Targeted α-therapy using astatine (211At)-labeled PSMA1, 5, and 6: a preclinical evaluation as a novel compound
Tadashi Watabe, Kazuko Kaneda‐Nakashima, Yoshifumi Shirakami, Yuichiro Kadonaga, Kazuhiro Ooe, Yang Wang, Hiromitsu Haba, Atsushi Toyoshima, Jens Cardinale, Frederik L. Giesel, Noriyuki Tomiyama, Koichi Fukase
Abstract
Abstract Purpose Targeted α-therapy (TAT) for prostate-specific membrane antigen (PSMA) is a promising treatment for metastatic castration-resistant prostate cancer (CRPC). Astatine is an α-emitter (half-life=7.2 h) that can be produced by a 30-MeV cyclotron. This study evaluated the treatment effect of 211 At-labeled PSMA compounds in mouse xenograft models. Methods Tumor xenograft models were established by subcutaneous transplantation of human prostate cancer cells (LNCaP) in NOD/SCID mouse. [ 211 At]PSMA1, [ 211 At]PSMA5, or [ 211 At]PSMA6 was administered to LNCaP xenograft mice to evaluate biodistribution at 3 and 24 h. The treatment effect was evaluated by administering [ 211 At]PSMA1 (0.40 ± 0.07 MBq), [ 211 At]PSMA5 (0.39 ± 0.03 MBq), or saline. Histopathological evaluation was performed for the at-risk organs at 3 and 6 weeks after administration. Results [ 211 At]PSMA5 resulted in higher tumor retention compared to [ 211 At]PSMA1 and [ 211 At]PSMA6 (30.6 ± 17.8, 12.4 ± 4.8, and 19.1 ± 4.5 %ID/g at 3 h versus 40.7 ± 2.6, 8.7 ± 3.5, and 18.1 ± 2.2%ID/g at 24 h, respectively), whereas kidney excretion was superior in [ 211 At]PSMA1 compared to [ 211 At]PSMA5 and [ 211 At]PSMA6. An excellent treatment effect on tumor growth was observed after [ 211 At]PSMA5 administration. [ 211 At]PSMA1 also showed a substantial treatment effect; however, the tumor size was relatively larger compared to that with [ 211 At]PSMA5. In the histopathological evaluation, regenerated tubules were detected in the kidneys at 3 and 6 weeks after the administration of [ 211 At]PSMA5. Conclusion TAT using [ 211 At]PSMA5 resulted in excellent tumor growth suppression with minimal side effects in the normal organs. [ 211 At]PSMA5 should be considered a new possible TAT for metastatic CRPC, and translational prospective trials are warranted.