Drug Design, Development and Therapy (Jul 2021)
Dual-Functional Peptide Driven Liposome Codelivery System for Efficient Treatment of Doxorubicin-Resistant Breast Cancer
Abstract
Kamel S Ahmed,1,2,* Shenhuan Liu,1,* Jing Mao,1 Jie Zhang,3 Lipeng Qiu1 1School of Pharmaceutical Sciences, Jiangnan University, Wuxi, 214122, Jiangsu, People’s Republic of China; 2Department of Pharmaceutics, Faculty of Pharmacy, Minia University, Minia, 19623, Egypt; 3The Jiaxing Key Laboratory of Oncological Photodynamic Therapy and the Targeted Drug Research, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, 314001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jie Zhang; Lipeng Qiu Email [email protected]; [email protected]: 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-R8H3) 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-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.Keywords: doxorubicin hydrochloride, celecoxib, co-delivery, targeting liposomes, multidrug resistance
