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

High Resolution Image Download MS PowerPoint Slide 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 cm 2 /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.