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Published on: May 8, 2017
Development of an optimized activatable MMP-14 targeted SPECT imaging probe
Gregory A Watkins1, Ella Fung Jones, M Scott Shell
1Center for Molecular and Functional Imaging, Department of Radiology and Biomedical Imaging, University of California, San Francisco, 185 Berry Street, Suite 350, Box 0946, San Francisco, CA 94107, United States.
Researchers developed novel probes to detect matrix metalloproteinase-14 (MMP-14), a key marker in metastatic cancers. The optimal probe showed targeted uptake in cancer cells, paving the way for new diagnostic and therapeutic strategies.
Area of Science:
- Biochemistry
- Molecular Biology
- Medical Imaging
Background:
- Matrix metalloproteinase-14 (MMP-14) is crucial in tissue remodeling and a hallmark of metastatic cancers.
- In vivo detection of MMP-14 is vital for understanding its role in pathology and developing targeted therapies.
Purpose of the Study:
- To design and evaluate novel MMP-14 specific probes for in vivo detection.
- To optimize probe design for enhanced cellular uptake upon MMP-14 cleavage.
Main Methods:
- Computational modeling (AMBER force field) of four MMP-14 specific probes with varying attenuating sequences.
- In vitro cleavage studies using recombinant human MMP-14 catalytic domain.
- Assessment of probe uptake in MMP-14 transfected human breast cancer cells using a technetium-99m labeled version.
Main Results:
- The probe with a 4egg attenuating sequence demonstrated optimal CPP/attenuator interaction, predicting minimized uptake until cleavage.
- Cleavage rate correlated with the linearity of the peptide substrate sequence.
- Successful cleavage, uptake in cancer cells, and reduced uptake with MMP inhibitors confirmed probe functionality.
Conclusions:
- Computational chemistry, synthesis, and screening are effective tools for developing protease-sensitive radiolabeled probes.
- The developed probes show promise for sensitive detection of MMP-14 activity in pathologic processes.
- This approach may guide the development of targeted molecular therapies for MMP-14-associated diseases.
