肝靶向载奥沙利铂胶束的制备及其评价

发布时间：2018-07-31 07:10

【摘要】：为了制备带有肝靶向配体的载奥沙利铂聚合物胶束,并对其体内外特性进行研究,以实现药物的的肝靶向传递,本实验以碳二亚胺盐酸盐、N-羟基琥珀酰亚胺为催化剂,通过酰胺化反应合成了两亲性聚合物：壳聚糖-硬脂酸以及甘草次酸修饰的壳聚糖-硬脂酸；利用核磁共振氢谱对嫁接物进行结构确认；用2,4,6-三硝基苯磺酸法测定聚合物的氨基取代度。采用直接溶解法制备空白聚合物胶束,以芘为荧光探针测定聚合物胶束的临界胶束浓度；以芘为荧光探针,十二烷基氯化毗啶为荧光淬灭剂,测定聚合物胶束的疏水核数；利用动态光散射法测定聚合物胶束的粒径和表面电位；透射电镜检测聚合物胶束的形态。利用透析法制备载奥沙利铂胶束；超滤离心法测定胶束的包封率。用透析法研究胶束的体外释药特性,并研究药物在小鼠体内的组织分布。从核磁图谱可判断：已成功合成了两亲性聚合物壳聚糖-硬脂酸以及甘草次酸修饰的壳聚糖-硬脂酸；聚合物中硬脂酸和甘草次酸的取代度分别为16.2%和5.6%。制备了壳聚糖-硬脂酸和甘草次酸-壳聚糖-硬脂酸空白胶束,并制备了其载奥沙利铂胶束。壳聚糖-硬脂酸和甘草次酸-壳聚糖-硬脂酸胶束的临界胶束浓度分别为23.20μg/mL和17.94μg/mL；疏水核数分别为1.96个和2.09个；粒径为131.7nm和121.1nm；表面电位为+19.7mV和+17.2mV；胶束表面光滑圆整,粒度较均匀。壳聚糖-硬脂酸和甘草次酸-壳聚糖-硬脂酸载奥沙利铂胶束的包封率分别66.93%和71.7%；胶束中药物体外释放较慢,释放持续时间较长。奥沙利铂在小鼠体内的组织分布实验结果表明：甘草次酸修饰的载奥沙利铂胶束使奥沙利铂在小鼠肝脏的分布相对增多,实现了一定的肝靶向性。所制备的胶束具有良好的体内外特性,有希望成为一种高效的肝靶向给药载体。
[Abstract]:In order to prepare oxaliplatin loaded polymer micelles with ligands targeting liver, and to study their characteristics in vitro and in vivo, the ligands were used as catalysts for the ligands delivery in vivo and in vitro. Amphiphilic polymers, chitosan stearic acid and glycyrrhetinic acid modified chitosan stearic acid, were synthesized by amidation reaction. The amino substitution degree of the polymer was determined by the method of 2'4'4'- trinitrobenzene sulfonic acid (trinitrobenzene sulfonic acid). Blank polymer micelles were prepared by direct dissolution, and the critical micelle concentration of polymer micelles was determined by pyrene as fluorescence probe, pyrene as fluorescence probe and pyridine chloride as fluorescence quenching agent to determine the hydrophobic nuclei of polymer micelles. The particle size and surface potential of polymer micelles were measured by dynamic light scattering method and the morphology of polymer micelles by transmission electron microscope. The micelles loaded with oxaliplatin were prepared by dialysis, and the encapsulation efficiency of micelles was determined by ultrafiltration centrifugation. The in vitro drug release characteristics of micelles and their tissue distribution in mice were studied by dialysis. The NMR spectra showed that the amphiphilic polymer chitosan stearic acid and glycyrrhetinic acid modified chitosan stearic acid were successfully synthesized and the degree of substitution of stearic acid and glycyrrhetinic acid in the polymer were 16. 2% and 5. 6% respectively. Chitosan stearic acid and glycyrrhetinic acid chitosan stearic acid blank micelles were prepared and oxaliplatin micelles were prepared. The critical micelle concentrations of chitosan stearic acid and glycyrrhetinic acid-chitosan stearic acid micelles are 23.20 渭 g/mL and 17.94 渭 g / mL, respectively; the hydrophobic nuclei are 1.96 and 2.09; the particle sizes are 131.7nm and 121.1 nm; the surface potentials are 19.7mV and 17.2 MV; the micelle surface is smooth and round. The particle size is more uniform. The encapsulation efficiencies of chitosan stearic acid and glycyrrhetinic acid-chitosan stearic acid-loaded oxaliplatin micelles were 66.93% and 71.7% respectively. The results of tissue distribution of oxaliplatin in mice showed that oxaliplatin micelles modified with glycyrrhetinic acid increased the distribution of oxaliplatin in mouse liver and achieved liver targeting. The prepared micelles have good characteristics in vivo and in vitro, and are expected to be an efficient liver-targeted drug delivery carrier.
【学位授予单位】：青岛大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R943

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