Alpha-Particle Therapy with an Actinium-225 Labeled Bivalent Inhibitor of Prostate-Specific Membrane Antigen is Therapeutically Efficacious in a Mouse Model of Prostate Cancer.

Prostate-Specific Membrane Antigen (PSMA) is overexpressed in some prostate cancers and is a viable candidate for targeted radionuclide therapy. PSMA targeted delivery of α2+ particle-emitting actinium-225 to tumors is a potential therapeutic option for prostate cancer. A substituted diazacrown ether macrocycle (Macropa) forms stable complexes with [225Ac]Ac3+. In this work, two PSMA-targeting lysine-ureido-glutamic acid pharmacophores are attached to a single Macropa macrocycle to give MacropaBisPSMA. The new conjugate was radiolabeled with [225Ac]Ac3+ to give [225Ac]AcMacropaBisPSMA. The therapeutic activity of [225Ac]AcMacropaBisPSMA was evaluated in mice bearing PSMA-positive PC3-PIP tumor xenografts. [225Ac]AcMacropaBisPSMA showed a high degree of tumor uptake and retention at 24 h post injection (23.0 ± 5.4%IA g-1). Untreated mice in this model had a median survival of 14.5 days. Mice treated with [225Ac]AcMacropaBisPSMA (15 kBq) had a median survival of 87 days, and all mice treated with 37 kBq of [225Ac]AcMacropaBisPSMA survived the duration of the 90-day study.