Dual-functional peptide driven liposome codelivery system for efficient treatment of doxorubicin-resistant breast cancer

Abstract

Background: The active-targeted drug delivery systems had attracted more and more attention to efficiently overcome multidrug resistance (MDR) in cancer treatments. The aim of the work was to develop a multifunctional nano-structured liposomal system for codelivery of doxorubicin hydrochloride (DOX) and celecoxib (CEL) to overcome doxorubicin resistance in breast cancer. Methods: A functional hybrid peptide (MTS-R8H3) with unique cellular penetrability, endolysosomal escape and mitochondrial targeting ability was successfully synthesized using solid phase synthesis technology. The peptide modified targeted liposomes (DOX/CELMTS-R8H3 lipo) for co-delivery of DOX and CEL were formulated to overcome the chemoresistance in MCF/ADR cells. Results: DOX/CEL-MTS-R8H3 lipo showed nanosized shape and displayed high stability for one month. The cytotoxicity effect of the co-delivery of DOX and CEL through peptide modified liposomes had remarkable treatment efficacy on killing MCF/ADR cells. Targeted liposome exhibited greater cellular entry ability about 5.72-fold stronger than DOX solution. Moreover, as compared with unmodified liposomes, the presence of MTS-R8H3 peptide entity on liposome surface enhanced the mitochondrial-targeting ability and achieved effective reactive oxygen species (ROS) production with significant inhibition of P-gp efflux activity. Conclusion: The study suggested that the DOX/CEL-MTS-R8H3 lipo is a promising strategy for overcoming drug resistance in breast cancer treatments with high targeting inhibition efficiency.