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 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

Acknowledgements

This work was supported by the Natural Science Foundation of Jiangsu Province (BK20201344), China Postdoctoral Science Foundation (2019M660166), National Natural Science Foundation of China (81703437 and 81872220), Postdoctoral Innovation Project of Shandong Province (202002039), Basic Public Welfare Research Project of Zhejiang Province (LGF20H300012) and the Science and Technology Bureau of Jiaxing (2019AY32009).

Data Sharing Statement

All data associated with this study are present in the paper and the Supplementary Materials.

Disclosure

The authors declare that they have no conflicts of interest for this work.