Membrane Interaction of Ibuprofen with Cholesterol-Containing Lipid Membranes.

Jan Kremkow,Meike Luck,Holger A Scheidt,Peter Müller,Daniel Huster

doi:10.3390/biom10101384

Jan Kremkow, Meike Luck + Show 3 more

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https://doi.org/10.3390/biom10101384

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Journal: Biomolecules	Publication Date: Sep 28, 2020
Citations: 19	License type: CC BY 4.0

Affiliation: Leipzig University, Humboldt-Universität zu Berlin

Abstract

Deciphering the membrane interaction of drug molecules is important for improving drug delivery, cellular uptake, and the understanding of side effects of a given drug molecule. For the anti-inflammatory drug ibuprofen, several studies reported contradictory results regarding the impact of ibuprofen on cholesterol-containing lipid membranes. Here, we investigated membrane localization and orientation as well as the influence of ibuprofen on membrane properties in POPC/cholesterol bilayers using solid-state NMR spectroscopy and other biophysical assays. The presence of ibuprofen disturbs the molecular order of phospholipids as shown by alterations of the 2H and 31P-NMR spectra of the lipids, but does not lead to an increased membrane permeability or changes of the phase state of the bilayer. 1H MAS NOESY NMR results demonstrate that ibuprofen adopts a mean position in the upper chain/glycerol region of the POPC membrane, oriented with its polar carbonyl group towards the aqueous phase. This membrane position is only marginally altered in the presence of cholesterol. A previously reported result that ibuprofen is expelled from the membrane interface in cholesterol-containing DMPC bilayers could not be confirmed.

Highlights

The binding to and molecular interactions of small amphiphilic drug molecules with lipid membranes are of fundamental interest for tailored drug delivery, prevention of unwanted side effects, and alterations of membrane properties which can influence the biological function of non-cognate receptors [1,2]
One very interesting finding from these studies is a dramatic difference of the membrane position of ibuprofen in cholesterol-free membranes as oppose to cholesterol-containing DMPC bilayers in the gel state, which was described by Alsop et al [3] using X-ray diffraction techniques
It should be noted that the membrane localization of ibuprofen in the absence of cholesterol was confirmed in numerous other studies using different experimental approaches as well as molecular dynamics simulations [4,5,6,7,8]

Summary

Introduction

The binding to and molecular interactions of small amphiphilic drug molecules with lipid membranes are of fundamental interest for tailored drug delivery, prevention of unwanted side effects, and alterations of membrane properties which can influence the biological function of non-cognate receptors [1,2]. One very interesting finding from these studies is a dramatic difference of the membrane position of ibuprofen in cholesterol-free membranes as oppose to cholesterol-containing DMPC bilayers in the gel state, which was described by Alsop et al [3] using X-ray diffraction techniques. These authors found that ibuprofen is expelled from the DMPC membrane in the presence of cholesterol, while the drug was localized in the hydrophobic chain region of phospholipid bilayers in the absence of cholesterol. The use of solid-state NMR implicates the advantage of higher hydration levels of the samples compared to scattering methods and can provide conditions, which are somewhat closer to a native environment

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