Sun Juan, Yang Jiangtao, Guo Jiakun, Tao Lei, Xu Bin, Wang Guanglin, Meng Fenghua, Zhong Zhiyuan
Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China; College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China.
J Control Release. 2025 Jun 10;382:113686. doi: 10.1016/j.jconrel.2025.113686. Epub 2025 Apr 3.
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 (Ac-S1R/PSMA-P) for targeted alpha therapy and alpha-immunotherapy of murine prostate tumor. Ac-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, Ac-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 Ac-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 Ac-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. Ac-S1R/PSMA-P with excellent targeting and immune activation ability has a great clinical potential for treating advanced prostate cancer patients.
发射能量高且发射范围短的α放射性核素已成为治疗晚期肿瘤的新工具；然而，其临床应用严格依赖于递送载体。在此，我们报道了具有高效225-锕标记（Ac-S1R/PSMA-P）的西格玛-1受体和前列腺特异性膜抗原双特异性肽，用于小鼠前列腺肿瘤的靶向α治疗和α免疫治疗。具有高比活度和放射性稳定性的Ac-S1R/PSMA-P在RM1-PSMA癌细胞中表现出增强的细胞结合和摄取，同时减少了流出。有趣的是，Ac-S1R/PSMA-P的峰值摄取为34.7±3.2%ID/g，并在7天内提高了肿瘤中的放射性，肿瘤/肾脏比值为12.2±1.2，在血液以及肝脏和肌肉等其他正常组织中的沉积极少。单次注射Ac-S1R/PSMA-P在1.85或5.5 kBq时有效缩小了大的LNCaP-FGC肿瘤，并在33.3 kBq时完全根除了高度恶性的小鼠RM1-PSMA/RM1肿瘤。我们进一步表明，低剂量3.7 kBq的Ac-S1R/PSMA-P可以增强小鼠RM1-PSMA/RM1肿瘤的免疫检查点阻断治疗，导致7只小鼠中有5只无肿瘤，显示出持久的抗肿瘤免疫记忆。具有优异靶向和免疫激活能力的Ac-S1R/PSMA-P在治疗晚期前列腺癌患者方面具有巨大的临床潜力。
