Cholesterol Reduces Partitioning of Antifungal Drug Itraconazole into Lipid Bilayers.

Chetan Poojari,Alex Bunker,Tomasz Róg,Monika Dzieciuch-Rojek,Mariusz Kepczynski,Agata Zak

doi:10.1021/acs.jpcb.9b11005

Chetan Poojari, Alex Bunker + Show 4 more

Open Access

https://doi.org/10.1021/acs.jpcb.9b11005

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Abstract

Cholesterol plays a crucial role in modulating the physicochemical properties of biomembranes, both increasing mechanical strength and decreasing permeability. Cholesterol is also a common component of vesicle-based delivery systems, including liposome-based drug delivery systems (LDSs). However, its effect on the partitioning of drug molecules to lipid membranes is very poorly recognized. Herein, we performed a combined experimental/computational study of the potential for the use of the LDS formulation for the delivery of the antifungal drug itraconazole (ITZ). We consider the addition of cholesterol to the lipid membrane. Since ITZ is only weakly soluble in water, its bioavailability is limited. Use of an LDS has thus been proposed. We studied lipid membranes composed of cholesterol, 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (POPC), and ITZ using a combination of computational molecular dynamics (MD) simulations of lipid bilayers and Brewster angle microscopy (BAM) experiments of monolayers. Both experimental and computational results show separation of cholesterol and ITZ. Cholesterol has a strong preference to orient parallel to the bilayer normal. However, ITZ, a long and relatively rigid molecule with weakly hydrophilic groups along the backbone, predominantly locates below the interface between the hydrocarbon chain region and the polar region of the membrane, with its backbone oriented parallel to the membrane surface; the orthogonal orientation in the membrane could be the cause of the observed separation. In addition, fluorescence measurements demonstrated that the affinity of ITZ for the lipid membrane is decreased by the presence of cholesterol, which is thus probably not a suitable formulation component of an LDS designed for ITZ delivery.

Highlights

Pharmaceutical nanotechnology, known as nanomedicine,[1] is the development of nanoscale drug delivery vehicles, known as nanoparticles
The liposome-based delivery system (LDS) is, so far, the most successful form of the nanoparticle, representing more than half of all currently approved nanomedicine-based drug therapies.[2−4] An liposome-based drug delivery systems (LDSs) is composed of a phospholipid membrane formed into an enclosed sac; use of phospholipids and other biocompatible molecules for the membrane possesses the advantage of automatic biocompatibility
The difference lies in the ITZ orientation after insertion: in the POPC bilayer, the drug molecules orient their long axis parallel to the bilayer surface, while in the POPC/Chol membrane, ITZ molecules remain perpendicular to the membrane surface

Summary

Introduction

Pharmaceutical nanotechnology, known as nanomedicine,[1] is the development of nanoscale drug delivery vehicles, known as nanoparticles. It can be seen as the development of mechanisms to both increase efficacy and reduce toxicity associated with a given drug by targeting the delivery to the desired tissue, through either active or passive means; a specific dose of the drug can have an increased efficacy with reduced side effects. The liposome-based delivery system (LDS) is, so far, the most successful form of the nanoparticle, representing more than half of all currently approved nanomedicine-based drug therapies.[2−4] An LDS is composed of a phospholipid membrane formed into an enclosed sac; use of phospholipids and other biocompatible molecules for the membrane possesses the advantage of automatic biocompatibility. Other amphiphilic biocompatible molecules can be added to the membrane to tune its properties; the most commonly used of these is cholesterol (Chol)

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