叶酸修饰载多柔比星靶向胶束的制备及其体外抗肿瘤作用

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目的制备载多柔比星(DOX)的叶酸修饰胆固醇-乙二醇壳聚糖(FCHGC)胶束,并研究其理化性质和体外细胞毒性。方法 在偶联剂的作用下,将叶酸与胆固醇-乙二醇壳聚糖进行反应得到叶酸修饰胆固醇-乙二醇壳聚糖聚合物,用核磁共振仪和芘荧光光度法进行表征。采用乳化-溶剂蒸发法制备载多柔比星胶束,利用动态光散射法和透射电镜测定胶束的粒径与形态,考察载药胶束在pH 7.4磷酸盐缓冲液的释药行为;应用四甲基偶氮唑盐(MTT)法和流式细胞仪对载药胶束进行体外评价。结果 叶酸修饰胆固醇-乙二醇壳聚糖聚合物的临界聚集质量浓度为0.016 3 mg·mL-1,粒径为227 nm;载多柔比星叶酸修饰胆固醇-乙二醇壳聚糖(DFCHGC)胶束的载药量为10.5%,包封率为78.5%,粒子形态呈类球形,体外释放呈两相行为,即前期的快速释放和后期的缓慢释放;多柔比星、载多柔比星的胆固醇-乙二醇壳聚糖胶束(DCHGC)和载多柔比星叶酸修饰胆固醇-乙二醇壳聚糖胶束对A549细胞在48 h中的IC50分别为1.493、0.620和0.974μg.mL-1,对HeLa细胞中的IC50分别为1.398、0.662和0.259μg.mL-1,DFCHGC胶束在A549细胞的毒性作用弱于载多柔比星叶酸修饰胆固醇-乙二醇壳聚糖胶束,但在HeLa细胞中的细胞毒性作用最强。载多柔比星叶酸修饰胆固醇-乙二醇壳聚糖胶束在HeLa细胞中的摄取量最多。结论以叶酸修饰胆固醇-乙二醇壳聚糖作为载体材料制备载多柔比星胶束,能选择性靶向叶酸受体表达阳性的HeLa细胞,提高多柔比星的抗肿瘤作用,FCHGC胶束能够作为主动靶向的潜在药物传递载体。 OBJECTIVE To prepare folate-modified cholesterol-ethylene glycol chitosan (FCHGC) micelles containing doxorubicin (DOX) and study its physicochemical properties and in vitro cytotoxicity. Methods Folic acid and cholesterol - ethylene glycol chitosan were reacted under the action of a coupling agent to obtain the folate - modified cholesterol - ethylene glycol chitosan polymer, which was characterized by means of nuclear magnetic resonance and pyrene fluorescence spectrophotometry. Preparation of doxorubicin-loaded micelles by emulsion-solvent evaporation method was used to determine the particle size and morphology of the micelles by dynamic light scattering and transmission electron microscopy. The release behavior of drug-loaded micelles in phosphate buffered saline at pH 7.4 was investigated. Tetramethylazolamide (MTT) method and flow cytometry in vitro drug-loaded micelles. Results The critical mass concentration of folate modified cholesterol-ethylene glycol chitosan polymer was 0.016 3 mg · mL-1 and the particle size was 227 nm. The concentration of folic acid-modified cholesterol-ethylene glycol chitosan (DFCHGC ) Drug-loaded micelles was 10.5%, the entrapment efficiency was 78.5%, the shape of the particles was spherical, in vitro release was two-phase behavior, that is, the early rapid release and late slow release; doxorubicin, contained more soft The IC50s of A549 cells with the cholesterol-glycol chitosan micelles (DCHGC) and the doxorubicin loaded folate-cholesterol chitosan micelles for 48 h were 1.493, 0.620 and 0.974, respectively μg.mL-1, the IC50 of HeLa cells were 1.398,0.662 and 0.259μg.mL-1, respectively, and the cytotoxicity of DFCHGC micelles in A549 cells was weaker than that of Doxorubicin-loaded folate- Sugar micelles, but the strongest cytotoxic effect in HeLa cells. Doxorubicin folic acid-modified cholesterol-glycol chitosan micelles in HeLa cells uptake. Conclusion Folic acid modified cholesterol-ethylene glycol chitosan as carrier material preparation of doxorubicin-containing micelles can selectively target folate receptor-positive HeLa cells to improve the anti-tumor effect of doxorubicin, FCHGC glue Bundles can serve as potential drug delivery vehicles for active targeting.
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