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学科主题: 药学
题名:
Roles of ligand and TPGS of micelles in regulating internalization, penetration and accumulation against sensitive or resistant tumor and therapy for multidrug resistant tumors
作者: 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
发表日期: 2015-06-01
DOI: 10.1016/j.biomaterials.2015.02.077
卷: 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
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
项目资助者: 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:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/57245
Appears in Collections:北京大学药学院_期刊论文

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作者单位: Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China

Recommended Citation:
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.
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