Click Covalent-Targeted Radionuclide Therapy for Prostate Cancer

Area of Science:

• Nuclear medicine
• Radiopharmaceutical chemistry
• Molecular imaging and therapy

Background:

• Targeted radionuclide therapy (TRT) is a promising cancer treatment.
• Current radioligands need enhanced tumor uptake and retention for improved efficacy.
• Prostate-specific membrane antigen (PSMA) is a key target in prostate cancer therapy.

Purpose of the Study:

• To design and evaluate a novel PSMA-targeting radioligand, PSMA-MAL-5, for targeted radionuclide therapy.
• To assess the radiolabeling efficiency, radiostability, and in vivo performance of PSMA-MAL-5.
• To compare the efficacy of PSMA-MAL-5 with an established radioligand, 177Lu-PSMA-617.

Main Methods:

• Molecular simulation was used to design PSMA-MAL-5 for covalent binding to PSMA.
• PSMA-MAL-5 was radiolabeled with 177Lu and 225Ac.
• Autoradiography confirmed covalent binding to PSMA.
• In vivo studies in PSMA-positive tumor models evaluated tumor uptake, retention, and therapeutic efficacy.

Main Results:

• PSMA-MAL-5 demonstrated efficient radiolabeling and high radiostability.
• Autoradiography confirmed covalent binding of 177Lu-PSMA-MAL-5 to PSMA.
• In vivo studies showed significantly higher tumor uptake for 177Lu-PSMA-MAL-5 compared to 177Lu-PSMA-617 (2517 ± 499 h %ID/cm³ vs 575 ± 75 h %ID/cm³).
• PSMA-MAL-5 exhibited notable tumor growth inhibition in PSMA-positive prostate cancer models.

Conclusions:

• PSMA-MAL-5 is a novel, highly effective PSMA-targeting radioligand.
• Its superior tumor uptake and retention show significant potential for targeted radionuclide therapy.
• PSMA-MAL-5 represents a promising advancement for treating PSMA-positive prostate cancer.