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Inhibition Mechanism of P-glycoprotein Mediated Efflux by mPEG-PLA and Influence of PLA Chain Length on P-glycoprotein Inhibition Activity
Li, Wenjing1; Li, Xinru1; Gao, Yajie1; Zhou, Yanxia1; Ma, Shujin1; Zhao, Yong1; Li, Jinwen1; Liu, Yan1; Wang, Xinglin2; Yin, Dongdong2
关键词Mpeg-pla Block Copolymer P-glycoprotein Efflux Inhibition Mechanism Caco-2 Cells
刊名MOLECULAR PHARMACEUTICS
2014
DOI10.1021/mp4004223
11期:1页:71-80
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Medicine, Research & Experimental ; Pharmacology & Pharmacy
研究领域[WOS]Research & Experimental Medicine ; Pharmacology & Pharmacy
关键词[WOS]CACO-2 CELL MONOLAYERS ; PLURONIC BLOCK-COPOLYMERS ; VITAMIN-E TPGS ; BREAST-CANCER CELLS ; ATPASE ACTIVITY ; IN-VITRO ; MEMBRANE FLUIDIZATION ; FLUORESCENCE POLARIZATION ; TRANSPORT MECHANISM ; DIBLOCK COPOLYMERS
英文摘要

The present study aimed to investigate the effect of monomethoxy poly(ethylene glycol)-block-poly(D,L-lactic acid) (mPEG-PLA) on the activity of P-glycoprotein (P-gp) in Caco-2 cells and further unravel the relationship between PLA chain length in mPEG-PLA and influence on P-gp efflux and the action mechanism. The transport results of rhodamine 123 (R123) across Caco-2 cell monolayers suggested that mPEG-PLA unimers were responsible for its P-gp inhibitory effect. Furthermore, transport studies of R123 revealed that the inhibitory potential of P-gp efflux by mPEG-PLA analogues was strongly correlated with their structural features and showed that the hydrophilic mPEG-PLA copolymers with an intermediate PLA chain length and 10.20 of hydrophilic-lipophilic balance were more effective at inhibiting P-gp efflux in Caco-2 cells. The fluorescence polarization measurement results ruled out the plasma membrane fluidization as a contributor for inhibition of P-gp by mPEG-PLA. Concurrently, mPEG-PLA inhibited neither basal P-gp ATPase (ATP is adenosine triphosphate) activity nor substrate stimulated P-gp ATPase activity, suggesting that mPEG-PLA seemed not to be a substrate of P-gp and a competitive inhibitor. No evident alteration in P-gp surface level was detected by flow cytometry upon exposure of the cells to mPEG-PLA. The depletion of intracellular ATP, which was likely to be a result of partial inhibition of cellular metabolism, was directly correlated with inhibitory potential for P-gp mediated efflux by mPEG-PLA analogues. Hence, intracellular ATP-depletion appeared to be possible explanation to the inhibition mechanism of P-gp by mPEG-PLA. Taken together, the establishment of a relationship between PLA chain length and impact on P-gp efflux activity and interpretation of action mechanism of mPEG-PLA on P-gp are of fundamental importance and will facilitate future development of mPEG-PLA in the drug delivery area.

语种英语
WOS记录号WOS:000329529700007
引用统计
被引频次:8[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/56812
专题北京大学药学院_药剂学系
作者单位1.Peking Univ, Sch Pharmaceut Sci, Dept Pharmaceut, Beijing 100191, Peoples R China
2.Tianjin Inst Pharmaceut Res, State Key Lab Drug Delivery Technol & Pharmacokin, Tianjin 300193, Peoples R China
推荐引用方式
GB/T 7714
Li, Wenjing,Li, Xinru,Gao, Yajie,et al. Inhibition Mechanism of P-glycoprotein Mediated Efflux by mPEG-PLA and Influence of PLA Chain Length on P-glycoprotein Inhibition Activity[J]. MOLECULAR PHARMACEUTICS,2014,11(1):71-80.
APA Li, Wenjing.,Li, Xinru.,Gao, Yajie.,Zhou, Yanxia.,Ma, Shujin.,...&Yin, Dongdong.(2014).Inhibition Mechanism of P-glycoprotein Mediated Efflux by mPEG-PLA and Influence of PLA Chain Length on P-glycoprotein Inhibition Activity.MOLECULAR PHARMACEUTICS,11(1),71-80.
MLA Li, Wenjing,et al."Inhibition Mechanism of P-glycoprotein Mediated Efflux by mPEG-PLA and Influence of PLA Chain Length on P-glycoprotein Inhibition Activity".MOLECULAR PHARMACEUTICS 11.1(2014):71-80.
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