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Multidrug resistance (MDR) against chemotherapeutic agents has become one of the major obstacles to successful cancer therapy and MDR-associated proteins (MRPs)-mediated drug efflux is the key factor for MDR. In this study, a redox-responsive polymer based on dextran (DEX) and indomethacin (IND), which could reduce MRPs-mediated efflux of chemotherapeutics, was synthesized, and the obtained polymer could spontaneously form stable micelles with well-defined core-shell structure and a uniform size distribution with an average diameter of 50 nm and effectively encapsulate doxorubicin (DOX); the micelles contain a disulfide bridge (cystamine, SS) between IND and DEX (DEX-SS-IND). In vitro drug release results indicated that DEX-SS-IND/DOX micelles could maintain good stability in a stimulated normal physiological environment and promptly depolymerized and released DOX in a reducing environment. After incubating DEX-SS-IND/DOX micelles with drug-resistant tumor (MCF-7/ADR) cells, the intracellular accumulation and retention of DOX were significantly increased under the synergistic effects of redox-responsive delivery and the inhibitory effect of IND on MRPs. In vitro cytotoxicity showed that DEX-SS-IND/DOX micelles exhibited higher cytotoxicity against MCF-7/ADR cells. Moreover, DEX-SS-IND/DOX micelles showed significantly enhanced inhibition of tumor in BALB/c nude mice bearing MCF-7/ADR tumors and reduced systemic toxicity. Overall, the cumulative evidence indicates that DEX-SS-IND/DOX micelles hold significant promise for overcoming MDR for cancer therapy.

Dendrobine, considered as the major active alkaloid compound, has been used for the quality control and discrimination of Dendrobium which is documented in the Chinese Pharmacopoeia. In this work, a sensitive and simple ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for determination of dendrobine in rat plasma is developed. After addition of caulophyline as an internal standard (IS), protein precipitation by acetonitrile-methanol (9:1, v/v) was used to prepare samples. Chromatographic separation was achieved on a UPLC BEH C18 (2.1 ×100 mm, 1.7 µm) column with acetonitrile and 0.1% formic acid as the mobile phase with gradient elution. An electrospray ionization source was applied and operated in positive ion mode; multiple reaction monitoring mode was used for quantification using target fragment ions m/z 264.2 → 70.0 for dendrobine and m/z 205.1 → 58.0 for IS. Calibration plots were linear throughout the range 2-1000 ng/mL for dendrobine in rat plasma. The RSDs of intra-day and inter-day precision were both <13%. The accuracy of the method was between 95.4 and 103.9%. The method was successfully applied to pharmacokinetic study of dendrobine after intravenous administration. Copyright © 2015 John Wiley & Sons, Ltd.