聚(2-乙基-2-噁唑啉)-胆固醇碳酸甲酯修饰的多西紫杉醇pH-敏感胶束的构建与性质考察  

Construction and Characterization of Docetaxel pH-Sensitive Micelles Modified by Poly(2-ethyl-2-oxazoline)-Cholesterol Methyl Carbonate

作　　者：张天宇 王凯乾 张婧[1] 苏红[2] 徐缓 ZHANG Tian-yu;WANG Kai-qian;ZHANG Jing;SU Hong;XU Huan(Jjiangxi Universiy of Chinese Medicine,Nanchang 330004,China;College of Chemistry and Chemical Engineering,liaoning Normal University,Dalian 116029,Chi-na;Northeast Pharmaceutical Group Co.,Ltd.,Shenyang 110027,China)

机构地区：[1]江西中医药大学,南昌33004 [2]辽宁师范大学化学化工学院,辽宁大连116029 [3]东北制药集团股份有限公司,沈阳110027

出　　处：《中国药学杂志》2022年第17期1453-1459,共7页Chinese Pharmaceutical Journal

基　　金：江西中医药大学现代中药制剂教育部重点实验室开放基金项目资助(TCM-201913);辽宁省教育厅高等学校自然科学类基本科研(面上)项目资助(LJKZ0981)

摘　　要：目的利用聚(2-乙基-2-噁唑啉)-胆固醇碳酸甲酯[poly(2-ethyl-2-oxazoline)-cholesteryl methyl carbonate,PEOz-CHMC,简称PC]构建多西紫杉醇(docetaxel,DOC)纳米胶束,并对其进行性质考察。方法利用芘荧光探针法测定PC的临界胶束浓度。利用薄膜分散法制备DOC-PC胶束(DOC-PC micelles,DOC-M),对DOC-M的粒径、形态、包封率等进行表征。采用透析法考察DOC-M的药物释放,并模拟肿瘤微环境考察DOC-M的稳定性和pH敏感性。通过MTT法评价DOC-M对体外HeLa细胞的抑制作用。利用流式细胞仪定量观察胶束对HeLa细胞的摄取情况。结果PC的临界胶束质量浓度为9.26μg·mL^(-1)(4.63×10^(-6)mol·L^(-1))。DOC-M的粒径小于130 nm,外观呈类球形,分布均匀,Zeta电位为(-7.32±0.98)mV。X-射线粉末衍射(XRD)和红外光谱(IR)结果表明,DOC被成功包封于胶束中,DOC-M的包封率为(80.55±2.44)%。体外药物释放和胎牛血清稳定性结果实验表明,DOC-M的pH敏感性和稳定性良好。细胞抑制实验结果表明,在微酸条件下DOC-M的细胞抑制作用更强。细胞摄取实验分析,DOC-M具有较低的毒性,显著地促进药物的细胞摄取。结论DOC-M表现出良好的稳定性和pH敏感性,以及较低毒性和较好的载药能力,有望成为药物递送的良好载体。OBJECTIVE To construct docetaxel(DOC) nano-micelles using poly(2-ethyl-2-oxazoline)-cholesteryl methyl carbonate(PEOz-CHMC, PC).METHODS The critical micelle concentration of PC was measured by the hydrazine fluorescence probe method, and DOC-PC micelles(DOC-micelles, DOC-M) were prepared by the thin-film dispersion method. The particle size, morphology, and encapsulation efficiency of DOC-M were characterized.Drug release of DOC-M was evaluated by the dialysis method.Stability and pH-sensitivity of micelles were investigated by simulating the tumor microenvironment.In vitro inhibitory effect of DOC-M was measured by the MTT method in Hela cells. Cell uptake experiments were performed to investigate the uptake of DOC-M in Hela cells by flow cytometry.RESULTS CMC of PC was 9.26μg·mL^(-1)(4.63×10^(-6)mol·L^(-1)).The appearance of DOC-M showed a regular spherical shape, and the particle size of DOC-M was less than 130 nm and the size distribution was uniform. The Zeta potential and the encapsulation efficiency of DOC-M were(-7.32±0.98) mV and(80.55±2.44)%, respectively.The results of XRD and IR showed that DOC was successfully encapsulated into micelles. In vitro drug release and fetal bovine serum stability results indicated that both the stability and pH-sensitivity of DOC-M were excellent. The results of cytostatic assay suggested that the cell inhibitory effect of DOC-M was stronger under slightly acidic conditions. Cellular uptake analysis showed that DOC-M had low toxicity and significantly promoted the cellular uptake of drugs.CONCLUSION DOC-M exhibits good stability and pH sensitivity, as well as low toxicity and good drug loading capacity, and is expected to become a good carrier for drug delivery.

关 键 词：胶束 PH敏感 聚(2-乙基-2-噁唑啉)-胆固醇碳酸甲酯 多西紫杉醇 

分 类 号：R944[医药卫生—药剂学]