Matrix metalloproteinases (MMPs) play a key role in extracellular matrix remodeling, metastasis, and angiogenesis in cancer. While MMPs are expressed in normal tissue, they are upregulated in proliferating cancer cells. Within the MMP family there is considerable sequence and structural homology in the pro-peptide, catalytic, and hemopexin domains. Membrane-type I matrix metalloproteinase (MT1-MMP or MMP-14), is a cell-surface transmembrane protein that catalyzes the hydrolysis of collagen, the main component of extracellular matrix and it is highly correlated with metastasis in breast cancer. Due to the over-expression of MMP-14 on metastatic cancer cells, it has been recognized as an attractive target for both targeted diagnostic and therapeutic applications. A characteristic of MMP-14 as a membrane biomarker is that it undergoes internalization, enhancing its value in targeted molecular imaging applications. The <i>hemopexin and catalytic domains</i> of MMP-14, which are essential for collagenolysis, have been shown to be inhibited by small-molecule and peptide ligands. However, due to the highly conserved domain structure across all MMPs, such ligands are prone to lack specificity toward MMP-14 or other MMPs. To address this specificity problem, we have designed a chimeric hetero-bivalent platform targeted to both the catalytic and hemopexin domains. This platform is designed to impart specificity toward MMP-14 by incorporating a PEG spacer equivalent to the length of the linker peptide between the two domains of MMP-14 (~50 Å). The chimeric platform is also outfitted with a near-IR fluorescent dye allowing for detection by confocal microscopy and <i>in vivo </i>opitcal imaging. Our progress towards the synthesis and initial preclinical imaging results of the platform will be presented.

Developing a chimeric heterobivalent platform as a selective imaging probe for MMP-14

253rd National Meeting (2017)

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