Her-2环肽修饰的多糖聚合物胶束的制备及体外评价

Preparation and in vitro evaluation of her-2 cyclic peptide modified polysaccharide-based polymeric micelles

目的合成Her-2环肽修饰的Heparosan多糖聚合物,制备阿霉素(doxorubicin,DOX)靶向聚合物胶束,并对其体外理化性质和靶向性进行评价。方法通过酰胺反应将Her-2环肽连接到Heparosan多糖-胱氨-维生素E琥珀酸酯(heparosan-cystamine-vitamin E succinate,KSV)聚合物上,合成两亲性靶向聚合物(Her-2 peptide-heparosan-cystamine-vitamin E succinate,PKSV),并包载阿霉素制备还原敏感型主动靶向的给药系统(DOX/PKSV),考察胶束粒径、包封率、体外释放等制剂学性质,同时,选择Her-2受体低表达的MCF-7细胞和Her-2受体高表达的SK-BR-3细胞进行体外肿瘤靶向性进行评价。结果经Her-2环肽修饰的DOX/PKSV靶向聚合物胶束的为粒径约200 nm的均匀的球形粒子,zeta电位为(-23.84±1.43)mV,载药量为(11.22±1.04)%,具有良好的血清稳定性和还原敏感释药特性。体外细胞实验表明,相比于DOX/KSV胶束,DOX/PKSV胶束对SK-BR-3细胞表现出更强的细胞毒性和细胞摄取。结论DOX/PKSV胶束能够提高肿瘤靶向性,为Heparosan多糖的主动靶向递送系统的设计提供借鉴。

Objective To synthesize her-2 cyclic peptide modified heparosan polysaccharide polymers,prepare doxorubicin(DOX) loaded targeted polymeric micelles,and investigate the physicochemical properties and in vitro tumor targeting of the micelles.Methods Her-2 cyclic peptide was linked to heparosan-cystamine-vitamin E succinate(KSV) polymer through an amide reaction to synthesize an amphiphilic targeting Her-2 peptide-heparosan-cystamine-vitamin E succinate(PKSV) polymer,and doxorubicin was encapsulated to prepare a reduction-sensitive targeted drug delivery system(DOX/PKSV).The particle size,encapsulation efficiency and in vitro release of the micelles were investigated.Moreover,MCF-7 cells and SK-BR-3 cells were chosen to evaluate the in vitro tumor targeting.Results DOX/PKSV micelles had uniform spherical structure with mean particle size of about 200 nm,zeta potential of(-23.84±1.43) mV and drug loading of(11.22±1.04)%.The micelles showed good serum stability and reduction-sensitive drug release characteristic.In vitro cell experiments showed that the cytotoxicity and uptake of DOX/PKSV micelles in SK-BR-3 cells was higher than that of DOX/KSV micelles and MCF-7 cells.Conclusion DOX/PKSV micelles can improve tumor targeting ability and provide a new idea for the design of heparosan polysaccharides-based active targeted delivery system.