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231226s2022 xx |||||o 00| ||eng c |
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|a 10.1021/acs.langmuir.2c00430
|2 doi
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|a pubmed25n1139.xml
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|a DE-627
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|a eng
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|a Ramezanpour, Mohsen
|e verfasserin
|4 aut
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|a Computational Insights into the Role of Cholesterol in Inverted Hexagonal Phase Stabilization and Endosomal Drug Release
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|c 2022
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|a Text
|b txt
|2 rdacontent
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|a ƒaComputermedien
|b c
|2 rdamedia
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|a ƒa Online-Ressource
|b cr
|2 rdacarrier
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|a Date Completed 22.06.2022
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|a Date Revised 10.06.2023
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|a published: Print-Electronic
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|a Citation Status MEDLINE
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|a Cholesterol is a major component of many lipid-based drug delivery systems, including cationic lipid nanoparticles. Despite its critical role in the drug release stage, the underlying molecular mechanism by which cholesterol assists in endosomal escape remains unclear. An efficient drug release from the endosome requires endosomal disruption. This disruption is believed to involve a lamellar-to-inverted hexagonal (Lα-HII) phase transition upon fusion of the lipid nanoparticle with the endosomal membrane. We used molecular dynamics simulations to study the structural properties of HII systems composed of an anionic lipid distearoyl phosphatidylserine (DSPS), an ionizable cationic lipid (KC2H), and cholesterol for several hydration levels and molar ratios. This system corresponds to the lipid mixtures in the hypothesized HII structure formed upon fusion and is of interest for the rational design of ionizable cationic lipids, including KC2, for an optimal drug release. Simulations suggest a geometry- and symmetry-driven lipid sorting and cholesterol-DSPS co-location around the water cores. Cholesterol preferentially co-locates with negatively charged saturated DSPS lipids at interstitial angles. The observed cholesterol-DSPS co-location results in an overall increase in the DSPS acyl chains' order parameters, which we propose to assist in stabilizing the HII phase by stretching the DSPS acyl chains for filling the voids formed by three adjacent lipid tubules. Furthermore, a systematic increase in the cholesterol concentration increased the lattice plane spacing and the water core radius but decreased the undulations along the lipid tubule axis. We propose that cholesterol and the degree of saturation/polyunsaturation of the lipid acyl chains, and not the lipid charge, are the main contributors in facilitating the Lα-HII phase transition and stabilizing/destabilizing the formed HII phase, whereas the positive charge of the ionizable cationic lipid promotes the LNP-endosomal membrane adhesion and assists in initiating the fusion process at the local contact area. We also propose that the effect of cholesterol on the HII structure and curvature is the main underlying reason for the well-documented HII stabilization and destabilization at low and high molar concentrations of cholesterol, respectively
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|a Journal Article
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|a Research Support, Non-U.S. Gov't
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|a Cations
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|a Lipid Nanoparticles
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|a Liposomes
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|a Phosphatidylethanolamines
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|a Water
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|a 059QF0KO0R
|2 NLM
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|a Cholesterol
|2 NLM
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|2 NLM
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|a Tieleman, D Peter
|e verfasserin
|4 aut
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| 773 |
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|i Enthalten in
|t Langmuir : the ACS journal of surfaces and colloids
|d 1985
|g 38(2022), 24 vom: 21. Juni, Seite 7462-7471
|w (DE-627)NLM098181009
|x 1520-5827
|7 nnas
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| 773 |
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|g volume:38
|g year:2022
|g number:24
|g day:21
|g month:06
|g pages:7462-7471
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|u http://dx.doi.org/10.1021/acs.langmuir.2c00430
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