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

Gregory A. Watkins, Ella Fung Jones, M. Scott Shell, Henry F. VanBrocklin, Mei Hsiu Pan, Stephen M. Hanrahan, Jin Jin Feng, Jiang He, Nor Eddine Sounni, Ken A. Dill, Christopher H. Contag, Lisa M. Coussens, Benjamin L. Franc

Research output: Contribution to journalArticle

41 Scopus citations

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 (r8) 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.

Original languageEnglish (US)
Pages (from-to)653-659
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume17
Issue number2
DOIs
StatePublished - Jan 15 2009

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Keywords

  • Cancer
  • MMP-14
  • Protease sensitive probe
  • SPECT imaging

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Watkins, G. A., Jones, E. F., Scott Shell, M., VanBrocklin, H. F., Pan, M. H., Hanrahan, S. M., Feng, J. J., He, J., Sounni, N. E., Dill, K. A., Contag, C. H., Coussens, L. M., & Franc, B. L. (2009). Development of an optimized activatable MMP-14 targeted SPECT imaging probe. Bioorganic and Medicinal Chemistry, 17(2), 653-659. https://doi.org/10.1016/j.bmc.2008.11.078