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Research ArticleCardiovascular

A Fibrinogen-Derived Peptide Provides Intercellular Adhesion Molecule-1-Specific Targeting and Intraendothelial Transport of Polymer Nanocarriers in Human Cell Cultures and Mice

Carmen Garnacho, Daniel Serrano and Silvia Muro
Journal of Pharmacology and Experimental Therapeutics March 2012, 340 (3) 638-647; DOI: https://doi.org/10.1124/jpet.111.185579
Carmen Garnacho
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Daniel Serrano
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Silvia Muro
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Abstract

Intercellular adhesion molecule-1 (ICAM-1), a transmembrane glycoprotein expressed on activated endothelium and many other cells, represents a suitable target for delivery of drug nanocarriers (NCs) to disease areas. Numerous works have shown efficient targeting and intracellular transport of ICAM-1-targeted NCs, rendering significant therapeutic potential. This is the case for enzyme delivery for treatment of multitissue lysosomal storage disorders. However, those studies used formulations targeted to ICAM-1 by antibodies (anti-ICAM NCs). This poses an obstacle to preclinical evaluation of long-term treatment of such chronic maladies, caused by immunogenicity of foreign proteins administered to animals, compelling development of alternative strategies. In this work, we used radioisotope tracing, fluorescence and electron microscopy, and in vitro, cell cultures, and mouse models to evaluate polymer nanocarriers targeted to ICAM-1 by a 17-mer linear peptide derived from the ICAM-1-binding sequence of fibrinogen (γ3). Our results show that γ3 NCs target ICAM-1 with efficiency and specificity similar to that of anti-ICAM NCs, determined by using immobilized ICAM-1, native ICAM-1 expressed on endothelial cell cultures, and intravenous administration in mice. Furthermore, γ3 NCs are internalized by cells in culture and in vivo and transported to lysosomes via cell adhesion molecule-mediated endocytosis, without apparent disruption of cell junctions, similar to anti-ICAM counterparts. The degree of conservation of fibrinogen γ3 sequence and its cognate site on ICAM-1 among species (e.g., mouse, chimpanzee, and humans) reflects the interspecies targeting found for γ3 NCs, providing an avenue for exploring the translation of ICAM-1-targeting platforms in the preclinical and, perhaps, future clinical realm.

Footnotes

  • This work was supported by the National Institutes of Health National Heart, Lung and Blood Institute [Grant R01-HL98416] (to S.M.); and the American Heart Association [Grant 09BGIA2450014] (to S.M.).

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.111.185579.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    ICAM-1
    intercellular adhesion molecule-1
    CAM
    cell adhesion molecule
    BSA
    bovine serum albumin
    EC
    endothelial cell
    HUVEC
    human umbilical vein EC
    FITC
    fluorescein isothiocyanate
    ID
    injected dose
    NC
    nanocarrier
    PKC
    protein kinase C
    PMA
    phorbol 12-myristate 13-acetate
    TNFα
    tumor necrosis factor α
    scFV
    single-chain Fv construct
    VE
    vascular endothelial
    NHE1
    sodium/proton exchanger 1.

  • Received June 27, 2011.
  • Accepted November 29, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 340 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 340, Issue 3
1 Mar 2012
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Research ArticleCardiovascular

ICAM-1 Targeting of Carriers by a Fibrinogen-Derived Peptide

Carmen Garnacho, Daniel Serrano and Silvia Muro
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 638-647; DOI: https://doi.org/10.1124/jpet.111.185579

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Research ArticleCardiovascular

ICAM-1 Targeting of Carriers by a Fibrinogen-Derived Peptide

Carmen Garnacho, Daniel Serrano and Silvia Muro
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 638-647; DOI: https://doi.org/10.1124/jpet.111.185579
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