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Published on: July 28, 2016
Highly Efficient Activatable MRI Probe to Sense Myeloperoxidase Activity
Cuihua Wang1,2, David Cheng3, Negin Jalali Motlagh1,2
1Institute for Innovation in Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, United States.
Abstract:
Myeloperoxidase (MPO) is a key component of innate immunity but can damage tissues when secreted abnormally. We developed a new generation of a highly efficient MPO-activatable MRI probe (heMAMP) to report MPO activity. heMAMP has improved Gd stability compared to bis-5-HT-Gd-DTPA (MPO-Gd) and demonstrates no significant cytotoxicity. Importantly, heMAMP is more efficiently activated by MPO compared to MPO-Gd, 5HT-DOTA(Gd), and 5HT-DOTAGA-Gd. Molecular docking simulations revealed that heMAMP has increased rigidity via hydrogen bonding intramolecularly and improved binding affinity to the active site of MPO. In animals with subcutaneous inflammation, activated heMAMP showed a 2-3-fold increased contrast-to-noise ratio (CNR) compared to activated MPO-Gd and 4-10 times higher CNR compared to conventional DOTA-Gd. This increased efficacy was further confirmed in a model of unstable atherosclerotic plaque where heMAMP demonstrated a comparable signal increase and responsiveness to MPO inhibition at a 3-fold lower dosage compared to MPO-Gd, further underscoring heMAMP as a potential translational candidate.
Insights
A novel MRI probe, heMAMP, efficiently detects myeloperoxidase (MPO) activity, offering improved diagnostic potential for inflammatory diseases and atherosclerosis.
Area of Science:
- Biomedical Imaging
- Molecular Imaging
- Diagnostic Tools
Background:
- Myeloperoxidase (MPO) is crucial for innate immunity but linked to tissue damage when dysregulated.
- Existing MRI probes for MPO activity have limitations in efficiency and stability.
Purpose of the Study:
- To develop and evaluate a new generation of MPO-activatable MRI probe, heMAMP.
- To assess heMAMP's efficiency, stability, and diagnostic performance compared to existing probes.
Main Methods:
- Synthesis and characterization of the heMAMP MRI probe.
- In vitro MPO activation assays and cytotoxicity testing.
- Molecular docking simulations to understand binding interactions.
- In vivo MRI studies in animal models of inflammation and atherosclerosis.
Main Results:
- heMAMP exhibits enhanced MPO activation and improved Gadolinium (Gd) stability over MPO-Gd.
- Molecular docking reveals increased rigidity and binding affinity of heMAMP to MPO.
- In vivo studies show significantly higher contrast-to-noise ratio (CNR) with heMAMP.
- heMAMP demonstrates efficacy at lower doses in an atherosclerosis model, responding to MPO inhibition.
Conclusions:
- heMAMP represents a highly efficient and stable MPO-activatable MRI probe.
- Its superior performance suggests significant potential as a translational diagnostic tool for MPO-related conditions.
- heMAMP offers improved sensitivity and lower dosage requirements compared to previous probes.
