Simultaneous liposomal delivery of quercetin and vincristine for enhanced estrogen-receptor-negative breast cancer treatment

Abstract

Breast cancers are either estrogen receptor-positive (ER+) or negative (ER-). ER- breast cancers are clinically more aggressive and have fewer effective treatment options. Quercetin and vincristine are both active against ER- breast cancers and exhibit synergism in vitro. However, the clinical use of quercetin is hampered by its low water solubility. In addition, optimal synergism can only be achieved at a particular ratio of the drugs. Therefore, the objectives of this study are to develop a liposomal formulation to solubilize quercetin, and to co-encapsulate and coordinate the release of quercetin and vincristine in their synergistic ratios to maximize anticancer activity. The optimal synergistic molar ratio of quercetin/vincristine was found to be 1: 2 by in-vitro MTT assay. Quercetin liposomes were prepared by the film hydration method followed by extrusion, and vincristine was subsequently loaded into the core of the liposomes by remote loading with manganese sulfate and the ionophore A23187. The optimal liposome formulation co-encapsulating quercetin and vincristine comprised egg sphingomyelin/cholesterol/PEG2000 ceramide/quercetin (72.5: 17.5: 5: 5mol ratio). This formulation was physically stable, enhanced quercetin solubility 8.6 times, co-encapsulated quercetin and vincristine with efficiencies of 78.3 and 78.5%, respectively, and displayed coordinated release of both drugs to maintain the synergistic molar ratio. In-vitro MTT assays of this liposomal formulation showed significant synergism, with a combination index of 0.113 and a dose-reduction index value of 115 at ED50 for vincristine. Therefore, liposomal delivery represents a strategy to solubilize poorly soluble drugs and coordinate the release of two drugs in their synergistic ratio for optimal anticancer effect. Copyright © 2010 by Lippincott Williams & Wilkins.