Dataset Information

Targeted α-therapy using astatine (²¹¹At)-labeled PSMA1, 5, and 6: a preclinical evaluation as a novel compound.

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 ²¹¹At-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. [²¹¹At]PSMA1, [²¹¹At]PSMA5, or [²¹¹At]PSMA6 was administered to LNCaP xenograft mice to evaluate biodistribution at 3 and 24 h. The treatment effect was evaluated by administering [²¹¹At]PSMA1 (0.40 ± 0.07 MBq), [²¹¹At]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

[²¹¹At]PSMA5 resulted in higher tumor retention compared to [²¹¹At]PSMA1 and [²¹¹At]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 [²¹¹At]PSMA1 compared to [²¹¹At]PSMA5 and [²¹¹At]PSMA6. An excellent treatment effect on tumor growth was observed after [²¹¹At]PSMA5 administration. [²¹¹At]PSMA1 also showed a substantial treatment effect; however, the tumor size was relatively larger compared to that with [²¹¹At]PSMA5. In the histopathological evaluation, regenerated tubules were detected in the kidneys at 3 and 6 weeks after the administration of [²¹¹At]PSMA5.

Conclusion

TAT using [²¹¹At]PSMA5 resulted in excellent tumor growth suppression with minimal side effects in the normal organs. [²¹¹At]PSMA5 should be considered a new possible TAT for metastatic CRPC, and translational prospective trials are warranted.

SUBMITTER: Watabe T

PROVIDER: S-EPMC9852121 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Targeted α-therapy using astatine (<sup>211</sup>At)-labeled PSMA1, 5, and 6: a preclinical evaluation as a novel compound.

Watabe Tadashi T Kaneda-Nakashima Kazuko K Shirakami Yoshifumi Y Kadonaga Yuichiro Y Ooe Kazuhiro K Wang Yang Y Haba Hiromitsu H Toyoshima Atsushi A Cardinale Jens J Giesel Frederik L FL Tomiyama Noriyuki N Fukase Koichi K

European journal of nuclear medicine and molecular imaging 20221108 3

<h4>Purpose</h4>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 <sup>211</sup>At-labeled PSMA compounds in mouse xenograft models.<h4>Methods</h4>Tumor xenograft models were established by subcutaneous transplantation of human prostate cancer cells (LNCaP) in ...[more]

PMID: 36344651

Similar Datasets

Project description:PURPOSE:Targeted alpha therapy (TAT) is a promising treatment for micrometastatic and minimal residual cancer. We evaluated systemic α-radioimmunotherapy (α-RIT) of metastatic castration-resistant prostate cancer (mCRPC) using the α-particle emitter 211At-labeled to the anti-PSCA A11 minibody. A11 is specific for prostate stem cell antigen (PSCA), a cell surface glycoprotein which is overexpressed in more than 90% of both localized prostate cancer and bone metastases. METHODS:PC3-PSCA cells were implanted subcutaneously (s.c.) and intratibially (i.t) in nude mice. Efficacy of α-RIT (two fractions-14-day interval) was studied on s.c. macrotumors (0, 1.5 and 1.9 MBq) and on i.t. microtumors (~100-200 μm; 0, 0.8 or 1.5 MBq) by tumor-volume measurements. The injected activities for therapies were estimated from separate biodistribution and myelotoxicity studies. RESULTS:Tumor targeting of 211At-A11 was efficient and the effect on s.c. macrotumors was strong and dose-dependent. At 6 weeks, the mean tumor volumes for the treated groups, compared with controls, were reduced by approximately 85%. The separate myelotoxicity study following one single fraction showed reduced white blood cells (WBC) for all treated groups on day 6 after treatment. For the 0.8 and 1.5 MBq, the WBC reductions were transient and followed by recovery at day 13. For 2.4 MBq, a clear toxicity was observed and the mice were sacrificed on day 7. In the long-term follow-up of the 0.8 and 1.5 MBq-groups, blood counts on day 252 were normal and no signs of radiotoxicity observed. Efficacy on i.t. microtumors was evaluated in two experiments. In experiment 1, the tumor-free fraction (TFF) was 95% for both treated groups and significantly different (p < 0.05) from the controls at a TFF of 66%). In experiment 2, the difference in TFF was smaller, 32% for the treated group versus 20% for the controls. However, the difference in microtumor volume in experiment 2 was highly significant, 0.010 ± 0.003 mm3 versus 3.79 ± 1.24 mm3 (treated versus controls, respectively), i.e., a 99.7% reduction (p < 0.001). The different outcome in experiment 1 and 2 is most likely due to differences in microtumor sizes at therapy, or higher tumor-take in experiment 2 (where more cells were implanted). CONCLUSION:Evaluating fractionated α-RIT with 211At-labeled anti-PSCA A11 minibody, we found clear growth inhibition on both macrotumors and intratibial microtumors. For mice treated with multiple fractions, we also observed radiotoxicity manifested by progressive loss in body weight at 30 to 90 days after treatment. Our findings are conceptually promising for a systemic TAT of mCRPC and warrant further investigations of 211At-labeled PSCA-directed vectors. Such studies should include methods to improve the therapeutic window, e.g., by implementing a pretargeted regimen of α-RIT or by altering the size of the targeting vector.

Dataset Information

Targeted α-therapy using astatine (²¹¹At)-labeled PSMA1, 5, and 6: a preclinical evaluation as a novel compound.

Purpose

Methods

Results

Conclusion

Publications

Targeted α-therapy using astatine (<sup>211</sup>At)-labeled PSMA1, 5, and 6: a preclinical evaluation as a novel compound.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Targeted α-therapy using astatine (211At)-labeled PSMA1, 5, and 6: a preclinical evaluation as a novel compound.

Purpose

Methods

Results

Conclusion

Publications

Targeted α-therapy using astatine (<sup>211</sup>At)-labeled PSMA1, 5, and 6: a preclinical evaluation as a novel compound.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Targeted α-therapy using astatine (²¹¹At)-labeled PSMA1, 5, and 6: a preclinical evaluation as a novel compound.