Dataset Information

Development of an optimized activatable MMP-14 targeted SPECT imaging probe.

ABSTRACT: Matrix metalloproteinase-14 (MT1-MMP or MMP-14) is a membrane-associated protease implicated in a variety of tissue remodeling processes and a molecular hallmark of select metastatic cancers. The ability to detect MMP-14 in vivo would be useful in studying its role in pathologic processes and may potentially serve as a guide for the development of targeted molecular therapies. Four MMP-14 specific probes containing a positively charged cell penetrating peptide (CPP) d-arginine octamer (r(8)) linked with a MMP-14 peptide substrate and attenuating sequences with glutamate (8e, 4e) or glutamate-glycine (4eg and 4egg) repeating units were modeled using an AMBER force field method. The probe with 4egg attenuating sequence exhibited the highest CPP/attenuator interaction, predicting minimized cellular uptake until cleaved. The in vitro MMP-14-mediated cleavage studies using the human recombinant MMP-14 catalytic domain revealed an enhanced cleavage rate that directly correlated with the linearity of the embedded peptide substrate sequence. Successful cleavage and uptake of a technetium-99m labeled version of the optimal probe was demonstrated in MMP-14 transfected human breast cancer cells. Two-fold reduction of cellular uptake was found in the presence of a broad spectrum MMP inhibitor. The combination of computational chemistry, parallel synthesis and biochemical screening, therefore, shows promise as a set of tools for developing new radiolabeled probes that are sensitive to protease activity.

SUBMITTER: Watkins GA

PROVIDER: S-EPMC2639212 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Development of an optimized activatable MMP-14 targeted SPECT imaging probe.

Watkins Gregory A GA Jones Ella Fung EF Scott Shell M M VanBrocklin Henry F HF Pan Mei-Hsiu MH Hanrahan Stephen M SM Feng Jin Jin JJ He Jiang J Sounni Nor Eddine NE Dill Ken A KA Contag Christopher H CH Coussens Lisa M LM Franc Benjamin L BL

Bioorganic & medicinal chemistry 20081206 2

Matrix metalloproteinase-14 (MT1-MMP or MMP-14) is a membrane-associated protease implicated in a variety of tissue remodeling processes and a molecular hallmark of select metastatic cancers. The ability to detect MMP-14 in vivo would be useful in studying its role in pathologic processes and may potentially serve as a guide for the development of targeted molecular therapies. Four MMP-14 specific probes containing a positively charged cell penetrating peptide (CPP) d-arginine octamer (r(8)) lin ...[more]

PMID: 19109023

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Dataset Information

Development of an optimized activatable MMP-14 targeted SPECT imaging probe.

Publications

Development of an optimized activatable MMP-14 targeted SPECT imaging probe.

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