期刊
MOLECULAR PHARMACEUTICS
卷 18, 期 7, 页码 2612-2621出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.1c00122
关键词
molecular dynamics simulations; PEGylated pH-sensitive liposomes; cholesteryl hemisuccinate; phase transition; bilayer hydrophilicity
资金
- Academy of Finland [287963]
- Center for international mobility [TM-15-9898]
- Magnus Ehrnrooth Foundation
- OLVI foundation [2020032]
- Tor, Joe and Pentti Borg foundation
- Finnish-Norwegian Medical Foundation
- Vare Children Cancer Foundation
- Academy of Finland (AKA) [287963, 287963] Funding Source: Academy of Finland (AKA)
In this study, molecular dynamics simulations were used to investigate the mechanism behind the reduced pH sensitivity of DOPE-CHMS liposomes containing PEG, as well as how CHSa stabilizes DOPE bilayers and the destabilization process triggered by the change to CHS at acidic pH. It was found that the presence of PEG increases the area per lipid in the bilayer, which stabilizes the liposomes and reduces their pH sensitivity.
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.
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