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.
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.
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 . 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.