Dataset Information

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

ABSTRACT: 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).

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. 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 ?-camera images, and microscale 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 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 ?-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: ?-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.

SUBMITTER: Kiess AP

PROVIDER: S-EPMC5367442 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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

Kiess Ana P AP Minn Il I Vaidyanathan Ganesan G Hobbs Robert F RF Josefsson Anders A Shen Colette C Brummet Mary M Chen Ying Y Choi Jaeyeon J Koumarianou Eftychia E Baidoo Kwamena K Brechbiel Martin W MW Mease Ronnie C RC Sgouros George G Zalutsky Michael R MR Pomper Martin G MG

Journal of nuclear medicine : official publication, Society of Nuclear Medicine 20160526 10

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, <sup>211</sup>At-labeled small molecule targeting prostate-specific membrane antigen (PSMA) for the treatment of micrometastases due to prostate cancer (PC).<h4>Methods</h4>PSMA-targeted (2S)-2-(3-(1-carboxy-5-(4-<sup>211</sup>At-astatobenzamido)pentyl)ureido)-pentanedioic acid (<sup>211</sup>At- 6: ) was synthesi ...[more]

PMID: 27230930

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