Thesis (Ph.D.) - Cairo University - Faculty of Pharmacy - Department of Pharmacology and Toxicology

Introduction: Colorectal cancer (CRC) remains a leading cause of death worldwide.The use of cisplatin as an anti-cancer drug in CRC is correlated with severe adverse effects and drug resistance. Utilizing combination of anticancer agents can effectively kill cancer through multiple pathways; nonetheless, improvements in their delivery are needed. Nano-cubosomes, thanks to the advantages of their liquid crystalline porous nano-architecture and capability for multi-drug encapsulation, appear to be of interest as nanocarriers for anti-cancer therapies. Hence, delivering cisplatin, as nano-cubosomes, concomitantly with other chemo-dugs can lead to a rationally designed therapy for chemo-resistant cancers and might overcome problems associated with conventional cisplatin treatment. Aim: The aim of the present study was to construct nano-cubosomes bearing cisplatin, metformin and cisplatin-metformin combination and investigate their effect on proliferation in Caco-2 and HCT-116 cell lines, as well as, tumorigenesis-associated metabolic markers in HCT-116 colorectal cancer cell line. Materials and methods: Nano-cubosomes bearing either cisplatin alone, metformin alone or cisplatin-metformin combination were formulated using emulsification technique. The loaded nano-cubosomes were characterized in vitro and the optimized formulations were selected.Their cytotoxic effects were investigated by Sulphorhodamine-B (SRB) assayin Caco-2 and HCT-116 cells. In HCT-116 cellsthe AMPK/mTOR metabolic pathwaywas analyzed using ELISA technique.Protein levels of AKT were determined using western blotting. Glucose, ATP, NADPH oxidase, LDH, glutathione (GSH) and caspase-3 activity were measured spectrophotometrically

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