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J Nucl Med. 2018 Aug;59(8):1225-1233. doi: 10.2967/jnumed.117.205054. Epub 2018 Mar 23.

PARP-1-Targeted Radiotherapy in Mouse Models of Glioblastoma.

Author information

1
Department of Biochemistry, Hunter College-The City University of New York, New York, New York.
2
Department of Biochemistry, The Graduate Center, The City University of New York, New York, New York.
3
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
4
Department of Radiology, Center for Advanced Imaging Innovation and Research, New York University Langone Medical Center, New York, New York.
5
Department of Chemistry, The Graduate Center, The City University of New York, New York, New York.
6
Department of Chemistry, Hunter College-The City University of New York, New York, New York.
7
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
8
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
9
Department of Pharmacology, Weill-Cornell Medical College, New York, New York.
10
Department of Radiology, Weill-Cornell Medical College, New York, New York.
11
Department of Neurological Surgery, Weill-Cornell Medical College, New York, New York.
12
Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, New York; and.
13
Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York.
14
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York reinert@mskcc.org.

Abstract

The DNA repair enzyme poly(ADP-ribose) polymerase 1 (PARP-1) is overexpressed in glioblastoma, with overall low expression in healthy brain tissue. Paired with the availability of specific small molecule inhibitors, PARP-1 is a near-ideal target to develop novel radiotherapeutics to induce DNA damage and apoptosis in cancer cells, while sparing healthy brain tissue. Methods: We synthesized an 131I-labeled PARP-1 therapeutic and investigated its pharmacology in vitro and in vivo. A subcutaneous tumor model was used to quantify retention times and therapeutic efficacy. A potential clinical scenario, intratumoral convection-enhanced delivery, was mimicked using an orthotopic glioblastoma model combined with an implanted osmotic pump system to study local administration of 131I-PARPi (PARPi is PARP inhibitor). Results:131I-PARPi is a 1(2H)-phthalazinone, similar in structure to the Food and Drug Administration-approved PARP inhibitor AZD-2281. In vitro studies have shown that 131I-PARPi and AZD-2281 share similar pharmacologic profiles. 131I-PARPi delivered 134.1 cGy/MBq intratumoral injected activity. Doses to nontarget tissues, including liver and kidney, were significantly lower. Radiation damage and cell death in treated tumors were shown by p53 activation in U87-MG cells transfected with a p53-bioluminescent reporter. Treated mice showed significantly longer survival than mice receiving vehicle (29 vs. 22 d, P < 0.005) in a subcutaneous model. Convection-enhanced delivery demonstrated efficient retention of 131I-PARPi in orthotopic brain tumors, while quickly clearing from healthy brain tissue. Conclusion: Our results demonstrate 131I-PARPi's high potential as a therapeutic and highlight PARP's relevance as a target for radionuclide therapy. Radiation plays an integral role in brain tumor therapy, and radiolabeled PARP therapeutics could ultimately lead to improvements in the standard of care.

KEYWORDS:

131I; 131I-PARPi; PARP; convection enhanced delivery (CED); radiotherapeutic

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