熊果酸/PF127/TPGS-多柔比星纳米胶束对HepG-2/ADR细胞增殖和凋亡的影响及其体内药动学研究  

Effects of ursolic acid/PF127/TPGS-Doxorubicin nano micelles on the proliferation and apoptosis of HepG-2/ADR cells and the in vivo pharmacokinetics study

作　　者：李嘉玮 耿雪[1] 张新宇 陈星宇 阚玉萍 侯雪 刘爽[1] 王维维 阎雪莹[1] LI Jiawei;GENG Xue;ZHANG Xinyu;CHEN Xingyu;KAN Yuping;HOU Xue;LIU Shuang;WANG Weiwei;YAN Xueying(Heilongjiang University of Chinese Medicine,Haerbin,Heilongjiang,300000 P.R.China)

机构地区：[1]黑龙江中医药大学,黑龙江哈尔滨300000

出　　处：《华西药学杂志》2023年第5期521-525,共5页West China Journal of Pharmaceutical Sciences

基　　金：黑龙江省自然科学基金项目(LH2020H096,LH2021H102)。

摘　　要：目的 研究熊果酸/PF127/TPGS-多柔比星(UPTD)纳米胶束的体外抗肿瘤作用及其在大鼠体内的药动学。方法 采用MTT法检测纳米胶束对耐药肿瘤细胞增殖的影响;采用Annexin V-FITC细胞凋亡检测试剂盒,用流式细胞仪检测纳米胶束诱导耐药肿瘤细胞凋亡的作用;采用PI单染流式细胞术检测纳米胶束对细胞周期的阻滞。经大鼠尾静脉单次注射纳米胶束,采用HPLC法测定血药浓度,用DAS 2.0软件、SPSS 17.0软件对药动学参数进行处理及统计学分析。结果 各组药物均能抑制耐药肿瘤细胞的正常生长,凋亡率呈浓度依赖性,纳米胶束组的凋亡率高于游离组药物;PI单染流式细胞术检测到纳米胶束作用于HepG-2/ADR细胞48 h后,明显阻滞G0/G1期及G2/M期;在相同给药剂量下,熊果酸+多柔比星乳剂组和纳米胶束组的药动学参数均存在显著差异,且两药在纳米胶束组中的药时曲线下面积均显著增加,纳米胶束组比注射乳组的平均滞留时间显著延长,且纳米胶束组中熊果酸和多柔比星的体内清除率比注射乳组分别减小了约2.5、1.5倍。结论 熊果酸和多柔比星联用,并制成UPTD纳米胶束后,其抗肿瘤效果明显优于游离多柔比星和熊果酸,且也强于游离多柔比星+熊果酸,具有较好促进肿瘤细胞凋亡的作用。在制成纳米胶束后可降低熊果酸与多柔比星在体内的清除率,延长药物在体内的时间。OBJECTIVE To study the in vitro anti-tumor effect of ursolic acid(UA)/PF127/TPGS-Doxorubicin(Dox)(UPTD)nano micelles,and conduct preliminary pharmacokinetic studies in rats.METHODS MTT assay was used to detect the effect of nano micelles on the proliferation of drug-resistant tumor cells.Using the Annexin V-FITC cell apoptosis detection kit,flow cytometry was used to detect the effect of nano micelles on inducing apoptosis of drug-resistant tumor cells.PI single staining flow cytometry was used to detect the cell cycle arrest of nano micelles.The nano micelles were injected into the tail vein of rats in a single dose,and the blood drug concentration was determined by HPLC.The pharmacokinetic parameters were processed and statistically analyzed using DAS 2.0 software and SPSS 17.0 software.RESULTS Each group inhibited the normal growth of drug-resistant tumor cells,and the apoptosis rate was concentration-dependent.The apoptosis rate of the nano micelle group was higher than that of the group of free drugs.PI single staining flow cytometry detected that the nano micelles significantly blocked the G0/G1 and G2/M phases after 48 hours of action on HepG-2/ADR cells.Pharmacokinetics showed that at the same dosage,there were significant differences in parameters between the UA+Dox emulsion group and the nano micelle group,and the AUC0-∞of both drugs in the nano micelle group increased significantly.In MRT0-∞,the nano micelle group was significantly longer than the injection milk group,and the in vivo clearance rate of UA in the nano micelle group decreased by about 2.5 times compared to the injection milk group.The in vivo clearance rate of Dox in the nano micelle group was also reduced by about 1.5 times compared to the injection milk group.CONCLUSION After the combination of UA and Dox and the preparation of UPTD nano micelles,its anticancer effect is significantly better than free Dox and free UA,and it alsohas a better promoting effect on tumor cell apoptosis than free Dox + UA. The nano micelles can reduce the

关 键 词：熊果酸 三萜类化合物 多柔比星 纳米胶束 HepG-2/ADR细胞 大鼠 药动学 药动学参数 肝癌 

分 类 号：R96[医药卫生—药理学]