透明质酸聚合物胶束的制备及其内涵体的pH敏感性

首先以脱氧胆酸（DOCA）和三苯甲基组氨酸甲酯盐酸盐（H-His（Trt）-OMe·HCl）为反应物，经催化剂缩合制得DOCA-His（Trt）中间体。然后将透明质酸（HA）经N-羟基琥珀酰亚胺（NHS）和1-乙基-（3-二甲基氨基丙基）碳酰二亚胺盐酸盐（EDC·HCl）活化形成活性酯。最后将活性酯接枝DOCA-His（Trt）中间体，制得HA-DOCA-His（Trt）聚合物，脱Trt保护，制得HA-DOCA-His聚合物。采用FT-IR鉴定HA-DOCA-His的化学结构，并评价其溶血性和pH敏感性，通过超声法制备载紫杉醇的HA-DOCA-His胶束，并以透析法考察其体外释药行为。采用MTT法考察胶束的细胞毒性。结果表明，HA-DOCA-His溶血性与聚氧乙烯蓖麻油（Cremophor EL）相当，远远低于Tween 80；载紫杉醇的HA-DCA-His胶束在模拟内涵体环境中具有触发释药行为；相比于紫杉醇溶液，HA-DOCA-His载药胶束在模拟内涵体pH环境下表现出高效抑制MCF-7肿瘤细胞的增殖作用；HA-DOCA-His胶束可作为CD44受体和内涵体pH敏感的多靶向胶束载药系统，用于难溶性抗肿瘤药物的肿瘤靶向递药和胞内靶向释药。

Preparation and Endosome pH Sensitivity of Hyaluronic Acid Polymeric Micelles

Deoxycholic acid-1-(triphenylmethyl)-L-histidine[DOCA-His(Trt)] was synthesized by amidation of deoxycholic acid (DOCA) with 1-(triphenylmethyl)-L-histidine methyl ester monohydrochloride (H-His(Trt)-OMe·HCl). HA-DOCA-His(Trt)was synthesized by grafting the carboxyl group of hyaluronic acid(HA) with an amine group of DOCA-His(Trt) in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS). HA-DOCA-His was obtained by deprotection of Trt group from HA-DOCA-His(Trt). FT-IR was used to confirm the chemical structure of HA-DOCA-His. Results showed that the hemolysis of HA-DOCA-His micelles was significantly lower than that of Tween 80, and was comparable to that of Cremophor EL. Paclitaxel (PTX) loaded HA-DOCA-His micelles were prepared by ultrasonication method. Dynamic dialysis method was employed to study the PTX release from HA-DOCA-His micelles, which showed a pH-dependent release manner. In vitro cytotoxicity exhibited HA-DOCA-His micelles performed stronger cell proliferation inhibition efficacy than PTX solution. HA-DOCA-His polymeric micellar system with CD44 receptor targeting and endosome pH sensitivity, could provide an effective approach for targeting intracellular delivery and endosome drug release of anticancer drugs.