Cholesterol-Driven Optimization of Liposomal Systems for Ivermectin Capture: Insights from Experimental and Molecular Dynamics Studies

This study investigates the interactions between ivermectin (IVM) and lipid membranes with varying cholesterol contents by using a combined molecular dynamics (MD) and experimental approach. DOPC bilayers containing 0, 10, 20, or 30% cholesterol were simulated, and SPC liposomes were employed for experimental validation. Mass density profiles indicated that the membrane thickness increased from 4.16 nm (0% cholesterol) to 4.60 nm (30% cholesterol), while ivermectin was most deeply embedded in membranes with 10% cholesterol with an average distance of 1.09 nm from the bilayer center. van der Waals interaction energies were most favorable at 10% cholesterol (-333.13 kJ/mol), correlating with an increased hydrogen-bond lifetime (2.10 ns) between IVM and lipid molecules. Mean square displacement (MSD) analysis revealed that ivermectin exhibited the lowest mobility (0.0019 × 10⁻⁵ cm²/s) in membranes with 10% cholesterol. ESR spectroscopy of 5-DSA-labeled SPC liposomes demonstrated a progressive increase in 2A|| values with increasing cholesterol content, with additional increases following IVM incorporation. IVM capture experiments showed that liposomes containing 10% cholesterol achieved the highest drug association, consistent across saline and plasma environments. These findings provide a mechanistic basis for the rational design of liposomal systems with high ivermectin-binding capacity, with potential implications for future applications requiring the sequestration of this compound in biological environments.