Hyperpolarised Liquids for Magnetic Resonance

Magnetic resonance imaging (MRI) and spectroscopy are two highly influential branches of the technique known as nuclear magnetic resonance (NMR). MRI has had a major impact in disease diagnosis; NMR spectroscopy provides a powerful method of investigating molecular structure, has proved invaluable in many areas of science and medicine, and is exploited widely in industry.
NMR detects the magnetic properties characteristic of certain atomic nuclei, most notably the hydrogen (1H) nucleus; other magnetic nuclei of interest include carbon (in the form of 13C), nitrogen (15N), and phosphorus (31P). Despite the great success of NMR, its lack of sensitivity imposes a number of constraints on the quantities of material that can be detected and/or on the spatial and temporal resolution that can be achieved. This has proved to be a major limitation, for example, in the use of NMR spectroscopy as a means of studying tissue chemistry in vivo.

The sensitivity of NMR is poor because, unlike compass needles, nuclear magnets (or spins) do not all point in the same direction when subjected to a strong magnetic field. This is because of the randomising effects of thermal agitation. As a result, the nuclei are very weakly polarised, and the detectable NMR signal arises from only a small proportion (typically about 1 in 100,000) of nuclear spins. It would clearly be an attractive proposition to increase the polarisation and hence tap into a larger proportion of the nuclei. Over the years, several strategies have been developed for generating high levels of nuclear spin polarisation. Here, we propose to develop and establish methods, based on the so-called brute-force approach, for achieving dramatic (up to 100,000-fold) gains in nuclear polarisation. The method is conceptually straightforward as it simply involves exposure of the material to very low temperature (as low as 0.01 K) and very high magnetic field (up to 14 T) leading to polarisation levels of more than 10%. However, this is not as straightforward as it sounds because of the time taken for the polarisation process to build up, characterised by the relaxation time, T1. Reducing the thermal agitation by lowering the temperature allows a high degree of alignment of the nuclear spins with the magnetic field, but as the lattice vibrations and hence the magnetic fluctuations that cause the relaxation are frozen out, the relaxation time T1 can become excessively long. Our recent research demonstrates that we are now well placed to overcome this problem as we have discovered a new class of materials that greatly reduce the relaxation time at very low temperatures.

In the proposed research, we shall polarise selected agents at very low temperatures and high fields using this relaxation-assisted brute-force method. The frozen, polarised material will then be removed and rewarmed rapidly and dissolved using hot solvent for use in the liquid state. One of our aims is to find ways of storing the frozen, polarised material ready for rewarming and dissolution at a later time.

Our proposal details methods for overcoming the technical issues and for making the brute-force method competitive with alternative approaches to achieving high levels of polarisation. The proposed methods build on our own research over the last few years in which we have used nanoparticles to reduce the time required to polarise the nuclei, linked in to the research of our partners Bruker, who have successfully integrated 'brute-force' and rapid warming/dissolution technology. Our main aim is to achieve polarisation levels of at least 10% in a range of 13C-containing compounds. We envisage a wide range of biomedical applications, both in vitro and in vivo; prominent amongst these applications would be the use of hyperpolarised 13C-labelled metabolites for the investigation of tumour biochemistry and response to treatment.

Hyperpolarisation of nuclear spins has the potential to transform the role of magnetic resonance in the physical sciences and in biomedicine. This is because of the dramatic (~100,000) fold increase in signal strength that it affords. The hyperpolarisation technique that we are proposing here has a number of potential advantages over other methods that are available, especially in terms of i) its scalability, ie its ability to yield large amounts of hyperpolarised materials, ii) its generality, ie its ability to polarise a wide range of materials and nuclear species, and iii) the possibility of preparing these materials at central sites for delivery to centres where these materials would be used. As a result, we envisage that, if successful, our research would have widespread implications for biomedical research scientists, for clinicians, for commercial organisations, and ultimately for overall quality of life. For research scientists using NMR to investigate structure and function of biomolecules, it would, for example, enable much smaller quantities of materials to be examined. More importantly from our perspective, for scientists involved in studies of human metabolism and in clinical imaging and spectroscopy, there would be a range of new applications resulting from the ability to inject hyperpolarised agents into the body. These applications include investigations of cardiac, brain and tumour metabolism, assessment of early response to therapy, and procedures in angiography, perfusion imaging and surgical intervention. For cryogenics, imaging, and engineering companies, there would be a new range of technologies to develop, manufacture and sell, and for the pharmaceutical companies there would be scope to develop and market a new range of reagents, some of which would be labelled with NMR-visible isotopes such as 13C and 15N. In the long term, the ability to obtain an improved understanding of human metabolism, and more specifically to provide an early indication of response to therapy (eg of tumours) should impact positively on health services and quality of life.

As scientists with a strong background in magnetic resonance physics, we have excellent clinical collaborations, for example with colleagues at the Queen's Medical Centre in Nottingham, and at Great Ormond Street Hospital for Children and University College Hospital in London. This will ensure an early and effective clinical outlet for our research. In addition, we have a number of links with industry, especially in the fields of magnetic resonance technology and cryogenics, the most important in the context of this application being Bruker. The University of Nottingham is renowned for its pioneering and continuing role in biomedical magnetic resonance and its applications, and provides an extremely strong infrastructure on which we can capitalise. It has an outstanding track record of IP commercialisation, and provides the necessary skills and experience that will enable us to capitalise optimally on IP issues.

We also have extensive skills and experience in presenting our research at leading national and international scientific conferences, in forums that have ranged from imaging physics (eg British Radiofrequency Spectroscopy Group and Euromar/ISMAR) to more clinically applied magnetic resonance (International Society for Magnetic Resonance in Medicine) and clinical or neuroscience meetings. In addition, we publish in a wide range of high-impact scientific journals encompassing a diverse array of disciplines. The proposed research will provide an excellent platform for us to continue to promote our research findings across a wide range of disciplines and, for example through its applications to cancer, offers the advantage of appealing both to our peers in the research community as well as to the general public.