Optimizing [²¹²Pb]Pb-AB001 Radiopharmaceutical Therapy Schedules in PSMA-Positive Subcutaneous Prostate Cancer Xenografts

Radiopharmaceutical therapies are typically administered in multiple cycles to improve tolerability, but optimal scheduling remains undefined. Targeted α-therapy with [²¹²Pb]Pb-AB001, a prostate-specific membrane antigen (PSMA)-targeting radioligand, is a promising approach for metastatic prostate cancer. This preclinical study evaluated how treatment schedules and cumulative activities affect therapeutic efficacy and toxicity. <b>Methods:</b> Male athymic nude mice bearing subcutaneous PC-3 PIP xenografts received a cumulative activity of 0.8 MBq of [²¹²Pb]Pb-AB001 as a single or as multiple injections at 7-d intervals (Q7d) or 14-d intervals (Q14d). [¹⁸F]PSMA-1007 PET/CT imaging was performed at 1 and 2 wk after treatment. Two additional therapy studies evaluated 0.4 MBq Q7d or every third day (Q3d), with cumulative activities of up to 1.6 MBq. Tumor growth, survival, toxicity, radioligand uptake, and histopathology were evaluated. <b>Results:</b> All regimens delayed tumor growth and prolonged survival compared with the controls. Tumor control was improved with the Q7d regimen compared with the Q14d and Q3d regimens. SUV_mean and SUV_max increased significantly 7 d after treatment compared with baseline. Among mice receiving 0.8 MBq cumulatively, the group receiving 4 × 0.2 MBq Q7d showed the best tumor control (median survival, 67 d). Increasing per-cycle activity to 0.4 MBq and extending to 4 cycles Q7d further prolonged median survival to 116 d, with 33% complete responses. Tumor uptake of [²¹²Pb]Pb-AB001 remained consistent across 1-4 injections Q7d. Repeated treatment induced progressive tumor necrosis and edema and reduced PSMA and vascular endothelial growth factor staining. No systemic toxicity was observed at studied activities. <b>Conclusion:</b> The efficacy of [²¹²Pb]Pb-AB001 radiopharmaceutical therapy depended on cycle number, interval, and per-cycle activity. Multicycle regimens enhanced tumor control without toxicity, supporting schedule optimization in clinical protocols for [²¹²Pb]Pb-PSMA therapy.