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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Anti-vascular cell adhesion molecule monoclonal antibody M/K-2.7 conjugated cross-linked iron oxide-Cy5.5 nanoparticles - Molecular Imaging and Contrast Agent Database (MICAD) - NCBI Bookshelf</title>
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<meta name="citation_title" content="Anti-vascular cell adhesion molecule monoclonal antibody M/K-2.7 conjugated cross-linked iron oxide-Cy5.5 nanoparticles">
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<meta name="citation_date" content="2007/10/29">
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<meta name="citation_author" content="Kam Leung">
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stroke-linecap="round" style="fill:#FFF" d="m320,350a153,153 0 1,0-2,2l170,170m-91-117 110,110-26,26-110-110"></path></svg></a><a id="jr-fip-done" class="wsprkl btn" title="Dismiss find">✘</a></nav><nav id="jr-fip-info-p"><a id="jr-fip-prev" class="wsprkl btn" title="Jump to previuos match">◀</a><button id="jr-fip-matches">no matches yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK23029_"><span class="title" itemprop="name">Anti-vascular cell adhesion molecule monoclonal antibody M/K-2.7 conjugated cross-linked iron oxide-Cy5.5 nanoparticles</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">VCAM-NP</div><p class="contribs">Leung K.</p><p class="fm-aai"><a href="#_NBK23029_pubdet_">Publication Details</a></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figVCAM1CLIOCy55T1"><a href="/books/NBK23029/table/VCAM-1-CLIO-Cy55.T1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figVCAM1CLIOCy55T1" rid-ob="figobVCAM1CLIOCy55T1"><img class="small-thumb" src="/books/NBK23029/table/VCAM-1-CLIO-Cy55.T1/?report=thumb" src-large="/books/NBK23029/table/VCAM-1-CLIO-Cy55.T1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="VCAM-1-CLIO-Cy55.T1"><a href="/books/NBK23029/table/VCAM-1-CLIO-Cy55.T1/?report=objectonly" target="object" rid-ob="figobVCAM1CLIOCy55T1">Table</a></h4><p class="float-caption no_bottom_margin">
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<i>In vitro</i>
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Rodents
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</p></div></div><div id="VCAM-1-CLIO-Cy55.Background"><h2 id="_VCAM-1-CLIO-Cy55_Background_">Background</h2><p>[<a href="/entrez/query.fcgi?cmd=PureSearch&db=pubmed&details_term=VCAM-1+nanoparticle" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PubMed</a>]</p><p>Optical fluorescence imaging is increasingly being used to obtain images of biological functions of specific targets <i>in vitro</i> and in small animals (<a class="bibr" href="#VCAM-1-CLIO-Cy55.EXTYLES.1" rid="VCAM-1-CLIO-Cy55.EXTYLES.1">1</a>, <a class="bibr" href="#VCAM-1-CLIO-Cy55.EXTYLES.2" rid="VCAM-1-CLIO-Cy55.EXTYLES.2">2</a>). Near-infrared (NIR) fluorescence (700–900 nm) detection avoids the background fluorescence interference of natural biomolecules, providing a high contrast between target and background tissues. NIR fluorescence imaging is becoming a non-invasive alternative to radionuclide imaging <i>in vitro</i> and in small animals.</p><p>Magnetic resonance imaging (MRI) maps information about tissues spatially and functionally. Protons (hydrogen nuclei) are widely used to create images because of their abundance in water molecules, which comprise >80% of most soft tissues. The contrast of proton MRI images depends mainly on the nuclear density (proton spins), the relaxation times of the nuclear magnetization (T1, longitudinal; T2, transverse), the magnetic environment of the tissues, and the blood flow to the tissues. However, insufficient contrast between normal and diseased tissues requires the use of contrast agents. Most contrast agents affect the T1 and T2 relaxation times of the surrounding nuclei, mainly the protons of water. T2* is the spin–spin relaxation time composed of variations from molecular interactions and intrinsic magnetic heterogeneities of tissues in the magnetic field (<a class="bibr" href="#VCAM-1-CLIO-Cy55.EXTYLES.3" rid="VCAM-1-CLIO-Cy55.EXTYLES.3">3</a>). Cross-linked iron oxide (CLIO) nanoparticles and other iron oxide formulations affect T2 primarily and lead to a decreased signal.</p><p>A multimodal nanoparticle probe that consists of a contrast agent and a NIR fluorochrome may provide consistent information. CLIO nanoparticles can be internalized by cells of the reticuloendothelial system and have long circulating times within an animal body. The blood half-life of CLIO is about 10 h in mice (<a class="bibr" href="#VCAM-1-CLIO-Cy55.EXTYLES.4" rid="VCAM-1-CLIO-Cy55.EXTYLES.4">4</a>). The accumulation of nanoparticles in cells causes a reduction in signal intensity with T2-weighted (T2*W) spin-echo pulse sequences. NIR fluorochromes (e.g., Cy5.5) provide an improved optical (NIR) signal from tissue. <a href="/books/n/micad/CLIO-Cy55/?report=reader">CLIO-Cy5.5</a> has been developed as a probe for multimodality imaging (<a class="bibr" href="#VCAM-1-CLIO-Cy55.EXTYLES.5" rid="VCAM-1-CLIO-Cy55.EXTYLES.5">5</a>).</p><p>Endothelial cells are important in inflammatory responses (<a class="bibr" href="#VCAM-1-CLIO-Cy55.EXTYLES.6" rid="VCAM-1-CLIO-Cy55.EXTYLES.6">6</a>, <a class="bibr" href="#VCAM-1-CLIO-Cy55.EXTYLES.7" rid="VCAM-1-CLIO-Cy55.EXTYLES.7">7</a>). Bacterial lipopolysaccharide (LPS), virus, inflammation, and tissue injury increase tumor necrosis factor α (TNFα), interleukin-1 (IL-1), and other cytokine and chemokine secretion. Emigration of leukocytes from blood is dependent on their ability to roll along endothelial cell surfaces and subsequently adhere to endothelial cell surfaces. Inflammatory mediators and cytokines induce chemokine secretion from endothelial cells and other vascular cells and increase their expression of cell-surface adhesion molecules, such as intracellular adhesion molecule-1, vascular cell adhesion molecule-1 (VCAM-1), integrins, and selectins. Chemokines are chemotactic toward leukocytes and toward sites of inflammation and tissue injury. The movement of leukocytes through endothelial junctions into the extravascular space are highly orchestrated through various interactions with different adhesion molecules on endothelial cells (<a class="bibr" href="#VCAM-1-CLIO-Cy55.EXTYLES.8" rid="VCAM-1-CLIO-Cy55.EXTYLES.8">8</a>).</p><p>VCAM-1 is found in very low levels on the cell surface of resting endothelial cells and other vascular cells, such as smooth muscle cells and fibroblasts (<a href="#VCAM-1-CLIO-Cy55.EXTYLES.9">9-13</a>). VCAM-1 binds to its counterligand, very late antigen-4 (VLA-4) integrin, on the cell surface of leukocytes. IL-1 and TNFα increase expression of VCAM-1 and other cell adhesion molecules on the vascular endothelial cells, which leads to leukocyte adhesion to the activated endothelium. Furthermore, VCAM-1 expression was also induced by oxidized low-density lipoproteins under atherogenic conditions (<a class="bibr" href="#VCAM-1-CLIO-Cy55.EXTYLES.14" rid="VCAM-1-CLIO-Cy55.EXTYLES.14">14</a>). Overexpression of VCAM-1 by atherosclerotic lesions plays an important role in their progression toward vulnerable plaques, which may erode and rupture. CLIO nanoparticles targeted with anti-VCAM-1 antibody are being developed as a non-invasive agent for VCAM-1 expression in vascular endothelial cells during different stages of inflammation in atherosclerosis (<a class="bibr" href="#VCAM-1-CLIO-Cy55.EXTYLES.15" rid="VCAM-1-CLIO-Cy55.EXTYLES.15">15</a>). Anti-VCAM-1 M/K-2.7 monoclonal antibody (mAb) conjugated cross-linked iron oxide-Cy5.5 nanoparticles (VCAM-CLIO-Cy5.5 or VCAM-NP) is a multimodal agent that consists of CLIO nanoparticles with attachment of M/K-2.7 mAb and Cy5.5.</p></div><div id="VCAM-1-CLIO-Cy55.Synthesis"><h2 id="_VCAM-1-CLIO-Cy55_Synthesis_">Synthesis</h2><p>[<a href="/sites/entrez?Db=pubmed&Cmd=DetailsSearch&Term=VCAM-1+nanoparticle+synthesis" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PubMed</a>]</p><p>The synthesis of VCAM-CLIO-Cy5.5 nanoparticles was described by Tsourkas et al. (<a class="bibr" href="#VCAM-1-CLIO-Cy55.EXTYLES.15" rid="VCAM-1-CLIO-Cy55.EXTYLES.15">15</a>). The amino-CLIO nanoparticles (~40 amino groups/nanoparticle, 32.5 nm in diameter; R1 = 21.5 mM<sup>-1</sup>s<sup>-1</sup> and R2 = 54.2 mM<sup>-1</sup>s<sup>-1</sup>) were labeled with Cy5.5 using monofunctional <i>N</i>-hydroxysuccinimide (NHS) to form amino-CLIO-Cy5.5 nanoparticles, which were then carboxylated with NHS-COOH. Anti-VCAM-1 M/K-2.7 mAb or a control antibody was conjugated to the purified carboxylated nanoparticles using carbodiimide and sulfo-NHS to yield the multimodal VCAM-CLIO-Cy5.5 and IgG-CLIO-Cy5.5 nanoparticles, which had ~10 Cy5.5 molecules per nanoparticle and 0.87 mg (5.8 nmol) of M/K-2.7 mAb or 0.63 mg (4.2 nmol) of control antibody per mg Fe.</p></div><div id="VCAM-1-CLIO-Cy55.In_Vitro_Studies_Tes"><h2 id="_VCAM-1-CLIO-Cy55_In_Vitro_Studies_Tes_"><i>In Vitro</i> Studies: Testing in Cells and Tissues</h2><p>[<a href="/sites/entrez?Db=pubmed&Cmd=DetailsSearch&Term=VCAM-1+nanoparticle+in+vitro" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PubMed</a>]</p><p>Tsourkas et al. (<a class="bibr" href="#VCAM-1-CLIO-Cy55.EXTYLES.15" rid="VCAM-1-CLIO-Cy55.EXTYLES.15">15</a>) performed cell-binding assays with VCAM-CLIO-Cy5.5 using murine heart endothelial cells (MHEC). Using fluorescence flow cytometry, VCAM-CLIO-Cy5.5 bound to individual MHEC cells, whereas IgG-CLIO-Cy5.5 did not. A corresponding decrease in MRI signal intensity of the cell lysates was observed on a T2*W 4.7T MRI image (T2*W value was 10.0 ms for VCAM-CLIO-Cy5.5 and 102.0 ms for IgG-CLIO-Cy5.5), indicating the present of VCAM-CLIO-Cy5.5 nanoparticles in the samples.</p></div><div id="VCAM-1-CLIO-Cy55.Animal_Studies"><h2 id="_VCAM-1-CLIO-Cy55_Animal_Studies_">Animal Studies</h2><div id="VCAM-1-CLIO-Cy55.Rodents"><h3>Rodents</h3><p>[<a href="/sites/entrez?Db=pubmed&Cmd=DetailsSearch&Term=VCAM-1+nanoparticle+rodentia" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PubMed</a>]</p><p>Tsourkas et al. (<a class="bibr" href="#VCAM-1-CLIO-Cy55.EXTYLES.15" rid="VCAM-1-CLIO-Cy55.EXTYLES.15">15</a>) performed <i>in vivo</i> intravital confocal microscopy in C57BL/6 mice subjected to subcutaneous injection of TNFα to the left ear to induce vascular inflammation within 24 h. After retino-orbital injection of either VCAM-CLIO-Cy5.5 or IgG-CLIO-Cy5.5 (165 μg Fe), both ears were imaged at 1, 6, and 24 h. VCAM-CLIO-Cy5.5 provided the greatest degree of cell-surface fluorescence intensity in the endothelium of the left ear at 6 h but not in the normal right ear. The fluorescence signal was lower at 24 h but was brighter than nonspecific IgG-CLIO-Cy5.5. The low fluorescence signal that came from IgG-CLIO-Cy5.5 is most likely because of nonspecific CLIO uptake at the site of inflammation at 24 h. No MR imaging or blocking experiments were performed.</p></div><div id="VCAM-1-CLIO-Cy55.Other_NonPrimate_Mam"><h3>Other Non-Primate Mammals</h3><p>[<a href="/sites/entrez?Db=pubmed&Cmd=DetailsSearch&Term=VCAM-1+nanoparticle+(dog+or+pig+or+sheep+or+rabbit)" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PubMed</a>]</p><p>No publication is currently available.</p></div><div id="VCAM-1-CLIO-Cy55.NonHuman_Primates"><h3>Non-Human Primates</h3><p>[<a href="/sites/entrez?Db=pubmed&Cmd=DetailsSearch&Term=VCAM-1+nanoparticle+(primate%20not%20human)" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PubMed</a>]</p><p>No publication is currently available.</p></div></div><div id="VCAM-1-CLIO-Cy55.Human_Studies"><h2 id="_VCAM-1-CLIO-Cy55_Human_Studies_">Human Studies</h2><p>[<a href="/sites/entrez?Db=pubmed&Cmd=DetailsSearch&Term=VCAM-1+nanoparticle+human" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PubMed</a>]</p><p>No publication is currently available.</p></div><div id="VCAM-1-CLIO-Cy55.NIH_Support"><h2 id="_VCAM-1-CLIO-Cy55_NIH_Support_">NIH Support</h2><p>T32 CA79443, P50 CA86355</p></div><div id="VCAM-1-CLIO-Cy55.references"><h2 id="_VCAM-1-CLIO-Cy55_references_">References</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="VCAM-1-CLIO-Cy55.EXTYLES.1">Achilefu S. 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</span>(5):1617–25.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/1704400" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1704400</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>13.</dt><dd><div class="bk_ref" id="VCAM-1-CLIO-Cy55.EXTYLES.13">Nagel T. , Resnick N. , Atkinson W.J. , Dewey C.F. , Gimbrone M.A. Shear stress selectively upregulates intercellular adhesion molecule-1 expression in cultured human vascular endothelial cells. <span><span class="ref-journal">J Clin Invest. </span>1994;<span class="ref-vol">
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</span>(2):885–91.</span> [<a href="/pmc/articles/PMC296171/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC296171</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/7518844" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7518844</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>14.</dt><dd><div class="bk_ref" id="VCAM-1-CLIO-Cy55.EXTYLES.14">Aikawa M. , Libby P. The vulnerable atherosclerotic plaque: pathogenesis and therapeutic approach. <span><span class="ref-journal">Cardiovasc Pathol. </span>2004;<span class="ref-vol">
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<strong>13</strong>
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</span>(3):125–38.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15081469" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15081469</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>15.</dt><dd><div class="bk_ref" id="VCAM-1-CLIO-Cy55.EXTYLES.15">Tsourkas A. , Shinde-Patil V.R. , Kelly K.A. , Patel P. , Wolley A. , Allport J.R. , Weissleder R. In vivo imaging of activated endothelium using an anti-VCAM-1 magnetooptical probe. <span><span class="ref-journal">Bioconjug Chem. </span>2005;<span class="ref-vol">
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<strong>16</strong>
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</span>(3):576–81.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15898724" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15898724</span></a>]</div></dd></dl></dl></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK23029_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Kam Leung</span>, PhD<div class="affiliation small">
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National Center for Biotechnology Information, NLM, NIH, Bethesda, MD,
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<span class="before-email-separator"></span><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="vog.hin.mln.ibcn@dacim" class="oemail">vog.hin.mln.ibcn@dacim</a>
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</div></div><h3>Publication History</h3><p class="small">Created: <span itemprop="datePublished">October 1, 2007</span>; Last Update: <span itemprop="dateModified">October 29, 2007</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div></div><h3>Publisher</h3><p><a href="http://www.ncbi.nlm.nih.gov/" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">National Center for Biotechnology Information (US)</a>, Bethesda (MD)</p><h3>NLM Citation</h3><p>Leung K. Anti-vascular cell adhesion molecule monoclonal antibody M/K-2.7 conjugated cross-linked iron oxide-Cy5.5 nanoparticles. 2007 Oct 1 [Updated 2007 Oct 29]. In: Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/micad/Anx-CLIO-Cy55/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/micad/CLIO-Cy55/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="table-wrap" id="figobVCAM1CLIOCy55T1"><div id="VCAM-1-CLIO-Cy55.T1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK23029/table/VCAM-1-CLIO-Cy55.T1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__VCAM-1-CLIO-Cy55.T1_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">
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<b>Chemical name:</b>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Anti-vascular cell adhesion molecule monoclonal M/K-2.7 conjugated cross-linked iron oxide-Cy5.5 nanoparticles</td><td rowspan="9" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">
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<b>Abbreviated name:</b>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">VCAM-NP</td></tr><tr><td rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">
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<b>Synonym:</b>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">VCAM-CLIO-Cy5.5, M/K-2.7-CLIO-Cy5.5</td></tr><tr><td rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">
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<b>Agent Category:</b>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Antibody</td></tr><tr><td rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">
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<b>Target:</b>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Vascular cell adhesion molecule-1 (VCAM-1)</td></tr><tr><td rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">
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<b>Target Category:</b>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Antibody-antigen binding</td></tr><tr><td rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">
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<b>Method of detection:</b>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Magnetic resonance imaging (MRI), optical near-infrared (NIR) fluorescence</td></tr><tr><td rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">
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<b>Source of signal/contrast:</b>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Iron oxide, Cy5.5</td></tr><tr><td rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">
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<b>Activation:</b>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">No</td></tr><tr><td rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">
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<b>Studies:</b>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<ul class="simple-list"><li class="half_rhythm"><div>
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<img alt="Checkbox" src="/corehtml/pmc/css/bookshelf/2.26/img/studies.checkbox.png" />
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<i>In vitro</i>
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</div></li></ul>
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<ul class="simple-list"><li class="half_rhythm"><div>
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<img alt="Checkbox" src="/corehtml/pmc/css/bookshelf/2.26/img/studies.checkbox.png" /> Rodents
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</div></li></ul>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Click on <a href="/entrez/viewer.fcgi?db=protein&id=54648638" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">protein</a>, <a href="/entrez/viewer.fcgi?db=nuccore&id=46249772" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">nucleotide</a> (RefSeq), and <a href="/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=7412" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">gene</a> for more information about VCAM-1.</td></tr></tbody></table></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script></div></div>
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