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

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99mTc-Fucoidan, a polysaccharidic ligand of P-selectin

99mTc-Fucoidan
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD
Corresponding author.

Created: ; Last Update: April 12, 2012.

Chemical name:99mTc-Fucoidan, a polysaccharidic ligand of P-selectin
Abbreviated name:99mTc-Fucoidan
Synonym:
Agent category:Polysaccharide
Target:P-selectin
Target category:Receptor
Method of detection:single-photon emission computed tomography (SPECT), gamma planar imaging
Source of signal:99mTc
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Click on protein, nucleotide (RefSeq), and gene for more information about P-selectin.

Background

[PubMed]

Endothelial cells are important cells in inflammatory responses (1, 2). Bacterial lipopolysaccharide, virus, inflammation, and tissue injury increase tumor necrosis factor α (TNFα), interleukin-1 (IL-1), and secretion of other cytokines and chemokines. Leukocyte emigration from blood is dependent on rolling of leukocytes along endothelial cell surfaces and subsequent 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 attracting them to sites of inflammation and tissue injury. The movement of leukocytes and tumor cells through endothelial junctions into the extravascular space is highly orchestrated through various interactions with different adhesion molecules on endothelial cells (3, 4).

P-selectin is found on the cell surface of endothelial cells and platelets (5, 6). It binds to glycoprotein on the cell surface of leukocytes. IL-1 and TNFα, released from inflammatory and ischemic stimuli, stimulate expression of P-selectin and other adhesion molecules on the vascular endothelial cells leading to leukocyte adhesion to the activated endothelium and platelets. P-selectin and other adhesion molecules are involved in rolling and arresting leukocytes on the endothelium prior to leukocyte migration into the extravascular space. Fucoidan (a sialy-Lewisx mimetic) is a sulfated polysaccharide in brown seaweed (7, 8). Fucoidan binds to P-selectin with high affinity and exerts antagonism of selective function on myocardial ischemia-perfusion injury models in rats (9) and pigs (10). Rouzet et al. (11) evaluated 99mTc-fucoidan as a noninvasive agent for P-selectin expression in vascular endothelial cells of inflamed and damaged tissues and in platelet-rich arterial thrombus.

Synthesis

[PubMed]

Rouzet et al. (11) prepared 99mTc-fucoidan by mixing 1.5 nmol fucoidan (7.2 kDa) with 740 MBq (20 mCi) 99mTc-pertechnetate, stannous chloride, and potassium borohydride for 1 h at room temperature. The radiochemical purity was >99%. The yield, specific activity and stability of 99mTc-fucoidan were not reported.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Rouzet et al. (11) showed that there was a 10-fold increase in 99mTc-fucoidan binding to a fibrinogen-coated plate with adhered platelets compared versus binding to a fibrinogen-coated plate without adhered platelets. No blocking studies were performed with unlabeled fucoidan.

Animal Studies

Rodents

[PubMed]

Rouzet et al. (11) performed ex vivo biodistribution of 50 MBq (1.35 mCi) 99mTc-fucoidan in normal male rats (n = 4/group). Radioactivity was cleared from the blood with an initial half-life of 19 min and a second half-life of 351 min. The organ with the highest accumulation at 2 h after injection was the kidney (4.8% injected dose/gram (ID/g), followed by the liver (0.62% ID/g), blood (0.62% ID/g), bone (0.56% ID/g), thyroid (0.25% ID/g), spleen (0.21% ID/g), lung (0.17% ID/g), heart (0.11% ID/g), muscle (0.04% ID/g), and brain (0.01% ID/g).

Rouzet et al. (11) performed scintigraphy imaging studies of 99mTc-fucoidan in rats with myocardial ischemia-reperfusion (n = 7) after coronary artery occlusion. Static images were obtained at 120 min after 99mTc-fucoidan injection. The ischemia/non-ischemia ratio was 4.1 (2.3–6.2). Autoradiography studies of the excised tissues showed the ischemia/non-ischemia ratio to be 24.9 (4.1–44.0). There was a good correlation between the 99mTc-fucoidan accumulation and the area of injured myocardium measured with autoradiography (P < 0.05). Immunohistochemistry analysis showed a co-localization of P-selectin with radioactivity in the vasculature in the ischemia area. Non-specific accumulation was assessed with injection of 99mTc-aprotinin (a glycoprotein with a molecular weight of 6.5 kDa) as a control in two rats. No focal accumulation of radioactivity was detected with single-photon computed tomography or autography studies. In another study, accumulation of 99mTc-fucoidan (120 min after injection) in platelet-rich arterial thrombi was measured in rats with abdominal aortic aneurysms (n = 9) and infective endocarditis (n = 6). The aneurysmal thrombi/control and vegetations (thrombi)/background ratios were 3.6 (2.2–8.5) and 5.2 (2.7–9.1), respectively. Autoradiography studies of the excised tissues showed the ratios to be 9.1 (6.3–15.8) and 17 (14–32), respectively. Immunohistochemistry analysis showed a co-localization of P-selectin with radioactivity in the affected regions. No direct blocking studies were performed with unlabeled fucoidan.

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.

References

1.
Cybulsky, M.I., D. Won, and M. Haidari, Leukocyte recruitment to atherosclerotic lesions. Can J Cardiol, 200420 Suppl B: p. 24B-28B. [PubMed: 15309201]
2.
Wang H.B., Wang J.T., Zhang L., Geng Z.H., Xu W.L., Xu T., Huo Y., Zhu X., Plow E.F., Chen M., Geng J.G. P-selectin primes leukocyte integrin activation during inflammation. Nat Immunol. 2007;8(8):882–92. [PubMed: 17632516]
3.
Woollard K.J., Chin-Dusting J. P-selectin antagonism in inflammatory disease. Curr Pharm Des. 2010;16(37):4113–8. [PubMed: 21247396]
4.
Laubli H., Borsig L. Selectins promote tumor metastasis. Semin Cancer Biol. 2010;20(3):169–77. [PubMed: 20452433]
5.
Chen M., Geng J.G. P-selectin mediates adhesion of leukocytes, platelets, and cancer cells in inflammation, thrombosis, and cancer growth and metastasis. Arch Immunol Ther Exp (Warsz) 2006;54(2):75–84. [PubMed: 16648968]
6.
Lowe J.B. Glycan-dependent leukocyte adhesion and recruitment in inflammation. Curr Opin Cell Biol. 2003;15(5):531–8. [PubMed: 14519387]
7.
Li B., Lu F., Wei X., Zhao R. Fucoidan: structure and bioactivity. Molecules. 2008;13(8):1671–95. [PubMed: 18794778]
8.
Bachelet L., Bertholon I., Lavigne D., Vassy R., Jandrot-Perrus M., Chaubet F., Letourneur D. Affinity of low molecular weight fucoidan for P-selectin triggers its binding to activated human platelets. Biochim Biophys Acta. 2009;1790(2):141–6. [PubMed: 19026722]
9.
Omata M., Matsui N., Inomata N., Ohno T. Protective effects of polysaccharide fucoidin on myocardial ischemia-reperfusion injury in rats. J Cardiovasc Pharmacol. 1997;30(6):717–24. [PubMed: 9436808]
10.
Barrabes J.A., Garcia-Dorado D., Mirabet M., Inserte J., Agullo L., Soriano B., Massaguer A., Padilla F., Lidon R.M., Soler-Soler J. Antagonism of selectin function attenuates microvascular platelet deposition and platelet-mediated myocardial injury after transient ischemia. J Am Coll Cardiol. 2005;45(2):293–9. [PubMed: 15653030]
11.
Rouzet F., Bachelet-Violette L., Alsac J.M., Suzuki M., Meulemans A., Louedec L., Petiet A., Jandrot-Perrus M., Chaubet F., Michel J.B., Le Guludec D., Letourneur D. Radiolabeled fucoidan as a p-selectin targeting agent for in vivo imaging of platelet-rich thrombus and endothelial activation. J Nucl Med. 2011;52(9):1433–40. [PubMed: 21849401]

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