labeled antibody were quite similar in tumor and normal tissues except stomach. These data were used to calculate human radiation doses for both intravenously and intrathecal administered 211At-labeled chimeric 81C6 using a quality factor of 5 for alpha-emissions.

Authors
Zalutsky, MR; Stabin, MG; Larsen, RH; Bigner, DD
MLA Citation
Zalutsky, MR, Stabin, MG, Larsen, RH, and Bigner, DD. "Tissue distribution and radiation dosimetry of astatine-211-labeled chimeric 81C6, an alpha-particle-emitting immunoconjugate." Nucl Med Biol 24.3 (April 1997): 255-261.
PMID
9228660
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
24
Issue
3
Publish Date
1997
Start Page
255
End Page
261

Synthesis and preliminary biological evaluation of (3-iodobenzoyl)norbiotinamide and ((5-iodo-3-pyridinyl)carbonyl)norbiotinamide: two radioiodinated biotin conjugates with improved stability.

A new class of radioiodinated biotin conjugated is described in which the amido bond between biotin and the labeled prosthetic group is reversed. One conjugate, (3-[125I]iodobenzoyl)norbiotinamide (4c, [125I]IBB) was labeled with Na125I in one step from (3-(tributylstannyl)benzoyl)norbiotinamide (4b, TBB) via a demetalation reaction. However, the analogous reaction with ((5-(tributylstannyl)-3-pyridinyl)carbonyl)norbiotinamide (6b, TPB) failed to yield ((5-[131I]iodo-3-pyridinyl)carbonyl)norbiotinamide (6c, [131I]IPB, necessitating a two-step approach for synthesizing [131I]IPB. The binding of [125I]IBB and [131I]IPB to streptavidin in vitro was identical to that of biotinyl-3-[125I]iodoanilide, a conjugate with an amido bond with normal configuration. Both [125I]IBB and [131I]IPB were stable in serum while the first-generation compound was rapidly degraded. The biodistribution patterns of [125I]IBB and [131I]IPB in mice are consistent with limited degradation of these conjugates by biotinidase and deiodinases.

Authors
Foulon, CF; Alston, KL; Zalutsky, MR
MLA Citation
Foulon, CF, Alston, KL, and Zalutsky, MR. "Synthesis and preliminary biological evaluation of (3-iodobenzoyl)norbiotinamide and ((5-iodo-3-pyridinyl)carbonyl)norbiotinamide: two radioiodinated biotin conjugates with improved stability." Bioconjug Chem 8.2 (March 1997): 179-186.
PMID
9095358
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
8
Issue
2
Publish Date
1997
Start Page
179
End Page
186
DOI
10.1021/bc970006m

Fluorine-18-labeled [Nle4,D-Phe7]-alpha-MSH, an alpha-melanocyte stimulating hormone analogue.

The alpha-melanocyte stimulating hormone (alpha-MSH) analogue [Nle4,D-Phe7]-alpha-MSH was labeled with 18F using N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB) in > 80% radiochemical yield. The IC50 values of [Nle4,D-Phe7]-alpha-MSH and para-fluorobenzoyl-[Nle4, D-Phe7]-alpha-MSH ([Nle4,D-Phe7, Lys 11 -(18F)PFB]-alpha-MSH) for inhibiting the binding of meta-[131I]iodobenzoyl -[Nle4,D-Phe7]-alpha-MSH ([Nle4,D-Phe7, Lys11-(131I)MIB]-alpha-MSH) to B16-F1 murine melanoma cells were 89 +/- 9 pM and 112 +/- 22 pM, respectively, suggesting that addition of 4-fluorobenzoate did not compromise alpha-MSH receptor binding affinity. Binding of [Nle4,D-Phe7,Lys11-(18F)PFB]-alpha-MSH was influenced by the specific activity of the preparation (400-1000 Ci/mmol). The normal tissue clearance of [Nle4, D-Phe7, Lys11-(18F) PFB]-alpha-MSH in mice was quite rapid, with little evidence for defluorination.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Fluorine-18-labeled [Nle4,D-Phe7]-alpha-MSH, an alpha-melanocyte stimulating hormone analogue." Nucl Med Biol 24.2 (February 1997): 171-178.
PMID
9089709
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
24
Issue
2
Publish Date
1997
Start Page
171
End Page
178

No-carrier-added iodine-131-FIBG: evaluation of an MIBG analog.

UNLABELLED: The purpose of this study was to evaluate the properties of 4-fluoro-3-[131I]iodobenzylguanidine ([131I]FIBG), a potential neuroendocrine tumor and myocardial imaging radiopharmaceutical. METHODS: The binding of [131I]FIBG and [125I]MIBG was compared in vitro using the SK-N-SH human neuroblastoma cell line. The role of the active uptake-1 mechanism was investigated by determining the effect on cell binding of desipramine (DMI), ouabain, norepinephrine (NE), unlabeled MIBG and FIBG and by incubation at 4 degrees C. Finally, the tissue distributions of [131I]FIBG and [125I]MIBG were compared in normal mice. RESULTS: The specific binding of [131I]FIBG remained fairly constant (45%-60%) over a 2-3-log activity range and consistently was 11%-14% higher (p < 0.05) than that of [125I]MIBG. The uptake of [131I]FIBG was reduced to 13% of control values by 1.5 microM DMI, to 31% by 1 mM ouabain, to 8% by lower temperature, to 8% by 50 microM NE and to 6% and 5% by 10 microM each of unlabeled MIBG and FIBG, respectively. The amount of [131I]FIBG retained by SK-N-SH cells was significantly higher than that of [125I]MIBG with the maximum difference observed at 72 hr. In mice, the uptake of [131I]FIBG was higher than that of [125I]MIBG not only in target tissues (heart and adrenals) but also in many other normal tissues; conversely, thyroidal uptake of [131I]FIBG was 2-3-fold lower than that of [125I]MIBG. The uptake of [131I]FIBG in the heart and adrenals was reduced by DMI. CONCLUSION: Iodine-131-FIBG is an analog of MIBG with prolonged binding to neuroblastoma cells in vitro and retention in the myocardium in vivo.

Authors
Vaidyanathan, G; Zhao, XG; Strickland, DK; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Zhao, XG, Strickland, DK, and Zalutsky, MR. "No-carrier-added iodine-131-FIBG: evaluation of an MIBG analog." J Nucl Med 38.2 (February 1997): 330-334.
PMID
9025764
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
38
Issue
2
Publish Date
1997
Start Page
330
End Page
334

Preparation and biological evaluation of an astatine-211 labeled biotin conjugate: biotinyl-3-[211 At]astatoanilide.

Biotinyl-3-[211 At]astatoanilide ([211 At]AtBA) was prepared in more than 80% yield by destannylation. In vitro, [211 At]AtBA exhibited a high affinity for streptavidin, and was stable after incubation in human serum, cerebrospinal fluid and distilled water, whereas it was rapidly degraded in mouse serum. HPLC analysis showed that the main degradation pathway in mouse serum was the cleavage of [211 At]astatoaniline. In mice, [211 At]AtBA and its 125I-labeled analogue cleared rapidly from most tissues; however, there was some evidence for dehalogenation of both tracers.

Authors
Foulon, CF; Schoultz, BW; Zalutsky, MR
MLA Citation
Foulon, CF, Schoultz, BW, and Zalutsky, MR. "Preparation and biological evaluation of an astatine-211 labeled biotin conjugate: biotinyl-3-[211 At]astatoanilide." Nucl Med Biol 24.2 (February 1997): 135-143.
PMID
9089706
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
24
Issue
2
Publish Date
1997
Start Page
135
End Page
143

Local hyperthermia improves uptake of a chimeric monoclonal antibody in a subcutaneous xenograft model.

This study was undertaken to determine the effect of local hyperthermia on the tissue distribution of a chimeric human/mouse IgG2 monoclonal antibody, 81C6, reactive with the extracellular matrix protein tenascin, which is expressed at high levels in gliomas, carcinomas of the breast and prostate, and other neoplasms. The D-54 MG s.c. glioma xenograft was treated with hyperthermia by immersion of the tumor-bearing leg in a circulating water bath. By 4 h after injection (immediately after heating), administration of chimeric 125I-labeled 81C6 (ch81C6) concomitantly with a 4-h local hyperthermia treatment at 41.8 degreesC resulted in an increase in tumor uptake of monoclonal antibody from a median of 12% of injected dose/g of tumor in normothermic mice to 42% of injected dose/g in mice receiving local hyperthermia. The increased level of uptake persisted in the heated tumors over the first 48 h and at 96 h. Additionally, heating increased the tumor:blood ratio of ch81C6 more than 7-fold at 4 h postinjection. The rate of uptake was also dramatically improved, with 60 and 90% of the maximum level of uptake achieved by 4 and 24 h, respectively, in the hyperthermia-treated mice, whereas the normothermic mice reached only 31 and 69% of their maximum uptake at those time points. In summary, local hyperthermia enhanced the absolute level and the rate of tumor uptake as well as tumor:normal tissue ratios for ch81C6. This approach may facilitate the clinical application of radionuclides with shorter half-lives, such as 211At, for the therapy of solid malignancies.

Authors
Hauck, ML; Dewhirst, MW; Bigner, DD; Zalutsky, MR
MLA Citation
Hauck, ML, Dewhirst, MW, Bigner, DD, and Zalutsky, MR. "Local hyperthermia improves uptake of a chimeric monoclonal antibody in a subcutaneous xenograft model." Clin Cancer Res 3.1 (January 1997): 63-70.
PMID
9815539
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
3
Issue
1
Publish Date
1997
Start Page
63
End Page
70

3-[211At]astato-4-fluorobenzylguanidine: a potential therapeutic agent with prolonged retention by neuroblastoma cells.

An analogue of meta-iodobenzylguanidine (MIBG) in which an aromatic hydrogen was replaced with fluorine has been found to possess many properties similar to those of the parent compound. Moreover, 4-fluoro-3-iodobenzylguanidine (FIBG) was retained in vitro by human neuroblastoma cells to a much greater extent than MIBG itself. Since alpha-emitters such as 211At could be valuable for the treatment of micrometastatic disease, an FIBG analogue in which the iodine atom is replaced by 211At would be of interest. In this study, we have evaluated the in vitro and in vivo properties of 3-[211At]astato-4-fluorobenzylguanidine ([211At]AFBG). The specific binding of [211At]AFBG to SK-N-SH human neuroblastoma cells remained fairly constant over 2- to 3-log activity range and was similar to that of [131I]MIBG. The uptake of [211At]AFBG by this cell line was reduced by desipramine, ouabain, 4 degrees C incubation, noradrenaline, unlabelled MIBG and FIBG, suggesting that its uptake is specifically mediated through an active uptake-1 mechanism. Over the 16 h period studied, the amount of [211At]AFBG retained was similar to that of [131I]FIBG, whereas the per cent of retained meta-[211At]astatobenzylguanidine ([211At]MABG) was considerably less than that of [131I]FIBG (53% vs 75%; P < 0.05). The IC50 values for the inhibition of uptake of [131I]MIBG, [211At]MABG, [125I]FIBG and [211At]AFBG by unlabelled MIBG were 209, 300, 407 and 661 nM respectively, suggesting that the affinities of these tracers for the noradrenaline transporter in SK-N-SH cells increase in that order. Compared with [211At]MABG, higher uptake of [211At]AFBG was seen in vivo in normal mouse target tissues such as heart and, to a certain extent, in adrenals. That the uptake of [211At]AFBG in these tissues was related to the uptake-1 mechanism was demonstrated by its reduction when mice were pretreated with desipramine. However, the stability of [211At]AFBG towards in vivo dehalogenation was less than that of [211At]MABG, as evidenced by the higher uptake of 211At in thyroid, spleen, lungs and stomach.

Authors
Vaidyanathan, G; Zhao, XG; Larsen, RH; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Zhao, XG, Larsen, RH, and Zalutsky, MR. "3-[211At]astato-4-fluorobenzylguanidine: a potential therapeutic agent with prolonged retention by neuroblastoma cells." Br J Cancer 76.2 (1997): 226-233.
Website
http://hdl.handle.net/10161/11044
PMID
9231923
Source
pubmed
Published In
British Journal of Cancer
Volume
76
Issue
2
Publish Date
1997
Start Page
226
End Page
233

Fluorine-18-labeled [Nle4,D-Phe7]-α-MSH, an α-melanocyte stimulating hormone analogue

The α-melanocyte stimulating hormone (α-MSH) analogue [Nle4,D-Phe7]-α-MSH was labeled with 18F using N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB) in >80% radiochemical yield. The IC50 values of [Nle4,D-Phe7]-α-MSH and para-fluorobenzoyl-[Nle4,D-Phe7]-α-MSH ([Nle4,D-Phe7,Lys11-(18F)PFB]-α-MSH for inhibiting the binding of meta-[131I]iodobenzoyl-[Nle4,D-Phe7]-α-MSH ([Nle4,D-Phe7,Lys11-(131I)MIB]-α-MSH to B16-F1 murine melanoma cells were 89 ± 9 pM and 112 ± 22 pM, respectively, suggesting that addition of 4-fluorobenzoate did not compromise α-MSH receptor binding affinity. Binding of [Nle4,D-Phe7,Lys11-(18F)PFB]-α-MSH was influenced by the specific activity of the preparation (400-1000 Ci/mmol). The normal tissue clearance of [Nle4,D-Phe7,Lys11-(18F)PFB]-α-MSH in mice was quite rapid, with little evidence for defluorination.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Fluorine-18-labeled [Nle4,D-Phe7]-α-MSH, an α-melanocyte stimulating hormone analogue." Nuclear Medicine and Biology 24.2 (1997): 171-178.
Source
scival
Published In
Nuclear Medicine and Biology
Volume
24
Issue
2
Publish Date
1997
Start Page
171
End Page
178
DOI
10.1016/S0969-8051(96)00211-9

3-[211At]astato-4-fluorobenzylguanidine: A potential therapeutic agent with prolonged retention by neuroblastoma cells

Authors
Vaidyanathan, G; Zhao, X-G; Larsen, RH; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Zhao, X-G, Larsen, RH, and Zalutsky, MR. "3-[211At]astato-4-fluorobenzylguanidine: A potential therapeutic agent with prolonged retention by neuroblastoma cells." British Journal of Cancer 76.2 (1997): 226-233.
Source
scival
Published In
British Journal of Cancer
Volume
76
Issue
2
Publish Date
1997
Start Page
226
End Page
233

Uptake and retention kinetics of para-fluorine-18-fluorobenzylguanidine in isolated rat heart.

UNLABELLED: Para-[18F]fluorobenzylguanidine ([18F]PFBG) is a newly developed tracer for imaging myocardial sympathetic neuronal innervation. This study investigated the uptake and retention mechanisms of [18F]PFBG in perfused, isolated rat heart. METHODS: Fluorine-18-PFBG was administered to working rat hearts within the perfusion medium at a constant activity concentration (1.5-2 MBq/liter) for 8 min, followed by a washout period (50 min). External scintillation probes with coincidence detection circuitry were used to measure myocardial radioactivity. Six groups of hearts (n = 6, except in Group 6) were studied: (Group 1) control; (Group 2) 100 nM desipramine (DMI); (Group 3) 0.8 microM SKF550; (Group 4) DMI + SKF550; (Group 5) SKF550 + 1.0 microM Ro 4-1284; and (Group 6) SKF550 with DMI chase at 30 min (n = 4). RESULTS: Groups 2, 3 and 4 showed a mean reduction of 19% (uptake-1 blockade), 58% (uptake-2 blockade) and 95% (uptake-1 and uptake-2 blockade) in uptake rates, respectively, compared with control (p < 0.01). A further 33% reduction in the uptake rate was noted with vesicular transport inhibition (Group 5 compared with 3, p = 0.054). Biphasic clearance consisting of rapid (T1/2 = 5.32 +/- 1.1 min) and slow (T1/2 = 35.2 +/- 9.6 min) components were noted in control hearts. The rapid (T1/2 = 1.6 +/- 0.3 min) and slow (T1/2 = 10.9 +/- 1.4 min) clearance rates were accelerated (p < 0.0001) in Group 5 compared to control. DMI chase conditions (Group 6) caused an inhibition of [18F]PFBG washout (p = 0.004) suggesting a role for reverse transport through the uptake-1 carrier. CONCLUSION: Fluorine-18-PFBG is specifically accumulated by sympathetic nerve terminals. However, further work is recommended in humans to evaluate the potential implications of specific extraneuronal uptake of [18F]PFBG through the uptake-2 mechanism.

Authors
Berry, CR; Garg, PK; Zalutsky, MR; Coleman, RE; DeGrado, TR
MLA Citation
Berry, CR, Garg, PK, Zalutsky, MR, Coleman, RE, and DeGrado, TR. "Uptake and retention kinetics of para-fluorine-18-fluorobenzylguanidine in isolated rat heart." J Nucl Med 37.12 (December 1996): 2011-2016.
PMID
8970525
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
37
Issue
12
Publish Date
1996
Start Page
2011
End Page
2016

Radioiodination of internalizing monoclonal antibodies using N-succinimidyl 5-iodo-3-pyridinecarboxylate.

Monoclonal antibodies (mAbs) that internalize following binding to cell-surface receptors require radiolabeling approaches that minimize loss of radioactivity from the cell after intracellular processing. One class of internalizing mAbs of great interest for imaging and radioimmunotherapy are those specific for EGFRvIII, a truncated form of the epidermal growth factor receptor found on gliomas, non-small cell lung carcinomas, breast carcinomas, and ovarian carcinomas. Because lysosomes are known to retain positively charged compounds, N-succinimidyl 5-iodo-3-pyridinecarboxylate (SIPC) might be ideal for radioiodination of these mAbs because of the positive charge on its pyridine ring. To investigate this hypothesis, the anti-EGFRvIII mAb L8A4 was labeled using SIPC, and internalization assays were performed using the EGFRvIII-positive cell lines HC2 20 d2 and NR6M. Compared with L8A4 labeled using Iodogen or N-succinimidyl 3-iodobenzoate, SIPC increased intracellular retention of activity by up to 65%. Reverse-phase high-performance liquid chromatography analyses indicated that a significantly higher fraction of the low molecular weight catabolites from mAbs labeled via SIPC were retained within cells (SIPC, 28.1%; Iodogen, 7.6% at 1 h). With SIPC, the primary labeled species in cell lysates was the 5-iodonicotinic acid (INA)-lysine conjugate, whereas in the supernatant, both INA-lysine and INA were seen. A 3-4-fold higher percentage of these catabolites were charged at lysosomal pH in comparison with those from mAb labeled using N-succinimidyl 3-iodobenzoate, in concert with the differences in cellular retention observed between these two labeling methods. In mice bearing HC2 20 d2 xenografts, a significant improvement in tumor retention of radioiodine and tumor:normal tissue ratios was seen when L8A4 was labeled using SIPC instead of the Iodogen method. These results suggest that SIPC is a promising reagent for the radioiodination of anti-EGFRvIII L8A4 and, possibly, other internalizing mAbs.

Authors
Reist, CJ; Garg, PK; Alston, KL; Bigner, DD; Zalutsky, MR
MLA Citation
Reist, CJ, Garg, PK, Alston, KL, Bigner, DD, and Zalutsky, MR. "Radioiodination of internalizing monoclonal antibodies using N-succinimidyl 5-iodo-3-pyridinecarboxylate." Cancer Res 56.21 (November 1, 1996): 4970-4977.
PMID
8895752
Source
pubmed
Published In
Cancer Research
Volume
56
Issue
21
Publish Date
1996
Start Page
4970
End Page
4977

Targeted therapy using alpha emitters.

Radionuclides such as 211At and 212Bi which decay by the emission of alpha-particles are attractive for certain applications of targeted radiotherapy. The tissue penetration of 212Bi and 211At alpha-particles is equivalent to only a few cell diameters, offering the possibility of combining cell-specific targeting with radiation of similar range. Unlike the beta-particles emitted by radionuclides such as 131I and 90Y, alpha-particles are radiation of high linear energy transfer and thus greater biological effectiveness. Several approaches have been explored for targeted radiotherapy with 212Bi- and 211At-labelled substances including colloids, monoclonal antibodies, metabolic precursors, receptor-avid ligands and other lower molecular weight molecules. An additional agent which exemplifies the promise of alpha-emitting radiopharmaceuticals is meta-[211At]astatobenzylguanidine. The toxicity of this compound under single-cell conditions, determined both by [3H]thymidine incorporation and by limiting dilution clonogenic assays, for human neuroblastoma cells is of the order of 1000 times higher than that of meta-[131I] iodobenzylguanidine. For meta-[211At] astatobenzylguanidine, the Do value was equivalent to only 6-7 211At atoms bound per cell. These results suggest that meta-[211At] astatobenzylguanidine might be valuable for the targeted radiotherapy of micrometastatic neuroblastomas.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Targeted therapy using alpha emitters." Phys Med Biol 41.10 (October 1996): 1915-1931. (Review)
PMID
8912371
Source
pubmed
Published In
Physics in Medicine and Biology
Volume
41
Issue
10
Publish Date
1996
Start Page
1915
End Page
1931

A method for the radiohalogenation of internalizing antibodies.

Authors
Reist, CJ; Garg, PK; Alston, KL; Bigner, DD; Zalutsky, MR
MLA Citation
Reist, CJ, Garg, PK, Alston, KL, Bigner, DD, and Zalutsky, MR. "A method for the radiohalogenation of internalizing antibodies." JOURNAL OF NUCLEAR MEDICINE 37.10 (October 1996): 1825-1825.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
37
Issue
10
Publish Date
1996
Start Page
1825
End Page
1825

Evaluation of meta-[211At]astatobenzylguanidine in an athymic mouse human neuroblastoma xenograft model.

A paired-label biodistribution was performed in athymic mice bearing SK-N-SH human neuroblastoma xenografts to compare the tissue uptake of meta-[211At]astatobenzylguanidine ([211At]MABG) and [131I]MIBG. Significantly higher (p < 0.05) uptake of [211At]MABG was seen in tumor (3.8 +/- 0.8% ID/g vs. 3.1 +/- 0.7% ID/g at 8 h) compared to [131I]MIBG. Desipramine reduced tumor uptake of [211At] MABG by 43%, suggesting that its accumulation was related to the specific uptake-1 mechanism. Higher uptake of [211At]MABG was also seen in normal tissue targets such as heart (6.0 +/- 0.9% ID/g vs. 4.5 +/- 0.8% ID/g at 8 h; p < 0.05). Pretreatment of mice with unlabeled MIBG increased tumor uptake of [211At]MABG by 1.5-fold while reducing uptake in heart and several other normal tissues. The vesicular uptake inhibitor tetrabenazine reduced heart uptake by 30% without reducing the tumor uptake. These results suggest such strategies might be useful for improving [211At]MABG tumor-to-normal tissue ratios.

Authors
Vaidyanathan, G; Friedman, HS; Keir, ST; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Friedman, HS, Keir, ST, and Zalutsky, MR. "Evaluation of meta-[211At]astatobenzylguanidine in an athymic mouse human neuroblastoma xenograft model." Nucl Med Biol 23.6 (August 1996): 851-856.
PMID
8940730
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
23
Issue
6
Publish Date
1996
Start Page
851
End Page
856

Intrathecal 131I-labeled antitenascin monoclonal antibody 81C6 treatment of patients with leptomeningeal neoplasms or primary brain tumor resection cavities with subarachnoid communication: phase I trial results.

We aimed to determine the maximum tolerated dose (MTD) of 131I-labeled 81C6 in patients with leptomeningeal neoplasms or brain tumor resection cavities with subarachnoid communication and to identify any objective responses. 81C6 is a murine IgG monoclonal antibody that reacts with tenascin in gliomas/carcinomas but does not react with normal adult brain. 131I-labeled 81C6 delivers intrathecal (IT) radiation to these neoplasms. This study was a Phase I trial in which patients were treated with a single IT dose of 131I-labeled 81C6. Cohorts of three to six patients were treated with escalating doses of 131I (starting dose, 40 mCi; 20 mCi escalations) on 10 mg 81C6. MTD is defined as the highest dose resulting in serious toxicity in no more than two of six patients. Serious toxicity is defined as grade III/IV nonhematological toxicity or major hematological toxicity. We treated 31 patients (8 pediatric and 23 adult). Eighteen had glioblastoma multiforme. Patients were treated with 131I doses from 40 to 100 mCi. Hematological toxicity was dose limiting and correlated with the administered 131I dose. No grade III/IV nonhematological toxicities were encountered. A partial response occurred in 1 patient and disease stabilization occurred in 13 (42%) of 31 patients. Twelve patients are alive (median follow-up, > 320 days); five are progression free >409 days median posttreatment. The MTD of a single IT administration of 131I-labeled 81C6 in adults is 80 mCi 131I-labeled 81C6. The MTD in pediatric patients was not reached at 131I doses up to 40 mCi normalized for body surface area.

Authors
Brown, MT; Coleman, RE; Friedman, AH; Friedman, HS; McLendon, RE; Reiman, R; Felsberg, GJ; Tien, RD; Bigner, SH; Zalutsky, MR; Zhao, XG; Wikstrand, CJ; Pegram, CN; Herndon, JE; Vick, NA; Paleologos, N; Fredericks, RK; Schold, SC; Bigner, DD
MLA Citation
Brown, MT, Coleman, RE, Friedman, AH, Friedman, HS, McLendon, RE, Reiman, R, Felsberg, GJ, Tien, RD, Bigner, SH, Zalutsky, MR, Zhao, XG, Wikstrand, CJ, Pegram, CN, Herndon, JE, Vick, NA, Paleologos, N, Fredericks, RK, Schold, SC, and Bigner, DD. "Intrathecal 131I-labeled antitenascin monoclonal antibody 81C6 treatment of patients with leptomeningeal neoplasms or primary brain tumor resection cavities with subarachnoid communication: phase I trial results." Clin Cancer Res 2.6 (June 1996): 963-972.
PMID
9816257
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
2
Issue
6
Publish Date
1996
Start Page
963
End Page
972

The effects of clinically relevant hyperthermic temperatures on the kinetic binding parameters of a monoclonal antibody.

Hyperthermia is a therapeutic modality under investigation for its ability to increase absolute levels of tumor uptake of radiolabeled monoclonal antibodies (MAbs). We have investigated whether hyperthermia may affect the binding parameters of MAbs. The effects of clinically relevant levels of hyperthermia on the kinetic binding parameters were investigated for 81C6, an antibody undergoing Phase I/II clinical trials for the treatment of brain tumors and neoplastic meningitis. No obvious effects of temperature in either the association or dissociation rate constants, nor in the equilibrium constants, were apparent between 37 degrees and 45 degrees C. The improved binding stability of the bivalent form of the MAb was apparent when compared with its monovalent Fab fragment.

Authors
Hauck, ML; Dewhirst, MW; Zalutsky, MR
MLA Citation
Hauck, ML, Dewhirst, MW, and Zalutsky, MR. "The effects of clinically relevant hyperthermic temperatures on the kinetic binding parameters of a monoclonal antibody." Nucl Med Biol 23.4 (May 1996): 551-557.
PMID
8832714
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
23
Issue
4
Publish Date
1996
Start Page
551
End Page
557

Localisation of [131I]MIBG in nude mice bearing SK-N-SH human neuroblastoma xenografts: effect of specific activity.

The biodistribution of no-carrier-added (n.c.a.) meta-[131I]iodobenzylguanidine ([131I]MIBG) and that prepared by the standard isotopic exchange method were compared in athymic mice bearing SK-N-SH human neuroblastoma xenografts. No advantage in tumour uptake was observed for the n.c.a. preparation. BALB/c nu/nu mice exhibited lower uptake in highly innervated normal tissues (heart and adrenals) than normal BALB/c mice. In another experiment, the distribution of n.c.a. [131I]MIBG in the absence or presence (3-9 micrograms) of MIBG carrier was determined. At both 4 h and 24 h, the heart uptake was reduced by a factor of 1.5 even at a dose of 3 micrograms MIBG. Tumour uptake was not significantly altered by various amounts of unlabelled MIBG at either time point.

Authors
Vaidyanathan, G; Friedman, HS; Keir, ST; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Friedman, HS, Keir, ST, and Zalutsky, MR. "Localisation of [131I]MIBG in nude mice bearing SK-N-SH human neuroblastoma xenografts: effect of specific activity." Br J Cancer 73.10 (May 1996): 1171-1177.
Website
http://hdl.handle.net/10161/11050
PMID
8630274
Source
pubmed
Published In
British Journal of Cancer
Volume
73
Issue
10
Publish Date
1996
Start Page
1171
End Page
1177

Chimeric anti-tenascin antibody 81C6: increased tumor localization compared with its murine parent.

When labeled using the Iodogen method, a chimeric antibody composed of the human IgG2 constant region and the variable regions of murine anti-tenascin 81C6 exhibited superior uptake in human glioma xenografts compared with its murine parent. In the current study, three paired-label experiments were performed in athymic mice with subcutaneous D-54 MG human glioma xenografts to evaluate further the properties of radioiodinated chimeric 81C6. These studies demonstrated that (a) the enhanced tumor uptake of chimeric 81C6 is specific; (b) when labeling was performed using N-succinimidyl 3-iodobenzoate, chimeric 81C6 again showed preferential accumulation in tumor compared with murine 81C6; and (c) the tumor uptake advantage observed previously with murine 81C6 for N-succinimidyl 3-iodobenzoate compared with Iodogen labeling did not occur with chimeric 81C6.

Authors
Zalutsky, MR; Archer, GE; Garg, PK; Batra, SK; Bigner, DD
MLA Citation
Zalutsky, MR, Archer, GE, Garg, PK, Batra, SK, and Bigner, DD. "Chimeric anti-tenascin antibody 81C6: increased tumor localization compared with its murine parent." Nucl Med Biol 23.4 (May 1996): 449-458.
PMID
8832699
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
23
Issue
4
Publish Date
1996
Start Page
449
End Page
458

PET imaging of pheochromocytoma (PHEO) in dogs using PARA [F-18]fluorobenzylguanidine (PFBG).

Authors
Garg, PK; Berry, CR; DeGrado, RT; Nutter, F; Breitschwerdt, E; Zalutsky, MR; Coleman, RE
MLA Citation
Garg, PK, Berry, CR, DeGrado, RT, Nutter, F, Breitschwerdt, E, Zalutsky, MR, and Coleman, RE. "PET imaging of pheochromocytoma (PHEO) in dogs using PARA [F-18]fluorobenzylguanidine (PFBG)." JOURNAL OF NUCLEAR MEDICINE 37.5 (May 1996): 915-915.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
37
Issue
5
Publish Date
1996
Start Page
915
End Page
915

Effects of specific activity on uptake and retention of metaiodobenzylguanidine (MIBG) in the heart: Revisited

Authors
DeGrado, TR; Zalutsky, MR; Coleman, RE; Vaidyanathan, G
MLA Citation
DeGrado, TR, Zalutsky, MR, Coleman, RE, and Vaidyanathan, G. "Effects of specific activity on uptake and retention of metaiodobenzylguanidine (MIBG) in the heart: Revisited." JOURNAL OF NUCLEAR MEDICINE 37.5 (May 1996): 701-701.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
37
Issue
5
Publish Date
1996
Start Page
701
End Page
701

Meta-[At-211]astatobenzylguanidine (MABG): In vivo evaluation in an athymic mouse human neuroblastoma xenograft model.

Authors
Vaidyanathan, G; Friedman, HS; Keir, ST; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Friedman, HS, Keir, ST, and Zalutsky, MR. "Meta-[At-211]astatobenzylguanidine (MABG): In vivo evaluation in an athymic mouse human neuroblastoma xenograft model." JOURNAL OF NUCLEAR MEDICINE 37.5 (May 1996): 236-236.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
37
Issue
5
Publish Date
1996
Start Page
236
End Page
236

Fluorine-18 labeling of [Nle(4),D-Phe(7)]-alpha-MSH, an alpha-melanocyte stimulating hormone (alpha-MSH) analogue.

Authors
Vaidyanathan, G; Affleck, DJ; Welsh, PC; Slade, SA; Alston, KL; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, Welsh, PC, Slade, SA, Alston, KL, and Zalutsky, MR. "Fluorine-18 labeling of [Nle(4),D-Phe(7)]-alpha-MSH, an alpha-melanocyte stimulating hormone (alpha-MSH) analogue." JOURNAL OF NUCLEAR MEDICINE 37.5 (May 1996): 875-875.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
37
Issue
5
Publish Date
1996
Start Page
875
End Page
875

Preparation and binding properties of an astatine-211 labeled biotin conjugate.

Authors
Foulon, CF; Larsen, RH; Zalutsky, MR
MLA Citation
Foulon, CF, Larsen, RH, and Zalutsky, MR. "Preparation and binding properties of an astatine-211 labeled biotin conjugate." JOURNAL OF NUCLEAR MEDICINE 37.5 (May 1996): 900-900.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
37
Issue
5
Publish Date
1996
Start Page
900
End Page
900

Radiotoxicity of systematically administered [211At]astatide in B6C3F1 and BALB/c (nu/nu) mice: a long-term survival study with histologic analysis.

PURPOSE: The present study undertook to establish the dose (LD) of systematically administered (via tail vein) sodium [211At]astatide that would kill 10% (LD10) of exposed animals in two mouse models and to evaluate the resulting histologic lesions. METHODS AND MATERIALS: Three dose escalation experiments were carried out using groups of 10 3- to 4-week-old, 20 +/- 2 g B6C3F1 mice, and one dose escalation experiment was carried out with groups of 10 4- to 6-week-old, 22 +/- 2 g BALB/c (nu/nu) mice. All animals were weighed daily and checked twice daily for general health; autopsies were performed within 12 h of death. RESULTS: The LD10 (95% confidence interval) level of free [211At]astatide at 360 days was 15.1 microCi (5.2-19.1 microCi) in B6C3F1 mice and was associated with a 37.8% weight difference from saline controls (p < 0.001). In the BALB/c (nu/nu) mice, the LD10 at 360 days was 7.7 microCi (0-14.2 microCi), while a dose of 10 microCi (0.42 microCi g(-1)) was associated with a 9.44% weight difference vs. saline controls (p < 0.05). Exclusive of the well-known effects on thyroid, [211At]astatide activity levels were associated with severe bone marrow depression, testicular atrophy, focal alopecia, and nuclear atypia of the epidermoid mucosa of the fore-stomach in the B6C3F1 mice; at activity levels approximating LD10 at 360 days, mild changes in the heart, liver, stomach, and spleen were observed. For BALB/c (nu/nu) mice, administration of 10 microCi was associated at autopsy with mild histologic lesions in the heart, stomach, liver, and spleen. CONCLUSIONS: These studies provide a basis for the design of further investigations of [211At]-labeled compounds as therapeutic agents.

Authors
McLendon, RE; Archer, GE; Garg, PK; Bigner, DD; Zalutsky, MR
MLA Citation
McLendon, RE, Archer, GE, Garg, PK, Bigner, DD, and Zalutsky, MR. "Radiotoxicity of systematically administered [211At]astatide in B6C3F1 and BALB/c (nu/nu) mice: a long-term survival study with histologic analysis." Int J Radiat Oncol Biol Phys 35.1 (April 1, 1996): 69-80.
PMID
8641929
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
35
Issue
1
Publish Date
1996
Start Page
69
End Page
80

5-[211 At]astato-2'-deoxyuridine, an alpha particle-emitting endoradiotherapeutic agent undergoing DNA incorporation.

When labeled with the subcellular range Auger electron emitters 125I and 123I, the thymidine analogue 5-iodo-2'deoxyuridine (IUdR) is highly cytotoxic but only to cells going through S-phase during exposure to these radiopharmaceuticals. Since 211 At emits alpha-particles of high linear energy transfer, but with a range of a few cell diameters, an IUdR analogue labeled with 211At could markedly improve the homogeneity of tumor dose deposition. Herein we describe the synthesis of 5-[211 At]astato-2'-deoxyuridine ([211 At]AUdR) in 85-90% radiochemical yield via the astatodestannylation of 5-(trimethylstannyl)-2'-deoxyuridine. In vitro studies using the human glioma cell line D-247 MG demonstrated that [211 At]AUdR was virtually identical to [131I]IUdr; both exhibited a linear increase in cell uptake with activity concentration, an inhibition of uptake by 10 micrometers IUdR, and the incorporation of about 50% of cell-bound activity into DNA. In a clonogenic assay, [211 At]AUdR exhibited a high cytotoxicity for D-247 MG cells, with a D(0) equivalent to less than 3 211At atoms/cell.

Authors
Vaidyanathan, G; Larsen, RH; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Larsen, RH, and Zalutsky, MR. "5-[211 At]astato-2'-deoxyuridine, an alpha particle-emitting endoradiotherapeutic agent undergoing DNA incorporation." Cancer Res 56.6 (March 15, 1996): 1204-1209.
PMID
8640798
Source
pubmed
Published In
Cancer Research
Volume
56
Issue
6
Publish Date
1996
Start Page
1204
End Page
1209

5-[At-211]astato-2'-deoxyuridine, an alpha-particle-emitting endoradiotherapeutic agent undergoing DNA incorporation

Authors
Vaidyanathan, G; Larsen, RH; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Larsen, RH, and Zalutsky, MR. "5-[At-211]astato-2'-deoxyuridine, an alpha-particle-emitting endoradiotherapeutic agent undergoing DNA incorporation." CANCER RESEARCH 56.6 (March 15, 1996): 1204-1209.
Source
wos-lite
Published In
Cancer Research
Volume
56
Issue
6
Publish Date
1996
Start Page
1204
End Page
1209

Enhanced binding and inertness to dehalogenation of alpha-melanotropic peptides labeled using N-succinimidyl 3-iodobenzoate.

Two peptides of potential utility for targeting melanoma cells, alpha-melanocyte-stimulating hormone (alpha-MSH) and its more potent analogue [Nle4,D-Phe7]-alpha-MSH, were radioiodinated in 45-65% yield using N-succinimidyl 3-[125I]iodobenzoate (SIB). To determine whether this labeling method resulted in improved in vitro and in vivo characteristics, these peptides also were labeled with 131I by direct iodination with the iodogen method. For alpha-MSH, the rapid tissue clearance of both radionuclides in mice was consistent with rapid degradation of the peptide; however, significantly lower levels of 125I were observed in thyroid and stomach, reflecting a greater inertness to deiodination. More extensive comparisons were performed with [Nle4,D-Phe7]-alpha-MSH. The in vitro binding of [Nle4,D-Phe7,Lys11-(125I)IBA]-alpha-MSH (prepared using SIB) to the murine B-16 melanoma cell line, 34.1 +/- 4.7%, was more than twice as high as that for [Tyr2(131I),Nle4,D-Phe7]-alpha-MSH (15.0 +/- 0.1%), and its KD was more than 10-fold lower than that for conventionally labeled peptide (10 +/- 5 versus 140 +/- 14 pM). The normal tissue clearance of [Nle4,D-Phe7,Lys11-(125I)IBA]-alpha-MSH in mice was faster than that of [Tyr2(131I),-Nle4,D-Phe7]-alpha-MSH. The 19-40-fold lower activity concentrations of [Nle4,D-Phe7,Lys11-(125I)IBA]-alpha-MSH in tissues accumulating free iodide (thyroid and stomach) suggest a greater inertness of this peptide to deiodination. The primary urinary catabolite of [Nle4,D-Phe7, Lys11-(125I)IBA]-alpha-MSH was the lysine conjugate of iodobenzoic acid, whereas radioiodide was the chief catabolite generated from [Tyr2(131I),Nle4,D-Phe7]-alpha-MSH. We conclude that further evaluation of [Nle4,D-Phe7,Lys11-(125I)IBA]-alpha-MSH for targeting alpha-MSH receptors is warranted and that SIB may be a useful method for the radioiodination of peptides.

Authors
Garg, PK; Alston, KL; Welsh, PC; Zalutsky, MR
MLA Citation
Garg, PK, Alston, KL, Welsh, PC, and Zalutsky, MR. "Enhanced binding and inertness to dehalogenation of alpha-melanotropic peptides labeled using N-succinimidyl 3-iodobenzoate." Bioconjug Chem 7.2 (March 1996): 233-239.
PMID
8983345
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
7
Issue
2
Publish Date
1996
Start Page
233
End Page
239
DOI
10.1021/bc960001+

Evaluation of an internal cyclotron target for the production of 211At via the 209Bi (alpha,2n)211 at reaction.

Astatine-211 is a 7.2 h half-life alpha-emitting radionuclide which has shown great promise for targeted radiotherapy. It is generally produced by cyclotron bombardment of bismuth metal targets with 28 MeV alpha-particles via the 209Bi(alpha,2n)211 At reaction. In order to provide 211At activity levels anticipated for clinical investigations, an internal target system has been designed and evaluated. The system has a grazing-angle configuration and leading- and trailing-edge monitors. Both aluminum and copper target backings were evaluated. With approx. 28 MeV alpha-particles, the 211At production efficiency was 41 +/- 7 MBq/microA.h, compared with 10.6 +/- 1.2 MBq/microA.h for an external target. Radionuclidic purity of 211At was high with no evidence of 210At.

Authors
Larsen, RH; Wieland, BW; Zalutsky, MR
MLA Citation
Larsen, RH, Wieland, BW, and Zalutsky, MR. "Evaluation of an internal cyclotron target for the production of 211At via the 209Bi (alpha,2n)211 at reaction." Appl Radiat Isot 47.2 (February 1996): 135-143.
PMID
8852627
Source
pubmed
Published In
Applied Radiation and Isotopes
Volume
47
Issue
2
Publish Date
1996
Start Page
135
End Page
143

No-carrier-added (4-fluoro-3-[131I]iodobenzyl)guanidine and (3-[211At]astato-4-fluorobenzyl)guanidine.

With 3-bromo-4-fluorotoluene as starting material, [4-fluoro-3-(trimethylsilyl)benzyl]guanidine was prepared in five steps in 1.5% overall yield. Radioiodination of this silicon precursor using N-chlorosuccinimide in trifluoroacetic acid at room temperature for 5 min gave (4-fluoro-3-[131I]-iodobenzyl)guanidine ([131I]FIBG) in 50-60% radiochemical yield. A byproduct which had a retention time in two HPLC systems similar to that of (m-iodobenzyl)guanidine (MIBG) was formed in about 30% yield. [131I]FIBG was stable up to 3 h under these conditions of iodination, indicating that the byproduct is not generated as a result of [131I]FIBG degradation. Using hydrogen peroxide as the oxidant in aqueous medium and a reaction time of 30 min at 50 degrees C, yields of [131I]FIBG could be increased to 75-80%, with less than 7% of the byproduct formed under these conditions. Astatination of the silicon precursor using N-chlorosuccinimide in trifluoroacetic acid at 70 degrees C gave 65-70% radiochemical yield of (3-[211At]astato-4-fluorobenzyl)guanidine ([211At]AFBG) in 10-15 min; about 17% of the byproduct formation was seen. Astatination of the silicon precursor under aqueous conditions using hydrogen peroxide was not successful.

Authors
Vaidyanathan, G; Affleck, DJ; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, and Zalutsky, MR. "No-carrier-added (4-fluoro-3-[131I]iodobenzyl)guanidine and (3-[211At]astato-4-fluorobenzyl)guanidine." Bioconjug Chem 7.1 (January 1996): 102-107.
PMID
8741997
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
7
Issue
1
Publish Date
1996
Start Page
102
End Page
107
DOI
10.1021/bc950078i

Two approaches for enhancing radioimmunotherapy: alpha emitters and hyperthermia.

Authors
Zalutsky, MR; Schuster, JM; Garg, PK; Archer, GE; Dewhirst, MW; Bigner, DD
MLA Citation
Zalutsky, MR, Schuster, JM, Garg, PK, Archer, GE, Dewhirst, MW, and Bigner, DD. "Two approaches for enhancing radioimmunotherapy: alpha emitters and hyperthermia." Recent Results Cancer Res 141 (1996): 101-122. (Review)
PMID
8722422
Source
pubmed
Published In
Recent Results in Cancer Research
Volume
141
Publish Date
1996
Start Page
101
End Page
122

Labeling of Monoclonal Antibodies (MAbs) with N-Succinimidyl 3-hydroxy-4-[131I]iodobenzoate (mSHIB)

Authors
Vaidyanathan, G; Affleck, DJ; Slade, SA; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, Slade, SA, and Zalutsky, MR. "Labeling of Monoclonal Antibodies (MAbs) with N-Succinimidyl 3-hydroxy-4-[131I]iodobenzoate (mSHIB)." Journal of Labelled Compounds and Radiopharmaceuticals (1996): 536-. (Academic Article)
Source
manual
Published In
Journal of Labelled Compounds and Radiopharmaceuticals
Publish Date
1996
Start Page
536

Radioimmunotherapy with alpha-particle emitting radioimmunoconjugates.

Radionuclides which decay by the emission of alpha-particles are attractive for certain radioimmunotherapeutic applications. These include the treatment of lymphomas, compartmentally spread malignancies such as ovarian cancer and neoplastic meningitis, and micrometastatic disease. Two alpha-emitting radionuclides of interest for this purpose are 212Bi (60.6 min half life) and 211At (7.2 hr half life). Compared with the beta-emitters commonly used for radiotherapy, the alpha-particles of 212Bi and 211At are of higher energy, much shorter range (less than 100 microm), and considerably higher linear energy transfer. Preliminary results obtained in a variety of in vitro systems and in vivo models have documented the exquisite toxicity of alpha-particles and have established a basis for initiating radiotherapy trials in humans with monoclonal antibodies labeled with alpha-emitting radionuclides.

Authors
Zalutsky, MR; Bigner, DD
MLA Citation
Zalutsky, MR, and Bigner, DD. "Radioimmunotherapy with alpha-particle emitting radioimmunoconjugates." Acta Oncol 35.3 (1996): 373-379. (Review)
PMID
8679269
Source
pubmed
Published In
Acta Oncologica (Informa)
Volume
35
Issue
3
Publish Date
1996
Start Page
373
End Page
379

Catabolism of Label from an F(ab')2 Fragment Radioiodinated Using N-Succinimidyl 3-iodobenzoate and Iodogen Methods

Authors
Garg, PK; Alston, KL; Zalutsky, MR
MLA Citation
Garg, PK, Alston, KL, and Zalutsky, MR. "Catabolism of Label from an F(ab')2 Fragment Radioiodinated Using N-Succinimidyl 3-iodobenzoate and Iodogen Methods." Journal of Labelled Compounds and Radiopharmaceuticals (1996): 539-. (Academic Article)
Source
manual
Published In
Journal of Labelled Compounds and Radiopharmaceuticals
Publish Date
1996
Start Page
539

Preliminary Evaluation of Radioiodinated Alpha-melanocyte Stimulating Hormone (a-MSH) and its Analogue Using N-succinimidyl 3-iodobenzoate and Iodogen Methods

Authors
Garg, PK; Alston, KL; Welsh, PC; Zalutsky, MR
MLA Citation
Garg, PK, Alston, KL, Welsh, PC, and Zalutsky, MR. "Preliminary Evaluation of Radioiodinated Alpha-melanocyte Stimulating Hormone (a-MSH) and its Analogue Using N-succinimidyl 3-iodobenzoate and Iodogen Methods." Journal of Labelled Compounds and Radiopharmaceuticals (1996): 496-. (Academic Article)
Source
manual
Published In
Journal of Labelled Compounds and Radiopharmaceuticals
Publish Date
1996
Start Page
496

Abundant tyrosine residues in the antigen binding site in anti-osteosarcoma monoclonal antibodies TP-1 and TP-3: Application to radiolabeling.

The variable (V) genes of TP-1 and TP-3 MAbs have been cloned and sequenced. Because of the potential use of these antibodies in the diagnosis and treatment of osteosarcoma, it is important to determine the presence and position of amino acid residues that may react with radiolabeling within the V domains. In this article, location of the tyrosine residues is determined using the knowledge of immunoglobulin structures in general. The TP-1V domains have a total of 19 tyrosines, whereas TP-3V domains have 18, with approximately half of these located within complementarity determining regions (CDRs). Thus, if equal reactivity of all tyrosines is assumed, smaller fragments of MAbs have a high probability of being radiolabeled at one of these sites with possible resultant loss of antigen binding.

Authors
Olafsen, T; Bruland, OS; Zalutsky, MR; Sandlie, I
MLA Citation
Olafsen, T, Bruland, OS, Zalutsky, MR, and Sandlie, I. "Abundant tyrosine residues in the antigen binding site in anti-osteosarcoma monoclonal antibodies TP-1 and TP-3: Application to radiolabeling." Acta Oncol 35.3 (1996): 297-301.
PMID
8679259
Source
pubmed
Published In
Acta Oncologica (Informa)
Volume
35
Issue
3
Publish Date
1996
Start Page
297
End Page
301

Particle-emitting endoradiotherapeutic agent undergoing DNA incorporation

When labeled with the subcellular range Auger electron emitters 125I and 123I, the thymidine analogue 5-iodo-2′-deoxyuridine (IUdR) is highly cytotoxic but only to cells going through S-phase during exposure to these radiopharmaceuticals. Since 211At emits α-particles of high linear energy transfer, but with a range of a few cell diameters, an IUdR analogue labeled with 211At could markedly improve the homogeneity of tumor dose deposition. Herein we describe the synthesis of 5-[211At]astato-2′-deoxyuridine ([211At]AUdR) in 85-90% radiochemical yield via the astatodestannylation of 5-(trimethylstannyl)-2′-deoxyuridine. In vitro studies using the human glioma cell line D-247 MG demonstrated that [211At]AUdR was virtually identical to [131I]IUdR; both exhibited a linear increase in cell uptake with activity concentration, an inhibition of uptake by 10 μM IUdR, and the incorporation of about 50% of cell-bound activity into DNA. In a clonogenic assay, [211At]AUdR exhibited a high cytotoxicity for D-247 MG cells, with a D0 equivalent to less than 3 211At atoms/cell.

Authors
Vaidyanathan, G; Larsen, RH; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Larsen, RH, and Zalutsky, MR. "Particle-emitting endoradiotherapeutic agent undergoing DNA incorporation." Cancer Research 56.6 (1996): 1204-1209.
Source
scival
Published In
Cancer Research
Volume
56
Issue
6
Publish Date
1996
Start Page
1204
End Page
1209

Evaluation of an internal cyclotron target for the production of 211at via the 209Bi (α,2n)211at reaction

Astatine-211 is a 7.2 h half-life α-emitting radionuclide which has shown great promise for targeted radiotherapy. It is generally produced by cyclotron bombardment of bismuth metal targets with 28 MeV α-particles via the 209Bi(α, 2n)211At reaction. In order to provide 211At activity levels anticipated for clinical investigations, an internal target system has been designed and evaluated. The system has a grazing-angle configuration and leading- and trailing-edge monitors. Both aluminum and copper target backings were evaluated. With approx. 28 MeV α-particles, the 211At production efficiency was 41 ± 7 MBq/μA·h, compared with 10.6 ± 1.2 MBq/μA·h for an external target. Radionuclidic purity of 211At was high with no evidence of 210At. Copyright © 1996 Elsevier Science Ltd. All rights reserved.

Authors
Larsen, RH; Wieland, BW; Zalutsky, MR
MLA Citation
Larsen, RH, Wieland, BW, and Zalutsky, MR. "Evaluation of an internal cyclotron target for the production of 211at via the 209Bi (α,2n)211at reaction." Applied Radiation and Isotopes 47.2 (1996): 135-143.
Source
scival
Published In
Applied Radiation and Isotopes
Volume
47
Issue
2
Publish Date
1996
Start Page
135
End Page
143

Para-[18F]fluorobenzylguanidine kinetics in a canine coronary artery occlusion model

Background: The kinetics of para-[18F]fluorobenzylguanidine ([18F]PFBG) were investigated in a canine coronary artery occlusion model. Methods and Results: Five dogs were imaged by positron emission tomography (PET) before and after complete surgical ligation of the left anterior descending coronary artery. PET studies included a 10-minute dynamic [13N]NH3 perfusion scan, followed 1 hour later by 3-hour dynamic [18F]PFBG scanning. [18F]PFBG and [13N]NH3 images demonstrated homogeneous myocardial uptake/perfusion before infarction. One hundred eighty minutes after [18F]PFBG administration, myocardial accumulation was decreased by 60% (day, 2, 0.0065% ±0.0015% injected dose/ml) and 58% (day 16, 0.0069%±0.003% injected dose/ml) compared with a similar myocardial region of interest from the preinfarction (0.016%±0.005% injected dose/ml) study. Myocardial accumulation of [13N]NH3 at 9 minutes showed a 52% (day 2) and 7% (day 16) decrease compared with the preinfarction study. The accumulation of [18F]PFBG in the infarction was decreased significantly at 120 and 180 minutes on all postinfarction studies (p=0.01). In three dogs a significant decrease in the myocardial norepinephrine concentration was documented in the area of infarction (237±94 ng/gm) versus the noninfarcted (1018±48 ng/gm) myocardium (p=0.001). Conclusions: A decreased accumulation of [18F]PFBG was observed in the area of myocardial infarct in this canine model. The magnitude of the decrease in [18F]PFBG was larger than that seen with [13N]NH3 on day 16 after infarction suggesting reperfusion and persistent sympathetic neuronal dysfunction. © 1996 American Society of Nuclear Cardiology.

Authors
Berry, CR; Garg, PK; DeGrado, TR; Hellyer, P; Weber, W; Garg, S; Hansen, B; Zalutsky, MR; Coleman, RE
MLA Citation
Berry, CR, Garg, PK, DeGrado, TR, Hellyer, P, Weber, W, Garg, S, Hansen, B, Zalutsky, MR, and Coleman, RE. "Para-[18F]fluorobenzylguanidine kinetics in a canine coronary artery occlusion model." Journal of Nuclear Cardiology 3.2 (1996): 119-129.
PMID
8799237
Source
scival
Published In
Journal of Nuclear Cardiology
Volume
3
Issue
2
Publish Date
1996
Start Page
119
End Page
129
DOI
10.1016/S1071-3581(96)90004-5

RADIOIMMUNOTHERAPY OF BREAST-CANCER XENOGRAFTS WITH MONOCLONAL-ANTIBODY ICR12 AGAINST C-ERBB2 P185 - COMPARISON OF IODOGEN AND N-SUCCINIMIDYL 4-METHYL-3-(TRI-N-BUTYLSTANNYL)BENZOATE RADIOIODINATION METHODS

Authors
SMELLIE, WJB; DEAN, CJ; SACKS, NPM; ZALUTSKY, MR; GARG, PK; CARNOCHAN, P; ECCLES, SA
MLA Citation
SMELLIE, WJB, DEAN, CJ, SACKS, NPM, ZALUTSKY, MR, GARG, PK, CARNOCHAN, P, and ECCLES, SA. "RADIOIMMUNOTHERAPY OF BREAST-CANCER XENOGRAFTS WITH MONOCLONAL-ANTIBODY ICR12 AGAINST C-ERBB2 P185 - COMPARISON OF IODOGEN AND N-SUCCINIMIDYL 4-METHYL-3-(TRI-N-BUTYLSTANNYL)BENZOATE RADIOIODINATION METHODS." December 1, 1995.
Source
wos-lite
Published In
Cancer Research
Volume
55
Issue
23
Publish Date
1995
Start Page
S5842
End Page
S5846

Tumor-specific anti-epidermal growth factor receptor variant III monoclonal antibodies: use of the tyramine-cellobiose radioiodination method enhances cellular retention and uptake in tumor xenografts.

Amplification and rearrangement of the epidermal growth factor receptor (EGFR) gene are characteristics of many types of tumors. One class of EGFR mutations, EGFRvIII, is characterized by an in-frame deletion resulting in a truncated external domain of the receptor. EGFRvIII was first identified in a subset of gliomas and has since been found in some non-small cell lung carcinomas and breast carcinomas. mAbs specific for this variant form of EGFR but unreactive with the wild-type EGFR have been reported from our laboratory. This study further characterizes three of these antibodies. We determined, via radiolabeling techniques and immunofluorescence microscopy, that, after cell binding in vitro, the anti-EGFRvIII-specific mAbs internalize at 37 degrees C. Furthermore, subsequent to internalization, the antibodies were processed intracellularly, presumably by lysosomal degradation. We also examined the use of an alternative radiolabeling procedure that uses nonmetabolizable radio-iodinated tyramine cellobiose. Our results show that the tyramine cellobiose labeling method allows for greater tumor cell retention of radiolabel in vitro (76% for tyramine cellobiose and 27% for Iodo-Gen after 24 h). Paired-label biodistribution studies in athymic mice indicate that anti-EGFRvIII mAb L8A4 localizes specifically to EGFRvIII-expressing tumor xenografts with a maximum of 34.3 +/- 7.6% injected dose/g when labeled using tyramine cellobiose compared with a maximum of 14.9 +/- 4.3% injected dose/g using Iodo-Gen; similar results were obtained with mAb H10. These results suggest that the anti-EGFRvIII mAbs may serve as potential carriers for radioconjugate- and immunotoxin-based therapies for tumors expressing EGFRvIII.

Authors
Reist, CJ; Archer, GE; Kurpad, SN; Wikstrand, CJ; Vaidyanathan, G; Willingham, MC; Moscatello, DK; Wong, AJ; Bigner, DD; Zalutsky, MR
MLA Citation
Reist, CJ, Archer, GE, Kurpad, SN, Wikstrand, CJ, Vaidyanathan, G, Willingham, MC, Moscatello, DK, Wong, AJ, Bigner, DD, and Zalutsky, MR. "Tumor-specific anti-epidermal growth factor receptor variant III monoclonal antibodies: use of the tyramine-cellobiose radioiodination method enhances cellular retention and uptake in tumor xenografts." Cancer Res 55.19 (October 1, 1995): 4375-4382.
PMID
7671250
Source
pubmed
Published In
Cancer Research
Volume
55
Issue
19
Publish Date
1995
Start Page
4375
End Page
4382

Fluorine-18 labeled chemotactic peptides: a potential approach for the PET imaging of bacterial infection.

A potent chemotactic peptide, formyl-norleucyl-leucyl-phenylalanyl-norleucyl-tyrosyl-lysine was derivatized by reaction with N-succinimidyl 4-fluorobenzoate. This derivatized peptide bound to human polymorphonuclear leukocytes in vitro and exhibited biological activity in a superoxide production assay. Peptide labeling using N-succinimidyl 4-[18F]fluorobenzoate was accomplished in reasonable yields with 10-15 mCi of labeled peptide available per 100 Ci of [18F]fluoride. With the exception of the gastrointestinal tract, clearance of activity from tissues following injection of this peptide in normal mice was rapid. Although preliminary in nature, these results suggest that 18F-labeled chemotactic peptides should be investigated as potential agents for positron emission tomographic imaging of bacterial infections.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Fluorine-18 labeled chemotactic peptides: a potential approach for the PET imaging of bacterial infection." Nucl Med Biol 22.6 (August 1995): 759-764.
PMID
8535336
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
22
Issue
6
Publish Date
1995
Start Page
759
End Page
764

Cloning and sequencing of V genes from anti-osteosarcoma monoclonal antibodies TP-1 and TP-3: location of lysine residues and implications for radiolabeling.

Monoclonal antibodies TP-1 and TP-3 are of potential utility for the radioimmunodiagnosis of osteosarcoma in both human and canine patients. The V genes of these antibodies were cloned and sequenced and to facilitate radiolabeling of these proteins, the location of the lysine residues within these sequences have been determined. The V-domains of TP-1 contain a total of 12 lysines, 10 in the framework region and 2 in the CDR region, while the V-domains of TP-3 contain a total of 14 lysines, 11 in the framework region and 3 in the CDR regions. Using space-filling models, the availability of each lysine residue for radiolabeling, and potential interference with antigen binding was predicted.

Authors
Olafsen, T; Bruland, OS; Zalutsky, MR; Sandlie, I
MLA Citation
Olafsen, T, Bruland, OS, Zalutsky, MR, and Sandlie, I. "Cloning and sequencing of V genes from anti-osteosarcoma monoclonal antibodies TP-1 and TP-3: location of lysine residues and implications for radiolabeling." Nucl Med Biol 22.6 (August 1995): 765-771.
PMID
8535337
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
22
Issue
6
Publish Date
1995
Start Page
765
End Page
771

Monoclonal antibodies against EGFRvIII are tumor specific and react with breast and lung carcinomas and malignant gliomas.

Despite molecular biological advances in understanding human cancers, translation into therapy has been less forthcoming; targeting neoplastic cells still requires that tumor-specific markers, preferably those on the cell surface, be identified. The epidermal growth factor receptor (EGFR) exists in a deletion-mutant form, EGFRvIII, which has been identified by genetic and immunological means in a subset of gliomas and non-small cell lung carcinomas. Specific polyvalent antisera to the extracellular portion of the variant were readily induced, but immunization using a synthetic linear peptide representing the unique EGFRvIII primary sequence has been unsuccessful in mice or macaques. We report here five specific monoclonal antibodies (mAbs) developed through long-term immunization protocols using the EGFRvIII-specific synthetic peptide and the intact variant in different formats that maintained secondary and tertiary conformation. These mAbs identify the EGFRvIII on the cell surface with relatively high affinity (KA range, 0.13 to 2.5 x 10(9) M-1) by live cell Scatchard analysis. These mAbs are specific for EGFRvIII as determined by RIA, ELISA, Western blot, analytical flow cytometry, autophosphorylation, and immunohistochemistry. Isolating specific mAbs enabled us to analyze normal and neoplastic human tissue and establish that EGFRvIII is truly tumor specific for subsets of breast carcinomas and for previously reported non-small cell lung carcinomas and gliomas. Also, this receptor is not expressed by any normal human tissues thus far examined, including elements of the peripheral, central nervous, and lymphoid systems. With mAbs, we identified a higher incidence of EGFRvIII positivity in gliomas than previously described and identified an EGFRvIII-positive subset of breast tumors; also, we observed that the EGFRvIII epitope is not expressed in normal tissues, and we demonstrated the localizing and therapeutic potential of the mAbs for tumors expressing this epitope. Our observations strongly warrant development of this mAb-antigen system as therapy for breast, lung, and central nervous system tumors.

Authors
Wikstrand, CJ; Hale, LP; Batra, SK; Hill, ML; Humphrey, PA; Kurpad, SN; McLendon, RE; Moscatello, D; Pegram, CN; Reist, CJ
MLA Citation
Wikstrand, CJ, Hale, LP, Batra, SK, Hill, ML, Humphrey, PA, Kurpad, SN, McLendon, RE, Moscatello, D, Pegram, CN, and Reist, CJ. "Monoclonal antibodies against EGFRvIII are tumor specific and react with breast and lung carcinomas and malignant gliomas." Cancer Res 55.14 (July 15, 1995): 3140-3148.
PMID
7606735
Source
pubmed
Published In
Cancer Research
Volume
55
Issue
14
Publish Date
1995
Start Page
3140
End Page
3148

Catabolism of radioiodinated murine monoclonal antibody F(ab')2 fragment labeled using N-succinimidyl 3-iodobenzoate and Iodogen methods.

The F(ab')2 fragment of monoclonal antibody (MAb) Me1-14 was labeled with 125I using the Iodogen method and by reaction with N-succinimidyl 3-[125I]iodobenzoate (SIB). The labeled catabolites generated after exposure to tissue homogenates in vitro and following administration of labeled F(ab')2 into normal mice were investigated by size-exclusion HPLC, gel electrophoresis, and reverse-phase HPLC. Rapid conversion of F(ab')2 to Fab was observed with both labeling methods. With F(ab')2 labeled using the Iodogen method, the primary low molecular weight catabolites appeared to be [125I]iodide and, to a lesser extent, mono[125I]iodotyrosine. With SIB, [125I]iodide and [125I]iodobenzoic acid (IBA) as well as the glycine and lysine conjugates of IBA were all observed. Differences in low molecular weight catabolic products could explain the more rapid normal tissue clearance with MAbs and MAb fragments labeled with SIB compared with those labeled using iodogen.

Authors
Garg, PK; Alston, KL; Zalutsky, MR
MLA Citation
Garg, PK, Alston, KL, and Zalutsky, MR. "Catabolism of radioiodinated murine monoclonal antibody F(ab')2 fragment labeled using N-succinimidyl 3-iodobenzoate and Iodogen methods." Bioconjug Chem 6.4 (July 1995): 493-501.
PMID
7578370
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
6
Issue
4
Publish Date
1995
Start Page
493
End Page
501

New MIBG preparation to improve targeted radiotherapy and reduce toxic side-effects in neuroblastoma patients undergoing combination treatment.

Authors
Mairs, RJ; Zalutsky, MR
MLA Citation
Mairs, RJ, and Zalutsky, MR. "New MIBG preparation to improve targeted radiotherapy and reduce toxic side-effects in neuroblastoma patients undergoing combination treatment." Br J Cancer 72.1 (July 1995): 250-. (Letter)
Website
http://hdl.handle.net/10161/11047
PMID
7599061
Source
pubmed
Published In
British Journal of Cancer
Volume
72
Issue
1
Publish Date
1995
Start Page
250

Preparation and preliminary evaluation of 4-[211At]astato-N-piperidinoethyl benzamide.

The potential therapeutic agent, 4-[211At]astato-N-piperidinoethyl benzamide (4-APAB) was synthesized via a halodestannylation reaction. Radiochemical yields were 69% for a 5 min reaction and reached 74% by 25 min, whereas 82% radiochemical yields were obtained under similar reaction conditions for radioiodination. A simplified procedure was adopted for the purification of the target compound. In vitro binding of 4-APAB to SK-MEL 28 melanoma and D247 glioma cell lines was 20.7 +/- 1.3% and 12.2 +/- 1.3%, respectively. In comparison, binding of 4-[131I]iodo-N-piperidinoethyl benzamide (4-IPAB) to SK-Mel 28 cells was 13.9 +/- 1.9%. Paired label biodistribution studies were performed in normal Balb/c mice using 4-IPAB and 4-APAB. Thyroid uptake at 1, 2, and 6 h was significantly higher for 4-APAB. Differences in liver accumulation between the two compounds were small but statistically significant at most time points. A higher accumulation of 211At compared with 131I was observed in lungs and spleen at all time points studied. These results indicate that 4-APAB is not stable in vivo, suggesting the need for a better sigma receptor ligand for use in 211At.

Authors
Garg, PK; John, CS; Zalutsky, MR
MLA Citation
Garg, PK, John, CS, and Zalutsky, MR. "Preparation and preliminary evaluation of 4-[211At]astato-N-piperidinoethyl benzamide." Nucl Med Biol 22.4 (May 1995): 467-473.
PMID
7550023
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
22
Issue
4
Publish Date
1995
Start Page
467
End Page
473

Validation of 4-[fluorine-18]fluoro-3-iodobenzylguanidine as a positron-emitting analog of MIBG.

UNLABELLED: This study evaluates the potential utility of 4-[18F]fluoro-3-iodobenzylguanidine ([18F]FIBG) as an MIBG analog. METHODS: In vitro assays of tracer binding were carried out using the SK-N-SH human neuroblastoma cell line in a paired-label format to compare [18F]FIBG directly with no-carrier-added [125I]MIBG. To ascertain whether [18F]FIBG, like MIBG, is taken up by the uptake-1 mechanism, the effects of desipramine, norepinephrine, and carrier MIBG and FIBG on cell binding were determined. Preincubation with ouabain and incubation at 4 degrees C was used to evaluate the energy-dependence of [18F]FIBG uptake by SK-N-SH cells. The tissue distribution of [18F]FIBG in mice was compared with no-carrier-added [125I]MIBG in a paired-label study. RESULTS: In paired-label binding studies, the percent binding of [18F]FIBG to neuroblastoma cells remained constant over a three-log activity range and the level was somewhat higher than that of no-carrier-added [125I]MIBG. Binding was blocked by desipramine, norepinephrine, carrier MIBG and FIBG, ouabain and by incubating at 4 degrees C, suggesting that [18F]FIBG is taken up by the uptake-1 mechanism. Radiation dosimetry calculations suggest that higher doses of [18F]FIBG, unlike [124I]MIBG, could be administered to patients. CONCLUSION: These in vitro and in vivo evaluations show that [18F]FIBG is an excellent analog of MIBG, suggesting that [18F]FIBG should be further evaluated for use in PET imaging of neuroendocrine tumors and cardiac abnormalities.

Authors
Vaidyanathan, G; Affleck, DJ; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, and Zalutsky, MR. "Validation of 4-[fluorine-18]fluoro-3-iodobenzylguanidine as a positron-emitting analog of MIBG." J Nucl Med 36.4 (April 1995): 644-650.
PMID
7699460
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
36
Issue
4
Publish Date
1995
Start Page
644
End Page
650

Uptake mechanisms of meta-[123I]iodobenzylguanidine in isolated rat heart.

In order to clarify the uptake and retention mechanisms of radioiodinated meta-iodobenzylguanidine (MIBG) in heart, the kinetics of no-carrier-added [123I]MIBG were studied in the isolated working rat heart in interaction with pharmacologic agents. The tracer was administered in the perfusate as a 10-min pulse, followed by a 90-min washout period. Kinetic analysis of the externally monitored time-activity curves of control hearts showed avid uptake (Ki = 4.4 +/- 0.7 mL/min/g), and monoexponential clearance (ko = 0.0056 +/- 0.0017 l/min), indicating a distribution volume (Vd = Ki/ko) of 834 +/- 214 mL/g. Blocking experiments (n = 41) were performed with neuronal uptake (uptake-1) inhibitor desipramine (DMI; 50-100 nM) and the extraneuronal uptake (uptake-2) inhibitor N-(9-fluorenyl)-N-methyl-beta-chloroethylamine (SKF550; 0.4-0.8 microM). Uptake rate was 27% reduced (P < 0.05) by 50 nM DMI but not significantly affected by 0.4 microM SKF550. Distribution volume was 88% reduced (P < 0.0005) by 50 nM DMI and 28% reduced (P < 0.05) by 0.4 microM SKF550. In DMI-blocked hearts, uptake rate was dramatically decreased (-80%, P < 0.0005) by SKF550 (0.4 microM), indicating uptake-2 transport contributed predominantly to the extraneuronal uptake of the tracer. The slow uptake rate seen with concomitant inhibition of uptake-1 and uptake-2 was further decreased by addition of unlabeled MIBG (1-10 microM) in a concentration-dependent manner, yet unaffected by addition of the vesicular uptake inhibitor Ro 4-1284 (1 microM). Thus, the uptake rate of [123I]MIBG is primarily dependent on uptake-1 and uptake-2 activity. Other possible mechanisms of uptake such as passive diffusion in association with intracellular binding are significant only in conditions where uptake-1 and uptake-2 mechanisms are largely inhibited.

Authors
Degrado, TR; Zalutsky, MR; Vaidyanathan, G
MLA Citation
Degrado, TR, Zalutsky, MR, and Vaidyanathan, G. "Uptake mechanisms of meta-[123I]iodobenzylguanidine in isolated rat heart." Nucl Med Biol 22.1 (January 1995): 1-12.
PMID
7735158
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
22
Issue
1
Publish Date
1995
Start Page
1
End Page
12

No-carrier-added meta-[123I]iodobenzylguanidine: synthesis and preliminary evaluation.

No-carrier-added [123I]MIBG was prepared from 3-(trimethylsilyl)benzylguanidine in 80-90% yield. Binding of this tracer to SK-N-SH human neuroblastoma cells maintained a constant level of > 50% over 2-3 log activity range. In comparison, the binding of [123I]MIBG prepared by isotopic exchange steadily decreased with dose. Biodistribution studies in normal mice demonstrated maximal concentrations in heart and adrenals for both preparations. In heart, significant 1.5-3.0 times higher levels (P < 0.05) were seen for the no-carrier-added preparation. Radiation dosimetry calculations suggest that the no-carrier-added preparation would increase the dose received by several tissues, most notably the heart where a 91% increase in dose is predicted.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "No-carrier-added meta-[123I]iodobenzylguanidine: synthesis and preliminary evaluation." Nucl Med Biol 22.1 (January 1995): 61-64.
PMID
7735171
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
22
Issue
1
Publish Date
1995
Start Page
61
End Page
64

Hyperthermic modulation of radiolabelled antibody uptake in a human glioma xenograft and normal tissues.

These experiments investigate the biodistribution of radiolabelled MAb in a human glioma xenograft model after 4 h of local hyperthermia (HT) with a twofold purpose: to maximize the ratio of cumulative isotope activity in tumour relative to normal tissues, and to examine the temperature dependence of the effect. Restrained, unanaesthetized athymic nude mice bearing 150-200 mm3 s.c. human glioma xenografts (D-54 MG) were given 5 micrograms 125I-labelled specific and 131I-labelled non-specific MAb immediately prior to HT (water bath) for 4 h. Cohorts of five animals were killed at 0, 4, 8, 12 and 24 h after HT, and normal and tumour tissues were analysed for activity of each isotope. MAb uptake in tumour was greater with HT than with controls, and greater for specific MAb than for non-specific MAb. Uptake in thyroid was not significantly affected by tumour HT, suggesting that HT does not increase the rate of dehalogenation. Uptake in several other normal tissues away from the heated site was significantly increased (as were reported previously in mice anaesthetized with pentobarbital sodium during treatment; Cope et al. 1990), but the temporal pattern was different from that observed in tumour, suggesting that short-lived isotopes might lead to preferential dose deposition in heated tumour. Doses to various tissues were calculated for isotopes having a range of half-lives; the results clearly indicated that maximum differential in uptake between tumour and normal tissues would occur for isotopes with half-lives < 3 days. A separate series of experiments compared tumour uptake for 40, 42 and 44 degrees C HT. These results demonstrated that 42 and 44 degrees C HT created maximum enhancement in specific antibody uptake over controls. Specific MAb was retained over time in 42 degrees C-heated tumours, whereas significant washout occurred for non-specific MAb, which indicates that MAb retention was due to increased specific binding at this temperature and not vascular damage with antibody trapping. Retention of both specific and non-specific MAb was seen at 44 degrees C, suggesting that vascular damage becomes an important non-specific mechanism for antibody retention at higher temperatures.

Authors
Schuster, JM; Zalutsky, MR; Noska, MA; Dodge, R; Friedman, HS; Bigner, DD; Dewhirst, MW
MLA Citation
Schuster, JM, Zalutsky, MR, Noska, MA, Dodge, R, Friedman, HS, Bigner, DD, and Dewhirst, MW. "Hyperthermic modulation of radiolabelled antibody uptake in a human glioma xenograft and normal tissues." Int J Hyperthermia 11.1 (January 1995): 59-72.
PMID
7714371
Source
pubmed
Published In
International Journal of Hyperthermia (Informa)
Volume
11
Issue
1
Publish Date
1995
Start Page
59
End Page
72

Quantitation of 211At in small volumes for evaluation of targeted radiotherapy in animal models.

We have evaluated SPECT and two planar imaging methods, geometric mean (GM) and buildup factor (BF), for their potential to quantitate in vivo 211At distributions in rat spinal subarachnoid spaces using phantom studies. The use of medium-energy collimators and the small diameter (3 mm) of the subarachnoid space complicate quantitation. Net activities from distributions in various backgrounds were obtained using a large region of interest with background subtraction. Results showed quantitation accuracy within 10% for SPECT and BF in low backgrounds increasing to 25% at higher background levels while GM errors ranged from 20 to 45%. We have also obtained images of [211At]astatide distributions, administered intrathecally, in rats.

Authors
Johnson, EL; Turkington, TG; Jaszczak, RJ; Gilland, DR; Vaidyanathan, G; Greer, KL; Coleman, RE; Zalutsky, MR
MLA Citation
Johnson, EL, Turkington, TG, Jaszczak, RJ, Gilland, DR, Vaidyanathan, G, Greer, KL, Coleman, RE, and Zalutsky, MR. "Quantitation of 211At in small volumes for evaluation of targeted radiotherapy in animal models." Nucl Med Biol 22.1 (January 1995): 45-54.
PMID
7735169
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
22
Issue
1
Publish Date
1995
Start Page
45
End Page
54

Enhanced tumour uptake and in vitro radiotoxicity of no-carrier-added [131I]meta-iodobenzylguanidine: implications for the targeted radiotherapy of neuroblastoma.

In vitro and in vivo neuroblastoma models were used to determine whether improvements in tumour targeting in vivo and therapeutic efficacy in vitro could result from the use of no-carrier-added (n.c.a.) [131I]MIBG. Results were compared with use of the conventional therapy MIBG preparation (ex. [131I]MIBG) of lower specific activity which is produced by iodide exchange reaction. The efficacy of n.c.a. [131I]MIBG was compared with that of [131I]MIBG over a range of specific activities by the assessment of neuroblastoma spheroid growth delay. Whereas n.c.a. [131I]MIBG at a radioactivity concentration of 2 MBq/ml prevented the regrowth of 84% of spheroids, toxicity was significantly reduced by the addition of non-radiolabelled MIBG to the incubation medium. The time-dependent biodistribution of n.c.a. [131I]MIBG in nude mice bearing human neuroblastoma xenografts was compared with that of the conventional therapy radiopharmaceutical. The n.c.a. agent gave improved tumour uptake but also significantly greater accumulation in normal tissues known to accumulate MIBG such as heart, adrenal and skin. However, uptake and retention in the blood was unaltered. For all tissues examined, the 3-day calculations were undertaken to predict organ to tumour dose ratios which would result in human neuroblastoma patients with each of the [131I]MIBG preparations. These results suggest that significant therapeutic gain may be achieved by the use of n.c.a. [131I]MIBG as a treatment agent in neuroblastoma. neuroblastoma.

Authors
Mairs, RJ; Russell, J; Cunningham, S; O'Donoghue, JA; Gaze, MN; Owens, J; Vaidyanathan, G; Zalutsky, MR
MLA Citation
Mairs, RJ, Russell, J, Cunningham, S, O'Donoghue, JA, Gaze, MN, Owens, J, Vaidyanathan, G, and Zalutsky, MR. "Enhanced tumour uptake and in vitro radiotoxicity of no-carrier-added [131I]meta-iodobenzylguanidine: implications for the targeted radiotherapy of neuroblastoma." Eur J Cancer 31A.4 (1995): 576-581.
PMID
7576972
Source
pubmed
Published In
European Journal of Cancer
Volume
31A
Issue
4
Publish Date
1995
Start Page
576
End Page
581

Meta-[131I]iodobenzylguanidine uptake and meta-[211At]astatobenzylguanidine treatment in human medulloblastoma cell lines.

Uptake of radioiodinated meta-iodobenzylguanidine (MIBG) has been demonstrated in the neural crest tumors, including neuroblastoma, pheochromocytoma, and carcinoid tumors, and is presently in use diagnostically and therapeutically in these settings. Cells comprising medulloblastoma, the most common central nervous system malignancy in childhood, may be derived from a common germinal neuroepithelial cell as neural crest tissue, and as a result, also may have the capacity for accumulating MIBG. To investigate this hypothesis, we measured the in vitro binding of [131I]MIBG to 9 medulloblastoma-derived cell lines and the SK-N-SH neuroblastoma line known to accumulate MIBG. Seven of the medulloblastoma lines exhibited MIBG binding. The cell line with the greatest uptake, D384 Med, bound 11.2 +/- 0.9% of added [131I]MIBG activity compared with 47.1 +/- 2.3% for the SK-N-SH cell line. When 2 of the cell lines, D384 Med and D458 Med, were treated with the alpha-particle emitting analogue meta-[211At]astatobenzylguanidine ([211At]MABG), as much as a 3-log cell kill was observed in limiting dilution clonogenic assays. Exposure to considerably higher activity levels of [211At]astatide was required to achieve a similar degree of cell kill, suggesting that this cytotoxicity was not related to nonspecific effects of alpha-particle irradiation. We conclude that the uptake capacity of medulloblastoma cell lines for [131I]MIBG uptake in vitro, while lower than that seen in SK-N-SH neuroblastoma cells, is sufficient to permit [211At]MABG to be used with significant therapeutic effectiveness.

Authors
Strickland, DK; Vaidyanathan, G; Friedman, HS; Zalutsky, MR
MLA Citation
Strickland, DK, Vaidyanathan, G, Friedman, HS, and Zalutsky, MR. "Meta-[131I]iodobenzylguanidine uptake and meta-[211At]astatobenzylguanidine treatment in human medulloblastoma cell lines." J Neurooncol 25.1 (1995): 9-17.
PMID
8523094
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
25
Issue
1
Publish Date
1995
Start Page
9
End Page
17

Phase I studies of treatment of malignant gliomas and neoplastic meningitis with 131I-radiolabeled monoclonal antibodies anti-tenascin 81C6 and anti-chondroitin proteoglycan sulfate Me1-14 F (ab')2--a preliminary report.

The advent of monoclonal antibody (MAb) technology has made Ehrlich's postulate of the 'magic bullet' an attainable goal. Although specific localization of polyvalent antibodies to human gliomas was demonstrated in the 1960s, the lack of specific, high affinity antibody populations and of defined target antigens of sufficient density precluded therapeutic applications. Not until the identification of operationally specific tumor-associated antigens (present in tumor tissue but not normal central nervous system tissue); production of homogeneous, high affinity MAbs to such antigens; and the use of compartmental administration (intrathecal or intracystic), has the promise of passive immunotherapy of primary and metastatic central nervous system neoplasms been recognized. We report here preliminary data from Phase I studies of the compartmental administration of the anti-tenascin MAb 81C6 and F(ab2)2 fragments of MAb Me1-14, which recognizes the proteoglycan chondroitin sulfate-associated protein of gliomas and melanomas, to patients with primary central nervous system tumors or tumors metastatic to the central nervous system. Phase I dose escalation studies of intracystically administered 131I-labeled anti-tenascin MAb 81C6 to either spontaneous cysts of recurrent gliomas or surgically created cystic resection cavities have resulted in striking responses. Of five patients with recurrent cystic gliomas treated, four had partial responses, clinically or radiographically. Similarly, in patients with surgically created resection cavities, a partial response at the treatment site and extended stable disease status has been obtained following intracystic administration of 131I-labeled 81C6. No evidence of hematologic or neurologic toxicity has been observed in either patient population, with the exception of transient exacerbation of a pre-existing seizure disorder in a single patient. Dosimetry calculations indicated high intracystic retention for four to six weeks with little or no systemic dissemination; estimated total doses intracystically ranged from 12,700-70,290 rad. Intrathecal administration of labeled MAbs to patients with neoplastic meningitis is more difficult to assess in terms of clinical responsiveness. Of patients so treated with either 131I-labeled 81C6 or 131I-labeled Me1-14 (F(ab)2, cerebrospinal fluid and radiographic responses have been achieved, and survival prolongation through maintenance of stable disease has been observed in several cases. Initial results from pHase I dose escalation trials are encouraging in terms of the proportion of cases of disease stabilization and partial and complete responses obtained. Importantly, neurotoxicity has been virtually nonexistent, and hematologic toxicity rare and rapidly responsive to treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Authors
Bigner, DD; Brown, M; Coleman, RE; Friedman, AH; Friedman, HS; McLendon, RE; Bigner, SH; Zhao, XG; Wikstrand, CJ; Pegram, CN
MLA Citation
Bigner, DD, Brown, M, Coleman, RE, Friedman, AH, Friedman, HS, McLendon, RE, Bigner, SH, Zhao, XG, Wikstrand, CJ, and Pegram, CN. "Phase I studies of treatment of malignant gliomas and neoplastic meningitis with 131I-radiolabeled monoclonal antibodies anti-tenascin 81C6 and anti-chondroitin proteoglycan sulfate Me1-14 F (ab')2--a preliminary report." J Neurooncol 24.1 (1995): 109-122.
PMID
8523067
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
24
Issue
1
Publish Date
1995
Start Page
109
End Page
122

Meta-[131I]iodobenzylguanidine uptake and meta-[211At]astatobenzylguanidine treatment in human medulloblastoma cell lines

Uptake of radioiodinated mefa-iodobenzylguanidine (MIBG) has been demonstrated in the neural crest tumors, including neuroblastoma, pheochromocytoma, and carcinoid tumors, and is presently in use diagnostically and therapeutically in these settings. Cells comprising medulloblastoma, the most common central nervous system malignancy in childhood, may be derived from a common germinal neuroepithelial cell as neural crest tissue, and as a result, also may have the capacity for accumulating MIBG. To investigate this hypothesis, we measured the in vitro binding of [131I]MIBG to 9 medulloblastoma-derived cell lines and the SK-N-SH neuroblastoma line known to accumulate MIBG. Seven of the medulloblastoma lines exhibited MIBG binding. The cell line with the greatest uptake, D384 Med, bound 11.2 ± 0.9% of added [131I]MIBG activity compared with 47.1 ± 2.3% for the SK-N-SH cell line. When 2 of the cell lines, D384 Med and D458 Med, were treated with the a-particle emitting analogue meta-[211At]astatobenzylguanidine ([211At]MABG), as much as a 3-log cell kill was observed in limiting dilution clonogenic assays. Exposure to considerably higher activity levels of [211At]astatide was required to achieve a similar degree of cell kill, suggesting that this cytotoxicity was not related to nonspecific effects of α-particle irradiation. We conclude that the uptake capacity of medulloblastoma cell lines for [131I]MIBG uptake in vitro, while lower than that seen in SK-N-SH neuroblastoma cells, is sufficient to permit [211At]MABG to be used with significant therapeutic effectiveness. © 1995 Kluwer Academic Publishers.

Authors
Strickland, DK; Vaidyanathan, G; Friedman, HS; Zalutsky, MR
MLA Citation
Strickland, DK, Vaidyanathan, G, Friedman, HS, and Zalutsky, MR. "Meta-[131I]iodobenzylguanidine uptake and meta-[211At]astatobenzylguanidine treatment in human medulloblastoma cell lines." Journal of Neuro-Oncology 25.1 (1995): 9-17.
Source
scival
Published In
Journal of Neuro-Oncology
Volume
25
Issue
1
Publish Date
1995
Start Page
9
End Page
17
DOI
10.1007/BF01054718

Enhanced tumour uptake and in vitro radiotoxicity of no-carrier-added [131i] metaiodobenzylguanidine: Implications for the targeted radiotherapy of neuroblastoma

In vitro and in vivo neuroblastoma models were used to determine whether improvements in tumour targeting in vivo and therapeutic efficacy in vitro could result from the use of no-carrier-added (n.c.a.) [131I]MIBG. Results were compared with use of the conventional therapy MIBG preparation (ex. [131I]MIBG) of lower specific activity which is produced by iodide exchange reaction. The efficacy of n.c.a. [131I]MIBG was compared with that of [131I]MIBG over a range of specific activities by the assessment of neuroblastoma spheroid growth delay. Whereas n.c.a. [131I]MIBG at a radioactivity concentration of 2 MBq/ml prevented the regrowth of 84% of spheroids, toxicity was significantly reduced by the addition of non-radiolabelled MIBG to the incubation medium. The time-dependent biodistribution of n.c.a. [131I]MIBG in nude mice bearing human neuroblastoma xenografts was compared with that of the conventional therapy radiopharmaceutical. The n.c.a. agent gave improved tumour uptake but also significantly greater accumulation in normal tissues known to accumulate MIBG such as heart, adrenal and skin. However, uptake and retention in the blood was unaltered. For all tissues examined, the 3-day cumulative tumour to normal tissue radiation dose ratio was greater for n.c.a. [131I]MIBG. Theoretical calculations were undertaken to predict organ to tumour dose ratios which would result in human neuroblastoma patients with each of the [131I]MIBG preparations. These results suggest that significant therapeutic gain may be achieved by the use of n.c.a. [131I]MIBG as a treatment agent in neuroblastoma. © 1995.

Authors
Mairs, RJ; Russell, J; Cunningham, S; O'Donoghue, JA; Gaze, MN; Owens, J; Vaidyanathan, G; Zalutsky, MR
MLA Citation
Mairs, RJ, Russell, J, Cunningham, S, O'Donoghue, JA, Gaze, MN, Owens, J, Vaidyanathan, G, and Zalutsky, MR. "Enhanced tumour uptake and in vitro radiotoxicity of no-carrier-added [131i] metaiodobenzylguanidine: Implications for the targeted radiotherapy of neuroblastoma." European Journal of Cancer 31.4 (1995): 576-581.
Source
scival
Published In
European Journal of Cancer
Volume
31
Issue
4
Publish Date
1995
Start Page
576
End Page
581

Radioimmunotherapy of breast cancer xenografts with monoclonal antibody ICR12 against c-erbB2 p185: Comparison of iodogen and N-succinimidyl 4-methyl-3-(tri-n-butylstannyl)benzoate radioiodination methods

C-erbB2 p185 is a proto-oncogene product expressed in 25-30% of human invasive breast cancers that is associated with poor prognosis and resistance to endocrine therapy and chemotherapy. It is minimally expressed in normal adult tissues (M. F. Press et al., Oncogene, 5: 953-962, 1990). For this reason, it is an attractive target for radioimmunotherapy and other antibody-directed therapies. ICR12 is a rat IgG2a monoclonal antibody directed against a protein epitope of the external domain of the c-erbB2 p185. We performed experiments to optimize the direct iodination of ICR12 with 131I using the IodoGen method, and we found impairment of immunoreactive fraction with increasing specific activity. N-Succinimidyl 4-methyl-3-(tri-n-butylstannyl)benzoate (MATE) is a tin ester that can be radioiodinated easily and then coupled to the c-amino group of lysine residues. This method has been shown to have improved uptake in tumors compared with antibody labeled by direct iodination (P. K. Garg et al., Nucl. Med. Biol., 20: 379-387, 1993). ICR12 could be labeled up to 16 mCi/mg by this technique without loss of immunoreactive fraction. Whole-body retention of MATE-labeled ICR12 was less than IodoGen (P < 0.0001). Radioimmunotherapy experiments in athymic mice bearing established MDA MB 361 human breast cancer xenografts showed growth inhibition for >24 days at a dose of 600 μCi/mouse (P < 0.0001) when labeled by the IodoGen technique, and 12 days using the MATE method (P < 0.0001).

Authors
Smellie, WJB; Dean, CJ; Sacks, NPM; Zalutsky, MR; Garg, PK; Carnochan, P; Eccles, SA
MLA Citation
Smellie, WJB, Dean, CJ, Sacks, NPM, Zalutsky, MR, Garg, PK, Carnochan, P, and Eccles, SA. "Radioimmunotherapy of breast cancer xenografts with monoclonal antibody ICR12 against c-erbB2 p185: Comparison of iodogen and N-succinimidyl 4-methyl-3-(tri-n-butylstannyl)benzoate radioiodination methods." Cancer Research 55.23 SUPPL. (1995): 5842S-5846S.
PMID
7493357
Source
scival
Published In
Cancer Research
Volume
55
Issue
23 SUPPL.
Publish Date
1995
Start Page
5842S
End Page
5846S

Cytotoxicity of alpha-particle-emitting m-[211At]astatobenzylguanidine on human neuroblastoma cells.

Radioiodinated m-iodobenzylguanidine (MIBG) has been used with only limited success for the treatment of neural crest tumors including neuroblastoma. Use of an MIBG analogue labeled with 211At could be advantageous because of the shorter range and higher linear energy transfer of its alpha-particle emissions compared with the beta-particles emitted by 131I. The potential utility of m-[211At]astatobenzylguanidine for the treatment of neuroblastoma was investigated in vitro using 3 human neuroblastoma cell lines known to take up MIBG [SK-N-SH, SK-N-BE(2C), and SK-SY5Y] and a control line lacking MIBG uptake (SK-N-MC). Maximum binding of m-[211At]astatobenzylguanidine ([211At] MABG) to 5 x 10(5) cells after a 2-h incubation ranged from 61% for SK-N-SH to 1% for SK-N-MC. Using a limiting dilution clonogenic assay, the cytotoxicity for SK-N-SH cells of [211At]MABG was compared with [211At]astatide and no-carrier-added [131I]MIBG. A D0 of 5.8 nCi/ml was calculated for [211At]MABG compared with 482 nCi/ml for [211At] astatide, indicating a more than 80-fold enhanced cytotoxicity for the specifically targeted alpha-particles of [211At]MABG. For [211At]MABG, the D0 corresponded to only 6.4 211At atoms bound/cell compared with 9000 atoms/cell for no-carrier-added [131I]MIBG. The D0 values measured for [211At]MABG treatment of SK-SY5Y, SK-N-BE(2C), and SK-N-MC cells were 50, 5.8, and 11,043 nCi/ml, respectively, corresponding to 7.04, 6.46, and 171.79 211At atoms bound/cell. In conclusion, these results have demonstrated that [211At]MABG is considerably more cytotoxic than [131I]MIBG and that [211At]MABG could have great potential as a radiotherapeutic agent for the treatment of neuroblastoma.

Authors
Strickland, DK; Vaidyanathan, G; Zalutsky, MR
MLA Citation
Strickland, DK, Vaidyanathan, G, and Zalutsky, MR. "Cytotoxicity of alpha-particle-emitting m-[211At]astatobenzylguanidine on human neuroblastoma cells." Cancer Res 54.20 (October 15, 1994): 5414-5419.
PMID
7923174
Source
pubmed
Published In
Cancer Research
Volume
54
Issue
20
Publish Date
1994
Start Page
5414
End Page
5419

(4-[18F]fluoro-3-iodobenzyl)guanidine, a potential MIBG analogue for positron emission tomography.

The aims of this investigation were to develop a no-carrier-added (nca) synthesis of (4-[18F]-fluoro-3-iodobenzyl)guanidine ([18F]FIBG) and to evaluate its potential as an MIBG analogue useful for positron emission tomography. [18F]FIBG was prepared in four steps starting from 4-cyano-2-iodo-N,N,N-trimethylanilinium trifluoromethanesulfonate in 5% decay-corrected radiochemical yield in a total synthesis time of 130 min. The specific activity was more than 1500 Ci per mmol. In vitro binding studies showed that the percent binding of [18F]FIBG to SK-N-SH human neuroblastoma cells remained constant over a 3-log activity range and was similar to that of nca [131I]MIBG. Specific and high uptake of FIBG was also seen in mouse heart and adrenals. The in vitro and in vivo properties of [18F]FIBG suggest that this compound may be a useful positron-emitting analogue of MIBG.

Authors
Vaidyanathan, G; Affleck, DJ; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, and Zalutsky, MR. "(4-[18F]fluoro-3-iodobenzyl)guanidine, a potential MIBG analogue for positron emission tomography." J Med Chem 37.21 (October 14, 1994): 3655-3662.
PMID
7932592
Source
pubmed
Published In
Journal of Medicinal Chemistry
Volume
37
Issue
21
Publish Date
1994
Start Page
3655
End Page
3662

(4-[F-18]FLUORO-3-IODOBENZYL) GUANIDINE, A POTENTIAL MIBG ANALOG FOR POSITRON EMISSION TOMOGRAPHY

Authors
VAIDYANATHAN, G; AFFLECK, DJ; ZALUTSKY, MR
MLA Citation
VAIDYANATHAN, G, AFFLECK, DJ, and ZALUTSKY, MR. "(4-[F-18]FLUORO-3-IODOBENZYL) GUANIDINE, A POTENTIAL MIBG ANALOG FOR POSITRON EMISSION TOMOGRAPHY." JOURNAL OF MEDICINAL CHEMISTRY 37.21 (October 14, 1994): 3655-3662.
Source
wos-lite
Published In
Journal of Medicinal Chemistry
Volume
37
Issue
21
Publish Date
1994
Start Page
3655
End Page
3662
DOI
10.1021/jm00047a022

Preclinical evaluation and PET imaging of 18F-labeled Mel-14 F(ab')2 fragment in normal dogs.

The F(ab')2 fragment of monoclonal antibody Mel-14, reactive with human melanomas and gliomas, was labeled with 18F using two acylation agents, N-succinimidyl 8-[(4'-[18F]fluorobenzyl)amino]suberate (SFBS) and N-succinimidyl 4-[18F]fluorobenzoate (SFB). The immunoreactivity and affinity for Mel-14 F(ab')2 labeled using the two methods were similar. As a prelude to human clinical evaluation, PET imaging, tissue distribution and pharmacokinetic measurements were performed in two groups of normal foxhounds. Similar in vivo behavior was seen for Mel-14 F(ab')2 labeled using SFBS and SFB. Radiation dosimetry calculations suggest that a 10 mCi dose could be used for this F(ab')2 fragment labeled using either acylation agent.

Authors
Page, RL; Garg, PK; Vaidyanathan, G; Zalutsky, MR
MLA Citation
Page, RL, Garg, PK, Vaidyanathan, G, and Zalutsky, MR. "Preclinical evaluation and PET imaging of 18F-labeled Mel-14 F(ab')2 fragment in normal dogs." Nucl Med Biol 21.7 (October 1994): 911-919.
PMID
9234344
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
21
Issue
7
Publish Date
1994
Start Page
911
End Page
919

Radioimmunotherapy of neoplastic meningitis in rats using an alpha-particle-emitting immunoconjugate.

Because of their short range and high linear energy transfer, alpha-particles may be particularly effective in the treatment of neoplastic meningitis. Monoclonal antibody 81C6 was labeled with alpha-particle-emitting 211At using N-succinimidyl3-[211At]astatobenzoate, and the efficacy and toxicity of this immunoconjugate were evaluated in an athymic rat model. Animals were given injections via a chronic indwelling catheter with 5 x 10(5) TE-671 human rhabdomyosarcoma cells and treated 8 days later with single intrathecal doses of either saline or 4-18 microCi of 211At-labeled specific 81C6 antibody or isotype-matched control 211At-labeled 45.6 antibody. In the first experiment, 4, 7, and 13 microCi 211At-labeled 81C6 produced statistically significant (P = 0.004-0.02) increases in median survival of 33, 29, and 51%, respectively, as compared with saline. Two of 10 animals receiving the 13-microCi dose lived for 6 months before being killed for histological analysis. In the second experiment, 12 microCi of 211At-labeled 45.6 did not increase median survival significantly relative to saline control, while 12 microCi of 211At-labeled 81C6 increased median survival by 113% (P < 0.005) and resulted in 33% apparent cures. Five of 10 animals receiving 18 microCi of 211At-labeled 81C6 survived until they were killed at 295 days. An additional study was performed in animals given intrathecal injections of 5 x 10(6) TE-671 cells and given a single dose of 18 microCi of 211At-labeled 81C6 or 211At-labeled 45.6. At this higher cell number, significantly prolonged survival was still seen for specific antibody as compared with saline (P < 0.001) and control antibody (P < 0.05). These results suggest that treatment with 211At-labeled monoclonal antibodies may be a valuable approach for neoplastic meningitis.

Authors
Zalutsky, MR; McLendon, RE; Garg, PK; Archer, GE; Schuster, JM; Bigner, DD
MLA Citation
Zalutsky, MR, McLendon, RE, Garg, PK, Archer, GE, Schuster, JM, and Bigner, DD. "Radioimmunotherapy of neoplastic meningitis in rats using an alpha-particle-emitting immunoconjugate." Cancer Res 54.17 (September 1, 1994): 4719-4725.
PMID
8062270
Source
pubmed
Published In
Cancer Research
Volume
54
Issue
17
Publish Date
1994
Start Page
4719
End Page
4725

PET imaging of osteosarcoma in dogs using a fluorine-18-labeled monoclonal antibody Fab fragment.

UNLABELLED: Four dogs with histologically confirmed osteogenic sarcoma were studied with PET following intravenous injection of the 18F-labeled Fab fragment of TP-3, a monoclonal antibody specific for human and canine osteosarcomas. METHODS: The antibody fragment was labeled using the N-succinimidyl 8-[(4'-[18F]fluorobenzyl)amino]suberate acylation agent. Blood clearance of activity was biphasic in all dogs but half-times were variable (T1/2 beta = 2-13 hr). Catabolism of labeled Fab was reflected by the decrease in protein-associated activity in serum from more than 90% at 1 min to 60%-80% at 4 hr. RESULTS: PET images demonstrated increased accumulation of 18F at the primary tumor site relative to normal contralateral bone in one dog as early as 15 min after injection. Biopsies obtained after euthanasia indicated higher uptake at the edges of the tumor as observed on the PET scans. Tumor uptake was 1-3 x 10(-3)% injected dose/g, a level similar to that reported for other Fab fragments in human tumors. In the three dogs with metastatic disease, early PET images reflected activity in the blood pool but later uptake was observed in suspected metastatic sites. CONCLUSIONS: These results, although preliminary, suggest that PET imaging of 18F-labeled antibody fragments is feasible and that dogs with spontaneous tumors could be a valuable model for preclinical research with radioimmunoconjugates.

Authors
Page, RL; Garg, PK; Garg, S; Archer, GE; Bruland, OS; Zalutsky, MR
MLA Citation
Page, RL, Garg, PK, Garg, S, Archer, GE, Bruland, OS, and Zalutsky, MR. "PET imaging of osteosarcoma in dogs using a fluorine-18-labeled monoclonal antibody Fab fragment." J Nucl Med 35.9 (September 1994): 1506-1513.
PMID
8071702
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
35
Issue
9
Publish Date
1994
Start Page
1506
End Page
1513

Improved synthesis of N-succinimidyl 4-[18F]fluorobenzoate and its application to the labeling of a monoclonal antibody fragment.

Our previously reported method for the 18F labeling of antibodies using N-succinimidyl 4-[18F]fluorobenzoate (SFB) involved a rather long synthesis time. Here we present an improved method for the synthesis of SFB which reduces the synthesis time by about 45 min. A reaction time of 5-8 min (versus 25 min for the original procedure) was sufficient in the fluorination step to form 4-[18F]fluorobenzaldehyde in high yield. In the original method, 30-35 min was necessary to convert 4-[18F]fluorobenzoic acid to SFB using dicyclohexylcarbodiimide and N-hydroxysuccinimide. When N,N'-disuccinimidyl carbonate was used, facile conversion of 4-fluorobenzoic acid to SFB was seen at a micromolar level. At a tracer level, no product was formed at room temperature; however, complete consumption of starting material was observed. Heating at 150 degrees C resulted in the formation of SFB in more than 80% yield in 1-3 min. HPLC purification of SFB was necessary since use of crude SFB, or SFB purified using a silica solid-phase cartridge column, resulted in lower protein coupling yields. Furthermore, use of crude SFB resulted in cross-linking and lower immunoreactivity of antibody. Largely as a result of the considerable reduction in total labeling time, these modifications have increased the amount of 18F-labeled antibody available per 100 mCi of [18F]fluoride by 30-35%.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Improved synthesis of N-succinimidyl 4-[18F]fluorobenzoate and its application to the labeling of a monoclonal antibody fragment." Bioconjug Chem 5.4 (July 1994): 352-356.
PMID
7948102
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
5
Issue
4
Publish Date
1994
Start Page
352
End Page
356

Generation and characterization of a mouse/human chimeric antibody directed against extracellular matrix protein tenascin.

The murine anti-tenascin monoclonal antibody 81C6, following iodination, has been shown to be an efficient localizing and therapeutic agent in both subcutaneous and intracranial human glioma xenograft models in athymic mice and rats. Similarly, effective monoclonal antibody 81C6 localization has been demonstrated in glioma patients, and Phase I trials with the intact murine IgG2b kappa molecule are currently in progress. In order to maximize the potential for repeated administration by minimizing murine Fc-mediated immunogenicity and reducing Fc-mediated immune effects, we created murine 81C6 variable region/human IgG2 chimeric monoclonal antibodies by the molecular cloning of the variable region genes of mouse 81C6 and their genetic linkage to human constant region exons. The resulting chimeric constructs were introduced into SP2/0 cells, and stable transfectomas were selected by G418 and mycophenolic acid resistance. The resistant clones were screened for anti-tenascin activity on tenascin-coated plates by enzyme-linked immunosorbent assay. The N-terminal amino acid sequence of both heavy and light chains of the purified chimeric 81C6 antibody matched exactly with that of the native mouse 81C6 as well as with that deduced from the nucleotide sequence. The production level of chimeric 81C6 (13.9 mg/ml) from ascites in the highest expressing transfectoma was much higher than that of native mouse 81C6 (2.5 mg/ml). The chimeric antibody showed the same specificity and equivalent affinity for human intact tenascin or tenascin-expressing cells as the native mouse 81C6 antibody. Direct comparison of radioiodinated chimeric and radioiodinated mouse 81C6 biodistribution in subcutaneous and intracranial xenograft-bearing mice showed higher tumor-to-normal tissue ratios for chimeric 81C6 as compared with native mouse 81C6. The improved localizing and clearance characteristics of chimeric 81C6 in xenograft model systems suggests that chimeric 81C6 would be an improved reagent for intracompartmental therapy of tenascin-expressing tumors in the human central nervous system.

Authors
He, X; Archer, GE; Wikstrand, CJ; Morrison, SL; Zalutsky, MR; Bigner, DD; Batra, SK
MLA Citation
He, X, Archer, GE, Wikstrand, CJ, Morrison, SL, Zalutsky, MR, Bigner, DD, and Batra, SK. "Generation and characterization of a mouse/human chimeric antibody directed against extracellular matrix protein tenascin." J Neuroimmunol 52.2 (July 1994): 127-137.
PMID
7518471
Source
pubmed
Published In
Journal of Neuroimmunology
Volume
52
Issue
2
Publish Date
1994
Start Page
127
End Page
137

Meta-[211At]astatobenzylguanidine: further evaluation of a potential therapeutic agent.

Meta-[211At]astatobenzylguanidine ([211At]MABG) is an astatinated analogue of meta-iodobenzylguanidine (MIBG) that could be of value for therapeutic applications. The initial goal of this study was to determine whether [211At]MABG is taken up, like MIBG, by a specific uptake-I mechanism. Norepinephrine and desipramine (DMI) decreased [211At]MABG uptake in SK-N-SH human neuroblastoma cells. This uptake was found to be energy-dependent: In mice, pre-treatment with DMI reduced uptake of [211At]MABG at 1 hr post-injection in the adrenal and in the heart. Tetrabenazine at a dose of 40 mg/kg reduced uptake of [211At]MABG in the mouse heart in vivo (69% of control) whereas up to 100 microM of tetrabenazine did not affect the in vitro uptake of [211At]MABG in SK-N-SH cells. In SK-N-SH cells, 53% and 38%, respectively, of the initial uptake of [211At]MABG was retained at 4 hr and 6 hr. For no-carrier-added (n.c.a.) [131I]MIBG these values were similar, 60% and 48%. The ability of SK-N-SH cells to incorporate [3H]thymidine was reduced to less than 50% of control values when treated with as little as 3.2 nCi of [211At]MABG. In contrast, no significant reduction in the thymidine uptake was observed, even with 80 nCi of n.c.a. MIBG.

Authors
Vaidyanathan, G; Strickland, DK; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Strickland, DK, and Zalutsky, MR. "Meta-[211At]astatobenzylguanidine: further evaluation of a potential therapeutic agent." Int J Cancer 57.6 (June 15, 1994): 908-913.
PMID
8206683
Source
pubmed
Published In
International Journal of Cancer
Volume
57
Issue
6
Publish Date
1994
Start Page
908
End Page
913

PARA[F-18] FLUOROBENZYLGUANIDINE (PFBG) KINETICS IN A CANINE CORONARY-ARTERY OCCLUSION MODEL

Authors
BERRY, CR; GARG, PK; DEGRADO, TR; GARG, S; HELLYER, P; WEBER, WJ; COLEMAN, RE; ZALUTSKY, MR
MLA Citation
BERRY, CR, GARG, PK, DEGRADO, TR, GARG, S, HELLYER, P, WEBER, WJ, COLEMAN, RE, and ZALUTSKY, MR. "PARA[F-18] FLUOROBENZYLGUANIDINE (PFBG) KINETICS IN A CANINE CORONARY-ARTERY OCCLUSION MODEL." JOURNAL OF NUCLEAR MEDICINE 35.5 (May 1994): P157-P157.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
35
Issue
5
Publish Date
1994
Start Page
P157
End Page
P157

QUANTITATIVE IMAGING OF AT-211 RADIOTHERAPEUTIC AGENTS IN SMALL VOLUMES

Authors
JOHNSON, EL; TURKINGTON, TG; JASZCZAK, RJ; ZALUTSKY, MR; GILLAND, DR; VAIDYANATHAN, G; GREER, KL; COLEMAN, RE
MLA Citation
JOHNSON, EL, TURKINGTON, TG, JASZCZAK, RJ, ZALUTSKY, MR, GILLAND, DR, VAIDYANATHAN, G, GREER, KL, and COLEMAN, RE. "QUANTITATIVE IMAGING OF AT-211 RADIOTHERAPEUTIC AGENTS IN SMALL VOLUMES." JOURNAL OF NUCLEAR MEDICINE 35.5 (May 1994): P180-P180.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
35
Issue
5
Publish Date
1994
Start Page
P180
End Page
P180

QUANTITATIVE MEASUREMENTS FOR SMALL ORGANS OF MONKEY

Authors
JANG, S; TURKINGTON, T; JASZCZAK, RJ; LI, J; GREER, KL; ZALUTSKY, MR; COLEMAN, RE
MLA Citation
JANG, S, TURKINGTON, T, JASZCZAK, RJ, LI, J, GREER, KL, ZALUTSKY, MR, and COLEMAN, RE. "QUANTITATIVE MEASUREMENTS FOR SMALL ORGANS OF MONKEY." JOURNAL OF NUCLEAR MEDICINE 35.5 (May 1994): P179-P179.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
35
Issue
5
Publish Date
1994
Start Page
P179
End Page
P179

MYOCARDIAL AND ADRENAL UPTAKE OF PARA [F-18] FLUOROBENZYLGUANIDINE (PFBG) IN THE DOG

Authors
GARG, PK; BERRY, CR; DEGRADO, TR; GARG, S; HELLYER, P; COLEMAN, RE; ZALUTSKY, MR
MLA Citation
GARG, PK, BERRY, CR, DEGRADO, TR, GARG, S, HELLYER, P, COLEMAN, RE, and ZALUTSKY, MR. "MYOCARDIAL AND ADRENAL UPTAKE OF PARA [F-18] FLUOROBENZYLGUANIDINE (PFBG) IN THE DOG." JOURNAL OF NUCLEAR MEDICINE 35.5 (May 1994): P255-P255.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
35
Issue
5
Publish Date
1994
Start Page
P255
End Page
P255

SYNTHESIS AND PRELIMINARY EVALUATION OF 4-[F-18]FLUORO-3-IODOBENZYLGUANIDINE (FIBG) - A METAIODOBENZYLGUANIDINE ANALOG FOR PET

Authors
VAIDYANATHAN, G; AFFLECK, DJ; SLADE, SA; WELSH, PC; ZALUTSKY, MR
MLA Citation
VAIDYANATHAN, G, AFFLECK, DJ, SLADE, SA, WELSH, PC, and ZALUTSKY, MR. "SYNTHESIS AND PRELIMINARY EVALUATION OF 4-[F-18]FLUORO-3-IODOBENZYLGUANIDINE (FIBG) - A METAIODOBENZYLGUANIDINE ANALOG FOR PET." JOURNAL OF NUCLEAR MEDICINE 35.5 (May 1994): P248-P248.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
35
Issue
5
Publish Date
1994
Start Page
P248
End Page
P248

MECHANISTIC STUDIES OF METAIODOBENZYLGUANIDINE (METAIODOBENZYLGUANIDINE) UPTAKE AND RETENTION IN ISOLATED RAT-HEART

Authors
DEGRADO, TR; ZALUTSKY, MR; AFFLECK, DJ; VAIDYANATHAN, G
MLA Citation
DEGRADO, TR, ZALUTSKY, MR, AFFLECK, DJ, and VAIDYANATHAN, G. "MECHANISTIC STUDIES OF METAIODOBENZYLGUANIDINE (METAIODOBENZYLGUANIDINE) UPTAKE AND RETENTION IN ISOLATED RAT-HEART." JOURNAL OF NUCLEAR MEDICINE 35.5 (May 1994): P57-P57.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
35
Issue
5
Publish Date
1994
Start Page
P57
End Page
P57

Carrier-free 131I-meta-iodobenzylguanidine: comparison of production from meta-diazobenzylguanidine and from meta-trimethylsilylbenzylguanidine.

Meta-iodobenzylguanidine (MIBG) is a drug which is selectively accumulated by the uptake-1 process in adrenergic tissues. When labelled with 131I, it may be used for the targetted radiotherapy of tumours such as phaeochromocytoma and neuroblastoma. This paper describes the preparation of carrier-free 131I-MIBG by radioiodination of meta-diazobenzylguanidine, and compares this process with one involving iododesilylation of meta-trimethylsilylbenzylguanidine. Both processes result in the formation of carrier-free 131I-MIBG whose specific activity at greater than 3 x 10(16) Bq mol-1 is at least 100 times higher than that of commercially available 131I-MIBG for therapeutic use. The therapeutic use of 131I-MIBG with a higher than usual specific activity is predicted to result in a greater target-to-nontarget ratio, and therefore enhanced efficacy because of an increased therapeutic index. As the radiochemical yield of the process involving the metadiazobenzylguanidine intermediate is only 13%, compared with 98% for the iododesilylation reaction, the latter is the preferred synthetic route.

Authors
Mairs, RJ; Gaze, MN; Watson, DG; Skellern, GG; Constable, P; McKellar, K; Owens, J; Vaidyanathan, G; Zalutsky, MR
MLA Citation
Mairs, RJ, Gaze, MN, Watson, DG, Skellern, GG, Constable, P, McKellar, K, Owens, J, Vaidyanathan, G, and Zalutsky, MR. "Carrier-free 131I-meta-iodobenzylguanidine: comparison of production from meta-diazobenzylguanidine and from meta-trimethylsilylbenzylguanidine." Nucl Med Commun 15.4 (April 1994): 268-274.
PMID
8072739
Source
pubmed
Published In
Nuclear Medicine Communications
Volume
15
Issue
4
Publish Date
1994
Start Page
268
End Page
274

Mouse/human chimeric Me1-14 antibody: genomic cloning of the variable region genes, linkage to human constant region genes, expression, and characterization.

Murine monoclonal antibody Me1-14, which recognizes an epitope on chondroitin proteoglycan sulfate expressed in malignant glioma and melanoma, has been used for radioimmunolocalization and therapy both in animal models and in patients. Here, we report the generation, characterization, and in vivo biodistribution of mouse/human chimeric Me1-14. Rearranged immunoglobulin genes from the Me1-14 hybridoma were identified by Southern blot analysis. Putative rearranged light- and heavy-chain genes were cloned from Lambda-ZapII Me1-14 genomic libraries and sequenced for nucleotide analysis. One of the putative heavy-chain Eco RI fragments (3.5 kb) had all the features of an intact variable region, including a functional leader sequence, in-frame V-D and D-J junctions, and cysteines 22 and 92. The deduced amino acid sequence from the heavy-chain variable region gene showed considerable homology with the invariant protein sequence of the mouse heavy-chain subgroup IIIB. Like the heavy-chain gene, one of the putative rearranged kappa-chain Hind III fragments (4 kb) had all of the characteristics of the functional variable region, and the deduced amino acid sequence showed homology to the invariant sequence of kappa-chain group V. The variable region genes for heavy- and light-chains were linked to human constant region exons in the expression vectors at the unique sites and cotransfected into mouse SP2/0 cells. The production level of chimeric Me1-14 from ascites in the highest expressing transfectoma was 1.8 mg/ml. The chimeric Me1-14 antibody exhibited the same specificity and similar affinity as that of parent Me1-14. Direct comparison of radioiodinated chimeric and murine Me1-14 in paired-label biodistribution analysis in subcutaneous xenograft-bearing mice showed higher tumor-to-normal organ ratios for chimeric Me1-14 IgG2, suggesting that this chimeric Me1-14 may be potentially useful in vivo for diagnostic and therapeutic purposes in patients.

Authors
Batra, SK; Niswonger, ML; Wikstrand, CJ; Pegram, CN; Zalutsky, MR; Morrison, SL; Bigner, DD
MLA Citation
Batra, SK, Niswonger, ML, Wikstrand, CJ, Pegram, CN, Zalutsky, MR, Morrison, SL, and Bigner, DD. "Mouse/human chimeric Me1-14 antibody: genomic cloning of the variable region genes, linkage to human constant region genes, expression, and characterization." Hybridoma 13.2 (April 1994): 87-97.
PMID
8050781
Source
pubmed
Published In
Hybridoma
Volume
13
Issue
2
Publish Date
1994
Start Page
87
End Page
97
DOI
10.1089/hyb.1994.13.87

Pinhole collimation for ultra-high-resolution, small-field-of-view SPECT.

The objective of this investigation was to evaluate small-field-of-view, ultra-high-resolution pinhole collimation for a rotating-camera SPECT system that could be used to image small laboratory animals. Pinhole collimation offers distinct advantages over conventional parallel-hole collimation when used to image small objects. Since geometric sensitivity increases markedly for points close to the pinhole, small-diameter and high-magnification pinhole geometries may be useful for selected imaging tasks when used with large-field-of-view scintillation cameras. The use of large magnifications can minimize the loss of system resolution caused by the intrinsic resolution of the scintillation camera. A pinhole collimator has been designed and built that can be mounted on one of the scintillation cameras of a triple-head SPECT system. Three pinhole inserts with approximate aperture diameters of 0.6, 1.2 and 2.0 mm have been built and can be mounted individually on the collimator housing. When a ramp filter is used with a three-dimensional (3D) filtered backprojection (FBP) algorithm, the three apertures have in-plane SPECT spatial resolutions (FWHM) at 4 cm of 1.5, 1.9 and 2.8 mm, respectively. In-air point source sensitivities at 4 cm from the apertures are 0.9, 2.6 and 5.7 counts s(-1) microCi(-1) (24, 70 and 154 counts s(-1) MBq(-1)) for the 0.6, 1.2 and 2.0 mm apertures, respectively. In vitro image quality was evaluated with a micro-cold-rod phantom and a micro-Defrise phantom using both the 3D FBP algorithm and a 3D maximum likelihood-expectation maximization (ML-EM) algorithm. In vivo image quality was evaluated using two (315 and 325 g) rats. Ultra-high-resolution pinhole SPECT is an inexpensive and simple approach for imaging small animals that can be used with existing rotating-camera SPECT system.

Authors
Jaszczak, RJ; Li, J; Wang, H; Zalutsky, MR; Coleman, RE
MLA Citation
Jaszczak, RJ, Li, J, Wang, H, Zalutsky, MR, and Coleman, RE. "Pinhole collimation for ultra-high-resolution, small-field-of-view SPECT." Phys Med Biol 39.3 (March 1994): 425-437.
PMID
15551591
Source
pubmed
Published In
Physics in Medicine and Biology
Volume
39
Issue
3
Publish Date
1994
Start Page
425
End Page
437

Meta-[211At]astatobenzylguanidine: Further validation of in vitro and in vivo uptake mechanisms

Authors
Vaidyanathan, G; Strickland, DK; Affleck, DA; Welsh, P; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Strickland, DK, Affleck, DA, Welsh, P, and Zalutsky, MR. "Meta-[211At]astatobenzylguanidine: Further validation of in vitro and in vivo uptake mechanisms." January 1, 1994.
Source
scopus
Published In
Journal of Labelled Compounds and Radiopharmaceuticals
Volume
35
Publish Date
1994
Start Page
589
End Page
591

Monoclonal antibody F(ab')2 fragment labeled with N-succinimidyl 2,4-dimethoxy-3-halobenzoates: in vivo comparison of iodinated and astatinated fragments.

N-Succinimidyl 3-[211At]astato-2, 4-dimethoxybenzoate (SADMB) was prepared from a trialkylstannyl precursor in about 70-75% yield. With either trimethyl or tri-n-butylstannyl precursor, no temporal effect was found in the astatodestannylation yield. However, the methyl analog gave slightly better yield which was found to be not statistically significant. A monoclonal antibody (MAb) fragment, Mel-14 F(ab')2, could be labeled using SADMB in 28% coupling efficiency. The specific binding of this labeled fragment to tumor homogenates in vitro was 61.0 +/- 0.5% (62.8 +/- 0.9% for the 131I labeled fragment). Paired-label tissue distribution in normal mice showed similar uptake of 131I and 211 At in many tissues. However, by 14.5 h selectivity of spleen, lungs and stomach for Mel-14 F(ab')2 labeled with 211At compared to 131I was 4.1, 3.8 and 6.4, respectively.

Authors
Vaidyanathan, G; Affleck, D; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, D, and Zalutsky, MR. "Monoclonal antibody F(ab')2 fragment labeled with N-succinimidyl 2,4-dimethoxy-3-halobenzoates: in vivo comparison of iodinated and astatinated fragments." Nucl Med Biol 21.1 (January 1994): 105-110.
PMID
9234271
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
21
Issue
1
Publish Date
1994
Start Page
105
End Page
110

Synthesis and preliminary evaluation of para- and meta-[18F]fluorobenzylguanidine.

meta-[18F]Fluorobenzylguanidine ([18F]MFBG) and para-[18F]fluorobenzylguanidine ([18F]PFBG) were synthesized in three steps beginning with a fluoro for nitro exchange reaction on 3- and 4-nitrobenzonitrile, respectively. Overall radiochemical yields were 10-15% for [18F]MFBG and 50-55% for [18F]PFBG in a total synthesis time of 60 min. However, impurities interfered with the binding of the product to target cells. A new route was adopted for the synthesis of [18F]PFBG using 4-nitrilophenyl trimethylammonium trifluoromethanesulfonate (Q.S.) as the starting material. In addition to shortening the overall synthesis time by 10 min, this precursor also eliminated problems associated with the presence of small amounts of starting material in the preparation. In vitro binding of [18F]PFBG prepared by the Q.S. method to SK-N-SH, human neuroblastoma cells was 26.5 +/- 1.1%, compared to 16.9 +/- 1.6% when the nitro precursor was used. Selective uptake of both 18F-labeled isomers in the heart and adrenal was seen in mice. At 4 h, adrenal and heart uptake of [18F]PFBG prepared using Q.S. was 20.3 +/- 4.8 and 5.9 +/- 0.8% ID/g respectively, compared to 23.8 +/- 5.0 and 10.5 +/- 1.7% ID/g for [18F]MFBG. Based on the 5-fold higher radiochemical yields obtained with [18F]PFBG, this isomer would appear to be the more practical choice; however, in vitro and in vivo results suggest that [18F]MFBG exhibits greater similarities to MIBG.

Authors
Garg, PK; Garg, S; Zalutsky, MR
MLA Citation
Garg, PK, Garg, S, and Zalutsky, MR. "Synthesis and preliminary evaluation of para- and meta-[18F]fluorobenzylguanidine." Nucl Med Biol 21.1 (January 1994): 97-103.
PMID
9234270
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
21
Issue
1
Publish Date
1994
Start Page
97
End Page
103

Synthesis of carrier-free 131I-meta-iodobenzyl-guanidine by novel routes to enhance therapeutic efficiency in neuroblastoma.

Authors
Gaze, MN; Mairs, RJ; Vaidyanathan, G; Zalutsky, MR
MLA Citation
Gaze, MN, Mairs, RJ, Vaidyanathan, G, and Zalutsky, MR. "Synthesis of carrier-free 131I-meta-iodobenzyl-guanidine by novel routes to enhance therapeutic efficiency in neuroblastoma." Prog Clin Biol Res 385 (1994): 347-353.
PMID
7972229
Source
pubmed
Published In
Progress in Clinical and Biological Research
Volume
385
Publish Date
1994
Start Page
347
End Page
353

Catabolism of label from Mel-14 F(ab')2 fragment radiohalogenated using N-succinimidyl 3-halobenzoates

Authors
Garg, PK; Garg, S; Zhao, XG; Welsh, PC; Zalutsky, MR
MLA Citation
Garg, PK, Garg, S, Zhao, XG, Welsh, PC, and Zalutsky, MR. "Catabolism of label from Mel-14 F(ab')2 fragment radiohalogenated using N-succinimidyl 3-halobenzoates." Journal of Labelled Compounds and Radiopharmaceuticals 35 (1994): 310-312.
Source
scival
Published In
Journal of Labelled Compounds and Radiopharmaceuticals
Volume
35
Publish Date
1994
Start Page
310
End Page
312

Meta-[211At]astatobenzylguanidine: Further validation of in vitro and in vivo uptake mechanisms

Authors
Vaidyanathan, G; Strickland, DK; Affleck, DA; Welsh, P; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Strickland, DK, Affleck, DA, Welsh, P, and Zalutsky, MR. "Meta-[211At]astatobenzylguanidine: Further validation of in vitro and in vivo uptake mechanisms." Journal of Labelled Compounds and Radiopharmaceuticals 35 (1994): 589-591.
Source
scival
Published In
Journal of Labelled Compounds and Radiopharmaceuticals
Volume
35
Publish Date
1994
Start Page
589
End Page
591

Fluorine-18 labeled chemotactic peptide: A potential agent for the PET imaging of focal infection

Authors
Vaidyanathan, G; Affleck, DA; Welsh, P; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DA, Welsh, P, and Zalutsky, MR. "Fluorine-18 labeled chemotactic peptide: A potential agent for the PET imaging of focal infection." Journal of Labelled Compounds and Radiopharmaceuticals 35 (1994): 365-367.
Source
scival
Published In
Journal of Labelled Compounds and Radiopharmaceuticals
Volume
35
Publish Date
1994
Start Page
365
End Page
367

Meta-[211At]astatobenzylguanidine: Further evaluation of a potential therapeutic agent

Meta-[211At]astatobenzylguanidine ([211At]MABG) is an astatinated analogue of meta-iodobenzylguanidine (MIBG) that could be of value for therapeutic applications. The initial goal of this study was to determine whether [211At]MABG is taken up, like MIBG, by a specific uptake-I mechanism. Norepinephrine and desipramine (DMI) decreased [211At]MABG uptake in SK-N-SH human neuroblastoma cells. This uptake was found to be energy-dependent: In mice, pre-treatment with DMI reduced uptake of [211At]MABG at 1 hr post-injection in the adrenal and in the heart. Tetrabenazine at a dose of 40 mg/kg reduced uptake of [211At]MABG in the mouse heart in vivo (69% of control) whereas up to 100 μM of tetrabenazine did not affect the in vitro uptake of [211At]MABG in SK-N-SH cells. In SK- N-SH cells, 53% and 38%, respectively, of the initial uptake of [211At]MABG was retained at 4 hr and 6 hr. For no-carrier-added (n.c.a.) [131I]MIBG these values were similar, 60% and 48%. The ability of SK-N-SH cells to incorporate [3H]thymidine was reduced to less than 50% of control values when treated with as little as 3.2 nCi of [211At]MABG. In contrast, no significant reduction in the thymidine uptake was observed, even with 80 nCi of n.c.a. MIBG.

Authors
Vaidyanathan, G; Strickland, DK; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Strickland, DK, and Zalutsky, MR. "Meta-[211At]astatobenzylguanidine: Further evaluation of a potential therapeutic agent." International Journal of Cancer 57.6 (1994): 908-913.
Source
scival
Published In
International Journal of Cancer
Volume
57
Issue
6
Publish Date
1994
Start Page
908
End Page
913
DOI
10.1002/ijc.2910570622

(4-[18F]fluoro-3-iodobenzyl)guanidine, a potential mibg analogue for positron emission tomography

The aims of this investigation were to develop a no-carrier-added (nca) synthesis of (4-[18F]-fluoro-3-iodobenzyl)guanidine ([18F]FIBG) and to evaluate its potential as an MIBG analogue useful for positron emission tomography. [18F]FIBG was prepared in four steps starting from 4-cyano-2-iodo-N,N,N-trimethylanilinium trifluoromethanesulfonate in 5% decay-corrected radiochemical yield in a total synthesis time of 130 min. The specific activity was more than 1500 Ci per mmol. In vitro binding studies showed that the percent binding of [18F]FIBG to SK-N-SH human neuroblastoma cells remained constant over a 3-log activity range and was similar to that of nca [131I]MIBG. Specific and high uptake of FIBG was also seen in mouse heart and adrenals. The in vitro and in vivo properties of [18F]FIBG suggest that this compound may be a useful positron-emitting analogue of MIBG. © 1994 American Chemical Society.

Authors
Vaidyanathan, G; Affleck, DJ; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, and Zalutsky, MR. "(4-[18F]fluoro-3-iodobenzyl)guanidine, a potential mibg analogue for positron emission tomography." Journal of Medicinal Chemistry 37.21 (1994): 3655-3662.
Source
scival
Published In
Journal of Medicinal Chemistry
Volume
37
Issue
21
Publish Date
1994
Start Page
3655
End Page
3662

PARA-[F-18]FLUOROBENZYLGUANIDINE ([F-18]PFBG) - FURTHER EVALUATION OF A POTENTIAL PET RADIOTRACER IN DOGS

Authors
GARG, PK; BERRY, CR; GARG, S; DEGRADO, TR; ZALUTSKY, MR; COLEMAN, RE
MLA Citation
GARG, PK, BERRY, CR, GARG, S, DEGRADO, TR, ZALUTSKY, MR, and COLEMAN, RE. "PARA-[F-18]FLUOROBENZYLGUANIDINE ([F-18]PFBG) - FURTHER EVALUATION OF A POTENTIAL PET RADIOTRACER IN DOGS." 1994.
Source
wos-lite
Published In
PROCEEDINGS OF THE XVI INTERNATIONAL CANCER CONGRESS - FREE PAPERS AND POSTERS, TOMES 1-4
Publish Date
1994
Start Page
113
End Page
118

NO-CARRIER-ADDED 4-FLUORO-3-IODOBENZYLGUANIDINE LABELED WITH I-131 ([I-131]FIBG) AND F-18 ([F-18]FIBG - POTENTIAL MIBG ANALOGS FOR PET IMAGING AND THERAPY OF NEUROENDOCRINE TUMORS

Authors
VAIDYANATHAN, G; AFFLECK, DJ; SLADE, SA; WELSH, P; ZALUTSKY, MR
MLA Citation
VAIDYANATHAN, G, AFFLECK, DJ, SLADE, SA, WELSH, P, and ZALUTSKY, MR. "NO-CARRIER-ADDED 4-FLUORO-3-IODOBENZYLGUANIDINE LABELED WITH I-131 ([I-131]FIBG) AND F-18 ([F-18]FIBG - POTENTIAL MIBG ANALOGS FOR PET IMAGING AND THERAPY OF NEUROENDOCRINE TUMORS." 1994.
Source
wos-lite
Published In
PROCEEDINGS OF THE XVI INTERNATIONAL CANCER CONGRESS - FREE PAPERS AND POSTERS, TOMES 1-4
Publish Date
1994
Start Page
3013
End Page
3017

RADIONUCLIDE THERAPY - A REVIEW

Authors
ZALUTSKY, MR
MLA Citation
ZALUTSKY, MR. "RADIONUCLIDE THERAPY - A REVIEW." 1994.
Source
wos-lite
Published In
International Congress Series
Volume
1077
Publish Date
1994
Start Page
664
End Page
676

Radioiodination of a monoclonal antibody using N-succinimidyl 5-iodo-3-pyridinecarboxylate.

The potential utility of N-succinimidyl 5-iodo-3-pyridinecarboxylate (SIPC) for the radioiodination of monoclonal antibodies was investigated. Paired-label studies were performed using the anti-tenascin antibody 81C6 in athymic mice bearing subcutaneous D-54 MG human glioma xenografts. Radiolabeling was also done using N-succinimidyl 3-iodobenzoate (SIB). Radioiodination of SIPC and SIB both proceeded in 60-80% yield, but protein coupling efficiencies with SIB were higher (76 +/- 16 vs 60 +/- 7%). Immunoreactivity and affinity of both preparations were similar. Using SIPC, thyroid uptake was quite low, decreasing from 0.3% at day 1 to 0.05% at day 8. Tumor uptake reached 46 +/- 11% injected dose/g at day 1 but declined gradually thereafter. This apparent decline reflected the rapid growth of these xenografts since tumor accumulation expressed as percentage of injected dose remained nearly constant up to day 9. These results suggest that SIPC, like SIB, offers significant advantages for labeling antibodies when compared with conventional protein iodination methods.

Authors
Garg, S; Garg, PK; Zhao, XG; Friedman, HS; Bigner, DD; Zalutsky, MR
MLA Citation
Garg, S, Garg, PK, Zhao, XG, Friedman, HS, Bigner, DD, and Zalutsky, MR. "Radioiodination of a monoclonal antibody using N-succinimidyl 5-iodo-3-pyridinecarboxylate." Nucl Med Biol 20.7 (October 1993): 835-842.
PMID
8241995
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
20
Issue
7
Publish Date
1993
Start Page
835
End Page
842

UPTAKE MECHANISMS OF I-123 METAIODOBENZYLGUANIDINE (METAIODOBENZYLGUANIDINE) IN ISOLATED RAT-HEART

Authors
DEGRADO, TR; ZALUTSKY, MR; AFFLECK, DJ; VAIDYANATHAN, G
MLA Citation
DEGRADO, TR, ZALUTSKY, MR, AFFLECK, DJ, and VAIDYANATHAN, G. "UPTAKE MECHANISMS OF I-123 METAIODOBENZYLGUANIDINE (METAIODOBENZYLGUANIDINE) IN ISOLATED RAT-HEART." CIRCULATION 88.4 (October 1993): 355-355.
Source
wos-lite
Published In
Circulation
Volume
88
Issue
4
Publish Date
1993
Start Page
355
End Page
355

Measuring astatine-211 distributions with SPECT.

We have investigated standard SPECT techniques (rotating gamma cameras, multi-hole collimators, and filtered backprojection reconstruction) for imaging astatine-211 distributions. Since 211At emits alpha particles, this nuclide has potential for use in radiotherapy. The capability of imaging this nuclide would allow in vivo evaluation of the distribution and stability of potential 211At-labelled radiotherapeutic agents. 211At decay yields x-rays in the 77-92 keV range in addition to 500-900 keV gamma rays. This study evaluates the feasibility of SPECT imaging using the x-ray emissions of 211At. We have evaluated several collimators, with the determination that the medium-energy collimators we used are suitable, with 7% penetration (uncollimated counts versus collimated counts). Several phantoms were imaged and attenuation coefficients were measured (narrow-beam mu = 0.182 cm-1 for 77-80 keV x-rays in water). Reconstructed images demonstrate qualitative capabilities and a simple quantitative study demonstrates good correction for attenuation and scatter (approximately 10% error), at low count densities, at least for the phantom geometries used in this study.

Authors
Turkington, TG; Zalutsky, MR; Jaszczak, RJ; Garg, PK; Vaidyanathan, G; Coleman, RE
MLA Citation
Turkington, TG, Zalutsky, MR, Jaszczak, RJ, Garg, PK, Vaidyanathan, G, and Coleman, RE. "Measuring astatine-211 distributions with SPECT." Phys Med Biol 38.8 (August 1993): 1121-1130.
PMID
8367523
Source
pubmed
Published In
Physics in Medicine and Biology
Volume
38
Issue
8
Publish Date
1993
Start Page
1121
End Page
1130

Distribution and dosimetry of I-123-labeled monoclonal antibody 81C6 in patients with anaplastic glioma.

RATIONALE AND OBJECTIVES: Monoclonal antibody 81C6 reacts with the extracellular matrix antigen, tenascin, present on gliomas and other tumors, as well as several normal tissues, including spleen and liver tissue. Single photon emission computed tomography (SPECT) and I-123-labeled 81C6 at various protein doses were used to maximize tumor to normal tissue uptake ratios. METHODS: The distribution of I-123-labeled monoclonal antibody 81C6 was determined in 16 patients with recurrent gliomas, using SPECT: Between 3.5 and 11.5 mCi of I-123 were administered to each patient, and the antibody doses were between 10.0 and 100.0 mg. Blood was obtained for pharmacokinetic studies, and patients were imaged 1 hour and 18 hours after antibody administration. RESULTS: All tumors were visualized readily on the SPECT study in areas that corresponded to the contrast, enhancing abnormalities on anatomic neuroimaging studies. The half-life in blood of the I-123 81C6 ranged from 16 to 37 hours. Radiation dosimetry calculations suggest that it might be possible to administer more than 700 cGy to intracranial glioma with I-131 labeled 81C6 under optimal conditions with acceptable non-neurologic organ radiation exposure. CONCLUSIONS: SPECT imaging with I-123 81C6 identified all tumors and suggests that, with this antibody, more favorable tumor-to-liver and tumor-to-spleen radiation dose ratios are obtained at higher protein doses.

Authors
Schold, SC; Zalutsky, MR; Coleman, RE; Glantz, MJ; Friedman, AH; Jaszczak, RJ; Bigner, SH; Bigner, DD
MLA Citation
Schold, SC, Zalutsky, MR, Coleman, RE, Glantz, MJ, Friedman, AH, Jaszczak, RJ, Bigner, SH, and Bigner, DD. "Distribution and dosimetry of I-123-labeled monoclonal antibody 81C6 in patients with anaplastic glioma." Invest Radiol 28.6 (June 1993): 488-496.
PMID
7686539
Source
pubmed
Published In
Investigative Radiology
Volume
28
Issue
6
Publish Date
1993
Start Page
488
End Page
496

N-succinimidyl 4-methyl-3-(tri-n-butylstannyl)benzoate: synthesis and potential utility for the radioiodination of monoclonal antibodies.

N-succinimidyl 4-methyl-3-(tri-n-butylstannyl)benzoate (MATE) was synthesized in two steps from 4-methyl-3-iodobenzoic acid. Radioiododestannylation of MATE proceeded more slowly than N-succinimidyl 3-(tri-n-butylstannyl)benzoate (ATE), but for reaction periods of 10 min or more, identical yields were obtained. Paired-label biodistribution studies were performed in mice with an intact monoclonal antibody and an F(ab')2 fragment labeled using MATE, ATE and Iodogen. Thyroid uptake with MATE was low, comparable to that seen with ATE, and considerably lower than that observed when the Iodogen method was used. With the F(ab')2 fragment, kidney uptake using MATE was 8-fold higher than that observed when either the ATE or Iodogen methods were used.

Authors
Garg, PK; Garg, S; Zalutsky, MR
MLA Citation
Garg, PK, Garg, S, and Zalutsky, MR. "N-succinimidyl 4-methyl-3-(tri-n-butylstannyl)benzoate: synthesis and potential utility for the radioiodination of monoclonal antibodies." Nucl Med Biol 20.4 (May 1993): 379-387.
PMID
8504279
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
20
Issue
4
Publish Date
1993
Start Page
379
End Page
387

PINHOLE COLLIMATION FOR ULTRA-HIGH-RESOLUTION, SMALL-FIELD-OF-VIEW SPECT STUDIES

Authors
JASZCZAK, RJ; LI, J; WANG, H; ZALUTSKY, MR; COLEMAN, RE
MLA Citation
JASZCZAK, RJ, LI, J, WANG, H, ZALUTSKY, MR, and COLEMAN, RE. "PINHOLE COLLIMATION FOR ULTRA-HIGH-RESOLUTION, SMALL-FIELD-OF-VIEW SPECT STUDIES." JOURNAL OF NUCLEAR MEDICINE 34.5 (May 1993): P10-P10.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
34
Issue
5
Publish Date
1993
Start Page
P10
End Page
P10

MEASURING ASTATINE-211 DISTRIBUTIONS WITH SPECT

Authors
TURKINGTON, TG; ZALUTSKY, MR; JASZCZAK, RJ; GARG, P; VAIDYANATHAN, G; COLEMAN, RE
MLA Citation
TURKINGTON, TG, ZALUTSKY, MR, JASZCZAK, RJ, GARG, P, VAIDYANATHAN, G, and COLEMAN, RE. "MEASURING ASTATINE-211 DISTRIBUTIONS WITH SPECT." JOURNAL OF NUCLEAR MEDICINE 34.5 (May 1993): P191-P191.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
34
Issue
5
Publish Date
1993
Start Page
P191
End Page
P191

PARA[F-18]FLUOROBENZYLGUANIDINE (PFBG) - A POTENTIAL TRACER FOR IMAGING HEART AND TUMOR USING PET

Authors
GARG, PK; GARG, S; COLEMAN, RE; ZALUTSKY, MR
MLA Citation
GARG, PK, GARG, S, COLEMAN, RE, and ZALUTSKY, MR. "PARA[F-18]FLUOROBENZYLGUANIDINE (PFBG) - A POTENTIAL TRACER FOR IMAGING HEART AND TUMOR USING PET." JOURNAL OF NUCLEAR MEDICINE 34.5 (May 1993): P79-P79.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
34
Issue
5
Publish Date
1993
Start Page
P79
End Page
P79

INVITRO CYTOTOXICITY OF M-[AT-211]ASTATOBENZYLGUANIDINE (MABG)

Authors
VAIDYANATHAN, G; HARRISON, C; WELSH, P; AFFLECK, D; ZALUTSKY, MR
MLA Citation
VAIDYANATHAN, G, HARRISON, C, WELSH, P, AFFLECK, D, and ZALUTSKY, MR. "INVITRO CYTOTOXICITY OF M-[AT-211]ASTATOBENZYLGUANIDINE (MABG)." JOURNAL OF NUCLEAR MEDICINE 34.5 (May 1993): P218-P218.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
34
Issue
5
Publish Date
1993
Start Page
P218
End Page
P218

IMAGING OSTEOSARCOMA IN DOGS USING F-18 LABELED TP-3 MONOCLONAL-ANTIBODY (MAB) FRAGMENT AND PET

Authors
PAGE, RL; GARG, PK; GARG, S; BRULAND, OS; ZALUTSKY, MR
MLA Citation
PAGE, RL, GARG, PK, GARG, S, BRULAND, OS, and ZALUTSKY, MR. "IMAGING OSTEOSARCOMA IN DOGS USING F-18 LABELED TP-3 MONOCLONAL-ANTIBODY (MAB) FRAGMENT AND PET." JOURNAL OF NUCLEAR MEDICINE 34.5 (May 1993): P216-P216.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
34
Issue
5
Publish Date
1993
Start Page
P216
End Page
P216

LABELING MONOCLONAL-ANTIBODIES (MABS) WITH AT-211 USING N-SUCCINIMIDYL 5-[AT-211]ASTATO-3-PYRIDINECARBOXYLATE (SAPC)

Authors
GARG, S; GARG, PK; ZALUTSKY, MR
MLA Citation
GARG, S, GARG, PK, and ZALUTSKY, MR. "LABELING MONOCLONAL-ANTIBODIES (MABS) WITH AT-211 USING N-SUCCINIMIDYL 5-[AT-211]ASTATO-3-PYRIDINECARBOXYLATE (SAPC)." JOURNAL OF NUCLEAR MEDICINE 34.5 (May 1993): P99-P100.
Source
wos-lite
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
34
Issue
5
Publish Date
1993
Start Page
P99
End Page
P100

GENERATION AND CHARACTERIZATION OF MOUSE-HUMAN CHIMERIC MEL-14 ANTIBODY

Authors
BATRA, SK; NISWONGER, M; WIKSTRAND, CJ; ZALUTSKY, MR; MORRISON, SL; BIGNER, DD
MLA Citation
BATRA, SK, NISWONGER, M, WIKSTRAND, CJ, ZALUTSKY, MR, MORRISON, SL, and BIGNER, DD. "GENERATION AND CHARACTERIZATION OF MOUSE-HUMAN CHIMERIC MEL-14 ANTIBODY." JOURNAL OF IMMUNOLOGY 150.8 (April 15, 1993): A150-A150.
Source
wos-lite
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
150
Issue
8
Publish Date
1993
Start Page
A150
End Page
A150

No-carrier-added synthesis of meta-[131I]iodobenzylguanidine.

No-carrier-added meta-[131I]iodobenzylguanidine ([131I]MIBG) was prepared starting with two different metallated precursors. Attempted preparation of 3-(tri-n-butylstannyl)benzylguanidine was not successful. An alternate two-step strategy using 3-(tri-n-butylstannyl)benzylamine could be used to prepare radio-iodinated [131I]MIBG in an overall radiochemical yield of 30-33%. Synthesis of [131I]MIBG via the radioiododesilylation of 3-trimethylsilylbenzylguanidine was also investigated. Yields were dependent on temperature, precursor concentration, solvent and nature of the oxidant. Radiochemical yields of 90% were obtained in 5 min at room temperature using either N-chlorosuccinimide or hydrogen peroxide in trifluoroacetic acid as oxidants. The percentage of specific binding in vitro of no-carrier-added MIBG to SK-N-SH neuroblastoma cells remained constant over a 2 log activity range, while the binding of MIBG prepared by isotopic exchange dropped by a factor of seven. In normal mice, heart and adrenal uptake of no-carrier-added [131I]MIBG was found to be higher than that of [131I]MIBG prepared by isotopic exchange.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "No-carrier-added synthesis of meta-[131I]iodobenzylguanidine." Appl Radiat Isot 44.3 (March 1993): 621-628.
PMID
8472027
Source
pubmed
Published In
Applied Radiation and Isotopes
Volume
44
Issue
3
Publish Date
1993
Start Page
621
End Page
628

Radioiodination of proteins using N-succinimidyl 4-hydroxy-3-iodobenzoate.

N-Succinimidyl 4-hydroxy-3-[131I]iodobenzoate ([131I]SHIB) was synthesized from 4-hydroxybenzoic acid in two steps. The overall radiochemical yield was 40-56%. A monoclonal antibody (mAb) was labeled in 10-15% yield by reaction with [131I]SHIB. The specific binding of [131I]SHIB mAb to tumor homogenates in vivo was 78 +/- 3%, compared to 84 +/- 3% for the same mAb labeled using N-succinimidyl 3-[125I]iodobenzoate ([125I]SIB). Paired-label studies in normal mice demonstrated similar tissue distributions of 131I and 125I except in thyroid. In thyroid, uptake of the two isotopes was similar on day 1; however, 131I levels increased gradually to 2-3 times those of 125I by day 6. Our results indicate that loss of label in vivo from mAbs labeled using SHIB is somewhat higher than seen with SIB but significantly lower than that observed when direct iodination methods are used.

Authors
Vaidyanathan, G; Affleck, DJ; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, and Zalutsky, MR. "Radioiodination of proteins using N-succinimidyl 4-hydroxy-3-iodobenzoate." Bioconjug Chem 4.1 (January 1993): 78-84.
PMID
8431515
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
4
Issue
1
Publish Date
1993
Start Page
78
End Page
84

1-(m-[211At]astatobenzyl)guanidine: synthesis via astato demetalation and preliminary in vitro and in vivo evaluation.

No-carrier-added 1-(m-[211At]astatobenzyl)guanidine ([211At]MABG) was synthesized by astato demetalation using two different routes. The overall yield for the two-step approach from 3-(tri-n-butylstannyl)benzylamine was 13%. N-Chlorosuccinimide-mediated astato desilylation of 1-[3-(trimethylsilyl)benzyl]guanidine in acetic acid gave poor yields. In trifluoroacetic acid, the reaction worked well. The radiochemical yield was independent of reaction time and the amount of precursor used; however, the temperature of the reaction had a marked effect. Yields of 85% were obtained in 5 min at 70 degrees C using 0.5 mumol of the precursor. The percentage specific binding in vitro of [211At]MABG was nearly constant over a 2-log activity range and was comparable to that of no-carrier-added [131]MIBG. The accumulation of [211At]MABG in the heart and adrenals of normal mice was similar to that observed for no-carrier-added [131]MIBG.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "1-(m-[211At]astatobenzyl)guanidine: synthesis via astato demetalation and preliminary in vitro and in vivo evaluation." Bioconjug Chem 3.6 (November 1992): 499-503.
PMID
1463779
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
3
Issue
6
Publish Date
1992
Start Page
499
End Page
503

Localization of fluorine-18-labeled Mel-14 monoclonal antibody F(ab')2 fragment in a subcutaneous xenograft model.

Positron emission tomography is an imaging method that might improve the effectiveness of radioimmunoscintigraphy and might provide more accurate estimates of monoclonal antibody dosimetry prior to therapy. Because of its widespread availability, 2-h half-life 18F could be a useful nuclide for labeling monoclonal antibody fragments, provided that adequate tumor uptake and satisfactory tumor:normal tissue ratios could be achieved rapidly. In this study, the tissue distribution of 18F-labeled Mel-14 F(ab')2, a monoclonal antibody reactive with gliomas, was evaluated in a s.c. athymic mouse human glioma xenograft model. 18F labeling was performed using N-succinimidyl-8-(4-[18F]fluorobenzylamino) suberate. For paired-label comparisons both in vitro and in vivo, Mel-14 F(ab')2 was also labeled using N-succinimidyl 3- [125I]- iodobenzoate. When 100-120 micrograms of disuccinimidyl suberate was used in the 18F-labeled acylation agent synthesis, the binding of 18F-labeled Mel-14 F(ab')2 to glioma homogenates was comparable to that of the radioiodinated fragment. Scatchard analyses indicated nearly identical affinity constants for fragments with both labels (18F, 6.4 x 10(8) M-1; 125I, 6.7 x 10(8) M-1). Tumor levels of 18F increased between 1 and 2 h and then were relatively constant between 2 and 6 h. When lower levels of disuccinimidyl suberate were used, there was an excellent correlation between 18F and 125I tumor uptake (r = 0.984, slope 1.03-1.04). At 4 h, tumor:normal tissue ratios for 18F-labeled Mel-14 F(ab')2 in liver, spleen, muscle, and brain were 2.3, 4.2, 14, and 40, respectively. Localization indices, determined by comparison with 18F-labeled nonspecific F(ab')2, were 3.7 at 4 h and 6.9 at 6 h for tumor and about 1 for normal tissues, indicating the specificity of 18F-labeled Mel-14 F(ab')2 tumor uptake.

Authors
Garg, PK; Garg, S; Bigner, DD; Zalutsky, MR
MLA Citation
Garg, PK, Garg, S, Bigner, DD, and Zalutsky, MR. "Localization of fluorine-18-labeled Mel-14 monoclonal antibody F(ab')2 fragment in a subcutaneous xenograft model." Cancer Res 52.18 (September 15, 1992): 5054-5060.
PMID
1516061
Source
pubmed
Published In
Cancer Research
Volume
52
Issue
18
Publish Date
1992
Start Page
5054
End Page
5060

Immunoreactivity, pharmacokinetics and bone marrow dosimetry of intrathecal radioimmunoconjugates.

Ten patients with neoplastic meningitis were treated with a variety of 131I-monoclonal antibody (MAb) conjugates, chosen to bind to their particular malignancy. Pharmacokinetic studies revealed that MAbs leave the ventricular compartment, enter the sub-arachnoid space and then pass into the blood. Once the MAbs enter the blood compartment, their clearance is determined by factors such as circulating anti-mouse Ig and circulating antigens. These lead to complex formations and the clearance of the conjugate by the reticuloendothelial system. In one individual, the anti-mouse Ig response observed systemically was not mirrored within the CSF, which has implications for planning future therapy of this type. In other patients, formation of immune complexes was due to binding to circulating antigen within the blood. The major toxicity associated with the intrathecal administration of 131I-MAbs was bone-marrow suppression. The doses to the bone marrow, resulting from the form of therapy, were calculated but showed no direct correlation with WHO grade 3/4 toxicity. Doses to the ventricular lining were also calculated, but due to the complex geometry of the compartment, calculation of potential tumour doses was not practicable.

Authors
Moseley, RP; Papanastassiou, V; Zalutsky, MR; Ashpole, RD; Evans, S; Bigner, DD; Kemshead, JT
MLA Citation
Moseley, RP, Papanastassiou, V, Zalutsky, MR, Ashpole, RD, Evans, S, Bigner, DD, and Kemshead, JT. "Immunoreactivity, pharmacokinetics and bone marrow dosimetry of intrathecal radioimmunoconjugates." Int J Cancer 52.1 (August 19, 1992): 38-43.
PMID
1500225
Source
pubmed
Published In
International Journal of Cancer
Volume
52
Issue
1
Publish Date
1992
Start Page
38
End Page
43

Fluorine-18-labeled monoclonal antibody fragments: a potential approach for combining radioimmunoscintigraphy and positron emission tomography.

Monoclonal antibody fragments labeled with 18F could be useful for PET if selective tumor uptake could be achieved within a few half-lives of this nuclide. To evaluate this possibility, the F(ab')2 fragment of Mel-14, an antibody reactive with gliomas and other tumors, was labeled by reaction with N-succinimidyl-4-[18F]fluorobenzoate. The in-vitro binding properties of 18F-labeled Mel-14 F(ab')2 were nearly identical to those observed when this F(ab')2 was labeled by reaction with N-succinimidyl-4-[125I]iodobenzoate (18F, affinity constant = (6.7 +/- 1.1) x 10(8) M-1; 125I, affinity constant = (8.8 +/- 0.6) x 10(8) M-1). The tissue distribution of the two labeled fragments was compared in paired-label studies performed in athymic mice with subcutaneous D-54 MG human glioma xenografts. Uptake of both nuclides in tumor was rapid with levels as high as 18.7% +/- 1.1% injected dose/g for 18F and 19.4% +/- 1.0% injected dose/g for 125I observed by 4 hr after injection. Tumor-to-normal tissue ratios for 18F-labeled Mel-14 F(ab')2 at 4 hr ranged between 0.8:1 for kidneys to 40:1 for brain. These results suggest that it may be feasible to use 18F-labeled antibody fragments for imaging tumors with PET.

Authors
Vaidyanathan, G; Bigner, DD; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Bigner, DD, and Zalutsky, MR. "Fluorine-18-labeled monoclonal antibody fragments: a potential approach for combining radioimmunoscintigraphy and positron emission tomography." J Nucl Med 33.8 (August 1992): 1535-1541.
PMID
1634947
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
33
Issue
8
Publish Date
1992
Start Page
1535
End Page
1541

Labeling proteins with fluorine-18 using N-succinimidyl 4-[18F]fluorobenzoate.

Two methods were investigated for the no-carrier-added synthesis of N-succinimidyl 4-[18F]fluorobenzoate (S[18F]FB). The first, an attempted nucleophilic aromatic substitution by [18F]fluoride on N-succinimidyl 4-nitrobenzoate was unsuccessful. The second method involved three steps; [18F]fluoride for trimethylammonium substitution on 4-formyl-N,N,N-trimethylanilinium triflate, oxidation to 4-[18F]fluorobenzoic acid, followed by reaction with N-hydroxysuccinimide and dicyclohexylcarbodiimide to form S[18F]FB. Total synthesis and purification time was 100 min and the overall radiochemical yield was 25% (decay corrected). A monoclonal antibody F(ab')2 fragment could be labeled in 40-60% yield by reaction with S[18F]FB for 15-20 min. The tissue distribution in normal mice and in vitro tumor binding of the antibody F(ab')2 labeled by reaction with S[18F]FB were comparable to those observed for the fragment after radioiodination using N-succinimidyl 4-[125I]iodobenzoate.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Labeling proteins with fluorine-18 using N-succinimidyl 4-[18F]fluorobenzoate." Int J Rad Appl Instrum B 19.3 (April 1992): 275-281.
PMID
1629016
Source
pubmed
Published In
International Journal of Radiation Applications and Instrumentation.
Volume
19
Issue
3
Publish Date
1992
Start Page
275
End Page
281

Fluorine-18-antimyosin monoclonal antibody fragments: preliminary investigations in a canine myocardial infarct model.

The purpose of this study was to determine in a canine model whether selective myocardial infarct uptake of 18F-labeled antimyosin monoclonal antibody fragments could be achieved in a time frame compatible with the short half-life of this nuclide. Antimyosin monoclonal antibody fragments were labeled with 18F using a succinimidyl [18F]fluorobenzylamine ester acylation agent. Six dogs had myocardial infarction induced by coronary artery occlusion and were reperfused prior to the intravenous administration of 0.6-4.7 mCi of 18F-labeled F(ab')2 (two dogs) or Fab (four dogs). Analysis of tissues obtained 2-4 hr after antibody administration revealed infarct:normal myocardium uptake ratios as high as 14-21:1 for F(ab')2 and 9-12:1 for Fab. Even with Fab, however, prolonged 18F activity in the blood pool interfered with delineation of infarcts by PET imaging. In one dog, perfusion imaging with [13N]ammonia before antimyosin administration was performed, and regions of normal and ischemic myocardium were determined. With these regions of interest, infarct:normal myocardium uptake ratios calculated from the 18F-labeled Fab images increased from 1.5:1 at 1 hr to 4.0:1 at 5 hr. We conclude that 18F-labeled antimyosin fragments may be of value for hot-spot imaging of damaged myocardium with PET; however, blood-pool subtraction techniques will probably be required.

Authors
Zalutsky, MR; Garg, PK; Johnson, SH; Utsunomiya, H; Coleman, RE
MLA Citation
Zalutsky, MR, Garg, PK, Johnson, SH, Utsunomiya, H, and Coleman, RE. "Fluorine-18-antimyosin monoclonal antibody fragments: preliminary investigations in a canine myocardial infarct model." J Nucl Med 33.4 (April 1992): 575-580.
PMID
1552343
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
33
Issue
4
Publish Date
1992
Start Page
575
End Page
580

4-Fluorobenzylamine and phenylalanine methyl ester conjugates of 2-nitroimidazole: evaluation as hypoxic cell radiosensitizers.

We have synthesized two 2-nitroimidazole derivatives and evaluated their hypoxic radiosensitization properties. The first, a 4-fluorobenzylamine conjugate of 2-nitroimidazole (PK-110), was designed so that it could also be labeled with the F-18 and used for positron emission tomographic imaging of hypoxia. The second, the L-phenylalanine methyl ester conjugate of 2-nitroimidazole (PK-130), was designed in an attempt to exploit amino acid transport channels to enhance drug transport into the tumor. The effects of these drugs (and SR-2508, for comparison) in vitro on the aerobic and hypoxic radiosensitivity of Chinese hamster V79 cells were evaluated using clonogenic assays. PK-130 and PK-110 at 0.1 and 1.0 mM were more efficient hypoxic cell radiosensitizers than obtained with 1.0 mM SR-2508. Marginal aerobic radiosensitization was observed for 1.0 mM treatment with PK-130 and PK-110, however, no aerobic radiosensitization was observed at 0.1 mM. Glutathione (GSH) depletion (less than 5% of control levels) by L-buthionine sulfoximine (BSO) further enhanced the SER for both PK-130 and PK-110 at 0.1 mM to 3.2 +/- 0.63 and 2.4 +/- 0.16, respectively. The results of this study encourage the in vivo tumor radiosensitization evaluation of PK-130 and PK-110.

Authors
Garg, PK; Garg, S; Degraff, WG; Zalutsky, MR; Mitchell, JB
MLA Citation
Garg, PK, Garg, S, Degraff, WG, Zalutsky, MR, and Mitchell, JB. "4-Fluorobenzylamine and phenylalanine methyl ester conjugates of 2-nitroimidazole: evaluation as hypoxic cell radiosensitizers." Int J Radiat Oncol Biol Phys 22.3 (1992): 593-596.
PMID
1531220
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
22
Issue
3
Publish Date
1992
Start Page
593
End Page
596

1-(m-[211At]astatobenzyl)guanidine: Synthesis via astato demetalation and preliminary in vitro and in vivo evaluation

No-carrier-added 1-(m-[211At]astatobenzyl)guanidine ([211At]MABG) was synthesized by astato demetalation using two different routes. The overall yield for the two-step approach from 3-(tri-n-butylstannyl)benzylamine was 13%. N-Chlorosuccinimide-mediated astato desilylation of 1-[3-(trimethylsilyl)benzyl]guanidine in acetic acid gave poor yields. In trifluoroacetic acid, the reaction worked well. The radiochemical yield was independent of reaction time and the amount of precursor used; however, the temperature of the reaction had a marked effect. Yields of 85% were obtained in 5 min at 70°C using 0.5 μmol of the precursor. The percentage specific binding in vitro of [211At]MABG was nearly constant over a 2-log activity range and was comparable to that of no-carrier-added [131I]MIBG. The accumulation of [211At]MABG in the heart and adrenals of normal mice was similar to that observed for no-carrier-added [131I]MIBG. © 1992 American Chemical Society.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "1-(m-[211At]astatobenzyl)guanidine: Synthesis via astato demetalation and preliminary in vitro and in vivo evaluation." Bioconjugate Chemistry 3.6 (1992): 499-503.
Source
scival
Published In
Bioconjugate Chemistry
Volume
3
Issue
6
Publish Date
1992
Start Page
499
End Page
503

Labeling proteins with fluorine-18 using N-succinimidyl 4-[18F]fluorobenzoate

Two methods were investigated for the no-carrier-added synthesis of N-succinimidyl 4-[18F]fluorobenzoate (S[18F]FB). The first, an attempted nucleophilic aromatic substitution by [18F]fluoride on N-succinimidyl 4-nitrobenzoate was unsuccessful. The second method involved three steps; [18F]fluoride for trimethylammonium substitution on 4-formyl-N,N,N-trimethylanilinium triflate, oxidation to 4-[18F]fluorobenzoic acid, followed by reaction with N-hydroxysuccinimide and dicyclohexylcarbodiimide to form S[18F]FB. Total synthesis and purification time was 100 min and the overall radiochemical yield was 25% (decay corrected). A monoclonal antibody F(ab')2 fragment could be labeled in 40-60% yield by reaction with S[18F]FB for 15-20 min. The tissue distribution in normal mice and in vitro tumor binding of the antibody F(ab')2 labeled by reaction with S[18F]FB were comparable to those observed for the fragment after radioiodination using N-succinimidyl 4-[125I]iodobenzoate.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Labeling proteins with fluorine-18 using N-succinimidyl 4-[18F]fluorobenzoate." Nuclear Medicine and Biology 19.3 (1992): 275-281.
Source
scival
Published In
International Journal of Radiation Applications and Instrumentation.
Volume
19
Issue
3
Publish Date
1992
Start Page
275
End Page
281
DOI
10.1016/0883-2897(92)90111-B

1-(M-[AT-211]ASTATOBENZYL)GUANIDINE - SYNTHESIS VIA ASTATO DEMETALATION AND PRELIMINARY INVITRO AND INVIVO EVALUATION

Authors
VAIDYANATHAN, G; ZALUTSKY, MR
MLA Citation
VAIDYANATHAN, G, and ZALUTSKY, MR. "1-(M-[AT-211]ASTATOBENZYL)GUANIDINE - SYNTHESIS VIA ASTATO DEMETALATION AND PRELIMINARY INVITRO AND INVIVO EVALUATION." BIOCONJUGATE CHEMISTRY 3.6 (1992): 499-503.
Source
wos-lite
Published In
Bioconjugate Chemistry
Volume
3
Issue
6
Publish Date
1992
Start Page
499
End Page
503
DOI
10.1021/bc00018a006

Improved therapeutic efficacy of a monoclonal antibody radioiodinated using N-succinimidyl-3-(tri-n-butylstannyl)benzoate.

Improvements in efficacy of radioimmunotherapy will require increased tumor uptake relative to normal tissue. We previously demonstrated that labeling the IgG2b glioma-reactive antitenascin monoclonal antibody 81C6 with 131I using N-succinimidyl-3-(tri-n-butylstannyl)benzoate (ATE) increased tumor uptake and tumor-to-normal tissue ratios and decreased deiodination compared with labeling using Iodo-Gen. The present study was conducted to determine whether 131I 81C6 labeled using ATE (81C6 ATE) would demonstrate a therapeutic advantage over 131I 81C6 labeled using Iodo-Gen (81C6 IOD) in treating s.c. D-54 MG human glioma xenografts in athymic mice. The subclass IgG2b MAb 45.6 labeled with 131I using ATE (45.6 ATE) was used as a control. Animals were injected with saline or 500 microCi of 45.6 ATE (23 microCi/microgram), 81C6 ATE (26 microCi/microgram), or 81C6 IOD (24 microCi/microgram). With approximately 150 mm3 initial tumor volumes, growth delay for 81C6 ATE was significantly better by Wilcoxon rank sum analysis than saline (P = 0.0006 to 0.003), 45.6 ATE (P = 0.0006 to 0.002), and 81C6 IOD (P = 0.0008 to 0.007). Biodistribution data from similarly injected animals gave estimated radiation doses to tumor of 7723, 5200, and 1667 rad for 81C6 ATE, 81C6 IOD, and 45.6 ATE, respectively. In addition, 81C6 ATE administered at this dosage to animals with 50% larger initial tumors also improved tumor growth delay in comparison with 81C6 IOD given to animals with standard-size tumors. A similar experiment was conducted at 1000 microCi and, although radiation toxicity was noted in all labeled groups, two animals in the 81C6 ATE group had tumor regression for more than 240 days, and the other groups had no regressors. We conclude that the use of the ATE method may significantly improve the therapeutic efficacy of radioiodinated monoclonal antibodies.

Authors
Schuster, JM; Garg, PK; Bigner, DD; Zalutsky, MR
MLA Citation
Schuster, JM, Garg, PK, Bigner, DD, and Zalutsky, MR. "Improved therapeutic efficacy of a monoclonal antibody radioiodinated using N-succinimidyl-3-(tri-n-butylstannyl)benzoate." Cancer Res 51.16 (August 15, 1991): 4164-4169.
PMID
1714341
Source
pubmed
Published In
Cancer Research
Volume
51
Issue
16
Publish Date
1991
Start Page
4164
End Page
4169

Fluorine-18 labeling of monoclonal antibodies and fragments with preservation of immunoreactivity.

A new method is reported for labeling proteins with the positron-emitting nuclide 18F. Initially, 4-[18F]-fluorobenzylamine was prepared in two steps from aqueous [18F]fluoride in high yield. The 18F acylation agent was formed by reaction of this product with disuccinimidyl suberate. Overall yields for the 4-[18F]fluorobenzylamine succinimidyl ester ([18F]SFBS), decay corrected to the end of cyclotron bombardment, were about 30% in a synthesis time of 60 min. After a 15-min reaction, 30-45% (decay corrected) of the [18F]SFBS could be coupled to intact antibodies and their F(ab')2 and Fab fragments. Coupling yields were dependent on protein concentration but not reaction time. HPLC purification of [18F]SFBS was necessary to obtain optimal coupling efficiency and immunoreactivity. The immunoreactivities of 18F-labeled F(ab')2 and Fab fragments of an antimyosin antibody were 89 +/- 5% and 75 +/- 9%, respectively. Biodistribution studies in normal mice demonstrated similar in vivo behavior of 18F-labeled antibody fragments and those labeled with 125I by using N-succinimidyl 3-[125I]iodobenzoate. These results indicate that this method may be useful for labeling monoclonal antibodies and other proteins and peptides with 18F.

Authors
Garg, PK; Garg, S; Zalutsky, MR
MLA Citation
Garg, PK, Garg, S, and Zalutsky, MR. "Fluorine-18 labeling of monoclonal antibodies and fragments with preservation of immunoreactivity." Bioconjug Chem 2.1 (January 1991): 44-49.
PMID
1878410
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
2
Issue
1
Publish Date
1991
Start Page
44
End Page
49

N-succinimidyl 5-(trialkylstannyl)-3-pyridinecarboxylates: a new class of reagents for protein radioiodination.

N-Succinimidyl 5-(trialkylstannyl)-3-pyridinecarboxylates (alkyl = Me, Bu) have been prepared and used as a precursor to label N-succinimidyl 5-[131I]iodo-3-pyridinecarboxylate (SIPC). SIPC was obtained in greater than 80% yield from either the methyl or butyl precursor with N-chlorosuccinimide and heating at 60-65 degrees C. Significantly lower yields were observed with tert-butyl hydroperoxide. After a 30-min incubation with [131I]SIPC at pH 8.5, goat IgG, an intact monoclonal antibody (MAb), and a MAb F(ab')2 fragment were labeled in 60-65% yield. Specific binding of the MAb and MAb fragment after SIPC labeling was identical with that observed with N-succinimidyl 3-iodobenzoate and higher than that reported previously for these MAbs after labeling by using the Iodogen method. When 5-[131I]iodonicotinic acid was injected into normal mice, thyroid uptake was less than 0.2% of the injected dose, reflecting the inertness of this compound to deiodination. Paired-label biodistribution studies indicate that for both the MAb and the F(ab')2 labeled by using SIPC, accumulation of activity in the thyroid and other tissues is comparable to that observed when these proteins were labeled by using N-succinimidyl 3-iodobenzoate. The results of this study suggest that SIPC may be a reagent for labeling MAbs with halogen nuclides.

Authors
Garg, S; Garg, PK; Zalutsky, MR
MLA Citation
Garg, S, Garg, PK, and Zalutsky, MR. "N-succinimidyl 5-(trialkylstannyl)-3-pyridinecarboxylates: a new class of reagents for protein radioiodination." Bioconjug Chem 2.1 (January 1991): 50-56.
PMID
1878411
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
2
Issue
1
Publish Date
1991
Start Page
50
End Page
56

Radioiodination and astatination of monoclonal antibodies using heterocyclic acylation agents

Authors
Garg, S; Garg, PK; Bigner, DD; Zalutsky, MR
MLA Citation
Garg, S, Garg, PK, Bigner, DD, and Zalutsky, MR. "Radioiodination and astatination of monoclonal antibodies using heterocyclic acylation agents." Journal of Labelled Compounds and Radiopharmaceuticals 30 (1991): 207-208.
Source
scival
Published In
Journal of Labelled Compounds and Radiopharmaceuticals
Volume
30
Publish Date
1991
Start Page
207
End Page
208

Aromatic acylation reagents for use in the radioiodination of proteins

Authors
Vaidyanathan, G; Affleck, DJ; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Affleck, DJ, and Zalutsky, MR. "Aromatic acylation reagents for use in the radioiodination of proteins." Journal of Labelled Compounds and Radiopharmaceuticals 30 (1991): 209-210.
Source
scival
Published In
Journal of Labelled Compounds and Radiopharmaceuticals
Volume
30
Publish Date
1991
Start Page
209
End Page
210

F-18 LABELING OF MONOCLONAL-ANTIBODIES AND FRAGMENTS WITH PRESERVATION OF IMMUNOREACTIVITY

Authors
GARG, PK; GARG, S; ZALUTSKY, MR
MLA Citation
GARG, PK, GARG, S, and ZALUTSKY, MR. "F-18 LABELING OF MONOCLONAL-ANTIBODIES AND FRAGMENTS WITH PRESERVATION OF IMMUNOREACTIVITY." BIOCONJUGATE CHEMISTRY 2.1 (1991): 44-49.
Source
wos-lite
Published In
Bioconjugate Chemistry
Volume
2
Issue
1
Publish Date
1991
Start Page
44
End Page
49
DOI
10.1021/bc00007a008

Radiolocalization of human pancreatic tumors in athymic mice by monoclonal antibody DU-PAN 1.

Monoclonal antibodies that selectively bind to pancreatic tumors may be useful in the therapy and diagnosis of pancreatic carcinoma. In this study we have examined the tumor localization of radioiodinated DU-PAN 1, a mouse monoclonal antibody that is selective for a human pancreatic cancer-associated antigen. After radiolabeling, both DU-PAN 1 intact monoclonal antibody and F(ab')2 fragments retained immunoreactivity and showed high affinity for the pancreatic tumor cell line CA13 in vitro. Paired-label biodistribution studies in nude mice bearing CA13 s.c. xenografts were performed. Mice received both 131I-labeled DU-PAN 1 immunoglobulin G2a or F(ab')2 fragment and 125I-labeled mouse myeloma immunoglobulin G2a or F(ab')2 fragment. Tumor uptake for 5-micrograms doses of DU-PAN 1 immunoglobulin ranged from 4.8 to 11.83% injected dose/g. Tumor uptake values for mice given 5-micrograms doses of DU-PAN 1 F(ab')2 ranged from 3.9 to 6.9% injected dose/g. Tumor uptakes of the respective myeloma controls were lower in all cases when compared with the DU-PAN 1 preparations. Tumor localization indices for 5-micrograms doses of DU-PAN 1 immunoglobulin were 3.0 and 24 h and 2.9 at 48 h. For 5-micrograms doses of DU-PAN 1 F(ab')2, tumor localization indices were 29.9 at 24 h and 90.0 at 48 h. In most cases, tumor:normal tissue ratios were greater than 3 at all time points, indicative of tumor selectivity for both DU-PAN 1 preparations, but the ratios were considerably higher using the DU-PAN 1 F(ab')2. The F(ab')2 fragment thus displays better tumor localization characteristics when compared with the intact immunoglobulin. Protein doses of DU-PAN 1 F(ab')2 of between 5 and 10 micrograms gave the best localization, although protein doses of up to 100 micrograms could be administered before apparent tumor saturation was seen.

Authors
Worlock, AJ; Zalutsky, MR; Metzgar, RS
MLA Citation
Worlock, AJ, Zalutsky, MR, and Metzgar, RS. "Radiolocalization of human pancreatic tumors in athymic mice by monoclonal antibody DU-PAN 1." Cancer Res 50.22 (November 15, 1990): 7246-7251.
PMID
2224857
Source
pubmed
Published In
Cancer Research
Volume
50
Issue
22
Publish Date
1990
Start Page
7246
End Page
7251

Radioiodination of antibodies via N-succinimidyl 2,4-dimethoxy-3-(trialkylstannyl)benzoates.

We have previously shown that use of N-succinimidyl 3-iodobenzoate (SIB) for radioiodination of monoclonal antibodies (MAbs) decreases the loss of radioiodine in vivo compared to MAbs labeled by using conventional methods. Herein, the synthesis of N-succinimidyl 2,4-dimethoxy-3-(trialkylstannyl)benzoates (alkyl = Me, Bu) are described as is their use as precursors for the radiosynthesis of N-succinimidyl 2,4-dimethoxy-3-iodobenzoate (SDMIB). A MAb F(ab')2 fragment labeled with SDMIB retained its ability to bind specifically to tumor homogenates. Paired-label tissue distribution studies indicate that the thyroid uptake (an indicator of deiodination) of hydrolyzed SDMIB was about 20 times that of hydrolyzed SIB. In contrast, thyroid uptake for SDMIB, when conjugated to a MAb, was only 1.4-2.8 times that for SIB and was considerably lower than levels reported in the literature for MAbs labeled by using direct, electrophilic iodination methods. Although MAbs labeled with SDMIB are significantly more inert to dehalogenation than those labeled by conventional methods, compared to the original SIB reagent, addition of two methoxy groups decreased retention of label in vivo.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Radioiodination of antibodies via N-succinimidyl 2,4-dimethoxy-3-(trialkylstannyl)benzoates." Bioconjug Chem 1.6 (November 1990): 387-393.
PMID
2099187
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
1
Issue
6
Publish Date
1990
Start Page
387
End Page
393

Monoclonal antibody and F(ab')2 fragment delivery to tumor in patients with glioma: comparison of intracarotid and intravenous administration.

Non-i.v. delivery of radiolabeled monoclonal antibodies (MAbs) has been shown to increase tumor uptake and decrease dose to normal tissues. In this study, we have examined the potential advantage of intracarotid (i.c.) versus i.v. administration for the delivery of an intact MAb and a F(ab')2 fragment to tumor in patients with gliomas. Three patients received 10-50 mg of 81C6 IgG2b, a MAb reactive with the glioma-associated extracellular matrix antigen tenascin, and three received 5-20 mg of the F(ab')2 fragment of Mel-14, which is reactive with gliomas and melanomas. Paired-injection protocols, in which one-half of the MAb was labeled with 131I and administered by i.c. injection, and one-half was labeled with 125I and simultaneously administered by i.v. injection, were used. For both 81C6 IgG2b and Mel-14 (Fab')2, no differences in blood clearance half-times or urinary excretion rates of radioiodine were observed between i.c.- and i.v.-administered activity. Analysis of biopsy samples revealed i.c.:i.v. uptake ratios of 1.02 +/- 0.04, 0.95 +/- 0.03, and 1.03 +/- 0.05 for the accumulation of 81C6 IgG2b in temporalis muscle, normal brain, and glioma, respectively. Similarly, the i.c.:i.v. uptake ratios for Mel-14 F(ab')2 in these tissues were 0.98 +/- 0.04 (SD), 1.00 +/- 0.05, and 1.04 +/- 0.05. When the differences in percentage of injected dose/g uptake after i.c. and i.v. administration were compared, no statistically significant advantage for i.c. delivery was seen (P = 0.22-0.61). These data indicate that i.c. administration of MAb 81C6 IgG2b and Mel-14 F(ab')2 fragments offers no delivery advantage to offset the small but finite risk involved in cannulation and injection of the internal carotid artery.

Authors
Zalutsky, MR; Moseley, RP; Benjamin, JC; Colapinto, EV; Fuller, GN; Coakham, HP; Bigner, DD
MLA Citation
Zalutsky, MR, Moseley, RP, Benjamin, JC, Colapinto, EV, Fuller, GN, Coakham, HP, and Bigner, DD. "Monoclonal antibody and F(ab')2 fragment delivery to tumor in patients with glioma: comparison of intracarotid and intravenous administration." Cancer Res 50.13 (July 1, 1990): 4105-4110.
PMID
2162252
Source
pubmed
Published In
Cancer Research
Volume
50
Issue
13
Publish Date
1990
Start Page
4105
End Page
4110

Protein radiohalogenation: observations on the design of N-succinimidyl ester acylation agents.

In previous studies we have demonstrated that antibodies radioiodinated with N-succinimidyl 3-iodobenzoate (SIB) are less susceptible to loss of radioiodine in vivo than antibodies iodinated directly by electrophilic substitution on their tyrosine residues with Iodogen. Since the Bolton-Hunter reagent, N-succinimidyl 3-(4-hydroxy-3-iodophenyl)propionate, is identical with SIB except that it contains a hydroxyl group on the aromatic ring and a two-methylene spacer, a comparison of their coupling chemistry and in vivo behavior was performed to better understand the structural requirements for a useful iodinated acylation agent. Protein concentration and pH had a significant effect on the coupling efficiency of both SIB and the Bolton-Hunter reagent; however, protein-labeling yields with SIB were generally higher by a factor of 2. Paired-label biodistribution studies in mice demonstrated that thyroid uptake (a monitor of dehalogenation) of antibody labeled by the Bolton-Hunter method was twice that of antibody labeled with SIB but only 7% of that observed for antibody labeled with Iodogen. These results suggest that even minor differences in iodination site can profoundly alter the retention of label on a protein in vivo.

Authors
Vaidyanathan, G; Zalutsky, MR
MLA Citation
Vaidyanathan, G, and Zalutsky, MR. "Protein radiohalogenation: observations on the design of N-succinimidyl ester acylation agents." Bioconjug Chem 1.4 (July 1990): 269-273.
PMID
2096920
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
1
Issue
4
Publish Date
1990
Start Page
269
End Page
273

Anti-synthetic peptide antibody reacting at the fusion junction of deletion-mutant epidermal growth factor receptors in human glioblastoma.

We have investigated human gliomas that amplify and rearrange the epidermal growth factor receptor gene, with generation of an in-frame deletion mutation of 802 nucleotides in the external domain. This in-frame deletion mutation generates a local amino acid sequence at the fusion junction of what normally were distant polypeptide sequences in the intact epidermal growth factor receptor. This 14-amino acid peptide was chemically synthesized, coupled to keyhole limpet hemocyanin, and used as an immunogen in rabbits. The elicited antibody reacted specifically with the fusion peptide in ELISA. The anti-fusion junction peptide antibody was purified by passage of the antiserum over a peptide affinity column with acidic elution. The purified antibody selectively bound the glioma deletion mutant as compared to the intact epidermal growth factor receptor as assessed by immunocytochemistry, immunofluorescence, immunoprecipitation with gel electrophoresis, and binding experiments using radioiodinated antibody. These data indicate that it is feasible to generate site-specific anti-peptide antibodies that are highly selective for mutant proteins in human tumors. The anti-peptide antibody described here, and other mutation site-specific antibodies, should be ideal candidates for tumor immunoimaging and immunotherapy.

Authors
Humphrey, PA; Wong, AJ; Vogelstein, B; Zalutsky, MR; Fuller, GN; Archer, GE; Friedman, HS; Kwatra, MM; Bigner, SH; Bigner, DD
MLA Citation
Humphrey, PA, Wong, AJ, Vogelstein, B, Zalutsky, MR, Fuller, GN, Archer, GE, Friedman, HS, Kwatra, MM, Bigner, SH, and Bigner, DD. "Anti-synthetic peptide antibody reacting at the fusion junction of deletion-mutant epidermal growth factor receptors in human glioblastoma." Proc Natl Acad Sci U S A 87.11 (June 1990): 4207-4211.
PMID
1693434
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
87
Issue
11
Publish Date
1990
Start Page
4207
End Page
4211

RADIOIODINATION AND ASTATINATION OF MONOCLONAL-ANTIBODIES

Authors
GARG, PK; VAIDYANATHAN, G; GARG, S; ZALUTSKY, MR
MLA Citation
GARG, PK, VAIDYANATHAN, G, GARG, S, and ZALUTSKY, MR. "RADIOIODINATION AND ASTATINATION OF MONOCLONAL-ANTIBODIES." ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 199 (April 22, 1990): 16-NUCL.
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
199
Publish Date
1990
Start Page
16
End Page
NUCL

Enhanced delivery of a monoclonal antibody F(ab')2 fragment to subcutaneous human glioma xenografts using local hyperthermia.

The purpose of this study was to investigate the effects of tumor-localized hyperthermia at 42 degrees C on the tissue distribution of radioiodinated monoclonal antibody F(ab')2 fragments. Paired-label biodistribution measurements were performed in athymic mice bearing D-54 MG human glioma xenografts on one leg. Mice received both the 131I-labeled F(ab')2 fragment of Mel-14, reactive with human gliomas and melanomas, and nonspecific 125I-labeled RPC 5 F(ab')2. Tumor-bearing legs were placed in a 42 degrees C water bath or a 37 degrees C water bath (control) for 2 or 4 h. In mice sacrificed immediately after 2 h of heating, no hyperthermia-induced differences in the distribution of either fragment were observed. In the 4-h groups, tumor uptake of Mel-14 F(ab')2 increased from 7.04 +/- 1.59% injected dose (ID)/g at 37 degrees C to 20.65 +/- 4.53% ID/g at 42 degrees C (P less than 0.0001), and tumor localization of the control fragment rose from 5.23 +/- 1.35% ID/g to 14.51 +/- 1.37% ID/g (P less than 0.0001). In another experiment, F(ab')2 fragments were injected, tumors were heated for 4 h, and groups were sacrificed at 4, 8, and 16 h after injection. Statistically significant 2- to 3-fold higher uptake of both fragments in tumor were observed at all time points. Hyperthermic conditions also resulted in higher tumor:tissue ratios for both fragments. These results suggest that it may be possible to use tumor-localized hyperthermia to increase the therapeutic utility of radiolabeled monoclonal antibodies, particularly when labeled with short lived nuclides such as the 7.2-h alpha-emitter 211At.

Authors
Cope, DA; Dewhirst, MW; Friedman, HS; Bigner, DD; Zalutsky, MR
MLA Citation
Cope, DA, Dewhirst, MW, Friedman, HS, Bigner, DD, and Zalutsky, MR. "Enhanced delivery of a monoclonal antibody F(ab')2 fragment to subcutaneous human glioma xenografts using local hyperthermia." Cancer Res 50.6 (March 15, 1990): 1803-1809.
PMID
2407344
Source
pubmed
Published In
Cancer Research
Volume
50
Issue
6
Publish Date
1990
Start Page
1803
End Page
1809

Radioimmunotherapy of intracerebral human glioma xenografts with 131I-labeled F(ab')2 fragments of monoclonal antibody Mel-14.

The administration of radiolabeled monoclonal antibodies to improve the treatment of malignant gliomas is dependent upon achieving effective tumor radiation dose while sparing normal tissues. We have evaluated the efficacy of 131I-labeled F(ab')2 fragment of monoclonal antibody Mel-14, an IgG2a reactive with the chondroitin sulfate proteoglycan antigen of gliomas, melanomas, and other neoplasms, in prolonging survival of athymic mice transplanted intracerebrally with D-54 MG human glioma xenografts. Studies indicated that in vitro immunoreactivity, affinity, and tumor localization in vivo of radiolabeled Mel-14 F(ab')2 were maintained at specific activities of 10-13 microCi/micrograms. Intravenous injection of 1500 microCi/115 micrograms or 2000 microCi/154 micrograms 131I-labeled Mel-14 F(ab')2 into mice 6-7 days after xenograft implantation resulted in significant survival prolongation over control animals (P = 0.009 using Wilcoxon rank sum analysis). In another experiment, 1500 microCi/126 micrograms 131I-labeled Mel-14 F(ab')2 improved survival significantly over controls (P = 0.006), while 1500 microCi/220 micrograms 131I-labeled nonspecific antibody did not (P = 0.2). Increasing the injected radiation dose to 3000 microCi 131I-labeled Mel-14 F(ab')2 did not significantly increase survival in tumor-bearing mice, because of supervening radiation toxicity. However, giving 3000 microCi 131I-labeled Mel-14 F(ab')2 in two doses of 1500 microCi, 48 h apart, did significantly prolong animal survival over controls (P = 0.001). Estimated radiation dose to tumor was 915 rad after injection of 3000 microCi 131I-labeled Mel-14 F(ab')2 in two doses, a dose higher than that delivered to normal tissues. The results of this study suggest that radiolabeled Mel-14 F(ab')2 be evaluated as an agent for radioimmunotherapy trials.

Authors
Colapinto, EV; Zalutsky, MR; Archer, GE; Noska, MA; Friedman, HS; Carrel, S; Bigner, DD
MLA Citation
Colapinto, EV, Zalutsky, MR, Archer, GE, Noska, MA, Friedman, HS, Carrel, S, and Bigner, DD. "Radioimmunotherapy of intracerebral human glioma xenografts with 131I-labeled F(ab')2 fragments of monoclonal antibody Mel-14." Cancer Res 50.6 (March 15, 1990): 1822-1827.
PMID
2407345
Source
pubmed
Published In
Cancer Research
Volume
50
Issue
6
Publish Date
1990
Start Page
1822
End Page
1827

Rhenium heptasulfide: a potential carrier system for radiation synovectomy.

Rhenium sulfide colloid was prepared by the thiosulfate acid reduction method and assessed for its applicability as a particle carrier for use in radiation synovectomy. In vitro stability studies demonstrated that greater than 95% of the 186Re activity remained in colloidal form over a 5 day period. Intraarticular knee injections of 186Re2S7 into normal and arthritic rabbit joints were followed by gamma camera imaging and by biodistribution in order to quantify the leakage to different organs. Mean retentions of 186Re in knees, determined by gamma camera imaging were 97(+/- 4)%, 92(+/- 7)%, 89(+/- 9)% and 88(+/- 10)% at 1 h, 1, 2 and 3 days, respectively. The percent injected dose was 0.0023% in the lymph nodes, 1.65% in the liver, 0.006% to the spleen, 0.013% in the lungs, 0.35% in the kidney, 0.014% in the heart, 0.12% in the bone, 0.7% in the muscle, 0.3% in the fat and 0.6% in the blood.

Authors
Venkatesan, PP; Shortkroff, S; Zalutsky, MR; Sledge, CB
MLA Citation
Venkatesan, PP, Shortkroff, S, Zalutsky, MR, and Sledge, CB. "Rhenium heptasulfide: a potential carrier system for radiation synovectomy." Int J Rad Appl Instrum B 17.4 (1990): 357-362.
PMID
2387743
Source
pubmed
Published In
International Journal of Radiation Applications and Instrumentation.
Volume
17
Issue
4
Publish Date
1990
Start Page
357
End Page
362

Labeling monoclonal antibodies with halogen nuclides.

Most studies with radiohalogenated monoclonal antibodies have involved the use of the iodine nuclides 131I and 123I. Methods are being developed for labeling antibodies with radioiodine that result in a decreased loss of the nuclide from the protein in vivo. In addition, the labeling of antibodies with nuclides of fluorine, bromine and astatine could provide reagents of potential utility for positron emission tomography and radioimmunotherapy.

Authors
Zalutsky, MR; Garg, PK; Narula, AS
MLA Citation
Zalutsky, MR, Garg, PK, and Narula, AS. "Labeling monoclonal antibodies with halogen nuclides." Acta Radiol Suppl 374 (1990): 141-145. (Review)
PMID
1966962
Source
pubmed
Published In
Acta radiologica. Supplementum
Volume
374
Publish Date
1990
Start Page
141
End Page
145

Comparative tissue distribution in mice of the α-emitter 211At and 131I as labels of a monoclonal antibody and F(ab′)2 fragment

Because it decays by the emission of short-range, high-energy α-particles, the radiohalogen 211At. might be a particularly useful nuclide for some types of radioimmunotherapy. However, no suitable 7-emitting nuclide of astatine exists whch would permit either imaging prior to therapy to obtain radiation dosimetry estimates or performing experiments in paired-label format. Since iodine is the halogen above astatine in the periodic table, we investigated whether the in vivo ditribution of 131I could be used to mimic the biodistribution of 211At. In this study, the N-succinimidyl 3-(trialkylstannyl)benzoate method was used to label C110 IgG, an antibody directed against carcinoembryonic antigen, and its (Fab′)2 fragment with 211At and 131I. Paired-label experiments were performed in normal mice comparing the tissue distribution of 211At-versus 131I-labeled C110 IgG and F(ab′)2 as well as [211At]astatide versus [131I]iodide and m-[211At]astatobenzoic acid versus m-[131I|iodobenzoic acid, potential catabolites of proteins radiohalogenated via the N-succinimidyl 3-(trialkylstannyl)benzoate method. With the exception of thyroid, retention of astatide in tissues was higher than that of iodide; and, with the halobenzoic acids, uptake of 211At was higher than 131I in thyroid, stomach, and spleen. Use of the N-succinimidyl 3-(trialkylstannyl)benzoate method to label C110 IgG with 211At and 131I resulted in similar distributions of the two nuclides. In contrast, loss of 211At from the F(ab′)2 fragment was considerably more rapid than 131I, suggesting that different astatination methods may be required for use with F(ab′)2 fragments.

Authors
Garg, PK; Harrison, CL; Zalutsky, MR
MLA Citation
Garg, PK, Harrison, CL, and Zalutsky, MR. "Comparative tissue distribution in mice of the α-emitter 211At and 131I as labels of a monoclonal antibody and F(ab′)2 fragment." Cancer Research 50.12 (1990): 3514-3520.
PMID
2340501
Source
scival
Published In
Cancer Research
Volume
50
Issue
12
Publish Date
1990
Start Page
3514
End Page
3520

Rhenium heptasulfide: A potential carrier system for radiation synovectomy

Rhenium sulfide colloid was prepared by the thiosulfate acid reduction method and assessed for its applicability as a particle carrier for use in radiation synovectomy. In vitro stability studies demonstrated that greater than 95% of the 186Re activity remained in colloidal form over a 5 day period. Intraarticular knee injections of 186Re2S7 into normal and arthritic rabbit joints were followed by γ camera imaging and by biodistribution in order to quantify the leakage to different organs. Mean retentions of 186Re in knees, determined by γ camera imaging, were 97(±4)%, 92(±7)%, 89(±9)% and 88(±10)% at 1 h, 1, 2 and 3 days, respectively. The percent injected dose was 0.0023% in the lymph nodes, 1.65% in the liver, 0.006% to the spleen, 0.013% in the lungs, 0.35% in the kidney, 0.014% in the heart, 0.12% in the bone, 0.7% in the muscle, 0.3% in the fat and 0.6% in the blood.

Authors
Venkatesan, PP; Shortkroff, S; Zalutsky, MR; Sledge, CB
MLA Citation
Venkatesan, PP, Shortkroff, S, Zalutsky, MR, and Sledge, CB. "Rhenium heptasulfide: A potential carrier system for radiation synovectomy." Nuclear Medicine and Biology 17.4 (1990): 357-362.
Source
scival
Published In
International Journal of Radiation Applications and Instrumentation.
Volume
17
Issue
4
Publish Date
1990
Start Page
357
End Page
362
DOI
10.1016/0883-2897(90)90101-6

Intrathecal administration of 131I radiolabelled monoclonal antibody as a treatment for neoplastic meningitis

Fifteen patients with neoplastic meningitis received a single intrathecal injection of between 11 and 60 mCi of a 131I radiolabelled monoclonal antibody (MoAb), chosen for its immunoreactivity to tumour. Major toxicity was manifest as nausea, vomiting and headache (7/15 patients), reversible bone marrow suppression (3/8 patients) and seizures (2/15 patients). Nine patients were evaluable for either a tumour or clinical response. Six of these demonstrated an event-free response that was maintained for periods of between 7 and 26 months.

Authors
Moseley, RP; Davies, AG; Richardson, RB; Zalutsky, M; Carrell, S; Fabre, J; Slack, N; Bullimore, J; Pizer, B; Papanastassiou, V; Kemshead, JT; Coakham, HB; Lashford, LS
MLA Citation
Moseley, RP, Davies, AG, Richardson, RB, Zalutsky, M, Carrell, S, Fabre, J, Slack, N, Bullimore, J, Pizer, B, Papanastassiou, V, Kemshead, JT, Coakham, HB, and Lashford, LS. "Intrathecal administration of 131I radiolabelled monoclonal antibody as a treatment for neoplastic meningitis." British Journal of Cancer 62.4 (1990): 637-642.
PMID
2223581
Source
scival
Published In
British Journal of Cancer
Volume
62
Issue
4
Publish Date
1990
Start Page
637
End Page
642

National Cancer Institute workshop statement: Advances in clinical imaging using positron emission tomography, September 14-16, 1988

Authors
Al-Aish, M; Coleman, E; Larson, SM; Barrio, J; Brodack, J; Brooks, D; Chiro, GD; Eckelman, W; Fowler, J; Frost, J; Gould, L; Krohn, K; Kuhl, D; Marcus, CS; Martin, W; Mazziotta, J; Mintun, M; Muehllehner, G; Mullani, N; Phelps, ME; Schelbert, H; Ter-Pogossian, MM; Wolf, AP; Zalutsky, MR
MLA Citation
Al-Aish, M, Coleman, E, Larson, SM, Barrio, J, Brodack, J, Brooks, D, Chiro, GD, Eckelman, W, Fowler, J, Frost, J, Gould, L, Krohn, K, Kuhl, D, Marcus, CS, Martin, W, Mazziotta, J, Mintun, M, Muehllehner, G, Mullani, N, Phelps, ME, Schelbert, H, Ter-Pogossian, MM, Wolf, AP, and Zalutsky, MR. "National Cancer Institute workshop statement: Advances in clinical imaging using positron emission tomography, September 14-16, 1988." Archives of Internal Medicine 150.4 (1990): 735-739.
PMID
2183729
Source
scival
Published In
Archives of internal medicine
Volume
150
Issue
4
Publish Date
1990
Start Page
735
End Page
739

Enhanced tumor localization and in vivo stability of a monoclonal antibody radioiodinated using N-succinimidyl 3-(tri-n-butylstannyl)benzoate.

Loss of radiolabel after in vivo administration of labeled monoclonal antibodies (MAbs) to cancer patients is a likely cause of the low levels of tumor uptake of MAb which have been observed. In this study, we have evaluated the utility of N-succinimidyl 3-(tri-n-butylstannyl)benzoate (ATE) for the radioiodination of 81C6, a MAb reactive with the extracellular matrix antigen tenascin associated with gliomas and other tumors. In vitro binding properties of MAb labeled via ATE were slightly better than those of the Iodogen preparations. Paired-label studies were performed in athymic mice bearing s.c. D-54 MG xenografts and injected with both 81C6 labeled with 125I using the ATE method and 131I using the Iodogen method. These studies demonstrated that use of the ATE method (a) decreased thyroid uptake by 40- to 100-fold, suggesting a lower rate of dehalogenation compared to MAb labeled using Iodogen; (b) increased tumor uptake by as much as a factor of 4 at Day 1 to more than 12-fold at Day 8; and (c) resulted in superior tumor-to-normal-tissue dose ratios. The specificity of MAb uptake was investigated in a paired-labeled study comparing the distribution of 81C6 and isotype-matched control 45.6, both labeled using the ATE procedure. Localization indices for tumor ranged between 6 at Day 1 to 34 at Day 7, values considerably higher than those reported previously for 81C6 and 45.6 radioiodinated using a conventional method (chloramine T). These results demonstrate that the ATE method may be a valuable approach for labeling MAbs with iodine nuclides.

Authors
Zalutsky, MR; Noska, MA; Colapinto, EV; Garg, PK; Bigner, DD
MLA Citation
Zalutsky, MR, Noska, MA, Colapinto, EV, Garg, PK, and Bigner, DD. "Enhanced tumor localization and in vivo stability of a monoclonal antibody radioiodinated using N-succinimidyl 3-(tri-n-butylstannyl)benzoate." Cancer Res 49.20 (October 15, 1989): 5543-5549.
PMID
2477144
Source
pubmed
Published In
Cancer Research
Volume
49
Issue
20
Publish Date
1989
Start Page
5543
End Page
5549

Labeling monoclonal antibodies and F(ab')2 fragments with the alpha-particle-emitting nuclide astatine-211: preservation of immunoreactivity and in vivo localizing capacity.

alpha-Particles such as those emitted by 211At may be advantageous for radioimmunotherapy since they are radiation of high linear energy transfer, depositing high energy over a short distance. Here we describe a strategy for labeling monoclonal antibodies and F(ab')2 fragments with 211At by means of the bifunctional reagent N-succinimidyl 3-(trimethylstannyl)benzoate. An intact antibody, 81C6, and the F(ab')2 fragment of Me1-14 (both reactive with human gliomas) were labeled with 211At in high yield and with a specific activity of up to 4 mCi/mg in a time frame compatible with the 7.2-hr half-life of 211At. Quantitative in vivo binding assays demonstrated that radioastatination was accomplished with maintenance of high specific binding and affinity. Comparison of the biodistribution of 211At-labeled Me1-14 F(ab')2 to that of a nonspecific antibody fragment labeled with 211At and 131I in athymic mice bearing D-54 MG human glioma xenografts demonstrated selective and specific targeting of 211At-labeled antibody in this human tumor model.

Authors
Zalutsky, MR; Garg, PK; Friedman, HS; Bigner, DD
MLA Citation
Zalutsky, MR, Garg, PK, Friedman, HS, and Bigner, DD. "Labeling monoclonal antibodies and F(ab')2 fragments with the alpha-particle-emitting nuclide astatine-211: preservation of immunoreactivity and in vivo localizing capacity." Proc Natl Acad Sci U S A 86.18 (September 1989): 7149-7153.
PMID
2476813
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
86
Issue
18
Publish Date
1989
Start Page
7149
End Page
7153

Pharmacokinetics and tumor localization of 131I-labeled anti-tenascin monoclonal antibody 81C6 in patients with gliomas and other intracranial malignancies.

We previously have reported that radioiodinated anti-tenascin monoclonal antibody 81C6 exhibits therapeutic potential against both s.c. and intracranial human glioma xenografts in athymic mice and rats. Herein we report the selective tumor localization of 131I-labeled 81C6 in patients with gliomas and other intracranial malignancies. Nine patients were simultaneously administered 5-50 mg of 131I-labeled 81C6 and 1-2 mg of 125I-labeled 45.6, an isotype-matched control monoclonal antibody. The blood clearance half-time for 81C6, normalized to that of 45.6 in the same patient, appeared to decrease with 81C6 protein dose. Gamma camera images obtained at 1 to 3 days exhibited increased uptake of 131I in regions corresponding to tumor with varying degrees of contrast to surrounding normal brain. Biopsy specimens of tumor and normal brain were obtained and analyzed histologically for tumor content. The average uptake of 81C6 in tumor ranged from 0.6 to 4.3 x 10(-3)% of the injected dose per gram. In patients receiving 20-50 mg of 81C6, the average tumor-to-normal-brain ratio was 25:1 with ratios as high as 200:1 seen in some samples. Localization indices were calculated by normalizing the uptake of 81C6 per gram tumor to the uptake of 81C6 per gram blood and dividing by the same ratio for 45.6 control monoclonal antibody. Localization indices for muscle and brain were about 1, in contrast to up to five for tumor. These studies demonstrate that the tumor uptake of 131I-labeled 81C6 in patients with gliomas and other intracranial malignancies is due to specific processes.

Authors
Zalutsky, MR; Moseley, RP; Coakham, HB; Coleman, RE; Bigner, DD
MLA Citation
Zalutsky, MR, Moseley, RP, Coakham, HB, Coleman, RE, and Bigner, DD. "Pharmacokinetics and tumor localization of 131I-labeled anti-tenascin monoclonal antibody 81C6 in patients with gliomas and other intracranial malignancies." Cancer Res 49.10 (May 15, 1989): 2807-2813.
PMID
2469537
Source
pubmed
Published In
Cancer Research
Volume
49
Issue
10
Publish Date
1989
Start Page
2807
End Page
2813

RADIOHALOGENATION OF ANTIBODIES

Authors
ZALUTSKY, MR; GARG, PK
MLA Citation
ZALUTSKY, MR, and GARG, PK. "RADIOHALOGENATION OF ANTIBODIES." ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 197 (April 9, 1989): 84-NUCL.
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
197
Publish Date
1989
Start Page
84
End Page
NUCL

Synthesis of radioiodinated N-succinimidyl iodobenzoate: optimization for use in antibody labelling.

N-succinimidyl-3-(tri-n-butylstannyl)benzoate (m-BuATE), N-succinimidyl-3-(tri-methylstannyl)benzoate (m-MeATE) and N-succinimidyl-4-(tri-n-butylstannyl)benzoate (p-BuATE) were synthesized and radioiodinated using either N-chlorosuccinimide (NCS) or t-butylhydroperoxide (TBHP) as the oxidant. Radiohalogenation of m-MeATE proceeded more rapidly than m-BuATE. NCS was the more efficient oxidant at reaction times less than 15 min; use of both TBHP and NCS resulted in nearly quantitative yields after 15 min when m-MeATE was used. Using NCS, achieving optimal antibody coupling and specific binding required purification of the active ester by HPLC; in contrast, with TBHP, only Sep-Pak purification was needed.

Authors
Garg, PK; Archer, GE; Bigner, DD; Zalutsky, MR
MLA Citation
Garg, PK, Archer, GE, Bigner, DD, and Zalutsky, MR. "Synthesis of radioiodinated N-succinimidyl iodobenzoate: optimization for use in antibody labelling." Int J Rad Appl Instrum A 40.6 (1989): 485-490.
PMID
2551846
Source
pubmed
Published In
International Journal of Radiation Applications and Instrumentation. Part A, Applied Radiation and Isotopes
Volume
40
Issue
6
Publish Date
1989
Start Page
485
End Page
490

Labeling proteins using aryl iodide acylation agents: influence of meta vs para substitution on in vivo stability.

The effect of para vs meta substitution on the biological behavior of an intact antibody and an F(ab')2 fragment was investigated. Paired-label studies were performed using 81C6 IgG and OC 125 F(ab')2 labeled using the N-succinimidyl esters of both p-[125I]- and m-[131I]iodobenzoate as well as with the potential catabolites, p-[125I]- and m-[131I]iodobenzoic acid. In all 3 studies, up to 55% lower uptake of 131I in thyroid and stomach was observed, suggesting that the m-substituted species were more inert to dehalogenation in vivo.

Authors
Garg, PK; Slade, SK; Harrison, CL; Zalutsky, MR
MLA Citation
Garg, PK, Slade, SK, Harrison, CL, and Zalutsky, MR. "Labeling proteins using aryl iodide acylation agents: influence of meta vs para substitution on in vivo stability." Int J Rad Appl Instrum B 16.7 (1989): 669-673.
PMID
2613522
Source
pubmed
Published In
International Journal of Radiation Applications and Instrumentation.
Volume
16
Issue
7
Publish Date
1989
Start Page
669
End Page
673

Pharmacokinetics of a radioiodinated monoclonal antibody F(ab')2 fragment in a xenograft model with circulating antigen.

The pharmacokinetics of 131I-labeled OC 125 F(ab')2 antibody fragment were investigated in athymic mice bearing OVCAR-3 ovarian carcinoma xenografts, a model in which the CA 125 antigen is present in serum. Nine antibody doses between 0.1 and 650 micrograms were studied. Optimal tumor to normal tissue ratios were obtained at 100-200 micrograms of F(ab')2. At most antibody doses, the pre-injection level of circulating CA 125 appeared to influence the localization of 131I activity in tumor, liver and spleen.

Authors
Zalutsky, MR; Bast, RC; Knapp, RC
MLA Citation
Zalutsky, MR, Bast, RC, and Knapp, RC. "Pharmacokinetics of a radioiodinated monoclonal antibody F(ab')2 fragment in a xenograft model with circulating antigen." Int J Rad Appl Instrum B 16.4 (1989): 405-411.
PMID
2777582
Source
pubmed
Published In
International Journal of Radiation Applications and Instrumentation.
Volume
16
Issue
4
Publish Date
1989
Start Page
405
End Page
411

Pharmacokinetics of a radioiodinated monoclonal antibody F(ab')2 fragment in a xenograft model with circulating antigen

The pharmacokinetics of 131I-labeled OC 125 F(ab')2 antibody fragment were investigated in athymic mice bearing OVCAR-3 ovarian carcinoma xenografts, a model in which the CA 125 antigen is present in serum. Nine antibody doses between 0.1 an 650 μg were studied. Optimal tumor to normal tissue ratios were obtained at 100-200 μg of F(ab')2. At most antibody doses, the pre-injection level of circulating CA 125 appeared to influence the localization of 131I activity in tumor, liver and spleen.

Authors
Zalutsky, MR; Jr, RCB; Knapp, RC
MLA Citation
Zalutsky, MR, Jr, RCB, and Knapp, RC. "Pharmacokinetics of a radioiodinated monoclonal antibody F(ab')2 fragment in a xenograft model with circulating antigen." Nuclear Medicine and Biology 16.4 (1989): 405-411.
Source
scival
Published In
Nuclear Medicine and Biology
Volume
16
Issue
4
Publish Date
1989
Start Page
405
End Page
411

NO-CARRIER-ADDED ASTATINATION OF N-SUCCINIMIDYL-3-(TRI-ETA-BUTYLSTANNYL) BENZOATE (ATE) VIA ELECTROPHILIC DESTANNYLATION

Authors
NARULA, AS; ZALUTSKY, MR
MLA Citation
NARULA, AS, and ZALUTSKY, MR. "NO-CARRIER-ADDED ASTATINATION OF N-SUCCINIMIDYL-3-(TRI-ETA-BUTYLSTANNYL) BENZOATE (ATE) VIA ELECTROPHILIC DESTANNYLATION." RADIOCHIMICA ACTA 47.2-3 (1989): 131-135.
Source
wos-lite
Published In
Radiochimica Acta
Volume
47
Issue
2-3
Publish Date
1989
Start Page
131
End Page
135

Comparative localization of murine monoclonal antibody Me1-14 F(ab')2 fragment and whole IgG2a in human glioma xenografts.

Monoclonal antibodies (MAbs) targeted to glioma-associated antigens may allow the selective delivery of imaging and therapeutic agents to brain tumors; the use of MAb fragments may be a strategy to further improve tumor uptake of such agents relative to normal tissues. In this study, we have examined the in vivo localization of radioiodinated MAb Me1-14, a murine immunoglobulin G2a (IgG2a) reactive with gliomas, and its F(ab')2 fragment in s.c. and intracranial xenografts of human glioma cell line D-54 MG in athymic mice. The radiolabeled F(ab')2 fragment of Me1-14 was demonstrated to possess in vitro binding affinity and immunoreactivity comparable to that of whole IgG. Direct comparison of IgG and F(ab')2 biodistribution in s.c. xenograft-bearing mice showed higher tumor: normal tissue ratios of the F(ab')2 fragment compared to IgG. In intracranial tumor-bearing mice paired-label analysis using a nonspecific protein control showed earlier specific tumor localization by the F(ab')2 fragment of Me1-14 compared to IgG. Blood-to-tumor transfer constants (K1) derived for Me1-14 F(ab')2 were significantly greater than those for whole Me1-14 (P = 0.01). Estimated radiation dosimetry revealed that 131I-labeled Me1-14 F(ab')2 would deliver higher radiation doses to tumor than to normal tissues. These studies demonstrate that the F(ab')2 fragment of Me1-14 may be a potential agent for immune-directed brain tumor diagnosis and therapy.

Authors
Colapinto, EV; Humphrey, PA; Zalutsky, MR; Groothuis, DR; Friedman, HS; de Tribolet, N; Carrel, S; Bigner, DD
MLA Citation
Colapinto, EV, Humphrey, PA, Zalutsky, MR, Groothuis, DR, Friedman, HS, de Tribolet, N, Carrel, S, and Bigner, DD. "Comparative localization of murine monoclonal antibody Me1-14 F(ab')2 fragment and whole IgG2a in human glioma xenografts." Cancer Res 48.20 (October 15, 1988): 5701-5707.
PMID
3167830
Source
pubmed
Published In
Cancer Research
Volume
48
Issue
20
Publish Date
1988
Start Page
5701
End Page
5707

ASTATINE-211 LABELED MONOCLONAL-ANTIBODY - A POTENTIAL AGENT FOR RADIOIMMUNOTHERAPY

Authors
GARG, PK; FRIEDMAN, H; SLADE, S; BIGNER, DD; ZALUTSKY, MR
MLA Citation
GARG, PK, FRIEDMAN, H, SLADE, S, BIGNER, DD, and ZALUTSKY, MR. "ASTATINE-211 LABELED MONOCLONAL-ANTIBODY - A POTENTIAL AGENT FOR RADIOIMMUNOTHERAPY." EUROPEAN JOURNAL OF NUCLEAR MEDICINE 14.5-6 (August 1988): 245-245.
Source
wos-lite
Published In
European journal of nuclear medicine
Volume
14
Issue
5-6
Publish Date
1988
Start Page
245
End Page
245

Treatment of intracranial human glioma xenografts with 131I-labeled anti-tenascin monoclonal antibody 81C6.

Lack of tumor specificity renders current modalities for treating malignant glioma ineffective. The administration of 131I-labeled monoclonal antibody (Mab) 81C6, which reacts with the glioma-associated extracellular matrix antigen, tenascin, to nude mice carrying s.c. human glioma xenografts has resulted in significant tumor growth delay and tumor regression. In this study, we evaluated the therapeutic efficacy of 131I-labeled 81C6 in athymic rats bearing intracranial human glioma xenografts, a more appropriate model for human gliomas. Mab 81C6, an IgG2b immunoglobulin, and an isotype-matched control Mab, 45.6, were labeled at 12.5-23.6 mCi/mg with chloramine-T. The Mabs were given i.v. at 1.25 and 2.5 mCi/animal for 131I-labeled 81C6, and 1.25 mCi for 131I-labeled 45.6 control. Therapeutic response was evaluated by survival prolongation using Wilcoxon rank sum analysis. Three experiments were done. No significant survival prolongation was found in the trial in which the average tumor size at the time of Mab administration was 60 +/- 14 mm3, two-thirds the size which causes animal death. In experiment 2, Mab was given at 16 +/- 14 mm3 average intracranial tumor volume. Statistically significant (P less than or equal to 0.005) survival prolongation was found for animals treated with 2.5 mCi 131I-labeled 81C6. In that experiment, male animals with intracranial xenografts had significantly shorter survival than females (P less than or equal to 0.005). When only female animals were used in the analysis, the 1.25-mCi 81C6 group also was found to have longer survival benefit (P less than or equal to 0.01). In the third experiment, only female animals were used and the tumor size at the initiation of treatment was 20 +/- 9 mm3. Highly significant survival prolongation again was found in both 1.25 (P = 0.001) and 2.5 mCi (P less than 0.001) 131I-labeled 81C6 groups. The estimated dose to intracranial tumors from 1.25 mCi of 131I-labeled Mab was 1585 rads for 81C6 and 168 rads for 45.6. Dose to other organs from 81C6 and 45.6 was similar, ranging between 31 rads to the brain and 734 rads to the bone marrow. However, normocellularity was observed in most marrow tissue examined microscopically. Three animals receiving the low dose (1.25 mCi 81C6) survived for more than 71 days with apparent cures. In conclusion, intracranial human glioma xenografts were treated successfully with 131I-labeled 81C6 but not control Mab.

Authors
Lee, Y; Bullard, DE; Humphrey, PA; Colapinto, EV; Friedman, HS; Zalutsky, MR; Coleman, RE; Bigner, DD
MLA Citation
Lee, Y, Bullard, DE, Humphrey, PA, Colapinto, EV, Friedman, HS, Zalutsky, MR, Coleman, RE, and Bigner, DD. "Treatment of intracranial human glioma xenografts with 131I-labeled anti-tenascin monoclonal antibody 81C6." Cancer Res 48.10 (May 15, 1988): 2904-2910.
PMID
2452014
Source
pubmed
Published In
Cancer Research
Volume
48
Issue
10
Publish Date
1988
Start Page
2904
End Page
2910

Radiohalogenation of a monoclonal antibody using an N-succinimidyl 3-(tri-n-butylstannyl)benzoate intermediate.

N-Succinimidyl 3-(tri-n-butylstannyl)benzoate (ATE) was elevated for its utility in the radiohalogenation of monoclonal antibodies. The F(ab')2 fragment of monoclonal antibody OC 125 was labeled with 125I using the ATE reagent and with 131I using a conventional electrophilic iodination method (Iodogen). N-Succinimidyl 3-[125I]iodobenzoate was synthesized from ATE in greater than 90% yield and purified using a disposable silica gel cartridge. About 60-65% of the radioiodinated product was coupled to the F(ab')2 fragment after a 30-min reaction. Two procedures were investigated, one involving exposure of antibody to 35 nmol of ATE and the other to 240 nmol of ATE. Using Scatchard analyses, affinity constants for binding to CA 125 antigen for OC 125 F(ab')2 labeled using the low ATE, Iodogen, and high ATE procedures were determined to be (5.2 +/- 1.0) x 10(10), (2.5 +/- 0.9) x 10(10), and (4.2 +/- 2.4) x 10(9) M-1, respectively. Paired-label studies in athymic mice bearing OVCAR-3 tumors treated with injections of antibody labeled via both ATE and Iodogen demonstrated that use of the ATE method (a) reduced thyroid uptake to less than 0.1% of the injected dose, more than 100 times less than that observed with Iodogen; (b) resulted in more rapid clearance of activity from normal tissues; and (c) with the low ATE preparations, increased the uptake of radioactivity in tumor from 27 to 49%. At 96 h, tumor:tissue ratios were generally at least 4-fold higher when antibody was labeled via ATE. These results suggest that the ATE method may be a valuable approach for the radiohalogenation of antibodies.

Authors
Zalutsky, MR; Narula, AS
MLA Citation
Zalutsky, MR, and Narula, AS. "Radiohalogenation of a monoclonal antibody using an N-succinimidyl 3-(tri-n-butylstannyl)benzoate intermediate." Cancer Res 48.6 (March 15, 1988): 1446-1450.
PMID
3345515
Source
pubmed
Published In
Cancer Research
Volume
48
Issue
6
Publish Date
1988
Start Page
1446
End Page
1450

Therapeutic efficacy of antiglioma mesenchymal extracellular matrix 131I-radiolabeled murine monoclonal antibody in a human glioma xenograft model.

The development of Mabs, particularly those reactive with primary brain tumors but not with normal brain, provides a potential means of delivering therapeutic agents selectively to human malignant gliomas. Mab 81C6, an IgG2b immunoglobulin, which defines an epitope of the glioma-associated extracellular matrix protein tenascin, has been shown to bind to human glioma cell lines, glioma xenografts in nude mice, and primary human gliomas, but not to normal adult or fetal brain. To test the therapeutic potential of this Mab for targeted delivery of isotopes, nude mice bearing progressively growing s.c. xenografts of D-54 MG, a human glioma cell line, were given injections via the tail vein of either buffer, unlabeled 81C6, 131I-labeled 81C6, or 131I-labeled 45.6, a nonspecific control Mab of the same isotype. Specific activities of the Mab range from 6.0 to 15.5 mCi/mg with protein doses from 7.6 to 167 micrograms. The doses given by injection per animal for labeled 81C6 were 50, 250, 500, and 1000 mu Ci and 500 and 1000 mu Ci for 45.6. Tumor response was measured by growth delay in reaching 1000 or 5000 mm3 tumor volumes using the Wilcoxon rank sum test, and by comparing the proportion of tumors that had regression in volume after treatment using the Fisher exact test. Statistically significant growth delays at 1000 mm3 were noted in 1 of 3 experiments with 500 mu Ci 81C6 (P less than 0.001) and 2 of 3 for 1000 mu Ci 81C6 (P = 0.001 and less than 0.001). At 5000 mm3, statistically significant growth delays were seen with radiolabeled 81C6 in 2 of 2 experiments at 250 mu Ci (P = 0.01 and 0.02), 4 of 4 at 500 mu Ci (P = 0.03-less than 0.001), and 2 of 2 at 1000 mu Ci (P = less than or equal to 0.001) and with radiolabeled 45.6 in 1 of 1 at 1000 mu Ci (P = 0.01). The percentage of animals with tumor regression progressively increased with increasing doses of isotope. For radiolabeled 45.6, there were 0 of 10 regressors at 500 and 1 of 10 at 1000 mu Ci. For radiolabeled 81C6, there were 0 of 6 regressors at 50 mu Ci, 1 of 16 (6%) at 250 mu Ci, 7 of 38 (18%) at 500, and 15 of 28 (54%) at 1000 mu Ci. Statistically significant tumor regression was seen only at doses of 500 and 1000 mu Ci of 131I-81C6.(ABSTRACT TRUNCATED AT 400 WORDS)

Authors
Lee, YS; Bullard, DE; Zalutsky, MR; Coleman, RE; Wikstrand, CJ; Friedman, HS; Colapinto, EV; Bigner, DD
MLA Citation
Lee, YS, Bullard, DE, Zalutsky, MR, Coleman, RE, Wikstrand, CJ, Friedman, HS, Colapinto, EV, and Bigner, DD. "Therapeutic efficacy of antiglioma mesenchymal extracellular matrix 131I-radiolabeled murine monoclonal antibody in a human glioma xenograft model." Cancer Res 48.3 (February 1, 1988): 559-566.
PMID
2446747
Source
pubmed
Published In
Cancer Research
Volume
48
Issue
3
Publish Date
1988
Start Page
559
End Page
566

Therapeutic Efficacy of Antiglioma Mesenchymal Extracellular Matrix 131I-Radiolabeled Murine Monoclonal Antibody in a Human Glioma Xenograft Model

The development of Mabs, particularly those reactive with primary brain tumors but not with normal brain, provides a potential means of delivering therapeutic agents selectively to human malignant gliomas. Mab 81C6 an IgG2b immunoglobulin, which defines an epitope of the 000 μC i (P = 0.01). The percentage of anhnals with tumor regression progressively increased with increasing doses of isotope. For radiolabeled 45.6, there were 0 of 10 re seen underestimated the dose observed in a directly measured therapeutic trial by 35-52%. In this xenograft model, a radiolabeled antiglioma Mab against the extracelluhir matrix protein temiscin demonstrated therapeutic efficacy. The promising results obtained in this animal model suggest a potential value for this form of therapy against human malignant gliomas. © 1988, American Association for Cancer Research. All rights reserved.

Authors
Lee, YS; Bullard, DE; Zalutsky, MR; Coleman, RE; Wikstrand, CJ; Friedman, HS; Colapinto, EV; Bigner, D
MLA Citation
Lee, YS, Bullard, DE, Zalutsky, MR, Coleman, RE, Wikstrand, CJ, Friedman, HS, Colapinto, EV, and Bigner, D. "Therapeutic Efficacy of Antiglioma Mesenchymal Extracellular Matrix 131I-Radiolabeled Murine Monoclonal Antibody in a Human Glioma Xenograft Model." Cancer Research 48.3 (January 1, 1988): 584-588.
Source
scopus
Published In
Cancer Research
Volume
48
Issue
3
Publish Date
1988
Start Page
584
End Page
588

The localisation of radiolabelled murine monoclonal antibody 81C6 and its Fab fragment in human glioma xenografts in athymic mice.

The localisation of the radioiodinated Fab fragment of monoclonal antibody (Mab) 81C6, reactive with a glioma-associated extracellular matrix antigen, was studied in athymic mice bearing subcutaneous and intracranial xenografts of D-54 MG glioma cells. In vitro 81C6 Fab showed a marked loss of immunoreactivity and affinity for antigen compared to intact Mab 81C6. In vivo, the plasma half-life of 81C6 Fab was 7.0 hours compared to 2.1 days for 81C6. 81C6 Fab levels in tumours peaked at 2.6-3.8% injected dose/g in 2-6 h; Mab 81C6 reached 33.9% dose/g at 48 h. Localisation indices and tumour:tissue ratios were superior for Mab 81C6. Estimated radiation doses to tumour and normal tissues were lower for 131I-81C6 Fab than 131I-81C6. To realise the theoretical benefits of fragments as localising agents, Fab fragments of higher immunoreactivity and affinity, or bivalent F(ab')2 fragments are required.

Authors
Colapinto, EV; Lee, YS; Humphrey, PA; Zalutsky, MR; Friedman, HS; Bullard, DE; Bigner, DD
MLA Citation
Colapinto, EV, Lee, YS, Humphrey, PA, Zalutsky, MR, Friedman, HS, Bullard, DE, and Bigner, DD. "The localisation of radiolabelled murine monoclonal antibody 81C6 and its Fab fragment in human glioma xenografts in athymic mice." Br J Neurosurg 2.2 (1988): 179-191.
PMID
3267302
Source
pubmed
Published In
British Journal of Neurosurgery (Informa)
Volume
2
Issue
2
Publish Date
1988
Start Page
179
End Page
191

Astatination of proteins using an N-succinimidyl tri-n-butylstannyl benzoate intermediate.

A method is described for labeling proteins with 7.2 h half-life 211 At. The alpha particle-emitting nuclide was coupled to goat IgG using an N-succinimidyl 3-(tri-n-butylstannyl) benzoate intermediate. The reaction and purification sequence requires about 2 h to produce 211 At-labeled IgG in 25-40% radiochemical yield. Comparative blood clearance measurements in mice suggest that the 211 At-labeled IgG conjugate is stable in vivo.

Authors
Zalutsky, MR; Narula, AS
MLA Citation
Zalutsky, MR, and Narula, AS. "Astatination of proteins using an N-succinimidyl tri-n-butylstannyl benzoate intermediate." Int J Rad Appl Instrum A 39.3 (1988): 227-232.
PMID
2836342
Source
pubmed
Published In
International Journal of Radiation Applications and Instrumentation. Part A, Applied Radiation and Isotopes
Volume
39
Issue
3
Publish Date
1988
Start Page
227
End Page
232

Influence of circulating antigen on blood pool activity of a radioiodinated monoclonal antibody.

Athymic mice with and without circulating CA 125 antigen were injected with 0.1-100 micrograms of 131I-labeled OC 125 F(ab')2 antibody fragment. Both the blood clearance of 131I activity and the change in serum CA 125 were monitored over 24 h. Influence of CA 125 on blood pool activity could be avoided only at the 100 micrograms dose. In patient studies, circulating CA 125 levels decreased for the first 2 h after injection of OC 125 F(ab')2 but generally returned to preinjection levels shortly thereafter. In vitro binding studies using the sera from patients injected with 131I-labeled OC 125 F(ab')2 suggest that circulating CA 125 could interfere with the tumor uptake of the labeled antibody.

Authors
Zalutsky, MR; Knapp, RC; Bast, RC
MLA Citation
Zalutsky, MR, Knapp, RC, and Bast, RC. "Influence of circulating antigen on blood pool activity of a radioiodinated monoclonal antibody." Int J Rad Appl Instrum B 15.4 (1988): 431-437.
PMID
3255739
Source
pubmed
Published In
International Journal of Radiation Applications and Instrumentation.
Volume
15
Issue
4
Publish Date
1988
Start Page
431
End Page
437

Effect of radioiodination on the binding of monoclonal antibody DF3 to breast carcinoma cells.

The murine monoclonal antibody (MAb) designated DF3 is an IgG1 prepared against a membrane enriched fraction of human breast carcinoma. MAb DF3 reacts with a family of large molecular weight glycoproteins expressed by 78% of breast cancer cells and 95% of epithelial ovarian cancer cells. Binding to the breast cancer cell line, MCF-7, of native MAb DF3 was compared to that of MAb DF3 exposed to different concentrations of Iodogen or Bolton-Hunter reagent. The amount of MAb DF3 required to obtain half-maximal binding (B1/2max) with MCF-7 extract for native MAb DF3 IgG was 180 ng, while the B1/2max for MAb DF3 IgG exposed to 1 and 10 micrograms Iodogen was 580 ng and 1800 mg, respectively. In contrast, the B1/2max for MAb DF3 IgG treated with Bolton-Hunter reagent was not different from that for native MAb DF3 IgG. Similar results were obtained with F(ab')2. Immunoreactive fractions for the 125I-labeled MAb DF3 were 0.13, 0.24 and 0.65 for IgG after exposure to 1 microgram Iodogen, 10 micrograms Iodogen and Bolton-Hunter, respectively. Immunoreactive fractions for F(ab')2 were 0.08, 0.08, and 0.53 for 1 and 10 micrograms Iodogen and Bolton-Hunter reagent, respectively. Association constants (Ka) were significantly higher for MAb DF3 IgG radioiodinated with Bolton-Hunter (3.97 +/- 0.38 x 10(8) M-1) than for IgG exposed to 1 microgram Iodogen (2.78 +/- 0.30 x 10(8) M-1) or 10 micrograms Iodogen (1.03 +/- 0.12 x 10(8) M-1). Similarly, the Ka ratio observed for the F(ab')2 radioiodinated with Bolton-Hunter reagent, 1 or 10 micrograms Iodogen was 22 to 3 to 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Authors
Hayes, DF; Noska, MA; Kufe, DW; Zalutsky, MR
MLA Citation
Hayes, DF, Noska, MA, Kufe, DW, and Zalutsky, MR. "Effect of radioiodination on the binding of monoclonal antibody DF3 to breast carcinoma cells." Int J Rad Appl Instrum B 15.3 (1988): 235-241.
PMID
2454899
Source
pubmed
Published In
International Journal of Radiation Applications and Instrumentation.
Volume
15
Issue
3
Publish Date
1988
Start Page
235
End Page
241

Use of liposomes as carriers for radiation synovectomy.

Using [99mTc]pertechnetate as an aqueous space marker, the permeability of liposomes composed of seven different mixtures of distearoylphosphatidylcholine (DSPC) and sphingomyelin (SM) was determined. Liposomes containing 20-33% SM were the least permeable in the presence of rheumatoid synovial fluid. Following injection of 99mTc-containing liposomes into the knee joints of rabbits, retention of 99mTc in the knee was more than 200 times greater than following injection of nonencapsulated [99mTc]pertechnetate. The knee clearance biologic half time of 99mTc with DSPC/SM (4:1) liposomes was 64 h. Most of the activity that had leaked from the knee was not found in extra-articular tissues, suggesting rapid excretion. When DSPC/SM (4:1) liposomes were labeled with 111In(oxine), a knee clearance biologic half time of greater than 1200 h was observed.

Authors
Zalutsky, MR; Noska, MA; Gallagher, PW; Shortkroff, S; Sledge, CB
MLA Citation
Zalutsky, MR, Noska, MA, Gallagher, PW, Shortkroff, S, and Sledge, CB. "Use of liposomes as carriers for radiation synovectomy." Int J Rad Appl Instrum B 15.2 (1988): 151-156.
PMID
2835332
Source
pubmed
Published In
International Journal of Radiation Applications and Instrumentation.
Volume
15
Issue
2
Publish Date
1988
Start Page
151
End Page
156

Influence of circulating antigen on blood pool activity of a radioiodinated monoclonal antibody

Athymic mice with and without circulating CA 125 antigen were injected with 0.1-100 μg of 131I-labeled OC 125 F(ab')2 antibody fragment. Both the blood clearance of 131I activity and the change in serum CA 125 were monitored over 24 h. Influence of CA 125 on blood pool activity could be avoided only at the 100 μg dose. In patient studies, circulating CA 125 levels decreased for the first 2 h after injection of OC 125 F(ab')2 but generally returned to preinjection levels shortly thereafter. In vitro binding studies using the sera from patients injected with 131I-labeled OC 125 F(ab')2 suggest that circulating CA 125 could interfere with the tu