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本研究构建了能够靶向肿瘤新生血管的RGD修饰阳离子脂质体(RGD-Lipo),作为靶向耐药相关基因MDR1的siRNA输送载体并评价其相关的药剂学性质。该脂质体与siRNA形成的复合物粒径控制在200 nm以内,并且对其中所包载的siRNA具有一定的保护作用。体外实验结果表明,经RGD修饰的脂质体(RGD-Lipo)细胞粘附能力显著增强,并可增加细胞内siRNA的转染效果。与利用前插法进行靶向修饰相比,利用后插法进行RGD修饰可有效地改善siRNA的溶酶体释放效率。细胞毒试验结果表明,后插法制备的pRGD-Lipo-siRNA能够有效逆转人卵巢癌SKV03/A细胞的耐药性,并增加阿霉素药物在细胞内的蓄积。体外研究结果证实,使用pRGD-Lipo-siRNA有利于提高耐药细胞对化疗药阿霉素的敏感度,并将有可能应用于临床耐药肿瘤的治疗。
In this study, RGD-Lipo, a RGD-Lipo targeting tumor neovascularization, was constructed as siRNA delivery vector targeting MDR1 gene and its related pharmacological properties were evaluated. The size of the complex formed by the liposome and siRNA was controlled within 200 nm, and had a certain protective effect on the siRNA contained therein. The results of in vitro experiments showed that the RGD-Lipo-modified liposomes (RGD-Lipo) significantly enhanced cell adhesion and increased the transfection efficiency of intracellular siRNA. RGD modification by post-insert method can effectively improve the lysosomal release efficiency of siRNA compared with the targeted modification by using the insert method. Cytotoxicity test results showed that pRGD-Lipo-siRNA prepared by post-insert method can effectively reverse drug resistance of human ovarian cancer SKV03 / A cells and increase the intracellular accumulation of doxorubicin. In vitro study confirmed that the use of pRGD-Lipo-siRNA is conducive to improve the sensitivity of drug-resistant cells to chemotherapeutic drug doxorubicin, and may be applied to the treatment of clinically resistant tumors.