【作者】 谢建峰；

【导师】 张阳德；

【作者基本信息】 中南大学 ， 外科学， 2008， 博士

【摘要】 奥沙利铂是一种治疗大肠癌的新药,但其毒副作用较大,并发症较多,靶向性不强,使其对大肠癌的治疗受到限制。研究目的:以脂质体为药物载体,以大肠靶向、低毒与缓释为目标,以奥沙利铂（Oxaliplatin）为模型药物,系统研究常规脂质体、长循环脂质体、长循环热敏脂质体和长循环免疫脂质体的处方、制备工艺、性质、靶向性和药动学规律。方法:以脂质体的包封率为指标综合评价,采用正交设计对制备工艺进行优化,用反相蒸发超声法制得奥沙利铂脂质体。同法制得奥沙利铂长循环脂质体、长循环热敏脂质体、长循环免疫脂质体。采用纳米粒径仪、高效液相色谱仪等检测其形态、粒径、含量等。结果:在选定波长下高液色相色谱中各辅料、组织、血清中的物质对奥沙利铂的检测无干扰。奥沙利铂常规脂质体其最佳制备工艺为磷脂浓度为40mg·ml^-1,药脂比为1:40,超声时间为6min,磷脂与胆固醇比为4:1,其平均包封率为85.46%±2.31%。平均粒径为空白脂质体69.4nm,常规脂质体9.3nm。奥沙利铂长循环脂质体为108.1nm,12h的累积释放量不足10%。奥沙利铂长循环热敏脂质体的包封率为85.24%,粒径为118.2nm。在42℃加热30min时,药物释放率89.4%达到最高值。奥沙利铂长循环免疫脂质体的粒径为130.9nm,包封率为85.17%。奥沙利铂长循环免疫脂质体的靶向效率为57.3%,是奥沙利铂长循环热敏脂质体的1.3倍,奥沙利铂长循环脂质体的4.6倍。结论:奥沙利铂几种新型脂质体的制备条件可行易工业化,产品稳定性较好,大肠靶向性增强,肾毒性降低,达到了本课题的预期目标。更多还原

【Abstract】 Oxaliplatin is a common drug for colon cancer with limited application because of strong adverse reaction,many complications and inferior targeting.Objective:To research common,long-circulating,long circulating thermosensitive, long circulating immunoliposomes about their formulas,preparation technology,characters,targeting and pharmacokinetics regularity with liposome as a carrier,Oxaliplatin as a model drug and target of colon targeting,low toxicity and delayed release.Methods:The enbedding ratio as an index was evaluated to the optimizing preparation technology with an orthogonal design.Oxaliplatin common liposome was prepared with reverse phase evaporation.Oxaliplatin long-circulating, long circulating thermosensitive and long circulating immunoliposomes were prepared with the same method.Their shapes,sizes,concents etc.were detected with nanosizer and HPLC.Results:Materials in preparation,tissues and serum did not trouble the detection of Oxaliplatin in HPLC at 250nm.The optimal preparation technology of Oxaliplatin common liposome was 40 mg·ml^-1 phospholipids,drug: phospholipids as 1:40,taking ultrasound for 6 min,phospholipids:cholesterol as 4:1 and with mean enbedding ratio as（85.46%±2.31%）.The mean size was 69.4 nm for Blank liposome,79.3 nm for common liposome.Accumulated release during 12 hours was＜10%for Oxaliplatin long-circulating liposome with 108.1 nm size.Oxaliplatin long-circulating thermosensitive lipsome was with 85.24%embedding ratio,118.2 nm size and 89.4%drug release as a peak when heating 30 min at 42℃.Targeting efficiency of Oxaliplatin long circulating immunoliposome group with 57.3%（Te） was 1.3 times of that of Oxaliplatin long circulating thermosensetive liposome group, and 4.6 times of that of Oxaliplatin long-circulating liposome group.Its concentrations in serum,lung,kidney and heart were lower than those in free drug group.Conclusions:Oxaliplatin complex liposome was easy for industry,stabile well, could increase markedly the targeting in colon,decrease kidney toxicity and reached objective of this research.更多还原