LAUSR

Simple Summary Prostate-specific membrane antigen (PSMA) is a protein overexpressed in metastatic castration-resistant prostate cancer and a promising target for targeted radionuclide therapy. PSMA-targeted alpha therapy is of growing interest due to the high-emission energy and short range of alpha particles, resulting in a prominent cytotoxic potency. This study assesses the influence of various factors on the in vitro and in vivo therapeutic efficacy of the alpha particle generating PSMA-targeting radioligand 212Pb-NG001. Abstract This study aimed to determine the influence of cellular PSMA expression, radioligand binding and internalization, and repeated administrations on the therapeutic effects of the PSMA-targeting radioligand 212Pb-NG001. Cellular binding and internalization, cytotoxicity, biodistribution, and the therapeutic efficacy of 212Pb-NG001 were investigated in two human prostate cancer cell lines with different PSMA levels: C4-2 (PSMA+) and PC-3 PIP (PSMA+++). Despite 10-fold higher PSMA expression on PC-3 PIP cells, cytotoxicity and therapeutic efficacy of the radioligand was only 1.8-fold better than for the C4-2 model, possibly explained by lower cellular internalization and less blood-rich stroma in PC-3 PIP xenografts. Mice bearing subcutaneous PC-3 PIP xenografts were treated with 0.2, 0.4, and 0.8 MBq of 212Pb-NG001 that resulted in therapeutic indexes of 2.7, 3.0, and 3.5, respectively. A significant increase in treatment response was observed in mice that received repeated injections compared to the corresponding single dose (therapeutic indexes of 3.6 for 2 × 0.2 MBq and 4.4 for 2 × 0.4 MBq). The results indicate that 212Pb-NG001 can induce therapeutic effects at clinically transferrable doses, both in the C4-2 model that resembles solid tumors and micrometastases with natural PSMA expression and in the PC-3 PIP model that mimics poorly vascularized metastases.