Background: Up to now, prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy mainly focused on β-emitting radionuclides. Herein, two new 213Bi-labeled agents for PSMA-targeted α therapy of prostate cancer (PCa) are reported. Methods: The biodistribution of 213Bi-labeled small-molecule inhibitor PSMA I&T and nanobody JVZ-008 was evaluated in mice bearing PSMA-positive LNCaP xenografts. DNA damage response was followed using LNCaP cells and LNCaP xenografts. Results: In vitro, 213Bi-PSMA I&T and 213Bi-JVZ-008 therapy of LNCaP cells led to increased number of DNA double-strand breaks (DSBs), detected as 53BP1 and γH2AX nuclear foci. In vivo, tumor uptake of 213Bi-PSMA I&T and 213Bi-JVZ-008 was 5.75% ± 2.70%ID/g (injected dose per gram) and 2.68% ± 0.56%ID/g, respectively, with similar tumor-to-kidney ratios. Furthermore, both agents induced in vivo DSBs in the tumors, which were detected between 1 hour and 24 hours after injection. 213Bi-PSMA I&T induced significantly more DSBs than 213Bi-JVZ-008 (p < 0.01). Conclusions: 213Bi-PSMA I&T and 213Bi-JVZ-008 showed efficient and rapid tumor targeting and produced DSBs in PSMA-expressing LNCaP cells and xenografts. These promising results require further evaluation of 213Bi-labeled agents with regard to their therapeutic efficacy and toxicity for PCa therapy.

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Keywords Bi-213, prostate cancer, PSMA, radionuclide therapy, targeted α therapy
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Journal Cancer Biotherapy and Radiopharmaceuticals
Nonnekens, J, Chatalic, K.L.S, Molkenboer-Kuenen, J.D.M. (Janneke D.M.), Beerens, C.E.M.T, Bruchertseifer, F, Morgenstern, A, … Heskamp, S. (2017). 213Bi-Labeled Prostate-Specific Membrane Antigen-Targeting Agents Induce DNA Double-Strand Breaks in Prostate Cancer Xenografts. Cancer Biotherapy and Radiopharmaceuticals, 32(2), 67–73. doi:10.1089/cbr.2016.2155