双胍基修饰聚酰胺-胺/阿霉素递药系统的构建及体外评价  

Construction and in vitro evaluation of biguanidine modified PAMAM/DOX delivery system

作　　者：丁伯美 严秀云 胡青[1] 程丽芳[1] 陈大为[1,2] DING Bo-mei;YAN Xiu-yun;HU Qing;CHENG Li-fang;CHEN Da-wei(School of Pharmacy,Soochow University,Suzhou 215123,China;School of Pharmacy,Shenyang Pharmacentical University,Shenyang 110016,China)

机构地区：[1]苏州大学药学院,苏州215123 [2]沈阳药科大学,沈阳110016

出　　处：《中国新药杂志》2018年第20期2426-2431,共6页Chinese Journal of New Drugs

基　　金：江苏省自然科学基金资助项目(BK20151224);苏州科技发展基金资助项目(SYS201713);国家自然科学基金资助项目(81302719)

摘　　要：目的:构建双胍基(biguanidine,BIG)和聚乙二醇修饰的pH/还原敏感聚酰胺-胺(PAMAM)聚合物(PSSPG),并考察其对阿霉素(DOX)细胞内递送的影响。方法:合成3种不同双胍基比例修饰的双胍基化聚酰胺-胺聚合物,物理包载抗肿瘤药物阿霉素制得3种载药复合物(PG25/DOX,PG50/DOX,PG100/DOX),考察双胍基化修饰程度对双胍基修饰聚酰胺-胺/阿霉素复合物细胞摄取的影响。随后制备PEG化聚酰胺-胺/阿霉素复合物和双胍基修饰PEG化聚酰胺-胺/阿霉素复合物,并对其粒径电位、载药量、包封率、细胞摄取、体外释放以及细胞毒性等进行考察。结果:3种双胍基修饰聚酰胺-胺/阿霉素复合物的粒径均在40~50 nm,具有较高的包封率和载药量;随双胍基修饰程度的增加,复合物摄取略有增加;体外释放结果表明二硫键修饰复合物具有明显pH/还原敏感性;与PEG化聚酰胺-胺/阿霉素复合物相比,双胍基修饰PEG化聚酰胺-胺/阿霉素复合物组体外细胞实验摄取增加,细胞毒性亦随之增加。结论:双胍基和PEG修饰的pH/还原敏感聚酰胺-胺载体可用于细胞对于阿霉素的高效转运。Objective： Construction and evaluation of biguanidine（ BIG） and polyethylene glycol（ PEG）modified p H/redox-sensitive polyamidoamine（ PAMAM） nanocarrier（ PSSPG） for intracellular delivery of doxorubicin（ DOX） against MCF-7 cells. Methods： Three different kinds of BIG modified PAMAM（ PAMAM-BIG,PG） were synthesized by controlling the ratio of biguanidine and PAMAM. Then DOX was physically loaded into PG to obtain the DOX-loaded complexes（ PG25/DOX,PG50/DOX,PG100/DOX）. The effect of biguanidine modification on DOX uptake was evaluated by flow cytometry. Both PSSP/DOX and PSSPG/DOX complexes were prepared and the particle size,Zeta potential,drug loading,encapsulation efficiency,cell uptake,in vitro release profiles and cytotoxicity were evaluated. Results： The particle sizes of all the PG/DOX complexes were about 40 ~ 50 nm,and have good drug loading and entrapment efficiency. The cell uptake efficiency was enhanced slightly as the degree of BIG modification increased. Results from in vitro release showed that PSSPG/DOX complex with disulfide bond modified has obvious pH/redox sensitivity. Compared to PSSP/DOX complex,biguanidine modified PSSPG/DOX complex has higher cell uptake in vitro and cytotoxicity. Conclusion： The biguanidine modified pH/redox-sensitive PSSPG carrier could be used for intracellular delivery of DOX.

关 键 词：双胍基 PH敏感 还原敏感 聚酰胺-胺 阿霉素 体外评价 

分 类 号：R915[医药卫生—微生物与生化药学]