title: Analysis of cause of failure of new targeting peptide in PEGylated liposome: molecular modeling as rational design tool for nanomedicine.
abstract: Drug nanocarriers are often derivatized with targeting moieties to achieve site specific delivery, however, the results from this approach have, as yet, not reached expectations. We have tested a new phage display based targeting moiety, the activated endothelium targeting peptide (AETP), for its vascular endothelium directed targeting efficiency, when anchored to a PEGylated liposome via maleimide chemistry. Our results have, however, not shown any evidence of improved targeting. We have hypothesized that the failure of the AETP moiety is due to its availability to target receptors being restricted, as a result of steric hindrance due to the PEG polymer, and possibly affinity for bloodstream proteins, particularly human serum albumin (HSA). In this context, molecular modeling was used to contrast the properties of the AETP moiety to those of the RGD targeting peptide, already found to be effective in previous trials. Our molecular dynamics simulation results indicate the AETP moiety is located within the PEG layer, and its hydrophobic nature causes it to be obscured by PEG to a greater extent than the more hydrophilic RGD targeting peptide. Protein-ligand docking results indicated similar affinities for HSA of both the AETP moiety and a PEG fragment, and a significantly lower affinity for the RGD peptide. We know of no means to investigate this experimentally with atomic level resolution, thus our use of computational methods to investigate this can be seen as a new tool for rational design in nanomedicine.
authors.affiliation: Centre for Drug Research, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
authors.forename: Julia
authors.initials: J
authors.lastname: Lehtinen
authors.forename: Aniket
authors.initials: A
authors.lastname: Magarkar
authors.forename: Michał
authors.initials: M
authors.lastname: Stepniewski
authors.forename: Satu
authors.initials: S
authors.lastname: Hakola
authors.forename: Mathias
authors.initials: M
authors.lastname: Bergman
authors.forename: Tomasz
authors.initials: T
authors.lastname: Róg
authors.forename: Marjo
authors.initials: M
authors.lastname: Yliperttula
authors.forename: Arto
authors.initials: A
authors.lastname: Urtti
authors.forename: Alex
authors.initials: A
authors.lastname: Bunker
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D002478:Cells, Cultured; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D042783:Endothelial Cells / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects; D005260:Female; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008081:Liposomes / Q000008:administration & dosage* / Q000737:chemistry*; D008301:Maleimides / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D058990:Molecular Targeted Therapy / Q000379:methods*; D050997:Nanomedicine / Q000379:methods; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry*; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D004337:Drug Carriers; D008024:Ligands; D008081:Liposomes; D008301:Maleimides; D010455:Peptides; D011956:Receptors, Cell Surface; C043592:maleimide; D011092:Polyethylene Glycols