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WO2019033139A1 - Fabrication d'agents hyperpolarisés - Google Patents

Fabrication d'agents hyperpolarisés Download PDF

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Publication number
WO2019033139A1
WO2019033139A1 PCT/AU2017/050877 AU2017050877W WO2019033139A1 WO 2019033139 A1 WO2019033139 A1 WO 2019033139A1 AU 2017050877 W AU2017050877 W AU 2017050877W WO 2019033139 A1 WO2019033139 A1 WO 2019033139A1
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WIPO (PCT)
Prior art keywords
quantum
agent
probe
magnetic field
spin
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PCT/AU2017/050877
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English (en)
Inventor
David Broadway
Jean-Philippe TETIENNE
Alastair STACEY
James Wood
David Simpson
Liam Hall
Lloyd Hollenberg
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The University Of Melbourne
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Priority to PCT/AU2017/050877 priority Critical patent/WO2019033139A1/fr
Publication of WO2019033139A1 publication Critical patent/WO2019033139A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/28—Details of apparatus provided for in groups G01R33/44 - G01R33/64
    • G01R33/282—Means specially adapted for hyperpolarisation or for hyperpolarised contrast agents, e.g. for the generation of hyperpolarised gases using optical pumping cells, for storing hyperpolarised contrast agents or for the determination of the polarisation of a hyperpolarised contrast agent

Definitions

  • This disclosure relates to systems and methods for manufacturing hyperpolarised agents.
  • this disclosure relates to manufacturing agents that can be used as contrast agents in MRI imaging.
  • Magnetic resonance imaging has improved medical diagnostics significantly as it is able to create a 3-dimensional representation of the human body.
  • Current MRI generally creates a static image of water and fat in the body.
  • contrast agents can also be used in order to image the passage of the contrast agent through the blood system, or the flow of air through the lungs, or in metabolic imaging.
  • the magnetic properties of the agent are changed, which results in a significantly increased response to the MRI stimulus and therefore a significantly increased contrast to the body tissue. Changing the magnetic properties in this context is referred to as hyperpolarisation.
  • This disclosure provides a method for hyperpolarizing an agent that addresses the problems of the prior art, such as the need for extremely low temperatures and strong magnetic fields.
  • the disclosed method uses an effect called cross-relaxation, where the spin of a probe is transferred to a particle of the agent, such as a nucleus of a molecule.
  • the lowest two probe spin states are tuned in a magnetic field to be in resonance with the agent's particular nuclear spin states.
  • the probe is put into a specific spin state where it exchanges spin with the agent's nuclear spin states that are opposite to the desired hyperpolarised spin state.
  • the probe spin then is re-initialised, leaving a higher number of agent nuclear spins in the desired spin energy state. The process is repeated until sufficient agent hyperpolarisation is acquired.
  • the result is an incremental polarisation of the agent's nuclear spins. Repeating these steps leads to a large number of polarized agents particles.
  • the strength of the magnetic field is set such that it tunes the spin energy levels of the probe to be in resonance with the energy levels of the agent's particular nuclear spins being targeted.
  • a method for manufacturing a hyperpolarised agent comprises:
  • the magnetic field is of a magnetic field strength that adjusts the energy states of the quantum probe to bring a probe spin transistion of the quantum probe into resonance with an agent spin transition of the agent to allow transfer of energy and thereby activate the cross- relaxation between the quantum probe and the agent to polarise the agent.
  • the magnetic field strength that brings the spin transitions of the quantum probe the agent into resonance is significantly weaker than the magnetic field strengths that are required for some other methods of polarisation.
  • a further advantage is that the polarisation can occur at room temperature due to the efficient initialisation of the quantum probe through optical pumping, which removes the need for external cooling. As a result, the method can be used without expensive and complex equipment so that the hyperpolarised agent can be produced more efficiently.
  • the method may further comprise removing the quantum control radiation while the magnetic field is applied.
  • the magnetic field may be aligned with a spin axis of the quantum probe.
  • Applying the magnetic field may comprise using a permanent magnet to apply the magnetic field.
  • Using the permanent magnet maycomprise tuning the magnetic field by moving the permanent magnet or controlling the temperature of the permanent magnet or both.
  • Transfer of energy may comprise magnetic interaction between the quantum probe and the agent.
  • the quantum probe may comprise an electron spin of a nitrogen-vacancy centre in a diamond.
  • the magnetic field may have a field strength between 1020 G and 1028 G.
  • the magnetic field may have a field strength of one of:
  • Applying the quantum control radiation may comprise applying light to the quantum probe.
  • the quantum control radiation may be applied for a time between 100 ns and 1 ms. [20] The quantum control radiation may be applied for a time between 1 and 10 microseconds.
  • the quantum control radiation may be removed to activate diffusion of polarisation via magnetic dipole interactions within the agent.
  • the quantum control radiation may be removed for 1 us to 1 s.
  • the quantum control radiation may be removed for 1 to 10 microseconds.
  • the method may further comprise repeating the method to increase an amount of the agent that is polarised.
  • the method may be repeated for a sufficient number of cycles to achive a polarisation level of 10-80%.
  • the method may be repeated for more than one hour.
  • the method may further comprise reading out a current energy state of the quantum probe during the application of quantum control radiation to allow real-time monitoring of an amount of polarisation transfer.
  • the reading out of the current energy state of the quantum probe may be achieved by measuring a luminescence intensity.
  • a system for manufacturing a hyperpolarised agent comprises:
  • a magnetic field source to apply a magnetic field to the quantum probe and the agent carrier
  • a quantum control radiation source to apply quantum control radiation to the quantum probe to bring the quantum probe to a second energy state to allow cross- relaxation between the quantum probe and the agent while the magnetic field is applied; wherein the magnetic field is of a magnetic field strength that adjusts the energy states of the quantum probe to bringe a probe spin transition of the quantum probe into resonance with an agent spin transition of the agent to allow transfer of energy and thereby activate the cross- relaxation between the quantum probe and the agent to polarise the agent.
  • the quantum probe may be located less than 20 nm from the agent.
  • the quantum probe may be below a surface of a substrate.
  • the agent may be a liquid, or in a liquid, of specified viscosity, and the carrier is configured to provide a flow of the agent past the quantum probe.
  • the system may comprise multiple quantum probes and the quantum control radiation and the magnetic field may be applied to the multiple quantum probes
  • the carrier may comprise multiple channels to provide multiple streams of liquid agent and the system comprises multiple quantum probes arranged in close proximity to the surfaces of each of the channels.
  • the magnetic field and the quantum control radiation may be applied to the multiple channels simultaneously.
  • Fig. la illustrates a system for manufacturing a hyperpolarised agent.
  • Fig. lb illustrates a method for manufacturing a hyperpolarised agent.
  • Figs. 2a, 2b, 2c and 2d illustrate the principle of cross -relaxation.
  • Fig. 3 illustrates an energy-level diagram of the NV showing the relative positions of various target nuclear spin resonance conditions.
  • Fig. 4 is a schematic of cross relaxation induced polarisation (CRIP) implemented on a spin system.
  • Fig. 5a illustrates a control sequence for polarisation using laser pulses.
  • Fig. 5b illustrates a control sequence for de-polarisation using laser pulses and RF pulses.
  • Fig. 6a illustrates the cross -relaxation spectrum obtained by measuring the photoluminescence (PL) during the CRIP 601, or depolarisation 602 sequence, with a constant interaction time T , while scanning the NV frequency ⁇ ⁇ .
  • Fig. 6b illustrates a cross-relaxation curve obtained by scanning T with m set at the resonance.
  • Fig. 7 illustrates measured cross-relaxation spectra of 13 C nuclear spins from CRIP applied to a single NV spin probe.
  • Fig. 8 illustrates calculated radial polarisation profiles of 13 C nuclear spins relative to the NV probe spin.
  • Fig. 9 illustrates a three-dimensional representation of the polarisation distribution for 1 i 3 3 C spins in the case shown in Fig 8..
  • the figure further illustrates cross-relaxation curves obtained by increasing T at the 1 H resonance with the CRIP sequence (middle) and depolarisation sequence (bottom), and off -resonance to obtain the background relaxation rate (top).
  • Fig. 11 illustrates a three-dimensional representation of the 1 H spin polarisation distribution in the PMMA in the steady state.
  • Fig. 12 illustrates a scale-up for a universal MRI contrast agent hyperpolarisation platform.
  • Fig. 13 illustrates a zoomed in representation of the polarisation stack in Fig. 12.
  • Fig. 14 illustrates average polarisation levels and volume rates for example target agents.
  • Fig. 15 is a simplified depiction of the energy levels of the NV spin at the ground state level anti-crossing GSLAC as a function of the applied magnetic field, and the polarisation transfer mechanism when on resonance with a target nuclear spin.
  • Fig. 16 illustrates the transition frequencies as a function of the applied magnetic field, showing the NV-nuclear spin resonance conditions for multiple different nuclear spin species.
  • the black lines represent the two allowed NV transitions which act as the probe frequency.
  • FIGs 17a and 17b illustrate spatial coupling distributions before and after the GSLAC comparison. Contours of constant coupling for after (Fig. 17a) and before (Fig. 17b) the GSLAC with (l 11) and (lOO) surfaces shown shaded.
  • Fig. 18 illustrates polarisation profiles at the diamond surface for four possible scenarios, considering the example of an NV located 10 nm below the surface and polarising a bath of PMMA spins.
  • Fig. 19 illustrates the effect of the protocol on the naturally occurring (1.1% abundant) 13 C nuclear spin bath in the diamond crystal using 1000 randomly initialised 13 C spins.
  • Solid lines represent the polarisation of 10 spins randomly chosen from the bath, the dashed line represents the average
  • T> state probability (i.e. polarisation) of all 1000 13 C spins with interaction time ⁇ 3.8 s.
  • Fig. 20 illustrates radial polarisation profiles for 13 C resonances before (top) and after (bottom) the GSLAC constructed using their respective experimentally measured longitudinal relaxation rates after approximately 5 hours of polarisation.
  • the top and bottom lines ( 1 0 > and I -1 > ) are obtained with a CRIP and CRIP _1 interleaved pulse sequence.
  • the pulse sequence acts to prevent polarising the bath and allows the NV- 13 C interaction to be measured.
  • the solid line is a guide to the eye.
  • Fig. 24 illustrates short time spin dynamics using the same interleaved pulse sequence and varying the interaction time, T .
  • the measurement is taken on resonance with the 13 C bath (after GSLAC), revealing flip-flop interaction between the NV and the 13 C bath with a total hyperfine coupling of 250 ⁇ 40 kHz.
  • Fig. 25 relates to polarising the 13 C bath and shows the 13 C spectrum (three peaks) obtained using the depolarisation sequence and the polarised spectrum (one peak) using CRIP. This is the same NV as the one in Fig. 6b.
  • FIG. 26 illustrates 13 C around the GSLAC with polarisation (top) and without polarisation (bottom two lines) on a different NV. With the interleaved sequence, both NV initialisation states are shown, 1 0 > (middle) and I -1 > (bottom).
  • Fig. 27 illustrates time dynamics of the NV-bath interaction at the after-GSLAC 13 C resonance.
  • Figs. 28a, 28b, 28c and 28d related to polarisation dynamics.
  • Fig. 28a shows a pulse sequence used to investigate the polarisation dynamics.
  • Fig. 28b shows a full sequence of 30 CRIP _1 pulses followed by 30 CRIP as shown in Fig. 28a, for different interaction times T .
  • Fig. 28c illustrates a characteristic time for polarisation as a function of interaction time.
  • Figs. 29a and 29b relate to polarisation extent measurements.
  • Fig. 29a shows full TJ measurements taken for the after GSLAC case in three conditions: measured on resonance with 13 C (top), closer to the GSLAC i.e. ⁇ 0.9 MHz (bottom) and further away from the GSLAC i.e. > 1.3 MHz (middle).
  • Fig. 29b shows the decay rate the of NV around the 13 C resonance, before the GSLAC (top, top, bottom) giving T Tes « 62 Hz and after (bottom, bottom, top), where no change is seen within noise, giving T ies « 19 Hz.
  • Figs. 30a-30f illustrate the effect of 13 C polarisation on the free induction decay.
  • Fig. 30a illustrates a pulse sequence for CRIP polarisation at the resonant frequency followed by an FID measurement at a different frequency, using a magnetic field offset pulse.
  • Fig. 30b illustrates a schematic of the experimental set up with the coil for the field offset.
  • Fig. 30c illustrates an example ODMR of the NV during the CRIP phase (left) and during FID measurements (right).
  • Fig. 30d illustrates an FID signal as a function of NV frequency as measured during the CRIP phase (top axis) and during the FID phase (bottom axis).
  • FIG. 30e illustrates an FID curves obtained from a similar sweep as in Fig. 30d. The two curves show the case where the CRIP phase is on resonance (earlier curve, polarisation) and off resonance (later curve, no polarisation).
  • Fig. 30f illustrates a long FID measurement taken at a fixed frequency with the CRIP phase on resonance (earlier curve, polarisation) and off resonance (later curve, no polarisation). The applied driving detuning was different in the two case in order to obtain the same oscillation frequency.
  • Fig. 31 illustrates the effect of 13 C polarisation on the resonance linewidth.
  • a clear trend is found from fitting the signal with a Lorentzian (solid line): there is an increase in the FWHM of the feature as the bath becomes less polarised.
  • Figs. 32a and 32b relate to additional 1 H polarisation measurements.
  • Fig. 32a shows a spectrum of 1 H unpolarised (bottom) and polarised (top) for NV2.
  • Fig. 32b shows full- length TJ measurements for NV3 on resonance unpolarised (bottom), polarised (midde) and a background off resonance measurement (top).
  • Hyperpolarisation is polarisation of the nuclear spin of a material far beyond thermal equilibrium conditions. This can be applied to liquids, gasses and solids.
  • hyperpolarisation of nuclear spins within target molecules is an important and complex challenge in magnetic resonance imaging (MRI) and nuclear magnetic resonance (NMR) spectroscopy.
  • MRI magnetic resonance imaging
  • NMR nuclear magnetic resonance
  • Hyperpolarisation offers gains in signal and spatial resolution which may ultimately lead to the development of molecular MRI and NMR.
  • This disclosure utilises room temperature solid-state spin qubits to circumvent these requirements to achieve direct nuclear spin hyperpolarisation using quantum control.
  • the disclosed method provides external nuclear spin hyperpolarisation achieved by a quantum probe, for example of 1 H molecular spins in poly(methyl methacrylate).
  • a quantum probe for example of 1 H molecular spins in poly(methyl methacrylate).
  • the technique can also be tuned to multiple spin species, such as 13 C and 1 H nuclear spin ensembles.
  • the disclosed system can be scaled up to a universal quantum hyperpolarisation platform for the production of macroscopic quantities of contrast agents at high polarisation levels for clinical applications.
  • the quantum probe should be capable of polarising a relatively large number of remote nuclear spins external to the probe substrate, ideally under ambient conditions.
  • these challenges are addressed using a quantum spin probe in diamond as a spin entropy pump, which enables polarisation of external molecular spin ensembles over relatively large volumes at room temperature. This allows scaling up to a universal hyperpolarisation platform suitable for clinical applications.
  • the proposed quantum polarisation approach can be tuned to a range of nuclear species, can operate at room temperature, and can be inherently free of radiofrequency (RF) fields and the need for extraneous chemistry prior to polarisation and/or use.
  • RF radiofrequency
  • Fig. la illustrates a system 100 for manufacturing a hyperpolarised agent.
  • the system comprises a near- surface nitrogen- vacancy (NV) spin probe 101 in diamond 102 and a nuclear spin target ensemble 103 in molecular Poly(methyl methacrylate) (PMMA) 104 on the surface of diamond 102.
  • the NV probe 101 is initialised by a green laser (532 nm) 105, and read out via its photo luminescence (PL) signal 106 by a photo detector 107.
  • a magnetic field 108 is applied to the probe 101 and the agent 103. In one example, the magnetic field 108 is applied by a permanent magnet.
  • the figure also shows different spatial regimes of polarisation capabilities 107 indicated by dashed lines arising from the spatial dependence of the nuclear spin coupling to the NV qubit 101.
  • Fig. lb illustrates a method for manufacturing a hyperpolarised agent, the method comprises locating 151 agent 103 in close proximity to quantum probe 101 that is in a first energy state. It is noted that the first energy state may be a mixture of quantum states.
  • Quantum probe means that probe 101 has different quantum states, like a qubit.
  • Quantum states may be nuclear spin states. Close proximity in this context means a proximity that is sufficiently close for hyperfine interaction to occur, such as closer than 20 nm or even closer than 10 nm, such as 5 nm.
  • the method 150 then proceeds by applying 152 magnetic field 108 to probe 103 and agent 103. In one example, the magnetic field 108 is applied over the entire time method 150 is performed.
  • the method 150 then comprises applying 153 quantum control radiation, such as laser light, to the probe to bring the probe in resonance with a second energy state. This may be a quantum energy state.
  • the second energy state is higher than the first energy state but in other cases, the second energy state can be lower than the first energy state.
  • the terms 'first' and 'second' are used to denote a sequence rather than a relative value of energies.
  • the magnetic field is of a magnetic field strength that aligns the energy states of the probe with the energy states of the agent to allow transfer of energy and thereby activate the cross-relaxation between the probe and the agent to polarise the agent.
  • the magnetic field leads to the energy gap in the probe 101 to be substantially equal to the energy gap in the agent 103.
  • System 100 employs the principle of cross-relaxation, which is illustrated in Figs. 2a to 2d.
  • Fig. 2a illustrates the probe energy states 201 of the probe 101 and the target energy states 202 of the target 103.
  • Probe energy states 201 comprise a low energy state 211, and high energy state 212. In this case, these two energy states result from Zeeman splitting caused by the external magnetic field 108.
  • target energy states 202 comprise low energy state 221, and high energy state 222.
  • the target energy states 202 are largely independent of magnetic field 108 because the target energy states 202 are also subject to Zeeman splitting in the magnetic field.
  • the energy states are not adjusted .
  • the probe spin transition (i.e. gap) between the low 211 and the high 212 states of the probe 201 is different to the agent spin transition (i.e. gap) between the low 221 and high 222 states of the agent 202.
  • the agent spin transition i.e. gap
  • the energy states are adjusted as shown in Fig. 2b.
  • the gap between the low 212 and high 212 states of the probe 201 is now equal to the gap between the low 221 and high 222 states of the agent 202, which brings the probe spin transition into resonance with the agent spin transition. Therfore, transfer of energy is possible and cross-relaxation can be used effectively.
  • both probe 101 and target 103 are in the low energy state 211 as indicated by circles 231 and 232.
  • the energy states relate to different spin of the probe 101 and target 103, respectively. It is noted, however, that probe 101 may also be in the high energy state 212 and the method below would work, which is useful because the probe can be manupilated into various spins states.
  • Fig. 2c illustrates how the application of quantum control radiation 204, such as laser light, brings the probe 101 to the high energy state 212. It is noted that this is a simplification and the applied light 240 may raise the probe state 231 significantly higher but the probe state 231 then drops back to high energy state 212. This occurs regardless of the state of the probe 101 before this initialisation. That is regardless of the state in Fig. 2b the probe 101 is initialised to high energy state 212.
  • Fig. 2d illustrates that when the laser light 240 is removed, cross-relaxation between the probe 101 and the target 103 leads to the probe state 231 'drop' to lower energy state 211.
  • target state 232 is 'lifted' to the high energy state 222 of target 103.
  • energy is transferred from the probe 101 to the target 103 leaving the target 103 polarised.
  • the external magnetic field, B is applied to adjust (or tune) the ground-state spin transition frequency of the NV ⁇ co m ) into resonance with target nuclear spins ( ⁇ ⁇ )by adjusting the Zeeman effect to split the energy levels by the right amount.
  • the probe 101 does not interact with the polarised agent 103 because their magnetic fields are aligned. This means there is a one-way energy transfer and the energy transferred to the agent cannot return back onto the probe.
  • this disclosure refers to the system as an entropy pump.
  • Fig. 3 illustrates an energy-level diagram of the NV showing the relative positions of various target nuclear spin resonance conditions.
  • the spin resonance condition is fulfilled at a magnetic field ⁇ note( ⁇ ⁇ ) « 2D I ( ⁇ ⁇ - ⁇ ⁇ )
  • Fig. 4 illustrates a schematic 400 of cross relaxation induced polarisation (CRIP) implemented on a spin system illustrating the build up of polarisation from repeated application of the CRIP sequence. Diffusion effects act in competition with the CRIP entropy pumping mechanism, but also allow for polarisation at distances beyond that reachable via the probe-target magnetic interaction interaction.
  • CRIP cross relaxation induced polarisation
  • Fig. 5a illustrates a control sequence using laser pulses 501 for polarising a target spin ensemble using CRIP.
  • Fig. 5b illustrates a control sequence using laser pulses 502 and RF pulses 503 for controlled depolarisation using the combined CRIP ⁇ ' x CRIP protocol.
  • Entropy pumping is facilitated by repeated application of the cross relaxation induced polarisation (CRIP) sequence, wherein the NV spin is optically initialised into
  • T of order microseconds
  • the transfer of magnetisation caused by this interaction thus polarises the target spins into their
  • depolarisation may be facilitated by interleaving the initialisation of the NV spin into the opposite state
  • the following disclosure provides a quantitative assessment of the effect of the CRIP protocol on the target spin ensemble based on an approach that explicitly includes the dipole interactions of ensemble spins and their interaction with a single NV quantum probe.
  • the polarisation of a spin at position R (relative to the NV) and time t can be defined as P(R,r)
  • w(R) A 2 (R) / 2 ⁇ 2 is the effective cooling coefficient resulting from the hyperfine coupling A(R) with the NV spin
  • ⁇ 2 is the dephasing rate of the NV spin
  • ⁇ is the effective polarisation diffusion coefficient related to the intra-target interactions
  • T SL is the spin-lattice relaxation rate of the target spin ensemble.
  • photo detector 107 monitors the spin-dependent photoluminescence (PL) from the NV [HALL 16], [WOOD16I], [WOOD16II]
  • T bg the background rate caused by lattice phonons or surface effects
  • T CR is due to cross -relaxation.
  • A* ⁇ [l- P(R,f)] A 2 (R)d 3 R, (3) where n t is the density of the target spin ensemble.
  • Fig. 6a illustrates the cross -relaxation spectrum of the target.
  • One indicator of significant polarisation is a reduction in T CR , which manifests as the disappearance of the target ensemble's spectral feature from the cross -relaxation spectrum as can be seen in the difference between the polarised spectrum 601 and the unpolarised spectrum 602 at reference numeral 603.
  • the polarisation can be quantified by measuring the cross-relaxation curve at resonance, which is shown in Fig. 6b.
  • 0) is shown). Sequences were repeated N 10 5 times at each point.
  • Fig. 7 also illustrates the cross-relaxation curves 704 obtained by increasing ⁇ at the 13 C resonance with the CRIP sequence 705 and depolarisation sequence 706, and off-resonance to obtain the background relaxation curve 707.
  • Inset: profile along dashed line, corresponding to T 2 h.
  • Fig. 12 illustrates a scale-up for a universal MRI contrast agent hyperpolarisation platform 1200 comprising a quantum polarisation stack 1201.
  • Fig. 13 is a more detailed schematic of the quantum polarisation stack 1201 comprising multiple diamond membranes 1202 (in Fig. 13 reference numerals are provided only for one membrane for clarity).
  • Each membrane 1202 contains NV array layers 1203 and 1204 on both sides, in a homogeneous magnetic field 1205 generated by coils 1206, for example.
  • the magnetic field 1205 tunes the NVs to the nuclear gyromagnetic ratio of the target agent spin species.
  • the unpolarised agent in concentrated solution 1210 flows into the stack channels 1201, where the liquid is polarised through the application of CRIP (via a pulsed laser).
  • the out-flowing polarised liquid 1211 is then diluted in mixer 1212 by dilution liquid 1212 for use.
  • scaling up for high-volume production can be achieved by stacking multiple NV arrays as shown in Fig. 12 and/or increasing the effective interaction area via surface patterning [KEHAYIAS 17].
  • Fig. 14 illustrates an average polarisation level 1401 from a single polarisation cell, for various targets (HEP 1402, H 2 O 1403, and 15 N-TMPA 1404), calculated for varying polarisation times assuming perfect mixing of a 1 M target agent solution with a cell height of 1 ⁇ and outflow rate 1411 (after dilution to ImM for application delivery) from 10 polarisation cells at different levels of polarisation (HEP 1412, H 2 O 1413, and 15 N-TMPA 1414).
  • this disclosure provides methods and systems for hyperpolarisation of molecular nuclear spins under ambient conditions by employing a quantum spin probe entropy pump.
  • the technique works at low field, room temperature, requires no RF fields, and operates directly on the target molecules without the need for catalysts or free radicals. With high polarisation rates and tunability, there are excellent prospects for scale-up of the system to produce macroscopic quantities of a range of contrast agents at polarisation levels required for molecular MRI/NMR.
  • the technique can be extended to other nuclear spin species and may also offer new pathways in quantum information for initialisation of quantum simulators, or increasing the fidelity of operations through spin-bath neutralisation.
  • the overarching principle of this disclosure is to bring the chosen environment into resonance with the NV centre via precise control of an external magnetic field aligned with the NV axis.
  • the NV may be optically initialised in its I 0) state, any proximate unpolarised environmental spins (of which there will initially be many) will absorb the polarisation of the NV spin via their mutual hyperfine interaction. This polarisation will then diffuse to distant environmental spins via their magnetic dipole interactions.
  • the system may produce polarised regions surrounding the NV of up to a few tens of nanometres in size.
  • H InDS + y m B 0 S z + ⁇ [S - A ⁇ . - ] + 3 ⁇ 4 ⁇ B jk ⁇ 3 ⁇ 4 , (2)
  • S x z are the Pauli spin matrices of the spin-1 system of the NV
  • D 2.87 GHz is the corresponding zero-field splitting
  • B 0 is the external field strength
  • y m and y a are the gyromagnetic ratios of the NV and target spins
  • y m is defined positive, while y a can be positive or negative depending on the species considered.
  • the consideration may be restricted to the NV subspace spanned by (
  • -l) NV transition frequency can be defined as &> NV ⁇ 2 ⁇ - y NY B 0 , and the target transition frequency as ⁇ ⁇ ⁇ y a B 0 .
  • Fig. 15 The relevant energy levels of the NV electron spin and target nuclear spin are depicted in Fig. 15. As the polarisation transfer is mediated by the NV-target hyperfine interaction, the resulting target spin state (
  • the target is polarised into the ⁇ i> state (Fig. 15 at 1502).
  • the NV-nuclear resonance conditions for various species of nuclear spins is shown are Fig. 16. This shows that some target nuclear spin species, including 1 H for example, do not have a resonance condition before the GSLAC, as the requisite NV spin transition is forbidden. After the GSLAC, however, there is no significant state mixing, which allows all spin species to be addressed via the CRIP protocol. In the following disclosure, only cases are considered where state mixing is negligible, so that the NV nuclear spin need not be not included in the model.
  • the NV-environment separation distance (approximately 10 nm) is much larger than the separation distances between adjacent 1 H spins.
  • the total hyperfine field strength may be evaluated via a standard integral over the effectively continuous, semi-infinite PMMA slab.
  • an NV is used in a standard (l00) cut diamond crystal, which gives a relatively good coupling.
  • R (x, y, z)
  • R' (X, Y, Z)
  • n 56nrrf 3 is the density of 1 H spins in PMMA, and h is the depth of the NV below the diamond-PMMA interface (measured to be approximately 10 nm herein).
  • p (R,r) is the average probability of spins in an infinitesimal volume at position R from the NV being in state
  • p (R,r) is the average probability of spins in an infinitesimal volume at position R from the NV being in state
  • ⁇ 2 can be obtained via the TJ -relaxometry spectrum (with the interleaved sequence), since ⁇ 2 defines the width of the cross-relaxation resonances
  • ⁇ 2 is expected to decrease upon polarisation of the 13 C bath. However, the effect is relatively small (see above), and as such in the calculations shown above ⁇ 2 is kept constant and equal to the off-resonance value (i.e. unpolarised case). For the
  • this technique may be scaled up for the purpose of polarising macroscopic quantities of arbitrary nuclear spin labels for clinical applications such as MRI imaging.
  • n is the numerical density of the target spins, is the distance of the NV from the a
  • ⁇ ⁇ is the nuclear magneton.
  • Table 2 Values used for the scaling up.
  • apparatus 100 in Fig. la consists of a custom-built confocal microscope and a permanent magnet mounted on a scanning stage, the same setup used, and described, in ref. [WOOD16I] .
  • a 20- ⁇ m copper wire is spanned on the surface of the diamond and connected to the output of a microwave generator (Agilent N5181A) modulated by a switch (Mini-Circuits ZASWA-2-50DR+). Laser and microwave modulations are controlled by a programmable pulse generator (SpinCore PulseBlasterESR-PRO 500 MHz).
  • the magnetic field direction and strength were varied by using a permanent magnet affixed to a set of three linear translation stages (PI M-511) allowing XYZ position control. These stages had a resolution of 100 nm which is sufficient to tune the NV into resonance and align along the field along the NV axis, thus avoiding any misalignment issues [TETIENNE12].
  • the sample (#132) used for the 13 C measurements may be a ⁇ l 11 ⁇ -oriented single crystal, electronic grade, chemical vapor deposition (CVD), 100 ⁇ thick diamond purchased from Delaware Diamond Knives.
  • the measurements reported in Figs. 6a and 6b are based on native (as grown) NV centres located far (several ⁇ ) from the surface.
  • the sample (#122) used for the 1 H measurements may be a (lOO) -oriented single crystal CVD overgrown on a HPHT substrate from Element Six. The overgrowth is roughly 50 ⁇ m and electronic grade.
  • the sample has been implanted with 15 N and 14 N at 3 keV at a density of 5 x 10 8 cm "2 each.
  • the sample was annealed at 950 ° C for 2 hours and was exposed to a soft O 2 plasma for 1 minute [FAVAR015].
  • the PMMA was baked onto the surface of the diamond by a heat gun at 85 " for 40 minutes.
  • the diamond has a range of near surface NV depths (approximately 3-13 nm) determined by NV-NMR spectroscopy using the dynamical decoupling method [PHAM16].
  • TETIENNE12, WOOD16II When doing this near the GSLAC, the alignment may be less than 0.1°.
  • the magnet was then stepped along the NV direction to vary the magnetic field strength B 0 .
  • an ODMR spectrum was recorded for about 1 minute from which we extract ⁇ ⁇ via a Lorentzian fit, before the CRIP sequence is applied.
  • the latter consists of a series of 3 ⁇ s laser pulses, sufficient to completely initialise the NV spin state, separated by a wait time ⁇ .
  • the signal plotted in Figs. 6a and 7 corresponds to the PL intensity integrated over the first 300 ns of the laser pulse, normalised by the intensity integrated over the last 300 ns.
  • the scan may be repeated but by interleaving CRIP and CRIP "1 pulse sequences, which acts to prevent polarisation build up in either direction.
  • the CRIP "1 adds a radiofrequency (RF) pulse to flip the NV spin from
  • RF radiofrequency
  • This ⁇ pulse was applied 1 ⁇ $, after the end of the laser pulse, was 300 ns in duration, and was followed by a wait time ⁇ identical to that used in the preceding CRIP sequence.
  • RF radiofrequency
  • the 7j -relaxometry spectrum of the 13 C bath was first obtained using the interleaved sequence, while scanning the magnetic field across the GSLAC.
  • the full spectrum is shown in Fig. 22 for the NV used in relation to Figs. 6a and 6b.
  • the spectrum resolves three peaks, the two outer peaks correspond to the signal from the 13 C (before and after the GSLAC), the inner peak is an intrinsic feature of the GSLAC [B ROADWAY 16].
  • 0) state (top, readout from the CRIP sequence) is narrower than that of the
  • — 1) states versus the transition frequency (o) NV ) is shown in Fig. 23.
  • ⁇ ⁇ ⁇ ⁇ ⁇ « 1.09 MHz.
  • ⁇ ⁇ ⁇ ⁇ ⁇ « 1.09 MHz.
  • ⁇ ⁇ ⁇ ⁇ ⁇ « 1.09 MHz.
  • There is a slight shift in the frequency measured which is possibly due to a hyperfine coupling between the NV and the nearest 13 C spins that remain slightly polarised.
  • Measuring the short time dynamics of the NV spin on resonance shows a coherent evolution caused by the hyperfine coupling to the surrounding 13 C spins.
  • the damping is given by fluctuations in the spin configuration of the remaining bath spins, which causes the detuning, ⁇ , to randomly vary. This is shown in Fig. 24 and has an approximate coupling strength of 250 ⁇ 40 kHz.
  • the NV-bath coupling strength depends on the particular configuration of the bath around a given NV. It can therefore be expected that there is a variability in the spectrum and degree of polarisation depending on the specific location of the 13 C spins in relation to the central NV spin.
  • the 13 C polarisation has been tested over a variety of diamonds including deep NVs near surface NVs in bulk diamond, and NVs in micro -pillars. All of the different samples and NVs have shown the capability to polarise the 13 C spin bath provided that the transition is observable around the GSLAC.
  • the full CRIP and interleaved spectra (including the GSLAC feature) for the NV used in Figs. 6a and 6b are shown in Fig. 25.
  • Also shown in Fig. 26 are the spectra from another NV.
  • the time dynamics for this NV on resonance with the 13 C bath is shown in Fig. 27, revealing a similar hyperfine coupling.
  • a magnetic sweep can be performed across both resonances and the GSLAC, shown in Fig. 28d.
  • Four features are present, two related to 13 C (outside peaks) and two related to the GSLAC (inside peaks).
  • the width of the polarisation region is roughly 0.1 - 0.2 MHz.
  • the width of this polarisation region is governed by the T * of the NV spin.
  • a comparison of the number of pulses required to polarise the nearest 13 C spins on both sides of the GSLAC shows a distinct difference, which is explained by the difference in the angular dependence of the dipole- dipole coupling before and after the GSLAC.
  • the NV frequency remained on resonance with the 13 C transition frequency (1.09 MHz) for several hours, before it drifted away by more than the NV intrinsic linewidth ( « 200 kHz).
  • the total acquisition time was 5 hours, during which the NV was on resonance within the NV linewidth, i.e. ⁇ ⁇ in the range 1.0- 1.2 MHz. This ensures nearly optimal interaction between NV and 13 C bath, which is important not only to polarise the 13 C bath but also to accurately probe the remaining NV- 13 C interaction which were used to estimate the polarisation extent.
  • a constant voltage induced current pulse was used to generate a DC field from the coil to act as a quick field switching mechanism, allowing the polarisation to occur at the resonance frequency and the measurement to be performed at another frequency, as illustrated by the ODMR spectra shown in Fig. 30c.
  • the field offset thus applied was B OFFSET « 0.7 G, turned on while a series of polarisation pulses was implemented.
  • a single- T FID measurement can be made as a function of the magnetic field, across the 13 C resonance (after GSLAC).
  • the resulting spectrum is shown in Fig. 30d, where CD M (measured by an ODMR spectrum at each magnet position) was scanned from - 1.0 MHz to 1.5 MHz during the CRIP polarisation phase (with the field offset on), corresponding to 1 MHz to 3.5 MHz during the FID measurement (field offset off).
  • the CRIP+FID sequence is repeated many times at each magnet position with the aim to polarise the 13 C bath.
  • full-length FID curves were measured while scanning the magnetic field.
  • Fig. 30e shows the resulting curves with the CRIP at the resonance or off the resonance.
  • the main difference between the two FID curves is in the frequency of the oscillation, which differ from each other by 58(27) kHz. This difference is attributed to a change in the DC magnetic field seen by the NV, induced by polarisation of the nearest 13 C spins. However, the envelope of the oscillation shows a similar decay time ( T * ) in both cases, which means the 13 C polarisation was not sufficient to significantly reduce the magnetic noise seen by the NV.
  • Fig. 32a shows a spectrum showing the polarisation effect for a different NV (NV2) than that used in Fig. 7.
  • NV2 a different NV
  • a signal is observed when the depolarisation sequence is used.
  • no measurable 1 H signal was observed in the absence of PMMA (removed with dichloromethane) even with the depolarisation sequence, and that the polarisation effect was observed again after reapplying PMMA. This suggests that the 1 H spins were detected and polarised are mainly from the PMMA, although it is difficult to exclude all contributions from contaminants trapped under the PMMA, e.g. water.
  • NVs the total acquisition time can be limited to about 30 minutes per T x curve.
  • the measurements were done on resonance ( ⁇ ⁇ « 4.4 MHz) and off resonance ( ⁇ ⁇ « 3.0 MHz).
  • Fig. 32b shows full-length T x curves from an additional NV (NV3) (bottom: unpolarised, middle: polarised, top: background).

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Abstract

La présente invention concerne un procédé d'hyperpolarisation d'un agent. L'agent est situé à proximité immédiate d'une sonde quantique qui est à un premier niveau d'énergie et un champ magnétique est appliqué à la sonde quantique et à l'agent. Un rayonnement de commande quantique appliqué à la sonde amène la sonde quantique à un deuxième niveau d'énergie pour permettre une relaxation croisée entre la sonde quantique et l'agent pendant que le champ magnétique est appliqué. Le champ magnétique est d'une intensité de champ magnétique qui ajuste les niveaux d'énergie de la sonde quantique pour amener une transition de spin de sonde de la sonde quantique en résonance avec une transition de spin d'agent de l'agent pour permettre le transfert d'énergie et activer ainsi la relaxation croisée entre la sonde quantique et l'agent pour polariser l'agent. Cela permet une polarisation à température ambiante avec des champs magnétiques relativement faibles.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050030026A1 (en) * 1996-03-29 2005-02-10 The Regents Of The University Of California Enhancement of NMR and MRI in the presence of hyperpolarized noble gases
WO2009136131A1 (fr) * 2008-03-10 2009-11-12 University Of Southampton Agent de transport d’ordre de spins nucleaires et d’imagerie par resonance magnetique
US20160054402A1 (en) * 2013-04-05 2016-02-25 Research Foundation Of The City University Of New York Method and apparatus for polarizing nuclear and electronic spins
US20160161583A1 (en) * 2014-12-08 2016-06-09 Research Foundation Of The City University Of New York Method for hyper-polarizing nuclear spins at arbitrary magnetic fields
WO2016188557A1 (fr) * 2015-05-22 2016-12-01 Universitaet Ulm Procédé pour l'hyperpolarisation de spins nucléaires

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050030026A1 (en) * 1996-03-29 2005-02-10 The Regents Of The University Of California Enhancement of NMR and MRI in the presence of hyperpolarized noble gases
WO2009136131A1 (fr) * 2008-03-10 2009-11-12 University Of Southampton Agent de transport d’ordre de spins nucleaires et d’imagerie par resonance magnetique
US20160054402A1 (en) * 2013-04-05 2016-02-25 Research Foundation Of The City University Of New York Method and apparatus for polarizing nuclear and electronic spins
US20160161583A1 (en) * 2014-12-08 2016-06-09 Research Foundation Of The City University Of New York Method for hyper-polarizing nuclear spins at arbitrary magnetic fields
WO2016188557A1 (fr) * 2015-05-22 2016-12-01 Universitaet Ulm Procédé pour l'hyperpolarisation de spins nucléaires

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ABRAMS, DANIEL ET AL.: "Dynamic nuclear spin polarization of liquids and gases in contact with nanostructured diamond", NANO LETTERS, vol. 14, no. 5, 2014, pages 2471 - 2478, XP055249154, DOI: doi:10.1021/nl500147b *
PAGLIERO, DANIELA ET AL.: "Recursive polarization of nuclear spins in diamond at arbitrary magnetic fields", APPLIED PHYSICS LETTERS, vol. 105, no. 24, 2014, pages 242402, XP012192804, DOI: doi:10.1063/1.4903799 *

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