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-external-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. • An H II PHY:FAR (90:10) model with F127 polymer was studied using AA-MD simulation • The model enabled detailed study of antibiotic localization and interactions • Hydrogen bonding between F127 and water enhanced water influx into the H II phase • The interfacial reorganization lowered the barrier for drug release processes • Simulated drug release matched experiments, validating the model’s predictions