title: Novel peptide ligand directs liposomes toward EGF-R high-expressing cancer cells in vitro and in vivo.
abstract: Epidermal growth factor receptor (EGF-R) is an important target in anticancer therapy. Here we report how a novel EGF-R peptide ligand (D4: Leu-Ala-Arg-Leu-Leu-Thr) is identified using a computer-aided design approach from a virtual peptide library of putative EGF-R binding peptides by screening against the EGF-R X-ray crystal structure in silico and in vitro. The selected peptide is conjugated with a polyethylene glycol (PEG) lipid, and the lipid moiety of the peptide-PEG-lipid conjugate is inserted into liposome membranes by a postmodification process. D4 peptide-conjugated liposomes are found to bind to and enter cells by endocytosis specifically and efficiently in vitro in a process apparently mediated by EGF-R high-expressing cancer cells (H1299). In vivo, the D4 peptide-conjugated liposomes are found to accumulate in EGF-R-expressing xenograft tumor tissues up to 80 h after intravenous delivery, in marked contrast to controls. These results demonstrate how structure-based peptide design can be an efficient approach to identify highly novel binding ligands against important receptors. These data could have important consequences for the development of peptide-directed drug delivery systems with engineered specificities and prolonged times of action.
authors.affiliation: School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Shuxian
authors.initials: S
authors.lastname: Song
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.forename: Jinliang
authors.initials: J
authors.lastname: Peng
authors.forename: Hongwei
authors.initials: H
authors.lastname: Deng
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.forename: Lisa X
authors.initials: LX
authors.lastname: Xu
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Miller
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D045744:Cell Line, Tumor; D003198:Computer Simulation; D017076:Computer-Aided Design; D066246:ErbB Receptors / Q000737:chemistry / Q000187:drug effects*; D005434:Flow Cytometry; D006801:Humans; D008024:Ligands; D008081:Liposomes / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D019151:Peptide Library; D010714:Phosphatidylethanolamines / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D008081:Liposomes; D009842:Oligopeptides; D019151:Peptide Library; D010714:Phosphatidylethanolamines; C540794:leucyl-alanyl-arginyl-leucyl-leucyl-threonine; C038089:1,2-distearoylphosphatidylethanolamine; D066246:ErbB Receptors