Note: Descriptions are shown in the official language in which they were submitted.
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
SYSTEMS AND METHODS FOR PRODUCING HYPERPOLARIZED MATERIALS AND
MIXTURES THEREOF
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of priority of U.S. Provisional Patent
Application Serial No. 61/238,647, filed August 31, 2009. This application is
also related to
U.S. Provisional Patent Application Serial No. 60/775,196 filed February 21,
2006, U.S.
Provisional Patent Application Serial No. 60/802,699 filed May 23, 2006, U.S.
Provisional
Patent Application Serial No. 61/042,239 filed April 3, 2008, U.S. Provisional
Patent
Application Serial No. 61/042,398, filed April 4, 2008, U.S. Provisional
Patent Application
Serial No. 61/111,050, filed November 4, 2008, U.S. Provisional Patent
Application Serial No.
61/238,647, filed August 31, 2009, U.S. Patent Application Serial No.
12/193,536, filed August
18, 2008 and International Application No. PCT/US2009/39696, filed April 6,
2009. The
disclosure of each of the aforementioned patent applications is incorporated
by reference herein
in its entirety.
BACKGROUND
Field of the Disclosure
The present disclosure relates to improved materials including hyperpolarized
nuclei and techniques for making the same.
Description of Related Art
Recent experiments have demonstrated that hyperpolarization of various nuclei
can survive the transition from one molecule to another that takes place
during a chemical
reaction. For example, it has been shown that hyperpolarized ("HP") 13C nuclei
in sodium
pyruvate can be metabolized by cancerous tissue and produce HP lactate,
alanine and the like.
A further example can be found in the production of HP fumarate, which can be
manufactured by first hyperpolarizing nuclei in fumaric acid and then allowing
the acid to react
with a base solution to form HP fumarate. HP sodium pyruvate (i.e., sodium
pyruvate including
hyperpolarized nuclei) may be manufactured in a similar fashion. In reactions
such as these the
amount of polarization lost during the chemical reaction has been shown to be
small.
1
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
These are examples of chemical reactions in which at least one precursor
molecule in the chemical reaction is hyperpolarized so that at least one of
the end products of the
chemical reaction is in turn hyperpolarized.
In each of the aforementioned examples, Dynamic Nuclear Polarization (DNP)
was used to hyperpolarize the precursor molecule. In this process, the
molecule to be
hyperpolarized is mixed with a polarization agent containing a source of free
electrons, typically
a trityl radical (TA). In some instances an electron paramagnetic agent (EPA)
may be used in
conjunction with the TA or by itself.
This method of hyperpolarization is problematic for in vivo applications, as
the
TA/EPA is strongly contraindicated for in vivo applications. The TA/EPA must
then be
stringently removed prior to injection of the HP material. However, the level
of polarization in
the HP material that survives after filtration of the TA/EPA is not presently
clear. Moreover,
safe levels of exposure to small amounts of TA/EPA have not been established
by the FDA.
Furthermore, use of this technique is not amenable to the ready transport or
storage of
hyperpolarized material.
Very high nuclear polarizations can be produced in materials containing nuclei
with non zero spin using a variety of methods well known in the art. The
simplest of these is to
subject the material to very high magnetic fields (typically, B > 10 T) and
very low temperatures
(typically, T < 100 mK) where the saturated nuclear polarization of any non
zero spin nuclei is
very high.
Unfortunately, under such conditions, the relaxation time of most nuclei is
extremely long because at low temperatures, molecular motion, which is a major
source of
nuclear magnetic relaxation, is greatly diminished. To address this drawback,
a variety of
relaxation agents have been used to reduce Ti in the high B/T environment
including dysposium,
gadolinium, oxygen and others.
An alternative to employing a relaxation agent is to incorporate a
polarization
agent such as a trityl radical and then transfer polarization from the agent
to nuclei in the target
material. This approach has the advantage of not requiring such low
temperatures or high fields
and has been used to demonstrably produce very large polarizations in small
amounts of
material. It has become the basis of a commercially available research device
with the trade
name Hypersense .
2
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
However, admixture of either an external relaxation agent or a polarization
agent
has a number of drawbacks. First off, they are generally equally effective at
depolarizing the
material while still in the solid state upon removal from the high B/T
environment. This makes it
very difficult to store/transport the hyperpolarized material any significant
distance from the
polarizer and therefore mandates that the polarizer be placed very close to
the MR machine in
which the study utilizing hyperpolarized material is to be carried out.
Secondly, most relaxation
or polarizations agents are frequently toxic. This makes such agents
problematic for use in in
vivo MR studies.
For this reason alternative relaxation agents that are non toxic and can
furthermore be removed without depolarizing the material have been developed.
For example,
U.S. Patent No. 6,651,459 teaches the use of 3He as a relaxation agent by
adsorbing layers of 3He
on a high surface area substrate constructed from the material to be
hyperpolarized. Quantum
tunneling in the 3He overlayers causes rapid relaxation in the underlying
material leading to rapid
saturation of the nuclear polarization in a high B/T environment. 3He is
chemically inert and can
moreover be thoroughly removed from the material prior to warm up from a high
B/T
environment which addresses in vivo usage concerns. U.S. Patent No. 6,651,459
further teaches
the use of 4He to remove the 3He from the surface of the polarized material to
minimize
depolarization upon warmup.
An aspect of the above process is that the 3He can only effectively relax the
substrate layer with which it is in intimate contact. Thus, the material must
be made into a very
high surface area substrate prior to polarization which may impose material
handling difficulties.
There is therefore a need in the art for a methods of manufacturing
hyperpolarized
("HP") material where the material is not mixed with any kind of external
relaxation or
polarization agent. More generally, there remains a need in the art for
improved approaches to
manufacture, transport and use of highly polarized materials. The present
disclosure provides a
solution for these problems.
SUMMARY OF THE DISCLOSURE
Advantages of the present disclosure will be set forth in and become apparent
from the description that follows. Additional advantages of the disclosure
will be realized and
3
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
attained by the methods and systems particularly pointed out in the written
description and
claims hereof, as well as from the appended drawings.
To achieve these and other advantages and in accordance with the purpose of
the
disclosure, as embodied herein, in one embodiment, the disclosure provides a
method of
producing a material containing hyperpolarized nuclei. The method includes
formatting a first
material into a high surface area configuration. Next, in a polarizing
cryostat, the first material is
exposed to 3He at a temperature below about 10K and a magnetic field in a
manner sufficient to
substantially increase the polarization of at least one nuclei in the first
material. The temperature
of the first material is then increased without melting or sublimating the
first material resulting in
nuclei in the first material becoming hyperpolarized. If desired, the first
material is then reacted
with at least one other material to form a mixture including hyperpolarized
nuclei.
In further accordance with the invention, the mixture may be a solution. If
desired, the first material may be melted prior to, or as a part of, the
reacting step. The first
material may be exposed to 4He after exposing the first material to 3He. If
desired, the first
material may be stored in a hyperpolarized condition in a separate cryostat.
The first material
may be transported in the separate cryostat to a site remote from where it was
hyperpolarized
prior to reacting the first material with at least one other material to form
a mixture including
hyperpolarized nuclei. In accordance with a preferred embodiment, the nuclei
in the first
material includes at least one material selected from the group consisting of
13C 15N iH 31P and
29Si.
In further accordance with the disclosure, the method may further include
substantially increasing the temperature of the first material without melting
or sublimating the
material after the initial temperature increase that results in nuclei in the
first material becoming
hyperpolarized. For example, the temperature may be increased from a first
temperature
substantially below the temperature at which the T, of the first material
experiences a minimum
to a second temperature substantially above the temperature at which the T, of
the first material
experiences a minimum. In accordance with one embodiment, the temperature of
the first
material is increased from a temperature below about 10K to a temperature of
about 200K. In
accordance with another embodiment, the temperature of the first material may
be increased in
the presence of a magnetic field at a rate wherein less than about 90 percent
of polarization
imparted to nuclei in the first material is lost. In accordance with certain
preferred embodiments,
4
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
the temperature of the first material may be increased in the presence of a
magnetic field at a rate
wherein less than about 80, 70, 60, 50, 40, 30, 20, 10 or 5 percent of
polarization imparted to
nuclei in the first material is lost. If desired, the first material may be
transported to a location
within the fringe field of an MR system after the first material has reached
the second
temperature.
In further accordance with the disclosure, the method may additionally include
the
step of removing the first material from the polarizing cryostat after the
initial temperature
increase that results in nuclei in the first material becoming hyperpolarized.
By way of further
example, the method may further include transferring the first material into a
transport cryostat
after the initial temperature increase that results in nuclei in the first
material becoming
hyperpolarized. Accordingly, the transport cryostat may be transported to an
end user. The first
material may then be transferred from the transport cryostat into a transfer
vessel. The transfer
vessel may include a permanent magnet or electromagnet for maintaining the
first material in a
magnetic field. The method may further include increasing the temperature from
a first
temperature below the temperature at which the Ti of the first material
experiences a minimum
to a second temperature above the temperature at which the Ti of the first
material experiences a
minimum. The temperature may be raised to the second temperature at
substantially the same
time the first material is transferred into the transfer vessel. The
temperature may be raised to
the second temperature in less than about thirty seconds in a magnetic field
having a strength
between about 0.1 Tesla and about 10 Tesla.
In further accordance with the disclosed embodiments, the method may further
include the step of disposing the first material in a mixing device within the
fringe field of a MR
system. Preferably, at least a portion of the reacting step occurs within the
mixing device. If a
transfer vessel is used, the magnet of the transfer vessel is preferably
turned off or otherwise
deactivated or shielded prior to performing an MR system operation.
In further accordance with the disclosure, the first material may include an
acid
and the at least one other material may include a base. On the other hand, the
first material may
include a base and the at least one other material may include an acid.
Accordingly, the acid
may include an acid selected from the group consisting of acetic acid, formic,
lactic and pyruvic
acid. Preferably, the acid is isotopically enhanced in one or more of its
carbon sites with 13C. In
accordance with one embodiment, the at least one other material includes
sodium, such as in the
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
form of sodium hydroxide and/or sodium bicarbonate. In accordance with still a
further aspect,
the first material may be a liquid, solid, and/or gas at standard temperature
and pressure ("STP").
In accordance with one embodiment, the first material may be frozen in a high
surface area
configuration such that it has a surface area to volume ratio greater than
about 0.1 m2/g.
In further accordance with the present disclosure, a method of magnetic
resonance
(MR) investigation of a subject including a human subject or other organism is
provided. The
method includes producing a mixture including hyperpolarized nuclei as
described herein,
administering the mixture to the subject, exposing the subject to radiation of
a frequency selected
to excite nuclear spin transitions in the hyperpolarized nuclei, and detecting
magnetic resonance
signals from the subject.
In further accordance with the disclosure, the method may further include
generating at least one of an image, dynamic flow data, diffusion data,
perfusion data,
physiological data or metabolic data from the detected signals. The
hyperpolarized nuclei in the
mixture preferably have a Ti value of at least 5 seconds at a field strength
in the range 0.01-5 T
and at a temperature in the range of 20-40 C.
The disclosure further provides a method of producing a material including
hyperpolarized nuclei. The method includes increasing the state of
polarization of a first
material in the absence of a source of free electrons (e.g., TA, discussed
above) or paramagnetic
impurities (e.g., EPA, discussed above) at a temperature below about 10K in
the presence of a
magnetic field, increasing the temperature of the first material without
melting it resulting in
nuclei in the first material becoming hyperpolarized, and reacting the first
material with at least
one other material to form a mixture including hyperpolarized nuclei. The
mixture may include
a solution, among other types of mixtures.
In further accordance with the disclosure, the methods described herein may
include embodiments wherein the first material includes a methyl group. By way
of further
example, the methods described herein may include embodiments wherein the
resulting mixture
includes pairs of bonded nuclei. Preferably, at least a portion of the bonded
nuclei are
hyperpolarized.
The disclosure further provides a method of producing a material containing
hyperpolarized nuclei. The method includes formatting a first material
including a methyl group
into a high surface area configuration, increasing the nuclear polarization of
the first material,
6
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
and increasing the temperature of the first material from a first temperature
below the
temperature at which the Ti of the first material experiences a minimum to a
second temperature
above the temperature at which the Ti of the first material experiences a
minimum without
melting or sublimating the first material within a time period less than about
thirty seconds. The
disclosure also provides a method of producing a material containing
hyperpolarized nuclei. The
method includes formatting a first material including a methyl group into a
high surface area
configuration, increasing the nuclear polarization of the first material, and
increasing the
temperature of the first material from a first temperature below the
temperature at which the Ti
of the first material experiences a minimum to a second temperature above the
temperature at
which the Ti of the first material experiences a minimum without melting or
sublimating the first
material within a time period less than about thirty seconds, wherein less
than about 90 percent
of the polarization is lost when increasing the temperature. In further
accordance with the
disclosure, the first material may be reacted with at least one other material
to form a mixture
including hyperpolarized nuclei. In accordance with certain preferred
embodiments, less than
about 80, 70, 60, 50, 40, 30, 20, 10 or 5 percent of the polarization is lost
when increasing the
temperature.
The disclosure yet further provides a method of producing a material
containing
hyperpolarized nuclei. The method includes hyperpolarizing a first material,
and increasing the
temperature of the first material from a first temperature below the
temperature at which the Ti
of the first material experiences a minimum to a second temperature above the
temperature at
which the Ti of the first material experiences a minimum without melting or
sublimating the first
material.
The disclosure still further provides a method of producing a material
containing
hyperpolarized nuclei. The method includes formatting a first material into a
high surface area
configuration and, in a polarizing cryostat, exposing the first material to
3He at a temperature
below about 10K and a magnetic field in a manner sufficient to substantially
increase the
polarization of the first material. The method also includes reacting the
first material with at
least one other material to form a mixture including hyperpolarized nuclei.
The disclosure also provides a method of producing a mixture including
hyperpolarized nuclei including providing a precursor including hyperpolarized
nuclei, disposing
7
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
the precursor in the stray field of an MR system, and reacting the precursor
with at least one
other material to form a mixture including hyperpolarized nuclei.
In further accordance with the disclosure, an embodiment of a system for
producing a material containing hyperpolarized nuclei is provided. The system
includes a
polarizing cryostat having a vessel for exposing a first material formatted
into a high surface area
configuration to 3He at a temperature below about 10K and a magnet adapted and
configured to
provide a magnetic field in a manner sufficient to substantially increase the
polarization of the
first material. The system further includes a first heat source for increasing
the temperature of
the first material without melting or sublimating the first material resulting
in nuclei in the first
material becoming hyperpolarized. The system still further provides a mixing
device for reacting
the first material with at least one other material to form a mixture
including hyperpolarized
nuclei.
In further accordance with the disclosure, the mixture may be a solution. The
system may further include a second heat source for melting the first material
to permit the first
material to react. The second heat source may include the material with which
the first material
is mixed in the mixing device. For example, the first material may be melted
by dropping it into
the material with which the first material is mixed. By way of further
example, the first material
may melt prior to contacting the material with which the first material is
mixed. The system may
further include means for exposing the first material to 4He after exposing
the first material to
3He.
In accordance with a further aspect, the system may further include a
transport
cryostat in which the first material in a hyperpolarized condition is stored.
The transport cryostat
is preferably suitable for transporting the first material to a site remote
from where the first
material was hyperpolarized. In accordance with a preferred embodiment, the
nuclei in the first
material includes at least one material selected from the group consisting of
13C 15N iH 31P and
29Si.
In accordance with another aspect, the system may include means for
substantially increasing the temperature of the first material without melting
or sublimating the
material after the first material becomes hyperpolarized. The system may be
adapted and
configured to increase the temperature from a first temperature substantially
below the
temperature at which the T, of the first material experiences a minimum to a
second temperature
8
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
substantially above the temperature at which the Ti of the first material
experiences a minimum.
The system is preferably adapted and configured to increase the temperature of
the first material
from a temperature below about 10K to a temperature of about 200K.
In further accordance with the present disclosure, the system may include a
transfer vessel for receiving the first material from the transport cryostat.
The transfer vessel
preferably includes a magnet for maintaining the first material in a magnetic
field. In accordance
with a further embodiment, the system includes a mixing device for receiving
the first material
from the transfer vessel. The mixing device and transfer vessel are preferably
adapted and
configured to be operated within the fringe field of a MR system. The magnet
of the transfer
vessel can be adapted and configured to be turned off prior to performing an
MR system
operation.
In further accordance with the system, the first material can be a liquid,
solid,
and/or a gas at STP. The first material is preferably in a high surface area
configuration that has
a surface area to volume ratio greater than about 0.1 m2/g.
The disclosure provides a system of magnetic resonance (MR) investigation of a
subject including a human subject or other organism. The MR system includes
means for
producing a mixture including hyperpolarized nuclei as described herein and an
injector for
administering the mixture to the subject. The system further includes at least
one radio
frequency coil for exposing the subject to radiation of a frequency selected
to excite nuclear spin
transitions in the hyperpolarized nuclei, and a detector for detecting
magnetic resonance signals
from the subject.
In further accordance with the disclosure, the system may further include
means
for generating at least one of an image, dynamic flow data, diffusion data,
perfusion data,
physiological data or metabolic data from signals received from the detector.
The disclosure also provides an exemplary system for producing a material
including hyperpolarized nuclei. The system includes means for increasing the
state of
polarization of a first material in the absence of a source of free electrons
or paramagnetic
impurities at a temperature below about 10K in the presence of a magnetic
field. The system
further includes means for increasing the temperature of the first material
without melting it
resulting in nuclei in the first material becoming hyperpolarized. The system
also includes
9
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
means for reacting the first material with at least one other material to form
a mixture including
hyperpolarized nuclei.
In further accordance with the disclosure, the disclosed systems may utilize a
first
material that includes a methyl group. If desired, the disclosed systems may
be used to make a
mixture that includes pairs of bonded nuclei. Preferably, at least a portion
of the bonded nuclei
are hyperpolarized.
In further accordance with the disclosed embodiments, a system for producing a
material containing hyperpolarized nuclei is provided. The system includes
means for
formatting a first material including a methyl group into a high surface area
configuration and
means for increasing the nuclear polarization of the first material. The
system further includes
means for increasing the temperature of the first material from a first
temperature below the
temperature at which the Ti of the first material experiences a minimum to a
second temperature
above the temperature at which the Ti of the first material experiences a
minimum without
melting or sublimating the first material within a time period less than about
thirty seconds.
In further accordance with the disclosure, a system for producing a material
containing hyperpolarized nuclei is provided. The system includes means for
formatting a first
material including a methyl group into a high surface area configuration, and
means for
increasing the nuclear polarization of the first material. The system further
includes means for
increasing the temperature of the first material from a first temperature
below the temperature at
which the Ti of the first material experiences a minimum to a second
temperature above the
temperature at which the Ti of the first material experiences a minimum
without melting or
sublimating the first material within a time period less than about thirty
seconds, wherein less
than about 90 percent of the polarization is lost during the warming step. In
accordance with
certain preferred embodiments, less than about 80, 70, 60, 50, 40, 30, 20, 10
or 5 percent of the
polarization is lost during the warming step.
In further accordance with the disclosure, the system may include means for
reacting the first material with at least one other material to form a mixture
including
hyperpolarized nuclei.
In yet further accordance with the disclosure, a system for producing a
material
containing hyperpolarized nuclei is provided. The system includes means for
hyperpolarizing a
first material and means for increasing the temperature of the first material
from a first
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
temperature below the temperature at which the T, of the first material
experiences a minimum
to a second temperature above the temperature at which the T, of the first
material experiences a
minimum without melting or sublimating the first material.
In still further accordance with the disclosure, system for producing a
material
containing hyperpolarized nuclei is provided. The system includes means for
formatting a first
material into a high surface area configuration, a polarizing cryostat having
means for exposing
the first material to 3He at a temperature below about 10K, and a magnet for
generating a
magnetic field in a manner sufficient to substantially increase the
polarization of the first
material. The system also includes a mixing device for reacting the first
material with at least
one other material to form a mixture including hyperpolarized nuclei.
In further accordance with the disclosed embodiments, a system for producing a
mixture including hyperpolarized nuclei is provided. The system includes means
for providing a
precursor including hyperpolarized nuclei and means for disposing the
precursor in the stray
field of an MR system. The system further includes means for reacting the
precursor with at
least one other material to form a mixture including hyperpolarized nuclei.
In accordance with another embodiment, the disclosure provides further
embodiments of manufacturing hyperpolarized material. One such exemplary
method includes
providing a first material to be polarized, increasing the polarization of at
least one nuclei
contained in the first material, and transferring the increased polarization
of the at least one
nuclei to other nuclei in the first material.
In accordance with further aspects, the first material preferably includes a
methyl
rotor group, the polarization of at least one hydrogen nuclei in the methyl
rotor group is
increased in the polarization step, and the increased polarization of the at
least one hydrogen
nuclei is transferred to other nuclei in the first material in the
transferring step. The first material
is preferably substantially purged of paramagnetic agents and polarization
agents prior to
polarization. For example, the first material is preferably substantially
purged of TA and EPA
prior to polarization. The first material is preferably isotopically enhanced
by substituting one or
more of its atomic sites with at least one of 129Xe, 13C 15N iH 2H 31P 19F and
29Si.
In accordance with another aspect, the polarization step preferably includes
exposing the first material to a polarizing environment. This preferably
includes at least one of
(i) decreasing the temperature of the first material, and (ii) subjecting the
first material to an
11
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
increased magnetic field, wherein the first material is exposed to the
polarizing environment for
a time sufficient to polarize at least one hydrogen nuclei contained in the
first material to
thermodynamic equilibrium. The first material may be a solid, liquid and/or
gas at STP.
Preferably, the method further includes the step of extracting the first
material from the
polarizing environment (e.g., crysostat) while the first material is in the
solid state. Also, the
polarization time is preferably sufficient to polarize the at least one
hydrogen nuclei in the
methyl group.
In accordance with another preferred aspect, the method can further include
directing the first material from the polarizing environment through a region
of decreased
magnetic field to a second location to facilitate the transfer of polarization
from the at least one
nuclei to other nuclei in the first material after the polarization step.
Preferably, the first material
is transferred from the polarizing environment through the region of decreased
magnetic field to
the second location over a time period greater than T2 but less than T1. For
example, the first
material can be transferred from the polarizing environment to the second
location in less than
1.0 seconds, than 0.1 seconds, less than 0.01 seconds, or in about 0.001
seconds, if desired.
In accordance with still further aspects, the second location can include a
cryogenic environment with a magnetic field. For example, the second location
can include a
transport cryostat including a magnet, wherein the magnet applies a magnetic
field to the first
material at a low temperature. Preferably, the first material is in a solid
state after the
polarization step and the first material is directed to the second location by
accelerating it with
fluid pressure. The first material can be directed to the second location by
directing it through a
conduit with a compressed gas. For example, the first material can be directed
through the
conduit by the compressed gas at a speed in excess of 10 m/s, 100 m/s or 1000
m/s. The
compressed gas preferably includes helium, and may include 3He.
In accordance with yet further aspects, the second location can include a
melting
vessel for melting the first material. In one embodiment, the region of
decreased magnetic field
can include magnetic shielding to lower the strength of the magnetic field in
the region of
decreased magnetic field to a magnitude less than the Earth's background
field. If desired, the
method can further include warming the first material while in the polarizing
environment prior
to expulsion. The warming step preferably increases the temperature of the
first material from
below the temperature at which the Ti of the first material experiences a
minimum (Tmin) to a
12
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
second temperature above the temperature at which the Ti of the first material
experiences a
minimum (Tmin) without substantially melting or sublimating the first
material.
In accordance with a further embodiment, the disclosure provides a method for
manufacturing a hyperpolarized material that includes providing a first
material to be polarized
in the form of a high surface area powder, increasing the polarization of at
least one nuclei
contained in the first material within a vessel in a polarizing environment by
performing at least
one of: (i) decreasing the temperature of the first material, and (ii)
subjecting the first material to
an increased magnetic field. The first material is exposed to the polarizing
environment for a
time sufficient to polarize at least one nuclei contained in the first
material to thermodynamic
equilibrium. The method further includes the step of transferring the
increased polarization of
the at least one nuclei to other nuclei in the first material while directing
the first material from
the polarizing environment through a region of decreased magnetic field to a
second location.
In accordance with further aspects, the high surface area first material can
be
exposed to 3He for a time sufficient to polarize at least one nuclei contained
in the material.
Subsequent to 3He exposure, the high surface area formatted first material can
be exposed to 4He
to remove the 3He. Subsequent to exposure to 4He, the first material can be
warmed without
substantially melting or sublimating the first material, resulting in nuclei
in the material
becoming hyperpolarized. Warming preferably increases the temperature of the
first material
from below the temperature at which the Ti of the first material experiences a
minimum (Tmin) to
a second temperature above the temperature at which the Ti of the first
material experiences a
minimum (Tmin) without substantially melting or sublimating the first
material. The first material
can be maintained in a magnetic field during the warming step. The first
material is preferably
directed from the polarizing environment to a second location in a time
greater than T2 and less
than T1. The second location preferably includes a cryogenic environment with
a magnetic field.
For example, the second location can include a transport cryostat including a
magnet, wherein
the magnet applies a magnetic field to the first material at a low
temperature.
In accordance with a further aspect of the method, the first material can be
polarized using a technique selected from the group consisting of (i) dynamic
nuclear
polarization, (ii) the Nuclear Overhauser effect, (ii) parahydrogen induced
polarization,
(iii)exposing the nuclei of the first material to hyperpolarized nuclei of a
previously
13
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
hyperpolarized gas, (iv) exposing the first material to a brute force
environment and
combinations thereof.
The disclosure further provides a method of forming a hyperpolarized solution,
comprising hyperpolarizing a first material that is a liquid at STP in as set
forth above, and
mixing the first hyperpolarized material with a second material to form a
solution. The first
material can be reacted with the second material to form the solution. The
first material can
include an acid and the second material includes a base, or vice versa. The
acid can include one
or more of acetic acid, lactic acid, pyruvic acid and formic acid. In one
embodiment, the acid(s)
can be isotopically enhanced at one or more of its atomic sites by
substitution of one or more
isotopes selected from the group consisting of 13C '5N 'H 2H 3'P '9F and 29Si.
In accordance
with a further aspect, the second material can include sodium, such as in the
form of sodium
hydroxide and/or sodium bicarbonate.
In accordance with further aspects, the first material can be a solution at
STP, and
the method can further include mixing the first material with a second
material to form a second
solution. In another embodiment, a method is provided as set forth above
wherein the first
material is a solid at STP, and the method further includes mixing the first
material with a second
material to form a solution. In still another embodiment, the method can
further include mixing
the first material with a second material to form a suspension. In one
embodiment, the first
material is a solid at STP, and the method can further include mixing the
first material with a
second material to form a colloid. In another embodiment, the first material
can be a solid at
STP, and the method can further include mixing the first material with a
second material to form
an emulsion. In yet another embodiment, the first material can be a solid at
STP, and the method
can further include mixing the first material with a second material to form a
composite material.
In another embodiment, the method can include encapsulating the first material
in an
encapsulating medium. The encapsulating medium can be porous.
In accordance with another aspect, the method can further include storing the
first
material in a hyperpolarized condition in the transport cryostat, and
transporting the first material
in the transport cryostat to a site remote from where it was hyperpolarized.
If desired, the first
material can be transported to a location within the fringe field of an MR
system. The method
can then include increasing the temperature of the first material from a first
temperature below
Tmin to a second temperature above Tmin. The first material can then be
disposed in a mixing
14
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
device within the fringe field of the MR system. The first material can then
react (e.g.,
chemically) with a second material within the mixing device. Preferably, the
magnet of the
transfer vessel is turned off prior to performing an MR system operation. The
above steps can be
carried out regardless of the initial mechanism used to hyperpolarize the
first material. In
accordance with still another embodiment, the first material is partially or
fully deuterated.
In accordance with another embodiment, a method is provided as set forth
above,
but further comprising increasing the temperature of the first material from a
first temperature
below Tmin to a second temperature above Tmin while the first material is
situated in the transport
cryostat or being directed into a transfer vessel. If desired, the first
material can then be directed
into the transfer vessel, wherein the transfer vessel is adapted and
configured to maintain the first
material at an elevated magnetic field and at a temperature lower than the
melting point of the
first material. For example, the transfer vessel can include a magnet and the
temperature of the
first material can be maintained in the transfer vessel at least in part with
the aid of dry ice. In
accordance with a further aspect, the method can further include mixing the
first material with a
second material to form a mixture. The mixing step can include melting the
first material in the
presence of an elevated magnetic field. The mixing step can occur while the
first material is
directed into the transfer vessel, while the first material is situated in the
transfer vessel or in a
further vessel in the fringe field of the MR system.. The first material can
react with a second
material within the transfer vessel.
The disclosure also provides a system for manufacturing a hyperpolarized
material. The system includes means for delivering a first material to be
polarized to a
polarizing region, means for increasing the polarization of at least one
nuclei contained in the
first material while in the polarization region, and means for transferring
the increased
polarization of the at least one nuclei to other nuclei in the first material.
If desired, the first
material can include a methyl rotor group, and the polarization of at least
one hydrogen nuclei in
the methyl rotor group can be increased by the means for increasing the
polarization, and the
increased polarization of the at least one hydrogen nuclei can be transferred
to other nuclei in the
first material by the transferring means. The first material is preferably
substantially purged of
paramagnetic agents and polarization agents prior to polarization.
In accordance with a further aspect of the system, the means for transferring
can
include means for directing the first material from the polarizing region
through a region of
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
decreased magnetic field to a second location to facilitate the transfer of
polarization from the at
least one nuclei to other nuclei in the first material. The means for
directing can be adapted and
configured to transfer the first material from the polarizing environment
through the region of
decreased magnetic field to the second location over a time period greater
than T2 but less than
T1. The means for directing is preferably adapted and configured to transfer
the first material
from the polarizing environment through the region of decreased magnetic field
to the second
location, for example, in less than 1.0 seconds, less than 0.1 seconds, less
than 0.01 seconds or in
about 0.001 seconds, if desired.
In accordance with yet a further aspect, the second location can include a
cryogenic environment with a magnetic field. For example, the second location
can include a
transport cryostat including a magnet, wherein the magnet applies a magnetic
field to the first
material at a low temperature. Preferably, the first material is in a solid
state after polarization
and the first material is directed to the second location by accelerating it
with fluid pressure. In
one embodiment, the first material is directed to the second location by
directing it through a
conduit with a compressed gas at a speed in excess of 10 m/s, in excess of 100
m/s, in excess of
1000 m/s, or as desired. The compressed gas can include helium, and may
include 3He. By way
of further example, the second location can include a melting vessel for
melting the first
material. In one embodiment, the region of decreased magnetic field includes
magnetic
shielding to lower the strength of the magnetic field in the region of
decreased magnetic field to
a magnitude less than the Earth's background field. In another aspect, the
system can further
include means (such as an electrical resistance heater) for warming the first
material while in the
polarizing environment. The warming means preferably increases the temperature
of the first
material from below the temperature at which the Ti of the first material
experiences a minimum
(Tmin) to a second temperature above the temperature at which the Ti of the
first material
experiences a minimum (Tmin) without substantially melting or sublimating the
first material. In
accordance with still a further aspect, the first material can be in the form
of a high surface area
powder prior to polarization. Moreover the nuclei of the first material can be
polarized initially
using a technique selected from the group consisting of (i) dynamic nuclear
polarization, (ii) the
Nuclear Overhauser effect, (ii) parahydrogen induced polarization,
(iii)exposing the hydrogen
nuclei to hyperpolarized nuclei of a previously hyperpolarized gas, (iv)
exposing the first
material to a brute force environment and combinations thereof.
16
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
The disclosure further provides a beneficial agent including a material having
at
least one methyl group, wherein the carbon nuclei within the methyl group is
hyperpolarized and
wherein the beneficial agent is adapted and configured to be in a solid state
outside of a
polarizing cryostat. The beneficial agent can be made according to any of the
teachings herein.
The disclosure further provides a method of performing NMR spectroscopy. The
method includes introducing a hyperpolarized material made in accordance with
any of the
teachings herein into a region of interest, transmitting a pulse of
electromagnetic energy into the
region of interest to excite the hyperpolarized encapsulated material, and
receiving NMR spectra
from the region of interest. The NMR spectra of an in vitro or in vivo sample
can be analyzed.
In accordance with a further aspect, another method is provided including
hyperpolarizing a
material suitable for being metabolized in a biological process in accordance
with any of the
teachings herein, introducing the hyperpolarized material into a region of
interest; and receiving
NMR data or MR images indicative of metabolism of the hyperpolarized material.
The accompanying drawings, which are incorporated in and constitute part of
this
specification, are included to illustrate and provide a further understanding
of the disclosed
methods and systems. Together with the description, the drawings serve to
explain principles of
the disclosure.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 depicts nuclear polarization decay times ("T ") vs temperature in
differing
magnetic fields for several different protonated and deuterated samples of
frozen 1-13C enriched
acetic acid.
Fig. 2 depicts a schematic view of an exemplary method and system in
accordance with the disclosed embodiments.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Reference will now be made in detail to the present preferred embodiments of
the
disclosed embodiments, examples of which are illustrated in the accompanying
drawings. The
method and corresponding steps of the disclosed embodiments will be described
in conjunction
with the detailed description of the system.
17
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
It is one object of this disclosure to provide exemplary methods whereby
nuclei in
various molecules may be hyperpolarized without the need for the addition (or
use) of toxic
catalysts such as a TA/EPA or other catalysts or any polarizing agents
(whether or not toxic). In
accordance with a preferred embodiment, nuclei in molecules are hyperpolarized
which may
then be reacted to form 13C-bearing molecules of biological interest such as
acetates and
pyruvates in solution.
In accordance with a particularly preferred embodiment, sodium acetate
including
hyperpolarized nuclei may be provided. Sodium acetate can play a particularly
vital role as a
reporter on the metabolic process. Although sodium acetate is typically not a
substrate found in
significant levels in the blood, it is readily taken up and activated to
acetyl-CoA. Acetyl-CoA is
oxidized in mitochondria by the TCA cycle to form carbon dioxide (CO2). In the
process of
acetyl-CoA oxidation, NADH is generated, which drives oxidative
phosphorylation, the
reduction of oxygen workload is tightly coupled to 02 consumption and to the
flux of acetyl-
CoA through the TCA cycle. Thus, measurement of TCA cycle flux reports the
metabolism
required for heart function.
In accordance with one exemplary embodiment, a method for making sodium
acetate solution including hyperpolarized nuclei may be produced. This may be
accomplished,
for example, by reacting acetic acid with sodium bicarbonate to produce sodium
acetate, water
and carbon dioxide gas, wherein nuclei in at least one of the precursors are
hyperpolarized. The
reaction thus naturally produces a mixture such as a solution that, when
optionally combined
with buffers, saline or other chemicals, is amenable for in vivo applications
as a tracer and/or as
a source of metabolic information. Other acids such as lactic, pyruvic and
formic acid may
additionally or alternatively be used.
Storage and Transfer of Polarized Materials:
Unlike radioactive tracers, the characteristic nuclear polarization decay
times (T 1)
of materials including hyperpolarized nuclei are a function of their ambient
environment.
Temperature, magnetic field and the physical state of the material (liquid,
solid, gas etc.) all play
a role in determining how long the induced nuclear polarization will last
before it decays away to
thermal equilibrium. Under appropriate conditions T 1 can be made to be quite
long. Longer
decay times open up the possibility of transporting HP materials (i.e.,
materials including
hyperpolarized nuclei) over large distances. Thus, HP materials can then be
supplied as a
18
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
consumable, removing the need for the user to site a polarizer on its premises
and reducing the
cost burden.
In addition to temperature and field, the physical state and the chemical
composition of the material influences its nuclear polarization decay time.
Applicant has
measured the T, of acetic acid and sodium acetate over a wide range of
temperatures and fields.
Applicant has discovered that the T I of hyperpolarized nuclei in sodium
acetate is quite short
over a wide range of temperature (e.g., from 4 K to 300 K). This is too short
for hyperpolarized
sodium acetate to be transported over any reasonable distance in any kind of
reasonable magnetic
field without severe loss of polarization. However, the Ti of acetic acid
(deuterated) can be very
long at T < 15 K and in a moderate magnetic field (typically B - 0.1 T). This
discovery permits
transporting HP acetic acid (i.e., acetic acid including hyperpolarized
nuclei) over large distances
and supplying it as a consumable item. Because it is sodium acetate, not
acetic acid, which is
required for use as an in vivo agent, the acetic acid is converted to sodium
acetate just before use.
The DNP method described above does not lend itself well to long term
transport
or storage of a hyperpolarized material. One reason for this is that the
TA/EPA present in the
frozen HP material shortens the T 1 in the solid state. The TA/EPA cannot be
removed without
melting the material into its liquid state. However, the T i of 13C in
materials in the liquid state
are typically on the order of 10 - 60 seconds. For this reason, long term
storage and/or transport
of materials hyperpolarized using DNP is not feasible. As a result, DNP
polarizers are typically
sited very close to the NMR/MRI system that is used to analyze the HP
materials they produce.
Placing the polarizer near the NMR/MRI system is problematic for a number of
reasons. First, the high cost of these machines imposes a very high cost
burden on the end user,
both in terms of capital equipment costs and overhead. In addition, the
limited payload
scalability of a DNP machine means only a small number of scans can be
performed per unit
time. This in turn limits the diagnostic information that can be obtained
using an HP material
polarized using DNP techniques. Transport of the final product in its liquid
form from the DNP
polarizer to the patient also consumes time that is then not available for
observation of the
desired metabolic process.
It is accordingly another object of this disclosure to describe methods and
systems
for storing and/or transporting HP materials. In accordance with a preferred
embodiment,
methods and systems are provided for storing and/or transporting materials
that may be used as
19
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
precursors in a chemical reaction to manufacture a material (e.g., solution)
of biological interest
including hyperpolarized nuclei. The present disclosure permits transportation
over significant
distances such that the HP materials may be supplied as a consumable material
manufactured at a
first location and transported to the end user.
Extraction of HP materials from a Cryostat
Many molecules of biological interest contain a methyl group. Such molecules
include sodium acetate, sodium pyruvate, and others. The presence of the
methyl group has a
profound effect in the handling of HP materials. As can be seen in Fig. 1, the
Ti of acetic acid
has a minimum well below its melting point. The position of the minimum is
somewhat field
dependent. The minimum in T, is a consequence of the rotation of the three iH
nuclei attached
to the methyl carbon. These hydrogen nuclei continue to rotate even at low
temperatures causing
nearby nuclei to relax under field/temperature conditions which would
otherwise have very long
Tis.
Because of the minimum, low temperature hyperpolarization methods to date
have relied on very rapid warming schemes to preserve the polarization of
various materials
during extraction from the polarizing environment. Typically, this involves
exposing the
material to superheated water or methanol in the presence of a magnetic field
to get the sample to
temperatures well above the minimum in a time << Ti.
This approach requires that the amount of material be kept small, so that it
may be
warmed rapidly. It also means that the polarizer must be very close to the
NMR/MRI system
that is used for analysis. This is extremely disadvantageous for many user
sites where space is at
a premium. In addition, when DNP is used to hyperpolarize materials, the DNP
device must be
kept a certain minimum distance away from the target device (NMR/MRI system).
As noted above, many metabolic substrates contain methyl groups which impose
a minimum in T, at temperatures between the polarizing temperature and the
melting
temperature. Applicant has discovered that at temperatures much warmer than
the minimum, but
still much less than the melting or sublimation temperature of the material,
T, is again long
enough that short term storage/transport is feasible. This enables the
possibility of placing the
polarizer (and/or a transport cryostat containing polarized material) well
outside the vicinity of
the MR magnet. Properly utilizing this discovery requires that the polarized
material's
temperature be changed from well below the minimum to well above it in a time
much less than
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
the relaxation time Ti at any point during this process, without melting or
sublimating the
material. Once the material is melted its Ti becomes quite short and it must
be used
immediately.
Applicant has discovered that, by configuring the material to be
hyperpolarized
into a form that has a high surface area to volume ratio, such as a powder or
sinter, the thermal
relaxation time of the material can be made very short. This allows its
temperature to be
adjusted very quickly. This has the significant advantage of allowing
materials to be warmed
from the very low temperatures (as an example, T < 10 K) required for long
term
storage/transport to the more moderate temperatures suitable for short term
transport (as an
example T - 200 K) without melting and/or undue loss of polarization that may
occur as the
result of a short Ti somewhere in the temperature profile of the material in
question. In
accordance with certain preferred embodiments, the temperature of the
hyperpolarized material
may be increased in the presence of a magnetic field at a rate wherein less
than about 90, 80, 70,
60, 50, 40, 30, 20, 10 or 5 percent of polarization imparted to nuclei in the
first material is lost.
The advantage of preparing polarized materials in this manner is that they may
then be transported over short distances (for example, from one part of the
user site to another)
using readily available cryogenic materials (e.g., liquid nitrogen or dry ice)
and in relatively low
magnetic fields. Another advantage is that the melting time of the material is
reduced as the
temperature differential between its starting point and melting temperature is
decreased.
Configuring materials that are solids at room temperature into high surface
area
powders is relatively straightforward. For example, well known techniques such
as ball milling
can be used to reduce the particle size of the solid material to less than a
micron if desired.
When the material to be powderized is a liquid at room temperature a different
approach must be
used. Ball milling is not useful for many frozen liquids as the heat of
milling melts the particles.
Applicant has developed methods to produce high surface area frozen powders of
various
materials that are liquid under normal standard temperature and pressures and
that, either
intrinsically or as the result of a chemical reaction, make suitable metabolic
substrates for HP
MR study purposes. Suitable methods are described, for example, in Applicant's
U.S. Patent
Application Serial No. 12/193,536, filed August 18, 2008. The aforementioned
patent
application also discloses various other mixtures that may be achieved in
accordance with the
present disclosure (e.g., colloids, suspensions, and the like).
21
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
Quantum Relaxation Switch "QRS" Process
Heretofore the use of a "brute force" environment to produce high levels of
nuclear polarization in materials other than gases has been problematic
because the relaxation
time of most nuclei under such conditions is very long. Applicant has
discovered that, by
configuring the material to be polarized as a high surface powder and exposing
the surfaces of
the powder to 3He, the magnetic relaxation time can be made much shorter and
amenable to
industrial levels of production. Applicant has further discovered that removal
of the 3He from
the surface of the material can be accomplished by exposing the material to
4He. This greatly
increases the Ti of the material thus allowing it to be warmed to room
temperature without undue
loss of polarization. Once the material has been returned to room temperature,
nuclei in the
material become "hyperpolarized." As alluded to above, that is to say that the
nuclear
polarization of some nuclei in the material is well above what it would
otherwise be in thermal
equilibrium. The material including the "hyperpolarized" nuclei can now be
used for a variety of
NMR/MRI protocols. Most notably, the material can in and of itself be used as
an in vivo MR
material or it can be reacted as a precursor with another material to form a
third material which is
itself useful as an NMR/MRI material.
U.S. Patent No. 6,651,459 (which is incorporated by reference herein in its
entirety) describes a technique of producing hyperpolarized gases (i.e.,
materials that are gaseous
at standard conditions). This can be done by way of the following exemplary
steps:
1) Configuring the gas as a high surface area powder or sinter. As an
illustrative non-limiting example, this can be done by freezing the material
out on the surface of
an aerogel or, more advantageously, as a high surface area "snow".
2) Cooling the gas to "brute force" (very low temperature, very high
magnetic field) conditions where the equilibrium nuclear polarization is very
high.
3) Exposing the frozen gas to overlayers of 3He. In addition to providing a
path for thermal relaxation, the layers of 3He act to efficiently magnetically
relax those nuclei in
the topmost layers of the frozen gas to thermal equilibrium which, in "brute
force" conditions, is
highly polarized. In this sense the unique properties of 3He are employed as a
relaxation agent to
hasten the nuclei's relaxation to a state of high polarization.
22
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
4) Exposing the frozen gas to overlayers of 4He. The layers of 4He act to
efficiently remove the 3He from the surfaces of the frozen gas. This
effectively isolates the
nuclei and allows them to be warmed back to room temperature without undue
loss of
polarization.
The above process is known as a "Quantum Relaxation Switch" (QRS) since it
describes a technique whereby efficient relaxation of nuclei in a brute force
environment can be
switched "on" and "off' so as to produce highly polarized nuclei that can be
warmed to room
temperature to produce HP precursor materials or HP materials for a variety of
NMR/MRI
applications. It is important to note that the process does not require the
addition of any catalysts
and that the brute force environment can be made highly sterile.
Applicant has discovered that the QRS process may be extended to operate on a
wide range of materials, rather than only materials that are gases at standard
conditions. This
requires that the material to be hyperpolarized be configured in a high
surface area. Applicant
has further discovered that a wide range of liquids may be frozen and
powderized so that their
surface area to volume ratio is very high. In particular, liquids such as
acetic acid that upon
chemical reaction make solutions of metabolic substrates suitable for
injection and in vivo
NMR/MRI protocols are preferred.
The various discoveries described above constitute methods and systems that
fully
enable the configuration of various materials as high surface area frozen
powders, polarizing the
material without exposing the materials to catalysts, extracting the polarized
materials from the
low temperature environment so that they become hyperpolarized (HP), and
transporting the
hyperpolarized materials to an end user site. It will be recognized that the
recitation of
"hyperpolarized material" herein is intended to refer to material including
hyperpolarized nuclei.
If desired, the hyperpolarized materials may be reacted with other materials
to form a third HP
material that is of use for MRUNMR applications (e.g., in vivo MRI
applications). In
accordance with a preferred embodiment, materials are used that contain
molecules of interest
for biological MRI applications. The following Example is based partially on
experience and
partially on insight.
Example 1:
Deuterated acetic acid is frozen into high surface area pellets by introducing
them
into LN2 in a finely divided form of droplets. The surface area of the pellets
is measured by
23
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
BET to be - 5 m2/g. The pellets are placed in the sample chamber of a dilution
refrigerator and
cooled to T < 100 mK in the presence of a 10 T magnetic field. 3He is added to
the sample
chamber to hasten magnetic relaxation. Once the sample is polarized (a process
which can be
monitored using NMR), 4He is added to the sample chamber to remove the 3He
from the surface
of the sample. The sample is warmed to T - 5 K and the helium gases are
removed. The pellets
are removed from the chamber of the polarizing cryostat while being kept in a
temperature T <
K and in a magnetic field > 0.1 Tesla. The pellets are transferred to a
transport cryostat where
similar field/temperature conditions are maintained. After transport, the
temperature of the
pellets is quickly raised from T < 10 K to T - 77 K, for example, by immersing
them in liquid
nitrogen. The pellets can then be removed from the transport cryostat and
brought into the
vicinity of the MR system using a small magnetic field and a suitable
cryogenic material to
maintain the polarization. The pellets may be rapidly melted by dropping them
into heated
sodium hydroxide solution in the presence of a magnetic field to create a
hyperpolarized mixture,
such as in the form of a hyperpolarized sodium acetate solution (i.e., a
sodium acetate solution
including hyperpolarized nuclei).
If desired, the stray field of the MR system can be used to maintain a
magnetic
field over the hyperpolarized precursor when the precursor is used to make a
hyperpolarized
mixture. For example, the hyperpolarized precursor (such as an acid or a base
including
hyperpolarized nuclei) may be transferred from the polarizing cryostat if
nearby (or transport
cryostat) into a transfer vessel as depicted in Fig. 2. The temperature of the
hyperpolarized
precursor may then be elevated from a first temperature below the temperature
at which the Ti of
the first material experiences a minimum to a second temperature above the
temperature at which
the Ti of the first material experiences a minimum. Preferably, the
temperature of the
hyperpolarized precursor is elevated from a first temperature substantially
below the temperature
at which the Ti of the first material experiences a minimum to a second
temperature substantially
above the temperature at which the Ti of the first material experiences a
minimum (e.g., from
below about 10K to about 200K). This may be achieved, for example, by
immersing the
precursor in a liquid cryogen, such as liquid argon, nitrogen, xenon or
krypton, that has a boiling
point well above the temperature at which the Ti for 13C is at a minimum.
Alternatively, the
precursor can be heated by passing a gas warmed to about 200K over its
surfaces.
24
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
As illustrated in Fig. 2, material formatted into a high surface area form is
polarized in a cryostat 1. Preferably, the material is polarized at a
temperature between about
lmK and 100mk, more preferably between about 10mK and about 40mK. The
temperature of
the material is then increased, resulting in hyperpolarization (i.e., a state
in which the
polarization is above that at which it would ordinarily be at thermal
equilibrium). The material is
then extracted and stored in a transport cryostat 2 that maintains a
temperature and magnetic
field environment such that decay of the nuclear polarization of the material
is slow. This
hyperpolarized material may then be transported via the transport cryostat 2
to storage or a
terminal location, such as a hospital. The hyperpolarized material is then
extracted from the
transport cryostat 2 into an interim cryostat or transfer vessel 3 that
maintains the hyperpolarized
material at a higher temperature and lower magnetic field suitable for short
term transport.
Before, during or after the transfer of the hyperpolarized material to
transfer vessel 3, its
temperature is preferably raised as quickly as possible across the temperature
at which the Ti for
the material is at a minimum.
For example, the temperature increase is preferably performed in a time period
less than 30, 20, 10, or most preferably, 5 seconds long. Preferably, the
applied field of the
transfer vessel 3 is not in excess of 500 Gauss such that it may be brought
safely into proximity
of the NMR/MRI system. The hyperpolarized material is then ejected from the
transfer vessel 3
into a mixing device 4 where it is converted into a mixture, such as a
solution, preferably suitable
for in vivo injection. The hyperpolarized solution is injected via a sterile
line 5 into a patient 6.
An NMR/MRI system 7 is then used to carry out a variety of NMR/MRI protocols.
The transfer vessel 3 includes a compartment 8 for receiving the
hyperpolarized
precursor material, and includes a magnet 9 such as an electromagnet or
permanent magnet for
maintaining a magnetic field over the material during the transfer process.
Preferably, the
mixing device 4 and transfer vessel 3 are disposed within the stray magnetic
field 10 of the MR
system 7. It will be noted that the depicted field lines are merely intended
to be illustrative.
Advantageously, this permits the hyperpolarized material to be melted in close
proximity to the
MR system, thus saving time delivering the resultant solution to the subject
during which the
polarization of will decay. As further illustrated in Fig. 2, the polarizing
cryostat 1 includes a
magnet 11 for applying a field thereto, a vessel for containing the material
to be hyperpolarized,
and a heat source for raising the temperature of the material to facilitate
hyperpolarization. Also
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
illustrated is the fact that the polarizing cryostat 1 is in operable
communication with a source 14
of 3He and a source 15 of 4He. A second heat source 16, that is, a source of
material that can be
used to heat the hyperpolarized material from a temperature below the
temperature at which the
hyperpolarized material experiences a minimum Ti to a higher temperature is
also illustrated.
Fig. 2 also illustrates that system 7 includes a transmit RF coil 17, a
detector 18 (such as a
receive coil array and supporting hardware), as well as a computer
terminal/processor 19 for
receiving and processing received data.
In a preferred embodiment, magnet 9 is an electromagnet. This permits the
magnetic field of the transfer vessel 3 to be selectively deactivated to
prevent the field of the
transfer vessel 3 from interfering with MR system operation. Alternatively,
the field can be
well-shielded to minimize interference. If desired, the hyperpolarized
precursor for making the
hyperpolarized mixture may be made on site in relatively close proximity to
the MR system.
Alternative To Relaxation Agents
An alternative to an external relaxation or polarization agent such as those
described above is to directly polarize a material containing nuclei that have
intrinsically rapid
relaxation rates in high B/T conditions. Such nuclei are unusual because under
these conditions,
as noted above, Ti is typically very long at very low temperatures and can be
on the order of
weeks to months for temperatures below 100 mK. However, by identifying one or
more classes
of rapidly relaxing nuclei, it becomes possible to produce high polarizations
at high B/T
conditions in reasonably short periods of time without the need for an
adulterating catalyst or
external agent of any kind.
Rapid proton nuclear relaxation rates in molecules containing methyl rotor
groups
such as potassium acetate have been observed down to 10 K. It is believed that
the unusually
fast relaxation rate in the hydrogen nuclei is a consequence of quantum
tunneling between
rotational states in the CH3 group and has been observed in many molecules
containing CH3
groups. The tunneling arises because the methyl protons are relatively free to
rotate about their
symmetry axes. Hindering potentials to rotation arise due to inter and intra
molecular
interactions between the methyl protons and their environment. Thus, a methyl
rotor can be well
described as a 3 dimensional quantized harmonic oscillator with a hindering
potential that
depends on the details of the molecular environment and the crystal structure
in the solid state.
26
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
When the hindering potential(s) separating the methyl protons are very high
the
proton rotor is localized in a fixed location. There are three degenerate
positions for the rotor.
When the hindering potential(s) are lower, quantum tunneling between these
positions becomes
possible. This splits the degeneracy so that there is a single ground state
(typically labeled A)
and two excited states (typically labeled Ea and Eb), which correspond to
clockwise or
counterclockwise rotation. At sufficiently low temperatures (typically, T < 10
K), where the
methyl rotors are in their ground state, quantum tunneling between the A and E
states goes on at
a fixed frequency labeled 00T.
Quantum tunneling in solid 3He layers has been observed to be a temperature
independent effect that persists down to arbitrarily low temperatures and
leads to relatively rapid
relaxation rates in solid 3He; the presence of quantum tunneling in 3He is the
basis for the
method described in 6,651,459. Similarly, quantum tunneling between rotational
states in CH3
groups reduces the relaxation rate of the methyl protons, which would
otherwise be expected to
become extremely long as T - 0. In the limit of low temperatures the Ti
relaxation time of the
methyl protons is governed by the following equation:
i CE9 2 2
i + .
where ti,=correlation time and CEE=constant. This equation shows that in the
low temperature
limit Ti is a constant since 00T does not depend on the ambient magnetic field
or temperature.
Thus, at sufficiently low temperatures and for magnetic fields where BOT > ,
(w,= Larmor frequency = 42.6 MHz/Tesla for protons) the Ti of the protons in a
methyl rotor is
both temperature and field independent. This is very different from Ti for
molecules that do not
exhibit quantum tunneling where Ti is expected to increase exponentially with
decreasing
temperature in this range. A surprising consequence of this is that saturation
polarization of
protons in CH3 groups can be rapidly produced even under very high B/T
conditions. This
occurs as a result of the temperature independent quantum tunneling of protons
in the CH3 group
and without the addition of a polarizing agent such as a trityl radical or an
externally added
relaxation agent.
27
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
Many molecules of interest for in vivo MR contain a methyl group. These
include acetate and pyruvate, for example, among others. In other molecules a
methyl group
may be incorporated through chemical processes well understood in the art so
that at least one or
more methyl groups can be attached to the molecule.
One aspect of the present disclosure relates to a method of rapidly producing
saturated polarization of one set of nuclei in a molecule, such as the protons
in a CH3 group.
Polarizing nuclei directly on the molecule of interest has many advantages
over the use of an
external relaxation agent or polarizing agent. First, as noted above, many
relaxation agents and
polarizing agents are toxic. Material handling becomes much easier as there is
no concern about
proper dispersion of an external agent. Nor is there a need to configure the
material in a high
surface area format as there is to use 3He as an effective relaxation agent.
The methyl protons themselves are of little interest for in vivo MR, because
their
relaxation rate in solution at room temperature is generally too fast. What is
of greater interest
are the nearby methyl and carbonyl carbons. These tend to have longer Tis (the
carbonyl in
particular). Moreover, the chemical shift of carbons is much wider than for
protons, making
them easier to resolve in a spectroscopy study. For this reason, a further
aspect of the present
disclosure relates to methods for efficiently transferring polarization
between nuclei in a
molecule; in particular, from methyl protons to nearby methyl and/or carbonyl
carbons so that
they be utilized in an MR study.
Several methods exist in the art to transfer polarization between nuclei in a
molecule. For example, pulse sequences can be used to transfer polarization
between nuclei.
However, these are not suitable for scalable production of hyperpolarized
materials as they
require highly homogenous magnets and an NMR resonator that can typically only
handle a
small amount of material at a time. An easier and more scalable method is to
expose the material
to a low field. Polarization may be transferred between nuclei in a molecule
by exposing it to a
low magnetic field. This is known as low field thermal mixing ("LFTM"). In
this process, the
molecule is exposed to a magnetic field sufficiently low such that the local
dipolar field of a
given nuclei upon another nearby nuclei exceeds that of the ambient field.
Under these
circumstances the "spin temperature" of the two nuclei will equilibrate at a
rate equal to:
28
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
( _.v2)
Where B is the ambient magnetic field, BL is the local dipolar field of nuclei
1 on nuclei 2, and
Y1,2 is the gyromagnetic ratio of nuclei 1,2 respectively. BL is typically on
the order of 1 - 5 G
for neighboring nuclei in a molecule so B must be on this order as well for
rapid transfer of
polarization. It is readily seen that for B < BL , i - T2. T2 in the solid
state is typically on the
order of tens of microseconds so polarization exchange takes place very
quickly for B < BL.
LFTM has been used to produce polarized materials in the solid state. For
example, in U.S. Patent No. 6,466,814, a sample of solid 2-13C-2,2-
bis(trideuteromethyl)-1,1,3,3-
tetradeuteropropane-1,3-diol was polarized to 13C thermodynamic equilibrium at
6.65 T and 2.5
K by repeatedly pulling it in and out of the polarizing magnet and into the
stray field of - 70 G
for - 1 second. These examples and others demonstrate that it is possible to
transfer polarization
from protons to heteronuclei such as 13C using low field thermal mixing.
However exposure of materials to low fields can also lead to rapid
depolarization
because Ti in the solid state is typically a strong function of the ambient
field. For example, in
U.S. Patent No. 6,466,814, solid 2- 13 C-2,2-bis(trideuteromethyl)-1,1,3,3-
tetradeuteropropane-
1,3-diol was polarized using LFTM, extracted by pulling it out of the
polarizing cryostat at the
end of a sample stick and finally dissolved to form a solution. The resultant
enhancement factor
vis-a-vis 13C was measured in solution to be - 12. The total potential gain,
or enhancement
factor, was - > 100 so more than 90% of the polarization induced at high B/T
was lost during
extraction.
Conventionally, the "enhancement factor" is considered to be the ratio of the
hyperpolarized NMR signal intensity (itself defined as the integral of the
Fourier Transform line)
divided by the NMR signal intensity of the molecule at thermal equilibrium. To
measure this
quantity in practice, it is typical to collect a series of Free Induction
Delay ("FID") signals with
an rf tuning set during a series of NMR pulses immediately after the
hyperpolarized sample is
inside the NMR magnet. This test is then repeated after the sample reaches
thermal equilibrium,
which for all practical purposes is on the order of - 5 Ti, or about 4 - 5
minutes for acetic acid,
29
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
for example. The ratio of the two FID signals is the enhancement factor. It
will be understood
that the enhancement factor will naturally be affected by how quickly the
sample can be
measured initially. An enhancement factor of 12, such as described above,
means that the signal
intensity from the hyperpolarized solution was 12 times what it would have
been for the same
solution in the same spectrometer had the sample not been enhanced.
For the reasons discussed above, most hyperpolarization schemes have relied on
dissolving the polarized material directly in the polarizing cryostat so that
the material is never
exposed to a low field. Once in the liquid state, external agents can be
quickly removed and also
Ti of the HP material is less sensitive to external relaxants and/or field
changes. U.S. Patent No.
7,102,354 describes a method of doing this where the material is dissolved by
injection of hot
water.
However, as noted above, a negative consequence of this is that hyperpolarized
materials cannot be stored for long periods of time or transported over
significant distances; with
the exception of noble gasses this can only be realized if the material can be
kept in the solid
state. Thus there is a need in the art for a method of extracting polarized
materials in the solid
state from a polarizing cryostat without undue loss of polarization. The
present disclosure
describes how to accomplish this objective below.
In accordance with one embodiment, for in vivo MR applications, the
hyperpolarized material is rendered in a form in which it can be introduced in
vivo. Depending
on the application and material this can take the form of a solution,
suspension, colloid or other
type of mixture. A suspension could furthermore include solid pellets
suspended in a
physiologically tolerable liquid or an encapsulation of a solid or liquid
hyperpolarized material.
U.S. Patent No. 6,466,814 and U.S. Patent No. 6,278,893 describe the
manufacture of HP solutions by dissolving a hyperpolarized solid in a
physiologically tolerable
liquid. But they do not teach the use of a liquid and/or a predissolved
solution. For many
applications it would be superior if the hyperpolarized material were a liquid
at STP or a
predissolved solution. One reason for this is that liquids can be directly
pelletized, for example
by droppering them into a cryogenic liquid such as liquid nitrogen.
Pelletizing a solid, in
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
particular a solid that is a powder, may require that it be mixed with binders
or other additives
that will reduce the overall payload of hyperpolarizable material in the
pellet. Furthermore,
liquids melt and mix more rapidly thus better preserving polarization during
the stage of forming
the solution. U.S. Patent No. 6,6466,814 and U.S. Patent No. 6,278,893 do not
teach how to
form a suspension, colloid or other type of mixture nor do they describe how
to polarize
encapsulated material. A further aspect of this disclosure teaches methods for
producing these
types of mixtures employing hyperpolarized materials.
The present disclosure thus describes a process for manufacturing
hyperpolarized
solutions in a novel manner; furthermore it teaches the manufacture of
hyperpolarized
suspensions and/or other mixtures. The disclosed methods do not require the
use of adulterating
catalysts, which removes the presence of potentially toxic materials and
furthermore permits the
material to be extracted from the polarizer in the solid state. If desired,
the hyperpolarized
material may be stored/transported that it may be used at a site remote from
the polarizing
cryostat, by dissolving or dispersing said material in an appropriate liquid,
or combination of
liquids, or solutions.
Accordingly, Applicant has developed methods of polarizing materials that do
not
incorporate a catalyst such as a trityl radical. The method permits materials
to be extracted from
a polarizing environment while still in the solid state so that they can be
stored/transported
without excessive polarization loss. The methods further permit the
hyperpolarized materials to
be rendered in the form of a solution, suspension, encapsulation and the like
so that they may be
made use of in an in vivo MR study.
When a spin ensemble consisting of spin 1/2 nuclei (such as 13C, 129Xe, 15N,
1H,
etc.) is placed in an external magnetic field, the interaction of the
quantized magnetic moment of
the nuclei (m = 1/2) with the field gives rise to two possible energy states
for the system.
Typically, these states are labeled "up" (m = 1/2) and "down" (m = -1/2),
referring to whether the
magnetic moment of the nuclei is parallel or anti parallel to the ambient
magnetic field.
In a non zero magnetic field, the "up" state is a lower energy arrangement
than the
"down" state. For this reason, in thermodynamic equilibrium, the population of
spins in the "up"
31
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
state will exceed that of the "down" state. The ratio of nuclear spins in the
"up" state to those in
the "down" state is known as the "Zeeman polarization" or "Boltzmann
polarization" of the
system; it can be calculated for any temperature T by means of the equation P
= tanh VB/kT
where = the gyromagnetic ratio of the spin and k = Boltzmann's constant.
"Hyperpolarization", as described herein, refers to the production of nuclear
polarization in
excess of thermodynamic equilibrium.
An ensemble of spins that is "hyperpolarized" will seek to relax back to
thermodynamic equilibrium. Typically, relaxation is exponential with respect
to time, the time
constant at which this occurs is known in the art as "T1". In NMR terminology,
Ti is the time
constant for the recovery of the z component (i.e., M, which is parallel to
the ambient magnetic
field) of nuclear magnetization and describes interactions between the spin
ensemble and the
lattice. Note that Ti is a function not only of the type of nuclei that is
hyperpolarized but also be
temperature, field, molecular structure, or a combination of all of the above.
Another characteristic time constant of NMR experiments is T2. This is
formally
known as the time constant for the recovery of the MR,y components of the
nuclear magnetization
(i.e., perpendicular to the ambient magnetic field) of nuclear magnetization.
Less formally, it is
the time constant that describes spin-spin interactions and is usually
associated with the line
width of the NMR signal in Fourier space. Like Ti, T2 can also be a function
of temperature,
field, molecular structure etc. Notably, in a solid, T2 is always less than Ti
whereas in a liquid
T2 - T1. In a low field thermal mixing experiment, the time for polarization
to transfer between
nuclei is typically - T2. The time for polarization to decay to the lattice
entirely is - T1. It is
therefore important that the time of exposure of a hyperpolarized material to
a low magnetic field
(to permit thermal mixing of protons in a methyl group with other nuclei (e.g.
carbon nuclei of
the methyl group)) be T2 > t > T1.
In accordance with a first exemplary embodiment, a method is provided that
first
includes the step of configuring a material. The material preferably contains
a molecule
containing at least one CH3 methyl group and a nuclei with a non zero spin,.
Preferably the
nuclei are of a high Ti material at STP. The method then optionally specifies
pelletizing the
32
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
sample so that it can be rapidly introduced into and extracted from the high
B/T environment
inside the polarizing cryostat.
Applicant has described in previous applications (e.g., PCT/US2009/39696,
filed
April 6, 2009) how a liquid may be frozen and pelletized, for example by
droppering it into LN2.
This has been used to create frozen pellets of glacial acetic acid, for
example. A similar process
can be used on solutions, emulsions, suspensions etc. Gases may also be
pelletized; as a non
exclusive example this can be done by freezing them onto the surface of a
powder.
Pelletizing molecules that are liquids at room temperature for use in MRI
studies
have been described in the art. For example U.S. Patent No. 5,617,859
describes the use of
pelletized liquids that can be polarized by subjecting them to a high magnetic
field. However,
that teaching does not disclose the use of methyl rotors or quantum tunneling
based phenomena
to rapidly relax one set of nuclei in a very high B/T environment. Nor does it
describe the use of
low fields to transfer polarization from one nuclei in the molecule to
another. Finally it does not
teach controlling the temperature/field of the pellet so as to avoid undue
relaxation loss during
extraction of the pellet from the polarizing environment. These steps, as
disclosed herein, are
used to manufacture polarized molecules, in particular molecules containing a
CH3 methyl
group, and incorporating them with a fluid at room temperature so as to form a
solution,
suspension or other type of mixture.
In accordance with a further aspect, the exemplary method further provides
exposing the pellet to a high B/T environment, such as can be produced using a
high field
superconducting magnet and a low temperature cryostat, for sufficient amounts
of time to
produce high levels of polarization in at least one nuclear species in the
material (in particular,
the methyl protons in a CH3 group). The method also provides directing the
pellet from the high
field region of the magnet such that it is exposed for a brief time to a low
magnetic field such as
that provided by the Earth's ambient field (- 0.5 G) or a shielded container
such as mu-metal.
The method of expulsion is preferably carried out using helium gas as a
propellant and the speed
of the pellet is preferably that such that the time of exposure to the low
field, t, is T2 < t < T1.
33
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
Applicant has discovered that, at certain temperatures, the relaxation time of
a
molecule containing a methyl group may be very rapid. These temperatures,
known as Tmin, can
provide a path for depolarization, if the molecule is allowed to linger at
such ambient conditions
for too long, and this can become more acute in low fields. The exemplary
method thus further
provides optionally controlling the temperature of the pellet such that during
exposure to the low
field environment it is well away from a temperature where its nuclear
relaxation time is very
fast. For example, the pellet can be warmed to be well above Tmin and then
directed from the
high B/T environment.
In a further aspect, the method also can provide that, after expulsion from
the high
field magnet, the material remains in the solid state. Once outside the
polarizing cryostat the
pellet can be maintained at a temperature where the Ti of the heteronuclei of
interest is of a
desired length of time. For example, this can be done by storing the pellet at
4 K and in a
magnetic field > 0.1 Tesla such as that provided by a permanent magnet. The
hyperpolarized
material may then be employed immediately or at some future/location to form a
solution,
suspension, colloid, or other mixture, which can then be used to generate an
image, dynamic
flow data, diffusion data, perfusion data, physiological data or metabolic
data. The following
further Examples are similarly based partially on experience and partially on
insight.
Example 2
Liquid 1-13C labeled acetic acid is frozen into pellets by droppering it into
liquid
nitrogen ("LN2"). The pellets are collected and introduced into a high B/T
environment (such as
a cryogenic environment at about 150 mK in a background field of 8-10 Tesla).
They are kept in
the high B/T environment until the protons in the methyl ("CH3") group in the
acetic acid have
fully relaxed, this can be observed using NMR or by measuring in advance the
proton Tl under
such conditions. The pellets are then directed/expelled from the high B/T
environment using
high pressure helium gas through a conduit. It will be appreciated that the
practice of
accelerating light frozen pellets is generally well-known, for example, in the
field of introducing
frozen hydrogen pellets into fusion tokamaks at speeds on the order of 1000
m/second. As they
are expelled, the pellets pass out of the polarizing field and into a region
of very low field so that
polarization flows from the protons to nearby 13C labeled carbonyls. The
pellets are collected in
34
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
a volume outside the high B/T environment where the ambient temperature/field
environment of
the pellets can be independently controlled. As a non exclusive example, the
volume can be
maintained at - 200 K through the use of dry ice. A small permanent magnet can
be used to
maintain a field on the pellets. Under such conditions the Ti of the 13C in
the acetic acid is on
the order of several minutes; long enough to transport the polarized acetic
acid a short distance.
The pellets can then be melted in the volume and reacted with a warmed
buffered solution to
produce highly polarized sodium acetate solution.
Example 3
Liquid 1-13C acetic acid pellets are manufactured and cooled to high B/T
conditions as described in embodiment 1. When the protons in the CH3 group
have been
polarized, the pellets are warmed while still in the polarizing field to a
temperature above Tmin
but still well below their melting temperatures (Tmelt for acetic acid - 17
C). Then they are
directed/expelled from the polarizing cryostat so that they can be collected
for storage/transport
or melted for immediate use.
Example 4
Powderized anhydrous 1-13C labeled sodium acetate is mixed with a suitable
solvent for in vivo MR applications such as buffered water or saline. The
solution is then frozen
into pellets, for example by droppering it into LN2. The pellets are then
exposed to a high B/T
environment. They are kept in the high B/T environment until the protons in
the CH3 group in
the sodium acetate have fully relaxed. The pellets are then directed/expelled
from the high B/T
environment using high pressure helium gas. The pellets can then be melted,
for example by
mixing them with heated water or saline solution, to produce highly polarized
sodium acetate
solution.
Example 5
Powderized anhydrous 1-13C labeled sodium acetate is mixed with a suitable
solvent for in vivo MR applications such as buffered water or saline. The
solution is then
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
encapsulated in a thin polymer shell to form individual beads sufficiently
small for in vivo
applications. The pellets can optionally be functionalized so as to produce a
desired in vivo
function; for example, to bind to a desired in vivo structure such as a
fibroid or tumor. The
optionally functionalized capsules are kept in the high B/T environment until
the protons in the
CH3 group in the sodium acetate have fully relaxed. The pellets are then
directed/expelled from
the high B/T environment using high pressure helium gas and mixed with a
physiologically
tolerable solution to form a hyperpolarized suspension.
The disclosure further provides one method of performing NMR spectroscopy.
The method includes introducing a hyperpolarized material made in accordance
with any of the
teachings herein into a region of interest, transmitting a pulse of
electromagnetic energy into the
region of interest to excite the hyperpolarized encapsulated material, and
receiving NMR spectra
from the region of interest. Accordingly, the materials provided herein can be
used to analyze
the NMR spectra of an in vitro or in vivo sample. Moreover, in accordance with
a further
aspect, it is possible to hyperpolarize a material suitable for being
metabolized in a biological
process in accordance with any of the teachings herein, introducing the
hyperpolarized material
into a region of interest; and receiving NMR data or MR images indicative of
metabolism of the
hyperpolarized material. Such techniques can be useful for diagnosing the
existence of particular
types of tissues, as set forth in U.S. Patent Application Serial No.
12/193,536, filed August 18,
2008, which is incorporated by reference herein in its entirety.
It will also be appreciated by those of skill in the art that the protons in
methyl
groups as described herein can be polarized in accordance with a variety of
techniques, such as
(i) by way of a quantum relaxation switch, (ii) dynamic nuclear polarization,
(iii) the Nuclear
Overhauser effect, (iv) parahydrogen induced polarization, (v)exposing the
nuclei of the first
material to hyperpolarized nuclei of a previously hyperpolarized gas, (vi)
exposing the first
material to a brute force environment and combinations thereof.
Dynamic nuclear polarization ("DNP") generally involves transfer of
polarization
from electron spins to nearby nuclear spins; typically, although not
exclusively, via saturation of
the electron resonance line using microwave irradiation. An example of DNP in
the patent
literature includes U.S. Patent No. 6,008,644 which is incorporated by
reference herein in its
entirety. In the context of certain of the embodiments of the present
disclosure, DNP can be
used, for example, to hyperpolarize the protons in the methyl group of a
material
36
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
The Nuclear Overhauser effect generally involves transfer of nuclear
polarization
from one set of nuclear to spins to another set of nearby nuclear spins;
typically, though not
exclusively, by saturation of the first set of spins nuclear resonance line.
Examples of the
Nuclear Overhauser effect in the literature are described in Schlichter,
Principles of Magnetic
Resonance, 2nd ed. Springer Velas, Berlin, 1978, which is incorporated by
reference herein in its
entirety. In the context of certain of the embodiments of the present
invention, the Nuclear
Overhauser effect can be employed by causing the hydrogen nuclei in methyl
groups to have a
higher than usual polarization.
Parahydrogen induced polarization ("PHIP") can be used to hyperpolarize the
hydrogen atoms in methyl groups. PHIP generally involves transfer of
polarization via catalyzed
hydrogenation by p-H2, followed by spin-order transfer to the nucleus of
interest. Examples of
PHIP in the patent literature include, for example, U.S. Patent No. 6,574,495,
which is
incorporated by reference herein in its entirety.
Brute force hyperpolarization, preferably using a quantum relaxation switch,
(referred to herein as "QRS") can be used to hyperpolarize the hydrogen atoms
in methyl groups
(or other material). As a term in the art, brute force refers to exposing the
material to be
hyperpolarized to very low temperature, high magnetic field conditions.
Materials in a "brute
force" environment will tend to naturally relax to a state of high nuclear
polarization. However,
without use of additional mechanisms, the time to achieve hyperpolarization is
generally too long
to be of practical use. By using a hyperpolarization facilitator such as 3He,
a quantum relaxation
switch provided by the 3He facilitates relaxation of the material under while
in brute force
conditions to rapidly induce hyperpolarization in the material. Application of
4He is then used to
remove the 3He from the hydrogen atoms in methyl groups to enable it to be
warmed to room
temperature without undue loss of hyperpolarization. An example of QRS in the
patent literature
includes U.S. Patent No. 6,651,459 which is incorporated by reference herein
in its entirety.
The hydrogen atoms in methyl groups may also be hyperpolarized by exposing
them to hyperpolarized nuclei of a previously hyperpolarized gas. This can be
carried out in a
variety of ways, such as by immersing the first material in liquefied
hyperpolarized 129Xe, or by
allowing gaseous polarized xenon to be bubbled through the material. An
example of nuclear
hyperpolarization transfer from a gas in the patent literature can be found in
U.S. Patent No.
6,426,058 which is incorporated by reference herein in its entirety.
37
CA 02772190 2012-02-24
WO 2011/026103 PCT/US2010/047310
The "Overhauser effect", is considered to be the transfer of polarization from
an
electron to a nucleus. As further described herein, the "Nuclear Overhauser
Effect" is a similar
phenomena, except that the transfer is from one nucleus to another. In each
case polarization is
transferred from one set of spins (electron - nucleus in the case of the
"Overhauser Effect",
nuclear - nuclear in the case of the "Nuclear Overhauser Effect"). The
techniques may utilize
application of radiofrequency ("RF") pulses to the material, or not, depending
on whether the
two sets of spins (i.e., (i) electron-nucleus or (ii) nucleus-nucleus) are in
motion with respect to
one another.
The methods and systems of the present disclosure, as described above and
shown
in the drawings, provide for superior hyperpolarized materials and methods for
making the same.
All patents, patent applications and references referred to herein are
incorporated by reference
herein in their entireties. It will be apparent to those skilled in the art
that various modifications
and variations can be made in the device and method of the disclosed
embodiments without
departing from the spirit or scope of the disclosed embodiments. Thus, it is
intended that the
present disclosure include modifications and variations that are within the
scope of the subject
disclosure and equivalents.
38
