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Journal of Controlled Release

Journal of Controlled Release

IF: 10.5
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Dual-targeted alpha therapy mitigates prostate cancer and boosts immune checkpoint blockade therapy

Published:3 April 2025 DOI: 10.1016/j.jconrel.2025.113686
Juan Sun , Jiangtao Yang , Jiakun Guo , Lei Tao , Bin Xu , Guanglin Wang , Fenghua Meng , Zhiyuan Zhong

Abstract

Alpha radionuclide with a high emitting energy and short emitting range has emerged as a new tool for the treatment of advanced tumors; however, its clinical usage stringently depends on delivery vehicle. Here, we report on Sigma-1 receptor and PSMA dual-specific peptide with efficient 225?actinium labeling (225Ac-S1R/PSMA-P) for targeted alpha therapy and alpha-immunotherapy of murine prostate tumor. 225Ac-S1R/PSMA-P with a high specific activity and radiostability exhibited upgraded cell binding and uptake while diminished efflux in RM1-PSMA+ cancer cells. Intriguingly, 225Ac-S1R/PSMA-P afforded a peak uptake of 34.7?±?3.2 %ID/g and elevated the radioactivity in the tumor over 7?days, with a tumor/kidney ratio of 12.2?±?1.2 and minimal deposition in blood and other normal tissues like liver and muscle. A single injection of 225Ac-S1R/PSMA-P effectively shrank large LNCaP-FGC tumors at 1.85 or 5.5?kBq, and completely eradicated highly malignant murine RM1-PSMA+/RM1 tumors at 33.3?kBq. We further showed that 225Ac-S1R/PSMA-P at a low dose of 3.7?kBq could boost immune checkpoint blockade therapy of murine RM1-PSMA+/RM1 tumor, leading to 5 out of 7 mice tumor-free that showed durable antitumor immune memory. 225Ac-S1R/PSMA-P with excellent targeting and immune activation ability has a great clinical potential for treating advanced prostate cancer patients.

Substances (4)

Materials
Procduct Name CAS Molecular Formula Supplier Price
PSMA-617 1702967-37-0 C49H71N9O16 49 suppliers Inquiry
PSMA-617 1702967-37-0 C49H71N9O16 49 suppliers Inquiry
PSMA-617 1702967-37-0 C49H71N9O16 49 suppliers Inquiry
PSMA-617 1702967-37-0 C49H71N9O16 49 suppliers Inquiry

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