Article (Scientific journals)
Development of an optimized activatable MMP-14 targeted SPECT imaging probe
Watkins, G. A.; Jones, E. F.; Scott Shell, M. et al.
2009In Bioorganic and Medicinal Chemistry, 15 (17), p. 653-9
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Keywords :
Cancer; MMP-14; Protease sensitive probe; SPECT imaging
Abstract :
[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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
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  ;  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.
More authors (3 more) Less
Language :
English
Title :
Development of an optimized activatable MMP-14 targeted SPECT imaging probe
Publication date :
2009
Journal title :
Bioorganic and Medicinal Chemistry
ISSN :
0968-0896
eISSN :
1464-3391
Publisher :
Elsevier Science, Oxford, United Kingdom
Volume :
15
Issue :
17
Pages :
653-9
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 22 June 2010

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