【摘要】：為了制備帶有肝靶向配體的載奧沙利鉑聚合物膠束,并對(duì)其體內(nèi)外特性進(jìn)行研究,以實(shí)現(xiàn)藥物的的肝靶向傳遞,本實(shí)驗(yàn)以碳二亞胺鹽酸鹽、N-羥基琥珀酰亞胺為催化劑,通過(guò)酰胺化反應(yīng)合成了兩親性聚合物：殼聚糖-硬脂酸以及甘草次酸修飾的殼聚糖-硬脂酸；利用核磁共振氫譜對(duì)嫁接物進(jìn)行結(jié)構(gòu)確認(rèn)；用2,4,6-三硝基苯磺酸法測(cè)定聚合物的氨基取代度。采用直接溶解法制備空白聚合物膠束,以芘為熒光探針測(cè)定聚合物膠束的臨界膠束濃度；以芘為熒光探針,十二烷基氯化毗啶為熒光淬滅劑,測(cè)定聚合物膠束的疏水核數(shù)；利用動(dòng)態(tài)光散射法測(cè)定聚合物膠束的粒徑和表面電位；透射電鏡檢測(cè)聚合物膠束的形態(tài)。利用透析法制備載奧沙利鉑膠束；超濾離心法測(cè)定膠束的包封率。用透析法研究膠束的體外釋藥特性,并研究藥物在小鼠體內(nèi)的組織分布。從核磁圖譜可判斷：已成功合成了兩親性聚合物殼聚糖-硬脂酸以及甘草次酸修飾的殼聚糖-硬脂酸；聚合物中硬脂酸和甘草次酸的取代度分別為16.2%和5.6%。制備了殼聚糖-硬脂酸和甘草次酸-殼聚糖-硬脂酸空白膠束,并制備了其載奧沙利鉑膠束。殼聚糖-硬脂酸和甘草次酸-殼聚糖-硬脂酸膠束的臨界膠束濃度分別為23.20μg/mL和17.94μg/mL；疏水核數(shù)分別為1.96個(gè)和2.09個(gè)；粒徑為131.7nm和121.1nm；表面電位為+19.7mV和+17.2mV；膠束表面光滑圓整,粒度較均勻。殼聚糖-硬脂酸和甘草次酸-殼聚糖-硬脂酸載奧沙利鉑膠束的包封率分別66.93%和71.7%；膠束中藥物體外釋放較慢,釋放持續(xù)時(shí)間較長(zhǎng)。奧沙利鉑在小鼠體內(nèi)的組織分布實(shí)驗(yàn)結(jié)果表明：甘草次酸修飾的載奧沙利鉑膠束使奧沙利鉑在小鼠肝臟的分布相對(duì)增多,實(shí)現(xiàn)了一定的肝靶向性。所制備的膠束具有良好的體內(nèi)外特性,有希望成為一種高效的肝靶向給藥載體。
[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.
【學(xué)位授予單位】：青島大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R943

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