目的 合成一种紫杉醇棕榈酸酯并将其制备成脂质体,并对该前药脂质体在荷瘤小鼠上的抗肿瘤效果和安全性进行评价。方法 以4-二甲氨基吡啶(DMAP)为缚酸剂、1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDC)为脱水剂,通过酯化法合成紫杉醇棕榈酸酯(PTX-PA),通过ESI-MS与1H-NMR进行结构确认。采用薄膜分散法制备紫杉醇棕榈酸酯长循环脂质体(PTX-PA-L)并对其外观进行表征;构建ICR小鼠S180腹水移植瘤模型,考察PTX-PA-L的抑瘤效果;对小鼠全血进行血常规检测,考察该制剂对小鼠的血液毒性以评价制剂的安全性。结果 成功合成了PTX-PA,制备的PTX-PA-L外观澄清半透明,有淡蓝色乳光,平均粒径为(104.82±1.23)nm。药效实验结果表明,与阳性药紫杉醇注射液相比,PTX-PA-L能够显著抑制小鼠S180移植瘤的增长,对小鼠血液的中性粒细胞和白细胞抑制作用降低,毒性减弱。结论 前药紫杉醇棕榈酸酯制备成脂质体后,能够显著提高抗肿瘤效果,降低药物毒性。
Abstract
OBJECTIVE To synthesize a prodrug of paclitaxel which is modified by palmitic acid at the 2′-hydroxyl position and prepare paclitaxel palmitate liposomes(PTX-PA-L), and then compare the pharmacodynamics and safety of PTX-PA-L in S180 tumor-bearing rats with paclitaxel injection. METHODS The derivative of paclitaxel was synthesized using 4-dimethylaminopyridine(DMAP) as acid binding agent and 1-(3-dimethylaminopropyl)-3-ethylenediamine(EDC) as dehydrating agent. PTX-PA was characterized by mass spectrometry and nuclear magnetic resonance spectroscopy(600 MHz 1H-NMR). PTX-PA-L were prepared using film dispersion-ultrasonic method. The particlesize and Zeta potential were measured using Malvern Zeta-sizer Nano S and the morphologywas characterized by TEM. The S180 sarcoma model in ICR mice was established to study the antitumor efficiency of PTX-PA-L in vivo. The hematological toxicity and body weight change of the mice were evaluated to study the safety of PTX-PA-L. RESULTS The prodrug PTX-PA was synthesized successfully. The liposomes had good morphological characteristics and light blue opalescence and the particle size was(104.82±1.23) nm. The pharmacodynamic study showed that compared with paclitaxel injection, PTX-PA-L had better antitumor efficacy on S180 tumor-bearing mice and the blood index indicated less decrease of white blood cells and neutrophils. CONCLUSION PTX-PA-L can improve the antitumor efficacy significantly and reduce the toxicity of paclitaxel injection.
关键词
紫杉醇棕榈酸酯 /
脂质体 /
药效学 /
安全性
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Key words
paclitaxel palmitate /
liposome /
pharmacodynamics /
safety evaluation
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中图分类号：
R944
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参考文献
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