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Non-invasive In Vivo Fluorescence Optical Imaging of Inflammatory MMP Activity Using an Activatable Fluorescent Imaging Agent
Published on: May 8, 2017
In vivo optical imaging of membrane-type matrix metalloproteinase (MT-MMP) activity
1Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland 20892, United States.
Abstract:
Herein we demonstrate for the first time that a fluorogenic probe can be used as an in vivo imaging agent for visualizing activities of membrane-tethered, membrane-type matrix metalloproteinases (MT-MMPs). An MT-MMP fluorogenic probe that consisted of an MT1-MMP (MMP-14) substrate and near-infrared (NIR) dye-quencher pair exhibited rapid, efficient boosts in fluorescence upon cleavage by MT1-MMP in tumor-bearing mice. In particular, unlike similar fluorogenic probes designed to target extracellular, soluble-type MMPs (EC-MMPs)--which can be cleared from the bloodstream after activation--the fluorescence signals activated by MT1-MMP enable clear visualization of MT1-MMP-positive tumors in animal models for up to 24 h. The results indicate that a simple form of a fluorogenic probe that is less effective in EC-MMP imaging is an effective probe for imaging MT-MMP activities in vivo. These findings can be widely applied to designing probes and to applications targeting various membrane-anchored proteases in vivo.
Insights
A novel fluorogenic probe effectively visualizes membrane-type matrix metalloproteinases (MT-MMPs) in vivo. This imaging agent allows for clear, long-lasting visualization of MT-MMP-positive tumors in animal models.
Area of Science:
- Biomedical Imaging
- Molecular Biology
- Protease Activity
Background:
- Matrix metalloproteinases (MMPs) play crucial roles in physiological and pathological processes.
- Membrane-type MMPs (MT-MMPs) are particularly important in tumor progression and metastasis.
- Current imaging strategies for MMPs often struggle with specificity and duration of signal.
Purpose of the Study:
- To develop and validate a novel fluorogenic probe for in vivo imaging of MT-MMP activity.
- To assess the efficacy of the probe in visualizing MT1-MMP (MMP-14) in a tumor model.
- To compare the performance of the MT-MMP probe with probes targeting extracellular MMPs (EC-MMPs).
Main Methods:
- Design of a fluorogenic probe incorporating an MT1-MMP substrate and a near-infrared (NIR) dye-quencher pair.
- Administration of the probe to tumor-bearing mice.
- In vivo fluorescence imaging to monitor probe activation and signal localization.
- Comparison of signal clearance and duration with EC-MMP-targeting probes.
Main Results:
- The MT-MMP fluorogenic probe demonstrated rapid and efficient fluorescence enhancement upon cleavage by MT1-MMP.
- Clear visualization of MT1-MMP-positive tumors was achieved in animal models for up to 24 hours.
- The probe's signal persisted longer compared to fluorogenic probes designed for EC-MMPs.
- A simple probe design proved effective for MT-MMP imaging, outperforming its utility in EC-MMP imaging.
Conclusions:
- Fluorogenic probes can serve as effective in vivo imaging agents for MT-MMP activity.
- The developed probe offers a promising tool for non-invasive visualization of MT-MMPs in disease models.
- These findings support the broader application of such probes for targeting various membrane-anchored proteases.
