Ionic Liquids as Antibacterial and Drug Delivery Agents: How Cationic Amphiphilic Structure Controls Morphology Changes in Lipid Bilayers and Penetration Mechanism

Ionic liquid-based technologies are promising both as antibacterial agents and in drug delivery, as they can improve drug solubility and capacity to bypass lipid bilayers while also taking advantage of ionic liquids' physical properties, such as negligible vapor pressure and stability. In both applications, it is imperative to understand how the molecular structure of the ionic liquid determines its interaction with cellular membranes. In this work, molecular dynamics simulations with coarse-grained models were applied to study the penetration of eight ionic liquids based on the 1,3-dialkyl-imidazolium cation with different alkyl group sizes into DPPC bilayers from both dilute and concentrated aqueous solutions. Potential of mean force calculations were performed to evaluate the thermodynamics of cation penetration, and graph theory was used to characterize their nonhomogeneous distributions inside the bilayers. Distinct effects were noticed over the bilayer morphology: Cations with a single small or medium alkyl tail do not induce significant changes over the bilayer structure, while cations with a 16-carbon-atom chain are water-insoluble and, in concentrated solutions, are capable of partially removing lipid molecules. Incorporated cations with two medium-sized tails remain close to the water interface, reducing the interaction between lipids and decreasing the bilayer thickness, while cations with two long tails penetrate into the hydrophobic center of the bilayer and increase its thickness instead. As a consequence of the different interactions, two distinct mechanisms have been proposed for the drug delivery action of ionic liquids, depending on their water solubility and clustering tendency.