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Dual-Modality Activity-Based Probes as Molecular Imaging Agents for Vascular Inflammation
Nimali P Withana1, Toshinobu Saito2, Xiaowei Ma3
1Department of Pathology, Stanford University School of Medicine, Stanford, California.
Summary
Activity-based probes (ABPs) targeting cysteine cathepsins enable noninvasive imaging of macrophage populations in atherosclerosis models. These probes can also label human carotid plaques, aiding in disease progression and vulnerability assessment.
Area of Science:
- Vascular Biology
- Immunology
- Medical Imaging
Background:
- Macrophages are key mediators of vascular inflammation and atherosclerotic plaque development.
- Activated macrophages secrete proteases like cathepsins, contributing to disease progression.
- Current imaging methods for atherosclerotic plaques have limitations in visualizing cellular activity.
Purpose of the Study:
- To evaluate activity-based probes (ABPs) targeting cysteine cathepsins for noninvasive imaging of activated macrophages in atherosclerosis.
- To assess the utility of these ABPs in both murine models and human carotid plaques.
- To determine the potential of ABPs for monitoring disease progression and plaque vulnerability.
Main Methods:
- Development and application of optical and PET/CT activity-based probes (BMV109, BMV101) targeting cysteine cathepsins.
- Induction of atherosclerotic lesions in mice via high-fat diet, streptozotocin, and carotid artery ligation.
- Noninvasive optical and small-animal PET/CT imaging of murine models.
- Ex vivo imaging and immunofluorescence staining of murine carotid arteries.
- Topical labeling and analysis (SDS-PAGE, immunofluorescence) of human carotid plaques.
Main Results:
- Significantly higher probe accumulation in ligated carotid arteries of mice compared to controls (P < 0.005 for BMV109, P < 0.05 for BMV101).
- Immunofluorescence confirmed substantial macrophage infiltration in murine atherosclerotic lesions.
- Human plaque analysis identified cathepsins X, B, S, and L as primary targets.
- Probe colocalized with macrophage markers (CD68) and plaque components in human tissues.
Conclusions:
- Activity-based probes targeting cysteine cathepsins effectively image activated macrophages in atherosclerosis models.
- These probes demonstrate potential for noninvasive imaging of human carotid plaques.
- ABPs offer a promising new tool for assessing atherosclerotic disease progression and plaque vulnerability.
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