2026
J Med Chem 2026 Jul 4. doi: 10.1021/acs.jmedchem.6c01378. Online ahead of print.
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
School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, 3010 Victoria, Australia. Australian Institute for Bioengineering and Nanotechnology, the University of Queensland, Brisbane, QLD 4072, Australia. ARC Research Hub for Advanced Manufacture of Targeted Radiopharmaceuticals (AMTAR), the University of Queensland, Brisbane, QLD 4072, Australia. Clarity Pharmaceuticals Ltd., National Innovation Centre, 4 Cornwallis Street, Eveleigh, New South Wales 2042, Australia.
Service type: Stock strains
Abstract
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.
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