Abstract
BackgroundMagnetic resonance imaging can reveal exquisite anatomical details. However several diseases would benefit from an imaging technique able to specifically detect biochemical alterations. In this context protease activity imaging is one of the most promising areas of research.Methodology/Principal FindingsWe designed an elastase substrate by grafting stable nitroxide free radicals on soluble elastin. This substrate generates a high Overhauser magnetic resonance imaging (OMRI) contrast upon digestion by the target proteases through the modulation of its rotational correlation time. The sensitivity is sufficient to generate contrasted images of the degranulation of neutrophils induced by a calcium ionophore from 2×104 cells per milliliter, well under the physiological neutrophils concentrations.Conclusions/SignificanceThese ex-vivo experiments give evidence that OMRI is suitable for imaging elastase activity from neutrophil degranulation. Provided that a fast protease-substrate is used these results open the door to better diagnoses of a number of important pathologies (cystic fibrosis, inflammation, pancreatitis) by OMRI or Electron Paramagnetic Resonance Imaging in vivo. It also provides a long-expected method to monitor anti-protease treatments efficiency and help pharmaceutical research.
Highlights
Anatomical imaging methods like X-ray tomography, ultra-sound and magnetic resonance imaging (MRI) can give fine details many pathologies still escape diagnosis
Pancreatitis, rheumatoid arthritis, cystic fibrosis and inflammatory diseases of various origins are significant examples associated with a persistent protease/inhibitor imbalance leaving uncontrolled proteolytic activity
In a previous paper we showed that the proteolytic hydrolysis of nitroxide-labeled bovine serum albumin could be followed in vitro by Overhauser magnetic resonance imaging (OMRI) with the generation of high contrast[4]
Summary
Anatomical imaging methods like X-ray tomography, ultra-sound and MRI can give fine details many pathologies still escape diagnosis. The trend has turned towards the molecular imaging approach to localize such processes This branch potentially gives access to antigens and receptors targeting or to biochemical activities like the redox status [1,2] and enzyme activity[3,4]. An uncontrolled protease activity is associated with many diseases In most situations this is the result of local secretion of a complex mixture of mutually activating proteases, each family of protease being able to inactivate the specific inhibitors of another family. Pancreatitis, rheumatoid arthritis, cystic fibrosis and inflammatory diseases of various origins are significant examples associated with a persistent protease/inhibitor imbalance leaving uncontrolled proteolytic activity. Several diseases would benefit from an imaging technique able to detect biochemical alterations In this context protease activity imaging is one of the most promising areas of research
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