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学科主题药学
Roles of ligand and TPGS of micelles in regulating internalization, penetration and accumulation against sensitive or resistant tumor and therapy for multidrug resistant tumors
Wang, Ai-ting; Liang, De-sheng; Liu, Yu-jie; Qi, Xian-rong
关键词Hybrid Micelles Multidrug Resistance P-gp Function Permeation And Accumulation In Solid Tumor Mitochondrial Membrane Potential Synergistic Effect
刊名BIOMATERIALS
2015-06-01
DOI10.1016/j.biomaterials.2015.02.077
53页:160-172
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Engineering, Biomedical ; Materials Science, Biomaterials
资助者National Key Basic Research Program ; NSFC ; Beijing NSF ; Doctoral Foundation of the Ministry of Education ; Innovation Team of Ministry of Education ; National Key Basic Research Program ; NSFC ; Beijing NSF ; Doctoral Foundation of the Ministry of Education ; Innovation Team of Ministry of Education
研究领域[WOS]Engineering ; Materials Science
关键词[WOS]SOLUBLE ANTICANCER DRUGS ; VITAMIN-E TPGS ; CANCER-CELLS ; MIXED MICELLES ; IN-VITRO ; ANTITUMOR EFFICACY ; POLYMERIC MICELLES ; P-GLYCOPROTEIN ; OVARIAN-CANCER ; DELIVERY
英文摘要

There are several obstacles in the process of successful treatment of malignant tumors, including toxicity to normal cells, inefficiency of drug permeation and accumulation into the deep tissue of solid tumor, and multidrug resistance (MDR). In this work, we prepared docetaxel (DTX)-loaded hybrid micelles with DSPE PEG and TPGS (TPGS/DTX-M), where TPGS serves as an effective P-gp inhibitor for overcoming MDR, and active targeting hybrid micelles (FA@TPGS/DTX-M) with targeting ligand of folate on the hybrid micelles surface offering active targeting to folate receptor-overexpressed tumor cells. A systematic comparative evaluation of these micelles on cellular internalization, sub-cellular distribution, antiproliferation, mitochondrial membrane potential, cell apoptosis and cell cycle, permeation and inhibition on 3-dimensional multicellular tumor spheroids, as well as antitumor efficacy and safety assay in vivo were well performed between sensitive KB tumors and resistant KBv tumors, and among P-gp substrate or not. We found that the roles of folate and TPGS varied due to the sensitivity of tumors and the loaded molecules in the micelles. Folate and folate receptor-mediated endocytosis played a leading role in internalization, permeation and accumulation for sensitive tumors and non-substrates of P-gp. On the contrary, TPGS played the predominant role which dramatically decreased the efflux of drugs both when the tumor is resistant and for P-gp substrate. These findings are very meaningful for guiding the design of carrier delivery system to treat tumors. The antitumor efficacy in xenograft nude mice model and safety assay showed that the TPGS/DTX-M and FA@TPGS/DTX-M significantly exhibited higher antitumor activity against resistant KBv tumors than the marketed formulation and normal micelles owing to the small size (approximately 20 nm), hydrophilic PEGylation, TPGS inhibition of P-gp function, and folate receptor-modified endocytosis, permeation and accumulation in solid tumor, as well as synergistic effects of DTX-induced cell division inhibition, growth restraint and TPGS-triggered mitochondrial apoptosis in tumor cells. In conclusion, folate-modified TPGS hybrid micelles provide a synergistic strategy for effective delivery of DTX into KBv cells and overcoming MDR. (C) 2015 Elsevier Ltd. All rights reserved.

语种英语
所属项目编号2013CB932501 ; 81273454 ; 81473156 ; 7132113 ; 20130001110055 ; BMU20110263
资助者National Key Basic Research Program ; NSFC ; Beijing NSF ; Doctoral Foundation of the Ministry of Education ; Innovation Team of Ministry of Education ; National Key Basic Research Program ; NSFC ; Beijing NSF ; Doctoral Foundation of the Ministry of Education ; Innovation Team of Ministry of Education
WOS记录号WOS:000353929800016
Citation statistics
Cited Times:45[WOS]   [WOS Record]     [Related Records in WOS]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/57245
Collection北京大学药学院
作者单位Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China
Recommended Citation
GB/T 7714
Wang, Ai-ting,Liang, De-sheng,Liu, Yu-jie,et al. Roles of ligand and TPGS of micelles in regulating internalization, penetration and accumulation against sensitive or resistant tumor and therapy for multidrug resistant tumors[J]. BIOMATERIALS,2015,53:160-172.
APA Wang, Ai-ting,Liang, De-sheng,Liu, Yu-jie,&Qi, Xian-rong.(2015).Roles of ligand and TPGS of micelles in regulating internalization, penetration and accumulation against sensitive or resistant tumor and therapy for multidrug resistant tumors.BIOMATERIALS,53,160-172.
MLA Wang, Ai-ting,et al."Roles of ligand and TPGS of micelles in regulating internalization, penetration and accumulation against sensitive or resistant tumor and therapy for multidrug resistant tumors".BIOMATERIALS 53(2015):160-172.
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