黏膜黏附性缺氧响应型壳聚糖胶束的制备与性能

Preparation and properties of mucoadhesive and hypoxia-responsive chitosan micelles

以2-硝基咪唑和6-溴己酸乙酯为原料,合成了缺氧响应型6-(2-硝基咪唑)己酸(NIHA),将其接枝改性壳聚糖合成了取代度分别为3.9%、6.3%和8.9%的两亲性壳聚糖-g-6-(2-硝基咪唑)己酰胺(CS-NID)。利用^(1)HNMR、UV和FTIR表征了CS-NID的化学结构。CS-NID在水中能自组装形成纳米胶束,并采用DLS、Zeta电位和UV对胶束进行了表征。结果表明,CS-NID胶束的平均粒径为165~190nm,粒径随NIHA取代度增加而减小。胶束具有优良的储存稳定性、黏膜黏附性、pH响应性和缺氧响应性。阿霉素(DOX)通过疏水相互作用被装载进胶束内,最大载药率(DLC)可达13.3%,最大包封率(DLE)可达44.3%。体外药物释放研究表明,CS-NID胶束具有明显的缺氧响应药物释放行为,在正常生理环境(常氧,pH 7.4)中24 h最大药物释放量仅为42%,而在缺氧的酸性(pH 5.4)条件下,2 h内药物释放量高达65%,24 h内药物释放量超过92%。

Amphiphilic chitosan-g-6-(2-nitroimidazole)hexanamide derivatives(CS-NID)with substitution degrees of 3.9%,6.3%and 8.9%were synthesized by graft of hypoxia-responsive 6-(2-nitroimidazole)hexanoic acid(NIHA),which was prepared from 2-nitroazole and 6-bromohexanoic acid ethyl ester,onto chitosan macromolecule,and then characterized by ^(1)HNMR,UV and FTIR.Next,the micelles,formed by CS-NID self-assembly in aqueous solution,were analyzed by DLS,Zeta potential and UV.The results showed that the average size of CS-NID micelles was 165~190 nm and negatively correlated to NIHA substitution degree.Meanwhile,the micelles exhibited excellent storage stability,mucoadhesion,pH responsiveness and hypoxia responsiveness.Doxorubicin(DOX)was encapsulated in micelles by hydrophobic interaction with the maximum drug loading content(DLC)and drug loading efficiency(DLE)of CS-NID micelles of 13.3%and 44.3%,respectively.In vitro drug release analysis demonstrated that DOX was delivered by CS-NID micelles with a distinctly hypoxia-responsive behavior.Under normoxic conditions,only 42%of loaded DOX was released from the CS-NID micelles within 24 h,while under hypoxic conditions,65%of loaded DOX was released in 2 h,and over 92%DOX was released within 24 h.