Indomethacin-grafted and pH-sensitive dextran micelles for overcoming inflammation-mediated multidrug resistance in breast cancer

Abstract

We first synthesized indomethacin (IND)-grafted dextran copolymer by acetal or ester linkage, which self-assembled with doxorubicin (DOX) into prodrug micelles (IDAC/DOX or IDES/DOX) with the size of ∼200 nm. In vitro drug release test verified IDAC/DOX could trigger more DOX and IND release by the hydrolysis of acetal than that of ester linkage. A series cells experiments demonstrated pH-sensitive IDAC/DOX could greatly improve cellular uptake and intracellular drug accumulation, thus enhancing DOX toxicity in drug-resistant tumor cells. IDAC/DOX was capable of reversing tumor multidrug resistance (MDR) through reducing multidrug resistance-associated protein 1 (MRP1) level (0.23-fold vs control group) and regulating bcl-2/bax pathway, eventually induced more apoptosis in MCF-7/ADR cells. These nanoparticles possessed long-term blood-circulation and high tumor accumulation, thereby reducing side effect and increasing bioavailability. Anti-tumor evaluation showed that IDAC/DOX possessed the highest tumor growth inhibition (TGI, 92.5 %), which might provide a promising way to overcome malignant tumor resistance.