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以前药三苯基膦(TPP)-白藜芦醇(1)为模型药,采用薄膜分散法制备RGD修饰的线粒体靶向长循环脂质体(RLP-TPP-1脂质体)。首先将TPP与抗肿瘤药1共价结合得到线粒体靶向前药TPP-1,然后将其包载于脂质双分子层中,最后通过后插法在脂质体表面连接长循环的聚乙二醇(PEG)和细胞靶向肽RGD。所得RLP-TPP-1脂质体呈球形,分布均匀,平均粒径(128.1±3.4)nm,ζ电位(-20.28±1.68)mV,包封率(75.6±0.8)%。体外细胞毒性试验表明,空白脂质体对表面过表达anb3受体的MDA-MB-231细胞无明显毒性,但载药脂质体对MDA-MB-231细胞的增殖具有明显抑制作用,且呈浓度依赖性。其中,RLP-TPP-1组IC50值最低(4.95mmol/L)。细胞摄取试验表明,孵育4 h后,肿瘤细胞对RGD修饰脂质体的摄取显著高于未修饰脂质体组。采用JC-1染色法考察制品的线粒体靶向作用,结果显示RLP-TPP-1脂质体组线粒体靶向效果最佳,凋亡细胞增多。
TPD-resveratrol (1) was used as a model drug, and RGD-modified mitochondria-targeting long circulating liposomes (RLP-TPP-1 liposomes) were prepared by membrane dispersion method. Firstly, TPP was covalently combined with antitumor drug 1 to obtain mitochondria-targeting prodrug TPP-1, which was then encapsulated in a lipid bilayer. Finally, a long-circulating polyethylene glycol Diol (PEG) and cell targeting peptide RGD. The obtained liposomes of RLP-TPP-1 were spherical and evenly distributed. The average particle size was (128.1 ± 3.4) nm, the zeta potential was (-20.28 ± 1.68) mV and the entrapment efficiency was (75.6 ± 0.8)%. In vitro cytotoxicity assay showed that the blank liposomes had no obvious toxicity on MDA-MB-231 cells overexpressing anb3 receptor, but the drug-loaded liposomes had a significant inhibitory effect on the proliferation of MDA-MB-231 cells Concentration dependence. Among them, the RLP-TPP-1 group had the lowest IC50 value (4.95mmol / L). Cell uptake assay showed that uptake of RGD-modified liposomes by tumor cells was significantly higher than that of the unmodified liposomes after 4 h incubation. The mitochondria targeting effect of the product was investigated by JC-1 staining. The results showed that mitochondria targeting RLP-TPP-1 liposomes had the best targeting effect and apoptotic cells increased.