title: A computational study suggests that replacing PEG with PMOZ may increase exposure of hydrophobic targeting moiety.
abstract: In a previous study we showed that the cause of failure of a new, proposed, targeting ligand, the AETP moiety, when attached to a PEGylated liposome, was occlusion by the poly(ethylene glycol) (PEG) layer due to its hydrophobic nature, given that PEG is not entirely hydrophilic. At the time we proposed that possible replacement with a more hydrophilic protective polymer could alleviate this problem. In this study we have used computational molecular dynamics modelling, using a model with all atom resolution, to suggest that a specific alternative protective polymer, poly(2-methyloxazoline) (PMOZ), would perform exactly this function. Our results show that when PEG is replaced by PMOZ the relative exposure to the solvent of AETP is increased to a level even greater than that we found in previous simulations for the RGD peptide, a targeting moiety that has previously been used successfully in PEGylated liposome based therapies. While the AETP moiety itself is no longer under consideration, the results of this computational study have broader significance: the use of PMOZ as an alternative polymer coating to PEG could be efficacious in the context of more hydrophobic targeting ligands. In addition to PMOZ we studied another polyoxazoline, poly(2-ethyloxazoline) (PEOZ), that has also been mooted as a possible alternate protective polymer. It was also found that the RDG peptide occlusion was significantly greater for the case of both oxazolines as opposed to PEG and that, unlike PEG, neither oxazoline entered the membrane. As far as we are aware this is the first time that polyoxazolines have been studied using molecular dynamics simulation with all atom resolution.
authors.affiliation: Drug Research Program, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland; Institute of Organic Chemistry and Biochemistry, Academy of the Sciences of the Czech Republic Prague, Czech Republic.
authors.forename: Aniket
authors.initials: A
authors.lastname: Magarkar
authors.affiliation: Department of Physics, University of Helsinki, Helsinki, Finland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Róg
authors.affiliation: Drug Research Program, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland. Electronic address: alex.bunker@helsinki.fi.
authors.forename: Alex
authors.initials: A
authors.lastname: Bunker
mesh_terms: D002784:Cholesterol / Q000737:chemistry; D016503:Drug Delivery Systems; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008081:Liposomes / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D009842:Oligopeptides / Q000737:chemistry; D010713:Phosphatidylcholines / Q000737:chemistry*; D011073:Polyamines / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D013499:Surface Properties
chemical_list: D008024:Ligands; D008081:Liposomes; D009842:Oligopeptides; D010713:Phosphatidylcholines; D011073:Polyamines; C511916:poly(2-ethyl-2-oxazoline); C000625732:poly(2-methyloxazoline); D011092:Polyethylene Glycols; C047981:arginyl-glycyl-aspartic acid; D002784:Cholesterol; C010942:1,2-distearoyllecithin
keywords: Liposome; Molecular dynamics; Nanomedicine; PEGylation; Polyoxazolines; Targeted delivery