Periodic Reporting for period 3 - FunMagResBeacons (Functionalized Magnetic Resonance Beacons for Enhanced Spectroscopy and Imaging)
Reporting period: 2021-10-01 to 2023-03-31
This project is aimed at resolving the general problem of imaging chemical reactions, physicochemical conditions such as acidity, and metabolism, deep inside opaque objects, such as the human body. Although magnetic resonance imaging (MRI) is a powerful method for imaging anatomic structure, its signal strength is generally too weak to detect compounds in low concentration such as common metabolites. The project aims to exploit a phenomenon called nuclear hyperpolarization to greatly enhance the MRI signals, and to exploit a property of certain molecules called long-lived states to store and transport such hyperpolarized spin order. The agents under development are called functional magnetic resonance beacons (fMRBs) and will provide a new set of versatile spectroscopic tools for the spatially resolved study of chemistry, biochemistry, diffusion, flow and percolation inside opaque objects. The fMRB agents support hyperpolarized long-lived spin order, and are functionalized, so that they “light up" in an NMR or magnetic resonance imaging (MRI) experiment, upon triggering by specific chemical signals or physical conditions (sensory functionality), and may also to bind to selected molecular targets (binding functionality). If successful, the project will provide medical practitioners, chemical engineers and other scientists with tools for imaging metabolism and physicochemical status, with one important application being the detection and staging of cancer.
The first stage of the project has mainly concerned the design and study of “core” modules which support the long-lived hyperpolarized states under ambient conditions, the development of methodology for hyperpolarizing these modules, and the technology for understanding the decay of the hyperpolarized spin order and for optimising its lifetime. During the project several candidate chemical systems have been synthesized and studied, including the very novel chemical systems known as endofullerenes, in which single atoms or molecules are encapsulated in closed carbon cages. In particular the novel 3He@C60 endofullerene was synthesized and studied. In this material a single atom of the helium isotope He-3 was encapsulated in a C60 cage, and a novel interaction was detected between the trapped 3He atoms and the 13C nuclei of the surrounding cage. This discovery is important for the project aims, since there are several known routes for hyperpolarizing 3He using circularly polarized light, and the discovery of the 3He/13C interaction makes it feasible to transfer that polarization to other parts of the molecule. In addition, during the project, we discovered some important deficiencies in the theory of magnetic resonance under highly non-equilibrium conditions, and developed a new theory to cover this novel but increasingly important regime. We also developed new methodology for generating long-lived nuclear spin order, and performed, in collaboration with other groups, some indicative proof-of-concept hyperpolarized MRI experiments showing that the release of strong NMR signals from long-lived nuclear spin states may be triggered by metabolism, and used for imaging.
We have progressed beyond the state-of-the-art on many different fronts: (1) new chemical compounds including highly novel atomic and molecular endofullerenes, and new synthetic routes to novel isotopically labelled “core modules” for the storage of hyperpolarized nuclear spin order; (2) new methodology for interconverting long-lived nuclear spin order and ordinary nuclear magnetization; (3) new theories of nuclear spin relaxation, far from equilibrium, and for the physical boundaries of such non-equilibrium states; (3) new methods for generating hyperpolarized nuclear spin order starting from hydrogen gas enriched in the para nuclear spin isomer; (4) new methods for generating hyperpolarized nuclear spin order through a sequence of applied radiofrequency fields; (5) proof-of-concept demonstrations of hyperpolarized magnetic resonance imaging, using the release of hyperpolarized spin order from a long-lived state, triggered by a metabolic process; (6) proof-of-concept demonstration of the hyperpolarization, purification and storage of a hyperpolarized metabolite fumarate. Although the project progress has been somewhat slower than initially anticipated, in part due to the discovery of unexpected issues which required thorough investigation (such as the discovery of the breakdown of standard theories for non-equilibrium systems, and the discovery of previously unknown decay mechanisms), we retain good prospects of attaining the main aims before the project end. In some respects, such as proof-of-concept MRI demonstrations, the progress has been faster than anticipated.