Combinational delivery of berbamine and 5-fluorouracil in cerium oxide nanoparticles for colon cancer therapy: Insights from in vitro and in silico studies

Abstract

Colon cancer is traditionally treated by an antimetabolite drug 5-fluorouracil (5FU) but has been linked to several drawbacks and systemic toxicity. To overcome drug associated toxicity, combination therapy is a promising strategy that synergistically enhances the therapeutic effects of co-delivered drugs while minimizing administration doses. Therefore, the current study aims to investigate the anti-colon cancer potency of 5FU co-delivered with a phytochemical i.e., berbamine (BERB) in a Cerium oxide nanoparticles (CONPs) delivery system. CONPs loaded 5FU (5FU-CONPs) and BERB (BERB-CONPs) were prepared and characterized using different analytical techniques. Successful entrapment of both drugs into CONPs formulations was detected under X-ray diffraction (XRD) observations. Drug-loaded CONPs in combination showed effective anti-oxidant activity by preventing reactive oxygen species (ROS) generations and had superior cytotoxic effects on HT-29 cell lines compared to treatment with native drugs singly or in combination. They also triggered apoptosis through p21, p53, Bax upregulation, and Bcl-2 downregulation, as confirmed by western blot studies. Additionally, in silico analysis was performed using molecular docking and molecular dynamics simulation (MDS) to validate the in vitro results. Results of the study suggest that 5FU and BERB CONPs in combination could be taken as a possible therapeutic approach for colon cancer treatment.