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Biochim Biophys Acta Biomembr. 2017 Oct;1859(10):1930-1940. doi: 10.1016/j.bbamem.2017.06.010. Epub 2017 Jun 20.

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

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.

Abstract

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.

KEYWORDS:

Cholesterol; Drug-membrane interaction; Fluidity; Langmuir; Liposomes; Permeability

PMID:
28642042
DOI:
10.1016/j.bbamem.2017.06.010
[Indexed for MEDLINE]
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