Preclinical Evaluation of 213Bi- and 225Ac-Labeled Low-Molecular-Weight Compounds for Radiopharmaceutical Therapy of Prostate Cancer

Prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical therapy is a new option for patients with advanced prostate cancer refractory to other treatments. Previously, we synthesized a beta-particle-emitting low-molecular-weight compound, Lu-177-L1 which demonstrated reduced off-target effects in a xenograftmodel of prostate cancer. Here, we leveraged that scaffold to synthesize alpha-particle-emitting analogs of L1, Bi-213-L1 and Ac-225-L1, to evaluate their safety and cell kill effect in PSMA-positive (1) xenograftmodels. Methods: The radiochemical synthesis, cell uptake, cell kill, and biodistribution of Bi-213-L1 and Ac-225-L1 were evaluated. The efficacy of Ac-225-L1 was determined in human PSMA+ subcutaneous and micrometastatic models. Subacute toxicity at 8 wk and chronic toxicity at 1 y after administration were evaluated for Ac-225-L1. The absorbed radiation dose of Ac-225-L1 was determined using the biodistribution data and a-camera imaging. Results: Bi-213-and Ac-225-L1 demonstrated specific cell uptake and cell kill in PSMA + cells. The biodistribution of Bi-213-L1 and Ac-225-L1 revealed specific uptake of radioactivity within PSMA+ lesions. Treatment studies of Ac-225-L1 demonstrated activity-dependent, specific inhibition of tumor growth in the PSMA+ flank tumor model. Ac-225-L1 also showed an increased survival benefit in the micrometastatic model compared with 177Lu-L1. Activity-escalated acute and chronic toxicity studies of Ac-225-L1 revealed off-target radiotoxicity, mainly in kidneys and liver. The estimated maximumtolerated activitywas about 1MBq/kg. alpha-Camera imaging of Ac-225-L1 revealed high renal cortical accumulation at 2 h followed by fast clearance at 24 h. Conclusion: Ac-225-L1 demonstrated activity-dependent efficacy with minimal treatment-related organ radiotoxicity. Ac-225-L1 is a promising therapeutic for further clinical evaluation.

Automated summary

PSMA-targeted radiopharmaceutical therapy shows promising results for patients with advanced prostate cancer. Bi-213-L1 and Ac-225-L1 demonstrate specific cell uptake and kill effect in PSMA+ models, with Ac-225-L1 showing potential for further clinical evaluation.