Heparosan多糖聚合物胶束的制备及体外抗肿瘤活性  

Preparation and properties of heparosan polysaccharide-vitamin E succinate polymer micelles

作　　者：葛璐 邱立朋 单晓甜 毛静 李志超 陈敬华 GE Lu, QIU Li-peng, SHAN Xiao-tian, MAO Jing, LI Zhi-chao, CHEN Jing-hua(School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, China)

机构地区：[1]江南大学药学院,江苏无锡214122

出　　处：《药学学报》2018年第4期621-629,共9页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(81503007)

摘　　要：聚合物胶束作为新型药物传递系统可以提高疏水性药物的溶解性并具有良好的生物相容性和稳定性。本研究通过合成heparosan多糖-维生素E琥珀酸酯(heparosan-adipic dihydrazide-vitamin E succinate,KV)载体,利用核磁共振氢谱(1~H NMR)对其进行结构确证。以疏水性抗肿瘤药多柔比星(doxorubicin,DOX)为模型药物,制备载DOX的KV聚合物胶束(DOX/KV),并对其进行表征。结果表明,胶束形貌为球形,粒径为140～150 nm,zeta电位为-20 m V左右,包封率为80%左右,载药量在10%～15%之间,并且具有良好的缓释行为。选择MGC80-3肿瘤细胞和COS7正常细胞考察体外细胞毒性和细胞摄取情况。体外细胞毒性结果显示,空白胶束对两种细胞几乎没有毒性,载药胶束对MGC80-3细胞的细胞毒性要大于COS7细胞。从细胞摄取考察也可以看出,载药胶束对MGC80-3细胞的摄取量更高。综上,KV可以很好地包载DOX,并且可以提高其对癌细胞的选择性,具有良好的抗肿瘤活性。Due to the advantages of polymer micelles and the anticancer activity of doxorubicin （DOX）, the polymer micelle of DOX is expected to be used for drug delivery in anticancer applications. As a biocompatible and biodegradable polymer, amphiphilic copolymer heparosan-adipic dihydrazide-vitamin E succinate （KV） can be self-assembled to form micelles with core-shell structure in aqueous phase. In this article, KV conjugates with two different degrees of substitution （DS） were synthesized to load DOX and were characterized by 1H NMR. The size distribution, morphology, zeta potential and release behavior in vitro of the DOX-loaded micelles were studied. In vitro cytotoxicity was investigated by MTT assay against MGC80-3 and COS7 cells. The cellular uptake of the DOX-loaded micelles was observed by fluorescence microscopy and flow cytometry. The 1H NMR spectra results confirmed the KV polymers were successfully conjugated and the degree of VES grafted on heparosan polysaccharide were 12% and 25%. Briefly, the micelles with two different DS were expressed as KV12 and KV25. The DOX-loaded micelles could resist serum adsorption because of the negative charge on the surface. The average particle size measured by dynamic light scattering （DLS） method was 140-150 nm and the TEM results indicated that the morphology of DOX-loaded micelles were spherical. The encapsulation efficiency and drug loading were 80% and 10%-15%, respectively. The DOX-loaded micelles had sustained release behavior and the cumulative release of DOX/KV12 was slightly higher than DOX/KV25. Moreover, the viabilities of cells which were co-incubated with blank micelles were greater than 90%. It is clear that the blank micelles almost non-toxic to both cells. The IC50 of drug-loaded micelles against COS7 cells was much higher than that of MGC80-3 cells and the DOX/KV12 exhibited greater cytotoxicity. The cellular uptake of DOX/KV on MGC80-3 was greater than COS7 cells. In this study, KV polymer micelles have a sustained drug release activity

关 键 词：Heparosan多糖 维生素E琥珀酸酯 聚合物胶束 多柔比星 

分 类 号：R943[医药卫生—药剂学]