紫杉醇/低分子肝素-胱胺-维生素E琥珀酸酯胶束的制备及其体外细胞毒性  

Preparation and in vitro cytotoxicity of PTX/LMWH-cys-TOS micelles

作　　者：艾丹[1] 万莉莉[2] 张琦[3] 雷铭道 AI Dan;WAN Li-li;ZHANG Qi;LEI Ming-dao(Jiangxi Maternal and Child Health Hospital,Nanchang 330004,China;College of Humanities,Jiangxi University of Chinese Medicines,Nanchang 330006,China;College of Life Science,Jiangxi University of Chinese Medicines,Nanchang 330006,China)

机构地区：[1]江西省妇幼保健院,江西南昌330004 [2]江西中医药大学人文学院,江西南昌330006 [3]江西中医药大学生命科学学院,江西南昌330006

出　　处：《现代药物与临床》2023年第12期2984-2989,共6页Drugs & Clinic

基　　金：江西省卫计委中医药课题(2019A213);中央引导地方科技发展基金项目(20222ZDH04094);江西省赣江新区重大科技攻关项目(2021007)。

摘　　要：目的优化紫杉醇/低分子肝素-胱胺-维生素E琥珀酸酯(PTX/LMWH-cys-TOS)胶束的处方,评价其制剂学特性和体外细胞活性。方法以载药率和包封率为指标,考察有机溶剂、药物载体比例对胶束载药能力的影响,优化最佳处方。利用冷冻干燥法制备了胶束冻干粉针并考察复溶稳定性,采用透析法研究了胶束在不同浓度的二硫素糖醇溶液中的释放动力学,采用CCK8法研究了胶束在紫杉醇敏感和耐药细胞上的抗肿瘤活性,利用HPLC法测定了紫杉醇在肿瘤细胞内的质量浓度。结果紫杉醇和LMWH-cys-TOS的最佳比例是1∶3.6,使用乙醇作为有机溶剂。加入冻干保护剂的胶束产品外观良好,复溶后的胶束应该在4℃保存,而且要尽快使用;在二硫苏糖醇存在的释放介质中,紫杉醇释放速度随着二硫苏糖醇浓度的增加而增加,二硫苏糖醇的浓度是20 mmol/L时,紫杉醇的36 h的累积释放量高达93%。胶束能提高紫杉醇在耐药细胞HCT-15/Taxol上的毒性和药物在肿瘤细胞内的质量浓度。结论PTX/LMWH-cys-TOS胶束改善了紫杉醇的溶解度,实现了靶向给药。Objective To optimize the preparation of paclitaxel/low molecular-weight heparin-cystamin-α-tocopherol succinate(PTX/LMWH-cys-TOS)micelles,and to evaluate its pharmaceutical property and in vitro cytotoxicity.Methods Using drug loading rate and encapsulation rate as indicators,the influence of organic solvent and drug carrier ratio on micelle drug loading capacity were investigated,and the optimal prescription was optimized.The freeze-drying method was used to prepare micelle freeze-dried powder injection and investigate their re-dissolution stability.The release characteristics of micelles in different concentrations of dithiothreitol solution were studied using dialysis method.The anti-tumor activity of micelles on paclitaxel sensitive and resistant cells was studied using CCK8 method.The concentration of paclitaxel in tumor cells was determined by HPLC method.Results The optimal ratio of paclitaxel to LMWH-cys-TOS was 1:3.6,using ethanol as the organic solvent.Micelle products with freeze-dried protectants had a good appearance,and the re-dissolved micelles should be stored at 4℃,and used as soon as possible.In the release medium of dithiothreitol,the release rate of paclitaxel increased with the increase of dithiothreitol concentration.When the concentration of dithiothreitol was 20 mmol/L,the cumulative release of paclitaxel after 36 h was as high as 93%.Micelles could enhance the toxicity of paclitaxel on drug-resistant cells HCT-15/Taxol and the concentration of the drug in tumor cells.Conclusion LMWH-cys-TOS micelles can improve the solubility of paclitaxel and achieve targeted drug delivery.

关 键 词：紫杉醇/低分子肝素-胱胺-维生素E琥珀酸酯胶束 紫杉醇 稳定性 累积释放率 抗肿瘤活性 

分 类 号：R284[医药卫生—中药学]