Click Covalent-Targeted Radionuclide Therapy for Prostate Cancer.

Targeted radionuclide therapy represents a promising therapeutic method for treating cancer. However, currently approved radioligands still require improvement in terms of tumor uptake and retention. This study employed molecular simulation to design a novel radioligand, designated PSMA-MAL-5, which covalently binds to the prostate-specific membrane antigen (PSMA). This ligand can be efficiently radiolabeled with the beta emitter (177Lu) and the alpha emitter (225Ac) and exhibits a high level of radiostability. Autoradiography confirmed that 177Lu-PSMA-MAL-5 binds covalently to PSMA. In vivo experiments demonstrated that the radioligand can effectively target PSMA-positive tumors, with an area under the curve of tumor uptake higher than that observed for 177Lu-PSMA-617 (2517 ± 499 h %ID/cm3 vs 575 ± 75 h %ID/cm3). Tumor inhibition studies indicated that the radioligand exhibited a notable tumor inhibitory effect on tumor growth, showing promise as a tool for targeted radionuclide therapy of PSMA-positive prostate cancer.