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

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Mahmoudzadeh , M , Magarkar , A , Koivuniemi , A , Róg , T & Bunker , A 2021 , ' Mechanistic Insight into How PEGylation Reduces the Efficacy of pH-Sensitive Liposomes from Molecular Dynamics Simulations ' , Molecular Pharmaceutics , vol. 18 , no. 7 , pp. 2612-2621 . https://doi.org/10.1021/acs.molpharmaceut.1c00122

Title: Mechanistic Insight into How PEGylation Reduces the Efficacy of pH-Sensitive Liposomes from Molecular Dynamics Simulations
Author: Mahmoudzadeh, Mohammad; Magarkar, Aniket; Koivuniemi, Artturi; Róg, Tomasz; Bunker, Alex
Contributor organization: Divisions of Faculty of Pharmacy
Pharmaceutical biophysics group
Division of Pharmaceutical Biosciences
Drug Research Program
Faculty of Pharmacy
Date: 2021-07-05
Language: eng
Number of pages: 10
Belongs to series: Molecular Pharmaceutics
ISSN: 1543-8384
DOI: https://doi.org/10.1021/acs.molpharmaceut.1c00122
URI: http://hdl.handle.net/10138/332757
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.
Subject: ATOM FORCE-FIELD
DRUG-DELIVERY
EFFECTIVE INCLUSION
HEXAGONAL PHASE
INDUCED DESTABILIZATION
LIPID-BILAYERS
PARTICLE MESH EWALD
PEGylated pH-sensitive liposomes
PHASE-TRANSITION
POTENTIAL FUNCTIONS
TRIGGERED RELEASE
bilayer hydrophilicity
cholesteryl hemisuccinate
molecular dynamics simulations
phase transition
317 Pharmacy
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: acceptedVersion


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