HER2靶向载HSV-TK基因并具核定位效应的纳米超声造影剂构建及其在胃癌治疗中的应用基础研究

单纯疱疹病毒胸苷激酶/更昔洛韦（HSV-TK/GCV）治疗系统是目前最成熟的肿瘤自杀基因疗法，如何安全高效地将自杀基因靶向运输至肿瘤细胞内仍是函待解决的科学问题。在课题组研究基因载体的基础上，采用前期构建的胍基化SS-PAAs类聚合物（AGM-CBA）作为自杀基因的核定位载体，再利用HER2靶向纳米超声造影剂包裹作为基因的靶向载体。借助超声靶向微泡破坏技术和AGM-CBA载体的核定位效应共同提高自杀基因在胃癌细胞内的转染率，最终利用自杀基因的特性功能和旁观者效应杀灭胃癌细胞。对构建的HER2靶向载HSV-TK基因纳米超声造影剂进行理化性质等考察，并优化构建；通过体外实验和裸鼠移植瘤体内实验评价其对HER2阳性胃癌的抑瘤作用，并评估自杀基因的转染效果。本项目通过构建HER2靶向载HSV-TK基因纳米超声造影剂为HER2阳性胃癌的治疗策略提供新思路，并为其疗效及应用风险提供理论支撑与实验依据。

The herpes simplex virus thymidine kinase / ganciclovir (HSV-TK/GCV) system is one of the most promising suicide gene approach. Carrying the suicide gene into the tumor cell safely and effectively is the key. In this research, guanidination SS-PAAs (AGM-CBA) was prepared as the carrier for HSV-TK gene with effect of nucleation location; HER2 targeting nano-sized ultrasound contrast agent was prepared as the targeted carrier. After HSV-TK suicide gene was transfected into gastric cancer cells by ultrasound microbubble destruction technology (UTMD) and effect of nucleation location by AGM-CBA, the gastric cancer cells would then killed by the suicide gene with direct killing and bystander effect. The physical and chemical properties of the constructed HER2 targeted HSV-TK gene nano ultrasound contrast agent were investigated and finally optimized. Then, its anti-tumor effect on HER2 positive gastric cancer was evaluated by experiments in vitro and vivo in nude mice; and the effect of suicide gene transfection was also evaluated. Therefore, this research provide a new strategy for gastric cancer treatment by constructing HER2-targeted nano-sized ultrasound contrast agent carrying HSV-TK gene.