Preclinical evaluation of <sup>213</sup>Bi-/<sup>225</sup>Ac-labeled low-molecular-weight compounds for radiopharmaceutical therapy of prostate cancer
Sangeeta Ray, Ala Lisok, Il Minn, Anders Josefsson, Vivek Kumar, Mary Brummet, Srikanth Boinapally, Cory Brayton, Ronnie C. Mease, George Sgouros, Robert F. Hobbs, Martin G. Pomper
Abstract
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 b-particle-emitting low-molecular-weight compound, 177 Lu-L1 which demonstrated reduced off-target effects in a xenograft model of prostate cancer. Here, we leveraged that scaffold to synthesize a-particle-emitting analogs of L1, 213 Bi-L1 and 225 Ac-L1, to evaluate their safety and cell kill effect in PSMApositive (1) xenograft models. Methods: The radiochemical synthesis, cell uptake, cell kill, and biodistribution of 213 Bi-L1 and 225 Ac-L1 were evaluated. The efficacy of 225 Ac-L1 was determined in human PSMA1 subcutaneous and micrometastatic models. Subacute toxicity at 8 wk and chronic toxicity at 1 y after administration were evaluated for 225 Ac-L1. The absorbed radiation dose of 225 Ac-L1 was determined using the biodistribution data and a-camera imaging. Results: 213 Bi-and 225 Ac-L1 demonstrated specific cell uptake and cell kill in PSMA1 cells. The biodistribution of 213 Bi-L1 and 225 Ac-L1 revealed specific uptake of radioactivity within PSMA1 lesions. Treatment studies of 225 Ac-L1 demonstrated activitydependent, specific inhibition of tumor growth in the PSMA1 flank tumor model. 225 Ac-L1 also showed an increased survival benefit in the micrometastatic model compared with 177 Lu-L1. Activityescalated acute and chronic toxicity studies of 225 Ac-L1 revealed off-target radiotoxicity, mainly in kidneys and liver. The estimated maximum tolerated activity was about 1 MBq/kg. a-Camera imaging of 225 Ac-L1 revealed high renal cortical accumulation at 2 h followed by fast clearance at 24 h. Conclusion: 225 Ac-L1 demonstrated activity-dependent efficacy with minimal treatment-related organ radiotoxicity. 225 Ac-L1 is a promising therapeutic for further clinical evaluation.