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Polyethylene glycol-Cys-Arg-Ser-Gly-Pro-Leu-Gly-Val-Tyr-[18F]fluorobenzoyl-Lys-Lys-tetramethylrhodamine.


Leung K.


Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.
2012 Feb 06 [updated 2012 May 10].


Extracellular matrix (ECM) adhesion molecules consist of a complex network of fibronectins, collagens, chondroitins, laminins, glycoproteins, heparin sulfate, tenascins, and proteoglycans that surround connective tissue cells, and they are mainly secreted by fibroblasts, chondroblasts, and osteoblasts (1). Cell substrate adhesion molecules are considered essential regulators of cell migration, differentiation, and tissue integrity and remodeling. These molecules play a role in inflammation and atherogenesis, but they also participate in the process of invasion and metastasis of malignant cells in the host tissue (2). Tumor cells adhere to the ECM, which provides a matrix environment for the permeation of tumor cells through the basal lamina and underlying interstitial stroma of the connective tissue. Overexpression of matrix metalloproteinases (MMPs) and other proteases by tumor cells allows intravasation of tumor cells into the circulatory system after degrading the basement membrane and ECM (3). Several families of MMPs are involved in atherogenesis, myocardial infarction, angiogenesis, and tumor invasion and metastases (4-7). MMP expression is highly regulated in normal cells, such as trophoblasts, osteoclasts, neutrophils, and macrophages. Elevated levels of MMPs have been found in tumors associated with a poor prognosis for cancer patients (8). The peptide Gly-Pro-Leu-Gly-Val-Arg-NH2 (GPLGVR) was found to be a MMP2/9 substrate and is cleaved between the Gly (G) and Val (V) residues (9). Chuang et al. (10) linked a hydrophilic polyethylene glycol (PEG) group to the N-terminus of Cys-Arg-Ser-Gly-Pro-Leu-Gly-Val-Tyr-Lys-Lys (CRSGPLGVYKK) and a hydrophobic tetramethylrhodamine (TMR) molecule to the C-terminus Lys (K) residue to form PEG-CRSGPLGVYKK-TMR (PEG-peptide-TMR) for optical imaging of protease activity in vivo. Upon MMP cleavage, the lipophilic VYKK-TMR was released and accumulated at the sites (cell surface) of protease activity. The accumulation was most likely attributed to the binding of the lipophilic VYKK-TMR to the cell membrane non-specifically. For positron emission tomography (PET) imaging, the other Lys residue in PEG-peptide-TMR was labeled with 4-[18F]fluorobenzoate to form PEG-peptide-[18F]-TMR. PEG-peptide-[18F]-TMR accumulated in HT1080 tumors (with high MMP2 expression) but not in MCF-7 tumors (with low MMP2 expression), as determined with optical imaging in nude mice.

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