Study of PEGylated Lipid Layers as a Model for PEGylated Liposome Surfaces: Molecular Dynamics Simulation and Langmuir Monolayer Studies

Abstract

We have combined Langmuir monolayer film experiments and all-atom molecular dynamics (MD) simulation of a bilayer to study the surface structure of a PEGylated liposome and its interaction with the ionic environment present under physiological conditions. Lipids that form both gel and liquid-crystalline membranes have been used in our study. By varying the salt concentration in the Langmuir film experiment and including salt at the physiological level in the simulation, we have studied the effect of salt ions present in the blood plasma on the structure of the poly(ethylene glycol) (PEG) layer. We have also studied the interaction between the PEG layer and the lipid bilayer in both the liquid-crystalline and gel states. The MD simulation shows two clear results: (a) The Na(+) ions form close interactions with the PEG oxygens, with the PEG chains forming loops around them and (b) PEG penetrates the lipid core of the membrane for the case of a liquid-crystalline membrane but is excluded from the tighter structure of the gel membrane. The Langmuir monolayer results indicate that the salt concentration affects the PEGylated lipid system, and these results can be interpreted in a fashion that is in agreement with the results of our MD simulation. We conclude that the currently accepted picture of the PEG surface layer acting as a generic neutral hydrophilic polymer entirely outside the membrane, with its effect explained through steric interactions, is not sufficient. The phenomena we have observed may affect both the interaction between the liposome and bloodstream proteins and the liquid-crystalline-gel transition and is thus relevant to nanotechnological drug delivery device design.

Thermotropic Phase Behavior of Hydrogenated Soybean Phosphatidylcholine–Cholesterol Binary Liposome Membrane

“…However, recent molecular dynamics simulations and Langmuir monolayer measurements suggested that PEG-lipids may insert their polyether moiety into the fluid phase phospholipid bilayers. 25) In this regard, the quantitative assessment of liposome membrane fluidity by using the GP values for Prodan (Fig. 6A) indicates that the hydrophilic region in liposome membrane appears to be somewhat perturbed by incorporated PEG-lipids.…”

The design of shape-tunable hairy vesicles

“…A common route to designing sterically stable liposomes is via the grafting of polyethylene glycol (PEG) chains to the lipid head groups [6][7][8]. PEG chains have been shown to control the size [8][9][10], morphology [10][11][12], compressibility [9,13], encapsulation efficiency [8,14,15] and permeability of liposomes [8,14]. Experimental and computational studies have investigated the morphology of binary mixtures of PEGylated and non-PEGylated lipids [10,11,13,16]; and their dynamics and stability [6,11,13], for species composed of the same hydrocarbon tail groups [8,10,14,17,18].…”

Repelling and ordering: the influence of poly(ethylene glycol) on protein adsorption

“…9,14 For our study we chose an intermediate chain length, namely PEG2000, since it is commonly used for nanoparticle functionalization and in PEGylated liposomes. 18,25,53 The small SFG signal present in the amide I region for the mixed monolayer with 5 mol% DMPE-PEG2000, is a feature sometimes observed, even in absence of proteins, and is most likely caused by a contribution from the water bending mode. However, below we will consider differential spectra with and without protein, so that this is not a problem (for further details see Section SIIB and Fig.…”