TY - JOUR
T1 - (2S)-2-(3-(1-carboxy-5-(4-211At-astatobenzamido)pentyl) ureido)-pentanedioic acid for PSMA-targeted α-particle radiopharmaceutical therapy
AU - Kiess, Ana P.
AU - Minn, Il
AU - Vaidyanathan, Ganesan
AU - Hobbs, Robert F.
AU - Josefsson, Anders
AU - Shen, Colette
AU - Brummet, Mary
AU - Chen, Ying
AU - Choi, Jaeyeon
AU - Koumarianou, Eftychia
AU - Baidoo, Kwamena
AU - Brechbiel, Martin W.
AU - Mease, Ronnie C.
AU - Sgouros, George
AU - Zalutsky, Michael R.
AU - Pomper, Martin G.
N1 - Funding Information:
The costs of publication of this article were defrayed in part by the payment of page charges. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734. This work was supported by NIH CA116477, CA184228, CA134675, CA183031, CA157542, and EB005324 and in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. No other potential conflict of interest relevant to this article was reported. We thank Dr. Warren Heston for providing the PSMA+ PC3 PIP and PSMA- PC3 flu cells and Dr. Mauricio Reginato for the PC3-ML-Luc cells.We also acknowledge Dr. Tom Bäck (University of Gothenburg), who invented the alpha camera and collaborated on its installation and use in this study.
Publisher Copyright:
Copyright © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
PY - 2016/10/1
Y1 - 2016/10/1
N2 - 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 α-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 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 microscale dosimetry.
AB - 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 α-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 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 microscale dosimetry.
KW - Alpha emitter
KW - Astatine
KW - Oncology: GU
KW - Prostate cancer
KW - Prostate-specific membrane antigen
KW - Radiation dosimetry
KW - Radionuclide therapy
KW - Radiopharmaceuticals
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U2 - 10.2967/jnumed.116.174300
DO - 10.2967/jnumed.116.174300
M3 - Article
C2 - 27230930
AN - SCOPUS:84991376228
SN - 0161-5505
VL - 57
SP - 1569
EP - 1575
JO - Journal of Nuclear Medicine
JF - Journal of Nuclear Medicine
IS - 10
ER -