Molecular dynamics simulations of a hexagonal liquid crystal phase to study drug partitioning and release mechanisms

Liquid crystal nanoparticles (LCNPs), such as hexosomes based on an internal hexagonal phase (H_II), enhance lipid nanoparticle-mediated drug delivery by improving drug solubility, stability and absorption. LCNPs can also be tailored for specific biological environments by incorporating non-ester-linker lipids into the H_II nanostructure. In this study, we developed an H_II model system with a 90:10 phytantriol:farnesol ratio based on experimental data and conducted all-atom molecular dynamics simulations. The model remained stable across various water-to-lipid ratios, and the structural effects observed were consistent with prior experimental data. We used this model to examine the localization and interactions of antibiotics vancomycin and clarithromycin. Clarithromycin, being highly lipophilic, associated mainly with the lipid phase, while vancomycin localized at the water-lipid interface due to its amphiphilic nature. An extended H_II system with repeating units enclosed in Pluronic F127 polymers was also constructed. Simulations showed that hydrogen bonding between Pluronic F127 and water facilitated water influx into the H_II phase, causing interfacial reorganization. To investigate drug release, we performed umbrella sampling simulations. The resulting energy profiles indicated that polymer-water-lipid interactions lowered the energy barrier for vancomycin release compared to clarithromycin. This was confirmed by in vitro release studies, where vancomycin exhibited a higher release rate. Overall, this model provides molecular-level insights into drug loading, partitioning, and release from H_II systems, supporting the design of more effective drug delivery formulations.