Extensive interest in the development of α-emitting radionuclides astatine-211 (²¹¹At) stems from the potential superiority for the treatment of smaller tumors, disseminated disease, and metastatic disease. VP2, a small molecule fusion peptide, can specifically bind to the VPAC1 receptor which is over-expressed in malignant epithelial tumors. In our recent study, we performed the preparation of ²¹¹At labelled VP2 through a one-step method. In this work, we explored the targeted radionuclide therapy with [²¹¹At]At-SPC-VP2 in vitro and in vivo. The cytotoxicity and specific cell killing of [²¹¹At]At-SPC-VP2 were evaluated using the CCK-8 assay. Compared with the [²¹¹At]NaAt, the VPAC1-targeted radionuclide compound [²¹¹At]At-SPC-VP2 showed more effective cytotoxicity in vitro. Targeted radioactive therapy trial was carried out in non-small-cell lung cancer (NSCLC) xenograft mice. For the therapy experiment, 4 groups of mice were injected via the tail vein with 370 kBq, 550 kBq, 740 kBq, 3 × ∼246 kBq of [²¹¹At]At-SPC-VP2, of which the second and third injections were given 4 and 8 days after the first injection, respectively. As controls, animals were treated with saline or 550 kBq [²¹¹At]NaAt. The body weight and tumor size of mice were monitored before the administration and every 2 days thereafter. Cytotoxic radiation of partial tissue samples such as kidneys, liver and stomach of mice were assessed by immunohistochemical examination. The tumor growth was inhibited and significantly improved survival was achieved in mice treated with [²¹¹At]At-SPC-VP2, two-fold prolongation of survival compared with the control group, which received normal saline or 550 kBq [²¹¹At]NaAt. No renal or hepatic toxicity was observed in the mice receiving [²¹¹At]At-SPC-VP2, but gastric pathological sections showed ²¹¹At uptake in stomach resulting in later toxicity, highlighting the importance of further enhancing the stability of labelled compounds.

中文翻译：

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stat 211标记的小分子肽：裸鼠模型中的特异性细胞体外杀伤和靶向治疗

对α发射放射性核素a 211（²¹¹ At）的开发引起了广泛的兴趣，这源于其在治疗较小的肿瘤，弥漫性疾病和转移性疾病方面的潜在优势。VP2是一种小分子融合肽，可以特异性结合在恶性上皮肿瘤中过度表达的VPAC1受体。在我们最近的研究中，我们通过一步法完成了²¹¹ At标记的VP2的制备。在这项工作中，我们探索与[靶向放射性核素治疗²¹¹在。在-SPC-VP2在体外和体内。使用CCK-8分析评估[ ²¹¹ At] At-SPC-VP2的细胞毒性和特异性细胞杀伤。与[ ²¹¹在At] NaAt处，靶向VPAC1的放射性核素化合物[ ²¹¹ At] At-SPC-VP2在体外显示出更有效的细胞毒性。在非小细胞肺癌（NSCLC）异种移植小鼠中进行了靶向放射治疗试验。为了进行治疗实验，通过尾静脉向4组小鼠注射了370 kBq，550 kBq，740 kBq，3×〜246 kBq的[ ²¹¹ At] At-SPC-VP2，分别进行了第二次和第三次注射第一次注射后分别为4天和8天。作为对照，动物用生理盐水或550 kBq [ ²¹¹在] NaAt。在给药前和给药后每两天监测小鼠的体重和肿瘤大小。通过免疫组织化学检查评估部分组织样品如小鼠的肾脏，肝脏和胃的细胞毒性辐射。在用[ ²¹¹ At] At-SPC-VP2处理的小鼠中，肿瘤的生长受到抑制，并且存活率显着提高，与接受了生理盐水或550 kBq [ ²¹¹ At] NaAt的对照组相比，存活时间延长了两倍。在接受[ ²¹¹ At] At-SPC-VP2的小鼠中未观察到肾脏或肝脏毒性，但胃病理切片显示²¹¹摄入后会导致后期毒性，这突出了进一步增强标记化合物稳定性的重要性。