Chemosensitizing indomethacin-conjugated dextran-based micelles for effective delivery of paclitaxel in resistant breast cancer therapy

Multidrug resistance (MDR) against chemotherapeutic agents has become the major obstacle to successful cancer therapy and multidrug resistance-associated proteins (MRPs) mediated drug efflux is the key factor for MDR. Indomethacin (IND), one of the non-steroidal anti-inflammatory agents, has been de...

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Veröffentlicht in:PloS one 2017-07, Vol.12 (7), p.e0180037-e0180037
Hauptverfasser: Ji, Weiping, Wang, Bo, Fan, Qiuping, Xu, Chao, He, Youwu, Chen, Youfen
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creator Ji, Weiping
Wang, Bo
Fan, Qiuping
Xu, Chao
He, Youwu
Chen, Youfen
description Multidrug resistance (MDR) against chemotherapeutic agents has become the major obstacle to successful cancer therapy and multidrug resistance-associated proteins (MRPs) mediated drug efflux is the key factor for MDR. Indomethacin (IND), one of the non-steroidal anti-inflammatory agents, has been demonstrated to increase cytotoxic effects of anti-tumor agents as MRP substrates. In this study, dextran-g-indomethacin (DEX-IND) polymeric micelles were designed to delivery paclitaxel (PTX) for the treatment of MDR tumors. The DEX-IND polymer could effectively encapsulate PTX with high loading content and DEX-IND/PTX micelles present a small size distribution. Compared with free PTX, the release of PTX from DEX-IND/PTX micelles could be prolonged to 48 h. Cellular uptake test showed that the internalization of DEX-IND/PTX micelles by drug-sensitive MCF-7/ADR cells was significantly higher than free PTX benefiting from the inhibitory effect of IND on MRPs. In vitro cytotoxicity test further demonstrated that DEX-IND/PTX micelles could enhance the cytotoxicity of PTX against MCF-7/ADR tumor cells. In vivo pharmacokinetic results showed that DEX-IND/PTX micelles had longer systemic circulation time and slower plasma elimination rate in comparison to PTX. The anti-tumor efficacy test showed that DEX-IND/PTX micelles exhibited greater tumor growth-inhibition effects on MDR tumor-bearing mice, with good correlation between in vitro and in vivo. Overall, the cumulative evidence indicates that DEX-IND/PTX micelles hold significant promise for the treatment of MDR tumors.
doi_str_mv 10.1371/journal.pone.0180037
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In vivo pharmacokinetic results showed that DEX-IND/PTX micelles had longer systemic circulation time and slower plasma elimination rate in comparison to PTX. The anti-tumor efficacy test showed that DEX-IND/PTX micelles exhibited greater tumor growth-inhibition effects on MDR tumor-bearing mice, with good correlation between in vitro and in vivo. Overall, the cumulative evidence indicates that DEX-IND/PTX micelles hold significant promise for the treatment of MDR tumors.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28686704</pmid><doi>10.1371/journal.pone.0180037</doi><orcidid>https://orcid.org/0000-0003-1993-9109</orcidid><oa>free_for_read</oa></addata></record>
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subjects Animals
Anti-inflammatory agents
Anticancer properties
Bile
Biocompatibility
Biology and Life Sciences
Breast cancer
Breast Neoplasms - drug therapy
Breast Neoplasms - pathology
Cancer
Cancer therapies
Chemotherapy
Circulation
Cytotoxicity
Dextran
Dextrans - administration & dosage
Dextrans - chemistry
Dosage and administration
Drug Delivery Systems
Drug resistance
Drug Resistance, Neoplasm - drug effects
Drug therapy
Efflux
Encapsulation
Female
Hemodialysis
Humans
In vitro methods and tests
In vivo methods and tests
Indomethacin
Indomethacin - administration & dosage
Indomethacin - chemistry
Inflammation
Inhibition
Internalization
Laboratory animals
Material requirements planning
MCF-7 Cells
Medicine and Health Sciences
Mice
Micelles
MRP protein
Multidrug resistance
Nanoparticles
Nonsteroidal anti-inflammatory drugs
Orthopedics
Paclitaxel
Paclitaxel - administration & dosage
Paclitaxel - chemistry
Pharmacology
Physical Sciences
Polymers
Proteins
Quantum dots
Rodents
Size distribution
Stress concentration
Substrates
Therapy
Toxicity testing
Tumor cells
Tumors
Xenograft Model Antitumor Assays
title Chemosensitizing indomethacin-conjugated dextran-based micelles for effective delivery of paclitaxel in resistant breast cancer therapy
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