Specific penetration and accumulation of a homing peptide within atherosclerotic plaques of apolipoprotein E-deficient mice

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-04, Vol.108 (17), p.7154-7159
• Main Authors: Hamzah, Juliana, Kotamraju, Venkata R, Seo, Jai W, Agemy, Lilach, Fogal, Valentina, Mahakian, Lisa M, Peters, David, Roth, Lise, Gagnon, M. Karen J, Ferrara, Katherine W, Ruoslahti, Erkki
• Format: Article
• Language: English
• Subjects: Amino acids; Animals; Antibodies; Aorta; Aorta - metabolism; Aorta - pathology; apolipoprotein E; Apolipoproteins; Apolipoproteins E; Atherosclerosis; Atherosclerosis - drug therapy; Atherosclerosis - genetics; Atherosclerosis - metabolism; Atherosclerosis - pathology; Biological Sciences; Cells; Drug Delivery Systems - methods; Female; Ferric Compounds - pharmacokinetics; Ferric Compounds - pharmacology; fluorescence; Gene expression; high fat diet; Homing; Imaging; intravenous injection; iron oxides; Macrophages; Mice; Mice, Mutant Strains; Nanoparticles; neoplasm cells; Oligopeptides - pharmacokinetics; Oligopeptides - pharmacology; Peptides; Peptides, Cyclic - pharmacokinetics; Peptides, Cyclic - pharmacology; Positron emission tomography; Rodents; tissues; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1104540108

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-[¹⁸F]fluorobenzoic acid ([¹⁸F]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 [¹⁸F]FBA-LyP-1(0.08% ID/g, P < 0.01) or aortas from atherosclerotic ApoE mice injected with [¹⁸F]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.