Monodistearoylphosphatidylethanolamine-hyaluronic acid functionalization of single-walled carbon nanotubes for targeting intracellular drug delivery to overcome multidrug resistance of cancer cells

Multidrug resistance (MDR) of cancers is a major cause for the failure of chemotherapy. Here we synthesized a multifunctional modifier of single-walled carbon nanotubes (SWCNTs), distearoylphosphatidylethanolamine-hyaluronic acid (DSPE-HA) conjugate with a single coupling point, to simultaneously disperse SWCNTs, improve the biocompatibility of SWCNTs and target SWCNTs to CD44-overexpressing MDR cancer cells for improving intracellular drug delivery and overcoming MDR. Taking epirubicin (EPI) as model drug and the DSPE-HA functionalized SWCNTs as carriers, a drug delivery system EPI-SWCNTs-DSPE-HA was constructed. The intracellular EPI delivery efficiency and MDR-reversing effects of EPI-SWCNTs-DSPE-HA were investigated in drug-resistant A549/Taxol cells and tumor spheroids. The results demonstrated that EPI-SWCNTs-DSPE-HA significantly increased the intracellular delivery and retention of EPI by circumventing the drug efflux through the mechanism of CD44 receptor-mediated endocytosis and bypassing P-glycoprotein (P-gp) pump. EPI-SWCNTs-DSPE-HA treatment effectively overcame the MDR of cancer cells and tumor spheroids and blank SWCNTs-DSPE-HA had no significant cytotoxicity, showing that SWCNTs-DSPE-HA is a promising carrier for drug delivery in MDR cancers.