title: Specific penetration and accumulation of a homing peptide within atherosclerotic plaques of apolipoprotein E-deficient mice.
abstract: The ability to selectively deliver compounds into atherosclerotic plaques would greatly benefit the detection and treatment of atherosclerotic disease. We describe such a delivery system based on a 9-amino acid cyclic peptide, LyP-1. LyP-1 was originally identified as a tumor-homing peptide that specifically recognizes tumor cells, tumor lymphatics, and tumor-associated macrophages. As the receptor for LyP-1, p32, is expressed in atherosclerotic plaques, we tested the ability of LyP-1 to home to plaques. Fluorescein-labeled LyP-1 was intravenously injected into apolipoprotein E (ApoE)-null mice that had been maintained on a high-fat diet to induce atherosclerosis. LyP-1 accumulated in the plaque interior, predominantly in macrophages. More than 60% of cells released from plaques were positive for LyP-1 fluorescence. Another plaque-homing peptide, CREKA, which binds to fibrin-fibronectin clots and accumulates at the surface of plaques, yielded fewer positive cells. Tissues that did not contain plaque yielded only traces of LyP-1(+) cells. LyP-1 was capable of delivering intravenously injected nanoparticles to plaques; we observed abundant accumulation of LyP-1-coated superparamagnetic iron oxide nanoparticles in the plaque interior, whereas CREKA-nanoworms remained at the surface of the plaques. Intravenous injection of 4-[(18)F]fluorobenzoic acid ([(18)F]FBA)-conjugated LyP-1 showed a four- to sixfold increase in peak PET activity in aortas containing plaques (0.31% ID/g) compared with aortas from normal mice injected with [(18)F]FBA-LyP-1(0.08% ID/g, P < 0.01) or aortas from atherosclerotic ApoE mice injected with [(18)F]FBA-labeled control peptide (0.05% ID/g, P < 0.001). These results indicate that LyP-1 is a promising agent for the targeting of atherosclerotic lesions.
authors.affiliation: Vascular Biology Laboratory, Center for Nanomedicine, The Sanford-Burnham Medical Research Institute, Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106-9610, USA.
authors.forename: Juliana
authors.initials: J
authors.lastname: Hamzah
authors.forename: Venkata R
authors.initials: VR
authors.lastname: Kotamraju
authors.forename: Jai W
authors.initials: JW
authors.lastname: Seo
authors.forename: Lilach
authors.initials: L
authors.lastname: Agemy
authors.forename: Valentina
authors.initials: V
authors.lastname: Fogal
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Mahakian
authors.forename: David
authors.initials: D
authors.lastname: Peters
authors.forename: Lise
authors.initials: L
authors.lastname: Roth
authors.forename: M Karen J
authors.initials: MK
authors.lastname: Gagnon
authors.forename: Katherine W
authors.initials: KW
authors.lastname: Ferrara
authors.forename: Erkki
authors.initials: E
authors.lastname: Ruoslahti
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E; D050197:Atherosclerosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D005290:Ferric Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D053758:Nanoparticles; D009842:Oligopeptides / Q000493:pharmacokinetics / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D001057:Apolipoproteins E; D005290:Ferric Compounds; C533969:LyP-1 peptide; D009842:Oligopeptides; D010456:Peptides, Cyclic; C542438:cysteinyl-arginyl-glutamyl-lysyl-alanyl; C000499:ferric oxide