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  • 3X FLAG br S M Ogbomo W Shi N K Wagh

    2020-08-30


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    Contents lists available at ScienceDirect
    Journal of Controlled Release
    journal homepage: www.elsevier.com/locate/jconrel
    Cationic block amphiphiles show anti-mitochondrial activity in multi-drug T resistant breast cancer cells
    Petro P. Czupiela,b,c, Vianney Delplacea,c, Molly S. Shoicheta,b,c,
    a Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, Toronto, ON M5S 3E5, Canada b Institute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College Street, Toronto, ON M5S 3G9, Canada c Donnelly Centre, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada
    Keywords:
    Peptides
    Mitochondrial targeting
    Cancer
    Multi-drug resistance
    Vitamin E
    Prodrug 
    Currently, there are limited treatment options for multi-drug resistant breast cancer. Lipid-modified cationic peptides have the potential to reach the mitochondria, which are attractive targets for the treatment of multi-drug resistant (MDR) breast cancer; yet, little is known about their mitochondrial targeting and anti-cancer activity. Interestingly, lipid-modified cationic peptides, typically used as gene transfection agents, exhibit similar structural features to mitochondrial targeted peptides. Using octahistidine-octaarginine (H8R8) as a model ca-tionic peptide for cell penetration and endosomal escape, we explored the anti-cancer potential of lipid-modified cationic peptides as a function of amphiphilicity, biodegradability and lipid structure. We found that cationic peptides modified with a lipid that is at least 12 carbons in length exhibit potent anti-cancer activity in the low micromolar range in both EMT6/P and EMT6/AR-1 breast cancer cells. Comparing degradable and non-de-gradable linkers, as well as L- and D-amino acid sequences, we found that the anti-cancer activity is mostly independent of the biodegradation of the lipid-modified cationic peptides. Two candidates, stearyl-H8R8 (Str-H8R8) and vitamin E succinate-H8R8 (VES-H8R8) were cytotoxic to cancer cells by mitochondria depolarization. We observed increased reactive oxygen species (ROS) production, reduced cell bioenergetics and drug efflux, triggering apoptosis and G1 cell cycle arrest. Compared to Str-H8R8, VES-H8R8 showed enhanced cancer cell selectivity and drug efflux inhibition, thereby serving as a potential novel therapeutic agent. This study deepens our understanding of lipid-modified cationic peptides and uncovers their potential in multi-drug resistant breast cancer.