Synergistic Drug Delivery By Lipid-polymer Hybrid Nanoparticles To Overcome Cancer Drug Resistance

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.