U.S. patent application number 12/193536 was filed with the patent office on 2009-01-15 for hyperpolarization methods, systems and compositions.
Invention is credited to Avrum Belzer, Neal Kalechofsky.
Application Number | 20090016964 12/193536 |
Document ID | / |
Family ID | 38723740 |
Filed Date | 2009-01-15 |
United States Patent
Application |
20090016964 |
Kind Code |
A1 |
Kalechofsky; Neal ; et
al. |
January 15, 2009 |
HYPERPOLARIZATION METHODS, SYSTEMS AND COMPOSITIONS
Abstract
The invention provides various methods and systems for providing
hyperpolarized materials as well as the hyperpolarized materials so
provided. In addition, a method of providing hyperpolarized
materials, such as agents, to end users from a remote location is
also provided.
Inventors: |
Kalechofsky; Neal; (Stow,
MA) ; Belzer; Avrum; (Brookline, MA) |
Correspondence
Address: |
EDWARDS ANGELL PALMER & DODGE LLP
P.O. BOX 55874
BOSTON
MA
02205
US
|
Family ID: |
38723740 |
Appl. No.: |
12/193536 |
Filed: |
August 18, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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PCT/US2007/004654 |
Feb 21, 2007 |
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12193536 |
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60775196 |
Feb 21, 2006 |
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60802699 |
May 23, 2006 |
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Current U.S.
Class: |
424/9.3 |
Current CPC
Class: |
A61K 49/1815 20130101;
A61K 49/1806 20130101 |
Class at
Publication: |
424/9.3 |
International
Class: |
A61K 49/06 20060101
A61K049/06; A61B 5/055 20060101 A61B005/055 |
Claims
1. A method of producing a hyperpolarized material comprising: a)
providing a solvent; b) hyperpolarizing the solvent; and c)
transferring hyperpolarization from the solvent to a target
material.
2. The method of claim 1, wherein the solvent is mixed with a
target material to create a mixture selected from the group
consisting of (i) a solution, (ii) a suspension, (iii) an emulsion,
(iv) a colloid and (v) a composite material.
3. The method of claim 2, further comprising hyperpolarizing the
target material.
4. The method of claim 3, wherein the target material is
hyperpolarized by mixing the target material with the solvent.
5. The method of claim 4, wherein the target material is dissolved
in the solvent.
6. The method of claim 3, wherein the target material is
hyperpolarized by way of electromagnetic coupling.
7. The method of claim 6, wherein the electromagnetic coupling is
provided by electromagnetic pulse sequences.
8. The method of claim 1, wherein the solvent includes a liquid
suitable for in vitro NMR analysis.
9. The method of claim 8, wherein the solvent includes a material
selected from the group consisting of water, deuterated water,
acetone- d.sub.6, ethanol- d.sub.6, acetonitrile- d.sub.3, formic
acid- d.sub.2, benzene- d.sub.6, methanol- d.sub.4, chloroform-
d.sub.1, nitromethane- d.sub.3, deuterium oxide, pyridine- d.sub.5,
dichloromethane- d.sub.2, 1,1,2,2-tetrachloroethane- d.sub.2,
dimethylformamide- d.sub.7, tetrahydrofurane- d.sub.8,
dimethylsulfoxide- d.sub.6, toluene- d.sub.8, 1,4-dioxane- d.sub.8,
trifluoroacetic acid- d.sub.1 and combinations thereof.
10. The method of claim 1, wherein the solvent includes a
physiologically tolerable liquid suitable for use in in vivo MRI
studies.
11. The method of claim 10, wherein the solvent includes a material
selected from the group consisting of water, deuterated water and
combinations thereof.
12. The method of claim 1, further comprising performing an
analysis of (i) a region proximate the target material (ii) or the
target material.
13. The method of claim 12, wherein the analysis includes forming
magnetic resonance images of a patient.
14. The method of claim 12, wherein the analysis includes analyzing
NMR spectra of an in vitro or in vivo sample.
15. The method of claim 1, further comprising solidifying the
solvent into a powder form.
16. The method of claim 15, wherein the solvent is solidified prior
to hyperpolarizing the solvent.
17. The method of claim 16, wherein the solidified solvent is
hyperpolarized using a technique selected from the group consisting
of (i) dynamic nuclear polarization, (ii) the Nuclear Overhauser
effect, (ii) parahydrogen induced polarization, (iii)
hyperpolarization using a quantum relaxation switch, (iv)
transferring hyperpolarization to molecules of the solvent by
exposing them to hyperpolarized nuclei of a previously
hyperpolarized gas, and combinations thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority from U.S.
Provisional Patent Application Ser. No. 60/775,196 filed Feb. 21,
2006 and U.S. Provisional Patent Application Ser. No. 60/802,699
filed May 23, 2006. This application is also a continuation of
International Application No. PCT/US2007/004654, filed Feb. 21,
2007. The disclosure of each of the aforementioned patent
applications is incorporated by reference herein in its
entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to hyperpolarization methods,
systems and compositions of hyperpolarizable materials suitable for
various applications. Particularly, the present invention is
directed to hyperpolarization methods, systems and compositions
that facilitate magnetic resonance imaging ("MRI") and nuclear
magnetic resonance ("NMR") analysis.
[0004] 2. Description of Related Art
[0005] A variety of techniques are known in the art for providing
hyperpolarization. Many of these techniques are directed to
providing hyperpolarized noble gases. The use of a hyperpolarized
noble gas, for example, can be advantageous in performing MRI or
NMR as it can dramatically increase the signal to noise ratio
("SNR") in MRI or NMR procedures. This permits MRI and NMR to be
used to analyze regions of interest in unprecedented ways.
[0006] To date the emphasis in the literature has been on providing
complex and expensive systems for hyperpolarization. While these
systems have been generally satisfactory for the purpose for which
they were intended, such systems still do not solve numerous
problems in the art. For example, use of these systems has
generally been limited to only those facilities and researchers
that can afford such expensive and complex systems, which typically
cost hundreds of thousands of dollars, or more.
[0007] Similarly, some efforts have been made at providing
hyperpolarized materials to transfer hyperpolarization to targets
of interest. To date these efforts have focused on hyperpolarized
xenon as a solvent for NMR analysis applications. For example, in
Navon, G., Song, Y.-Q., Room, T., Appelt, S., Taylor, R. E. and
Pines, A., (1996). Science 271, 1848, the disclosure of which is
incorporated by reference in its entirety herein, hyperpolarized
xenon gas was liquefied and used as a solvent; transfer of
polarization to several dissolved species was demonstrated. In a
similar work, Polarization Transfer using Hyperpolarized
Supercritical Xenon," Jason C. Leawoods, Brian T. Saam, and Mark S.
Conradi, Chem. Phys. Lett. 327, 359-364 (2000), supercritical xenon
((P>5.83 MPa, T>290 K) was employed as a solvent and transfer
of polarization to several solutes was achieved.
[0008] However, xenon is very unsatisfactory as a solvent as highly
specialized physical conditions are necessary for most materials of
interest to dissolve in it. These conditions are not ones that lend
themselves to the great bulk of actual NMR/MRI studies. There is
therefore a need in the art for a method that can provide
hyperpolarized materials suitable for use at standard
conditions.
[0009] In U.S. Pat. No. 6,466,814, a method of producing a
hyperpolarized solution is described wherein a high T1 agent is
first polarized and then dissolved in a solvent. This method has
the drawback that the polarization is limited by the T1 of the
agent. There is therefore a significant need in the art for new
methods of manufacturing hyperpolarized solutions.
[0010] There is a also significant need in the art for
hyperpolarization systems, methods and compositions that reduce the
cost of obtaining hyperpolarized material, and increase the
practicality of using hyperpolarized material to enhance MRI and
NMR. The present invention provides solutions for these and other
problems, as described herein.
SUMMARY OF THE INVENTION
[0011] The purpose and advantages of the present invention will be
set forth in and become apparent from the description that follows.
Additional advantages of the invention will be realized and
attained by the methods and systems particularly pointed out in the
written description and claims hereof, as well as from the appended
drawings.
[0012] To achieve these and other advantages and in accordance with
a first aspect of the invention, a method of producing a
hyperpolarized material is provided. The method includes providing
a first material that is a liquid or a non-noble gas at standard
conditions, increasing the nuclear hyperpolarization of the first
material until the first material becomes hyperpolarized, and
subsequently transferring the nuclear hyperpolarization from the
first material to a second material or other materials, as
desired.
[0013] In accordance with a further aspect the first material can
also include solid material. The first material may be mixed with
the second material to create a mixture, such as (i) a solution,
(ii) a suspension, (iii) an emulsion, (iv) a colloid, or (v) a
composite material at standard conditions suitable for use in an
NMR study and/or suitable for injection in vivo. In accordance with
one embodiment, nuclear hyperpolarization may be transferred from
the first material to the second material via thorough mixing. For
example, the second material may be dissolved in the first
material. In accordance with another embodiment, nuclear
hyperpolarization may be transferred from the first material to the
second material by way of electromagnetic coupling. For example,
the electromagnetic coupling may be provided by electromagnetic
pulse sequences. The first material may then be removed or it may
be retained depending on the desired application.
[0014] By way of further example, the second material may first be
hyperpolarized instead of the first material. By way of still
further example, the first and second material may be mixed
together and then be hyperpolarized. By way of still further
example, a mixture of more than two materials (such as three, four,
five, six or more materials) may be provided, wherein one or more
of the materials may be hyperpolarized before they are introduced
into the mixture. By way of further example, a subset of the
materials may be hyperpolarized and then mixed with the remaining
materials. Moreover, if desired, all of the materials may be
hyperpolarized at the same time. Moreover, if desired, materials as
described herein may be hyperpolarized while they are being
mixed.
[0015] In accordance with a further aspect, the first material
and/or second material may be suitable for in vitro NMR analysis.
Preferably, for in vitro NMR analysis purposes, the first material
is selected from a group of materials commonly used as solvents in
NMR studies such as water, saline solution, deuterated water,
acetone- d.sub.6, ethanol- d.sub.6, acetonitrile- d.sub.3, formic
acid- d.sub.2, benzene- d.sub.6, methanol- d.sub.4, chloroform-
d.sub.1, nitromethane- d.sub.3, deuterium oxide, pyridine- d.sub.5,
dichloromethane- d.sub.2, 1,1,2,2-tetrachloroethane- d.sub.2,
dimethylformamide- d.sub.7, tetrahydrofurane- d.sub.8,
dimethylsulfoxide- d.sub.6, toluene- d.sub.8, 1,4-dioxane- d.sub.8,
trifluoroacetic acid- d.sub.1 and combinations thereof. Moreover,
at least one of the first material and/or second material may
include a physiologically tolerable liquid suitable for use in in
vivo MRI studies.
[0016] For in vivo MRI purposes, the first material is preferably
selected from a group of materials commonly used for injection of
in vivo solutions and/or suspensions such as water, deuterated
water, other FDA approved liquids, and the like. In accordance with
yet another aspect, the method may further include performing an
analysis of a region proximate the target material and/or the
target material itself. For example, the analysis may include
forming magnetic resonance images of a region of interest such as
of a patient. By way of further example, the analysis may include
analyzing NMR spectra of an in vitro or in vivo sample, such as a
target or targets.
[0017] A system for producing a hyperpolarized material is also
provided herein. The system includes a means for providing a first
material, where the first material is a liquid, a solid or a
non-noble gas at standard conditions, a means for increasing the
nuclear polarization of the first material until the first material
becomes hyperpolarized, and means for transferring the
hyperpolarization from the first material to a second material.
[0018] The invention also provides a method of hyperpolarizing a
material, including providing an object having a solid surface, the
solid surface including hyperpolarized material. The method further
includes transferring hyperpolarization from the hyperpolarized
material to a fluid in contact with the solid surface.
[0019] In accordance with a further aspect, the object may be
spherical in shape, or have any other suitable shape. Moreover, the
solid surface may include material containing nuclei selected from
the group including .sup.13C, .sup.15N, .sup.1H, .sup.2H, .sup.31P,
.sup.19F, .sup.29Si and combinations thereof, among others. In
accordance with one embodiment, the fluid may be a liquid. For
example, the liquid may be selected from the group commonly used as
solvents in NMR studies including water, deuterated water, acetone-
d.sub.6, ethanol- d.sub.6, acetonitrile- d.sub.3, formic acid-
d.sub.2, benzene- d.sub.6, methanol- d.sub.4, chloroform- d.sub.1,
nitromethane- d.sub.3, deuterium oxide, pyridine- d.sub.5,
dichloromethane- d.sub.2, 1,1,2,2-tetrachloroethane- d.sub.2,
dimethylformamide- d.sub.7, tetrahydrofurane- d.sub.8,
dimethylsulfoxide- d.sub.6, toluene- d.sub.8, 1,4-dioxane- d.sub.8,
trifluoroacetic acid- d.sub.1 and combinations thereof. In
accordance with another aspect, the fluid may be a gas. The gas may
be selected from those commonly used for inhalation therapy
purposes including, for example, air, nitrogen, carbon dioxide,
xenon, .sup.3He, and combinations thereof, among others.
[0020] In further accordance with the invention, an apparatus for
transferring hyperpolarization is provided. The apparatus includes
a surface having hyperpolarized material disposed thereon and/or
therein. The apparatus further includes means for directing a fluid
(e.g., liquid or gas) into contact with the surface. The apparatus
also includes means for transferring hyperpolarization from the
surface to the fluid.
[0021] In accordance with a further aspect, the surface may include
a plurality of spherical objects, or objects of any other suitable
shape. The surface may include material containing nuclei selected
from the group including .sup.13C, .sup.15N, .sup.1H, .sup.31P,
.sup.19F, .sup.29Si .sup.2Hand combinations thereof, among others.
The fluid may be a liquid, such as those commonly used as NMR
solvents such as water, saline, deuterated water, acetone- d.sub.6,
ethanol- d.sub.6, acetonitrile- d.sub.3, formic acid- d.sub.2,
benzene- d.sub.6, methanol- d.sub.4, chloroform- d.sub.1,
nitromethane- d.sub.3, deuterium oxide, pyridine- d.sub.5,
dichloromethane- d.sub.2, 1,1,2,2-tetrachloroethane- d.sub.2,
dimethylformamide- d.sub.7, tetrahydrofurane- d.sub.8,
dimethylsulfoxide- d.sub.6, toluene- d.sub.8, 1,4-dioxane- d.sub.8,
trifluoroacetic acid- d.sub.1 and combinations thereof, among
others. In accordance with a further aspect, the fluid may
additionally or alternatively include a gas, such as one commonly
used in inhalation therapy applications including air, nitrogen,
carbon dioxide, xenon, .sup.3He, and combinations thereof, among
others.
[0022] In further accordance with the invention, a method of
producing a hyperpolarized material is provided. The method
includes providing a solvent, hyperpolarizing the solvent, and
transferring hyperpolarization from the solvent to a target
material.
[0023] In accordance with a further aspect, the solvent may be
mixed with a target material to create a mixture selected from the
group including (i) a solution, (ii) a suspension, (iii) an
emulsion, (iv) a colloid and (v) a composite material, among
others. If desired, the method may further include hyperpolarizing
the target material. The target material may be hyperpolarized, for
example, through mixing. For example, the target material may be
dissolved in the solvent. By way of further example,
hyperpolarization may be transferred to the target material by way
of electromagnetic coupling. The electromagnetic coupling may be
provided, for example, by electromagnetic pulse sequences and used
to transfer hyperpolarization from the hyperpolarized solvent to
the target.
[0024] In accordance with a further aspect, the solvent and target
material may be hyperpolarized after they are mixed. If desired,
the solvent and/or target material may each be composed of a
plurality of component materials that are mixed together. These
component materials may be hyperpolarized prior to mixture, during
mixture or after mixture.
[0025] In accordance with still a further aspect, the solvent may
include a liquid suitable for in vitro NMR analysis. For example,
the solvent may include a material commonly used as solvents in NMR
studies such as water, deuterated water, acetone- d.sub.6, ethanol-
d.sub.6, acetonitrile- d.sub.3, formic acid- d.sub.2, benzene-
d.sub.6, methanol- d.sub.4, chloroform- d.sub.1, nitromethane-
d.sub.3, deuterium oxide, pyridine- d.sub.5, dichloromethane-
d.sub.2, 1,1,2,2-tetrachloroethane- d.sub.2, dimethylformamide-
d.sub.7, tetrahydrofurane- d.sub.8, dimethylsulfoxide- d.sub.6,
toluene- d.sub.8, 1,4-dioxane- d.sub.8, trifluoroacetic acid-
d.sub.1 and combinations thereof. For in vivo MRI purposes, the
liquid is preferably a material commonly used for injection of in
vivo solutions and/or suspensions as described herein.
[0026] In accordance with yet a further aspect, the method may
further include performing an analysis of a region proximate the
target material and/or the target material. For example, the
analysis may include forming magnetic resonance images of a region
of interest such as of a patient. By way of further example, the
analysis may include analyzing NMR spectra of an in vitro or in
vivo sample or target. The invention also provides a system for
producing a hyperpolarized material. The system includes means for
providing a solvent, means for hyperpolarizing the solvent, and
means for transferring hyperpolarization from the solvent to a
target material.
[0027] In further accordance with the invention, a method of
hyperpolarizing a solvent is provided, as well as a hyperpolarized
solvent made in accordance with the method. In accordance with the
method, the molecules of the solvent are hyperpolarized by way of a
technique selected from the group including (i) dynamic nuclear
polarization, (ii) the Nuclear Overhauser effect, (ii) parahydrogen
induced polarization, (iii) hyperpolarization using a brute force
environment, most preferably in conjunction with a quantum
relaxation switch, (iv) transferring hyperpolarization to molecules
of the solvent by exposing them to hyperpolarized nuclei of a
previously hyperpolarized gas, and combinations thereof.
[0028] In accordance with a further aspect, the solvent may include
a liquid suitable for in vitro NMR analysis. By way of further
example, the solvent may include a physiologically tolerable liquid
suitable for use in in vivo MRI studies. For example, the solvent
may include a material commonly used as a solvent in NMR studies
such as water, deuterated water, acetone- d.sub.6, ethanol-
d.sub.6, acetonitrile- d.sub.3, formic acid- d.sub.2, benzene-
d.sub.6, methanol- d.sub.4, chloroform- d.sub.1, nitromethane-
d.sub.3, deuterium oxide, pyridine- d.sub.5, dichloromethane-
d.sub.2, 1,1,2,2-tetrachloroethane- d.sub.2, dimethylformamide-
d.sub.7, tetrahydrofurane- d.sub.8, dimethylsulfoxide- d.sub.6,
toluene- d.sub.8, 1,4-dioxane- d.sub.8, trifluoroacetic acid-
d.sub.1 and combinations thereof.
[0029] In accordance with still a further aspect, the method may
further include arranging the solvent into a high surface area
configuration prior to being hyperpolarized. For example, the
solvent may be arranged into a high surface area configuration by
distributing it onto a high surface area substrate prior to being
hyperpolarized. Preferably, the method also includes cleaning the
surface of the high surface area substrate of magnetic impurities,
such as but not limited to oxygen groups, iron oxides, unpaired
electron groups, and the like. In accordance with another aspect,
the high surface area substrate is also preferably magnetically
inert. By way of example, the high surface area substrate is
preferably selected from the group including an aerogel material,
silicon beads, fumed silica, carbon nanostructures, silicon
nanofibers, exfoliated carbon and combinations thereof, among
others.
[0030] The method may further include arranging the solvent into a
high surface area configuration without use of a substrate. For
example, the solvent may be powderized using well understood
methods such as spray freezing into liquid (SFL) or spray
condensation (SC) techniques.
[0031] In accordance with yet a further aspect, the method further
includes cooling the solvent prior to hyperpolarizing the solvent.
In accordance with one embodiment, the solvent is cooled to a
temperature below about 100K prior to hyperpolarizing the solvent.
More preferably, the method includes cooling the solvent to a
temperature below about 80K, 60K, 40K, 20K, 10K, 5K, or even 1K
prior to hyperpolarizing the solvent.
[0032] In accordance with another aspect, the method may include
exposing the solvent to a magnetic field to facilitate
hyperpolarization of the solvent. In accordance with one
embodiment, the strength of the magnetic field is greater than
about 10 mT. More preferably, the magnetic field has a strength
greater than about 0.5 T, 1.0 T, 1.5 T, 2.0 T, 3.0 T, 5.0 T, 7.0 T
10.0 T, 15.0 T, 20.0 T or even 25.0 T. In accordance with yet a
further aspect, the method also preferably includes exposing the
solvent to helium to facilitate hyperpolarization of the solvent.
Even more preferably, the helium includes .sup.3He. In accordance
with one embodiment, the solvent is exposed to a sufficient
quantity of .sup.3He to cause at least a monolayer of .sup.3He to
form on the solvent.
[0033] In accordance with a further aspect, the solvent is
maintained at a cooled temperature in a magnetic field for a time
sufficient to permit relaxation of a substantial portion of the
solvent into a state of hyperpolarization. For example, the time
sufficient to permit relaxation may vary between several minutes to
several hours or even several days, as appropriate, in any time
increment.
[0034] In accordance with yet another aspect, the method further
includes exposing the solvent to .sup.4He to displace the .sup.3He
from the solvent. If desired, the method may also include
increasing the temperature of the hyperpolarized solvent.
Preferably, the temperature of the hyperpolarized solvent is
increased in the presence of a magnetic field having a strength
greater than about 1.0 Gauss. Even more preferably, the temperature
of the hyperpolarized solvent is increased in the presence of a
magnetic field having a strength greater than or equal to about
1.0, 1.5, 3.0, 7.0 Tesla or about 10.0 Tesla. The solvent is
preferably increased in temperature within a time sufficient to
avoid substantial loss of hyperpolarization. If desired, the
temperature of the solvent may be increased to room temperature. If
desired, the hyperpolarized solvent may be eluted from the high
surface area substrate.
[0035] In accordance with still a further aspect the method may
include arranging the solvent into a high surface area
configuration by converting the solvent into a finely divided form.
For example, the solvent may be converted into a powder. The
solvent may be converted into a powder, for example, by atomizing
and freezing the solvent. If desired, the solvent may be maintained
at a low temperature and in a magnetic field for an extended period
of time. For example, the extended period of time may be between
about one tenth of a second and about one week.
[0036] In accordance with still a further aspect, the method may
further include transporting the hyperpolarized solvent in a
container from a first location to a second location. In accordance
with still another aspect, hyperpolarization may be transferred
from the hyperpolarized solvent to a sample or other material to be
analyzed. The hyperpolarized solvent may be mixed with additional
unpolarized solvent containing an analyte to form a solvent mixture
before, during or after transport. The resultant mixture may then
be delivered to a region of interest to be analyzed. For example,
magnetic resonance images may be generated of the region of
interest. By way of further example, NMR spectra of the analyte or
the metabolic products of the analyte may be measured.
[0037] By way of further example, a system for hyperpolarizing
various solutions is also provided. In a first system, a solvent is
polarized in the manner described above, and an analyte of choice
is then dissolved in it. In a second system, the analyte is first
dissolved in unpolarized solvent, the resulting solution is then
configured as a high surface area arrangement and then
hyperpolarized. The high surface area can be achieved either by
plating the solution out onto a suitable substrate or by
powderizing the solution in the manner described herein.
[0038] The system includes means for manufacturing hyperpolarized
solutions. As described above, this may include hyperpolarizing a
solvent and then dissolving an analyte in it. The method of
hyperpolarizing the solvent may include using a technique selected
from the group including (i) dynamic nuclear polarization, (ii) the
Nuclear Overhauser effect, (ii) parahydrogen induced polarization,
(iii) hyperpolarization using a brute force environment, most
preferably in conjunction with a quantum relaxation switch, (iv)
transferring hyperpolarization to molecules of the solvent by
exposing them to hyperpolarized nuclei of a previously
hyperpolarized gas, and combinations thereof. Preferably,
hyperpolarization is also transferred from the solvent to the
analyte added to the solvent. Preferably, the system also includes
means for transporting the hyperpolarized solution from a first
location to a second location.
[0039] By way of further example, the method may include first
mixing an analyte with a desired solvent and then hyperpolarizing
the resultant solution. The method of hyperpolarizing the solution
may include using a technique selected from the group including i)
dynamic nuclear polarization, (ii) the Nuclear Overhauser effect,
(ii) parahydrogen induced polarization, (iii) hyperpolarization
using a brute force environment, most preferably in conjunction
with a quantum relaxation switch, (iv) transferring
hyperpolarization to molecules of the solvent by exposing them to
hyperpolarized nuclei of a previously hyperpolarized gas, and
combinations thereof. Preferably, the system also includes means
for transporting the hyperpolarized solution from a first location
to a second location.
[0040] In still further accordance with the invention, a method of
making a hyperpolarized suspension is provided as well as the
hyperpolarized suspension itself. The method includes providing a
hyperpolarized material and dispersing the hyperpolarized material
in a medium to create a hyperpolarized suspension. By way of
further example, a hyperpolarized suspension may be provided by
hyperpolarizing a medium, dispersing a material in the medium and
creating a hyperpolarized suspension. This may include transferring
hyperpolarization to the material added to the medium. Moreover, a
hyperpolarized suspension may be made by making a suspension from
non-hyperpolarized components, and hyperpolarizing the suspension
after it is made. Also, a suspension may be provided that is
composed of more than two components, wherein one or more of the
components of the suspension are hyperpolarized prior to mixing
them.
[0041] In accordance with a further aspect, the hyperpolarized
component or components of the suspension or the suspension itself
may be hyperpolarized using a technique selected from the group
including i) dynamic nuclear polarization, (ii) the Nuclear
Overhauser effect, (ii) parahydrogen induced polarization, (iii)
hyperpolarization using a brute force environment, most preferably
in conjunction with a quantum relaxation switch, (iv) transferring
hyperpolarization to molecules of the component(s) by exposing them
to hyperpolarized nuclei of a previously hyperpolarized gas, and
combinations thereof. In accordance with yet another aspect, the
hyperpolarized component(s) may have a diameter of less than about
one thousand microns. More preferably, the hyperpolarized
component(s) has a diameter of less than about one hundred microns.
Even more preferably, the hyperpolarized component(s) has a
diameter of less than about ten microns, five microns or one
micron. Preferably, the medium that the hyperpolarized material is
dispersed in to form a hyperpolarized suspension is a
physiologically tolerable medium. In accordance with another
embodiment, the hyperpolarized material is itself a physiologically
tolerable material.
[0042] In accordance with yet another aspect, the method may
further include dispersing the material in the presence of a
magnetic field. The magnetic field may have a field strength in
excess of 1.0 Gauss. In accordance with still a further aspect, the
medium may be selected from the group including (i) a solid, (ii) a
liquid and (iii) a gas. For example, the medium may be air.
Accordingly, if desired, the method may further include introducing
the hyperpolarized suspension into the region of interest, such as
the respiratory tract of a patient.
[0043] In accordance with still a further aspect, a system for
making a hyperpolarized suspension is provided, including means for
providing a hyperpolarized material, and means for dispersing the
hyperpolarized material in a medium to create a hyperpolarized
suspension. Means may also be provided to hyperpolarize a medium
and for dispersing a material in the medium to create a
hyperpolarized suspension. Moreover, means may be provided for
hyperpolarizing the suspension after it is made. Also, means may be
provided for making a hyperpolarized suspension that is composed of
more than two components, wherein one or more of the components of
the suspension are hyperpolarized prior to mixing them by the
means. Preferably, the system further includes means for
transporting the hyperpolarized suspension from a first location to
a second location. It will be understood that the dispersing may
occur prior to, during or after transport.
[0044] In further accordance with the invention, a method of making
a hyperpolarized emulsion is provided, as well as the
hyperpolarized emulsion itself. The method includes providing a
hyperpolarized material, and mixing the hyperpolarized material
with a medium to create a hyperpolarized emulsion. This may include
transferring hyperpolarization to the medium from the
hyperpolarized material. The method may alternatively include
hyperpolarizing a medium and mixing a material into the medium to
create a hyperpolarized emulsion. Moreover, a hyperpolarized
emulsion may be made by making an emulsion from non-hyperpolarized
components, and hyperpolarizing the emulsion after it is made.
Also, an emulsion may be provided that is composed of more than two
components, wherein one or more of the components of the emulsion
are hyperpolarized prior to mixing them.
[0045] In accordance with a further aspect, the hyperpolarized
material or other component of the emulsion or the emulsion itself
may be hyperpolarized using a technique selected from the group
including i) dynamic nuclear polarization, (ii) the Nuclear
Overhauser effect, (ii) parahydrogen induced polarization, (iii)
hyperpolarization using a brute force environment, most preferably
in conjunction with a quantum relaxation switch, (iv) transferring
hyperpolarization to molecules of the emulsion or component thereof
by exposing them to hyperpolarized nuclei of a previously
hyperpolarized gas, and combinations thereof. Preferably, the
medium that the hyperpolarized material is mixed with to form the
hyperpolarized emulsion is a physiologically tolerable medium. In
accordance with another embodiment, the hyperpolarized material is
itself a physiologically tolerable material.
[0046] In accordance with a further aspect, the mixing step may
take place in the presence of a magnetic field. Preferably, the
mixing step takes place in a magnetic field having a strength of at
least about 1.0 Gauss. Moreover, the mixing step may take place at
a temperature at which the hyperpolarized material and medium are
both in a liquid form. However, if desired, the either
hyperpolarized material and medium may be in a solid, liquid or
gaseous form when they are mixed.
[0047] In accordance with yet a further aspect, a system for making
a hyperpolarized emulsion is provided. The system includes means
for providing a hyperpolarized material, and means for mixing the
hyperpolarized material with a medium to create a hyperpolarized
emulsion. This may include means for transferring hyperpolarization
to the medium from the hyperpolarized material. Means may also be
provided to hyperpolarize a medium and for mixing a material with
the medium to create a hyperpolarized emulsion. Moreover, means may
be provided for hyperpolarizing the emulsion after it is made.
Also, means may be provided for making a hyperpolarized emulsion
that is composed of more than two components, wherein one or more
of the components of the emulsion are hyperpolarized prior to
mixing them by the means. If desired, the system may further
include means for transporting the hyperpolarized emulsion from a
first location to a second location. It will be understood that the
mixing may occur prior to, during or after transport.
[0048] In further accordance with the invention, a method of making
a hyperpolarized colloid is provided as well as the hyperpolarized
colloid itself. The method includes providing a hyperpolarized
material, and mixing the hyperpolarized material with a medium to
create a hyperpolarized colloid. This may include transferring
hyperpolarization to the medium from the hyperpolarized material.
The method may alternatively include hyperpolarizing a medium and
mixing a material into the medium to create a hyperpolarized
colloid. Moreover, a hyperpolarized colloid may be made by making a
colloid from non-hyperpolarized components, and hyperpolarizing the
colloid after it is made. Also, a colloid may be provided that is
composed of more than two components, wherein one or more of the
components of the colloid are hyperpolarized prior to mixing
them.
[0049] In accordance with a further aspect, the hyperpolarized
material or other component of the colloid or the colloid itself
may be hyperpolarized using a technique selected from the group
including i) dynamic nuclear polarization, (ii) the Nuclear
Overhauser effect, (ii) parahydrogen induced polarization, (iii)
hyperpolarization using a brute force environment, most preferably
in conjunction with a quantum relaxation switch, (iv) transferring
hyperpolarization to molecules of the colloid or component thereof
by exposing them to hyperpolarized nuclei of a previously
hyperpolarized gas, and combinations thereof. Preferably, the
medium that the hyperpolarized material is mixed with to form the
hyperpolarized colloid is a physiologically tolerable medium. In
accordance with another embodiment, the hyperpolarized material is
itself a physiologically tolerable material.
[0050] In accordance with a further aspect, the mixing step may
take place in the presence of a magnetic field, such as one having
a strength of at least about 1.0 Gauss. Moreover, the mixing step
may take place at a temperature at which the hyperpolarized
material and medium are both in a liquid form. However, if desired,
the either hyperpolarized material and medium may be in a solid,
liquid or gaseous form when they are mixed.
[0051] In accordance with yet a further aspect, a system for making
a hyperpolarized colloid is provided. The system includes means for
providing a hyperpolarized material, and means for mixing the
hyperpolarized material with a medium to create a hyperpolarized
colloid. This may include transferring hyperpolarization to the
medium from the hyperpolarized material. Means may also be provided
to hyperpolarize a medium and for mixing a material with the medium
to create a hyperpolarized colloid. Moreover, means may be provided
for hyperpolarizing the colloid after it is made. Also, means may
be provided for making a hyperpolarized colloid that is composed of
more than two components, wherein one or more of the components of
the colloid are hyperpolarized prior to mixing them by the means.
If desired, the system may further include means for transporting
the hyperpolarized colloid from a first location to a second
location. It will be understood that the mixing may occur prior to,
during or after transport.
[0052] In further accordance with the invention, a method of making
a hyperpolarized composite material is provided, as well as the
hyperpolarized composite material made in accordance with the
method. The method includes providing a hyperpolarized material,
and mixing the hyperpolarized material with a second material, such
as a medium, to create a hyperpolarized composite material. This
may include transferring hyperpolarization to the second material
from the hyperpolarized material. The method may alternatively
include hyperpolarizing a medium and mixing a material into the
medium to create a hyperpolarized composite material. Moreover, a
hyperpolarized composite material may be made by making a composite
material from non-hyperpolarized components, and hyperpolarizing
the composite material after it is made. Also, a composite material
may be provided that is composed of more than two components,
wherein one or more of the components of the composite material are
hyperpolarized prior to mixing them.
[0053] In accordance with a further aspect, the hyperpolarized
material, component of the composite material or composite material
itself may be hyperpolarized using a technique selected from the
group including (i) dynamic nuclear polarization, (ii) the Nuclear
Overhauser effect, (ii) parahydrogen induced polarization, (iii)
hyperpolarization using a brute force environment, most preferably
in conjunction with a quantum relaxation switch, (iv) transferring
hyperpolarization to a component of the composite by exposing it to
hyperpolarized nuclei of a previously hyperpolarized gas, and
combinations thereof. Preferably, the medium that that the
hyperpolarized material is mixed with to form the hyperpolarized
composite material is a physiologically tolerable medium. In
accordance with another embodiment, the hyperpolarized material is
itself a physiologically tolerable material.
[0054] By way of further example, the composite material may
include an encapsulated material such as one having a polymeric
shell and may include a substance such as TentaGel. By way of
further example, the composite material may also include a liposome
containing or otherwise including hyperpolarized material.
[0055] In accordance with still a further aspect, the mixing step
may take place in the presence of a magnetic field. Preferably, the
magnetic field has a strength of at least about 1.0 Gauss. The
hyperpolarized material may be selected from the group including
(i) a solid material, (ii) a liquid material, (iii) a gaseous
material and combinations thereof. The medium may be selected from
the group including water and saline, among others. If desired, one
could also select as the dispersing medium gases commonly used in
inhalation therapy such as air, nitrogen, carbon dioxide, xenon,
.sup.3He and the like.
[0056] In accordance with yet a further aspect, a system for making
a hyperpolarized composite material is provided. The system
includes means for providing a hyperpolarized material, and means
for mixing the hyperpolarized material with a medium to create a
hyperpolarized composite material. Means may also be provided to
hyperpolarize a medium and for mixing a material with the medium to
create a hyperpolarized composite material. Moreover, means may be
provided for hyperpolarizing the composite material after it is
made. Also, means may be provided for making a hyperpolarized
composite material that is composed of more than two components,
wherein one or more of the components of the composite material are
hyperpolarized prior to mixing them by the means. If desired, the
system may further include means for transporting the
hyperpolarized composite material from a first location to a second
location. It will be understood that the mixing may occur prior to,
during or after transport. If desired, the hyperpolarized composite
material or components thereof may be selected from the group
including (i) a solid material, (ii) a liquid material, (iii) a
gaseous material and combinations thereof, for example.
[0057] In further accordance with the invention, a beneficial agent
is provided. In accordance with one embodiment of the invention,
the beneficial agent includes a hyperpolarized core material
surrounded by a porous encapsulating medium.
[0058] In accordance with a further aspect, the porosity of the
encapsulating medium may substantially permit passage of gas
through the encapsulating medium to the core material. For example,
the porosity of the encapsulating medium may substantially permit
passage of helium through the encapsulating medium, but may also
substantially prohibit passage of gas molecules through the
encapsulating medium larger than helium.
[0059] In accordance with still a further aspect, the
hyperpolarized core material may have a relatively long
spin-lattice relaxation time. For example, the hyperpolarized core
material may include material containing nuclei such as .sup.13C,
.sup.15N, .sup.1H, .sup.2H, .sup.31P, .sup.19F, .sup.29Si and
combinations thereof, among others.
[0060] In accordance with still another aspect, the encapsulating
medium may include polymeric material. The polymeric material may
include a material selected from the group including
polytetrafluoroethylene, poly(lactic-co-glycolic acid),
polyanhydrides, polyorthoesters, polyvinylalchols, and combinations
thereof. Preferably, the encapsulating material is adapted and
configured to substantially maintain its structural integrity at
temperatures below 100K, 10K and 1K, if desired. By way of further
example, the encapsulating material may also include hyperpolarized
material.
[0061] In accordance with another embodiment, the encapsulating
medium includes a biologically derived medium such as a liposome.
The liposome may be adapted and configured to include
hyperpolarized material therein or thereon. The material of the
liposome itself may also be hyperpolarized using any suitable
technique disclosed herein. For example, the liposome may be
exposed to a hyperpolarized liquid (e.g., solvent, solution,
suspension, emulsion, colloid, etc.) or gas. The liposome may
absorb hyperpolarized fluid (e.g., liquid) and then be directed to
a region of interest. Alternatively, the large dipolar field
generated by any of the above hyperpolarized materials may be used
to transfer polarization through the liposome barrier. The
hyperpolarized material that is in, on, or that composes, the
liposome can be used, for example, to pinpoint the location of a
tumor or other anatomy of interest in MR imaging, or may be used in
NMR studies, as appropriate.
[0062] In accordance with one embodiment, the liposome is provided
with hyperpolarized pyruvate. The liposome can be used to target
delivery of the hyperpolarized pyruvate to a desired location in a
region of interest such as a portion of a patient to permit
detection of the presence of metabolic processes that consume the
pyruvate by using NMR/MRI techniques.
[0063] In accordance with a further aspect, the hyperpolarized core
material may include material that is solid at standard conditions.
For example, the hyperpolarized core material may include material
that is liquid, gaseous or solid at standard conditions. If
desired, the beneficial agent may be provided in the form of a
capsule having an average diameter between about 0.001 microns and
about 100 microns that may be used for in vivo or in vitro studies.
Preferably, the beneficial agent is provided in the form of a
capsule having an average diameter between about 0.001 microns and
about 10 microns.
[0064] In accordance with a further aspect, the beneficial agent
may include a functional element disposed proximate the
encapsulating medium, the functional element being adapted and
configured to facilitate a beneficial result in use. The core
material may be selected from the group including
hexafluorobenzene, perfluorocarbons, and the like.
[0065] The invention also provides a beneficial agent including a
hyperpolarized core material surrounded by an encapsulating medium,
wherein the hyperpolarized core material includes material selected
from the group including (i) liquid material, (ii) solid material,
(iii) gaseous material interspersed with a solid material, (iv)
gaseous material interspersed with a liquid material, and
combinations thereof.
[0066] In accordance with a further aspect, the encapsulating
medium may be porous. The porosity of the encapsulating medium may
substantially permit passage of gas through the encapsulating
medium to the core material. For example, the porosity of the
encapsulating medium may substantially permits passage of helium
through the encapsulating medium, and if desired, may substantially
prohibit passage of gas molecules through the encapsulating medium
larger than helium.
[0067] In accordance with still a further aspect, the
hyperpolarized core material may have a relatively long
spin-lattice relaxation time. For example, the hyperpolarized core
material may include material selected from the material containing
nuclei such as .sup.13C, .sup.15N, .sup.1H, .sup.2H, .sup.31P,
.sup.19F, .sup.29Si and combinations thereof. If desired, the
encapsulating medium may include polymeric material. The polymeric
material may include a material selected from the group including
polytetrafluoroethylene, poly(lactic-co-glycolic acid),
polyanhydrides, polyorthoesters, polyvinylalchols, and combinations
thereof. Preferably, the encapsulating medium is adapted and
configured to substantially maintain its structural integrity at
temperatures below 100K. More preferably, the encapsulating medium
is adapted and configured to substantially maintain its structural
integrity at temperatures below 10K. Even more preferably, the
encapsulating medium is adapted and configured to substantially
maintain its structural integrity at temperatures below 1K. If
desired, the encapsulating material may include hyperpolarized
material.
[0068] In accordance with yet a further aspect, the beneficial
agent may be composed of materials that are acceptable for use in
vivo. If desired, the beneficial agent may be provided in the form
of a capsule having an average diameter between about 0.001 microns
and about 100 microns. Even more preferably, the beneficial agent
may be provided in the form of a capsule having an average diameter
between about 0.001 microns and about 10 microns. As with other
embodiments described herein, the beneficial agent may further
include a functional element disposed proximate the encapsulating
medium that is adapted and configured to facilitate a beneficial
result in use. For example, the core material may be selected from
the group including hexafluorobenzene, perfluorocarbons, and the
like.
[0069] In further accordance with the invention, a kit for
providing hyperpolarized material is provided. The kit includes at
least one encapsulated material. The encapsulated material includes
a core material, which in turn includes a material having a
relatively long spin-lattice relaxation time. The encapsulated
material further includes an encapsulating medium surrounding the
core material. The kit also includes instructions for facilitating
hyperpolarization of the encapsulated material.
[0070] In accordance with a further aspect, the encapsulating
medium may be porous as described herein. The core material may
include material selected from the group including those materials
containing nuclei such as .sup.13C, .sup.15N, .sup.1H, .sup.2H
.sup.31P, .sup.19F, .sup.29Si and combinations thereof. The
encapsulating medium may also include polymeric material as
described herein. For example, the polymeric material may include a
material selected from the group including polytetrafluoroethylene,
poly(lactic-co-glycolic acid), polyanhydrides, polyorthoesters,
polyvinylalchols, and combinations thereof. In accordance with a
further aspect, the encapsulating medium may be adapted and
configured to substantially maintain its structural integrity at
depressed temperatures such as those below 100K, 10K and 1K.
Moreover, the encapsulating medium may be adapted and configured to
substantially maintain its structural integrity in the presence of
a magnetic field of varying strengths, such as those in excess of
10 mT, 1 T and 10 T among others. In accordance with still a
further aspect, the encapsulating material of the kit may include
material having a relatively long spin-lattice relaxation time. The
core material may include material that is solid, liquid and/or
gaseous at standard conditions.
[0071] In accordance with yet a further aspect, the instructions
for the kit may describe how to facilitate hyperpolarization of the
encapsulated material using a quantum relaxation switch. By way of
further example, the instructions of the kit may describe how to
facilitate hyperpolarization of the encapsulated material by
transferring hyperpolarization from a hyperpolarization carrier to
the core material.
[0072] In accordance with still a further aspect, the core material
may be hyperpolarized using a technique selected from the group
including (i) dynamic nuclear polarization, (ii) the Nuclear
Overhauser effect, (ii) parahydrogen induced polarization, (iii)
hyperpolarization using a brute force environment, most preferably
in conjunction with a quantum relaxation switch (iv) transferring
hyperpolarization to molecules of the core material by exposing
them to hyperpolarized nuclei of a previously hyperpolarized gas,
and combinations thereof.
[0073] In further accordance with the invention, a method of
preparing and providing hyperpolarized encapsulated material is
provided. In accordance with a first aspect, the method includes
providing an encapsulated material, providing a hyperpolarization
carrier or hyperpolarization facilitator (e.g., .sup.3He), exposing
the encapsulated material to the hyperpolarization carrier or
facilitator and transferring hyperpolarization from the
hyperpolarization carrier to the encapsulated material or using the
hyperpolarization facilitator to facilitate hyperpolarization of
the material.
[0074] In accordance with a further aspect, the hyperpolarization
carrier may be hyperpolarized using a technique selected from the
group including (i) dynamic nuclear polarization, (ii) the Nuclear
Overhauser effect, (ii) parahydrogen induced polarization, (iii)
hyperpolarization using a brute force environment, most preferably
in conjunction with a quantum relaxation switch, (iv) transferring
hyperpolarization to molecules of the solvent by exposing them to
hyperpolarized nuclei of a previously hyperpolarized gas, and
combinations thereof.
[0075] In accordance with still a further aspect, the encapsulated
material may have a porous surface portion to permit passage of the
hyperpolarization carrier or hyperpolarization facilitator
therethrough as described herein. The porous surface portion
preferably permits passage of the hyperpolarization carrier or
hyperpolarization facilitator therethrough into a core portion of
the encapsulated material. The core portion may include material
that is solid, liquid and/or gaseous at standard conditions. The
porous surface portion of the capsule may include polymeric
material, such as polytetrafluoroethylene, poly(lactic-co-glycolic
acid), polyanhydrides, polyorthoesters, polyvinylalchols, and
combinations thereof.
[0076] In accordance with another aspect, the hyperpolarization
carrier may pass through the surface portion to the core portion.
For example, the hyperpolarization carrier may include gaseous
hyperpolarized xenon. In accordance with still a further aspect,
the core portion may include material selected from the group
including .sup.13C, .sup.15N, .sup.1H, .sup.31P, .sup.19F,
.sup.29Si and combinations thereof.
[0077] In accordance with a further aspect, the method may further
include cooling the encapsulated material. Preferably, the
encapsulated material is cooled to a temperature below about 100K,
10K or 1K. The method may additionally or alternatively include
exposing the encapsulated material to a magnetic field, such as a
magnetic field having a maximum strength in excess of 10 mT, 1 T,
or 10 T, for example.
[0078] The invention also provides a method of preparing and
providing hyperpolarized encapsulated material using a
hyperpolarization facilitator that acts as a quantum relaxation
switch. The method includes providing an encapsulated material, and
facilitating the hyperpolarization of the encapsulated material
using a quantum relaxation switch.
[0079] In accordance with a further aspect, the encapsulated
material may be exposed to .sup.3He. Preferably, the encapsulated
material has a porous surface portion to permit passage of the
.sup.3He therethrough. Even more preferably, the porous surface
portion permits passage of a gas therethrough into a core portion
of the encapsulated material. The core portion may include a
material that is solid, liquid and/or gaseous at standard
conditions. In accordance with another aspect, the porous surface
portion of the capsule may include polymeric material, such as
polytetrafluoroethylene, poly(lactic-co-glycolic acid),
polyanhydrides, polyorthoesters, polyvinylalchols, and combinations
thereof, among others. In accordance with one embodiment, the
porosity of the encapsulating medium may substantially permit
passage of helium through the encapsulating medium and may
substantially prohibit passage of molecules through the
encapsulating medium larger than helium. Preferably, the core
portion includes material containing nuclei selected from the group
including .sup.13C, .sup.15N, .sup.1H, .sup.2H, .sup.31P, .sup.19F,
.sup.29Si and combinations thereof, among others.
[0080] In accordance with still a further aspect, the encapsulated
material may be cooled and/or maintained in a magnetic field to
facilitate hyperpolarization of the encapsulated material. For
example, the encapsulated material may be cooled to a temperature
below about 100K, 10K or 1K, among others. By way of further
example, the magnetic field may have a maximum strength in excess
of about 10 mT, 1 T or 10 T, among others. Preferably, the core
material is maintained at a cooled temperature in a magnetic field
for a time sufficient time to permit relaxation of at least a
portion of the core material into a state of hyperpolarization.
[0081] In accordance with a further aspect, the core material may
be exposed to .sup.4He to displace the .sup.3He from the core
material, thus preserving the hyperpolarization of the core
material, but removing the .sup.3He. In accordance with one
embodiment, the hyperpolarized encapsulated material may be
maintained at a low temperature and/or in a magnetic field for an
extended period of time. Maintaining the hyperpolarized material in
such a manner facilitates storage and/or transport of the material,
and minimizes loss of hyperpolarization from the material. The
extended period of time can be any suitable time period, between
about one tenth of a second and about one week, for example, and in
any suitable time increment. If transporting the material for an
end use at another location, the hyperpolarized encapsulated
material may be transported in a suitable container from a first
location to a second location, preferably at a low temperature and
in the presence of a magnetic field.
[0082] If desired, the encapsulated material may be maintained at a
low temperature and in a magnetic field for an extended period of
time, such as between about one tenth of a second and about one
week. The encapsulated hyperpolarized material may be transported
in a container from a first location to a second location. Prior to
using the encapsulated hyperpolarized material, the temperature of
the encapsulated material may first be increased in a manner such
that substantial loss of hyperpolarization is avoided. The
encapsulated hyperpolarized material may then be introduced into a
region of interest to be analyzed. For example, magnetic resonance
images of the region of interest may be generated. By way of
further example, NMR spectra of an in vitro or in vivo target or
sample may be analyzed.
[0083] In accordance with still another aspect, the hyperpolarized
encapsulated material may be increased in temperature for use.
Preferably, the temperature of the encapsulated material is
increased in a manner that minimizes a substantial loss of the
material's hyperpolarization. The encapsulated hyperpolarized
material may then be introduced into a region of interest to be
analyzed. If desired, magnetic resonance images may then be
generated of the region of interest. By way of further example, NMR
spectra of an in vitro or in vivo sample or target may be analyzed
using the hyperpolarized material.
[0084] In still further accordance with the invention, a method of
obtaining a magnetic resonance image of a region of interest such
as of a patient is provided. The method includes introducing a
hyperpolarized encapsulated material into a region of interest such
as of a patient, transmitting a pulse or pulses of electromagnetic
energy into the region of interest to excite the hyperpolarized
encapsulated material, and creating a magnetic resonance image of
the region of interest using a signal received from the
hyperpolarized encapsulated material.
[0085] The invention also provides a method of performing NMR
spectroscopy. The method includes introducing a hyperpolarized
encapsulated material into a region of interest, transmitting a
pulse or pulses of electromagnetic energy into the region of
interest to excite the hyperpolarized encapsulated material, and
receiving NMR spectra from the region of interest.
[0086] It is to be understood that both the foregoing general
description and the following detailed description are exemplary
and are intended to provide further explanation of the invention
claimed.
[0087] The accompanying drawings, which are incorporated in and
constitute part of this specification, are included to illustrate
and provide a further understanding of the method and system of the
invention. Together with the description, the drawings serve to
explain the principles of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0088] FIG. 1 is a schematic view of a first system made in
accordance with the present invention.
[0089] FIG. 2 is a schematic view of a second system made in
accordance with the present invention.
[0090] FIG. 3 is a schematic view of a third system made in
accordance with the present invention.
[0091] FIG. 4 is a schematic view of a fourth system made in
accordance with the present invention.
[0092] FIG. 5 is a schematic view of a fifth system made in
accordance with the present invention.
[0093] FIG. 6 is a schematic view of a sixth system made in
accordance with the present invention.
[0094] FIGS. 7(A)-7(F) are schematic views of a method and process
for manufacturing a beneficial agent made in accordance with the
present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0095] Reference will now be made in detail to the present
preferred embodiments of the invention, examples of which are
illustrated in the accompanying drawings. The method and
corresponding steps of the invention will be described in
conjunction with the detailed description of the system.
[0096] The devices, methods and compositions presented herein may
be used for enhancing the efficacy of MRI and/or NMR. Certain
embodiments of the present invention are particularly suited for
providing hyperpolarized material to an end user at a location that
is remote from the location where the material was initially
hyperpolarized. Moreover, other embodiments of the invention
provide an encapsulated hyperpolarized material that facilitates
analysis of samples, materials and patients, as desired.
[0097] In accordance with a first embodiment of the invention, a
method of producing a hyperpolarized material is provided. The
method includes providing a first material, increasing the nuclear
hyperpolarization of the first material until the first material
becomes hyperpolarized, and transferring the hyperpolarization from
the first material to a second material.
[0098] For purpose of explanation and illustration, and not
limitation, a schematic view depicting method steps of an exemplary
method and system carried out in accordance with the invention is
shown in FIG. 1 and is designated generally by reference character
100. Other embodiments of a method and/or system in accordance with
the invention, or aspects thereof, are provided in FIGS. 2-7, as
will be described.
[0099] Thus, as illustrated in FIG. 1, for example, a first
material 112 is provided that is directed into a hyperpolarization
platform 110. The nuclear hyperpolarization of the first material
112 is increased until the first material 112 becomes
hyperpolarized.
[0100] Nuclear hyperpolarization can be written as
(N.sup..uparw.-N.sub..dwnarw.)/(N.sup..uparw.+N.sub..dwnarw.),
where NT represents the number of nuclei in the material with their
nuclear magnetic moment aligned parallel to the direction of an
external magnetic field, and N.sub..dwnarw. represents the number
of nuclei in the material with their nuclear magnetic moment
aligned antiparallel to the direction of an external magnetic
field. As used herein, the term hyperpolarization is intended to
refer to an increase in the spin ordering of an ensemble or set of
ensembles of nuclear spins such that the MR signal from the
ensemble(s) is enhanced over and above what it would otherwise be
under standard operating conditions. This increase may be
accomplished artificially. Under standard NMR/MRI operating
conditions (T=300 K, B=1-10 Tesla)
N.sup..uparw..about.N.sup..dwnarw. and the overall polarization of
even protons is still quite low, on the order of a few ppm.
Hyperpolarization refers to the act of artificially aligning a high
percentage of the nuclear spins in a given direction; typically,
along the direction of the applied magnetic field. The signal to
noise ratio in an NMR/MRI is a direct function of the polarization
P:
S/N.about.(Qf.sub.0t.sub.exp/T.sub.1).sup.1/2c(xyz)P
Hence by hyperpolarizing spins to a value of (for example) 10%, the
signal to noise ratio can be increased by a factor of 10,000 or
more depending on the target nuclei.
[0101] A variety of techniques can be used by hyperpolarization
platform 110 to hyperpolarize the first material 112. It will be
understood in the context of the subject disclosure that these
techniques as described herein can be used to hyperpolarize any of
the useful hyperpolarized compositions described herein (e.g.,
solvents, solutions, suspensions, emulsions, colloids, composite
materials, and the like) or one or more components thereof.
[0102] As a first example, dynamic nuclear polarization ("DNP") may
be used to hyperpolarize the first material 112 (or other
material). 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. Pat. No. 6,008,644 which is incorporated by reference
herein in its entirety. In the context of certain of the
embodiments of the present invention, DNP can be used to
hyperpolarize the solvent and/or physiologically tolerable fluid.
The hyperpolarization of the solvent or fluid is then later
transferred to the analyte of interest.
[0103] As a second example, the Nuclear Overhauser effect can be
used to hyperpolarize the first material 112 (or other material).
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.
[0104] In the context of certain of the embodiments of the present
invention, the Nuclear Overhauser effect can be employed by causing
one set of nuclear spins in the solvent and/or physiologically
tolerable fluid to have a higher than usual polarization. This
excess polarization of the solvent and/or physiologically tolerable
fluid may then later transferred to the analyte of interest.
[0105] As a third example, parahydrogen induced polarization
("PHIP") can be used to hyperpolarize the first material 112 (or
other material). PHIP generally involves transfer of polarization
via catalyzed hydrogenation by p-H.sub.2, followed by spin-order
transfer to the nucleus of interest. Examples of PHIP in the patent
literature include, for example, U.S. Pat. No. 6,574,495, which is
incorporated by reference herein in its entirety. In the context of
certain of the embodiments of the present invention, PHIP can be
employed, for example, by using PHIP to hyperpolarize the nuclei of
the solvent and/or physiologically tolerable fluid. The nuclear
hyperpolarization of the solvent and/or physiologically tolerable
fluid may then later be transferred to the analyte of interest.
[0106] As a fourth example, brute force hyperpolarization
preferably using a quantum relaxation switch (referred to herein as
"QRS") can be used to hyperpolarize the first material 112 (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
.sup.3He, a quantum relaxation switch provided by the .sup.3He
facilitates relaxation of the material under while in brute force
conditions to rapidly induce hyperpolarization in the material.
Application of .sup.4He is then used to remove the .sup.3He from
the surface of the first material 112 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. Pat. No.
6,651,459 which is incorporated by reference herein in its
entirety. In the context of certain of the embodiments of the
present invention, QRS can be employed by causing the nuclei in the
solvent to relax to a state of high nuclear polarization. The
hyperpolarization of the solvent and/or physiologically tolerable
fluid can then later be transferred to nuclei in the analyte of
interest.
[0107] As a fifth example, molecules of the first material 112 or
other material may 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 .sup.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. Pat. No. 6,426,058 which is
incorporated by reference herein in its entirety. In the context of
certain of the embodiments of the present invention, this can be
employed by hyperpolarizing the solvent and/or physiologically
tolerable fluid. The nuclear hyperpolarization of the solvent
and/or physiologically tolerable fluid may then later be
transferred to nuclei in the analyte of interest.
[0108] As described herein, 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.
[0109] Preferably, in accordance with one embodiment of the
invention, when performing DNP, the electrons are highly polarized
and in close contact with the nuclei of interest to be polarized.
This may advantageously be accomplished by employing low
temperatures (such as about 1.6 K or below) while in the presence
of a magnetic field, such as on the order of 3 Tesla. In DNP, the
electron spins are static with respect to the nuclei of interest.
As such, the electron resonance line may be saturated using
microwave radiation. Moreover, it is also preferable to irradiate
the nuclei of interest with microwaves to facilitate the transfer
of polarization when performing DNP.
[0110] More broadly speaking, by employing the teachings herein, it
is possible to transfer hyperpolarization to a first material
without a need to resort to applying microwave pulses to facilitate
hyperpolarization transfer including even the Nuclear Overhauser
effect, although the use of microwaves for this purpose, if
desired, is clearly within the scope of the instant disclosure.
[0111] Once first material 112 (or other material) has been
hyperpolarized it may be used for a variety of purposes. First
material 112 may be used to hyperpolarize a second material,
discussed in detail below, or may be used for other purposes. First
material 112 may be stored in hyperpolarized form for an extended
period of time at the location where it was polarized, or may be
transported to a second location for storage and/or further use. If
desired, first material may be liquefied or frozen for storage
and/or transport.
[0112] As further depicted in FIG. 1, if desired, hyperpolarization
may be transferred from the first material 112 to a second material
122 using the mixing platform 120. A magnet and probe 121 may be
optionally included in the mixing platform to allow for application
of RF pulses of appropriate frequency and magnitude to facilitate
transfer of polarization. Transfer of hyperpolarization may be
achieved in a number of ways.
[0113] The availability of several techniques to transfer
hyperpolarization between unlike nuclear species is well understood
in the art and has been discussed in Pietra.beta., T.: Optically
Polarized .sup.129Xe in Magnetic Resonance Techniques. Magn. Reson.
Rev. 17, 263-337 (2000), the contents of which are incorporated
herein by reference in their entirety. These techniques are:
[0114] 1) Cross polarization
[0115] 2) The Nuclear Overhauser effect
[0116] 3) Thermal mixing; and
[0117] 4) Larmor/Rabi Frequency Cross Coupling
[0118] The above techniques all refer to methods of transferring
polarization between unlike spins. In addition, intimate coupling
between like spins in the two materials can be facilitated by
ensuring good thermal, chemical and/or dipolar contact between the
materials. It will be recognized that the mixing platform may
therefore include apparatus to expose the materials or materials to
RF pulses of appropriate frequency and magnitude; or, in the case
where RF excitation of the materials is not required, the mixing
apparatus may include an appropriate mixing system (e.g., a
mechanical mixing system) to ensure good thermal, chemical and/or
dipolar contact between the two materials to provide intimate
contact between the materials to facilitate hyperpolarization
transfer.
[0119] All of the above techniques may be used to transfer nuclear
hyperpolarization from the first material to a second material.
Advantageously, there needs to be good dipolar coupling between the
two sets of nuclear spins in the first and second materials.
Cross-Polarization:
[0120] In cross polarization, radiofrequency pulses are used to
induce mutual spin flips between dissimilar, dipolar coupled, spins
where one set of spins is in, or is caused to be in, a higher state
of nuclear order. The assumption is that the spins are in static
motional relationship (i.e., their mutual tumbling rate is low) to
one another and satisfy the condition
.gamma..sub.IB.sub.S=.gamma.SB.sub.I.
[0121] Radiofrequency pulses are then applied to one set of spins
to cause saturation of its resonance line. This can be accomplished
by use of a spectrometer capable of delivering radiofrequency
pulses to the materials of interest. By way of further example,
most installed NMR/MRI magnets either already have this capability
or could be readily upgraded to have such a capability. This
technique may therefore be used to transfer hyperpolarization from
a first material to a second material or to create a hyperpolarized
(i) solution, (ii) suspension, (iii) emulsion or (iv) composite
material as described herein, such as by hyperpolarizing these
mixtures after they are made, or by hyperpolarizing one or more
constituents of these mixtures before they are made.
Nuclear Overhauser Effect:
[0122] In contrast to cross polarization described above, the
Nuclear Overhauser Effect proceeds by mutual "flip flop"
transitions between dipolar coupled spins. If the physical
situation is one in which one set of spins is tumbling rapidly in
relation to the other (a situation well described by two liquids
mixing together or one liquid flowing past a solid object) then the
rapidly varying dipolar field from one set of spins causes
transitions in the other and irradiating radiofrequency pulses are
not required for hyperpolarization to be transferred between
dissimilar nuclei. For applications embodied herein, for example,
this effect can be facilitated by ensuring that the hyperpolarized
material 112 be thoroughly mixed with the second material 122.
[0123] Even if the spins are not tumbling with respect to one
another, a rapidly varying dipolar field can be created by
saturation of the hyperpolarized nuclei's resonance line. It will
be understood that in either case the technique can be used to
transfer hyperpolarization from a first material to a second
material or to create a hyperpolarized (i) solution, (ii)
suspension, (iii) emulsion or (iv) composite material, as embodied
herein.
Thermal Mixing:
[0124] Thermal mixing usually refers to the act of transferring
polarization between dissimilar nuclei by quickly decreasing an
external magnetic field such that the Zeeman energy of the separate
nuclei for a brief time are overlapping. The main criterion is
generally that the Zeeman energy reservoirs E=.gamma..sub.I,SB of
the dissimilar nuclei I, S be as closely matched as possible.
[0125] This technique has the advantage of not requiring
application of radiofrequency pulses to achieve hyperpolarization
transfer. A disadvantage of ordinary thermal mixing is that it
normally requires the materials being mixed to be exposed for a
brief time to a very low magnetic field. Since T.sub.1 is often a
strong function of magnetic field this can lead to a steep loss of
polarization in at least one of the materials and degradation of
results.
[0126] However, in various applications disclosed herein, the first
material and second material may be pre arranged to contain
identical and dipolar coupled nuclei. For example, .sup.13C spins
in a material such as a solvent may be dipolar coupled with
.sup.13C spins in the analyte. In this instance it is not necessary
to lower the field to achieve good hyperpolarization transfer. The
spins in the solvent and in the analyte should be in good dipolar
coupling with one another for a sufficiently long time to achieve
hyperpolarization transfer. In the case of good coupling the time
to transfer hyperpolarization can be quite short (e.g., on the
order of 1E-4 sec). As such, the systems and methods embodied
herein achieves good coupling by assuring good mixture between, for
example, the hyperpolarized solvent and the analyte as described
above.
[0127] Thermal mixing therefore can be used to transfer
hyperpolarization from a first material to a second material or to
create a hyperpolarized (i) solution, (ii) suspension, (iii)
emulsion and/or (iv) composite material, as desired, among
others.
Larmor/Rabi Frequency Cross Coupling:
[0128] Under conditions where
.gamma..sub.SB.sub.1=.gamma..sub.IB.sub.0, coupling between spins
S,I may be accomplished. This technique requires only a single RF
excitation but does require that the B.sub.1 tipping field be very
large if the coupling is carried out in a large field B.sub.0.
[0129] In each of the situations described above it will be
recognized that it is desirable to have the following
characteristics in transferring hyperpolarization from a first
material to a second material:
[0130] 1) A high degree of hyperpolarization in the first material.
This may be achieved by any of the methods described above. In
accordance with a preferred embodiment, this is achieved by
employing a brute force ("BF") quantum relaxation switch
("QRS").
[0131] 2) Good thermal and dipolar contact between the first
material and the second material. This can be achieved by causing
the first material and second material to be mixed in a manner to
achieve good dipolar contact between the nuclear spins in the first
material, and, if desired, employing irradiating electromagnetic
pulses as needed to ensure good hyperpolarization transfer between
the nuclei in the two materials.
Polarization Transfer Between Nuclear Spins in Dissimilar
Materials
[0132] In the art, all the above techniques are typically used to
transfer hyperpolarization between nuclei in a molecular bond.
However, hyperpolarization transfer between dissimilar species and
in dissimilar physical states has been amply demonstrated. For
example, transfer of hyperpolarization between dissimilar solid
species has been demonstrated in "Nuclear spin polarization
transfer across an organic-semiconductor interface," Journal of
Chemical Physics Volume 119, Number 19 15 Nov. 2003, Lucas Goehring
and Carl A. Michal. This publication is expressly incorporated by
reference In this reference an organic material was overlaid on top
of a polarizable substrate such as InP. Polarization from the
.sup.31P nuclei in the InP was transferred to the spins in the
organic overlayer via application of radiofrequency pulses, and
hyperpolarization transfer in the overlaid layer itself proceeded
via spin diffusion.
[0133] Similarly, nuclear hyperpolarization can be transferred
between spins in a solvent and spins in a solute. For example, in
J. Am. Chem. Soc. 2001, 123, 1010-1011, which is incorporated by
reference herein in its entirety, nuclear polarization in the
proton ensemble spread by spin diffusion between the solvent and
solute. In this particular instance, application of electromagnetic
pulses are not needed as the Zeeman energy levels of the nuclei are
identical.
[0134] Similarly, polarization transfer between hyperpolarized
xenon and dissimilar spins has been demonstrated using thermal
mixing in Volume 205, number 2,3 Chemical Physics Letters, 9 Apr.
1993 "Cross polarization from laser-polarized solid xenon to
.sup.13C0.sub.2 by low-field thermal mixing" C. R. Bowers, H. W.
Long, T. Pietrass, H. C. Gaede and A. Pines. This publication is
also incorporated by reference herein in its entirety.
[0135] As further embodied herein, thorough mixing may be achieved
by passing first material 112 over or through second material 122
in platform 120 to achieve sufficient physical contact to permit
hyperpolarization of second material 122. For example, as discussed
below with reference to FIG. 2, first material 112 can be provided
in the form of solid beads 212 having hyperpolarized material at
the surface. Particular examples of suitable beads or materials for
making those beads include, for example, silicon microspheres,
carbon microspheres, carbon nanotubes, carbon nanofibers, polymer
resins such as TentaGel.TM. (Rapp Polymere GmbH, Ernst-Simon-Str.
9, D 72072 Tubingen, Germany), and the like. TentaGel resins are
grafted copolymers consisting of a low crosslinked polystyrene
matrix on which polyethylene glycol (PEG or POE) is grafted. As PEG
is a "chameleon type" polymer with hydrophobic and hydrophilic
properties, the graft copolymer shows modified physio-chemical
properties.
[0136] It will be recognized that, although alteration of the
external field, either of the main NMR/MRI magnet 150 and/or the
holding field arising from the holding magnet 360 in the transfer
Dewar 300, is not necessarily an optimum route to achieve increased
hyperpolarization in the analyte, such a method may also be used
for hyperpolarization transfer.
[0137] In accordance with a further aspect, at least one of the
first material and second material are preferably suitable for in
vitro or in vivo NMR analysis. Moreover, at least one of the first
material and second material are preferably tolerable liquid
suitable for use in in vivo MRI studies. Liquid materials may be
used for the first material 112 and/or second material 114, such as
water, saline solution, deuterated water, acetone- d.sub.6,
ethanol- d.sub.6, acetonitrile- d.sub.3, formic acid- d.sub.2,
benzene- d.sub.6, methanol- d.sub.4, chloroform- d.sub.1,
nitromethane- d.sub.3, deuterium oxide, pyridine- d.sub.5,
dichloromethane- d.sub.2, 1,1,2,2-tetrachloroethane- d.sub.2,
dimethylformamide- d.sub.7, tetrahydrofurane- d.sub.8,
dimethylsulfoxide- d.sub.6, toluene- d.sub.8, 1,4-dioxane- d.sub.8,
trifluoroacetic acid- d.sub.1 and combinations thereof. In
accordance with a further aspect, the fluid may additionally or
alternatively include a gas, such as one selected from the group
including air, nitrogen, carbon dioxide, xenon, .sup.3He, and
combinations thereof, among others. Moreover, solid materials may
also be used for one or more of first material 112 and second
material 122, such as including .sup.13C, .sup.15N, .sup.1H,
.sup.2H, .sup.31P, .sup.19F, .sup.29Si and combinations
thereof.
[0138] After hyperpolarizing first material 112 or second material
122 (or other material), if desired, it is possible to preserve the
hyperpolarization of the material, such as by maintaining the
material at a depressed temperature and in a magnetic field, and
transporting it to a location where it may be used in analysis.
Thus, it is possible to create a hyperpolarized material 112 in a
first location, and transport it to a second location where the
hyperpolarization may be transferred to second material 122. A
suitable container, such as container 205 described in detail
below, may be used for such a purpose. Alternatively, if desired
the hyperpolarization transfer may take place in the first
location, and the second material may then be stored and/or
transported to a second location. Moreover, second material can be
transported to a final location where it may be used, for example,
in an analysis of a material such as a sample or target.
Effectively "transporting" and transferring hyperpolarization
permits a generic material to be hyperpolarized by individuals that
have made an investment in capital equipment, and to then transport
that hyperpolarized material to an end user. This creates the
significant benefit of the end user not needing to invest in
expensive equipment to take advantage of the superior results that
may be provided by using hyperpolarized material. Aspects relating
to transporting hyperpolarized material are described in detail
below.
[0139] As further depicted in FIG. 1, an analysis may be performed
of a region proximate the target material and/or the target
material itself. For example, the analysis may include forming
magnetic resonance images of a region of interest, such as of a
patient using a commercial MRI scanner (e.g., GE Sigma 1.5 T or 3.0
T scanners) or other scanners such as for research having higher
field capabilities (e.g., 7.0 T main field strength) and the like
having a main magnet 150 and associated transmit and receive
coils/antennas 152 and supporting hardware 154 as known in the art.
It will be understood that similar hardware (e.g., imaging coils
connected to transmitters and computer controls connected to a
scanner, etc.) may be used in accordance with other embodiments of
the invention as disclosed herein. By way of further example, the
analysis may include analyzing NMR spectra of an in vitro or in
vivo sample or target using transmit and/or receive coils as known
in the art (not shown). It will be recognized that the depiction of
magnet 150 generally refers to a large magnet that applies a steady
state magnetic field to a region of interest to be imaged, whether
it be for MRI, NMR or other analysis.
[0140] When employed for MR imaging applications, hyperpolarized
material has a number of advantages over traditional MR contrast
agents. Traditional contrast agents contain a paramagnetic compound
and operate by influencing the magnetic environment of the
surrounding tissue. As many paramagnetic compounds have toxicity
concerns there are severe constraints on the use of these for in
vivo purposes. Moreover, traditional contrast agents often give
rise to "wash out" problems in that their effect cannot be easily
controlled. This leads to the production of artifacts in the
image.
[0141] Because the polarization of a hyperpolarized ("HP") agent is
a function of time, its "wash out" effect can be readily accounted
for. In addition, the nuclear hyperpolarization of the agent may be
destroyed very quickly through application of appropriate
electromagnetic pulses, thus eliminating any "wash out" effects.
Moreover, the HP agent can be made from nuclei that have very low
backgrounds in vivo, giving a very high achievable resolution.
Lastly, HP agents may be made from non toxic materials allowing for
repeat use without toxicity concerns. Moreover, as described
herein, if the hyperpolarized material includes a material that may
be metabolized, it is possible to obtain NMR spectra/MR images of
such a material as it is metabolized and turned into hyperpolarized
metabolites. Traditional contrast agents do not participate in
metabolic events. Use of non hyperpolarized materials does not give
sufficient signal for the metabolites to be detected by the MRI
machine. Thus, use of agents made in accordance with the present
invention may directly quantify metabolic activity.
[0142] A system 100 for producing a hyperpolarized material is
depicted in FIG. 1. System 100 provides a means for providing a
first material 112 (which can be any suitable material as described
herein provided in any suitable manner, such as a mixture or a
component thereof), a means 110 for increasing the nuclear
polarization of the first material 112 until the first material
becomes hyperpolarized, and means 120 for transferring the
hyperpolarization from the first material 112 to second material
122.
[0143] For purposes of further illustration and not limitation, as
embodied herein and as depicted in FIG. 2, a system 200 is provided
for transferring nuclear hyperpolarization via thorough mixing.
With reference to FIG. 2, system 200 includes a means for providing
a first material 212 such as a container 210 including a plurality
of spheres 212 of first material 212, each of which preferably
includes hyperpolarized material. It will be recognized that first
material 212 may be provided in any suitable high surface area
configuration, and that the recitation of a spherical particle bed
geometry is merely intended to be exemplary. The first material 212
may be hyperpolarized using any technique embodied herein.
[0144] System 200 further includes a container 205 such as a Dewar
as known in the art adapted and configured to receive container 210
and having a holding magnet 250 (which may be a permanent magnet, a
conventional electromagnet, or a magnet having windings including
high temperature or low temperature superconductive materials
(HTS/LTS materials) for applying a magnetic holding field, such as
a magnetic dipole, about the particle bed 210 to help maintain
hyperpolarization of material in the spheres. A source 208 of
coolant and electrical power, if required, for the magnet 250 may
be provided.
[0145] A stream of second material 222 in fluid form is directed
over bed 210 by a fluid source 220 in communication with a conduit
224 by operation of valves 230. Second material 222 may be provided
as a gas or liquid passing over first material 212, creating
physical contact between the two materials, permitting a transfer
of hyperpolarization. If desired, RF pulses may be applied to help
facilitate the transfer of hyperpolarization as described herein.
The hyperpolarized second material 222 may then be further directed
through conduit 224 to NMR sample tube 190 or a patient (not shown)
and MRI/NMR analyses can be performed as described herein.
[0146] A variety of other configurations can be provided for
transferring hyperpolarization thorough mixing. For example, the
particle bed could include material that can be quickly melted by a
heater 270, for example, and dispersed through the second material.
The materials may further be caused to mix by causing them to flow
over a series of obstructions made preferably, though not
exclusively, from reasonably non depolarizing material such as PTFE
coated glass.
[0147] By way of further example, FIG. 3 depicts an exemplary
system 300 for transferring hyperpolarization using electromagnetic
coupling. In this example a frozen hyperpolarized material 312 is
melted and dispersed into a previously unpolarized solution 322 in
a container 320 inside of a refrigerated container 305 having a
holding field provided by a magnet 350 whose solvent is chemically
identical to the first material. Non depolarizing flow obstructions
324 may be provided to promote mixing of the polarized and
unpolarized material. Optionally, the magnetic field of magnet 350
may be of sufficient homogeneity to provide for good RF pulses of
appropriate frequency and magnitude to be applied to the mixture.
If desired, a heater 370 may provide heat to promote melting of the
frozen material 312. By application of pressure, the mixed solution
326 is caused to flow into the bore of a system having a magnet 150
and a probe 160 (similar in concept to components 152, 154
described above) suitable for application of RF pulses. RF pulses,
typically selected to excite the resonance line of the
hyperpolarized nuclei, are applied to cause spin flip transitions
between the nuclei in the melted solvent and the spins in the
analyte. As will be appreciated, system 300 may be suitably adapted
for in vivo MRI studies.
[0148] In further accordance with the invention, a method and
system of producing a hyperpolarized material is provided. The
method includes providing a solvent, hyperpolarizing the solvent,
and transferring hyperpolarization from the solvent to a target
material. The system provides the necessary components to carry out
the steps of the method. Accordingly a hyperpolarized solvent is
also provided.
[0149] In accordance with a further aspect, the solvent and target
material may be hyperpolarized after they are mixed. If desired,
the solvent and/or target material may each be composed of a
plurality of component materials that are mixed together. These
component materials may be hyperpolarized prior to mixture, during
mixture or after mixture.
[0150] For purposes of illustration and not limitation, as embodied
herein, the solvent may include a liquid suitable for in vitro NMR
analysis. For example, the solvent may include a material selected
from the group including water, deuterated water, acetone- d.sub.6,
ethanol- d.sub.6, acetonitrile- d.sub.3, formic acid- d.sub.2,
benzene- d.sub.6, methanol- d.sub.4, chloroform- d.sub.1,
nitromethane- d.sub.3, deuterium oxide, pyridine- d.sub.5,
dichloromethane- d.sub.2, 1,1,2,2-tetrachloroethane- d.sub.2,
dimethylformamide- d.sub.7, tetrahydrofurane- d.sub.8,
dimethylsulfoxide- d.sub.6, toluene- d.sub.8, 1,4-dioxane- d.sub.8,
trifluoroacetic acid- d.sub.1 and combinations thereof. By way of
further example, the solvent may include a physiologically
tolerable liquid suitable for use in in vivo MRI studies.
Physiologically tolerable solvents include water, saline and the
like.
[0151] The molecules of the solvent itself may be hyperpolarized,
for example, by way of a technique selected from the group
including (i) dynamic nuclear polarization, (ii) the Nuclear
Overhauser effect, (ii) parahydrogen induced polarization, (iii)
hyperpolarization using a quantum relaxation switch, (iv)
transferring hyperpolarization to molecules of the solvent by
exposing them to hyperpolarized nuclei of a previously
hyperpolarized gas, and combinations thereof.
[0152] In accordance with still a further aspect, the method may
further include arranging the solvent into a high surface area
configuration prior to being hyperpolarized. This can be
particularly advantageous when practicing the QRS method for
achieving hyperpolarization.
[0153] For example, as depicted in FIG. 4, the solvent 400 may be
arranged into a high surface area configuration by distributing the
solvent onto a high surface area substrate 410 prior to being
hyperpolarized. The high surface area substrate 410 may include,
for example, an aerogel material, silicon beads, fumed silica,
carbon nanostructures, silicon nanofibers, exfoliated carbon and
combinations thereof, among others.
[0154] The high surface area substrate 410 is preferably arranged
in a sample chamber 420 adapted and configured to contain the
material. Any suitable method may be used to hyperpolarize the
solvent, such as a brute force method as described herein making
use of a quantum relaxation switch employing .sup.3He, among other
techniques. Accordingly, a magnet 150 may be used to expose the
sample to a high magnetic field, and sample chamber 420 may be
maintained at extremely low temperatures (such as below 1.0K) to
create the brute force environment. Good thermal contact between
the sample chamber 420 and the cold section of a refrigeration
mechanism, such as the mixing chamber 450 of a dilution
refrigerator, is provided by a heat switch 421. .sup.3He may be
added to the chamber to facilitate hyperpolarization of the sample,
and .sup.4He may be subsequently added to remove the .sup.3He to
allow the sample to be warmed without undue loss of polarization.
The solvent and/or other fluids may be delivered into chamber by
way of inlet capillary 430. Fluids may exit chamber 420 by way of
drain line 435. After the solvent is hyperpolarized, a heat
switch/heater 440 may be used to melt frozen hyperpolarized solvent
400 from the high surface area substrate 410, and to deliver it to
a mixing chamber 450 where the hyperpolarized solvent may be mixed
with solvent that has not been hyperpolarized for delivery.
[0155] Preferably, the method and system also provides for cleaning
the surface of the high surface area substrate 410 of magnetic
impurities, such as but not limited to oxygen groups, iron oxides,
unpaired electron groups, and the like. In accordance with another
aspect, the high surface area substrate is also preferably
magnetically inert.
[0156] In accordance with still a further aspect the method may
include arranging the solvent into a high surface area
configuration by converting the solvent into a finely divided form.
For example as depicted in FIG. 5, the solvent 500 may be converted
into a powder 590. The spraying operation may be performed, for
example, inside of a spray chamber 530, and subsequently freezing
the solvent 500 into solvent powder 590. The solvent 500 may be
converted into a powder 590, for example, by introducing the
solvent through an inlet conduit 515 and atomizing the solvent 500
into a spray 518 from a nozzle 510 in the presence of a cooled
atmosphere 520 (provided, for example, by a bath 560 of a cryogenic
fluid, such as liquid nitrogen). The cooled atmosphere may later be
removed, for example, by simply heating the sample volume for a
brief period, leaving the micronized powder 590 ready for
hyperpolarization. Accordingly, the solvent may be powderized using
methods such as spray freezing into liquid (SFL) or spray
condensation (SC) techniques, among others. After the solvent 500
is frozen into a powder 590 form, it may be stored in a frozen
state before being hyperpolarized.
[0157] If desired, a powder 590 may also be provided formed from a
material that is solid at standard conditions. This solid material
may be converted into powdered form using any known technique
(e.g., grinding, attrition mills, plasma sputtering techniques and
the like). The solid material may include any material that can be
hyperpolarized, and preferably includes material selected from the
group including .sup.13C, .sup.15N, .sup.1H, .sup.31P, .sup.19F,
.sup.29Si and combinations thereof. A solid powdered material 590
may then be hyperpolarized as disclosed herein.
[0158] If desired, powder 590 may be hyperpolarized using any
methods described herein. Preferably, solvent powder 590 is
hyperpolarized using a quantum relaxation switch. If a QRS
technique is used, for example, the chamber may be cooled by using
a heat switch to facilitate good thermal contact to the cold
portion of a low temperature refrigerator such as the mixing
chamber of a dilution refrigerator 550. The .sup.3He and .sup.4He
may be introduced into chamber 530, and magnet 150 may be used to
facilitate hyperpolarization of the powder 590. By way of further
example, the powder may be hyperpolarized using QRS or other
technique as described herein in a different apparatus. After the
solvent 500 is hyperpolarized, as with the embodiment of FIG. 4, a
heater 540 may be used to melt frozen hyperpolarized powder 590,
and to deliver it via a drain line 535 to a mixing platform (not
shown in FIG. 5) where the hyperpolarized solvent 500 may be mixed
with solvent that has not been hyperpolarized for delivery.
[0159] Whether the solvent is sprayed and frozen or not,
particularly when the QRS method is practiced, the solvent is
preferably cooled prior to hyperpolarizing the solvent. In
accordance with one embodiment, the solvent is cooled to a
temperature below about 100K prior to hyperpolarizing the solvent.
More preferably, the method includes cooling the solvent to a
temperature below about 80K, 60K, 40K, 20K, 10K, 5K, or even 1K
prior to hyperpolarizing the solvent. As a general matter, when
materials are cooled, it becomes easier to hyperpolarize them.
Specifically, nuclear polarization in a given field is a hyperbolic
tangent function P tan h (uB/k.sub.BT)
Where
[0160] u gyromagnetic ratio of nuclei [0161] B applied magnetic
field [0162] K.sub.B=Boltzmann's constant [0163] T=temperature From
this it can be seen that in general the lower the temperature the
higher the degree of polarization that can be achieved in a given
magnetic field.
[0164] The method may include exposing the solvent to a magnetic
field. This can be used to facilitate hyperpolarization of the
solvent, particularly when employing the QRS method Moreover,
application of a field is necessary for DNP, in order to polarize
the electron spins before transfer of polarization to nearby
nuclear spins. Typical field strengths in the context of DNP here
are from about 1 T to about 3 T. Larger fields are generally not
needed as the polarization of the electron spins saturates at these
values (at temps .about.1.6 K). As will be further appreciated by
those of skill in the art, even a small magnetic field (e.g.,
several hundred Gauss) is used in production of hyperpolarized
gases.
[0165] As indicated above, hyperpolarization in the brute force/QRS
environment increases with increasing magnetic field. At
sufficiently high B/T values the relationship becomes linear so
that the hyperpolarization .about.B/T. In accordance with one
embodiment, the strength of the magnetic field is greater than
about 10 mT. More preferably, the magnetic field has a strength
greater than about 0.5 T, 1.0 T, 1.5 T, 2.0 T, 3.0 T, 5.0 T, 7.0 T,
10.0 T, 15.0 T, 20.0 T or even 25.0 T.
[0166] In practicing the QRS method, the solvent is next exposed to
.sup.3He to facilitate hyperpolarization of the solvent. The
solvent is preferably exposed to a sufficient quantity of .sup.3He
to cause at least a monolayer of .sup.3He to form on the solvent.
This can be carried out, for example, in accordance with the
teachings in U.S. Pat. No. 6,651,459. While that reference
discloses hyperpolarizing a frozen gas, the inventors of this
patent application have recognized herein that this technique is
applicable to frozen liquids as well as other solid materials.
Importantly, it is highly desirable for the material to be
polarized to be configured to have a high surface area. While this
is straightforward when the material is a gas, when the material is
a liquid or a solid this is more difficult. In the case of a
liquid, a preferred embodiment is that the liquid may be polarized
by first atomizing it into submicron sized droplets, for example,
as described above. The droplets may be quickly solidified to form
a powder. As a second embodiment, the liquid can be caused to
adhere to the surface of a substrate such as silica aerogel using
surface tension. Excess liquid in the pores of the substrate may be
dried so that the pores are largely empty and the liquid forms a
layer in the strands less than 5 microns thick. Layers thicker than
this can be expected to not polarize quickly during the QRS
process.
[0167] In the case of a solid, the solid is preferably powderized
until the typical diameter of a particle in the powder is less than
about 5 microns. Particles substantially larger than this can be
expected to not polarize quickly during the QRS process.
[0168] The QRS process requires operation in a regime of low
temperature and preferably, high magnetic field. Moreover,
structural elements such as capillary lines may be provided that
are capable of allowing introduction of .sup.3He and .sup.4He to
the material(s) to be hyperpolarized in appropriate amounts and at
appropriate steps in the process. It will be appreciated that the
capillary lines must be carefully constructed to minimize heat
loading into the sample region.
[0169] In the case of QRS, the solvent is then maintained at a
cooled temperature in a magnetic field for a time sufficient to
permit relaxation of a substantial portion of the solvent into a
state of hyperpolarization. Similarly, in a DNP process, the amount
of hyperpolarization improves with increasing time, but while
applying microwaves to the material to be polarized. In the case of
employing QRS, for example, the time sufficient to permit
relaxation may vary between several hours or even several days, as
appropriate, in any time increment. Furthermore, when employing the
QRS method, the frozen hyperpolarized solvent is further exposed to
.sup.4He to displace the .sup.3He from the solvent.
[0170] As will be further appreciated by those of skill in the art,
in addition to processing a solvent, it is also possible to
dissolve an analyte in a solvent to make a solution and powderize
it as described herein. This powder can also become hyperpolarized
in accordance with the invention. As such, in accordance with the
invention, it is possible to powderize any liquid and/or solution
for the purposes of making a hyperpolarized solution as well as a
hyperpolarized suspension, emulsion, colloid, and composite
material or component thereof, as described herein.
[0171] Regardless of how it has been hyperpolarized, once
hyperpolarized, the solvent is in a condition where it may be
stored for extended periods of time. Maintenance of the
hyperpolarization is facilitated by storing the hyperpolarized
solution in a magnetic field and/or at low temperatures, for
example, in a Dewar container (e.g., 305) as described herein that
is able to maintain a magnetic holding field. Generally, for
purposes of storage and/or transport of hyperpolarized material,
application of a magnetic field at least in excess of 1 G and
maintenance of a low temperature environment are preferred.
[0172] Moreover, once frozen and in a substantially stable state of
hyperpolarization, the solvent may be transported in a container
(e.g., 305, 605 as described herein) from a first location to a
second location. The hyperpolarized solvent may be used at the
second location, or may be stored at the second location. For
example, the frozen hyperpolarized solvent may be maintained in an
inventory until it is ordered for purchase by an end user and then
delivered to the end user at a third location. It will be
recognized that these teachings of storing and transporting
hyperpolarized material to storage and/or an end user applies to
all hyperpolarized materials described herein, regardless as to how
the material is put into a state of hyperpolarization.
[0173] Any of a variety of containers may be used for storing
and/or transporting hyperpolarized material. As will be
appreciated, FIG. 6 shows how such an exemplary container 605 can
be configured for storing/transporting hyperpolarized materials to
a customer site and how the hyperpolarized material may be accessed
to facilitate an NMR or MRI study. As depicted in FIG. 6, a storage
vessel 605 comprising, for example, a vacuum insulated Dewar may be
provided for storing and transporting a stabilized hyperpolarized
material 600. It will be understood from the figure that the design
of the Dewar is to allow a hyperpolarized material to be maintained
at a low temperature while in an adequate magnetic field, the
purpose of which is to allow the hyperpolarization of the material
to be retained during transport/storage for as long a time as
possible.
[0174] Preferably, vessel 605 includes a sealed chamber 620 for
isolating the material 600 from the environment, a first means for
maintaining a depressed temperature 630, such as a portable
cryocooler and/or a bath of liquid cryogenic fluid (e.g., LN.sub.2
and the like), and a means (e.g., a magnet) 640 for maintaining a
magnetic field about the material 600.
[0175] Various cryogenic fluids may be used to maintain a depressed
temperature, such as liquid helium, liquid hydrogen, liquid neon,
liquid nitrogen, liquid argon, liquid oxygen, liquid carbon
dioxide, and the like. Additionally or alternatively, a
transportable cryocooler can be used to maintain temperatures as
low as 4 K in the sample region. The design and construction of
such lightweight cryocoolers are well understood in the art and
commercially available. Moreover, materials with very high specific
heats at low temperatures may be loaded inside the cryostat to keep
the hyperpolarized material cooled during storage/transport.
[0176] Besides application of low temperatures and magnetic fields,
various techniques for extending the lifetime of nuclear
polarization have been described in the literature. For example, it
is known that singlet states often have longer lifetimes-sometimes
as much as 10 times longer--than the standard T.sub.1 of the spin
ensemble. As described in Caravetta and Levitt, Journal of Chemical
Physics 122, 2145059 (2005), pulse sequences can be formulated to
load the nuclear polarization of a dipolar coupled system of 1/2
spins into its singlet state. The singlet state itself is
undetectable using NMR but the resultant spin order can be
recaptured after a time by application of further RF pulses. As
such, these and other techniques known in the art for extending the
lifetime of nuclear polarization may be employed with any of the
methods and systems of the invention described herein.
[0177] Magnet 640 may be a permanent magnet, or a solenoidal
configuration made either from superconducting and/or "normal" non
superconducting wire. If desired, magnet 640 can be configured to
have a higher than standard homogeneity to permit efficient
application of RF pulses to materials contained in its interior. It
will be appreciated that many superconducting materials used as
windings are integrated with conventional conducting material to
permit transition to the superconducting state, whereby electrons
will begin flowing through the superconducting material at a point
where the superconducting material can carry the given current
density provided that the particular temperature and background
magnetic field are both low enough to permit a superconducting
state. For ease of use, a solenoidal or permanent magnet
configuration could also be made so as to minimize the creation of
stray field outside the sample region.
[0178] The magnetic field in the sample region should be sufficient
to freeze out as much as possible events that cause transitions
between the nuclei from up to down states or vice versa,
particularly to minimize Zeeman transitions. In addition,
optionally, one may use magnetic screening to minimize access of
depolarizing radiation to the hyperpolarized material or materials.
For example, it is within the scope of the invention to employ a
material, such as Mu-Metal as a shield to prevent events that cause
nuclei to lose their polarization. Mu-metal is a nickel-iron alloy
(75% nickel, 15% iron, plus copper and molybdenum) that has a very
high magnetic permeability. The high permeability makes Mu-metal
very effective at screening static or low-frequency magnetic
fields, which cannot be attenuated by other methods.
[0179] Moreover, where a hyperpolarized material is provided that
may be later liquefied for use, the material 600 may be disposed in
the pathway of a conduit 650. Conduit includes an input end 652 and
input valve 656 for receiving a flow of material, and a discharge
end 654 with a discharge valve 658 for directing a mixture of the
material and the hyperpolarized material 600 to an end location for
use. Stated another way, conduit 650 may be used to "flush" the
hyperpolarized material through vessel 610 in order to use it. The
conduit 650 should be made from material that is as non
depolarizing as possible such as Teflon or polyethylene. Valves
656, 658 are preferably also made from non depolarizing
material.
[0180] When a user, such as a customer wishes to perform an NMR
study, the user first preferably makes a solution from a solvent
identical to the one in the sample region and the analyte of
interest. The user would use less solvent than normal as the rest
will be made up from the frozen hyperpolarized solvent contained in
the sample region. Next, the user attaches the end of his sample
outlet line to the open end of valve 656 that seals input end 652.
The user attaches the inlet line to his or her NMR sample tube
(e.g., 190 described herein) to the open end of valve 658 that
seals output end 654. By exerting slight pressure on their sample,
for example via use of a syringe or other pressure source (e.g.,
compressed gas and the like) or even the pressure from heating the
sample in the container 605, by opening valve 656, the user's
sample flows through the sample region. Heater 670 is used to melt
the polarized solvent in the sample region. The two solvents are
mixed together by using slight pressure to drive them through a
mixing region, such as a small volume having a narrowed diameter
that causes the unpolarized solvent and polarized solvent to
thoroughly mix. This increases the overall hyperpolarization of the
mixture that is then driven into the NMR region by continued
application of pressure from the syringe.
[0181] U.S. Pat. No. 5,642,625 describes the use of low
temperatures to extend the lifetime of hyperpolarized xenon at
cryogenic temperatures. U.S. Pat. No. 7,066,319 describes a
transport Dewar to facilitate transport of hyperpolarized gas by
application of a magnetic field. U.S. Pat. No. 6,807,810 describes
a method of minimizing polarization loss in transported
hyperpolarized gases by exclusion of stray RF fields. U.S. Pat. No.
5,612,103 describes the use of specialized coatings to minimize
polarization loss during transportation or storage of a
hyperpolarized gas. Each of these patents is incorporated by
reference herein in its entirety.
[0182] In U.S. Pat. No. 6,466,814 ("the '814 patent"), a method of
producing a hyperpolarized solution is described wherein a high T1
agent is first polarized and then dissolved in a solvent. This
patent is also incorporated by reference herein in its entirety.
This method has a number of drawbacks.
[0183] As a first example, the hyperpolarization is limited by the
T1 of the agent in the '814 patent. By hyperpolarizing a solvent
first as with certain embodiments disclosed herein, the longer T1s
available in certain solvents can be used to enhance the overall
hyperpolarization of a product that may be manufactured.
[0184] As a second example, the method in the '814 patent describes
a method that requires exposing a material to be hyperpolarized to
low temperatures. In various aspects of the invention disclosed
herein, it is possible to hyperpolarize a medium, warm the medium
to room temperature, mix the analyte in the medium at room
temperature and send the mixture for NMR analysis, MR imaging
and/or to transfer hyperpolarization from the medium to the
analyte. By freezing the medium instead of the analyte, it is
possible to analyze materials that would be damaged or destroyed by
freezing, such as cells or other biological organisms that could
rupture, among other things. Moreover, while the '814 patent
teaches hyperpolarization of the analyte by DNP and the brute force
technique (low temperature, high field, extended time periods), it
fails to teach use of a quantum relaxation switch in combination
with the brute force environment.
[0185] In addition, the method described in '814 polarizes the
analyte or target material, whereas the method disclosed herein
polarizes the solvent and then transfers polarization to the
analyte. This approach has significant advantages for
transportation of hyperpolarized materials in that it allows for
the selection of a solvent that has a very long T.sub.1 both in
solidified and liquid form.
[0186] In addition, the solvent in a typical NMR/MRI study
typically has far more spins than the analyte of interest. By
polarizing the solvent a large ensemble of polarized spins is made
available for transfer to the analyte. This transfer can be used to
extend the time over which the NMR/MRI operation may be performed.
Under appropriate conditions, this technique can also be used to
allow site selective transfer of polarization to analyte nuclei of
interest.
[0187] Moreover, as described herein, the QRS method does not
require use of a trityl radical, and it is also scalable. Also, by
hyper polarizing a solvent first as discussed herein, and then
transferring hyperpolarization to the analyte, an added benefit is
provided in that it is possible to transfer the hyperpolarized
solution to an end location such as an NMR magnet or into a region
of interest such as a patient with a minimum of polarization
loss.
[0188] By way of further example, by providing ready access to many
hyperpolarized solvents, it is possible to avoid the necessity of
using RF pulses to transfer polarization from one material to the
other. For example, employing RF pulses to transfer polarization
using a material disposed in hyperpolarized liquid Xenon, while
possible, is not easily accomplished, and may result in artifacts
in NMR data that need to be accounted for. In contrast, in
accordance with some of the embodiments disclosed herein, by
providing a hyperpolarized solvent having nuclei identical to those
in the solute, hyperpolarization transfer may be accomplished from
solvent to solute by spin diffusion which requires no RF pulses or
does not produce unwanted artifacts in the end data. As such, the
present invention also provides hyperpolarized solvents in addition
to Xenon that may be used to transfer hyperpolarization to an
unpolarized material that contains nuclei that are preferably the
same or substantially the same material as the solvent so as to
facilitate transfer of polarization via spin diffusion.
[0189] However, it will be appreciated that Xenon may be used in
accordance with the invention as a first material that may be
hyperpolarized and used to hyperpolarize a second material in a
variety of contexts, as discussed herein. For example, Xenon may be
used as a hyperpolarization carrier to help hyperpolarize a core
portion of an encapsulated agent having a porous encapsulating
layer as described elsewhere herein. More generally, Xenon may be
used as a first hyperpolarized material that can be used to
hyperpolarize a second material that, in turn, is transported to
another location to be used in studies or for other reasons.
[0190] For all of the methods described in the above patents,
delivery of the hyperpolarized material can be accomplished, for
example, only by warming up the hyperpolarized material and then
flushing it from the transport container. By contrast, the
utilization of a hyperpolarized solvent requires not only that the
hyperpolarization of the solvent survive the trip to the customer's
site but that melting of the HP solvent be correlated with the
input of unpolarized solvent to the sample region as well as to the
customer's NMR magnet. In addition, to ensure efficient transfer of
hyperpolarization to the customer's analyte requires that the
customer's original solution and the melted polarized solvent be
mixed as quickly and as thoroughly as possible. Without this, the
hyperpolarization may become greatly diminished. As such, there is
a significant need for a container that can transport
hyperpolarized solvents and accomplish thorough mixing of the
unpolarized solution and the melted polarized solvent when an
NMR/MRI study is ready to be performed.
[0191] It will be understood that, if desired, the transport
container could be used to transport previously mixed solutions
manufactured in a manner distinct from that described in U.S. Pat.
No. 6,466,814. In this case, the entire solution is transported to
the site of interest. When it is desired to perform an NMR./MRI
study, the solution may be warmed and introduced either into the
sample region of the NMR magnet (for in vitro NMR purposes) or in
vivo, e.g., to a patient (for in vivo MRI purposes).
[0192] Once the hyperpolarized solvent has been transported to a
location where it will be used, the hyperpolarized solvent may be
mixed with a material, such as a sample to be analyzed. Any of a
variety of end users are possible, including research institutions,
hospitals, universities, imaging clinics, drug development
laboratories, contract NMR research facilities and the like. This
can be carried out in a variety of ways. For example, if a frozen
liquid, the hyperpolarized solvent may be mixed with additional
unpolarized solvent in liquid form to form a solvent mixture as
described in detail above. The unpolarized solvent may contain the
analyte of interest already dissolved in it. Alternatively, the
mixture of unpolarized and polarized solvent may be directed to a
container with the analyte, so that the analyte dissolves into the
mixture of polarized and unpolarized solvent; the resulting
solution and/or suspension, colloid, emulsion etc may then be
directed to the NMR magnet for analysis. Alternatively, no
unpolarized solution may be added to the polarized solvent, the
polarized solvent is warmed and directed to a container with the
analyte of interest, the resulting solution and/or suspension,
colloid, emulsion etc may then be directed to the NMR magnet for
analysis. As such, conduit 650 of vessel 605 described above can be
used to deliver a stream of unpolarized material over frozen
hyperpolarized material 600, thereby creating a mixture containing
hyperpolarized material, which can then be used for in vivo MRI or
in vitro NMR analysis.
[0193] In using the hyperpolarized solvent for analysis, it is
generally desirable to increase the temperature of the material so
that it may be used. Preferably, the temperature of the
hyperpolarized solvent is increased in the presence of a magnetic
field having a strength greater than about 1.0 Gauss. A good
example of an embodiment of this aspect of the method can be
demonstrate by use of vessel 605, which preferably includes a means
640 for providing a magnetic field. By way of further example, any
vessel used to transport the hyperpolarized solvent may be disposed
in a magnetic field to facilitate this embodiment of the
invention.
[0194] Even more preferably, the temperature of the hyperpolarized
solvent is increased in the presence of a magnetic field having a
strength greater than about 1.0, 1.5, 3.0, 7.0 Tesla or even 10.0
Tesla. The solvent is preferably increased in temperature within a
time sufficient to avoid substantial loss of hyperpolarization. If
desired, the temperature of the solvent may be increased to room
temperature. If desired, the hyperpolarized solvent may be eluted
from the high surface area substrate, in the event the solution was
initially frozen and hyperpolarized over a high temperature
substrate. By way of further example, if the solution is frozen by
spray freezing as described herein, the frozen particulate may just
be melted. As a general matter, raising the temperature of the
hyperpolarized solvent in the presence of a higher field will
generally preserve hyperpolarization better than a weaker field
will, with all other variables remaining constant.
[0195] By way of further example, once the hyperpolarized solvent
has been provided, it may be mixed with a target material to create
a mixture, such as (i) a solution, (ii) a suspension, (iii) an
emulsion, (iv) a colloid and (v) a composite material, among
others. These could be solutions made from pyruvate in water or
saline, suspensions made from composite materials as described
herein, hyperpolarized hexafluorobenzene or other halogens
suspended directly in water/saline or another physiologically
tolerable fluid, suspensions of solid particles in air or another
gas for inhalation therapy purpose, among others. Emulsions may be
made from Propofol or Diprivan or other emulsions typically
suitable for use in vivo. Colloids may be colloidal silver or
keratinous protein, or Tc-99m sulfur, and the like. Composite
materials may be two phase encapsulated agents such as encapsulated
decafluorobutane gas, and the like.
[0196] Upon mixing the target material with the hyperpolarized
solution, if desired, it is possible to transfer hyperpolarization
to the target material. As a first example, the target material may
be hyperpolarized by way of thorough mixing as described above.
Moreover, the target material may be hyperpolarized by way of
electromagnetic coupling as described above.
[0197] Hyperpolarized solvents may accordingly be used to
hyperpolarize a target material to facilitate analysis thereof.
Thus, in contrast to prior art techniques, such as those described
in U.S. Pat. No. 6,466,814, which is incorporated herein by
reference in its entirety, the solvent in the present invention is
polarized and then used to hyperpolarize a material to be analyzed,
as opposed to introducing hyperpolarized particulate into a
non-hyperpolarized solvent to provide a hyperpolarized solution. As
such, using the hyperpolarized solvent of the invention, it is
possible to facilitate analysis of a material to be analyzed using
NMR spectroscopy, or by way of MR imaging. A hyperpolarized solvent
can be used to greatly speed analysis of a material to be analyzed,
or to facilitate performing an study on a sample that was
previously of too low a concentration to be detectable in an NMR
protocol. In addition, by storing hyperpolarization in the solvent
(which can be selected to have a relatively long T1 relaxation
time), it is possible to use the benefits of hyperpolarization on a
wide variety of materials.
[0198] In still further accordance with the invention, a system and
method for making a hyperpolarized suspension are provided as well
as the hyperpolarized suspension itself.
[0199] In still further accordance with the invention, a method of
making a hyperpolarized suspension is provided as well as the
hyperpolarized suspension itself. The method includes providing a
hyperpolarized material and dispersing the hyperpolarized material
in a medium to create a hyperpolarized suspension. By way of
further example, a hyperpolarized suspension may be provided by
hyperpolarizing a medium and dispersing a material in the medium to
create a hyperpolarized suspension. Moreover, a hyperpolarized
suspension may be made by making a suspension from
non-hyperpolarized components, and hyperpolarizing the suspension
after it is made. Also, a suspension may be provided that is
composed of more than two components, wherein one or more of the
components of the suspension are hyperpolarized prior to mixing
them.
[0200] The hyperpolarized material used to make the suspension may
be hyperpolarized using any technique disclosed herein, such as (i)
dynamic nuclear polarization, (ii) the Nuclear Overhauser effect,
(ii) parahydrogen induced polarization, (iii) hyperpolarization
using a quantum relaxation switch, and (iv) transferring
hyperpolarization to molecules of the material by exposing them to
hyperpolarized nuclei of a previously hyperpolarized gas and
combinations thereof.
[0201] The hyperpolarized material used to make the suspension is
preferably provided in a particulate form, having an average
diameter of less than about one thousand microns. More preferably,
the hyperpolarized material has a diameter of less than about one
hundred microns. Even more preferably, the hyperpolarized material
has a diameter of less than about ten microns, five microns or one
micron. Preferably, the medium is a physiologically tolerable
medium, as illustrated above herein.
[0202] Preferably, the hyperpolarized material is dispersed in the
medium to create the suspension in the presence of a magnetic
field. The magnetic field may have a field strength in excess of
1.0 Gauss. In accordance with still a further aspect, the medium
may be selected from the group including (i) a solid, (ii) a liquid
and (iii) a gas. For example, the medium may be air. Accordingly,
if desired, the method may further include introducing the
hyperpolarized suspension into a region of interest such as the
respiratory tract of the patient. Materials that may be suspended
include, for example, powdered danizol, powdered insulin, and other
powdered APIs and/or excipients, among others.
[0203] Preferably, the system further includes means for
transporting the hyperpolarized suspension from a first location to
a second location, similar to the hyperpolarized solvent above,
such as a container similar to container 605. As such, it will be
appreciated that the hyperpolarized suspension may be made at the
same location as the location where the hyperpolarized material is
initially hyperpolarized, or a different location, such as at a
production facility, or at the location of an end user, such as a
hospital or clinic.
[0204] In further accordance with the invention, a method of making
a hyperpolarized emulsion is provided, as well as the
hyperpolarized emulsion itself. The method includes providing a
hyperpolarized material, and mixing the hyperpolarized material
with a medium to create a hyperpolarized emulsion. The method may
alternatively include hyperpolarizing a medium and mixing a
material into the medium to create a hyperpolarized emulsion.
Moreover, a hyperpolarized emulsion may be made by making an
emulsion from non-hyperpolarized components, and hyperpolarizing
the emulsion after it is made. Also, an emulsion may be provided
that is composed of more than two components, wherein one or more
of the components of the emulsion are hyperpolarized prior to
mixing them.
[0205] For purposes of illustration and not limitation, as embodied
herein, a hyperpolarized material is provided, which is then mixed
with a medium to create a hyperpolarized emulsion. The
hyperpolarized material may be hyperpolarized using a technique
selected from the group including (i) dynamic nuclear polarization,
(ii) the Nuclear Overhauser effect, (ii) parahydrogen induced
polarization, (iii) hyperpolarization using a quantum relaxation
switch, and (iv) transferring hyperpolarization to molecules of the
material by exposing them to hyperpolarized nuclei of a previously
hyperpolarized gas and combinations thereof. Preferably, the medium
is a physiologically tolerable medium.
[0206] The mixing of the hyperpolarized material and medium
preferably takes place in the presence of a magnetic field having a
strength of at least about 1.0 Gauss. Moreover, the mixing step
preferably takes place at a temperature at which the hyperpolarized
material and medium are both in a liquid form. However, if desired,
the either hyperpolarized material and medium may be in a solid,
liquid or gaseous form when they are mixed. Emulsions might be
made, for example, from Propofol or Diprivan or other emulsions
typically suitable for use in vivo. Various hardware used to create
mixtures using solutions described above and transporting
hyperpolarized materials may also be employed in practicing this
aspect of the invention.
[0207] In further accordance with the invention, a method of making
a hyperpolarized colloid is provided as well as the hyperpolarized
colloid itself. The method includes providing a hyperpolarized
material, and mixing the hyperpolarized material with a medium to
create a hyperpolarized colloid. The method may alternatively
include hyperpolarizing a medium and mixing a material into the
medium to create a hyperpolarized colloid. Moreover, a
hyperpolarized colloid may be made by making a colloid from
non-hyperpolarized components, and hyperpolarizing the colloid
after it is made. Also, a colloid may be provided that is composed
of more than two components, wherein one or more of the components
of the colloid are hyperpolarized prior to mixing them.
[0208] For purposes of illustration and not limitation, as embodied
herein, a hyperpolarized material is first provided that is mixed
with a medium to create a hyperpolarized colloid. As will be
appreciated, a colloid generally includes a system of particles
with linear dimensions in the range of about 1.times.10.sup.-7 to
5.times.10.sup.-5 cm dispersed in a continuous gaseous, liquid, or
solid medium whose properties depend on the large specific surface
area. The particles can be large molecules like proteins, or solid,
liquid, or gaseous aggregates. The particles generally remain
dispersed indefinitely. Examples include colloidal silver or
keratinous protein, or Tc-99m sulfur, among others.
[0209] The hyperpolarized material may be hyperpolarized using any
of the techniques described herein. Moreover, the medium is
preferably a physiologically tolerable medium.
[0210] In accordance with a further aspect, the mixing step may
take place in the presence of a magnetic field, such as one having
a strength of at least about 1.0 Gauss. In accordance with yet a
further aspect, a system for making a hyperpolarized colloid is
provided. The system includes means for providing a hyperpolarized
material, and means for mixing the hyperpolarized material with a
medium to create a hyperpolarized colloid. If desired, the system
may further include means for transporting the hyperpolarized
colloid from a first location to a second location, as described
herein. Various hardware used to create mixtures using solutions
described above and transporting hyperpolarized materials may also
be employed in practicing this aspect of the invention.
[0211] In further accordance with the invention, a method and
system of making a hyperpolarized composite material is provided,
as well as the hyperpolarized composite material made in accordance
with the method. The method includes providing a hyperpolarized
material, and mixing the hyperpolarized material with a medium to
create a hyperpolarized composite material. The method may
alternatively include hyperpolarizing a medium and mixing a
material into the medium to create a hyperpolarized composite
material. Moreover, a hyperpolarized composite material may be made
by making a composite material from non-hyperpolarized components,
and hyperpolarizing the composite material after it is made. Also,
a composite material may be provided that is composed of more than
two components, wherein one or more of the components of the
composite material are hyperpolarized prior to mixing them. The
system includes means for carrying out each aspect of the method.
Various hardware used to create mixtures using solutions described
above and transporting hyperpolarized materials may also be
employed in practicing this aspect of the invention as well.
[0212] The hyperpolarized composite material may be produced, for
example, by providing a hyperpolarized material, and mixing the
hyperpolarized material with a medium to create a hyperpolarized
composite material. The hyperpolarized material may be produced
using any of the techniques described herein. Preferably, the
medium is a physiologically tolerable medium.
[0213] In accordance with still a further aspect, the mixing step
may take place in the presence of a magnetic field. Preferably, the
magnetic field has a strength of at least about 1.0 Gauss. The
hyperpolarized material may be selected from the group including
(i) a solid material, (ii) a liquid material, (iii) a gaseous
material and combinations thereof. The medium may be any suitable
medium for forming a hyperpolarized composite material, such as
water and saline, among others.
[0214] In further accordance with the invention, a beneficial agent
is provided. The beneficial agent includes a hyperpolarized core
material surrounded by a porous encapsulating medium.
[0215] For purposes of illustration and not limitation, as embodied
herein and as depicted in FIGS. 7(A)-7(F), a method and system are
provided for preparing a beneficial agent 700 having an
encapsulating layer or medium, 710 and a core portion 720.
[0216] The porosity of the encapsulating medium 710 may
substantially permit passage of gas through the encapsulating
medium to the core material 720. For example, the porosity of the
encapsulating medium 710 may substantially permit passage of helium
through the encapsulating medium, but may also substantially
prohibit passage of gas molecules through the encapsulating medium
larger than helium. This can be particularly useful when a
technique such as QRS is used to hyperpolarize the core material,
as the .sup.3He and .sup.4He may pass into the core 720 to help
hyperpolarize it. The .sup.3He may be allowed to pass through the
encapsulating material either before or after cooling and in either
gas or liquid form. The superfluid .sup.4He is most advantageously
applied after the material is cooled and hyperpolarized and is
therefore in liquid form only.
[0217] In accordance with still a further aspect, the
hyperpolarized core material may have a relatively long
spin-lattice relaxation time. For example, the hyperpolarized core
material may include material containing nuclei selected from the
group including .sup.13C, .sup.15N, .sup.1H, .sup.2H, .sup.31P,
.sup.19F, .sup.29Si and combinations thereof, among others.
[0218] In accordance with still another aspect, the encapsulating
medium may include polymeric material. The polymeric material may
include a material selected from the group including
polytetrafluoroethylene, poly(lactic-co-glycolic acid),
polyanhydrides, polyorthoesters, polyvinylalchols, and combinations
thereof. Preferably, the encapsulating medium is adapted and
configured to substantially maintain its structural integrity at
temperatures below 100K, 10K and 1K, if desired. By way of further
example, the encapsulating material may also include hyperpolarized
material.
[0219] In accordance with a further aspect, the hyperpolarized core
material may include material that is solid at standard conditions.
The term "standard conditions" as used herein is intended to convey
conditions of room temperature (about 60 to about 80 degrees
Fahrenheit) and atmospheric pressure (about one atmosphere).
[0220] The hyperpolarized core material may include material that
is liquid, gaseous or solid at standard conditions. If desired, the
beneficial agent may be provided in the form of a capsule having an
average diameter between about 0.001 microns and about 100 microns.
Preferably, the beneficial agent is provided in the form of a
capsule having an average diameter between about 0.001 microns and
about 10 microns. Particularly advantageous size ranges are those
that allow for the capsules to pass through small in vivo
capillaries (several microns or less) that speed penetration across
the blood brain barrier or into any other tissue type.
[0221] As a non exclusive example, decafluorobutane gas
encapsulated in porous microparticles are currently in advanced FDA
trials for use as in ultrasound imaging protocols. In accordance
with the teachings herein, the .sup.19F spins in the
decafluorobutane may be used as an HP agent. .sup.19F spins in
similarly configured halogens have been shown to have reasonably
long T.sub.1 relaxation times and .sup.19F has a very low natural
background in vivo.
[0222] In accordance with a further aspect, the beneficial agent
may include a functional element disposed proximate the
encapsulating medium, the functional element being adapted and
configured to facilitate a beneficial result in use. The functional
element may be selected from the group including proteins, mRNA,
genetic probes, or any other material that binds preferentially to
or otherwise seeks out biological activity and combinations
thereof, among others. The functional element may be added to the
beneficial agent prior to, during, or after hyperpolarization, as
desired.
[0223] Thus, as will be appreciated, a coating 770 of a functional
element may be provided on the surface of the beneficial agent 700
as depicted in FIG. 7(F). The functional element may be deposited
directly on surface of shell 710, or may be caused to adhere to the
surface of beneficial agent 700 according with a suitable surface
treatment.
[0224] Another example of a composite material and beneficial agent
700 is a liposome containing hyperpolarized material. Liposomes may
be used for drug delivery due to their unique properties. A
liposome encapsulates a region on aqueous solution inside a
hydrophobic membrane such that dissolved hydrophilic solutes can
not readily pass through the lipids. Hydrophobic chemicals can be
dissolved into the membrane, and in this way liposome can carry
both hydrophobic molecules and hydrophilic molecules. To deliver
the molecules to sites of action, the lipid bilayer can fuse with
other bilayers such as the cell membrane, thus delivering the
liposome contents. By making liposomes in a solution of DNA or
drugs, (which would normally be unable to diffuse through the
membrane), they can be (indiscriminately) delivered past the lipid
bilayer.
[0225] Liposomes also have a natural ability to target cancer. The
endothelial wall of all healthy human blood vessels are
encapsulated by endothelial cells that are bound together by tight
junctions. These tight junctions stop any large particle in the
blood from leaking out of the vessel. Tumor vessels do not contain
the same level of seal between cells and are diagnostically leaky.
This ability is known as the Enhanced Permeability and Retention
effect. Liposomes of certain sizes, typically less than 400 nm, can
rapidly enter tumor sites from the blood, but are kept in the
bloodstream by the endothelial wall in healthy tissue
vasculature.
[0226] As will be appreciated, liposomes can be used as a vehicle
to deliver hyperpolarized materials. For example, a hyperpolarized
material (e.g., a hyperpolarized solvent or other mixture or
material as described herein) may be incorporated into liposomes or
material of the liposome itself may be caused to be hyperpolarized.
These liposomes may be injected into a region of interest, such as
a portion of a patient. The liposomes will seek out particular
anatomy, and effectively deliver hyperpolarized materials to cells
such where the contents of the liposome may be metabolized. For
example, the metabolite products of the metabolism of
hyperpolarized pyruvate delivered to a cancer cell by a liposome
can accordingly be detected using NMR/MR techniques to determine
the presence of a tumor. In the end, what happens is that the
hyperpolarization from the pyruvate is transferred to the
metabolites.
[0227] Moreover, it is possible to transfer hyperpolarization from
a first material to a second material through a barrier, even when
the two materials are not in direct physical contact. Specifically,
if at least one of the two materials has a high "distant dipolar
field" or "DDF", if desired, in accordance with the invention, one
may hyperpolarize the contents of a body, such as a liposome or
encapsulated material across the barrier (e.g., liposome body or
encapsulating material) by taking advantage of this phenomenon.
[0228] Thus, in accordance with the invention, it is possible to
administer a beneficial agent in the form of a hyperpolarized
mixture such as a solution, suspension, emulsion, colloid or
composite material, among others, to a region of interest, such as
a patient. The mixture may be exposed to radiation of a frequency
selected to excite nuclear spin transitions in the mixture. Next,
it is possible to detect magnetic resonance signals from the
mixture. As will be appreciated, optionally, it is possible to
generate an image, dynamic flow data, diffusion data, perfusion
data, physiological data, metabolic data or any other suitable data
from the detected signals, and to transport such a material from a
first location to a second location.
[0229] Thus, when delivered in vivo intravenously, for example, a
layer 770 of functional element (or liposome as described herein)
will tend to adhere to tissue that it is desired to image, such as
tumors and the like. This will facilitate obtaining a strong MR
signal from that region of interest, thus facilitating definitively
localizing tissue of interest with great sensitivity.
[0230] By way of further example, the invention also provides a
beneficial agent including a hyperpolarized core material
surrounded by an encapsulating medium, wherein the hyperpolarized
core material includes material selected from the group including
(i) liquid material, (ii) solid material, (iii) gaseous material
interspersed with a solid material, (iv) gaseous material
interspersed with a liquid material, and combinations thereof. The
encapsulating medium need not be porous in accordance with this
aspect of the invention. Other aspects of the encapsulated medium
described above are equally applicable to this embodiment of the
invention. Accordingly, the encapsulating medium may be closed
without pores, and the core material may be hyperpolarized, for
example, by using DNP.
[0231] In further accordance with the invention, a kit for
providing hyperpolarized material is provided.
[0232] For purposes of illustration and not limitation, as embodied
herein, the kit includes at least one encapsulated material,
similar to material 700 above. The encapsulated material includes a
core material 720, which in turn includes a material having a
relatively long spin-lattice relaxation time as described herein.
The encapsulated material further includes an encapsulating medium
710 surrounding the core material. The kit also includes
instructions for facilitating hyperpolarization of the encapsulated
material.
[0233] The instructions for the kit preferably describe how to
facilitate hyperpolarization of the encapsulated material. For
example, the instructions may provide guidance for hyperpolarizing
the core material using a quantum relaxation switch. By way of
further example, the instructions of the kit may describe how to
facilitate hyperpolarization of the encapsulated material by
transferring hyperpolarization from a hyperpolarization carrier to
the core material. In accordance with still a further aspect, the
core material may be hyperpolarized using a technique selected from
the group including (i) dynamic nuclear polarization, (ii) the
Nuclear Overhauser effect, (ii) parahydrogen induced polarization,
(iii) hyperpolarization using a quantum relaxation switch, and (iv)
transferring hyperpolarization to molecules of the core material by
exposing them to hyperpolarized nuclei of a previously
hyperpolarized gas and combinations thereof.
[0234] In further accordance with the invention, a method of
preparing and providing hyperpolarized encapsulated material is
provided.
[0235] For purposes of illustration and not limitation, as embodied
herein, in accordance with a first aspect, the method includes
providing an encapsulated material, exposing the encapsulated
material to a hyperpolarization carrier (and/or hyperpolarization
facilitator, such as .sup.3He in the context of QRS, which
facilitates hyperpolarization but is not necessarily a
hyperpolarization carrier itself), hyperpolarizing the
hyperpolarization carrier, and transferring hyperpolarization from
the hyperpolarization carrier to the encapsulated material.
[0236] The hyperpolarization carrier may be hyperpolarized using a
technique selected from the group including (i) dynamic nuclear
polarization, (ii) optical pumping, (iii) parahydrogen induced
polarization, (iv) hyperpolarization using a quantum relaxation
switch, (v) transferring hyperpolarization to molecules of the
hyperpolarization carrier by exposing them to hyperpolarized nuclei
of a previously hyperpolarized gas, (vi) the Nuclear Overhauser
effect and combinations thereof.
[0237] The encapsulated material may include a porous surface
portion to permit passage of the hyperpolarization carrier
therethrough as described herein. As such, the hyperpolarization
carrier may pass through the surface portion to the core portion.
For example, the hyperpolarization carrier may include gaseous
hyperpolarized xenon. In accordance with still a further aspect,
the core portion may include material containing nuclei selected
from the group including .sup.13C, .sup.15N, H, .sup.31P, .sup.19F,
.sup.29Si and combinations thereof.
[0238] The encapsulated material may further be cooled and/or
subjected to a magnetic field to help induce and/or maintain
hyperpolarization. Preferably, the encapsulated material is cooled
to a temperature below about 100K, 10K or 1K. The magnetic field
may have a maximum strength in excess of 10 mT, 1 T, or 10 T, for
example.
[0239] If desired, the encapsulated material may be maintained at a
low temperature and in a magnetic field for an extended period of
time, such as between about one tenth of a second and about one
week. The encapsulated hyperpolarized material may be transported
in a container from a first location to a second location, as
described herein. Prior to using the encapsulated hyperpolarized
material, the temperature of the encapsulated material may first be
increased such that substantial loss of hyperpolarization is
avoided. The encapsulated hyperpolarized material may then be
introduced into a region of interest to be analyzed. For example,
magnetic resonance images of the region of interest may be
generated. By way of further example, NMR spectra of an in vitro or
in vivo sample may be analyzed.
[0240] It will be appreciated that the advantages of using
encapsulated material is that the hyperpolarized core may be
delivered to a desired region in vivo with minimum loss of
hyperpolarization. In particular, by employing an encapsulating
agent that excludes passage of oxygen or other depolarizing
elements, the hyperpolarization of the encapsulated material may be
extended as long as possible. Encapsulating materials that have
already been approved for use in vivo are commercially
available.
[0241] In accordance with a preferred embodiment, QRS is used to
hyperpolarize the encapsulated material. Accordingly, the
encapsulated material is exposed to .sup.3He in lieu of a different
material that has been previously hyperpolarized, such as a gas
(e.g., .sup.129Xe or others). Preferably, as embodied herein and as
depicted in FIGS. 7(A)-7(F), the encapsulated material 700 has a
porous outer shell portion 710 to permit passage of the .sup.3He
therethrough. However, it will be recognized that the capsule may
have a surface portion that can be hyperpolarized, and a separate
core portion need not be provided. However, the surface portion may
nonetheless permit passage of a gas therethrough into a core
portion of the encapsulated material, as described herein
above.
[0242] In order to hyperpolarize the capsules and/or encapsulated
material, as depicted in FIG. 7(C), at least one monolayer of
.sup.3He is formed on the structures to be hyperpolarized, for
example, by pumping all other gas from a chamber 730 in which the
beneficial agent 700 is contained. In accordance with one
embodiment, the agent 720 may then freeze and contract away from
polymer shell 710, leaving a gap 740 as depicted in FIG. 7(D).
Layer 710 is preferably permeable to liquid .sup.3He to permit a
layer of .sup.3He to form around the agent 720. The .sup.3He
relaxes nuclei in agent 720 to facilitate hyperpolarization
condition. The agent 720 is then exposed to a high magnetic field
at low temperatures for a time sufficient for nuclear
hyperpolarization to occur.
[0243] As depicted in FIG. 7(F), the agent 700 may then be exposed
to .sup.4He to displace the .sup.3He from the material, thus
preserving the hyperpolarization of the material, but removing the
.sup.3He. In accordance with one embodiment, the hyperpolarized
material may be maintained at a low temperature and/or in a
magnetic field for an extended period of time. Maintaining the
hyperpolarized material in such a manner facilitates storage and/or
transport of the material, and minimizes loss of hyperpolarization
from the material as described herein over significant periods of
time. The hyperpolarized encapsulated material/capsules may be
increased in temperature for use as described herein, if desired.
Preferably, the temperature of the encapsulated material/capsules
is increased in a manner that minimizes a substantial loss of the
material's hyperpolarization.
[0244] It will be appreciated that the compositions methods and
systems of the present invention, as described above and shown in
the drawings, provide hyperpolarized materials in novel and useful
forms, as well as facilitating the manufacture and delivery of
hyperpolarized materials to end users.
[0245] It will be apparent to those skilled in the art that various
modifications and variations can be made in the device and method
and compositions of the present invention without departing from
the spirit or scope of the invention. For example, it will be
understood that any component in any solution, suspension,
emulsion, colloid, composite material, or the like disclosed herein
may be hyperpolarized. By way of further example, multiple
components of such mixtures may be hyperpolarized. Moreover, it
will be further appreciated that any such material may be
hyperpolarized by way of at least: i) dynamic nuclear polarization,
(ii) the Nuclear Overhauser effect, (ii) parahydrogen induced
polarization, (iii) hyperpolarization using a brute force
environment, most preferably in conjunction with a quantum
relaxation switch, (iv) transferring hyperpolarization to molecules
of the particles composed of various materials by exposing them to
hyperpolarized nuclei of a previously hyperpolarized gas, and
combinations thereof.
[0246] Mixing of components in the various mixtures disclosed
herein may take place either before or after inducing
hyperpolarization as described herein. Thus, it is intended that
the present invention include modifications and variations that are
within the scope of the appended claims and their equivalents.
* * * * *