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

## TL;DR

This study explores how cholesterol affects how ivermectin interacts with and is captured by liposomal membranes, offering insights for designing better drug delivery systems.

## Contribution

The study combines molecular dynamics and experiments to reveal how cholesterol content optimizes ivermectin capture in liposomes.

## Key findings

- Ivermectin is most deeply embedded in membranes with 10% cholesterol, at an average distance of 1.09 nm from the bilayer center.
- Liposomes with 10% cholesterol show the highest drug association in both saline and plasma environments.
- Van der Waals interactions and hydrogen-bond lifetimes are most favorable at 10% cholesterol.

## Abstract

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.