Peng Cheng-Liang, Chen Chun-Tang, Tang I-Chung
Department of Isotope Application Research, National Atomic Research Institute, Taoyuan 325207, Taiwan.
Int J Mol Sci. 2025 Jun 21;26(13):5970. doi: 10.3390/ijms26135970.
Prostate cancer is the second leading cause of cancer-related death in men, with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases representing a critical clinical challenge. Although radium-223 (Ra-223) is approved for treating mCRPC with bone metastases, its efficacy remains limited, necessitating the development of more effective therapies. This study investigates the therapeutic potential of Lu-PSMA-617, a PSMA-targeted radiopharmaceutical, in a murine model of prostate cancer bone metastases. To our knowledge, this is the first study to systematically evaluate Lu-PSMA-617 in an orthotopic bone metastatic prostate cancer model, providing a clinically relevant preclinical platform to assess both imaging and therapeutic performance. We conducted comprehensive preclinical evaluations, including synthesis, stability analysis, cell binding assays, nuclear imaging, in vivo biodistribution, pharmacokinetics, and antitumor efficacy. The synthesis of Lu-PSMA-617 demonstrated high radiochemical yield (99.2%), molar activity (25.5 GBq/μmol), and purity (>98%), indicating high product quality. Stability studies confirmed minimal release of free Lutetium-177, maintaining the compound's integrity under physiological conditions. In vitro assays showed selective binding and internalization in PSMA-positive LNCaP prostate cancer cells, with negligible uptake in PSMA-negative PC-3 cells. In vivo biodistribution studies demonstrated efficient tumor targeting, with peak uptake in LNCaP tumors (23.31 ± 0.94 %IA/g) at 4 h post-injection. The radiopharmaceutical exhibited favorable pharmacokinetics, with high tumor-to-background ratios (tumor-to-blood, 434.4; tumor-to-muscle, 857.4). Therapeutic efficacy was confirmed by significant survival extension in treated mice (30.7% for 37 MBq and 53.8% for 111 MBq), with median survival times of 34 and 40 days, respectively, compared to 26 days in the control group. Radiation dosimetry analysis indicated a favorable safety profile with a calculated effective dose of 0.127 mSv/MBq. These findings highlight the novelty and translational relevance of using Lu-PSMA-617 in a clinically relevant bone metastasis model, reinforcing its potential as a dual-purpose agent for both targeted therapy and molecular imaging in advanced prostate cancer.
前列腺癌是男性癌症相关死亡的第二大主要原因，转移性去势抵抗性前列腺癌（mCRPC）和骨转移是一项严峻的临床挑战。尽管镭-223（Ra-223）已被批准用于治疗伴有骨转移的mCRPC，但其疗效仍然有限，因此需要开发更有效的治疗方法。本研究在前列腺癌骨转移小鼠模型中研究了PSMA靶向放射性药物Lu-PSMA-617的治疗潜力。据我们所知，这是第一项在原位骨转移性前列腺癌模型中系统评估Lu-PSMA-617的研究，提供了一个临床相关的临床前平台来评估成像和治疗性能。我们进行了全面的临床前评估，包括合成、稳定性分析、细胞结合试验、核成像、体内生物分布、药代动力学和抗肿瘤疗效。Lu-PSMA-617的合成显示出高放射化学产率（99.2%）、摩尔活度（25.5 GBq/μmol）和纯度（>98%），表明产品质量高。稳定性研究证实游离镥-177的释放极少，在生理条件下保持了化合物的完整性。体外试验显示在PSMA阳性的LNCaP前列腺癌细胞中有选择性结合和内化，而在PSMA阴性的PC-3细胞中的摄取可忽略不计。体内生物分布研究表明肿瘤靶向效率高，注射后4小时LNCaP肿瘤中的摄取达到峰值（23.31±0.94 %IA/g）。该放射性药物表现出良好的药代动力学，肿瘤与本底比值高（肿瘤与血液比值为434.4；肿瘤与肌肉比值为857.4）。治疗效果通过治疗小鼠的显著生存期延长得到证实（37 MBq组为30.7%，111 MBq组为53.8%），中位生存期分别为34天和40天，而对照组为26天。辐射剂量学分析表明安全性良好，计算出的有效剂量为0.127 mSv/MBq。这些发现突出了在临床相关的骨转移模型中使用Lu-PSMA-617的新颖性和转化相关性，增强了其作为晚期前列腺癌靶向治疗和分子成像两用药物的潜力。
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