Mechanistic Insight into How PEGylation Reduces the Efficacy of pH-Sensitive Liposomes from Molecular Dynamics Simulations.

Mohammad Mahmoudzadeh,Aniket Magarkar,Alex Bunker,Artturi Koivuniemi,Tomasz Róg

doi:10.1021/acs.molpharmaceut.1c00122

Mohammad Mahmoudzadeh, Aniket Magarkar + Show 3 more

Open Access

https://doi.org/10.1021/acs.molpharmaceut.1c00122

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Abstract

Liposome-based drug delivery systems composed of DOPE stabilized with cholesteryl hemisuccinate (CHMS) have been proposed as a drug delivery mechanism with pH-triggered release as the anionic form (CHSa) is protonated (CHS) at reduced pH; PEGylation is known to decrease this pH sensitivity. In this manuscript, we set out to use molecular dynamics (MD) simulations with a model with all-atom resolution to provide insight into why incorporation of poly(ethyleneglycol) (PEG) into DOPE–CHMS liposomes reduces their pH sensitivity; we also address two additional questions: (1) How CHSa stabilizes DOPE bilayers into a lamellar conformation at a physiological pH of 7.4? and (2) how the change from CHSa to CHS at acidic pH triggers the destabilization of DOPE bilayers? We found that (A) CHSa stabilizes the DOPE lipid membrane by increasing the hydrophilicity of the bilayer surface, (B) when CHSa changes to CHS by pH reduction, DOPE bilayers are destabilized due to a reduction in bilayer hydrophilicity and a reduction in the area per lipid, and (C) PEG stabilizes DOPE bilayers into the lamellar phase, thus reducing the pH sensitivity of the liposomes by increasing the area per lipid through penetration into the bilayer, which is our main focus.

Highlights

Lipid bilayers are of great importance in pharmaceutical nanotechnology
To understand why PEGylation reduces the sensitivity of pHsensitive liposomes and, how CHSa stabilizes di-oleoyl PE (DOPE) bilayers and how the change from CHSa to CHS destabilizes them, we have conducted molecular dynamics (MD) simulations of DOPE systems containing CHOL, CHS, and CHSa with and without PEG
Since the stabilization and destabilization of the DOPE ensemble result from the phase transition, using our results and those obtained by experimental evaluations, we attempt to justify this observed behavior in the context of lipid hydration and the dynamic molecular shape theory applied to lipids, introduced by Cullis et al.[70]

Summary

Introduction

Lipid bilayers are of great importance in pharmaceutical nanotechnology. They can be formed into liposomes that can, in turn, be used as a nanoscale delivery system for small drug molecules,[1−4] nucleic acids,[4−7] and proteins.[8] The dominant mechanism through which liposomes enter the cell is endocytosis, where they undergo enzymatic degradation by lysosomes.[9] To disrupt this process, pH-sensitive liposomes have been proposed; in an acidic environment found within endosomes, they can destabilize the endosomal membrane, disrupting the formation of the lysosomal environment.[9] pHsensitive liposomes are formulated from a variety of lipid molecule types with the pH sensitivity achieved through several different possible mechanisms. Mamasheva et al constructed liposomes in which pH change triggers phase separation

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