Permeation of low molecular compounds and macromolecules across lipid bilayers

The membrane crossing potential of drug candidates is a major issue in drug development. The main route for lipophilic compounds to cross mammalian cell membranes is the lipid bilayer permeation. We developed a liposomal assay to determine the permeation kinetics of aromatic carboxylic acids across lipid bilayers. The kinetic studies reveal new information on the influence of both the ionization state of the permeant and of the membrane lipid composition on permeation. One outstanding finding is that the permeation of all studied acids is fully controlled by their anions around physiological pH, i.e. pH 7. This is in contrast to the generally accepted pH-partition hypothesis, which assumes that the neutral forms of acids or bases exclusively control permeation. The same assay is used to investigate the possible lipid bilayer permeation of cell penetrating peptides. The behavior of the latter in cell culture is studied in parallel by confocal laser scanning microscopy.

Our online tool PermSim allows to simulate lipid bilayer permeation based on the single rate constants for bilayer partitioning and permeation and on the volume ratios between aqueous and membrane phases.

ETH Research Database: id 8916

Contacts: Prof. Dr. Heidi Wunderli-Allenspach, Dr. Stefanie Krämer