Abstract
Introduction: 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 treatment of micrometastases due to prostate cancer (PC). Methods: 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. Anti-tumor 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. 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. Results: [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 subcutaneous 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. 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. Conclusion: 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 micro-scale dosimetry.
- Oncology: GU
- Radionuclide Therapy
- Radiopharmaceuticals
- alpha emitter
- astatine
- prostate cancer
- prostate-specific membrane antigen
- radiation dosimetry
- Copyright © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.