Rapid-Transfer Dynamic Nuclear Polarization

Nuclear magnetic resonance (NMR) is a powerful method that probes the structure and dynamics of small and large molecules. NMR is also at the heart of magnetic resonance imaging (MRI). In both cases the signal arises from nuclear spins, which can be pictured as tiny magnets. These nuclear magnets can be aligned in an external magnetic field, but because they are so weak, the net alignment in a typical magnetic field is extremely small, and on average only 1 in 100 000 spins is aligned. The signal in magnetic resonance is obtained by sending and receiving radio-frequency waves to and from the nuclei, but only the aligned spins contribute to the signal.

Using a method referred to as hyperpolarization, it is possible to increase the alignment, or the fraction of spins that contribute to the signal, by orders of magnitude. In one method, referred to as dissolution-dynamic nuclear polarization (D-DNP), a sample containing a molecule of interest is hyperpolarized in a device called polarizer. In the polarizer the sample is kept in a magnetic field of several Tesla at a temperature of 1 Kelvin. Free electrons present in the sample also act as little magnets, and they are about 700 times more magnetic than protons. The electron alignment can be transferred to the nuclei using microwave irradiation. The material is then dissolved using a jet of hot solvent, propelled by helium gas, and the signal is recorded in a secondary apparatus which can be an MRI scanner or a liquid-state NMR spectrometer. Signal enhancements of more than 10 000 are achieved on small metabolite molecules like pyruvate, an important imaging agent in cancer research.

While D-DNP is already a powerful technology, serious disadvantages are associated with the dissolution procedure. For spectroscopic applications, the transfer of the dissolved material to the secondary apparatus takes several seconds, and the propulsion of the sample with helium gas causes foaming in particular for biomolecules. During the transfer time the nuclei loose their alignment - often most of the alignment is already lost by the time a spectrum is recorded. The procedure is also not scalable towards small volumes, as a minimum of 3 mL of hot solvent is needed to prevent freezing of the solvent in the cold regions of the polarizer. Lastly the procedure is not very robust and difficult to automate.

Our preliminary research that underpins this grant application shows that it is possible to transfer the polarized sample in the solid state while keeping most of the nuclei aligned. In our prototype apparatus the hyperpolarized sample is located in a Teflon capsule that is shot from the polarizer to the secondary magnet within 200 ms, and a signal enhancement of 16000 is obtained. This new scheme addresses all the above mentioned issues: The transfer is fast, foaming can be avoided, and the method is scalable towards small volumes.

Within this grant application we will establish the scope of the new technology by optimizing the transfer, and by quantifying the alignment loss for a range of relevant samples. We will capitalize on the new methodological approach and seek to develop dissolution-DNP into a technology that can quickly generate and reveal structural information of a broad range of small and large molecules, with greatly increased sensitivity.

The new approach in addition offers benefits for the hyperpolarization of substrates for clinical applications. For example the new dissolution method can yield solutions with larger concentrations, giving better contrast in MRI, and the geometry of the apparatus facilitates cross-polarization, a technology by which nuclei can be more strongly polarized in shorter time. Both these improvements can ultimately lead to more accurate images of cancerous tissue in clinical studies.

Beneficiaries of this research will be primarily in academia, but medium to long-term perspectives exist for economy and society.

Academia.
As outlined in academic beneficiaries, the research in this proposal will lead to more powerful spectroscopic and imaging tools, opening the way to new applications in physical and biomedical sciences.

In addition the researchers working on this proposal (myself, Karel Kouril and a faculty-financed PhD student) will have the chance to deliver an ambitious, interdisciplinary research proposal that will substantially further their careers.

Economy.
The research described in the current proposal is anticipated to broaden the scope of our recently filed UK patent application, and may result in the technology being licensed by Oxford Instruments or GE Healthcare. If the research yields the anticipated results, rapid-transfer DNP may be established as a superior alternative to conventional dissolution-DNP, creating new market opportunities, including the formation of a startup company.

Society.
Longer-term benefits to society may result from this research as the anticipated gains in sensitivity increase the amount of medical information that can be obtained in pre-clinical and ultimately clinical studies. Together with project partner Brindle we will seek to timely exploit such opportunities where they arise.