Droplet Interface Bilayers as a Physico-Chemical Tool to Assess and Investigate the Cellular Membrane Crossing of Small Molecules

Abstract

The cell membrane interface separates the cellular milieu from the external environment. It is self-assembled as a bilayer and made of phospholipids, cholesterol and proteins. Its main purpose is to regulate chemical gradients between the inside and the outside of the cell. In the frame of pharmacology, understanding the process of drug permeation through the cell membrane is essential. In fact, medicines that feature a poor ability to cross bilayers often fail during the development thread. Therefore, this question is both of research interest and highly valued by the pharmaceutical industry. Several methods have been developed to evaluate the ability of a drug to cross membranes. Design of artificial membrane systems that best mimic that of real cells has come as a good option to reach this objective. However, a clear knowledge of the physical chemistry properties of the produced bilayer is still lacking. Consequently, the main screening technologies mis-predicted drugs permeability. Here, we tackle this question by studying the permeation of fluorophores through droplet interface bilayers (DIBs) made of a range of phospholipids and solvents. We find that both acyl chains and polar heads could independently affect the permeability of artificial bilayers. Our findings offer a clearer understanding of the contribution of phospholipid unsaturation, charge, and shape in membrane permeability. All these parameters alter membrane lateral pressure, i.e. membrane phospholipid packing level, which we identify as a major determinant in membrane permeability. We thereupon determine relevant physical chemistry conditions that properly mimic biological membranes.