Effect of Cyclodextrins on Membrane Biophysical Properties

Abstract

Ordered domains enriched in cholesterol and sphingolipids, commonly known as lipid rafts, have been linked to the activity of certain membrane receptors involved, for example, on inflammation and cell death processes. Consequently, the characterization of cell membrane properties and drug/membrane interactions has become increasingly relevant. Cyclodextrins (CDs) are biocompatible hydrophilic molecules with a hydrophobic core able to form inclusion complexes with poorly soluble molecules. As a result, β-CDs, safer for pharmaceutical applications, are currently used for solubilizing and safely administer poorly soluble drugs. Recent evidence indicating a possible anti-inflammatory effect of β-CDs in vivo has prompted the study of the mechanism of action of β-CDs. Knowing that β-CDs have long been used to both extract and insert cholesterol in membranes in vitro, this study is aimed at the effect of β-CDs on the biophysical properties of cell membranes, specifically on the cholesterol-enriched lipid raft domains.This study focused on the β-CD mediated extraction of membrane cholesterol and the consequent effects in global and localised membrane order. The interaction of β-CDs, both free and complexed with a drug, with model membrane systems and cellular membranes was evaluated using fluorescence spectroscopy and microscopy techniques. The results showed that β-CDs effectively removed cholesterol from both model membrane systems and cellular membranes. In model systems, a concomitant increase in overall membrane fluidity and permeability and decrease in the cholesterol-enriched raft-like domains was observed. Furthermore, β-CD complexation with a drug did not limit its effect. The results showed the potential synergistic action of β-CD as both a drug delivery system and disruptor of the lipid raft domains. In this way, we aim to further elucidate the effect of β-CDs on membrane biophysical properties, namely the destabilization of lipid raft domains and cellular processes dependent thereof.