(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, (211)At-labeled small-molecule targeting prostate-specific membrane antigen (PSMA) for treatment of micrometastases due to prostate cancer (PC).

PSMA-targeted (2S)-2-(3-(1-carboxy-5-(4-[(211)At]astatobenzamido)pentyl)ureido)-pentanedioic acid ([(211)At]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 [(211)At]6 treatment. Anti-tumor efficacy of [(211)At]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. Sub-organ distribution was evaluated using α-Camera images, and micro-scale dosimetry was modeled. Long-term toxicity was assessed in mice for 12 mo.

[(211)At]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 subcutaneous tumors. Significantly improved survival was achieved in the newly developed PSMA+ micrometastatic PC model. Biodistribution showed uptake of [(211)At]6 in PSMA+ PC3 PIP tumors and in kidneys. Micro-scale 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 [(211)At]6 α-particle radiotherapy yielded significantly improved survival in mice bearing PC micrometastases after systemic administration. [(211)At]6 also showed uptake in renal proximal tubules resulting in late nephrotoxicity, highlighting the importance of long-term toxicity studies and micro-scale dosimetry.

Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2016 May 26 [Epub ahead of print]

Ana Kiess, I L Minn, Ganesan Vaidyanathan, Robert F Hobbs, Anders Josefsson, Colette Shen, Mary Brummet, Ying Chen, Jaeyeon Choi, Eftychia Koumarianou, Kwamena Baidoo, Martin Brechbiel, Ronnie C Mease, George Sgouros, Michael R Zalutsky, Martin Pomper

Johns Hopkins Medical Institute, United States;, Johns Hopkins University, United States;, Duke University Medical Center, United States;, Johns Hopkins University, United States;, Johns Hopkins University School of Medicine, United States;, Johns Hopkins Medical Institute, United States;, Johns Hopkins Medical Institute, United States;, Johns Hopkins Medical Institute, United States;, Duke University Medical Center, United States;, Duke University Medical Center, United States;, National Institutes of Health, United States;, NCI, United States;, Johns Hopkins University, United States;, Johns Hopkins University, School of Medicine, United States;, Duke University Medical Center, United States;, Johns Hopkins Medical Institutions, United States.

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