Molecular dynamic simulations of a hexagonal liquid crystalline phase to study drug partitioning and release mechanisms

Liquid crystalline nanoparticles (LCNPs), such as hexosomes (HII), can enhance lipid nanoparticle-mediated drug delivery by improving drug absorption, solubility, and chemical stability. Additionally, LCNPs can be tailored to optimize their function in specific biological environments by incorporating non-external-linker lipids into the HII system lipid composition. In this study, we constructed an HII model system composed of a 90:10 phytantriol:farnesol ratio and performed all-atom molecular dynamics simulations. The simulations demonstrated that the model remained stable across various water-to-lipid ratios, and the impact of the water-to-lipid ratio on the HII structural properties was consistent with previous experimental observations. We then used this model to investigate the localization and interactions of two drug molecules: vancomycin and clarithromycin. The results show that the highly lipophilic clarithromycin predominantly associates with the lipid phase, whereas vancomycin, due to its combination of hydrophobic and hydrophilic residues, tends to localize at the water-lipid interface, interacting with both phases. We also constructed an HII system with repeating HII units enclosed within Pluronic F127 polymers. Simulations revealed that the F127 polymers interact with the lipid phases at the HII interface region, facilitating excess water permeation into the HII phase system. To investigate the initial surface release mechanism of the drug molecules, we performed umbrella sampling (US) simulations. The energy profiles from the umbrella sampling indicate that polymer-lipid-water interactions at the HII interface reduce the energy barrier for drug release, making the release of vancomycin easier compared to clarithromycin. Our in vitro release study further confirmed that vancomycin exhibited higher release compared to clarithromycin. Overall, the model developed in this study provided important molecular-level insights into drug loading, partitioning, and release kinetics from the HII phase system, enabling the design of effective drug delivery formulations.