CuO Nanoparticles as Copper-Ion Reservoirs for Elesclomol-Mediated Intracellular Oxidative Stress: Implications for Anticancer Therapies

Dissolution of metal/metal oxide nanoparticles has been widely exploited to be one of the mechanisms of inducing oxidative stress within bacterial and mammalian cells. Elesclomol has been already evaluated in clinical trials, and the reports have demonstrated a greater therapeutic activity with a prolonged progression-free time for survival of patients. Computational modeling (density functional theory and classical molecular dynamics) and UV–vis spectroscopy analysis showed that the dissolved Cu (II) ions from CuO nanoparticles preferentially bind to Elesclomol in cell culture media. CuO nanoparticles (50–200 ng/mL) when co-delivered with 50 ng/mL Elesclomol drug significantly reduced the cell viability of A549 cells compared to their respective standalone exposure. A time-dependent study showed a reduced cell viability (up to 80%) and enhanced reactive oxygen species generation (up to three folds), which was explained by the dissolution profile of CuO nanoparticles. Stable isotope tracing confirmed the intracellular accumulation of copper inside A549 cells to increase by up to four times when 1000 ng/mL 65CuO nanoparticles were exposed in the presence of 50 ng/mL Elesclomol. The cytotoxicity was rapid, with 70% of the cell death occurring within the span of 12 h through apoptosis pathways with a very minimal drug concentration. In our work, we exploited the ability of CuO nanoparticles to act as a reservoir with slow and sustained release of Cu (II) ions to bind with Elesclomol, which helped in enhanced generation of intracellular oxidative stress and can be used as a promising approach for Elesclomol-based anticancer therapy.