A liver metastasis from a primary gastric cancer (LMGC) is relatively common and results in an extremely poor prognosis due to a lack of effective therapeutics. We here demonstrate in a clinically relevant mouse model that an α-particle radioimmunotherapy approach with ²¹¹At-labeled trastuzumab has efficacy against LMGCs that are positive for human epidermal growth factor receptor 2 (HER2). Methods: ²¹¹At was produced in a cyclotron via a ²⁰⁹Bi (α,2n) ²¹¹At reaction. ²¹¹At-trastuzumab was subsequently generated using a single-step labeling method. NCI-N87 cells (HER2-positive human gastric cancer cells) carrying a luciferase gene were intrasplenically transplanted into severe combined immunodeficiency mice to generate an HER2-positive LMGC model. A biodistribution study was then conducted through the intravenous injection of ²¹¹At-trastuzumab (1 MBq) into these LMGC xenograft mice. In parallel with this experimental therapy, phosphate-buffered saline, intact trastuzumab, or ²¹¹At-nonspecific human IgG (1 MBq) was injected into control groups. The therapeutic efficacy was evaluated by monitoring tumor changes by chemiluminescence imaging. Body weights, white blood cell counts, and serum markers of tissue damage were monitored at regular intervals. Microdosimetry using a CR-39 plastic detector was also performed. Results: The biodistribution analysis revealed an increased uptake of ²¹¹At-trastuzumab in the metastasized tumors that reached approximately 12% of the injected dose per gram of tissue (%ID/g) at 24 h. In contrast, its uptake to the surrounding liver was about 4 %ID/g. The LMGCs in the mouse model reduced dramatically at 1 wk after the single systemic injection of ²¹¹At-trastuzumab. No recurrences were observed in 6 of 8 mice treated with this single injection, and their survival time was significantly prolonged compared with the control groups, including the animals treated with ²¹¹At-nonspecific antibodies. No severe toxicities or abnormalities in terms of body weight, white blood cell number, liver function, or kidney parameters were observed in the ²¹¹At-trastuzumab group. Microdosimetric studies further revealed that ²¹¹At-trastuzumab had been delivered at an 11.5-fold higher dose to the LMGC lesions than to the normal liver. Conclusion: α-radioimmunotherapy with ²¹¹At-trastuzumab has considerable potential as an effective and safe therapeutic option for LMGC.

原发性胃癌（LMGC）的肝转移相对常见，由于缺乏有效的治疗方法，预后极差。我们在临床相关的小鼠模型中证明，使用²¹¹ At 标记的曲妥珠单抗的 α 粒子放射免疫治疗方法对人表皮生长因子受体 2 (HER2) 呈阳性的 LMGC 有效。方法： ²¹¹ At 在回旋加速器中通过²⁰⁹ Bi (α,2n) ²¹¹ At 反应产生。随后使用单步标记方法生成²¹¹ At-trastuzumab。将携带荧光素酶基因的 NCI-N87 细胞（HER2 阳性人胃癌细胞）脾内移植到严重联合免疫缺陷小鼠体内，形成 HER2 阳性 LMGC 模型。然后通过向这些 LMGC 异种移植小鼠静脉注射²¹¹ At-trastuzumab (1 MBq) 进行生物分布研究。与该实验疗法平行，将磷酸盐缓冲盐水、完整曲妥珠单抗或²¹¹ At 非特异性人 IgG (1 MBq) 注射到对照组中。通过化学发光成像监测肿瘤变化来评估治疗效果。定期监测体重、白细胞计数和组织损伤的血清标志物。还使用 CR-39 塑料探测器进行微剂量测定。结果：生物分布分析显示，转移肿瘤中²¹¹ At-trastuzumab 的摄取增加，24 小时时达到每克组织注射剂量 (%ID/g) 的约 12%。相反，周围肝脏对其的摄取量约为4%ID/g。 单次全身注射²¹¹ At-trastuzumab 后 1 周，小鼠模型中的 LMGC 急剧减少。接受单次注射治疗的 8 只小鼠中，有 6 只没有观察到复发，并且与对照组（包括接受²¹¹ At 非特异性抗体治疗的动物）相比，它们的生存时间显着延长。 ²¹¹ At-trastuzumab 组未观察到严重毒性或体重、白细胞数量、肝功能或肾脏参数异常。微剂量研究进一步表明， ²¹¹ At-trastuzumab 递送至 LMGC 病变的剂量是正常肝脏的 11.5 倍。结论： ²¹¹ At-曲妥珠单抗 α 放射免疫疗法作为 LMGC 有效且安全的治疗选择具有相当大的潜力。