Dual-Functional Peptide Driven Liposome Codelivery System for Efficient Treatment of Doxorubicin-Resistant Breast Cancer
Kamel S. Ahmed, Shenhuan Liu, Jing Mao, Jie Zhang, Lipeng Qiu
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 co-delivery of doxorubicin hydrochloride (DOX) and celecoxib (CEL) to overcome doxorubicin resistance in breast cancer. Methods: A functional hybrid peptide (MTS-R 8 H 3 ) with unique cellular penetrability, endo-lysosomal escape and mitochondrial targeting ability was successfully synthesized using solid phase synthesis technology. The peptide modified targeted liposomes (DOX/CEL-MTS-R 8 H 3 lipo) for co-delivery of DOX and CEL were formulated to overcome the chemoresistance in MCF/ADR cells. Results: DOX/CEL-MTS-R 8 H 3 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-R 8 H 3 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-R 8 H 3 lipo is a promising strategy for overcoming drug resistance in breast cancer treatments with high targeting inhibition efficiency. Keywords: doxorubicin hydrochloride, celecoxib, co-delivery, targeting liposomes, multidrug resistance