多柔比星-维生素E琥珀酸酯聚合物胶束的制备及体外抗肿瘤活性评价  

Preparation and in Vitro Anticancer Activity of DOX-VES-Loaded Copolymer Micelles

作　　者：朱梦琴 邱立朋[1] 李志超[1] 李凡[1] 蔺默含 陈敬华[1] 

机构地区：[1]江南大学药学院,江苏无锡214122

出　　处：《中国药学杂志》2016年第23期2030-2036,共7页Chinese Pharmaceutical Journal

基　　金：国家青年科学基金资助项目(81503007)

摘　　要：目的合成多柔比星-维生素E琥珀酸酯前药(DOX-VES),并利用透明质酸-十八胺聚合物(HA-C_(18))对其进行包载,以增强其体外抗肿瘤功效。方法通过酰胺反应合成DOX-VES,采用超声法制备得到载DOX-VES的HA-C_(18)胶束(DOX-VES/HA-C_(18))。通过透射电镜观察其形态,粒径仪测定其粒径和Zeta电位,用动态光散射法测定载药胶束在pH7.4PBS溶液及在10%的胎牛血清(FBS)中的稳定性。采用超速离心法测定载药量和包封率,透析法测定其体外释放。荧光显微镜观察MCF-7细胞对载药胶束摄取情况及胞内分布,流式细胞仪测定载药胶束摄取的摄取量,噻唑蓝比色法(MTT)测定其对肿瘤细胞的毒性。结果 DOX-VES/HA-C_(18)胶束为规整的球形纳米粒子,平均粒径为(184.6±9.42)nm,多分散系数为(0.222±0.012)nm,Zeta电位为(-20.7±1.23)m V,表现出良好的粒径稳定性。载药量和包封率分别为(15.8±2.85)%和(94.2±1.32)%,且具有较好的缓释效果。DOX-VES/HA-C_(18)胶束可被MCF-7细胞较好的摄取,且可摄取入核,且其毒性显著性大于游离DOX和DOX/HA-C_(18)胶束。结论 DOX-VES具有较强的抗肿瘤活性,以及良好的应用前景。OBJECTIVE To enhance the anticancer activity of doxorubicin（DOX） by conjugating DOX and vitamin E succinate （VES） and loading the conjugate into hyaluronic acid-octadecylamine （ HA-CIs ） copolymer micelles. METHODS DOX and VES were conjugated by amide reaction. DOX-VES/HA-ClsmicelIes were prepared via a probe-type uhrasonication technique. The morpholo- gy of the micelles was determined using a transmission electron microscopy （ TEM）. Dynamic light scattering （DLS） technique was used to determine the particle size distribution, hydrodynamic diameters, and stability of the nficelles. Ultracentrifugation was exploited for measuring the drug loading （DL） and encapsulation efficiency （ EE）, and the in vitro release was investigated using a dialysis tub- ing. The cellular uptake and cellular distribution of drug-loaded micelles in MCF-7 cells were observed by fluorescence microscope, and the fluorescence intensity of DOX was evaluated by flow cytometer. The eytotoxieity of free DOX and drug-loaded micelles was tested by MTT assay against MCF-7 cells. RESULTS DOX-VES/HA-CIa showed a nearly spherical morphology and good stability in PBS （pH 7.4） and 10% FBS. The particle size and zeta potential were （184. 6±9.42） nm and （ -20. 7 ± 1.23） mY, respectively. The DL and EE were （15.8 ±2. 85）% and （ 94. 2 ± 1.32 ）% , respectively. DOX-VES/HA-C18 had a good controlled dnlg release property. Furthermore, DOX-VES/HA-Cjawith aeemnulation in nueleipresented higher anti-tumor activity than free DOX and DOX/HA- C18. CONCLUSION DOX-VES conjugate has synergistic anti-tumor effect and good application prospects.

关 键 词：多柔比星 维生素E琥珀酸酯 聚合物胶束 抗肿瘤活性 

分 类 号：R944[医药卫生—药剂学]