摘要
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(PTXPA-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。
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.
作者
程丹
余侬
许幼发
傅志勤
陈建明
CHENG Dan;YU Nong;XU You-fa;FU Zhi-qin;CHEN Jian-ming(School of Pharmacy, The Second Military Medical University, Shanghai 200433, China;School of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China;Tasly Group Co. Ltd., Tianjin 300402,China)
出处
《中国药学杂志》
CAS
CSCD
北大核心
2018年第8期614-619,共6页
Chinese Pharmaceutical Journal
关键词
紫杉醇棕榈酸酯
脂质体
药效学
安全性
paclitaxel palmitate liposome pharmacodynamics safety evaluation
