pH响应型透明质酸胶束的制备及其药物传递性能

Preparation of pH-Responsive Micelle Based on Hyaluronic Acid for Drug Delivery

制备透明质酸-脱氧胆酸两亲性缀合物(HAAD),用于制备胶束并包载模型抗肿瘤药物阿霉素(DOX),研究其理化性质以及体外抗肿瘤性能。通过酰胺反应制备硼酸功能化脱氧胆酸(AD),之后基于硼酸酯键制备具有pH响应性的HAAD并包载DOX,研究胶束的微观形貌、DOX的包封率、载药量和体外药物释放行为。通过癌细胞(MCF-7)和正常细胞(COS7)对其细胞毒性和细胞摄取进行评价,成功制备HAAD,其在水溶液中能自组装形成胶束并包载DOX,DOX载药量为9.15%。体外药物释放实验显示,其具有pH响应的释药行为,在酸性环境下药物释放速率较快。流式细胞分析结果显示,载药HAAD胶束能被CD44受体过表达的MCF-7细胞有效摄取,而对正常细胞的毒性远小于肿瘤细胞,表现出选择性抑制细胞生长的特性。

To prepare the CD44-targeted hyaluronic acid-deoxycholic acid(HAAD) amphiphile to form micelles for the encapsulation of model anticancer drug doxorubicin(DOX),and its properties and anticancer activity were characterized. The boronate derived deoxycholic acid was synthesized via amidation reaction. Afterwards,HAAD was prepared by conjugating hyaluronic acid and boronate derived deoxycholic acid via boronate ester bond. The DOX encapsulated HAAD micelles were prepared and their properties,such as encapsulation efficiency(EE),drug loading level(DL) of DOX,in vitro drug release behavior were characterized. The cytotoxicity and cellular internalization were evaluated against model tumor cells(MCF-7) and normal cells(COS7). HAAD was successfully prepared and could self assemble into micelles with DOX loaded inside. The DL value of DOX was 9.15%. Moreover,the DOX-loaded HAAD micelles could show pH-responsive drug release behavior,the drug release rate was faster at acidic milieu. The flow cytometry analysis demonstrated the DOX-loaded HAAD micelles could be internalized by CD44-overexpressed MCF-7 cells more effectively. Additionally,the cytotoxicity assay showed DOX-loaded HAAD micelles had less toxicity against normal cells than that of tumor cells,showing selectivity.