Simultaneous delivery of doxorubicin and GG918 (Elacridar) by new Polymer-Lipid Hybrid Nanoparticles (PLN) for enhanced treatment of multidrug-resistant breast cancer

摘要

Multidrug-resistant (MDR) cancer may be treated using combinations of encapsulated cytotoxic drugs and chemosensitizers. To optimize for the effectiveness of this combinational approach, novel polymer-lipid hybrid nanoparticle (PLN) formulations capable of delivering a cytotoxic drug, doxorubicin (Dox), a chemosensitizer, GG918, or their combination were prepared. Both acute and long-term anticancer activities of various combinations of Dox and GG918 in solution or PLN form were evaluated in a human MDR breast cancer cell line (MDA435/LCC6/MDR1) using trypan blue exclusion and clonogenic assays. Cellular Dox uptake and drug distribution within the cells were determined by fluoremetry and fluorescence microscopy. The results showed that the encapsulation efficiencies of Dox and GG918 in PLN were up to 89% and were not compromised by co-encapsulation of the two agents. Of various combinational treatment approaches, the Dox and GG918 co-encapsulated PLN formulation ((DG)n) demonstrated the greatest Dox uptake and anticancer activity to the MDR cells, while co-administration of two single-agent loaded PLN was least effective. Fluorescence microscopy indicated cellular internalization of (DG)n. These findings suggest that in addition to the total drug concentrations, the simultaneous delivery of Dox and GG918 to the same cellular location is critical in determining the therapeutic effectiveness of this anticancer drug-chemosensitizer combination. (c) 2006 Elsevier B.V. All rights reserved.