靶向于胰岛素样生长因子受体的基因导入系统

A GENE DELIVERY SYSTEM TARGETING TO INSULIN-LIKE GROWTH FACTOR RECEPTOR

目的 建立一种新的以细胞表面受体为靶向的基因导入系统。方法 根据胰岛素样生长因子Ⅰ号及Ⅱ号受体(IGFIR,IGFⅡR)在人原发性肝癌中过量表达,设计并合成了针对IGFIR及IGFⅡR的14肽E5,同时合成了流感病毒血凝素功能域20肽HA20作为内吞小体释放寡肽(Endosomereleasing oligopeptide,EROP),将它们分别与多聚阳离子多肽(Polycationic polypeptide,PCP)-多聚赖氨酸(Polylysine,PL)共价连接,通过静电效应与DNA形成受体介导的靶向性非病毒型基因导入系统(E5-PCP,PCP-HA20)。结果 体内、外实验证实此基因导入系统能高效且相对靶向地将外源基因导入人肝癌细胞并表达。应用此系统将细胞周期素依赖的蛋白激酶抑制物基因p15,pl6,p21导入肝癌细胞,明显抑制肝癌细胞生长。体内将p21导入荷瘤裸鼠,显著抑制裸鼠皮下肿瘤的生长。结论 受体介导的非病毒型基因导入系统高效且具有相对靶向性,有可能成为新的肝癌基因治疗途径。

ve To construct a new gene delivery systemtargeting to the receptors on cell surface. Methods Based on thefact that insulin-like growth factor Ⅰand Ⅱ receptors (IGF IR,IGFⅡ R) were highly expressed in human primary hepatic cancer cellE5, a l4-residue peptide targeted IGF IR and IGF Ⅱ R wasdesigned and synthesized, meanwhile a 2O-residue peptied derivedfrom the N-terminal sequence of the influenza virus hemagglutinsubunit HA20 was synthesized as an endosome releasing oligopeptide(EROP). E5 and HA 20 were linkde to polycatinic polypeptide(PCP) polylysine(PL) respectivley. Results Experiments in vitroand in vivo demonstrated that this gene delivery system coule transfergene to human hepatoma cell with high efficiency and relativetargetability.The growth of transfected hepatoma cells was inhibitedby transduced CKI genes(pl5, p16, p2l) in vitro by this genedeklivery system. The growth of human hepatoma SMMC-772ltransplanted in of nude mice was remarkably inhibited after CKIgene p21 was transferred into nude mice by using this gene deliverysystem. Conclusion The present receptor-mediated non-viral genedalivery system has high efficientcy and relative targetability intransferring exogenous gene into cancer cells in which the re1evantreceptor is over-expressed.Thiss system will be a new promising genedelivery system for gene therapy of human hepatic cancer.