Molecular Dynamics Simulation of PEGylated Membranes with Cholesterol: Building Toward the DOXIL Formulation

PEGylation has been used successfully to increase the circulation time of drug delivery liposomes by providing an external steric sheath. In all FDA approved PEGylated drug delivery liposomes, cholesterol is a key component. In a continuation of our previous work we have simulated a PEGylated membrane with cholesterol added to the membrane formulation to determine the effect on membrane structure of the cholesterol–PEG interaction. We show that, like the case for the liquid crystalline membrane, PEG enters into the lipid bilayer, however, in a specific fashion: the PEG winds along the β face of the cholesterol. Additionally, PEG interferes with the role cholesterol plays in structuring and compacting the membrane; when the membrane is PEGylated, the area per lipid increases, rather than decreases, with increasing cholesterol. Our studies provide mechanistic explanations for existing experimental results concerning the effect of adding cholesterol to the PEGylated liposome, including alteration to the liposome compressibility and permeability, and the possible PEG-induced release of cholesterol from the membrane.