甘草次酸修饰酶敏感多柔比星脂质体的处方筛选及体外靶向肝癌干细胞作用的评价  

Formulation Optimization of Glycyrrhetinic Acid Modified Enzyme Sensitive Doxorubicin Liposomes and Evaluation of Targeting Liver Cancer Stem Cells in vitro

作　　者：孔亮[1] 郭睿博 张璐 李学涛[1] 贾连群[2] KONG Liang;GUO Ruibo;ZHANG Lu;LI Xuetao;JIA Lianqun(School of Pharmacy,Liaoning University of Traditional Chinese Medicine,Dalian 116600;Key Lab.of Education Ministry on Chinese Medicine Viscera Image Theory and Application,Liaoning University of Traditional Chinese Medicine,Shenyang 110847)

机构地区：[1]辽宁中医药大学药学院,辽宁大连116600 [2]辽宁中医药大学中医脏象理论及应用教育部重点实验室,辽宁沈阳110847

出　　处：《中国医药工业杂志》2023年第10期1459-1466,共8页Chinese Journal of Pharmaceuticals

基　　金：国家自然科学基金项目(82204629);中国博士后科学基金项目(2022MD713762);辽宁省自然科学基金博士科研启动基金项目(2022-BS-197)。

摘　　要：该研究利用薄膜分散-硫酸铵梯度法制备甘草次酸(GA)修饰的酶敏感多柔比星(1)脂质体(GA-1-PVGLIG-Lip),以1包封率为评价指标,以磷脂与胆固醇(EPC/Chol)质量比、磷脂与1(EPC/1)质量比及水化时间为自变量,通过BoxBehnken设计-响应面法优化处方和工艺。并考察了该脂质体对基质金属蛋白酶2(MMP-2)的响应能力和对肝癌干细胞(LCSCs)的体外靶向作用。结果显示,优化处方和工艺参数为:EPC/Chol质量比为6.88,EPC/1质量比为27.74,水化时间为35.12 min。所得优化脂质体的1平均包封率为(92.58±0.92)%。GA-1-PVGLIG-Lip具有较好的MMP-2响应能力,且在MMP-2存在时靶向LCSCs的能力显著增强。该研究成功制备了MMP-2响应性逐级靶向LCSCs的脂质体,为肝细胞癌的治疗提供了新策略。Glycyrrhetinic acid(GA)modified enzyme sensitive doxorubicin(1)liposomes(GA-1-PVGLIGLip)were prepared by thin film dispersion-ammonium sulfate gradient method.The Box-Behnken design-response surface methodology was used to optimize the formulation and process parameters,with the encapsulation rate of 1 as an index,and the mass ratio of phospholipid-to-cholesterol(EPC-to-Chol),the mass ratio of EPC-to-1 and the hydration time as independent variables.Then,the response ability of the liposomes to matrix metalloproteinase 2(MMP-2)and the targeting effect in vitro on liver cancer stem cells(LCSCs)were investigated.The results showed that the optimized formulation and process parameters were as follows:EPC-to-Chol mass ratio of 6.88,EPC-to-1 mass ratio of 27.74,and hydration time of 35.12 min.The average encapsulation rate of the obtained optimal liposomes reached(92.58±0.92)%.In conclusion,the GA-1-PVGLIG-Lip had a good MMP-2 response and showed a significant targeting ability to LCSCs in the presence of MMP-2.In this study,MMP-2-responsive liposomes targeting to LCSCs were successfully prepared,which provided a new strategy for hepatocellular carcinoma treatment.

关 键 词：多柔比星 肝细胞癌 脂质体 甘草次酸 基质金属蛋白酶2 Box-Behnken设计 响应面法 靶向 肝癌干细胞 

分 类 号：R979.1[医药卫生—药品]