不同疏水结构的两亲性聚合物对MDCK-MDR1细胞P-糖蛋白功能的影响  

Effects of Hydrophobic Structure of Amphiphilic Polymers on the Activity of P-glycoprotein in MDCK-MDR1 Cell

作　　者：吴琪[1] 孙明辉 赵娟[1] 李根云 黄建耿[1] 李高[1] 斯陆勤[1] 

机构地区：[1]华中科技大学同济医学院药学院,武汉430030 [2]华中科技大学同济医学院附属同济医院药学部,武汉430030

出　　处：《中国药学杂志》2018年第2期122-128,共7页Chinese Pharmaceutical Journal

基　　金：国家自然科学基金资助项目(81473170)

摘　　要：目的研究不同疏水结构的两亲性聚合物单甲醚聚己二醇-聚己内酯聚合物(m PEG-PCL)、单甲醚聚乙二醇-聚D,L-乳酸聚合物(m PEG-PDLLA)、单甲醚聚乙二醇-聚(乳酸-羟基乙酸)聚合物(m PEG-PLGA)对P-糖蛋白(P-glycoprotein,P-gp)外排功能的影响。方法采用薄膜分散法制备聚合物胶束,动态光散射仪测定胶束粒径,芘荧光探针法测定临界胶束浓度(CMC);以P-gp特异性底物罗丹明123(Rhodamine 123,R123)为荧光探针,采用摄取和外排实验评价聚合物及其形成的胶束对MDCK-MDR1细胞P-gp功能的影响。结果m PEG-PCL、m PEG-PDLLA、m PEG-PLGA的粒径分别为(55.9±0.2)、(53.7±1.1)和(61.6±0.6)nm;CMC值分别为2.08、5.42和26.4μg·m L^(-1);摄取实验结果显示,当m PEG-PCL质量浓度在250μg·m L^(-1)、m PEG-PDLLA在1~25μg·m L^(-1)、m PEG-PLGA在1~25μg·m L^(-1)时,可显著增加细胞内R123累积量,表明三者对P-gp外排功能均有抑制作用;外排实验中m PEG-PCL、m PEG-PDLLA、m PEG-PLGA分别在CMC以上、CMC附近及以下、CMC以下时会显著降低R123外排率,与摄取实验结果相对应。结论 m PEG-PCL、m PEG-PDLLA、m PEG-PLGA聚合物对P-gp外排活性均有一定的抑制作用,其作用程度与疏水段结构、聚合物浓度及存在状态有关。OBJECTIVE To determine the effects of the amphiphilic block polymers, which have the same hydrophilic block with the different hydrophobic block,on the function of P-glycoprotein（P-gp）. METHODS The three different micelles were prepared by film dispersion method. The particle sizes and distributions were measured by dynamic light scattering. Critical micelle concentrations （ CMC ） were detected by fluorescence probe technique with the pyrene. Rhodamine 123, a specific probe snbstrate of P-gp, was applied to determine the effects of polymers on the function of P-gp using uptake and efflux method. RESULTS The particle sizes of mPEG- PCL,mPEG-PDLLA,mPEG-PLGA were （55.9 ± 0.2） , （53.7 ± 1.1 ） and （61.6 ±0.6 ）nm. The CMC values were 2.08, 5.42 and 26.4 μg · mL-l. R123 accumulation in Madin-Darby canine kidney/multidrug resistance 1 （ MDCK-MDR1 ） cell detected by uptake as- say increased to a maximum in the presence of polymers at concentrations of 250 μg · mL-1 for mPEG-PCL, 1 -25 μg ·mL-l for mPEG-PDLLA and mPEG-PLGA. In efflux assay, mPEG-PCL, mPEG-PDLLA, mPEG-PLGA decreased the percentage of efflux of R123 at concentrations above the CMC,below/at the CMC or below the CMC respectively, showed the similar results with uptake assay. CONCLUSION The mPEG-PCL, mPEG-PDLLA,mPEG-PLGA polymers might have a potential to inhibit the efflux activity of P-gp, which was likely related to the structures of hydrophobic segments, concentrations and existing states of the polymers.

关 键 词：单甲醚聚乙二醇-聚己内酯聚合物 单甲醚聚乙二醇-聚D L-乳酸聚合物 单甲醚聚乙二醇-聚乳酸-羟基乙酸聚合物 P-糖蛋白 罗丹明123 MDCK-MDR1细胞 

分 类 号：R944[医药卫生—药剂学]