A novel strategy to tag matrix metalloproteinases-positive cells for in vivo imaging of invasive and metastatic activity of tumor cells
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- 作者：Tao Zhao ; Hiroshi Harada ; Yuji Teramura ; Shotaro Tanaka ; Satoshi Itasaka ; Akiyo Morinibu ; Kazumi Shinomiya ; Yuxi Zhu ; Hirofumi Hanaoka ; Hiroo Iwata ; Hideo Saji ; MasahiroHiraoka
- 关键词：Molecular imaging ; Matrix metalloproteinase ; ECM (extracellular matrix) ; Tumor malignancy ; Metastasis ; Invasion
- 刊名：Journal of Controlled Release
- 出版年：2010
- 出版时间：21 May 2010
- 年：2010
- 卷：144
- 期：1
- 页码：109-114
- 全文大小：414 K
文摘
Matrix metalloproteinases (MMPs) are endopeptidases responsible for degrading the extracellular matrix (ECM) and remodeling tissue in both physiological and pathological processes. MMP2 and membrane-type 1 MMP (MT1-MMP) have been associated with tumor invasion, metastasis and angiogenesis; therefore, a molecular imaging strategy assessing their activity may help to predict the malignancy of tumors. Here, we established a novel method of specifically tagging the surface of MMP2- and MT1-MMP-positive cells, and applied it to the development of an optical imaging probe. We constructed a protein-based probe composed of a glutathione-S-transferase (GST)-tag (Inhibitory [I]-domain), a polypeptide as a specific substrate for both MMP2 and MT1-MMP (Cleaved [C]-domain), a transmembrane domain of the epidermal growth factor receptor (Transmembrane [TM]-domain), and DsRed2 (Fluorescent [F]-domain). In vitro experiments clearly demonstrated that, after the probe was cleaved at the C-domain by the MMPs, the resultant TM–F-domain was inserted into the cellular membrane. Optical imaging experiments in vivo demonstrated that the probe was cleaved and specifically remained in tumor xenografts in a MMP-dependent manner. These results indicate that the release of the I–C-domain through the proteolytic cleavage of the C-domain by MMP2 and MT1-MMP triggers the tagging of cellular membranes with the TM–F-domain. The present feasibility study opens the door to the development of a novel imaging probe for tumor malignancy using positron emission tomography as well as an optical imaging device.