负载呋喹替尼酸敏感靶向胶束的制备及其体外抗肿瘤活性评价

Preparation and in vitro anti-tumor activity of fruquintinib-loaded acid-sensitive targeted micelle

目的:构建一种负载呋喹替尼(FRU)的高选择性酸敏感靶向胶束cRGD-FRU-ASM。方法:以环状精氨酸-甘氨酸-天冬氨酸肽(cRGD)为靶头,磷脂-聚(2-乙基-2-噁唑啉)、磷脂-聚乙二醇2000-环肽为药物载体,FRU为模型药物,通过薄膜分散法制备cRGD-FRU-ASM。测定该胶束表征及临界浓度,分析药物释放情况。以人宫颈癌Hela细胞为观察对象评估该胶束的体外抗肿瘤活性。结果:cRGD-FRU-ASM为均一、乳白色混悬液,粒径约31.89 nm,呈规整的近圆形,分散性良好,分散指数为0.231,电位为-17.4 mV。临界浓度低,为4.267 mg/L。当pH为5.0时,FRU的累积释放量最多,约为80%。体外抗肿瘤活性结果显示cRGD-FRU-ASM能够抑制Hela细胞的增殖和转移,且具有抗血管生成作用(P<0.05)。结论:cRGD-FRU-ASM靶向胶束可提高FRU的利用度,增强药物对肿瘤细胞的增殖抑制作用,同时降低药物对正常组织的毒性,达到优异的抗肿瘤效果。

Aim:To construct a highly selective fruquintinib(FRU)-loaded acid sensitive targeted micelle cRGD-FRU-ASM.Methods:Using cyclic arginine-glycine-aspartate peptide(cRGD) as the target, phospholipid poly(2-ethyl-2-oxazoline) and phospholipid-polyethylene glycol2K-cyclic peptide as the drug carrier, anti-angiogenic drug FRU as the model drug, cRGD-FRU-ASM was prepared by thin film dispersion method.Characterization, critical concentration and drug release of cRGD-FRU-ASM were analyzed.In vitro anti-tumor activity of the micelles was evaluated using human cervical cancer Hela cells.Result:cRGD-FRU-ASM was a uniform milky white suspension, its particles were nearly circular, with particle size of about 31.89 nm and potential of-17.4 mV,and it had good dispersion with PDI of 0.231.Critical concentration of cRGD-FRU-ASM was low(4.267 mg/L),indicated that it had higher stability and longer blood circulation time.When pH was 5.0,the cumulative release of FRU was the highest, about 80%.In vitro anti-tumor activity results showed that cRGD-FRU-ASM could significantly inhibit the proliferation and metastasis of Hela cells and had effective anti-angiogenesis effect(P<0.05).Conclusion:cRGD-FRU-ASM targeted micelles can improve the availability of FRU,enhance the proliferation inhibition effect of FRU on tumor cells, reduce the toxicity of drugs on normal tissues, and had excellent anti-tumor effects.