Indomethacin-based stimuli-responsive micelles combined with paclitaxel to overcome multidrug resistance
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Shuanghu Wang1,*, Xueying Tan2,*, Shujuan Li2, Yunfang Zhou1, Peiwu Geng1, Ailian Hua1, Aiping Deng3 and Zhihong Yu3
1The Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People's Hospital of Lishui, Lishui 323000, China
2College of Pharmacy, Zhejiang Pharmaceutical College, Ningbo 315000, China
3Department of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
*These authors have contributed equally to this work
Zhihong Yu, email: firstname.lastname@example.org
Keywords: breast cancer; multidrug resistance; paclitaxel; indomethacin; drug delivery system
Received: June 06, 2017 Accepted: November 19, 2017 Published: November 30, 2017
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.
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