Reference : Development of an optimized activatable MMP-14 targeted SPECT imaging probe
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Development of an optimized activatable MMP-14 targeted SPECT imaging probe
Watkins, G. A. [ > > ]
Jones, E. F. [ > > ]
Scott Shell, M. [ > > ]
VanBrocklin, H. F. [ > > ]
Pan, M. H. [ > > ]
Hanrahan, S. M. [ > > ]
Feng, J. J. [ > > ]
He, J. [ > > ]
Sounni, Nor Eddine mailto [Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement >]
Dill, K. A. [ > > ]
Contag, C. H. [ > > ]
Coussens, L. M. [ > > ]
Franc, B. L. [ > > ]
Bioorganic & Medicinal Chemistry
Elsevier Science
Yes (verified by ORBi)
United Kingdom
[en] Cancer ; MMP-14 ; Protease sensitive probe ; SPECT imaging
[en] 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.
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