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Alpha-Particle Therapy with an Actinium-225 Labeled Bivalent Inhibitor of Prostate-Specific Membrane Antigen is
Katherine A Morgan1, Melyssa L Grieve2,3, Dewan T Akhter2,3
1School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, 3010 Victoria, Australia.
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.
Insights
New targeted therapy using actinium-225 (225Ac) linked to PSMA-targeting molecules significantly improved survival in prostate cancer models. This approach shows promise for treating PSMA-positive prostate cancer.
Area of Science:
- Nuclear medicine
- Oncology
- Radiopharmaceutical chemistry
Background:
- Prostate-Specific Membrane Antigen (PSMA) is a key biomarker overexpressed in prostate cancer.
- Targeted radionuclide therapy offers a promising avenue for prostate cancer treatment.
- Actinium-225 (225Ac) is an alpha-particle-emitting radionuclide suitable for targeted therapy.
Purpose of the Study:
- To develop and evaluate a novel 225Ac-based targeted therapy for prostate cancer.
- To assess the efficacy of a new conjugate, [225Ac]AcMacropaBisPSMA, in preclinical models.
Main Methods:
- A novel conjugate, MacropaBisPSMA, was synthesized by attaching two PSMA-targeting pharmacophores to a Macropa macrocycle.
- The conjugate was radiolabeled with 225Ac to form [225Ac]AcMacropaBisPSMA.
- Therapeutic efficacy was evaluated in mice with PSMA-positive PC3-PIP tumor xenografts.
Main Results:
- [225Ac]AcMacropaBisPSMA demonstrated high tumor uptake and retention (23.0 ± 5.4%IA g-1 at 24 h).
- Treatment with 15 kBq of [225Ac]AcMacropaBisPSMA extended median survival to 87 days.
- All mice treated with 37 kBq survived the 90-day study period.
Conclusions:
- [225Ac]AcMacropaBisPSMA is a highly effective targeted alpha therapy for PSMA-positive prostate cancer.
- This novel radiopharmaceutical shows significant potential for improving patient outcomes in prostate cancer treatment.
