紫杉醇饱和脂肪酸酯脂质体的药效学及组织分布研究  

Pharmacodynamics and tissue distribution of paclitaxel saturated fatty acid ester liposomes

作　　者：韦武豪 陈新美 陈建明[1] 武鑫 WEI Wu-hao;CHEN Xin-mei;CHEN Jian-ming;WU Xin(Fujian University of Traditional Chinese Medicine,Fuzhou 350122,China;Shanghai WeiEr 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：《中国新药杂志》2023年第7期728-734,共7页Chinese Journal of New Drugs

基　　金：国家自然科学基金资助项目(81772749);福建中医药大学高层次人才科研启动资金项目(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2022-7)。

摘　　要：目的:制备3种紫杉醇(PTX)饱和长链脂肪酸酯脂质体,初步比较3种紫杉醇饱和脂肪酸酯脂质体在抗肿瘤方面的差异,通过组织分布研究,探讨造成疗效差异的原因。方法:采用薄膜分散法制备3种紫杉醇脂肪酸酯脂质体,分别测定粒径、Zeta电位、包封率以及载药量情况;构建小鼠乳腺癌模型,尾静脉分别注射紫杉醇注射液(Taxol^(Ⓡ))、紫杉醇肉豆蔻酸酯脂质体(PTX-MA-L)、紫杉醇棕榈酸酯脂质体(PTX-PA-L)和紫杉醇硬脂酸酯脂质体(PTX-SA-L),考察它们的抗肿瘤效果,同时通过血常规检测对制剂的安全性进行初步评价。最后,对3种前药脂质体进行体内组织分布实验,考察前药代谢情况。结果:成功构建了3种紫杉醇饱和脂肪酸酯脂质体,PTX-MA-L,PTX-PA-L,PTX-SA-L的粒径分别为(69.56±1.08),(72±0.86),(75±1.02)nm,聚合物分散性指数(PDI)分别为(0.185±0.009),(0.165±0.012),(0.171±0.024),Zeta电位分别为-(11.26±1.37),-(12.18±1.86),-(13.92±0.59)mV,包封率分别为(95±0.39)%,(97±0.28)%,(98±0.19)%。4T1乳腺癌移植瘤模型药效评价中,等剂量下PTX-PA-L的药效好于Taxol,PTX-MA-L和PTX-SA-L。血常规检测结果表明,紫杉醇脂肪酸酯脂质体的血细胞水平明显高于紫杉醇注射液。组织分布实验结果显示,PTX-MA-L代谢出的PTX速率最快,半衰期短,消除率快;PTX-PA-L代谢出的PTX随时间缓慢增加,半衰期在3种前药脂质体中最长,AUC最大,清除率最慢;PTX-SA-L代谢出的PTX最慢,在肿瘤中最大血药浓度最小。结论:饱和脂肪酸修饰的紫杉醇前药脂质体有较好的抗肿瘤疗效,能减轻传统紫杉醇剂型带来的不良反应。其中PTX-PA-L的抗肿瘤效果优于PTX-MA-L和PTX-SA-L,这与脂肪酸前药在体内的代谢有关。Objective:Three kinds of paclitaxel saturated fatty acid ester liposomes were prepared to preliminarily compare the difference between them in anti-tumor,and to explore the reasons for the difference of efficacy by the study of tissue distribution.Methods:Three kinds of paclitaxel fatty acid ester liposomes were prepared by thin film dispersion method,and the particle size,potential,encapsulation efficiency and drug loading were measured,respectively.A mouse model of breast cancer was established,and paclitaxel injection(Taxol^(Ⓡ)),paclitaxel myristate liposome(PTX-MA-L),paclitaxel palmitate liposome(PTX-PA-L)and paclitaxel stearate liposome(PTX-SA-L)were injected via the tail vein,respectively.The anti-tumor effects of the two preparations were investigated,and the safety of the preparations was evaluated by routine blood tests.Finally,the prodrug metabolism for three prodrug liposomes was evaluated by in vivo tissue distribution.Results:Three taxol saturated fatty acid ester liposomes were successfully constructed.The particle sizes of PTX-MA-L,PTX-PA-L and PTX-SA-L are(69.56±1.08),(72±0.86)and(75±1.02)nm;Polymer dispersity index(PDI)are(0.185±0.009),(0.165±0.012),(0.171±0.024);Zeta potentials are-(11.26±1.37),-(12.18±1.86),-(13.92±0.59)mV,respectively.Encapsulation rates are(95±0.39)%,(97±0.28)%and(98±0.19)%,respectively.In pharmacodynamic evaluation in 4T1 breast cancer transplanted tumor model,the pharmacodynamic of PTX-PA-L at equal dose was stronger than that of taxol,PTX-MA-L and PTX-SA-L.The results of routine blood test showed that the blood cell level of paclitaxel fatty acid ester liposome was significantly higher than that of paclitaxel injection.The tissue distribution results showed that PTX-MA-L was metabolized to PTX at a fast rate,short half-life and fast elimination rate.PTX metabolized from PTX-PA-L increases slowly with time.Its half-life is the longest among the three prodrug liposomes,the area under the drug-time curve is the largest,and the clearance rate is the lowest.PTX-SA

关 键 词：紫杉醇 饱和脂肪酸 前药 脂质体 药效 组织分布 代谢 

分 类 号：R965[医药卫生—药理学]