Lipid–polymer hybrid nanoparticles for synergistic drug delivery to overcome cancer drug resistance

Abstract

To overcome the major obstacle of successful cancer chemotherapy, multidrug resistance (MDR), we prepared lipid-shell and polymer-core nanoparticles (LPNPs) to co-deliver an anticancer drug and a drug resistance inhibitor to achieve a synergistic effect and to overcome cancer drug resistance. LPNPs are composed of a core of cholic acid functionalized star poly(DL-lactide) with a fast degradation and surface erosion degradation mechanism and a shell of lecithin decorated by DSPE-PEG. A chemotherapeutic drug (paclitaxel, PTX) and a cyclooxygenase-2 inhibitor (celecoxib, CXB) to down-regulate P-gp expression were co-loaded in the lipid–polymer hybrid nanoparticles to obtain PTX/CXB@LPNP. As compared with liposomes without polymer cores, PTX/CXB@LPNP sustains the drug release more efficiently. The in vitro cell inhibition efficiency of the drug loaded nanoparticles was evaluated in drug resistant cells (MCF-7/ADR) and nonresistant cells (HeLa). The results demonstrate that dual-drug loaded PTX/CXB@LPNP exhibits a significantly enhanced cell inhibitory effect as compared with mono-drug loaded PTX@LPNP. Consistently, apoptosis assay by flow cytometry indicates that PTX/CXB@LPNP can induce both early apoptosis and late apoptosis more effectively than PTX@LPNP. The enhanced therapeutic efficiency of PTX/CXB@LPNP is attributed to the down-regulation of P-gp expression mediated by CXB, which results in decreased drug-efflux mediated by P-gp. In addition, PTX/CXB@LPNP results in a significant decrease in cytokine IL-10 produced by the drug resistant tumor cells, implying that the drug delivery system is favorable in reversal of the immunosuppressive environment. The lipid–polymer hybrid nanoparticles have promising applications in synergistic drug delivery to overcome cancer drug resistance.