1. Biochim Biophys Acta. 2017 Jun 20;1859(10):1930-1940. doi:
10.1016/j.bbamem.2017.06.010. [Epub ahead of print]

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

Dos Santos AG(1), Bayiha JC(2), Dufour G(3), Cataldo D(4), Evrard B(3), Silva
LC(5), Deleu M(6), Mingeot-Leclercq MP(7).

Author information: 
(1)Université catholique de Louvain, Louvain Drug Research Institute, Cellular
and Molecular Pharmacology Unit, Avenue E. Mounier 73, B1.73.05, B-1200
Bruxelles, Belgium; Universidade de Lisboa, Faculdade de Farmácia, iMed.ULisboa -
Research Institute for Medicines, Av. Prof. Gama Pinto, 1649-003 Lisboa,
Portugal; Centro de Química-Física Molecular and Institute of Nanoscience and
Nanotechnology, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco
Pais, 1049-001 Lisboa, Portugal.
(2)Université catholique de Louvain, Louvain Drug Research Institute, Cellular
and Molecular Pharmacology Unit, Avenue E. Mounier 73, B1.73.05, B-1200
Bruxelles, Belgium.
(3)Université de Liège, CIRM, Laboratoire de Technologie Pharmaceutique et
Biopharmacie, Avenue de l'Hôpital 3, B-4000 Liège, Belgium.
(4)Université de Liège and CHU, Laboratory of Tumor & Development Biology
(GIGA-Cancer), Avenue Hippocrate 13, B-4000 Liège, Belgium.
(5)Universidade de Lisboa, Faculdade de Farmácia, iMed.ULisboa - Research
Institute for Medicines, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal; Centro 
de Química-Física Molecular and Institute of Nanoscience and Nanotechnology,
Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001
Lisboa, Portugal.
(6)Université de Liège, Gembloux Agro Bio-Tech, Laboratoire de Biophysique
Moléculaire aux Interfaces, Passage des Déportés, 2, B-5030 Gembloux, Belgium.
(7)Université catholique de Louvain, Louvain Drug Research Institute, Cellular
and Molecular Pharmacology Unit, Avenue E. Mounier 73, B1.73.05, B-1200
Bruxelles, Belgium. Electronic address: marie-paule.mingeot@uclouvain.be.

Budesonide (BUD), a poorly soluble anti-inflammatory drug, is used to treat
patients suffering from asthma and COPD (Chronic Obstructive Pulmonary Disease). 
Hydroxypropyl-β-cyclodextrin (HPβCD), 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 HPβCD
(BUD:HPβCD) 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:HPβCD on the
biophysical properties of membrane lipids. On cellular models (A549, lung
epithelial cells), BUD:HPβCD extracted cholesterol similarly to HPβCD. On large
unilamellar vesicles (LUVs), by using the fluorescent probes diphenylhexatriene
(DPH) and calcein, we demonstrated an increase in membrane fluidity and
permeability induced by BUD:HPβCD in vesicles containing cholesterol. On giant
unilamellar vesicles (GUVs) and lipid monolayers, BUD:HPβCD induced the
disruption of cholesterol-enriched raft-like liquid ordered domains as well as
changes in lipid packing and lipid desorption from the cholesterol monolayers,
respectively. Except for membrane fluidity, all these effects were enhanced when 
HPβCD was complexed with budesonide as compared with HPβCD. Since
cholesterol-enriched domains have been linked to membrane signaling including
pathways involved in inflammation processes, we hypothesized the effects of
BUD:HPβCD could be partly mediated by changes in the biophysical properties of
cholesterol-enriched domains.

Copyright © 2017 Elsevier B.V. All rights reserved.

DOI: 10.1016/j.bbamem.2017.06.010 
PMID: 28642042