雷公藤甲素前药脂质体纳米递送系统的构建及抗胰腺癌活性评价  

Construction of Triptolide Prodrug Liposome Nanosystem and Evaluation of Its Anti-Pancreatic Cancer Activity

作　　者：刘梦梦 陈行 钱洁成 冯兰妮 魏如婷 陈建明[1] 武鑫 LIU Mengmeng;CHEN Hang;QIAN Jiecheng;FENG Lanni;WEI Ruting;CHEN Jianming;WU Xin(Fujian University of Traditional Chinese Medicine,Fuzhou 350122,China;Shanghai Wei Er Lab,Shanghai 201712,China)

机构地区：[1]福建中医药大学,福州350122 [2]上海维洱实验室,上海201712

出　　处：《中国药学杂志》2024年第10期911-920,共10页Chinese Pharmaceutical Journal

基　　金：国家自然科学基金项目资助(81772749);福建中医药大学高层次人才科研启动资金项目资助(X2019006-人才);上海青浦区产学研合作发展资金项目资助(青产学研2021-7)。

摘　　要：目的制备雷公藤甲素木蜡酸酯脂质体(triptolide lignoceric acid ester liposome,TPL-LA-lip),对其进行表征,并考察其对胰腺癌的治疗效果。方法首先采用薄膜水合法制备TPL-LA-lip,以单因素试验与Box-Behnken响应面法对处方工艺进行优化筛选;其次对脂质体的形态、粒径分布、Zeta电位及初步稳定性进行表征,并评价其在体外介质中的释放行为;最后采用鼠源胰腺癌细胞(Panc 02)荷瘤小鼠模型,评价TPL-LA-lip的体内抗胰腺癌活性。结果制备出的TPL-LA-lip呈类球形,粒径分布均一,初步稳定性良好。平均粒径为(105.60±0.01)nm,Zeta电位为(-34.54±0.17)mV,包封率为(98.30±0.32)%,载药量为(8.33±0.24)%。在含有30%乙醇的磷酸盐缓冲液(PBS)介质中,24 h时前药脂质体的体外累积释放度为40.35%,显示出明显的缓释作用。第15天药效学实验结束时,阴性对照、空白脂质体、雷公藤甲素(triptolide,TP)溶液、Minnelide溶液和TPL-LA-lip各组的小鼠肿瘤体积分别为(849.45±53.72)(880.45±121.45)(602.09±56.80)(265.67±23.12)(237.67±38.30)mm3,体质量变化率分别是18.12%、21.29%、-3.62%、13.06%、和19.97%。与阴性对照、TP溶液两组相比,TPL-LA-lip组肿瘤体积具有显著统计学差异(P<0.05);此外,TPL-LA-lip组小鼠体质量及器官指数与阴性对照组无明显差异,而经TP溶液治疗后的小鼠体质量及器官指数明显降低,初步显示出TPL-LA-lip良好的生物安全性。结论高脂溶性的雷公藤甲素木蜡酸酯前药,改善了TP的制剂成药性,制成的脂质体具有较高的包封率,且稳定性良好。前药技术结合脂质体载体递送TP,可以显著增强药物的抗胰腺癌作用,降低毒副作用,为TP前药纳米给药系统的开发提供新的思路与实验基础。OBJECTIVE To prepare triptolide lignoceric acid ester liposome and characterize it,investigate its therapeutic effect on pancreatic cancer.METHODS Firstly,triptolide lignoceric acid ester liposome was prepared by thin film dispersion method,the single factor test and Box-Behnken response surface method were used to optimize the formulation process.Secondly,liposome form was observed using transmission electron microscope,the particle size,the polydispersity index and Zeta potential of the liposome was observed using Malvin particle size instrument and the initial stability of the TPL-LA-lip was investigated.Finally,the anti-pancreatic activity of TPL-LA-lip in vivo was evaluated by Panc 02 tumor bearing mouse model.RESULTS Triptolide lignoceric acid ester liposome was prepared successfully,and the optimal process and prescription were determined.The liposome was prepared by thin film water method,phospholipid was selected PC-98T,the ratio of drug to phospholipid was 1∶10,cholesterol to phospholipid ratio was 1∶10,DSPE-mPEG2000 was 0.05%,and the preparation temperature was 55℃.The liposome was spherical in appearance,the encapsulation rate(EE%)was(98.30±0.32)%,the loading efficiency rate(LE%)was(8.33±0.24)%,the particle size was(105.60±0.01)nm,the Zeta potential was(-34.54±0.17)mV,and had good stability.In PBS medium containing 30%ethanol,the cumulative release of prodrug liposome was 40.35%at 24 h,and it showed good sustained-release effect.At the end of the pharmacokinetics experiment on day 15,the tumor bodies of mice in control,blank lip,TP solution,minnelide and TPL-LA-lip were(849.45±53.72)(880.45±121.45)(602.09±56.80)(265.67±23.12)(237.67±38.30)mm3,respectively.The change rates of body weight were 18.12%,21.29%,-3.62%,13.06%and 19.97%,respectively.Compared with the control and TP groups,the TPL-LA-lip group tumor volume was significantly different(P<0.05).In addition,there was no significant difference in body weight between the TPL-LA lip group and the negative control group,while the body w

关 键 词：雷公藤甲素 脂质体 Box-Behnken响应面法 胰腺癌 

分 类 号：R944[医药卫生—药剂学]