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. 2016 Oct;57(10):1569-1575.
doi: 10.2967/jnumed.116.174300. Epub 2016 May 26.

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

Ana P Kiess  1 , Il Minn  2 , Ganesan Vaidyanathan  3 , Robert F Hobbs  1 , Anders Josefsson  2 , Colette Shen  1 , Mary Brummet  2 , Ying Chen  2 , Jaeyeon Choi  3 , Eftychia Koumarianou  3 , Kwamena Baidoo  4 , Martin W Brechbiel  4 , Ronnie C Mease  2 , George Sgouros  5 , Michael R Zalutsky  3 , Martin G Pomper  6
Affiliations

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

Ana P Kiess et al. J Nucl Med. 2016 Oct.

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 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.

Keywords: alpha emitter; astatine; oncology: GU; prostate cancer; prostate-specific membrane antigen; radiation dosimetry; radionuclide therapy; radiopharmaceuticals.

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Figures

FIGURE 1.
FIGURE 1.
Synthesis of 131I-5 and 211At-6. (A) N-succinimidyl-4-tributylstannyl benzoate, triethylamine, methylene chloride. (B) 211At, N-chlorosuccinimide, acetic acid, methanol, room temp 30 min. (C) Na[1311]N-chlorosuccinimide, acetic acid, methanol, room temp 30 min. (D) Trifluoroacetic acid/water 50°C 30 min or room temperature 60–90 min. PMB = para-methoxybenzyl.
FIGURE 2.
FIGURE 2.
(A) Paired-label uptake of 131I-5 and 211At-6 in PSMA+ PC3 PIP and PSMA– PC3 flu cells. Uptake in PSMA+ cells also was determined in presence of PSMA inhibitor, 2-PMPA. Values indicate mean ± SD. Asterisks indicate difference between radiotracers using paired t test (P < 0.05). (B) Clonogenic survival of PSMA+ cells after incubation with 211At-astatide and 211At-6. Dashed line indicates 95% confidence limit for regression fit.
FIGURE 3.
FIGURE 3.
Uptake of 131I and 211At in PSMA+ PC3 PIP and PSMA– PC3 flu xenografts after administration of 0.2 MBq of 131I-5 and 211At-6 in athymic mice. Values indicate mean ± SD.
FIGURE 4.
FIGURE 4.
PSMA+ PC3 PIP tumor-to-tissue ratios after administration of 0.2 MBq of 131I-5 and 211At-6 in athymic mice. Values indicate mean ± SD.
FIGURE 5.
FIGURE 5.
211At-6 showed significant tumor growth delay in flank xenograft model. Kaplan–Meier curve illustrating time for flank tumors to grow 10-fold in volume in athymic mice after 740 kBq of 211At-6 treatment or control.
FIGURE 6.
FIGURE 6.
211At-6 showed significant improvement in survival in micrometastatic model. Kaplan–Meier curve shows survival time after treatment.
FIGURE 7.
FIGURE 7.
Renal histopathology from nontreated mouse (A and B) and mouse treated with 1.5 MBq of 211At-6 (C and D). Treated kidney showed subcortical atrophy and degenerative loss of proximal tubules (arrows) consistent with late nephropathy due to α-particle irradiation. A, C: 2×; B, D: 10×.
FIGURE 8.
FIGURE 8.
α-camera images at 1 h showing relative 211At-6 activity concentrations for PSMA+ and PSMA– tumors and kidneys. Scale shows activity concentration relative to whole tumor/kidney average concentration. White bar = 1 mm.
See this image and copyright information in PMC

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