Periodic Reporting for period 2 - PRIMOGAIA (Prepolarized MRI at Earth Field to seek new contrasts linked to molecular events for very early detection of pathologies)
Okres sprawozdawczy: 2020-12-01 do 2021-11-30
MRI (Magnetic Resonance Imaging) is a major tool for contemporary medicine and biological research, many progresses has been made since first years applications in the 1980’s. It uses high magnetic field for polarization and an electromagnetic field (Radio-Frequency domain) to interact with matter recovering the signal from proton resonance. It’s non invasiveness to acquire image of deep tissues by spatial encoding in 3 dimensions is a great advantage. Neuroimaging is one of the most important field of application and many progresses have been made to diagnose pathologies and to better understand brain functionality. Many other medicine application fields gain from using MRI, for its unreachable soft tissue contrast and it would be too long to cite all of them (musculoskeletal, cardiac, vascular...)
With this project we attend to explore another way to approach some human body functions, not targeted up-to-now by conventional MRI or other imaging modalities, using an enhancement process, known as Overhauser effect, developed since 2003 by the CNRS laboratory CRMSB, in Bordeaux, France. The phenomenon takes place in water or tissues when a specific molecule with an unpaired electron, we will call it “nitroxide contrast agent”, is present. This electron can be excited by a resonance phenomenon using another RF electromagnetic wave, increasing drastically the signal intensity at the location of electron-proton interaction. It results on the images by an intense signal at the interaction locations, giving a highly contrasted image. The goal of the project is to develop and do MRI with more sophisticated nitroxide contrast agent, to assess human functions “disorders” appearing in some pathologies. In our oblectives this constructed molecule is made sensitive to certain enzyme present in pathologies or is able to targetbiological receptors. When the enzymatic process takes place it affects the contrast agent molecule, at the end leaving the nitroxide part free and able to generate signal enhancement. Thus these smart molecules can be used to detect theses specific enzymatic activities, linked to pathologies (pulmonary COPD or pancreatitis for example). This project benefits from the years of accumulated experience of all partners that have already been able to prove the in-vivo non-toxicity of such contrast agents. For this a new instrumentation has to be build, based on very low magnetic field or Earth Magnetic Field.
To target this objective PRIMOGAIA project is built around a European consortium of 7 partners from 4 different countries which gathers 4 research laboratories and 2 SME’s. The developments will be made and proof validated on a small size demonstrator. While a human body sized demonstrator will be constructed step by step to overcome all locks and make a proof of concept, giving a breakthrough in molecular imaging domain. It will open a new imaging domain involving standard and cost effective technologies, making them available anywhere around the world, even for countries without high end technology and support.
With this project we attend to explore another way to approach some human body functions, not targeted up-to-now by conventional MRI or other imaging modalities, using an enhancement process, known as Overhauser effect, developed since 2003 by the CNRS laboratory CRMSB, in Bordeaux, France. The phenomenon takes place in water or tissues when a specific molecule with an unpaired electron, we will call it “nitroxide contrast agent”, is present. This electron can be excited by a resonance phenomenon using another RF electromagnetic wave, increasing drastically the signal intensity at the location of electron-proton interaction. It results on the images by an intense signal at the interaction locations, giving a highly contrasted image. The goal of the project is to develop and do MRI with more sophisticated nitroxide contrast agent, to assess human functions “disorders” appearing in some pathologies. In our oblectives this constructed molecule is made sensitive to certain enzyme present in pathologies or is able to targetbiological receptors. When the enzymatic process takes place it affects the contrast agent molecule, at the end leaving the nitroxide part free and able to generate signal enhancement. Thus these smart molecules can be used to detect theses specific enzymatic activities, linked to pathologies (pulmonary COPD or pancreatitis for example). This project benefits from the years of accumulated experience of all partners that have already been able to prove the in-vivo non-toxicity of such contrast agents. For this a new instrumentation has to be build, based on very low magnetic field or Earth Magnetic Field.
To target this objective PRIMOGAIA project is built around a European consortium of 7 partners from 4 different countries which gathers 4 research laboratories and 2 SME’s. The developments will be made and proof validated on a small size demonstrator. While a human body sized demonstrator will be constructed step by step to overcome all locks and make a proof of concept, giving a breakthrough in molecular imaging domain. It will open a new imaging domain involving standard and cost effective technologies, making them available anywhere around the world, even for countries without high end technology and support.
On the first year of the project a small sized equipment called “first kernel” has been developed (Pure-Device and Fraunhofer) and is now running . This small kernel system is able to do MR imaging at low-field, with magnetic field optimization in direction and homogeneity. One image at Earth field has been produced, this system is fully software controlled. The design of this control electronics is such that it will be able to drive either the small kernel experimental system or the full sized equipment in good time. The specification basis allows to start the development of the final experiment setup. Stelar designed a whole body sized pre-polarization magnet and developed fully controlled power supply. On the chemistry group side, preliminary processes were involved to create the first molecular bricks being evaluated at Earth magnetic field. New compounds, like Nano-diamonds particles from University of Mons, and nanoprobes created at Torino University, have been prepared and send to CNRS Bordeaux, for Earth field NMR characterization. Aix-Marseille University, has delivered molecules used to produce Ketone (usable as nitroxide contrast agent) by in-vitro enzymatic reaction for DNP test purposes. Nano-diamonds are ready to be tested for DNP experiment, but it needs some complementary instrumentation development, at least a new RF coil specific to the frequency domain.
During the first period CNRS Bordeaux started to characterize the DNP process at Earth field on the basis of known nitroxide molecules that will be involved in future contrast agent. In parallel this group refined the Overhauser theory in the context of Earth magnetic field for these nitroxide molecules. With a homemade spectrometer working at Earth field and a developed radio-frequency channel, DNP experiment were conducted. At this time in-vitro preliminary DNP results has been produced for standard Nitroxide (Oxo-Tempo) and for Ketone issued from an enzymatic reaction.
During the second year of the project, based on results from the first year activity, the consortium made a lot of progresses either in instrumentation, in chemistry development and on testing OMRI contrast agents. On the instrumentation side, the First-Kernel system is now fully functional in Bordeaux at CNRS laboratory and has been used to obtain Magnetically Polarized and Electron Polarized imaging. In order to do this, a complete Electron Spin Resonance RF channel has been developed. Dedicated MR sequence acquisition were also optimized on this first kernel system to obtain for the first time 2D and 3D imaging at 3 mm spatial resolution at ultra-low magnetic fields. The development of the whole body system is also in very good progress. The other components of the whole-body MRI equipment are now ready: electronics, gradient coil, B0 coils or under progress: NMR coils, a second MRI controller has been set to test the system. Partners involved in the WP3 have designed several strategies complying with specific biological and imaging requirements. These developments include strategies to synthetize agents, including EPR properties (off/on or permanent active), solubility, stability of the systems, etc. In-vitro enzymatic studies and preliminary characterizations of various contrast agents were performed and characterized with the first kernel system in Bordeaux.
Among the strategies developed, the one based on the monitoring of the enzymatic activity is the most advanced one. Indeed, the work of the consortium shows for the first time that the strategy developed in the PrimoGAIA project allows to generate a new type of biological contrast at earth magnetic field.
During the first period CNRS Bordeaux started to characterize the DNP process at Earth field on the basis of known nitroxide molecules that will be involved in future contrast agent. In parallel this group refined the Overhauser theory in the context of Earth magnetic field for these nitroxide molecules. With a homemade spectrometer working at Earth field and a developed radio-frequency channel, DNP experiment were conducted. At this time in-vitro preliminary DNP results has been produced for standard Nitroxide (Oxo-Tempo) and for Ketone issued from an enzymatic reaction.
During the second year of the project, based on results from the first year activity, the consortium made a lot of progresses either in instrumentation, in chemistry development and on testing OMRI contrast agents. On the instrumentation side, the First-Kernel system is now fully functional in Bordeaux at CNRS laboratory and has been used to obtain Magnetically Polarized and Electron Polarized imaging. In order to do this, a complete Electron Spin Resonance RF channel has been developed. Dedicated MR sequence acquisition were also optimized on this first kernel system to obtain for the first time 2D and 3D imaging at 3 mm spatial resolution at ultra-low magnetic fields. The development of the whole body system is also in very good progress. The other components of the whole-body MRI equipment are now ready: electronics, gradient coil, B0 coils or under progress: NMR coils, a second MRI controller has been set to test the system. Partners involved in the WP3 have designed several strategies complying with specific biological and imaging requirements. These developments include strategies to synthetize agents, including EPR properties (off/on or permanent active), solubility, stability of the systems, etc. In-vitro enzymatic studies and preliminary characterizations of various contrast agents were performed and characterized with the first kernel system in Bordeaux.
Among the strategies developed, the one based on the monitoring of the enzymatic activity is the most advanced one. Indeed, the work of the consortium shows for the first time that the strategy developed in the PrimoGAIA project allows to generate a new type of biological contrast at earth magnetic field.
The first steps and results of the project were substantial, each partner has provided original ideas in instrumental or contrast agent chemistry developments. At this time, imaging at low or Earth magnetic field is already made possible thanks to innovative concept developed within the project. These first results will give the opportunity to explore DNP imaging in the next months. Recent results on the first-kernel system, proved the feasibility of OMRI at ultra-low field. Further development and trials are necessary to setup the experiment for in-vivo application and to build the large scale system. Monitoring an in-vivo enzymatic activity with the small scaled system, First-kernel, will be the next main challenge.