Simulation of adsorption and release of doxepin onto ZIF-8 including in vitro cellular toxicity and viability

Abstract Doxepin hydrochloride is an antidepressant drug commonly used to treat mild to moderate depression. However, this drug has poor oral bioavailability, with the percentage of drug that can enter the bloodstream being weak and variable. The present study seeks to investigate the ZIF-8 nanoparticles for doxepin delivery and to assess this drug uptake and release in ZIF-8 frameworks using the Gibbs-ensemble Monte Carlo method in the Simulated Materials Studio. This study also adopted a model for showing surface adsorbent (ZIF-8S) capabilities. ZIF-8 nano-frameworks have many advantages such as easy flowing through capillaries leading to a satisfactory drug release into the systemic circulation and preventing high plasma concentration. Additionally, the study examined the diffusion of drug molecules using the simulated molecular dynamics with regard to the structural flexibility of the MOF. Proper loading of 8.6% and slow diffusion of 7.353 × 10−6 cm2/s doxepin molecules from ZIF-8 pores confirmed that this material could be recommended as an effective carrier for doxepin. Furthermore, the fixed ZIF-8S model is also used by keeping the opening of cavities fixed, thereby attaining a higher loading amount 12%. Moreover, since ethanol has been applied as a suitable solvent in many biological systems, of adsorption, diffusion processes are also repeated in this solvent. Thus, presence of such adsorption sites as zinc ions may facilitate the interaction of the framework with large molecules to provide desirable loading and diffusion amounts. Furthermore, more adsorption can be reached with less energy at the surface of the ZIF-8 in the presence of ethanol, which is due to the greater adsorption of solvent molecules. Finally, to ascertain the in vitro cellular toxicity and viability of the prepared nanoparticles, they are treated with PC3 human prostate cancer cells and the average growth curves are monitored via MTT assay. This study confirmed a decrease in the MTT signal compared to the untreated cells, so ZIF-8 can reduce the metabolic activity of the performed cancer cells. This study shows that this nanomaterial can be achieved as a vehicle for delivery of doxepin.