靶向肝细胞的非病毒基因传递系统介导的实体肿瘤治疗研究

Non-viral gene delivery materials provide hopeful application prospects on targeted tumor gene therapy; however, there are still many obstacles in this process. In this project, instead of delivering gene into tumor cells directly, hepatocytes are chosen as the target for therapeutic gene delivery because the liver is much easier than other organs for in vivo gene transfer. The hepatocytes express and secrete therapeutic protein into blood, and the protein can automatically recognize and specifically bind to tumor cells, resulting in tumor destruction by the immune system. In the project, the ligand molecule galactoses will be linked to polyrotaxane, generating the self-assembly gene delivery material capable of hepatocyte recognization. The modified polyrotaxane possesses excellent ability for hepatocyte-targeted in vivo gene delivery through the increased motion range of ligand molecule, as well as timely release of loaded plasmid DNA in cytoplasm through the fracture of sensitive bond. As soon as the therapeutic fusion proteins LFⅦ/IgG1 Fc are expressed in hepatocytes, they will be secreted into blood circulation. The LFⅦ fragment in fusion protein can bind with TF receptor specifically expressed on tumor vascular endothelial cells, and the IgG1 Fc fragment can stimulate immune system to lyses and destroy the tumor. Our therapeutic system greatly decreases the difficulty of in vivo gene transfer. Meanwhile, the whole process, including expression, secretion, targeting and function, of the therapeutic protein will be automatically preceded in living body. This strategy will offer a promising tumor-targeted gene therapy schedule with satety, innovation and validity.

非病毒载体材料介导的靶向肿瘤基因传递和治疗具有良好的应用前景，但该过程障碍多、实现难度大。本项目避开对肿瘤细胞的基因传递，将治疗基因靶向传递到相对容易转染的肝细胞中，利用肝细胞来表达治疗蛋白；蛋白在血液循环中特异性靶向识别肿瘤细胞并利用机体免疫系统清除肿瘤。以阳离子化聚轮烷为非病毒基因载体，键合半乳糖为肝靶向配体，通过增加配体的活动范围来提高配体-受体结合效率、实现对肝细胞的高效靶向基因传递，并利用胞内环境敏感键来及时释放所携带质粒DNA；构建的质粒携带促DNA入核元件，所表达的分泌型融合蛋白LFⅦ/IgG1 Fc在进入血液循环后，LFⅦ与肿瘤血管内皮细胞上的TF受体特异性结合、IgG1 Fc引发免疫系统裂解、清除靶细胞，达到治疗肿瘤的目的。该体系极大地降低了体内基因传递的难度，其治疗性融合蛋白的合成、分泌和功能发挥等环节都在体内自动进行，有望成为一种安全、新颖、高效的肿瘤靶向基因治疗方案

非病毒载体材料介导的靶向肿瘤基因传递和治疗具有良好的应用前景，但该过程障碍多、实现难度大。本项目避开对肿瘤细胞的基因传递，将治疗基因靶向传递到相对容易转染的肝细胞中，利用肝细胞来表达治疗蛋白，该蛋白在血液循环中特异性靶向识别进而引发机体杀伤肿瘤细胞。本项目用于基因传递的自组装聚轮烷材料以半乳糖分子为配体，通过增加配体的活动范围、提高配体-受体结合效率来实现对肝细胞的高效靶向基因传递，并利用胞内环境敏感键来及时释放所携带质粒DNA；构建的质粒携带促DNA入核元件，所表达的分泌型融合蛋白LFⅦ/IgG1 Fc在进入血液循环后，LFⅦ与肿瘤血管内皮细胞上的TF受体特异性结合、IgG1 Fc引发免疫系统裂解、清除靶细胞，达到治疗肿瘤的目的。该体系极大地降低了体内基因传递的难度，且治疗性融合蛋白的表达、分泌、自动靶向和发挥作用等环节都在体内自动进行，有望成为一种简便、新颖、高效的肿瘤靶向基因治疗方案。

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