右旋糖酐基氧化还原响应性胶束的制备与性能

Preparation and properties of dextran based redox-responsive micelles

摘要:

通过右旋糖酐（dextran）羧甲基化反应合成羧甲基右旋糖酐（CMD），以甘草次酸（GA）为疏水基团，以胱胺（CYS）为连接臂，经酰胺化反应合成甘草次酸-胱胺（GA-SS-NH2），再经CMD和GA-SS-NH2的酰胺化反应合成了一种两亲性聚合物羧甲基右旋糖酐-胱胺-甘草次酸（CMD-SS-GA），并通过自组装制备了包封阿霉素（DOX）的氧化还原响应性载药胶束CMD-SS-GA/DOX。采用MS、FTIR、1HNMR、DLS、TEM表征了CMD、GA-SS-NH2、CMD-SS-GA、CMD-SS-GA/DOX的结构组成和形貌，采用返滴定法测定了CMD的羧甲基取代度、1HNMR法测定了CMD-SS-GA的疏水基取代度，经药物释放实验测试CMD-SS-GA/DOX的氧化还原敏感性释药性能。结果表明，CMD的羧甲基取代度为2.04；CMD-SS-GA的疏水基取代度为0.32~0.83；最佳条件制备的CMD-SS-GA/DOX为均匀球状，平均粒径为117.7 nm，多分散系数（PDI）为0.139；载药量和包封率分别为11.6%、57.1%；CMD-SS-GA/DOX在10 mmol/L的谷胱甘肽磷酸盐缓冲溶液中（pH＝6.5、7.4）24 h的DOX累积释放量达80%以上，具有氧化还原敏感性。

Abstract:

Through the carboxymethylation reaction of dextran to synthesize carboxymethyl dextran (CMD). With glycyrrhetinic acid (GA) as the hydrophobic group and cysteamine (CYS) as the linking arm, the glycyrrhetinic acid-cysteamine (GA-SS-NH2) was synthesized through amidation reaction. Then through the amidation reaction of CMD and GA-SS-NH2, a kind of amphiphilic polymer carboxymethyl dextran-cysteamine-glycyrrhetinic acid (CMD-SS-GA) was synthesized. Ultimately, the redox-responsive drug-loaded micelles encapsulating doxorubicin (DOX) were prepared via self-assembly, which is CMD-SS-GA/DOX. The structural composition and morphology of CMD, GA-SS-NH2, CMD-SS-GA, and CMD-SS-GA/DOX were characterized by using MS, FTIR, 1HNMR, DLS, and TEM. The carboxymethyl substitution degree of CMD was determined by the back titration method, and the hydrophobic group substitution degree of CMD-SS-GA was determined by the 1HNMR method. Through the drug release experiment, the redox sensitive drug release feature of CMD-SS-GA / DOX was tested. The results showed that the carboxymethyl substitution degree of CMD was 2.04 and the hydrophobic group substitution degree of CMD-SS-GA was 0.32 to 0.83. The CMD-SS-GA / DOX prepared under the optimal conditions was a uniform spherical shape, with an average particle size of 117.7 nm and a polydispersity coefficient (PDI) of 0.139. The loading capacity and encapsulation efficiency were 11.6% and 57.1% respectively. The cumulative release amount of DOX of CMD-SS-GA / DOX in 10 mmol/L glutathione phosphate buffer solution (pH = 6.5, 7.4) within 24 hours reaches more than 80%, which has redox sensitivity.