Preclinical Evaluation of 203/212Pb-Labeled Low-Molecular-Weight Compounds for Targeted Radiopharmaceutical Therapy of Prostate Cancer

Sangeeta Ray Banerjee, Il Minn, Vivek Kumar, Anders Josefsson, Ala Lisok, Mary Brummet, Jian Chen, Ana P. Kiess, Kwamena Baidoo, Cory Brayton, Ronnie C. Mease, Martin Brechbiel, George Sgouros, Robert F. Hobbs, and Martin G. Pomper - Johns Hopkins University School of Medicine, Baltimore, Maryland

Targeted radiopharmaceutical therapy (TRT) using α-particle radiation is a promising approach for treating both large and micrometastatic lesions. Researchers developed prostate-specific membrane antigen (PSMA)–targeted low-molecular-weight agents for 212Pb-based TRT of patients with prostate cancer (PC) by evaluating the matching γ-emitting surrogate.

Targeted radiopharmaceutical therapy using α-particles (α-TRTs), which cause deposition of ionizing radiation of high-linear-energy transfer, is accelerating in importance for managing prostate cancer (PC). This acceleration is due in part to the unexpected survival benefit conferred by 223RaCl2 in patients with castration-resistant PC metastatic to bone. Also contributing to this acceleration has been the remarkable decrease in tumor burden demonstrated on images of patients who received 225Ac-PSMA-617, which targets prostate-specific membrane antigen (PSMA) in patients with metastatic castration-resistant PC who failed prior standard treatment. However, salivary and lacrimal gland radiotoxicity may affect the overall survival benefit by reducing quality of life. As an alternative to 225Ac (half-life, 10 d), 212Pb, which has a shorter physical half-life (10.6 h), is a promising source of α-emissions that has proved safe and effective in both preclinical models and clinical studies for several indications. 212Pb is commercially available from a 224Ra generator and has well-described radiochemistry. It is a β-emitter but serves as an in vivo nanogenerator of 212Bi (half-life, 1.01 h), which decays with an α-particle in its decay chain. 212Pb has been successfully used as a stand-alone treatment and in combination with chemotherapy using peptides and monoclonal antibodies as targeting vectors. Although PSMA-based TRT using low-molecular-weight agents and monoclonal antibodies is expanding in management of metastatic castration-resistant PC, to date this has primarily used agents that deliver β-emitting payloads. Few preclinical studies describe detailed evaluation of α-TRT.