Co-Delivery of Itraconazole and Docetaxel by Core/Shell Lipid Nanocells for Systemic Antiangiogenesis and Tumor Growth Inhibition.

Abstract

The combination of antiangiogenesis with chemotherapy has become a promising multi-modal combinational therapy for solid tumor. However, hypoxia-mediated resistance and the subsequent treatment failure associated with antiangiogenesis therapy have limited the maximization of this promising approach. It remains a major challenge to balance the effect of angiogenesis and the accumulation of the cytotoxic drug within the tumor microenvironment. In this study, we report a nanotechnology based drug delivery solution that would improve both the antiangiogenic activity and cytotoxic efficacy of the loaded drugs. We designed core-shell 'lipid nanocells' drug delivery systems (denoted as DTX/ITZ-LNCs), which entrapped the antiangiogenic drug itraconazole (ITZ) in the outside liposomal shell and encapsulated anticancer drug docetaxel (DTX) in the inner hydrophobic PLGA core. In vitro evaluations showed that the dual drug loaded DTX/ITZ-LNCs retained the cytotoxic efficacy of the DTX against both the sensitive and multidrug resistant breast cancer cell line MCF-7. DTX/ITZ-LNCs also effectively inhibited the vascular endothelial growth factor (VEGF) induced migratory and invasive actions of HUVECs and neovascularization of subcutaneously implanted matrigel plugs. The tumor growth of MCF-7 tumor xenograft model was effectively inhibited by the systemic administration of the DTX/ITZ-LNCs. Taken together, these results showed that the DTX/ITZ-LNCs provided a drug delivery platform that can optimize the combinatory effects of the antiangiogenic agent with a conventional chemotherapeutic agent.