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

Juliana Hamzah, Venkata R. Kotamraju, Jai Seo, Lilach Agemy, Valentina Fogal, Lisa M. Mahakian, David Peters, Lise Roth, M. Karen J Gagnon, Katherine W. Ferrara, Erkki Ruoslahti

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73 Scopus citations

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-[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.

Original languageEnglish (US)
Pages (from-to)7154-7159
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number17
DOIs
StatePublished - Apr 26 2011

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Keywords

  • Cell-penetrating peptide
  • In vivo imaging
  • p32/gC1qR/hyaluronic acid binding protein1
  • Plaque-associated macrophages

ASJC Scopus subject areas

  • General

Cite this

Hamzah, J., Kotamraju, V. R., Seo, J., Agemy, L., Fogal, V., Mahakian, L. M., Peters, D., Roth, L., Gagnon, M. K. J., Ferrara, K. W., & Ruoslahti, E. (2011). Specific penetration and accumulation of a homing peptide within atherosclerotic plaques of apolipoprotein E-deficient mice. Proceedings of the National Academy of Sciences of the United States of America, 108(17), 7154-7159. https://doi.org/10.1073/pnas.1104540108