Inexhaustible Spring of Hyperpolarization For Magnetic Resonance

Project Information

HypFlow

Grant agreement ID: 101044726

DOI

10.3030/101044726

EC signature date 22 July 2022

Start date 1 January 2023

End date 31 December 2027

Funded under

• European Research Council (ERC)

Total cost

€ 2 990 000,00

EU contribution

€ 2 990 000,00

Coordinated by

UNIVERSITE LYON 1 CLAUDE BERNARD
France

Periodic Reporting for period 1 - HypFlow (Inexhaustible Spring of Hyperpolarization For Magnetic Resonance)

Reporting period: 2023-01-01 to 2025-06-30

Summary of the context and overall objectives of the project

Magnetic Resonance has become a well-established and versatile tool in numerous fields of research, clinics and industry. Still, it features a relatively low sensitivity (typ. uM concentration in liquids) if compared to other analytical methods such as mass spectrometry (typ. pM). It is precisely this low sensitivity that makes it unsuitable to solve many of today’s most interesting problems of modern science.

Hyperpolarization by dissolution dynamic nuclear polarization (dDNP) has recently evolved into a robust method providing a decisive solution to this lack of sensitivity as it enhances nuclear spin polarization - and therefore sensitivity - by up to four orders of magnitude. High electron spin polarization is transferred to nuclear spins of interest in the frozen state. It is then followed by a ‘single shot’ irreversible melt, dilution, and transfer to a room-temperature liquid-state NMR apparatus. This strategy is compatible with a few applications in which exhaustibility and pollution can be accommodated.

Most NMR applications are multi-scan by essence and incompatible with hyperpolarization. These approaches involve phased-cycled coherence selection, 2- or 3-dimensional sequences, or additional time-domain dimensions. This situation is untenable, preventing numerous laboratories and industries to greatly benefit from a simple and accessible hyperpolarization strategy.

Based on previous contributions, new ideas of instrumental, methodological and chemical developments, we will provide a radically new approach enabled through the three following objectives:
1. design and build a pulsed-DNP freeze&flow polarizer apparatus (HypFlow polarizer, at 77K and 0.3T) in which pure solutions will be recirculated and repolarized,
2. Integrate the use of electron-polarized hyperpolarizing matrices.
3. Validate high-impact multi-scan NMR applications in metabolomics, drug discovery and chemistry.

Pure liquid samples will flow and freeze in the HypFlow system (polarizer and matrix) where high levels of polarization will be generated. Then it will melt and flow toward the NMR spectrometer, and will recirculate repeatedly. For the first time, HypFlow will provide pure and inexhaustible hyperpolarization, compatible with the arsenal of NMR experiments.

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

During the HypFlow project, we are working on the three following objectives:


1. design and build a pulsed-DNP freeze&flow polarizer apparatus in which pure solutions will be recirculated and repolarized.

We have so far been developing the first version of the HypFlow polarizer operating at 1T and 77K with continuous wave microwave irradiation (30 GHz) and heteronuclear pulsed NMR up to 45 MHz, including CP, and published our work here.

Bocquelet, C.; Rougier, N.; Le, H.-N.; Veyre, L.; Thieuleux, C.; Melzi, R.; Purea, A.; Banks, D.; Kempf, J. G.; Stern, Q.; Vaneeckhaute, E.; Jannin, S. Boosting 1H and 13C NMR Signals by Orders of Magnitude on a Bench. Science Advances 2024, 10 (49), eadq3780. https://doi.org/10.1126/sciadv.adq3780.

Vaneeckhaute, E.; Bocquelet, C.; Rougier, N.; Jegadeesan, S. A.; Vinod-Kumar, S.; Mathies, G.; Melzi, R.; Kempf, J.; Stern, Q.; Jannin, S. Dynamic Nuclear Polarization Mechanisms Using TEMPOL and Trityl OX063 Radicals at 1 T and 77 K. arXiv December 13, 2024. https://doi.org/10.48550/arXiv.2412.10325.

2. Integrate the use of electron-polarized hyperpolarizing matrices.

We have implemented the use of porous polymer polarizing matrices (HYPOPs) with our new polarizer, and we have published our work here.

Vaneeckhaute, E.; Bocquelet, C.; Bellier, L.; Le, H.-N.; Rougier, N.; Jegadeesan, S. A.; Vinod-Kumar, S.; Mathies, G.; Veyre, L.; Thieuleux, C.; Melzi, R.; Banks, D.; Kempf, J.; Stern, Q.; Jannin, S. Full Optimization of Dynamic Nuclear Polarization on a 1 Tesla Benchtop Polarizer with Hyperpolarizing Solids. Phys. Chem. Chem. Phys. 2024, 26 (33), 22049–22061. https://doi.org/10.1039/D4CP02022G.

We have also investigated how hyperpolarization could be transferred during sample flow to the NMR spectrometer.

Stern, Q.; Reynard-Feytis, Q.; Elliott, S. J.; Ceillier, M.; Cala, O.; Ivanov, K.; Jannin, S. Rapid and Simple 13 C-Hyperpolarization by 1 H Dissolution Dynamic Nuclear Polarization Followed by an Inline Magnetic Field Inversion. J. Am. Chem. Soc. 2023, 145 (50), 27576–27586. https://doi.org/10.1021/jacs.3c09209.

In parallel, we have been investigating how these matrices could be filtered out, and we have tested new matrices in which electrons could potentially be polarized.

Pokochueva, E. V.; Le, N. H.; Guibert, S.; Gioiosa, C.; Stern, Q.; Tolchard, J.; Bocquelet, C.; Cala, O.; Cavaillès, M.; Veyre, L.; Mankinen, O.; Telkki, V.-V.; Thieuleux, C.; Jannin, S. Hybrid Polarizing Solids with Extended Pore Diameters for Dissolution Dynamic Nuclear Polarization. Chemistry October 10, 2024. https://doi.org/10.26434/chemrxiv-2024-6nmt0.

Stern, Q.; Verhaeghe, G.; El Daraï, T.; Montarnal, D.; Le, N. H.; Veyre, L.; Thieuleux, C.; Bocquelet, C.; Cala, O.; Jannin, S. Dynamic Nuclear Polarization with Conductive Polymers. Angew Chem Int Ed 2024, e202409510. https://doi.org/10.1002/anie.202409510.

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)

Amongst these results, our benchtop DNP system is a new device, beyond state of the art that could become a commercial product in the future. In order to ensure further uptake and success, we will take the following actions:
- Instrumental development: we will make it even more compact by designing a new cryostat and a new magnet.
- IP: we will apply for patents on key aspects of our design.
- PoC: We will apply for a PoC grant to study IP, market, etc. and evaluate pathways to commercialization.