Hyperpolarised MR technologies and molecular probes as alternatives for conventional metal-containing contrast agents for MRI examinations

Project Information

AlternativesToGd

Grant agreement ID: 858149

DOI

10.3030/858149

Project closed

EC signature date 24 September 2019

Start date 1 October 2019

End date 30 September 2023

Funded under

• EXCELLENT SCIENCE - Future and Emerging Technologies (FET)

Total cost

€ 3 065 956,25

EU contribution

€ 3 065 956,25

Coordinated by

HADASSAH MEDICAL ORGANIZATION
Israel

Periodic Reporting for period 3 - AlternativesToGd (Hyperpolarised MR technologies and molecular probes as alternatives for conventional metal-containing contrast agents for MRI examinations)

Reporting period: 2022-04-01 to 2023-09-30

Summary of the context and overall objectives of the project

The AlternativesToGd project has identified and validated radically new compounds and technologies as alternatives to conventional gadolinium-bearing contrast agents (GBCAs) for medical imaging. There are potential major health concerns resulting from long-term accumulation of gadolinium in patients’ bodies. The project has developed a new class of contrast agents that is metal-free, safe, and fully eliminated from the human body and the environment. The compounds and technologies have been tested in animal models of disease and the most promising ones have been selected for further clinical development. The outcomes of this project are expected to radically impact the field, likely leading to a paradigm shift in magnetic resonance (MR)- based diagnosis and thus be highly beneficial to society.

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 AlternativesToGd vision has been to identify and validate radically new compounds and technologies as alternatives to Gadolinium-bearing contrast agents. New compounds and technologies have been tested in animal models of disease and the most promising ones have been selected for further clinical development. Pending further development, the outcome of this project should radically impact the field, likely leading to a paradigm shift in MR-based diagnosis and thus being highly beneficial to society.
We have focused on the following aspects:

WP1 - Unconventional agents for dDNP HP MRI:
The polarization level of [15N2]urea and water protons has been increased. Novel encapsulation protocols aimed at encapsulating D2O with the above agents were further developed.

WP2 - Non-dDNP HP approaches: PHIP-SAH and nano-diamonds:
The PHIP-SAH technology has been further optimized and automated to reach high 13C polarization values and hydrogenation yields. An automated system has been developed that is fully open to the knowledgeable user. Nanodiamond polarisation via light sources was comprehensively studied and multiple setups were investigated in attempt transfer polarisation to small molecules external to the nanodiamond (without success). This warrants further investigation of dDNP polarisation of nanodiamonds. The reproducible production of synthetic nanodiamonds in the lab was established and well characterised. Desirable coating of the nanodiamonds has been established and warrants utility in multiple applications.

WP3 - MRI tools for HP X-nuclei:
The project has completed an independent transmit/receive insert prototype for MRI scanners. The quality of imaging using this insert was beyond expectations and will be instrumental in further development of the AlternativesToGd approach. In vivo application of a B1-insensitive transfer of spin polarization between hyperpolarized 15N and coupled protons has shown utility. In vivo application of low-coherence gradient trajectories for hyperpolarized acquisitions has been tested in vivo in clinical scanners and showed superb imaging quality.

WP4 - Validation:
Imaging of hyperpolarized compounds in vivo has been performed with hyperpolarized water and hyperpolarized [15N2]urea. Models for imaging cardiovascular conditions were established. PHIP-SAH driven hyperpolarized 13C-labelled agents were optimized and imaged in vivo. Most importantly, cancer tumours were visualized in vivo using dDNP hyperpolarized [15N2]urea dissolved in D2O. With this result, the project has achieved its goal which was “to demonstrate the feasibility of replacing GBCA with a metal-free approach in at least one type of contrast-enhanced MRI examination.

The results of the project have been published in more than 32 papers in high quality journals and in multiple conference presentations. Dedicated project sessions have been held in major conferences. The project shared primary data for all of the work curried out during the project on freely available archives. About 8 additional papers are in preparation and several continuation applications for funding to further develop the project’s results have been submitted.

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 use of hyperpolarized agents for perfusion imaging or tissue-retention imaging for diagnostic MRI is a new technology that does not exist today. We have laid the foundation for such a technology by providing the contrast agents, the means to increase their MR signal (hyperpolarisation technologies), and the routes for MR imaging of these signals on clinical MRI scanners.

Society will gain by having access to medical imaging that does not leave potentially toxic deposits in the bodies of children and adults undergoing MRI examinations and does not contaminate the environment.

Our results have the potential to access new markets for medical imaging and contrast media companies, whether established or young start-ups. There is clearly a market for new contrast agents that are free of the undesirable properties of GBCAs.

European scientists in academia and industry have been at the forefront of the fields of molecular imaging and contrast media for many years. AlternativesToGd has established new contrast mechanisms for contrast enhanced MRI. The outcomes of AlternativesToGd have the potential to build a new medical application, thereby building new leadership capacity in the field of novel non Gd-based contrast agents through collaboration of the key actors in related fields, ambitious biotech industries, as well as through contributions from excellent young researchers.

Other substantial impacts include:
• Build nascent European industry focused on betterment of MRI diagnostics and efficient hyperpolarisation.
• Provide tailored diagnostic tools for coronary heart disease, ischemic stroke, and cancer.
• Introduce long lived hyperpolarized nitrogen-15 compounds for clinical use.
• Introduce hyperpolarized water to clinical use in MRI diagnostics.
• Revolutionise PHIP technologies for generating contrast agents on the spot, for clinical use.
• New encapsulation technologies for use in hyperpolarized MRI for enhanced performance of medical imaging.

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