Changes in membrane biophysical properties induced by the Budesonide/Hydroxypropyl-β-cyclodextrin complex

Budesonide (BUD), a poorly soluble anti-inflammatory drug, is used to treat patients suffering from asthma and COPD (Chronic Obstructive Pulmonary Disease). Hydroxypropyl-beta-cyclodextrin (HP beta CD), a biocompatible cyclodextrin known to interact with cholesterol, is used as a drug-solubilizing agent in pharmaceutical formulations. Budesonide administered as an inclusion complex within HP beta CD (BUD:HP beta CD) required a quarter of the nominal dose of the suspension formulation and significantly reduced neutrophil-induced inflammation in a COPD mouse model exceeding the effect of each molecule administered individually. This suggests the role of lipid domains enriched in cholesterol for inflammatory signaling activation. In this context, we investigated the effect of BUD:HP beta CD on the biophysical properties of membrane lipids. On cellular models (A549, lung epithelial cells), BUD:HP beta CD extracted cholesterol similarly to HP beta CD. On large unilamellar vesicles (LUV5), by using the fluorescent probes diphenylhexatriene (DPH) and calcein, we demonstrated an increase in membrane fluidity and permeability induced by BUD:HP beta CD in vesicles containing cholesterol. On giant unilamellar vesicles (GUVs) and lipid monolayers, BUD:HP beta CD induced the disruption of cholesterol-enriched raft-like liquid ordered domains as well as changes in lipididity, all t packing and lipid desorption from the cholesterol monolayers, respectively. Except for membrane fluhese effects were enhanced when HPpCD was complexed with budesonide as compared with HP beta CD. Since cholesterol-enriched domains have been linked to membrane signaling including pathways involved in inflammation processes, we hypothesized the effects of BUD:HP beta CD could be partly mediated by changes in the biophysical properties of cholesterol-enriched domains. (C) 2017 Elsevier B.V. All rights reserved.