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(Circulation Research. 2005;96:327.)
© 2005 American Heart Association, Inc.

Cellular Biology

Detection of Vascular Adhesion Molecule-1 Expression Using a Novel Multimodal Nanoparticle

Kimberly A. Kelly^*, Jennifer R. Allport^*, Andrew Tsourkas, Vivek R. Shinde-Patil, Lee Josephson, Ralph Weissleder

From the Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown.

Correspondence to Ralph Weissleder, MD, PhD, Professor, Harvard Medical School Director, Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, 149 13th St, Room 5404, Charlestown, MA 02129. E-mail weissleder{at}helix.mgh.harvard.edu

Endothelial vascular adhesion molecule-1 (VCAM-1) is a critical component of the leukocyte–endothelial adhesion cascade, and its strict temporal and spatial regulation make it an ideal target for imaging and therapy. The goal of this study was to develop novel VCAM-1–targeted imaging agents detectable by MRI and fluorescence imaging using phage display–derived peptide sequences and multimodal nanoparticles (NPs). We hypothesized that VCAM-1–mediated cell internalization of phage display–selected peptides could be harnessed as an amplification strategy to chaperone and trap imaging agents inside VCAM-1–expressing cells, thus improving target-to-background ratios. To accomplish our goal, iterative phage display was performed on murine endothelium under physiological flow conditions to identify a family of VCAM-1–mediated cell-internalizing peptides. One specific sequence, containing the VHSPNKK motif that has homology to the -chain of very late antigen (a known ligand for VCAM-1), was shown to bind VCAM-1 and block leukocyte–endothelial interactions. Compared with VCAM-1 monoclonal antibody, the peptide showed 12-fold higher target-to-background ratios. A VHSPNKK-modified magnetofluorescent NP (VNP) showed high affinity for endothelial cells expressing VCAM-1 but surprisingly low affinity for macrophages. In contrast, a control NP without VCAM-1–targeting sequences showed no affinity for endothelial cells. In vivo, VNP successfully identified VCAM-1–expressing endothelial cells in a murine tumor necrosis factor-–induced inflammatory model and colocalized with VCAM-1–expressing cells in atherosclerotic lesions present in cholesterol-fed apolipoprotein E apoE^–/– mice. These results indicate that: (1) small peptide sequences can significantly alter targeting of NPs, (2) the used amplification strategy of internalization results in high target-to-background ratios, and (3) this technology is useful for in vivo imaging of endothelial markers.

Key Words: cardiovascular diseases • cell adhesion molecules • imaging • inflammation • vasculature

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