Human epidermal growth factor receptor 2 (HER2) is used as a tumor biomarker and therapeutic target. Pertuzumab is an anti-HER2 antibody, and its binding to tumor cells requires HER2 to be present at the cell membrane. However, the cellular distribution of HER2 protein in gastric tumors is dynamic, and HER2 internalization decreases antibody binding to tumor cells. These features preclude the use of pretargeted strategies for molecular imaging and therapy. We explored the pharmacological modulation of HER2 endocytosis as a strategy to improve pertuzumab uptake in HER2-positive gastric tumors and allow the use of a pretargeted imaging approach. Methods: We conducted in vitro and in vivo studies with NCI-N87 gastric cancer cells to determine how HER2 endocytosis affects pertuzumab binding to tumor cells. Lovastatin, a clinically approved cholesterol-lowering drug, was used to modulate caveolae-mediated HER2 endocytosis. Results: Administration of lovastatin to NCI-N87 cancer cells resulted in significant accumulation of non-activated HER2 dimers at the cell surface. Pretreatment of NCI-N87 cells with lovastatin increased in vitro specific accumulation of membrane-bound 89Zr-labeled pertuzumab. Lovastatin-enhanced pertuzumab tumor uptake was also observed in NCI-N87 gastric cancer xenografts, allowing tumor detection as early as 4 h and high-contrast images at 48 h after tracer administration via PET. Temporal enhancement of HER2 membrane availability by lovastatin allowed imaging of cell surface HER2 with transcyclooctene-conjugated antibodies and 18F-labeled tetrazine. Conclusion: Temporal pharmacological modulation of membrane HER2 may be clinically relevant and exploitable for pretargeted molecular imaging and therapy in gastric tumors.

中文翻译：

---

HER2膜可用性的时间调控增加了帕妥珠单抗的摄取和胃肿瘤的预靶向分子成像。

人表皮生长因子受体2（HER2）被用作肿瘤生物标志物和治疗靶标。帕妥珠单抗是抗HER2抗体，其与肿瘤细胞的结合需要HER2存在于细胞膜上。但是，HER2蛋白在胃肿瘤中的细胞分布是动态的，HER2内在化会降低抗体与肿瘤细胞的结合。这些特征排除了将预靶向策略用于分子成像和治疗的可能性。我们探讨了HER2内吞作用的药理学调节，以作为改善HER2阳性胃肿瘤中帕妥珠单抗摄取的策略，并允许使用预先靶向的影像学方法。方法：我们对NCI-N87胃癌细胞进行了体外和体内研究，以确定HER2内吞作用如何影响帕妥珠单抗与肿瘤细胞的结合。洛伐他汀，临床上认可的降胆固醇药物用于调节小窝介导的HER2内吞作用。结果：将洛伐他汀用于NCI-N87癌细胞会导致未活化的HER2二聚体在细胞表面大量积聚。用洛伐他汀预处理NCI-N87细胞可增加膜结合的89Zr标记的帕妥珠单抗的体外特异性蓄积。在NCI-N87胃癌异种移植物中还观察到了洛伐他汀增强的帕妥珠单抗肿瘤的摄取，可以在通过PET示踪剂给药后的4小时内检测出肿瘤，并在48 h时获得高对比度的图像。洛伐他汀可暂时增强HER2膜的利用率，从而可通过反式环辛烯偶联的抗体和18F标记的四嗪对细胞表面HER2进行成像。结论：