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Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

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Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

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Microbubbles coated with antibody to mucosal addressin cellular adhesion molecule-1

MBMAdCAM-1
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD

Created: ; Last Update: February 27, 2007.

Chemical name:Microbubbles coated with antibody to mucosal addressin cellular adhesion molecule-1
Abbreviated name:MBMAdCAM-1
Synonym:
Agent category:Antibody
Target:Mucosal addressin cellular adhesion molecule-1 (MAdCAM-1)
Target category:Adhesion molecule
Method of detection:Ultrasound (US)
Source of signal:Microbubbles
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Click on protein, nucleotide (RefSeq), and gene for more information about MAdCAM-1.

Background

[PubMed]

Ultrasound is the most widely used imaging modality (1) and is expanding its role in noninvasive molecular imaging with ligand-carrying microbubbles (2). Microbubbles are comprised of spherical cavities filled by a gas encapsulated in a shell. The shells are made of phospholipids, surfactant, denatured human serum albumin or synthetic polymer. Ligands and antibodies can be incorporated into the shell surface of microbubbles. Microbubbles are usually 2 to 8 μm in size. They provide a strongly reflective interface and resonate to ultrasound waves. They are used as ultrasound contrast agents in imaging of inflammation, angiogenesis, intravascular thrombus, and tumors (3-5). They are also potentially used for drug and gene delivery (6).

Endothelial cells are important cells in inflammatory responses (7, 8). Bacterial lipopolysaccharide (LPS), virus, inflammation, and tissue injury increase tumor necrosis factor α (TNFα), interleukin-1 (IL-1) and other cytokine and chemokine secretion. Leukocyte emigration from blood is dependent on their rolling along endothelial cell surfaces and subsequently adherence 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 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), integrins and selectins. Chemokines are chemotactic to leukocytes to sites of inflammation and tissue injury. The movements of leukocytes through endothelial junctions into the extravascular space are highly orchestrated through various interactions with different adhesion molecules on endothelial cells (9).

Mucosal addressin cellular adhesion molecule-1 (MAdCAM-1) is found on cell surface of endothelial cells in the mucosal lymphoid tissues, mesenteric lymph nodes, intestines and mammary gland (10, 11). It binds to α4β7 integrin receptors on the cell-surface of leukocytes (12). IL-1 and TNFα stimulate MAdCAM-1 expression on these endothelial cells (13). Inflammation leads to leukocyte adhesion to the activated endothelium. It has been shown that MAdCAM-1 expression is up-regulated in humans with active ulcerative colitis and Crohn’s disease (14). Microbubbles targeted with antibody against MAdCAM-1 are being developed as a noninvasive agent for MAdCAM-1 expression in vascular endothelial cells of dysfunctional endothelium (15).

Synthesis

[PubMed]

For targeted microbubbles, Bachmann et al. (15) prepared biotinylated microbubbles by sonication of an aqueous dispersion of decafluorobutane gas, phosphatidylcholine, polyethyleneglycol-(PEG-)stearate, and distearoylphosphatidylethanolamine-PEG-biotin. Microbubbles were combined with streptavidin, washed, and conjugated with biotinylated mouse monoclonal antibody against MAdCAM-1 (MBMAdCAM-1) or isotype control monoclonal antibody (MBiso). The microbubbles are about 3.9 µm in diameter. An antibody to microbubble ratio was estimated to be ~100,000 by flow cytometry.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Bachmann et al. (15) reported that MBMAdCAM-1 (5 x 105/ml) perfused through the flow chamber coated with MAdCAM-1 at a wall shear rate of 0.5 dyne/cm2. There were >600 MBMAdCAM-1/mm2 and less than 10 MBiso/mm2. Pre-incubation with anti-MAdCAM-1 antibody prior to infusion of MBMAdCAM-1 decreased the binding of MBMAdCAM-1 to ~50 MBMAdCAM-1/mm2. There was a significantly greater number of MBMAdCAM-1 attached to TNF-activated endothelial cells (484 ± 50 microbubbles/mm2) than to normal endothelial cells (75 ± 19 microbubbles/mm2) in the flow chamber experiments. MBiso attachment to activated and normal endothelial cells was 26 ± 3 and 11 ± 2 microbubbles/mm2, respectively.

Animal Studies

Rodents

[PubMed]

Bachmann et al. (15) performed ultrasound assessment of spontaneous ileal inflammation in SAMP mice as compared to normal AKR mice after injection of 5 X 106 microbubbles. Transabdominal ultrasound imaging of inflamed ileal segments in SAMP mice (10 U ± 2, n = 14) showed that video intensity signal was significantly higher (P<0.01) than control non-inflamed segments in AKR mice (1 U ± 1, n = 6) for MBMAdCAM-1. On the other hand, control MBiso exhibited a minimal contrast in both the SAMP (3 U ± 1, n = 14) and AKR (2 U ± 1, n = 6) ileal segments. Postmortem histology confirmed that the SAMP ileal segments had a significantly higher infiltration of inflammatory cells than the control ARK ileal segments. There was a strong positive correlation (R2 = 0.92) of video intensities with total inflammatory scores in SAMP mice.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

No publication is currently available.

NIH Support

P01 DK57880, P30 DK56703

References

1.
Wells P.N. Physics and engineering: milestones in medicine. Med Eng Phys. 2001;23(3):147–53. [PubMed: 11410379]
2.
Liang H.D., Blomley M.J. The role of ultrasound in molecular imaging. Br J Radiol. 2003;76(Spec No 2):S140–50. [PubMed: 15572336]
3.
Klibanov A.L. Ligand-carrying gas-filled microbubbles: ultrasound contrast agents for targeted molecular imaging. Bioconjug Chem. 2005;16(1):9–17. [PubMed: 15656569]
4.
Lindner J.R. Microbubbles in medical imaging: current applications and future directions. Nat Rev Drug Discov. 2004;3(6):527–32. [PubMed: 15173842]
5.
Villanueva F.S., Wagner W.R., Vannan M.A., Narula J. Targeted ultrasound imaging using microbubbles. Cardiol Clin. 2004;22(2):283–98. [PubMed: 15158940]
6.
Dijkmans P.A., Juffermans L.J., Musters R.J., van Wamel A., ten Cate F.J., van Gilst W., Visser C.A., de Jong N., Kamp O. Microbubbles and ultrasound: from diagnosis to therapy. Eur J Echocardiogr. 2004;5(4):245–56. [PubMed: 15219539]
7.
Cybulsky M.I., Gimbrone M.A. Jr. Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science. 1991;251(4995):788–91. [PubMed: 1990440]
8.
Lowe J.B. Glycosylation in the control of selectin counter-receptor structure and function. Immunol Rev. 2002;186:19–36. [PubMed: 12234359]
9.
Vanderslice P., Woodside D.G. Integrin antagonists as therapeutics for inflammatory diseases. Expert Opin Investig Drugs. 2006;15(10):1235–55. [PubMed: 16989599]
10.
Connor E.M., Eppihimer M.J., Morise Z., Granger D.N., Grisham M.B. Expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in acute and chronic inflammation. J Leukoc Biol. 1999;65(3):349–55. [PubMed: 10080539]
11.
Nakache M., Berg E.L., Streeter P.R., Butcher E.C. The mucosal vascular addressin is a tissue-specific endothelial cell adhesion molecule for circulating lymphocytes. Nature. 1989;337(6203):179–81. [PubMed: 2911352]
12.
Berlin C., Berg E.L., Briskin M.J., Andrew D.P., Kilshaw P.J., Holzmann B., Weissman I.L., Hamann A., Butcher E.C. Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell. 1993;74(1):185–95. [PubMed: 7687523]
13.
Ando T., Jordan P., Wang Y., Itoh M., Joh T., Sasaki M., Elrod J.W., Carpenter A., Jennings M.H., Minagar A., Alexander J.S. MAdCAM-1 expression and regulation in murine colonic endothelial cells in vitro. Inflamm Bowel Dis. 2005;11(3):258–64. [PubMed: 15735432]
14.
Arihiro S., Ohtani H., Suzuki M., Murata M., Ejima C., Oki M., Kinouchi Y., Fukushima K., Sasaki I., Nakamura S., Matsumoto T., Torii A., Toda G., Nagura H. Differential expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in ulcerative colitis and Crohn's disease. Pathol Int. 2002;52(5-6):367–74. [PubMed: 12100519]
15.
Bachmann C., Klibanov A.L., Olson T.S., Sonnenschein J.R., Rivera-Nieves J., Cominelli F., Ley K.F., Lindner J.R., Pizarro T.T. Targeting mucosal addressin cellular adhesion molecule (MAdCAM)-1 to noninvasively image experimental Crohn's disease. Gastroenterology. 2006;130(1):8–16. [PubMed: 16401463]
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