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

Date Published: July 7, 2017

Publisher: Public Library of Science

Author(s): Weiping Ji, Bo Wang, Qiuping Fan, Chao Xu, Youwu He, Youfen Chen, Aamir Ahmad.

http://doi.org/10.1371/journal.pone.0180037

Abstract

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.

Partial Text

Multidrug resistance (MDR) is a great obstacle for cancer chemotherapy, which leads to the poor treatment outcomes [1,2]. The overexpression of drug efflux transporters on the cell surface has been confirmed based on the clinical and experimental studies [3]. The most commonly reported efflux membrane transporter multidrug resistance-associated proteins (MRPs) are extensively overexpressed in various tumor cells and actively pump the broad spectrum of chemotherapeutics outward from the cells [4,5].

DEX-IND was synthesized successfully with low CMC in this study. The DEX-IND could spontaneously form nanosized micelles in aqueous medium and encapsulate the hydrophobic anti-tumor agent PTX. The PTX release from DEX-IND micelles could be maintained for more than 48h. DEX-IND/PTX micelles were effective for suppressing both drug sensitive and resistant MCF-7 cells. The assay of anti-tumor activity indicated that DEX-IND/PTX micelles could increase anti-tumor activity in comparison to commercial PTX. Overall, the results indicated that DEX-IND/PTX micelles were a promising potential candidate for oncotherapy.

 

Source:

http://doi.org/10.1371/journal.pone.0180037

 

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