还原响应性肝靶向聚合物胶束的制备及其载药性能  

Preparation of Reduction-Responsive Liver-Targeted Polymeric Micelles and Their Drug-Loading Properties

作　　者：冯荟如 刘艳勤 董营 于香香 巩凯 FENG Huiru;LIU Yanqin;DONG Ying;YU Xiangxiang;GONG Kai(School of Life Science and Health Engineering,Jiangnan University,Wuxi 214122,Jiangsu,China)

机构地区：[1]江南大学生命科学与健康工程学院,江苏无锡214122

出　　处：《功能高分子学报》2022年第6期566-574,共9页Journal of Functional Polymers

基　　金：中央高校基本科研业务费专项资金(JUSRP21940)。

摘　　要：首先,以七(6-叠氮-6-脱氧)-β-环糊精、3-炔基丁基-β-D-半乳糖苷为原料,经Click反应合成具有肝靶向功能的半乳糖-β-环糊精(Gal_(7)-CD);其次,以胱胺二盐酸盐、十八烷酸为原料,经氨基保护、酰化反应、脱保护等步骤,得到胱胺基十八酰胺(NH_(2)-SS-SA);再次,以金刚烷甲酸活性酯、双端氨基聚乙二醇为原料,经酰化反应得到金刚烷基聚乙二醇胺(Ad-PEG_(1000)-NH_(2)),该产物与丁二酸酐反应,得到金刚烷基聚乙二醇胺丁二酸(Ad-PEG_(1000)-COOH);接下来,NH_(2)-SS-SA和Ad-PEG_(1000)-COOH反应得到金刚烷基聚乙二醇胺十八酰胺(Ad-PEG_(1000)-SS-C_(18));最后,采用透析法,Gal_(7)-CD与Ad-PEG_(1000)-SS-C_(18)经主客体自组装形成两亲性聚合物,进而形成聚合物胶束半乳糖-胱胺-十八酰胺(Gal_(7)-SS-C_(18)),并以阿霉素(DOX)为模型药物,制备了相应载药聚合物胶束Gal_(7)-SS-C_(18)-DOX。利用动态光散射仪(DLS)测得聚合物胶束和载药聚合物胶束粒径分别为(169.2±1.3)nm和(177.9±3.0)nm。利用紫外-可见分光光度计测得载药聚合物胶束的载药量为(21.2±0.7)%,包封率为(71.1±0.5)%。在模拟正常生理环境的磷酸盐缓冲液(PBS)中,载药聚合物胶束的药物释放缓慢;在模拟癌细胞还原性微环境下的PBS中,48 h内药物释放率可达到82.38%。以肝癌细胞(HepG2)和正常组织细胞(HEK-293)为细胞模型,评价聚合物胶束的细胞毒性及抗肿瘤活性。研究结果表明,聚合物胶束具有良好的生物相容性,载药聚合物胶束表现出良好的靶向性和药物可控释放性能,对肝癌细胞的抑制作用强于游离DOX,对正常细胞的毒性较低,具有良好的治疗选择性。Firstly,using hepta(6-azido-6-deoxy)-β-cyclodextrin and butyl-3-ynyl-β-d-galactoside as the raw material,galactose-β-cyclodextrin(Gal_(7)-CD)with liver-targeting function was synthesized by Click reaction.Secondly,using cystamine dihydrochloride and octadecanoic acid as the raw material,cystamine octadecyl amide(NH_(2)-SS-SA)was obtained through amino protection,acylation reaction and deprotection reaction.Next,adamantyl polyethylene glycol amine(Ad-PEG_(1000)-NH_(2))was synthesized by using the acylation reaction of adamantanecarboxylic acid and amino polyethylene glycol,and then,which reacted with succinic anhydride to obtain adamantyl polyethylene glycol succinic acid(Ad-PEG_(1000)-COOH).Then NH_(2)-SS-SA reacted with Ad-PEG_(1000)-COOH to obtain adamantyl polyethylene glycol amine octadecanamide(Ad-PEG_(1000)-SS-C_(18)).Finally,using dialysis method,Gal_(7)-CD and Ad-PEG_(1000)-SS-C_(18) self-assembled to form amphiphilic polymer through host-guest self-assembly,and then form polymer micelle(Gal_(7)-SS-C_(18)).Doxorubicin(DOX)was then used as a model drug to incorporate into Gal_(7)-SS-C_(18) micelles.The particle size of polymer micelles and drug-loaded polymer micelles were determined by dynamic light scattering(DLS)to be(169.2±1.3)nm and(177.9±3.0)nm,respectively.The drug-loading capacity of the drug-loaded polymer micelles was measured by UV-Vis spectrophotometer to be(21.2±0.7)%and the encapsulation efficiency was(71.1±0.5)%.In the in vitro release experiment,the cumulative release of drug-loaded polymer micelles was lower in the simulated normal physiological environment of PBS,while the cumulative DOX release reached 82.38%within 48 h in the simulated tumor reduction microenvironment of PBS.The cytotoxicity and antitumor activity of polymer micelles were evaluated by using liver cancer cells(HepG2)and normal tissue cells(HEK-293)as cell models.The research results show that the polymer micelles have good biocompatibility.The drug-loaded polymer micelles show good targeting and controllable relea

关 键 词：聚合物胶束 还原敏感 半乳糖 肝靶向 药物载体 

分 类 号：R94[医药卫生—药剂学]