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Cy5.5-Conjugated matrix metalloproteinase cleavable peptide nanoprobe.

Authors

Chopra A1.

Source

Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.
2012 Mar 19 [updated 2012 Apr 12].

Author information

1
National Center for Biotechnology Information, NLM, Bethesda, MD 20894

Excerpt

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidase enzymes that are known to regulate diverse physiological processes such as cell growth, differentiation, and migration, and they play an important role in the development and progression of osteoarthritis (1) and cancer (2, 3). The classification, structural characteristics, induction, regulation, and biological functions of >25 MMPs have been reviewed by Klein and Bischoff (3). Because MMPs are overexpressed in malignant tumors and support the establishment of neoplasms, these enzymes are the target of many anti-cancer drugs (4). In addition, researchers are interested to develop and evaluate imaging probes that target the MMPs so as to detect cancers at an early stage, track progression of the disease, and monitor the response to cancer therapy (5). A strategy using activatable cell-penetrating peptides (ACPPs) labeled with a radionuclide (6) or an optical imaging dye (7) has been utilized by investigators for the successful detection of tumors that overexpress MMPs in mice. However, it was shown that the ACPP probe was probably not suitable for the detection of these lesions because the probe was most likely activated in the vasculature and the tumors showed nonspecific uptake of the label (6). Investigators have used fluorogenic probes that consist of a fluorophore and a quencher attached to a targeting peptide for in vivo detection of the MMP activity (1). A characteristic feature of these probes is that, in the normal state, fluorescence emitted by the fluorophore is absorbed by the quencher through resonance energy transfer and no signal is detected from the peptide (for a schematic diagram, see Ryu et al. (1)). The fluorescence generated by the probe is detectable only when the targeting peptide is cleaved by a suitable protease such as the MMP and the quencher is released from the complex. A limitation of using these probes in vivo is that they exhibit low stability and the constituent peptides may be cleaved nonspecifically by different proteases (1). Therefore, it was apparent that a probe containing a substrate peptide that is specific for an MMP would be most suitable for the detection of these enzymes. On the basis of this information, a fluorogenic probe containing an MMP-13–specific peptide substrate (Gly-Pro-Leu--Gly-Met-Arg-Gly-Leu-Gly-Lys; the substrate amino acid sequence is italicized, and the MMP cleavage site is indicated with a double hyphen) sandwiched between the Cy5.5 fluorescence dye and the black hole quencher-3 (BHQ-3) was developed (1). The intact probe (Cy5.5-MMP probe) exhibited low background fluorescence that increased significantly only after the peptide substrate was cleaved by the MMP. The biodistribution of the Cy5.5-MMP probe and its ability to detect neoplastic lesions in mice bearing murine squamous cell carcinoma SCC-7 cell tumors were investigated by Yhee et al. (8).

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