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Indomethacin-based stimuli-responsive micelles combined with paclitaxel to overcome multidrug resistance

Development of multidrug resistance against antitumor agents is a major limiting factor for the successful chemotherapy. Currently, both amphiphilic polymeric micelles and chemosensitizers have been proposed to overcome MDR during chemotherapy. Herein, the redox-responsive polymeric micelles compose...

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Detalles Bibliográficos
Autores principales: Wang, Shuanghu, Tan, Xueying, Li, Shujuan, Zhou, Yunfang, Geng, Peiwu, Hua, Ailian, Deng, Aiping, Yu, Zhihong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762321/
https://www.ncbi.nlm.nih.gov/pubmed/29340053
http://dx.doi.org/10.18632/oncotarget.22781
Descripción
Sumario:Development of multidrug resistance against antitumor agents is a major limiting factor for the successful chemotherapy. Currently, both amphiphilic polymeric micelles and chemosensitizers have been proposed to overcome MDR during chemotherapy. Herein, the redox-responsive polymeric micelles composed of dextran and indomethacin (as chemosensitizer) using a disulfide bond as the linker are prepared (DEX-SS-IND) for delivery of antitumor agent paclitaxel (PTX). The high level of glutathione in tumor cells selectively breaks the disulfide bond, leading to the rapid breakdown and deformation of redox-responsive polymeric micelles. The data show that DEX-SS-IND can spontaneously form the stable micelles with high loading content (9.48 ± 0.41%), a favorable size of 45 nm with a narrow polydispersity (0.157), good stability, and glutathione-triggered drug release behavior due to the rapid breakdown of disulfide bond between DEX and IND. In vitro antitumor assay shows DEX-SS-IND/PTX micelles effectively inhibit the proliferation of PTX-resistant breast cancer (MCF-7/PTX) cells. More impressively, DEX-SS-IND/PTX micelles possess the improved plasma pharmacokinetics, enhanced antitumor efficacy on tumor growth in the xenograft models of MCF-7/PTX cells, and better in vivo safety. Overall, DEX-SS-IND/PTX micelles display a great potential for cancer treatment, especially for multidrug resistance tumors.