Targeting Tumorigenicity of Breast Cancer Stem Cells Using SAHA/Wnt-b Catenin Antagonist Loaded Onto Protein Corona of Gold Nanoparticles

Azam Shamsian,1,2 Mohammad Reza Sepand,3 Marziye Javaheri Kachousangi,1,2 Tahereh Dara,4 Seyed Nasser Ostad,3 Fatemeh Atyabi,1,2 Mohammad Hossein Ghahremani1,3 1Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 2Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 3Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 4Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, IranCorrespondence: Mohammad Hossein GhahremaniDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, New Building, Room 2-318, Tehran 1417614411, IranTel/Fax +982166959102Email mhghahremani@tums.ac.irBackground: Among various theories for the origin of cancer, the “stemness phenotype model” suggests a dynamic feature for tumor cells in which non-cancer stem cells (non-CSCs) can inter-convert to CSCs. Differentiation with histone-deacetylase inhibitor, vorinostat (SAHA), can induce stem cells to differentiate as well as enforces non-CSCs to reprogram to CSCs. To avoid this undesirable effect, one can block the Wnt-βcatenin pathway. Thus, a dual delivery system of SAHA and a Wnt-βcatenin blocker will be beneficial in the induction of differentiation of CSCs. Protein corona (PC) formation in nanoparticle has a biologic milieu, and despite all problematic properties, it can be employed as a medium for dual loading of the drugs.Materials and Methods: We prepared sphere gold nanoparticles (GNPs) with human plasma protein corona loaded with SAHA as differentiating agent and PKF118-310 (PKF) as a Wnt-βcatenin antagonist. The MCF7 breast cancer stem cells were treated with NPs and the viability and differentiation were evaluated by Western blotting and sphere formation assay.Results: We found that both drugs loaded onto corona-capped GNPs had significant cytotoxicity in comparison to bare GNP-corona. Data demonstrated an increase in stem cell population and upregulation of mesenchymal marker, Snail by SAHA-loaded GNPs treatment; however, the combination of PKF loaded GNPs along with SAHA-loaded GNPs resulted in a reduction of stem cell populations and Snail marker. We have shown that in MCF7 and its CSCs simultaneous treatment with SAHA and PKF118-310 induced differentiation and inhibition of Snail induction.Conclusion: Our study reveals the PC-coated GNPs as a biocompatible career for both hydrophilic (PKF) and hydrophobic (SAHA) agents which can decrease breast cancer stem cell populations along with reduced stemness state regression.Keywords: co-delivery, HDAC inhibitor, Wnt, cancer stem cell, protein corona