Photochemical spin-hyperpolarization in confined environments

Nuclear Magnetic Resonance (NMR) is a tremendously powerful and versatile analytical technique for the investigation of the structure and dynamics of molecules from the simplest chemical species to complex biomolecules. The key limitation of NMR is that is suffers from low sensitivity because the obtainable nuclear spin polarization is small; lengthy signal averaging is therefore necessary making NMR slow which hinders new applications and because of finite equipment access even limits routine exploitation. This project will develop a new method for photochemically generating nuclear spin-hyperpolarization which by increasing sensitivity and reducing experiment times will provide the opportunity for a number of exciting new applications of NMR to be explored.

To observe a magnetic resonance signal spin-polarization is required, that is more nuclear spins (which act like tiny bar magnets) must line up with than against the applied magnetic field (or vice-versa). Even in strong magnetic fields, however, typically less than one in ten thousand nuclei do so at room temperature. The polarization of electron spins is higher than that of nuclear spins (by ~660 versus protons) making them more sensitive probes of molecular environment, but most molecules don't have the unpaired electron spins needed to use electrons as probes directly. However, a number of Dynamic Nuclear Polarization (DNP) techniques are under development which aim to generate nuclear hyperpolarization (greater than equilibrium polarization) by transfer of polarization from thermally polarized electrons to nuclear spins. However, these techniques rely on microwave pumping of the electron spins which causes problems with sample heating, and for liquid state NMR the biggest gains come when long pumping periods are combined with rapid heating and dissolution of molecules polarized at very low temperatures. Such approaches generate large nuclear hyperpolarizations but cannot be rapidly repeated hence little time-saving is achieved. Such methods will not make feasible the time-consuming multi-dimensional experiments needed to examine complex biological molecules, or speed-up NMR analysis to enable high throughput screening for medical diagnostics. The project will use a short pulse of laser light to hyperpolarize electron spins to hundreds of times their thermal polarization and then rapidly transfer this large hyperpolarization to the nuclei, achieving nuclear spin-hyperpolarizations far in excess of those possible when using thermally polarized electrons. This will provide a room temperature nuclear hyperpolarization method that can be combined with the high repetition rates conventionally employed in NMR when signal averaging or incrementing experimental parameters.

This project will exploit the as yet under-utilized Radical Triplet Pair Mechanism (RTPM) by which a stable radical interacts with a short-lived triplet state generated photochemically from a suitable precursor, resulting in electron spin-hyperpolarization of the radical. Such hyperpolarization can be conveniently observed by Electron Paramagnetic Resonance (EPR) spectroscopy. EPR will be used to investigate the key interactions giving rise to this effect, and in particular the effect of confining the radical and triplet molecules in cage-like structures on the size of the hyperpolarization generated. By restricting the relative separation of the radical and triplet molecules, and hence increasing their chances of encounter in solution, the electron hyperpolarization generated will be maximised. The effect of this encapsulation on the efficiency of the transfer to nuclear hyperpolarization will also be assessed. This project will test and further develop the underlying theory of the RTPM and provide a proof of principle that this method can be used as a new way to enhance sensitivity in NMR experiments, a result with potentially far reaching applications throughout analytical and medical science.

Who will benefit from the research?

The proposed research will have both economic and societal impact. Magnetic resonance (MR) spectroscopy represents a multi-billion pound global market in which UK industry is a key player, with the future success of companies including Bruker, Oxford Instruments, Thomas Keating, Tesla Engineering and Cryogenic being dependent on continued innovation in this area. Bruker are supporting the project with an equipment loan and I will regularly discuss results and their potential exploitation with the Bruker UK team. Being a core technique within the analytical science arsenal the step-change in sensitivity of MR that this project aims to deliver will increase uptake of MR in industrial applications and further scientific understanding in a range of areas from catalysis to biochemistry. The project will therefore have long-term impact, maintaining the health of many other research areas by enhancing the analytical tools on which they rely. The wider public will also benefit through public engagement and outreach initiatives.

How will they benefit from the research?

UK industry will derive economic benefit from the research in two ways. In the first instance UK companies already at the forefront of MR technology will be well placed to exploit advances in this field. The development of a new technique for sensitivity enhancement will give rise to a need for commercial instruments offering this capability, and increased demand for MR equipment (of which the UK is a major exporter) as new applications become possible. Such increased demand could arise not only for high-end research instruments, but also for benchtop NMR (nuclear magnetic resonance) systems used for routine analysis (e.g. in the food industry) which could also benefit from improved sensitivity. The technique to be developed requires integration of optical excitation sources with magnetic resonance hardware and in the long term use of specific chemical polarizing agents, leading to further industrial opportunities within the optics and chemicals sectors. Furthermore, as sensitivity improvements are made, the routine exploitation of NMR in additional industrial settings will become plausible, with possibilities for use in quality control and real-time process monitoring. These benefits could be realised in the medium to long term, with necessary proof of principle work carried out within the 1 year time frame of this project, paving the way for the first applications to be demonstrated and commercialised in the following 3-5 years.

Low sensitivity currently makes NMR slow which hinders routine academic and industrial exploitation due to both limited equipment access and the low throughput of samples on high resolution machines. New applications such as certain multi-dimensional experiments needed to characterize complex biological macromolecules are unfeasibly time-consuming, while sensitivity is insufficient to allow NMR analysis of low concentration metabolites in clinical samples. Through sensitivity enhancement the speed of experiments can be increased, removing this research bottleneck. While the initial beneficiaries will be the research community, wider societal impact of the research will be achieved in the long term. Improvement of the underpinning technology enabling advances in biological NMR will contribute to improved understanding of countless biological systems and diseases, leading in future decades to new pharmaceutical targets and agents with eventual health benefits. In a clinical setting NMR detection of metabolites could be used for routine screening for disease biomarkers, and sensitivity of MR imaging scanners improved.

The project will also deliver benefits through public engagement work. Key research findings will be made publicly available through video podcasts, in order to interest the next generation of scientists in the development of analytical techniques that underpin scientific endeavour.