Hyperpolarization method and system

Abstract

A method for performing polarization transfer between electron spins of a nitrogen vacancy (NV) center and nuclear spins of a carbon-13 labeled metabolite (13C metabolite) under ambient conditions, the method comprising the steps of: (i) providing a mixture comprising a host vector providing a source of the NV center and the 13C metabolite; (ii) converting the mixture into a solid glassy state, wherein the spatial orientation of the host and the electron spin state of the NV center are randomly distributed within the mixture taking a solid state; and (iii) applying a hyperpolarization process to the mixture taking a solid state wherein both the electron spins of the NV center and the nuclear spins of carbon-13 are strongly polarized in one direction at ambient temperature at the end of the polarization transfer process.

Description

Technical Field

[0001] The present invention relates to a method for combining the electron spin of a nitrogen vacancy (NV) center with a carbon-13 labeled metabolite ( 13 Methods and systems for polarization transfer between nuclear spins of C metabolites), and magnetic resonance imaging (MRI) contrast agents for subsequent magnetic resonance imaging (MRI) applications. Background Art

[0002] Magnetic resonance imaging (MRI) has been widely used in medical disciplines to obtain three-dimensional structural information from the human body for different investigation and diagnostic purposes of the subject.

[0003] By obtaining three-dimensional images, medical practitioners are able to see through and inside a patient's organs and determine if any structural and physiological abnormalities are present within the patient's body and organs.

[0004] One such abnormality is the presence of tumor tissue. Conventional MRI techniques detect 1H nuclei within the human body, allowing the distribution of water and fat to be seen. Since no ionizing radiation is involved, it can be considered a safer method of investigation than X-ray imaging techniques.

[0005] However, detection of 1H nuclei alone cannot always distinguish normal tissue from abnormal or cancerous tissue, and therefore the technique can be considered less applicable than X-ray computed tomography (CT) and positron emission tomography (PET).

[0006] Therefore, in order to enhance the contrast between normal tissue and cancerous tissue, it is usually necessary to introduce a contrast agent into the body of a subject.

[0007] These MRI contrast agents usually contain gadolinium, which, however, has certain toxic effects, for example on the patient's kidneys and nervous system.

[0008] Patients with kidney disease are considered susceptible to kidney failure after gadolinium-based contrast agents are injected into their bodies. In addition, gadolinium can remain in the body for a long time after an MRI scan, which inherently increases the risk of patient safety-related issues.

[0009] In addition to gadolinium-based contrast agents, 13 Some studies have been conducted on MRI imaging of C nuclei to differentiate normal tissue from cancerous tissue. As we all know, carbon is the building block of all organic compounds.

[0010] because 13 The C core is stable, so 13 C is considered harmless for MRI imaging of living organisms such as humans.

[0011] However, carbon neutrality13 The natural abundance of C nuclei is only 1.1%, which is much lower than the 99.98% natural abundance of 1H nuclei in hydrogen. 13 The C signal is much weaker than that of 1H.

[0012] These two factors together can be considered to make 13 C MRI is very difficult to apply in practice. However, there are already methods for enriching in biomolecules. 13 C abundance technology. Therefore, high purity can be obtained commercially 13 C enhancing compound for MRI imaging.

[0013] Considering that compared with 1H 13 The signal of C is low, and there are also techniques for enhancing it in the art. 13 The nuclear spin alignment of C is small.

[0014] Purpose of the Invention

[0015] The object of the present invention is to provide a method and system for polarization transfer between the electron spin of a nitrogen vacancy (NV) center and the nuclear spin of a carbon-13 labeled metabolite (13C metabolite), as well as a magnetic resonance imaging (MRI) contrast agent for subsequent magnetic resonance imaging (MRI) applications, which overcomes or at least partially improves some of the shortcomings associated with the prior art. Summary of the invention

[0016] In a first aspect, the present invention provides a method for polarization transfer between the electron spin of a nitrogen vacancy (NV) center and the nuclear spin of a carbon-13 labeled metabolite (13C metabolite) under ambient conditions, the method comprising the steps of:

[0017] (i) providing a mixture comprising a host vector providing a source of NV centers and a 13C metabolite;

[0018] (ii) converting the mixture into a solid glassy state, wherein the spatial orientation of the host and the electronic spin states of the NV centers are randomly distributed within the mixture in the solid state; and

[0019] (iii) applying a hyperpolarization process to the mixture in a solid state, wherein at the end of the polarization transfer process both the electron spin of the NV centre and the nuclear spin of the carbon-13 are strongly polarized in one direction at ambient temperature.

[0020] The NV center can be the source of electron spins to be polarized under the hyperpolarization process under ambient conditions

[0021] The pathway for spin transfer between the electron spin of the NV center and the 13C metabolite may be single.

[0022] Alternatively, as a result of the spacing between molecules, the pathways for spin transfer between the electron spin of the NV center and the 13C metabolite are multiple.

[0023] The spacing between the molecules can include the spacing between hosts of NV centers, between 13C metabolites, from hosts of NV centers to 13C metabolites, from nuclear spins of 13C nuclei within hosts to 13C metabolites; including the spacing between charges of NV centers within the same host and between NV centers of different hosts; or between various surrounding charges and corresponding spin states, magnetic impurities, etc.

[0024] The spacing between the molecules may be provided by a spacer, wherein the spacer is the physical size of a water molecule, a solvent, a brine salt, or a host of NV centers.

[0025] The host of the NV center is preferably a wide bandgap material with high optical transparency to deep UV to green light.

[0026] The host of the NV centre is preferably a wide bandgap material with high optical transparency to deep UV to green light in the range of 200 nm to 600 nm.

[0027] The host of the NV center is preferably a micron-sized or nano-sized powder.

[0028] The host of the NV centre is preferably selected from the group consisting of boron nitride, diamond or sapphire.

[0029] The host of the NV centre preferably has a size between 10 nm and 100 um.

[0030] The 13C metabolite can be selected from a group including acetic acid, acetone, L-alanine, dimethyl sulfoxide, ethyl pyruvate, D-fructose, fumaric acid, D-glucose, L-glutamic acid, L-glutamine, α-ketoisocaproate (sodium salt), D-mannitol, propionic acid, pyruvic acid, sodium acetate, sodium bicarbonate, sodium butyrate, sodium L-lactate, sodium propionate, sodium pyruvate, succinic acid, urea, etc., which are enriched in carbon-13 isotope.

[0031] Most of the final polarizations of nuclear spins in 13C metabolites preferably have the same direction, with a tolerance of only a few degrees of difference in any spatial coordinate.

[0032] The glassy state may be provided by quasi-lattice bonding between the 13C metabolite, the host and the other molecules mentioned above.

[0033] The hyperpolarization process preferably comprises irradiating microwave energy and coherent light to the mixture of 13C metabolites and hosts of NV centres under the application of a magnetic field.

[0034] The hyperpolarization process may include multiple cycles of excitation and manipulation of the electron spin of the NV center under ambient conditions and relaxation of the spin transfer to the nuclear spin of the 13C metabolite.

[0035] The hyperpolarization of the 13C metabolites is provided under ambient conditions.

[0036] The solid glassy state may be formed by lowering the temperature of the mixture.

[0037] The temperature can be lowered to below -20°C.

[0038] The temperature can be lowered to -35°C or -80°C.

[0039] In a second aspect, the present invention provides a method for preparing a contrast agent for MRI imaging of a human or animal body under ambient conditions by hyperpolarization, the method comprising the steps of:

[0040] (i) providing a mixture comprising a host vector having an NV center and a 13C metabolite;

[0041] (ii) converting the mixture into a solid glassy state, wherein the spatial orientation of the host and the electronic spin states of the NV centres are randomly distributed within the mixture in the solid state.

[0042] The spacing between the molecules can include the spacing between hosts of NV centers, between 13C metabolites, from hosts of NV centers to 13C metabolites, from nuclear spins of 13C nuclei within hosts to 13C metabolites; including the spacing between charges of NV centers within the same host and between NV centers of different hosts; or between various surrounding charges and corresponding spin states, magnetic impurities, etc.

[0043] The spacing between the molecules may be provided by a spacer, wherein the spacer is the physical size of a water molecule, a solvent, a brine salt, or a host of NV centers.

[0044] The host of the NV center is preferably a wide bandgap material with high optical transparency to deep UV to green light.

[0045] The host of the NV centre is preferably a wide bandgap material with high optical transparency to deep UV to green light in the range of 200 nm to 600 nm.

[0046] The solid glassy state may be formed by lowering the temperature of the mixture.

[0047] The temperature can be lowered to below -20°C.

[0048] The temperature can be lowered to -35°C or -80°C.

[0049] The host of the NV center is preferably a micron-sized or nano-sized powder.

[0050] The host of the NV centre is preferably selected from the group consisting of boron nitride, diamond or sapphire.

[0051] The host of the NV centre preferably has a size between 10 nm and 100 um.

[0052] The 13C metabolite can be selected from a group including acetic acid, acetone, L-alanine, dimethyl sulfoxide, ethyl pyruvate, D-fructose, fumaric acid, D-glucose, L-glutamic acid, L-glutamine, α-ketoisocaproate (sodium salt), D-mannitol, propionic acid, pyruvic acid, sodium acetate, sodium bicarbonate, sodium butyrate, sodium L-lactate, sodium propionate, sodium pyruvate, succinic acid, urea, etc., which are enriched in carbon-13 isotope.

[0053] In a third aspect, there is provided a contrast agent for MRI imaging of a human or animal body under ambient conditions by hyperpolarization, the contrast agent comprising:

[0054] A mixture comprising a host carrier having an NV center and a 13C metabolite, wherein the mixture is provided in a solid glass state, wherein the spatial orientation of the host and the electronic spin state of the NV center are randomly distributed within the mixture in the solid state.

[0055] The spacing between the molecules can include the spacing between hosts of NV centers, between 13C metabolites, from hosts of NV centers to 13C metabolites, from nuclear spins of 13C nuclei within hosts to 13C metabolites; including the spacing between charges of NV centers within the same host and between NV centers of different hosts; or between various surrounding charges and corresponding spin states, magnetic impurities, etc.

[0056] The spacing between the molecules may be provided by a spacer, wherein the spacer is the physical size of a water molecule, a solvent, a brine salt, or a host of NV centers.

[0057] The host of the NV center is preferably a wide bandgap material with high optical transparency to deep UV to green light.

[0058] The host of the NV centre is preferably a wide bandgap material with high optical transparency to deep UV to green light in the range of 200 nm to 600 nm.

[0059] The host of the NV center is preferably a micron-sized or nano-sized powder.

[0060] The host of the NV centre is preferably selected from the group consisting of boron nitride, diamond or sapphire.

[0061] The host of the NV centre preferably has a size between 10 nm and 100 um.

[0062] The 13C metabolite can be selected from a group including acetic acid, acetone, L-alanine, dimethyl sulfoxide, ethyl pyruvate, D-fructose, fumaric acid, D-glucose, L-glutamic acid, L-glutamine, α-ketoisocaproate (sodium salt), D-mannitol, propionic acid, pyruvic acid, sodium acetate, sodium bicarbonate, sodium butyrate, sodium L-lactate, sodium propionate, sodium pyruvate, succinic acid, urea, etc., which are enriched in carbon-13 isotope.

[0063] In a fourth aspect, a contrast agent for MRI imaging of a human or animal body under hyperpolarization under ambient conditions is provided, the contrast agent comprising: a mixture comprising a host carrier having an NV center and a 13C metabolite; wherein the mixture is provided for subsequent conversion into a solid glass state, such that the spatial orientation of the host and the electronic spin state of the NV center are randomly distributed within the mixture in the solid state.

[0064] The host carrier of the NV center can be a micron-sized or nano-sized powder.

[0065] The host support of the NV center may be selected from the group consisting of boron nitride, diamond or sapphire, and the like.

[0066] The host of the NV center has a size between 10 nm and 100 um.

[0067] The 13C metabolite can be selected from a group including acetic acid, acetone, L-alanine, dimethyl sulfoxide, ethyl pyruvate, D-fructose, fumaric acid, D-glucose, L-glutamic acid, L-glutamine, α-ketoisocaproate (sodium salt), D-mannitol, propionic acid, pyruvic acid, sodium acetate, sodium bicarbonate, sodium butyrate, sodium L-lactate, sodium propionate, sodium pyruvate, succinic acid, urea, etc., which are enriched in carbon-13 isotope.

[0068] In a fifth aspect, a hyperpolarization system is provided, comprising:

[0069] (i) a storage container for receiving the contrast medium according to the third aspect;

[0070] (ii) a laser for providing excitation;

[0071] (iii) microwave systems; and

[0072] (iv) Magnetic resonator. BRIEF DESCRIPTION OF THE DRAWINGS

[0073] In order that a more accurate understanding of the above-described invention can be obtained, a more particular description of the invention briefly described above will be rendered by reference to specific embodiments of the invention which are illustrated in the appended drawings.

[0074] The drawings presented herein may not be drawn to scale, and any reference to dimensions in the drawings or the following description are specific to the disclosed embodiments.

[0075] Figure 1a – Figure 1c The hyperpolarization process used to enhance the MRI signal of carbon-13 nuclei is shown;

[0076] Figure 2a – Figure 2b An example of a glassy state between an electron center provided by NV and a 13C-pyruvate metabolite molecule according to the present invention is shown;

[0077] Figure 3a Schematic diagram of potential spin transfer pathways between the NV center and nearby 13C nuclei, and then between nearby 13C in the host and 13C metabolites;

[0078] Figure 3b is a diagram of the electron spin of the NV center to the 13C metabolites around the host surface due to the glassy state achieved in the entire mixture;

[0079] Figure 4a is an image depicting MRI imaging of a hyperpolarized 13C-pyruvate mixture according to the present invention and untreated 13C-pyruvate obtained by echo planar spectroscopy imaging (EPSI) pulse sequence measurement, and showing a chemical shift spectrum of the hyperpolarized 13C-pyruvate mixture hyperpolarized according to the present invention;

[0080] Figure 4b yes Figure 4a Line graph of

[0081] Figure 5a yes Figure 4a An image showing the time of the cursor pointing to untreated 13C-pyruvate (right sample in left frame) and showing that the chemical shift spectrum shows a very weak signal compared to the hyperpolarized 13C-pyruvate mixture;

[0082] Figure 5b yes Figure 5a a line graph of

[0083] Figure 6 A schematic diagram showing an embodiment of a hyperpolarization system for use in the present invention is shown. DETAILED DESCRIPTION

[0084] The present inventors have identified the problems and shortcomings associated with the prior art and have provided a method and system that overcomes the problems of the prior art.

[0085] The present invention

[0086] The present inventors have developed a method and system for polarization transfer between the electron spin of a nitrogen vacancy (NV) center and the nuclear spin of a carbon-13 labeled metabolite (13C metabolite) under ambient conditions, which can be used for image contrast purposes in MRI (magnetic resonance imaging).

[0087] Background of the Invention Theory

[0088] It is known in the field of diagnostic imaging that cancer cells exhibit a unique metabolic fingerprint that provides a means of distinguishing such cancer cells from benign tissue in a subject.

[0089] To study such cancer cells, magnetic resonance imaging (MRI) is one of the tools used in imaging diagnosis.

[0090] In particular, 13 C magnetic resonance imaging (MRI) is attractive for metabolic imaging because carbon serves as the backbone of nearly all organic molecules, allowing studies in the field of cancer metabolism.

[0091] However, in practice, due to 13 The natural abundance of the C isotope is very low, coming from 13 The signal of the C-labeled tracer was considered too weak for in vivo imaging in subjects.

[0092] To improve 13 The MRI signal of C nuclei can be used for imaging purposes, and enrichment detection probes can be synthesized to improve the molecular 13 The MRI signal can be further significantly enhanced by the hyperpolarization process.

[0093] To enhance 13 To generate a C signal, the ratio of nuclear spins aligned under a magnetic field needs to be greatly increased, beyond thermal equilibrium. This phenomenon is known in the art and is called "hyperpolarization."

[0094] The following will refer to Figure 1a –1c Describe this phenomenon in detail.

[0095] Dynamic nuclear polarization (DNP) is a method that can 13 C hyperpolarization method, compared with the thermal equilibrium at room temperature, 13 The C signal can be enhanced 10,000 times.

[0096] This utilizes compounds with free radicals that provide lone pairs of electrons whose aligned spins can make 13 The nuclear spin polarization of C is achieved by adding free radicals to the 13C compound 30min to 90min, 13 C nuclear spins can be hyperpolarized, where K = Kelvin and T = Tesla.

[0097] Since the free radicals used in DNP are toxic to human cells and the DNP process must be carried out in a low temperature environment, it is proposed to develop 13 C Other methods of hyperpolarization.

[0098] The principle of hyperpolarization is that the high spin polarization of a paramagnetic free radical can be transferred to another molecule under resonant microwave irradiation. 13 C core.

[0099] However, as the present inventors have pointed out, conventional methods generally involve conditions of low temperature (~<=K) and high magnetic field (>=3T) to first generate electron polarization.

[0100] According to reports, 13 The hyperpolarized signal of C nuclei can be increased 720 times over the thermal signal at 7 T and maintained for long periods of time of several minutes by optical hyperpolarization.

[0101] It is well known that diamond contains nitrogen vacancy (NV) centers, which have a negative charge captured from the surrounding environment.

[0102] The diamond NV center is paramagnetic, with spin S=1 and a large zero-field splitting, D=2.87 GHz, where D is the energy difference between the electron spin states of the zero-field splitting of the NV center, and the energy range is in the microwave band.

[0103] Lasers can be used for optical pumping, providing excitation for the electron spins in the NV centres.

[0104] When the Rabi frequency of the NV center is 13 When the Larmor frequency of C matches, the electron spin at the NC center can be transferred to 13 C atom.

[0105] Details of the Invention

[0106] According to the present invention, a method for hyperpolarizing a 13 A process system for producing a C isotope magnetic resonance imaging (MRI) contrast agent for subsequent magnetic resonance imaging (MRI) applications.

[0107] The present invention is a method for promoting the electron spin of a nitrogen vacancy (NV) center and a carbon-13 labeled metabolite ( 13 Techniques, methods and systems for polarization transfer between nuclear spins of C metabolites) for use in MRI image contrast applications in human subjects or animal subjects.

[0108] Such transfer is performed under ambient conditions, which are typical of laboratory or clinical environments, such as room temperature.

[0109] According to the present invention, initially the NV center and its host carrier are in a glassy state. 13 C metabolites are provided together, while the spatial orientation of the host carrier and the electronic spin states of the NV centers are randomly distributed.

[0110] The glassy state is composed of NV-containing nanodiamonds and 13 The icy state of a randomly mixed solution made of C metabolites. Glass is a nonequilibrium, amorphous condensed state of matter that exhibits a glass transition. The structure of glasses is similar to that of their parent supercooled liquid (SCL), and they relax spontaneously toward the SCL state. In infinite time, their ultimate fate is to crystallize.

[0111] 13 The mixture of C metabolites is in a glassy state, while the spatial orientations and spin states are randomly distributed around the NV center and its host material.

[0112] The host material used to provide such NV centres is nanodiamond, which may be suitable for use in the present invention.

[0113] At the end of the polarization transfer process, the electron spin of the NV center and 13 The nuclear spins of C are both strongly polarized in one direction at ambient temperature and are ready for injection into animals or human subjects for in vivo metabolic imaging using a magnetic resonance imaging system.

[0114] According to the invention, the NV centre is the source of the electron spins to be polarised in the hyperpolarisation process under ambient conditions.

[0115] The electron spin of the NV center is related to 13 The pathway of spin transfer between C metabolites is not necessarily a single one, but rather is due to the molecular interactions (i.e., between the hosts of NV centers, 13 C metabolites, NV center hosts 13 C metabolites, host 13 The nuclear spin of the C nucleus is 13 The spin transfer pathways may be multiple, depending on the distance between the NV center and the corresponding spin state, magnetic impurities, etc.

[0116] This spacing is provided by a spacer, which can be one or a mixture of, for example, the physical dimensions of a water molecule, a solvent, a brine salt, and a host of NV centers.

[0117] The host of the NV center may be a wide bandgap material with high optical transparency to deep UV to green light (eg, about 200 nm to 600 nm), such as micro- or nano-sized powder of boron nitride, diamond, or sapphire.

[0118] The host of the NV center may have a variable size between 10 nm and 100 um.

[0119] Said 13 The C metabolite can be selected from the group consisting of acetic acid, acetone, L-alanine, dimethyl sulfoxide, ethyl pyruvate, D-fructose, fumaric acid, D-glucose, L-glutamic acid, L-glutamine, α-ketoisocaproate (sodium salt), D-mannitol, propionic acid, pyruvic acid, sodium acetate, sodium bicarbonate, sodium butyrate, sodium L-lactate, sodium propionate, sodium pyruvate, succinic acid, urea, and the like enriched in carbon-13 isotope.

[0120] 13 Most of the final polarizations of nuclear spins in C metabolites typically have the same direction, with a difference tolerance of only a few degrees in any spatial coordinate.

[0121] The glassy state is 13 C provides quasi-lattice bonding between metabolites, hosts and other molecules including those described above.

[0122] The physical conditions of the hyperpolarization process of the present invention include: 13 The mixture of C metabolites and the host of NV centers is irradiated with microwave energy and coherent light.

[0123] In addition, the principle of the hyperpolarization process of the present invention includes the excitation and manipulation of the electron spin of the NV center and the 13 Multiple cycles of relaxation of the spin transfer of the nuclear spins of C metabolites.

[0124] According to the invention, advantageously, it is possible to achieve under ambient conditions 13 C metabolites are hyperpolarized, and subjects can benefit from freshly prepared, strong-signal MRI metabolic probes.

[0125] refer to Figure 1a – Figure 1b , for illustrative purposes, the hyperpolarization process used to enhance the MRI signal of carbon 13 nuclei is shown.

[0126] like Figure 1a , showing a normal equilibrium, where very few carbon atoms are 13 C labeling, and the spins are not well aligned. Figure 1b As shown in 13 C enrichment, where 13 The C-labeled carbon atoms are increased.

[0127] refer to Figure 1c , hyperpolarization, DNP (dynamic nuclear polarization) increases the number of aligned spins.

[0128] As shown, Figure 2a The structural formula of an example of a glassy state between the electron center provided by NV and the 13C pyruvate metabolite molecule according to the present invention is depicted, wherein the glassy state refers to a non-equilibrium, non-crystalline state of matter that is solid on a short time scale but continuously relaxes toward a liquid state. Visually, the glassy mixture of NV and 13C metabolite appears in the form of an amorphous solid, such as Figure 2b shown.

[0129] refer to Figure 3a , showing the NV center and the nearby 13 Illustration of potential spin transfer pathways between C nuclei. In this illustration, a single NV center 301 is used as the source of polarization transfer. 13 To transfer polarization between C nuclei, the electron spin needs to be transferred in multiple steps: (i) from the NV center 301 to the first 13 C core 302, and (ii) further transferred to the first 13 C core 301 second 13 C core 303. Therefore, such a polarization transfer process will be slow and inefficient.

[0130] Now Figure 3b This is a diagram of the electron spin of the NV (nitrogen vacancy) center 304 to the 13C metabolites around the surface of the host carrier 305. Using the host carrier 305 containing the NV center 304 instead of a single free radical as the source of polarization transfer, due to the glassy state achieved in the entire mixture, the polarization transfer can be from the NV center 304 to the 13C metabolites around the surface of the host carrier 305. 13 C cores 306 and 307 occur simultaneously.

[0131] Advantageously, and in accordance with the present invention and embodiments thereof, the polarization transfer process will therefore be more efficient.

[0132] As shown, Figure 4a The image 400a is obtained by EPSI (echo planar spectral imaging) pulse sequence measurement, depicting the 13C pyruvate mixture 410a hyperpolarized according to the present invention (left sample in the upper figure) and 420a untreated 13 MRI imaging of C pyruvate (right sample in the upper image).

[0133] As Figure 4aAs shown in the lower figure, the chemical shift spectrum 403a shows a very strong signal peak at 0.1e+04 from the hyperpolarized 13C pyruvate mixture.

[0134] Figure 4b yes Figure 4a Graphs of the invention, wherein 400b depicts MRI images of 410b a hyperpolarized 13C pyruvate mixture according to the present invention (the left sample in the upper graph) and 420b untreated 13C pyruvate (the right sample in the upper graph) obtained by EPSI.

[0135] As Figure 4b As shown in the lower figure, the chemical shift spectrum 403b shows a very strong signal peak at 0.1e+04 from the hyperpolarized 13C pyruvate mixture.

[0136] refer to Figure 5a , image 500a depicts an MRI image 510a of an untreated 13C pyruvate mixture (the right sample in the upper image).

[0137] As shown, the chemical shift spectrum 503a of untreated 13C pyruvate shows very weak signals compared to the hyperpolarized 13C pyruvate mixture. No distinct peaks exist in the chemical shift spectrum 503a.

[0138] Figure 5b yes Figure 5a , where 500b depicts MRI imaging 510b of an untreated 13C pyruvate mixture (right sample in the upper figure).

[0139] As shown, the chemical shift spectrum 503b of untreated 13C pyruvate shows a very weak signal compared to the hyperpolarized 13C pyruvate mixture. No obvious peaks are present in the chemical shift spectrum 503b.

[0140] Figure 6 A schematic diagram showing an embodiment of a hyperpolarization system 600 used in the present invention comprises:

[0141] (i) a container 605 for containing a mixture of nanodiamonds and 13C metabolites in a glassy state,

[0142] (ii) a laser 601 for providing excitation,

[0143] (iii) a microwave system 602, and

[0144] (iv) Magnetic resonator 603.

[0145] Further explanatory comments on the present invention

[0146] According to the present invention, a mixture of a host carrier for providing NV centers, such as nanodiamond (as a host carrier) and a 13C metabolite is prepared to form a solution.

[0147] Such mixed solutions of host vector and 13C metabolite are kept perfectly sealed under ambient conditions before use and storage. The mixture is converted into a glassy state only before hyperpolarization for MRI imaging.

[0148] The solution mixture is then frozen to form a glassy state, which can be seen as one or more solid blocks of ice in which the components of the solution are suspended, thereby preventing sedimentation.

[0149] In order to convert the mixture solution into a glassy state, the mixture is frozen in a refrigerator at a temperature below -20°C. In one embodiment, the mixture is kept at a temperature of -35°C and -80°C, and it has been shown that when the mixture is frozen at a temperature of -80°C, it can achieve the fastest freezing speed and a more durable frozen state of the mixture.

[0150] A hyperpolarization process is then applied to the solid mixture. During the hyperpolarization process, the mixture eventually melts and returns to solution.

[0151] At the end of the hyperpolarization process, the mixture will be completely melted and in solution form.

[0152] In one embodiment, another carrier is added to the mixture to form a solution, such carrier comprising one or a mixture of water molecules, solvent, saline salt, and the physical size of the host of the NV center.

[0153] Therefore, after filtering out the source of NC centers (in this example, nanodiamonds), the remaining solution can be injected into an animal or human body as a contrast agent to enhance MRI imaging for research purposes in the animal or human body.

[0154] Advantages of the present invention

[0155] As will be appreciated, the hyperpolarization process presented provides several advantages over prior art techniques and advantageously, the use of a glassy structure provides a structure that is inherently frozen, which reduces or prevents sedimentation of the host vector and 13C metabolite molecules to the bottom of the solution.

[0156] Advantageously, polarization in the frozen state offers advantages including longer thawing times and ease of delivery to a subject for subsequent MRI imaging applications.

[0157] The existing method includes thermal shock. It involves the use of an electron paramagnetic agent as a spin transfer medium. In this existing method, repeated thermal shocks from room temperature to ultra-low temperatures are required. Therefore, the subsequent filtration procedure is very difficult in the case of using an electron paramagnetic agent, and the prior art machine is generally bulky and expensive due to the use of a temperature control unit.

[0158] Compared with the prior art, the method of the present invention utilizes nanodiamond as a spin transfer medium. Nanodiamond is biocompressible, non-toxic to the human body, and easy to filter out of the solution. More importantly, no thermal cycle is required in the method of the present invention. Therefore, its operating procedures and machine size are much simpler than the prior art.

[0159] Advantageously, according to the present invention, hyperpolarization of 13C metabolites can be achieved at ambient temperature and pressure, and subjects can benefit from freshly prepared, strong signal MRI metabolic probes.

Claims

1. A method for polarization transfer between the electron spin of a nitrogen vacancy (NV) center and the nuclear spin of a carbon-13 labeled metabolite (13C metabolite) under ambient conditions, the method comprising the steps of: (i) providing a mixture comprising a host vector providing a source of NV centers and a 13C metabolite; (ii) converting the mixture into a solid glassy state, wherein the spatial orientation of the host and the electronic spin states of the NV centers are randomly distributed within the mixture in the solid state; and (iii) applying a hyperpolarization process to the mixture in a solid state, wherein at the end of the polarization transfer process both the electron spin of the NV centre and the nuclear spin of the carbon-13 are strongly polarized in one direction at ambient temperature.

2. The method of claim 1, wherein the NV center in claim 1 is the source of electron spins to be polarized under a hyperpolarization process under ambient conditions.

3. The method according to claim 1 or claim 2, wherein the pathway of spin transfer between the electron spin of the NV center and the 13C metabolite is single.

4. The method according to any one of claims 1 or 2, wherein the pathways of spin transfer between the electron spin of the NV center and the 13C metabolite are multiple as a result of the spacing between the molecules.

5. The method according to claim 4, wherein the spacing between molecules includes the spacing between hosts of NV centers, between 13C metabolites, from hosts of NV centers to 13C metabolites, from nuclear spins of 13C nuclei within hosts to 13C metabolites; including the spacing between charges of NV centers within the same host and between NV centers of different hosts; or between various surrounding charges and corresponding spin states, magnetic impurities, etc.

6. The method of claim 5, wherein the spacing between the molecules is provided by a spacer, wherein the spacer is the physical size of a water molecule, a solvent, a brine salt, or a host of NV centers.

7. The method according to any one of the preceding claims, wherein the host of the NV centre is a wide bandgap material with high optical transparency to deep UV to green light.

8. The method of claim 7, wherein the host of the NV center is a wide bandgap material having high optical transparency to deep UV to green light in the range of 200 nm to 600 nm.

9. The method according to any one of the preceding claims, wherein the host of the NV centres is a micro- or nano-scale powder.

10. The method of claim 9, wherein the host of the NV center is selected from the group consisting of boron nitride, diamond or sapphire.

11. A method according to any one of the preceding claims, wherein the host of the NV centre has a size between 10 nm and 100 um.

12. The method according to any one of the preceding claims, wherein the 13C metabolite is selected from the group consisting of acetic acid, acetone, L-alanine, dimethyl sulfoxide, ethyl pyruvate, D-fructose, fumaric acid, D-glucose, L-glutamic acid, L-glutamine, α-ketoisocaproate (sodium salt), D-mannitol, propionic acid, pyruvic acid, sodium acetate, sodium bicarbonate, sodium butyrate, sodium L-lactate, sodium propionate, sodium pyruvate, succinic acid, urea, etc. enriched in carbon-13 isotope.

13. A method according to any one of the preceding claims, wherein the majority of the final polarisations of the nuclear spins in the 13C metabolites have the same direction, with a tolerance of only a few degrees of difference in any spatial coordinate.

14. The method according to any one of the preceding claims, wherein the glassy state is provided by quasi-lattice bonding between the 13C metabolite, the host and the other molecules of claim 12.

15. A method according to any one of the preceding claims, wherein the hyperpolarisation process comprises radiating microwave energy and coherent light to a mixture of 13C metabolites and hosts of NV centres under the application of a magnetic field.

16. The method according to any of the preceding claims, wherein the hyperpolarization process comprises multiple cycles of excitation and manipulation of the electron spins of NV centres and relaxation of the spin transfer to the nuclear spins of 13C metabolites under ambient conditions.

17. The method according to any one of the preceding claims, wherein the hyperpolarization of the 13C metabolite is provided under ambient conditions.

18. A method according to any one of the preceding claims, wherein the solid glassy state is formed by reducing the temperature of the mixture.

19. The method of claim 18, wherein the temperature is reduced to below -20°C.

20. The method according to claim 18 or 19, wherein the temperature is lowered to -35°C or -80°C.

21. A method of preparing a contrast agent for MRI imaging of the human or animal body under ambient conditions by hyperpolarization, the method comprising the steps of: (i) providing a mixture comprising a host vector providing a source of NV centers and a 13C metabolite; (ii) converting the mixture into a solid glassy state, wherein the spatial orientation of the host and the electronic spin states of the NV centres are randomly distributed within the mixture in the solid state.

22. The method of claim 21, wherein the spacing between molecules includes the spacing between hosts of NV centers, between 13C metabolites, from hosts of NV centers to 13C metabolites, from nuclear spins of 13C nuclei within hosts to 13C metabolites; including the spacing between charges of NV centers within the same host and between NV centers of different hosts; or between various surrounding charges and corresponding spin states, magnetic impurities, etc.

23. The method of claim 22, wherein the spacing between the molecules is provided by a spacer, wherein the spacer is the physical size of a water molecule, a solvent, a brine salt, or a host of NV centers.

24. The method of any one of claims 21 to 23, wherein the host of the NV centre is a wide bandgap material with high optical transparency to deep UV to green light.

25. The method of claim 24, wherein the host of the NV center is a wide bandgap material having high optical transparency to deep UV to green light in the range of 200 nm to 600 nm.

26. A method according to any one of claims 21 to 25, wherein the solid glassy state is formed by reducing the temperature of the mixture.

27. The method of claim 26, wherein the temperature is reduced to below -20°C.

28. A method according to claim 26 or claim 27, wherein the temperature is reduced to -35°C or -80°C.

29. The method of any one of claims 21 to 28, wherein the host of the NV centres is a micro- or nano-sized powder.

30. The method of claim 29, wherein the host of the NV centre is selected from the group consisting of boron nitride, diamond or sapphire.

31. The method of any one of claims 21 to 30, wherein the host of the NV centre has a size between 10 nm and 100 um.

32. The method according to any one of claims 21 to 31, wherein the 13C metabolite is selected from the group consisting of acetic acid, acetone, L-alanine, dimethyl sulfoxide, ethyl pyruvate, D-fructose, fumaric acid, D-glucose, L-glutamic acid, L-glutamine, α-ketoisocaproate (sodium salt), D-mannitol, propionic acid, pyruvic acid, sodium acetate, sodium bicarbonate, sodium butyrate, sodium L-lactate, sodium propionate, sodium pyruvate, succinic acid, urea, etc. enriched in carbon-13 isotope.

33. A contrast agent for MRI imaging of the human or animal body under ambient conditions for hyperpolarization, the contrast agent comprising: A mixture comprising a host carrier having an NV center and a 13C metabolite, wherein the mixture is provided in a solid glass state, wherein the spatial orientation of the host and the electronic spin state of the NV center are randomly distributed within the mixture in the solid state.

34. A contrast agent according to claim 33, wherein the spacing between molecules includes the spacing between hosts of NV centers, between 13C metabolites, from hosts of NV centers to 13C metabolites, and from nuclear spins of 13C nuclei within hosts to 13C metabolites; including the spacing between charges of NV centers within the same host and NV centers between different hosts; or between various surrounding charges and corresponding spin states, magnetic impurities, etc.

35. A contrast agent according to claim 33 or claim 34, wherein the spacing between molecules is provided by a spacer, wherein the spacer is the physical size of a water molecule, a solvent, a saline salt or a host of NV centres.

36. The contrast agent according to any one of claims 33 to 35, wherein the host of the NV centre is a wide bandgap material with high optical transparency to deep UV to green light.

37. A contrast agent according to any one of claims 33 to 36, wherein the host of the NV centre is a wide bandgap material with high optical transparency to deep UV to green light in the range of 200nm to 600nm.

38. The contrast agent according to any one of claims 33 to 37, wherein the host of the NV centres is a micro- or nano-sized powder.

39. The contrast agent according to claim 38, wherein the host of the NV centre is selected from the group consisting of boron nitride, diamond or sapphire.

40. The contrast agent of any one of claims 33 to 39, wherein the host of NV centres has a size between 10 nm and 100 um.

41. A contrast agent according to any one of claims 33 to 40, wherein the 13C metabolite is selected from the group consisting of acetic acid, acetone, L-alanine, dimethyl sulfoxide, ethyl pyruvate, D-fructose, fumaric acid, D-glucose, L-glutamic acid, L-glutamine, α-ketoisocaproate (sodium salt), D-mannitol, propionic acid, pyruvic acid, sodium acetate, sodium bicarbonate, sodium butyrate, sodium L-lactate, sodium propionate, sodium pyruvate, succinic acid, urea, etc. enriched in carbon-13 isotope.

42. A contrast agent for MRI imaging of the human or animal body under ambient conditions for hyperpolarization, the contrast agent comprising: A mixture comprising a host carrier having an NV center and a 13C metabolite; wherein the mixture is provided for subsequent conversion into a solid glassy state such that the spatial orientation of the host and the electronic spin states of the NV centres are randomly distributed within the mixture in the solid state.

43. The contrast agent of claim 42, wherein the host carrier of the NV center is a micro- or nano-sized powder.

44. A contrast agent according to claim 42 or claim 43, wherein the host of the NV centre is selected from the group consisting of boron nitride, diamond or sapphire.

45. The contrast agent of any one of claims 42 to 44, wherein the host of NV centres has a size between 10 nm and 100 um.

46. ​​A contrast agent according to any one of claims 42 to 45, wherein the 13C metabolite is selected from the group consisting of acetic acid, acetone, L-alanine, dimethyl sulfoxide, ethyl pyruvate, D-fructose, fumaric acid, D-glucose, L-glutamic acid, L-glutamine, α-ketoisocaproate (sodium salt), D-mannitol, propionic acid, pyruvic acid, sodium acetate, sodium bicarbonate, sodium butyrate, sodium L-lactate, sodium propionate, sodium pyruvate, succinic acid, urea, etc. enriched in carbon-13 isotope.

47. A hyperpolarization system comprising: (i) a container for receiving a contrast medium according to any one of claims 27 to 35; (ii) a laser for providing excitation; (iii) microwave systems; and (iv) Magnetic resonator.

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