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目的制备四环素介导的聚乙二醇-聚(乳酸-羟基乙酸)载阿托伐他汀(TC-PEG-PLGA/ATO)胶束,并且考察载药胶束的理化性质及其体外靶向性。方法通过脱水反应合成具有两亲性的TC-PEG-PLGA嫁接物并对其进行结构确证,利用透析法实现对水难溶性药物阿托伐他汀的负载,采用透射电镜观察载药胶束的形态,激光粒度分析仪测定载药胶束的粒径和Zeta电位,HPLC测定胶束载药量和包封率,透析法考察载药胶束的体外释放行为。对TC-PEG-PLGA嫁接物胶束的体外细胞毒性(MTT法)和羟基磷灰石靶向能力进行评价。结果本实验成功制备了TC-PEG-PLGA/ATO载药胶束,其平均粒径为(47.2±4.7)nm,电位值为(-14.25±0.31)mV,包封率为(98.2±1.51)%,载药量为(8.71±0.23)%,体外释放研究表明,48 h时药物的累计释放率接近70%,具有明显的缓释作用。MTT结果表明,空白胶束在100~500μg·mL~(-1)内生物相容性良好。骨靶向TC-PEG-PLGA胶束(87.94%)的羟基磷灰石亲和能力相比于比PEG-PLGA胶束(18.59%)提高了4.73倍。结论本实验成功构建TC-PEG-PLGA/ATO载药胶束,其粒径小,稳定性好,可显著提高ATO在水相中的浓度,在体外具有良好的缓释效果、安全性及对羟基磷灰石的亲和力。
OBJECTIVE To prepare tetracycline-mediated PEG-PLGA / ATO micelles and investigate the physicochemical properties of the drug-loaded micelles and their in vitro targeting . Methods The amphiphilic TC-PEG-PLGA grafts were synthesized by dehydration reaction and their structures were confirmed. The loading of atorvastatin, a poorly water-soluble drug, was achieved by dialysis. The morphology of drug-loaded micelles was observed by transmission electron microscopy , Particle size and Zeta potential of drug-loaded micelles were measured by laser particle size analyzer. The drug loading and entrapment efficiency of micelles were determined by HPLC. The release behavior of drug-loaded micelles in vitro was investigated by dialysis. The in vitro cytotoxicity (MTT method) and hydroxyapatite targeting ability of TC-PEG-PLGA grafted micelles were evaluated. Results The micelles of TC-PEG-PLGA / ATO were successfully prepared in this study. The mean particle size was (47.2 ± 4.7) nm and the potential value was (-14.25 ± 0.31) mV. The encapsulation efficiency was (98.2 ± 1.51) %, And the drug loading was (8.71 ± 0.23)%. The in vitro release study showed that the cumulative release rate of drug reached nearly 70% at 48 h, which showed a significant sustained release effect. MTT results showed that the blank micelles in 100 ~ 500μg · mL -1 (-1) good biocompatibility. Hydroxyapatite affinity of bone-targeted TC-PEG-PLGA micelles (87.94%) was 4.73 fold greater than PEG-PLGA micelles (18.59%). CONCLUSIONS: The micelles of TC-PEG-PLGA / ATO were successfully constructed in this study. Their particle size is small and their stability is good. The concentration of ATO in the aqueous phase can be remarkably increased and has good sustained-release effect and safety in vitro Hydroxyapatite affinity.