Prepolarized MRI at Earth Field to seek new contrasts linked to molecular events for very early detection of pathologies

Project Information

PRIMOGAIA

Grant agreement ID: 863099

DOI

10.3030/863099

Project closed

EC signature date 4 September 2019

Start date 1 December 2019

End date 30 November 2023

Funded under

• EXCELLENT SCIENCE - Future and Emerging Technologies (FET)

Total cost

€ 3 387 821,33

EU contribution

€ 3 387 821,25

Coordinated by

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
France

Periodic Reporting for period 3 - PRIMOGAIA (Prepolarized MRI at Earth Field to seek new contrasts linked to molecular events for very early detection of pathologies)

Reporting period: 2021-12-01 to 2023-11-30

Summary of the context and overall objectives of the project

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 (200mT).
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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The project's first year focused on creating a small-scale MR imaging system, achieving imaging at ultra-low magnetic fields and producing images at Earth's magnetic field. Chemistry groups developed molecular structures like Nano-diamond particles and nanoprobes, crucial for characterizing Earth field NMR. Additionally, progress was made in synthesizing Ketone molecules for contrast agents, although further instrument development was needed.

In the second year, significant strides were made, with the First-Kernel system operational for Magnetically and Electron Polarized imaging at impressive spatial resolutions. Advanced imaging sequences were optimized, allowing groundbreaking 2D and 3D imaging at ultra-low magnetic fields. Development progressed on the whole-body MRI system, along with strategies for specific contrast agent properties and enzymatic studies, enhancing understanding and refinement for imaging purposes.

In the project's final phase, CNRS tailored coils for rat imaging. Contributions from Fraunhofer, Pure Devices, UNITO, UMONS, and AMU resulted in the calibration of the whole-body system, development of enzyme-sensitive probes, exploration of nanostructures for targeted delivery, and provision of a modified nitroxide probe. These advancements facilitated high-resolution 3D imaging of rat anatomy and the detection of nitroxides in vital organs, promising exciting prospects for studying various medical conditions.

Overall, the tangible results of the project are :

1) The development of the first instrument, i.e. First-Kernel’, with a fully integrated RF channel, is an optimized solution for ULF imaging, on small volume, compatible with small animal models (rodents).This instrumentation is protected by a patent.
2) The development of different contrast agent strategies Nitroxide (NO) based, applicable using the OMRI investigation tool: Dendrimers-linked NO, NO functionalized nanoparticles, NO loaded liposomes, peptide locked on/off NO and phenol/anilide-based substrate (precursor of NO and alkyl radicals). All these contrast agent are targeting specific enzymatic reactions, already proved in-vitro.
3) The ability to use targeted contrast agents, specific to an enzymatic activity and to monitor the process in real time for in-vitro experiment using OMRI, with the project instrumentation.
4) The feasibility of ULF imaging, at 200µT, on large objects comparable to the human head volume with 20mT magnetic prepolarization.

The project has been presented in 28 international conferences (ISMRM, EUROMAR…). A total of six scientific publications have been published in renowned journal such at JMR. The PrimoGaïa worshop “1st Workshop on Emerging Trends in Molecular Imaging 2023” held in Turin was a great success and gathered over one hundred researchers and industry stakeholders.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The PrimoGaia project holds immense importance for society due to its groundbreaking implications in medical diagnostics and imaging technology. Low-field MRI, a cornerstone of this project, presents a paradigm shift by offering cost-effective, portable, and potentially safer imaging solutions. These systems could widen accessibility to healthcare, especially in underserved regions or resource-limited settings. Additionally, the development of a new strategy capable of mapping and quantifying enzymatic activity in a non-invasive manner within intact living animals marks a significant leap in medical research and diagnostics. Such an advance could revolutionize disease detection and monitoring, enabling early identification and precise tracking of pathological conditions. This breakthrough has profound implications for understanding disease progression, evaluating treatment responses, and potentially developing targeted therapies, ushering in a new era of personalized medicine and improved patient outcomes.

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