前列腺特异性膜抗原（PSMA）靶向α疗法被认为是转移性去势抵抗性前列腺癌（mCRPC）的一种有前途的替代疗法。尽管砹-211 (211At) 是回旋加速器产生的潜在有用的α发射体，但其临床应用因体内不稳定和去砹倾向而受到限制。为了克服这些挑战，我们开发了[211At]At-NpG-PSMA，这是一种具有新戊二醇结构的新型PSMA配体，可增强体内抗脱脂的稳定性。本研究旨在评价[211At]At-NpG-PSMA在小鼠体内的稳定性、抗肿瘤作用和安全性。通过将PSMA阳性PC-3 PIP细胞皮下移植到BALB/c nu/nu中制备异种移植模型老鼠。给予[211At]At-NpG-PSMA以评估生物分布，并与盐水相比，以0.32、1.00和1.93MBq的剂量评估抗肿瘤效果。进行组织病理学检查以评估对正常器官的损害。[211At]At-NpG-PSMA 表现出较高的肿瘤摄取量（3 小时时为 42.0 ± 13.1%ID/g），而非靶组织（包括甲状腺、胃和唾液腺）的摄取量最低Grands（3小时时分别为0.28 ± 0.20%ID、0.71 ± 0.12%ID/g和0.88 ± 0.10%ID/g）。观察到剂量依赖性抗肿瘤作用，对照组的肿瘤体积增加了 796.0±437.6%，而 0.32、1.00 和 1.93 MBq 组的肿瘤体积增加了 161.0±213.4%、-76.4±19.2% 和 -59.5±41.6%。分别到第 15 天。1.00 MBq 组中出现轻度肾小管再生。[211At]At-NpG-PSMA 表现出显着的体内稳定性和抗肿瘤作用，副作用最小，表明其作为新治疗药物的潜力mCRPC 中的 PSMA 靶向 α 疗法。© 2024。作者。

Prostate-specific membrane antigen (PSMA)-targeted alpha therapy is considered a promising alternative treatment for metastatic castration-resistant prostate cancer (mCRPC). Though astatine-211 (211At) is potentially useful alpha-emitter producible by cyclotrons, its clinical application has been limited by instability and a tendency to deastatination in vivo. To overcome these challenges, we developed [211At]At-NpG-PSMA, a novel PSMA ligand with a neopentyl-glycol structure that enhances in vivo stability against deastatination. This study aimed to evaluate the stability, anti-tumour effect, and safety of [211At]At-NpG-PSMA in mice.Xenograft models were prepared by subcutaneous transplantation of PSMA-positive PC-3 PIP cells into BALB/c nu/nu mice. [211At]At-NpG-PSMA was administered to assess biodistribution, and the anti-tumour effect was evaluated at doses of 0.32, 1.00 and 1.93 MBq in comparison with saline. Histopathological examinations were performed to evaluate damage to normal organs.[211At]At-NpG-PSMA demonstrated high tumour uptake (42.0 ± 13.1%ID/g at 3 h) with minimal uptake in non-target tissues, including thyroid, stomach and salivary grands (0.28 ± 0.20%ID, 0.71 ± 0.12%ID/g and 0.88 ± 0.10%ID/g at 3 h, respectively). A dose-dependent anti-tumour effect was observed, with tumour volumes increasing by 796.0 ± 437.6% in the control versus 161.0 ± 213.4%, -76.4 ± 19.2% and - 59.5 ± 41.6% in the 0.32, 1.00 and 1.93 MBq groups, respectively, by day 15. Mild renal tubule regeneration was noted in the 1.00 MBq group.[211At]At-NpG-PSMA demonstrated significant stability in vivo and anti-tumour effects with minimal side effects, indicating its potential as a new therapeutic drug for PSMA-targeted alpha therapy in mCRPC.© 2024. The Author(s).