title: Nanoparticle delivery of a peptide targeting EGFR signaling.
abstract: EGFR serves as an important therapeutic target because of its over-expression in many cancers. In this study, we investigated a peptide-based therapy aimed at blocking intracellular protein-protein interactions during EGFR signaling and evaluated a targetable lipid carrier system that can deliver peptides to intracellular targets in human cancer cells. EEEEpYFELV (EV), a nonapeptide mimicking the Y845 site of EGFR which is responsible for STAT5b phosphorylation, was designed to block EGFR downstream signaling. EV was loaded onto LPH nanoparticles that are comprised of a membrane/core structure including a surface-grafted polyethylene glycol (PEG) used to evade the reticuloendothelial system (RES) and anisamide (AA) for targeting the sigma receptor over-expressed in H460 human lung cancer cells. EV formulated with PEGylated and targeted LPH (LPH-PEG-AA) was taken up by the tumor cells and trafficked to the cytoplasm with high efficiency. Using this approach, EV acted as a dominant negative inhibitor of STAT5b phosphorylation, arrested cell proliferation, and induced massive apoptosis. Intravenous administration of EV loaded in LPH-PEG-AA led to efficient EV peptide delivery to the tumor in a xenograft mouse model, and multiple injections inhibited tumor growth in a dose-dependent manner. Our findings offer proof-of-concept for an intracellular peptide-mediated cancer therapy that is delivered by carefully designed nanoparticles.
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Sang Kyoon
authors.initials: SK
authors.lastname: Kim
authors.forename: Leaf
authors.initials: L
authors.lastname: Huang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004337:Drug Carriers / Q000008:administration & dosage*; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006493:Heparin / Q000008:administration & dosage; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D053758:Nanoparticles / Q000008:administration & dosage*; D009369:Neoplasms / Q000473:pathology / Q000628:therapy*; D009842:Oligopeptides / Q000008:administration & dosage*; D010766:Phosphorylation / Q000187:drug effects; D011479:Protamines / Q000008:administration & dosage; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D004337:Drug Carriers; D008081:Liposomes; D009842:Oligopeptides; D011479:Protamines; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; D006493:Heparin; D066246:ErbB Receptors