Combination Therapy of Doxorubicin and Quercetin on Multidrug-Resistant Breast Cancer and Their Sequential Delivery by Reduction-Sensitive Hyaluronic Acid-Based Conjugate/d-α-Tocopheryl Poly(ethylene glycol) 1000 Succinate Mixed Micelles.

The therapeutic efficacy of chemotherapy in many types of hematological malignancies and solid tumors is dramatically hindered by multidrug resistance (MDR). This work presents a combination strategy of pretreatment of MDA-MB-231/MDR1 cells with quercetin (QU) followed by doxorubicin (DOX) to overcome MDR, which can be delivered by mixed micelles composed of the reduction-sensitive hyaluronic acid-based conjugate and d-α-tocopheryl poly(ethylene glycol) 1000 succinate. The combination strategy can enhance the cytotoxicity of DOX on MDA-MB-231/MDR1 cells by increasing intracellular DOX accumulation and facilitating DOX-induced apoptosis. The probable MDR reversal mechanisms are that the pretreatment cells with QU-loaded mixed micelles downregulate P-glycoprotein expression to decrease DOX efflux as well as initiate mitochondria-dependent apoptotic pathways to accelerate DOX-induced apoptosis. In addition, this combination strategy can not only potentiate in vivo tumor-targeting efficiency but also enhance the antitumor effect in MDA-MB-231/MDR1-bearing nude mice without toxicity or side effects. This research suggests that the co-administration of natural compounds and chemotherapeutic drugs could be an effective strategy to overcome tumor MDR, which deserves further exploration.