U.S. patent application number 12/646258 was filed with the patent office on 2010-04-22 for method of hyperthemia treatment.
This patent application is currently assigned to FLORIDA STATE UNIVERSITY RESEARCH FOUNDATION. Invention is credited to Ching-Jen Chen, Yousef Haik.
Application Number | 20100099941 12/646258 |
Document ID | / |
Family ID | 35239702 |
Filed Date | 2010-04-22 |
United States Patent
Application |
20100099941 |
Kind Code |
A1 |
Haik; Yousef ; et
al. |
April 22, 2010 |
METHOD OF HYPERTHEMIA TREATMENT
Abstract
Magnetic nanoparticle compositions are provided which provide an
inherent temperature regulator for use in magnetic heating,
particularly for use in magnetic hyperthermia medical treatments.
The composition includes magnetic nanoparticles having a Curie
temperature of between 40 and 46.degree. C., preferably about
42.degree. C., and may further include a polymeric material and
optionally a drug or radiosensitizing agent. Methods of
hyperthermia treatment of a patient in need thereof are provided
which include administering to the patient a composition comprising
magnetic nanoparticles having a Curie temperature of between 40 and
46.degree. C.; and exposing the magnetic nanoparticles in the
patient to an alternating magnetic field effective to generate
hysteresis heat in the nanoparticles.
Inventors: |
Haik; Yousef; (Tallahassee,
FL) ; Chen; Ching-Jen; (Tallahassee, FL) |
Correspondence
Address: |
SUTHERLAND ASBILL & BRENNAN LLP
999 PEACHTREE STREET, N.E.
ATLANTA
GA
30309
US
|
Assignee: |
FLORIDA STATE UNIVERSITY RESEARCH
FOUNDATION
Tallahassee
FL
|
Family ID: |
35239702 |
Appl. No.: |
12/646258 |
Filed: |
December 23, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11125488 |
May 10, 2005 |
|
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12646258 |
|
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60569726 |
May 10, 2004 |
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Current U.S.
Class: |
600/12 |
Current CPC
Class: |
A61K 33/34 20130101;
A61N 1/406 20130101; A61K 33/32 20130101; Y10T 428/2998 20150115;
A61K 33/26 20130101; A61K 33/24 20130101 |
Class at
Publication: |
600/12 |
International
Class: |
A61N 2/00 20060101
A61N002/00 |
Claims
1. A method of hyperthermia treatment of a patient in need thereof
comprising: administering to the patient a composition comprising
magnetic nanoparticles having a Curie temperature of between 40 and
46.degree. C.; and exposing the magnetic nanoparticles in the
patient to an alternating current magnetic field effective to
generate hysteresis heat in the nanoparticles.
2. The method of claim 1, wherein the composition is administered
to a tumor or other diseased tissue in the patient.
3. The method of claims 1, wherein the nanoparticles are coated by
a biocompatible polymeric matrix material.
4. The method of claim 1, wherein the nanoparticles are
administered to a cancerous tissue site and the cancerous tissue
site is further treated with one or more therapeutic drugs, one or
more therapeutic radiation treatments, or a combination
thereof.
5. The method of claim 1, wherein the magnetic nanoparticles have a
Curie temperature between 41 and 44.degree. C.
6. The method of claim 1, wherein the magnetic nanoparticles have a
Curie temperature of 42.degree. C.
7. The method of claim 1, wherein the nanoparticles comprise an
alloy of copper and nickel.
8. The method of claim 7, wherein the alloy comprises from 71 to
71.4 wt % nickel.
9. The method of claim 7, wherein the alloy comprises 71 wt %
nickel and 29 wt % copper.
10. The method of claim 1, wherein the nanoparticles comprise a
ferrite.
11. The method of claim 10, wherein the ferrite is selected from
the group consisting of Zn ferrite, Gd-substituted Zn ferrite,
Mn--Zn ferrite, Gd-substituted Mn--Zn-ferrite, and Fe--Zn
ferrite.
12. The method of claim 10, wherein the ferrite is selected from
the group consisting of Zn ferrite, Mn--Zn ferrite, and Fe--Zn
ferrite.
13. The method of claim 10, wherein the nanoparticles have a
composition of the formula
Mn.sub.0.5Zn.sub.0.5Gd.sub.xFe.sub.(2-x)O.sub.4, where x is from 0
to 1.5, inclusive.
14. The method of claim 10, wherein the nanoparticles have a
composition of the formula Zn.sub.xMn.sub.(1-x)Fe.sub.2O.sub.4,
where x is between 0.6 and 0.8.
15. The method of claim 10, wherein the nanoparticles have a
composition of the formula Fe.sub.(1-x)Zn.sub.xFe.sub.2O.sub.4,
where x is between 0.7 and 0.9.
16. The method of claim 10, wherein the nanoparticles have a
composition of the formula ZnGd.sub.xFe.sub.(2-x)O.sub.4, where x
is between 0.01 and 0.8.
17. The method of claim 1, wherein the nanoparticles have an
effective mean diameter between 5 nm and 400 nm.
18. The method of claim 1, wherein the magnetic nanoparticles and a
drug are contained in a biodegradable polymeric material.
19. The method of claim 1, where the magnetic nanoparticles are
administered to the patient in a pharmaceutically acceptable
vehicle for injection.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 11/125,488, filed May 10, 2005, which claims the benefit
of U.S. Provisional Application No. 60/569,726, filed May 10, 2004.
The applications are incorporated herein by reference in its
entirety.
BACKGROUND OF THE INVENTION
[0002] This invention relates generally to magnetic nanoparticle
compositions, and more particularly to magnetic nanoparticle
compositions useful in self-controlled hyperthermia treatment.
[0003] Diseases of the human body such as malignant tumors are
generally treated by excision, chemotherapy, radiotherapy or a
combination of these approaches. Each approach has limitations
affecting it clinical utility. For example, excision may not be
appropriate where the disease presents as a diffuse mass or is in a
surgically inoperable location. Chemotherapeutic agents are
generally non-specific, thus resulting in the death of both normal
and diseased cells. Radiotherapy is also nonspecific and results in
the death of normal tissues exposed to ionizing radiation. In
addition, some diseases such as tumors, particularly the core of a
tumor mass, may be relatively resistant to ionizing radiation or
chemotherapeutic agents.
[0004] Hyperthermia has been proposed as a cancer treatment, and
published evidence confirms that hyperthermia is effective in
treating diseases like cancerous growths. It is understood that
malignant cells are reliably more sensitive to heat than normal
cells. The therapeutic benefit of hyperthermia therapy is mediated
through two principal mechanisms: (1) a directly tumoricidal effect
on tissue by raising temperatures to greater than 42.degree. C.,
resulting in irreversible damage to cancer cells; and (2)
hyperthermia sensitizes cancer cells to the effects of radiation
therapy or to certain chemotherapeutic drugs. The lack of any
cumulative toxicity associated with hyperthermia therapy, in
contrast to radiotherapy or chemotherapy, further suggests the
desirability of developing improved systems for hyperthermia
therapy. While considerable success has been observed in treating
superficial tumors using hyperthermia therapy, there remains a need
for a method of selectively targeting and treating diseased tissue
in a patient.
[0005] A large fraction of a tumor's mass is made of hypoxic
(poorly oxygenated) cells. Hypoxic cells are much more resistive to
radiation therapy than euoxic (well oxygenated) cells. It has been
reported that when heat and a radiosensitizing agent (e.g.,
misonidazole) are used in combination with each other, they produce
synergistic potentiation effects. See Schneiderman, et al., Radial.
Res. 155:529-35 (2001); Billi, et al., Appl. & Environm.
Microbiology 66: 1489-92 (2000); and Hofer, "Hyperthermia and
Cancer," 4.sup.th Int. Conf. Scientific and Clinical Applications
of Magnetic Carriers, Tallahassee-Fla., pp. 78-80 (2002). In
Hofer's report, hypoxic cancer cells subjected to the two agents
during irradiation showed a response enhanced by a factor of 4.3,
which far exceeded the euoxic cells. However, Hofer's whole body
heating approach is not optimal for clinical application on human,
because whole-body heating limits the heat dose that can be given.
It would be more desirable to provide a combination therapy in
which only the tumor region is heated, i.e., selective
hyperthermia.
[0006] Clinical feasibility of treating cancer by hyperthermia
alone has been investigated (Jordan, et al., 2nd Int. Conf.
Scientific and Clinical Applications of Magnetic Carriers,
Cleveland-Ohio, 29 (1998); Hofer et al., Cancer 58: 279-87 (1976)).
Limitations of these methods are due either to the invasive
thermometry or in their inability to reach optimal temperature for
the tumor sites when noninvasive techniques are used, especially in
the treatment of deep-seated tumors.
[0007] Localized heating utilizing a ferromagnetic alloy as
"thermoseeds" has been investigated. These particles will generate
heat when subjected to an applied alternating magnetic field
(Jordan, et al., 2nd Int. Conf. Scientific and Clinical
Applications of Magnetic Carriers, Cleveland-Ohio, 29 (1998)).
However, at least two impediments to clinical implementation have
been identified: (1) the lack of uniform heat distribution at the
tumor site and the resultant creation of spot overheating that
leads to necrosis; and (2) the size of these thermoseed particles
are on the order of 1 to 5 cm, making them highly
non-biocompatible.
[0008] The ability to produce magnetic nanoparticles in recent
years has enhanced interest in localized heating. In this
technique, magnetic particles are confined on site and are heated
by an external oscillating electromagnetic field (Lilly et al.,
Radiology, 154:243 (1985); Chan, et al., J. Magn. Mater. 122:374
(1993); Jordan, et al., Int. J. Hyperthermia, 12:705 (1996)). Other
examples are disclosed in Pankhurst et al., Phys. D: Appl. Phys.,
36:R167-81 (2003); Kuznetsov et al., Eur. Cells Mater., 3:75-77
(2003); Jordan et al., J. Magn. Magn. Mater., 201:413-19 (1999).
The use of nanomagnetic particles to induce heat at the tumor
tissue potentially would minimize side effects by localized heating
of only the desired parts of the organism, including tumors located
deep inside a patient's body. Unfortunately, conventional magnetic
particles make it impossible to control the uneven heating at the
tumor site, which may cause local overheating and necrosis of
healthy tissue.
[0009] It therefore would be desirable to provide improved magnetic
particle compositions that reduce or eliminate the problem of
uneven heating, and possess a property to self regulate the maximum
temperature it can attain making magnetic hyperthermia a more
viable therapeutic option.
SUMMARY OF THE INVENTION
[0010] Magnetic nanoparticle compositions are provided which
provide an inherent temperature regulator for use in magnetic
heating, particularly for use in magnetic hyperthermia medical
treatments. In one aspect, a composition is provided that includes
magnetic nanoparticles having a Curie temperature of between 40 and
46.degree. C., for example, between 41 and 44.degree. C.,
preferably about 42.degree. C.
[0011] In one embodiment, the magnetic nanoparticles comprise an
alloy of copper and nickel. For example, the alloy can be 71 to
71.4 wt % nickel, e.g., where the alloy is 71 wt % nickel and 29 wt
% copper.
[0012] In another embodiment, the nanoparticles comprise a ferrite.
For example, the ferrite can be selected from Zn ferrite,
Gd-substituted Zn ferrite, Mn--Zn ferrite, Gd-substituted
Mn--Zn-ferrite, and Fe--Zn ferrite. In one particular embodiment,
the nanoparticles have a composition of the formula
Mn.sub.0.5Zn.sub.0.5Gd.sub.xFe.sub.(2-x)O.sub.4, where x is between
0 and 1.5. In another particular embodiment, the nanoparticles have
a composition of the formula Zn.sub.xMn.sub.(1-x)Fe.sub.2O.sub.4,
where x is between 0.6 and 0.8. In still another particular
embodiment, the nanoparticles have a composition of the formula
Fe.sub.(1-x)Zn.sub.xFe.sub.2O.sub.4, where x is between 0.7 and
0.9. In yet another particular embodiment, the nanoparticles have a
composition of the formula ZnGd.sub.xFe.sub.(2-x)O.sub.4, where x
is between 0.01 and 0.8.
[0013] In various embodiments, the magnetic nanoparticles have an
effective mean diameter of between 5 nm and 400 nm.
[0014] In several embodiments, the composition further includes a
polymeric material. For example, the nanoparticles may be coated by
or dispersed in a biocompatible polymeric material.
[0015] In another embodiment, the composition further includes at
least one drug. In one particular embodiment, the magnetic
nanoparticles and the drug are contained (e.g., encapsulated) in a
biodegradable polymeric material, which may be in the form of
microparticles or nanoparticles.
[0016] The nanoparticles of the composition can be made by various
techniques. In one embodiment, the nanoparticles are made by a
process comprising the steps of: (a) forming a melt which comprises
at least two different metals; (b) solidifying the melt to form a
bulk solid alloy of the metals; (c) grinding the bulk solid alloy
to form particles of the alloy; and (d) subjecting the particles to
a ball milling process effective to form magnetic nanoparticles of
the alloy. For example, the at least two elemental metals may
include copper and nickel. In another embodiment, the magnetic
nanoparticles are made by a chemical coprecipitation process.
[0017] In another aspect, methods are provided for hyperthermia
treatment of a patient in need thereof. In one embodiment, the
method includes administering to the patient a composition
comprising magnetic nanoparticles having a Curie temperature of
between 40 and 46.degree. C.; and then exposing the magnetic
nanoparticles in the patient to an alternating magnetic field
effective to generate hysteresis heat in the nanoparticles. In a
preferred embodiment, the composition is administered to a tumor or
other diseased tissue in the patient. The nanoparticles may be
coated by a biocompatible polymeric material. In another
embodiment, the magnetic nanoparticles are administered to a
cancerous tissue site and the cancerous tissue site is further
treated with one or more therapeutic drugs, one or more therapeutic
radiation treatments, or a combination thereof.
[0018] In another aspect, a pharmaceutical composition is provided
that includes magnetic nanoparticles having a Curie temperature of
between 41 and 44.degree. C., and a pharmaceutically acceptable
carrier.
BRIEF DESCRIPTION OF THE FIGURES
[0019] FIG. 1 is a graph showing the magnetization and magnetic
phase transition (Curie temperature) for a copper/nickel alloy in
bulk, ground powder, and ball milled nanoparticulate forms, in a
magnetic field of 100 Oe, illustrating the change in magnetic
characteristics that occurs as the alloy is processed into
nanoparticle form.
[0020] FIG. 2 shows a hysteresis plot of a ball milled
nanoparticulate form of a copper/nickel alloy, exhibiting magnetic
behavior similar to superparamagentic materials.
[0021] FIG. 3 is a graph illustrating XRD diffraction pattern of
94.37 wt % Ni and 5.63 wt % Cr.
[0022] FIG. 4 is a graph illustrating the mass magnetization of
Ni.sub.1-xCr.sub.x alloys versus temperature at H=100 Oe applied
magnetic field parallel to the normal direction. The Curie
temperatures of the samples were determined by M.sup.3 versus T
plots by extrapolating M.sup.3 to zero.
[0023] FIG. 5 is a graph illustrating Arrot's of Ni-5.63 wt %
Cr.
[0024] FIG. 6 is a graph illustrating the Curie temperature of
Ni.sub.1-xCr.sub.x alloys versus Cr wt % concentration.
[0025] FIG. 7 is a graph illustrating the field dependence of the
magnetization of Ni.sub.1-xCr.sub.x alloys at 300 K.
[0026] FIG. 8 is a graph illustrating X-ray powder diffraction
results for samples of Mn--Zn-Ferrite nanoparticles and
Gd-substituted Mn--Zn-Ferrite nanoparticles with different amounts
of Gd in the composition.
[0027] FIG. 9 is a plot of hystersis curves for various
Gd-substituted Mn--Zn-Ferrite nanoparticles.
[0028] FIG. 10 is a graph illustrating the change in saturation
magnetization with increasing Gd substitution for one embodiment of
Gd-substituted Mn--Zn-Ferrite nanoparticles.
[0029] FIG. 11 is a graph illustrating the change in coercivity
with increasing Gd substitution for one embodiment of
Gd-substituted Mn--Zn-Ferrite nanoparticles.
[0030] FIG. 12 is a graph illustrating the change in retentivity
with increasing Gd substitution for one embodiment of
Gd-substituted Mn--Zn-Ferrite nanoparticles.
[0031] FIG. 13 is a graph illustrating the temperature dependence
of magnetization for Mn--Zn-Ferrite nanoparticles and
Gd-substituted Mn--Zn-Ferrite nanoparticles with different amounts
of Gd in the composition.
[0032] FIG. 14 is a graph illustrating the change in Curie
temperature with increasing Gd substitution for one embodiment of
Gd-substituted Mn--Zn-Ferrite nanoparticles.
DESCRIPTION OF THE INVENTION
[0033] Magnetic materials, such as particles, more particularly
nanoparticles, have been developed that have specific and narrow
Curie temperatures (Tc), which allows the materials to be
magnetically heated to a predetermined, limiting temperature,
thereby enhancing their desirability in therapeutic hyperthermia or
other applications. One advantage of the magnetic material is that
the treatment or therapy can be applied safely on patients without
fear of overheating. Another advantage of this material is that by
controlling the temperature at the limiting temperature, the
effectiveness of a radio-sensitizing agent or drug may be
significantly enhanced. In a preferred embodiment, the
self-controlling magnetic material is used for magnetic
hyperthermia, alone or in conjunction with targeted drug delivery,
diagnostic imaging, or both drug delivery and imaging. For
instance, the magnetic particles described herein can be used as a
contrast agent for magnetic resonance imaging (MRI) and as a
self-controlled heating element at a tissue (e.g., tumor) site.
[0034] In a preferred embodiment, the magnetic material is in the
form of nanoparticles, provided in a biocompatible form, wherein
the magnetic nanoparticles have a Curie temperature in the range of
40 to 46.degree. C., more preferably between 41 to 43.degree. C.,
which is desirable to provide a safeguard against overheating of
normal cells, due to the decrease of magnetic coupling in the
paramagnetic regime above Tc. In one embodiment for hyperthermia
treatment of a tumor, the magnetic particles are administered at
the tumor site, an external alternating current (AC) magnetic field
is applied to heat the particles, and the heat is conducted to the
tumor cells.
[0035] As used herein, the terms "comprise," "comprising,"
"include," and "including" are intended to be open, non-limiting
terms, unless the contrary is expressly indicated.
The Composition
[0036] In one embodiment, a composition is provided which includes
magnetic nanoparticles having a Curie temperature of between 40 and
46.degree. C., for example between 41 and 45.degree. C., between 42
and 44.degree. C., or between 42 and 43.degree. C. In a preferred
sub-embodiment, the magnetic nanoparticles have a Curie temperature
of about 42.degree. C. The composition preferably is biocompatible,
so that it is suitable for administration to human and animal
patients. Preferably, the nanoparticles have a high saturation
magnetization and pyromagnetic coefficient (i.e., high
(.differential.M/.differential.T).sub.H) so that a small change in
magnetic field can cause a larger change in the temperature.
[0037] The magnetic nanoparticles preferably have an effective mean
diameter of between 3 nm and 400 nm, although in certain
applications it may be suitable or desirable to have larger
nanoparticles. In one embodiment, the nanoparticles have an average
diameter greater than about 5 nm (e.g., 10 nm, 20 nm, 40 nm, 50 nm,
etc.) and less than about 350 nm (e.g., 325 nm, 300 nm, 275 nm, 250
nm, 200 nm, etc.).
[0038] As used herein, the term "magnetic nanoparticles" includes
magnetic, paramagnetic, superparamagnetic ferromagnetic and
ferrimagnetic materials. The magnetic nanoparticles can have any
essentially composition that has the selected Curie temperature and
that can be effectively heated by application of a magnetic field.
The nanoparticles may comprise iron, nickel, cobalt, gadolinium,
manganese and/or their alloys. In one embodiment, the magnetic
nanoparticles of the composition comprise an alloy of copper and
nickel. In a particular embodiment, the alloy is 71 to 71.4 wt %
nickel, with the balance consisting essentially of copper. In a
preferred embodiment, the alloy is 71 wt % nickel and 29 wt %
copper. In another embodiment, the magnetic nanoparticles comprise
a Mn--Zn Ferrite, having the formula:
Zn.sub.xMn.sub.(1-x)Fe.sub.2O.sub.4 where x is between 0.6 and 0.8.
In one particular embodiment, the magnetic nanoparticles comprise a
Gd-substituted Mn--Zn-Ferrite. In a particular embodiment, the
ferrite has the composition
Mn.sub.0.5Zn.sub.0.5Gd.sub.xFe.sub.(2-x)O.sub.4, where x is between
0 and 1.5. In another embodiment, the iron has a composition of
Fe.sub.(1-x)Zn.sub.xFe.sub.2O.sub.4 where x is between 0.7 and 0.9.
In another embodiment, the combination is in the form of
ZnFe.sub.2O.sub.4. In another embodiment, the combination is in the
form of ZnGd.sub.xFe.sub.(2-x)O.sub.4, where x between 0.01 and
0.8.
[0039] The magnetic nanoparticles preferably are administered in a
pharmaceutically acceptable carrier. In one embodiment, the
magnetic particles with the selected Curie temperature are mixed
into a liquid suspension or are encapsulated into microcapsules,
which may then be mixed with a suitable biocompatible medium. For
example, the magnetic particles can be bound in a matrix material
to form a microcapsule. Important properties of microcapsules are
their density and their diameter. The density affects the
efficiency of their carriage by the blood stream to the site of
immobilization in the diseased tissues vascular network while the
size determines the proximity of the point of immobilization to the
diseased tissue. In one embodiment, biocompatible coatings may be
used to minimize the metallic interaction of the alloy particles
with biological compounds, if necessary to enhance biocompatibility
of the magnetic particles.
[0040] In one embodiment, the composition includes a polymeric
material. For example, the magnetic nanoparticles can be dispersed
in or encapsulated by a biocompatible polymer. The term "polymeric"
is understood to mean that the composition comprises one or more
oligomers, polymers, copolymers, or blends thereof. In one
embodiment, the matrix material comprises a thermoplastic polymer.
Examples of polymers include polyvinyl alcohol, poly ethylene
glycol, ethyl cellulose, polyolefins, polyesters, nonpeptide
polyamines, polyamides, polycarbonates, polyalkenes, polyvinyl
ethers, polyglycolides, cellulose ethers, polyvinyl halides,
polyhydroxyalkanoates, polyanhydrides, polystyrenes, polyacrylates,
polymethacrylates, polyurethanes, and copolymers and blends
thereof.
[0041] For use in vivo, the polymeric material is biocompatible,
and preferably biodegradable. Examples of suitable polymers include
ethylcelluloses, polystyrenes, poly(g-caprolactone),
poly(d,l-lactic acid) and poly(d,l-lactic acid-co-glycolic acid).
The polymer is preferably a copolymer of lactic acid and glycolic
acid (e.g., PLGA).
[0042] In one embodiment, the magnetic nanoparticles and a drug are
encapsulated in a thermosensitive material. In a preferred
sub-embodiment, the melting temperature of the thermosensitive
encapsulant material is equal to or slightly less than the
nanomagnetic particle's Curie temperature. When these magnetic
nanoparticles are heated, the heat generated melts the
thermosensitive encapsulant, thus releasing the carried drug, at,
for example, the site of tumor or treatment, and heats the tumor to
further facilitate the treatment at the tumor site.
[0043] In various embodiments, the magnetic nanoparticles are
encapsulated as described in U.S. Application Publication No.
2004/0065969 to Chatterjee, et al. and U.S. Application Publication
No. 2004/0146529 to Chen, et al. The disclosures of these
publications are expressly incorporated by reference herein.
[0044] In a further embodiment, the composition further includes a
drug or radiosensitizing agent, as known in the art. In a preferred
embodiment, the drug is a chemotherapeutic agent. Representative
examples of chemotherapeutic agents known in the art include
platins, such as carboplatin and cisplatin, taxanes, such as
docetaxel and paclitaxel, gemcitabine, VP16, mitomycin,
idoxuridine, topoisomerase 1 inhibitors, such as irinotecan,
topotecan and camptothecins, nitrosoureas, such as BCNU, ACNU or
MCNU, methotrexate, bleomycin, adriamycin, cytoxan and vincristine,
immunomodulating cytokines, such as IL2, IL6, IL12 and IL 13, and
interferons. Certain chemotherapeutic agents are known to be
potentiated by heating the tissue and/or the chemotherapeutic
agent. Examples of possible heat-activated or heat-enhanced
chemotherapeutic agents include bleomycin, BCNU, cisplatin,
cyclophosphamide, melphalan, mitoxantrone, mitomycin C, thiotepa,
misonidazole, 5-thi-D-glucose, amphotericin B, cysteine, cysteamine
and AET. Representative examples of radiosensitizing agent include
misonidazole, pimonidazole, 5-fluorouracil, and
2,4-dinitroimidazole-1-ethanol. Those skilled in the art can select
the appropriate agent(s) for the particular patient, cancer or
indication.
[0045] In one embodiment, the composition includes a suitable
pharmaceutically acceptable carrier. For example, the carrier may
be a pharmaceutically acceptable vehicles for injection. The
pharmaceutically acceptable vehicle can be any aqueous or
non-aqueous vehicle known in the art. Examples of aqueous vehicles
include physiological saline solutions, solutions of sugars such as
dextrose or mannitol, and pharmaceutically acceptable buffered
solutions, and examples of non-aqueous vehicles include fixed
vegetable oils, glycerin, polyethylene glycols, alcohols, and ethyl
oleate. The vehicle may further include antibacterial
preservatives, antioxidants, tonicity agents, buffers, stabilizers,
or other components.
Methods of Making the Magnetic Nanoparticles
[0046] The magnetic nanoparticles can be made by essentially any
process that yields the appropriate Curie temperature for the
materials of construction. In one technique, the nanoparticles are
made by a mechanical/physical size reduction process. In another
technique a co-precipitation process is used to make the magnetic
nanoparticles.
[0047] Preferably, the production process optimizes characteristics
(besides Curie temperature) of the nanoparticles (e.g.,
crystallinity, grain size) that influences the nanoparticles
effectiveness for use in magnetic hyperthermia. For instance, the
nanoparticles desirably have a high pyromagnetic coefficient.
Bimetallic nanoparticles can be synthesized by a wide variety of
physical methods, such as, sputtering, mechanical alloying (ball
milling), electrodeposition or partial recrystallization of
amorphous materials. Most of the methods yield two-phase
nanocrystalline materials. Control of the composition in the
nanolevel is typically difficult, since molecules and atoms in
common techniques (e.g., chemical vapor deposition, plasma vapor
deposition) do not necessarily arrange in the preferred
composition, which was determined on bulk material on the
macroscopic level.
[0048] In a preferred embodiment, the nanoparticles are made by a
process comprising the steps of: (a) forming a melt which comprises
at least two different metals; solidifying the melt to form a bulk
solid alloy of the metals; (b) grinding the bulk solid alloy to
form particles of the alloy; and (c) milling the particles into
magnetic nanoparticles of the alloy. In a preferred embodiment, the
milling step is carried out by a ball milling process. In a
preferred embodiment, the two different metals are copper and
nickel. In one embodiment, the melt is formed by mixing a measured
quantity of a first metal in powder form with a measured quantity
of a second metal in powder form. This mixing step, as well as the
grinding and milling steps may be performed in an inert liquid. One
embodiment of this process is described in Example 1 below, wherein
copper-nickel alloy particles in the sub-micron range were
made.
[0049] In yet another embodiment, Mn--Zn Ferrite nanoparticles are
made by physical means. For example, in one process, Mn(II), Zn(II)
and Fe(III) oxides or carbonates are sintered at high temperatures
(up to 1200.degree. C.), followed by high-energy ball milling and
other means to reduce the particle size.
[0050] In another embodiment, a binary alloy is prepared by an arc
melting technique. For example, nickel-chromium alloys with
different compositions of Ni and Cr can be prepared using arc
melting under argon gas atmosphere. To insure homogeneity, the
composition can be re-melted. The material then can be annealed,
for example, under argon gas atmosphere. The material can be then
balled milled to reduce the size to a suitable nanoparticle
size.
[0051] In another embodiment, the nanoparticles are synthesized by
a chemical process. The primary advantage that chemical processes
offer over other methods is good chemical homogeneity, as chemical
synthesis offers mixing at molecular level.
[0052] In a preferred embodiment, a chemical co-precipitation
method is used to make the magnetic nanoparticles. For example,
chemical co-precipitation can be used to synthesize ferrite
(Fe.sub.3O.sub.4) nanoparticles, as well as many other ferrites,
such as Zn ferrite, Mn--Zn ferrite, and Cu ferrite. Ferrite fine
particles are obtained by the co-precipitation from aqueous
solutions of trivalent Fe.sup.3+ and bivalent metal Me.sup.2+,
where Fe.sup.2+, Mn.sup.2+, Co.sup.2+, Ni.sup.2+ and/or Zn.sup.2+
may serve as Me.sup.2+. The initial molar proportion
(Me.sup.2+/Fe.sup.3+) is always taken as the stoichiometric 1/2.
The co-precipitation reaction generally takes place in two steps: a
co-precipitation step and a ferritisation step. In the first step,
solid hydroxides of metals in the form of colloidal particles are
obtained by the co-precipitation of metal cations in alkaline
medium. For the case of Mn--Zn ferrite, this reaction is as
follows:
##STR00001##
In the second step, the product of the first step is subjected to
heating in a precipitation alkaline solution to provide the
transformation of solid solution of metal hydroxides to the
ferrite. For the case of Mn--Zn ferrite, this can be illustrated as
follows:
##STR00002##
A particular feature of "the co-precipitation method" is that the
product contains a certain amount of associated water even after
several hours of heating in alkaline solution.
[0053] The rate of mixing of reagents plays a vital role in the
size of the resultant particles. Co-precipitation consists of two
processes: nucleation (formation of centers of crystallization) and
a subsequent growth of particles. The relative rates of these two
processes determine the size and polydispersity of obtained
particles. Polydispersed colloids are obtained as a result of
simultaneous formation of new nuclei and growth of the earlier
formed particles. Less dispersed in size colloid is formed when the
rate of nucleation is high and the rate of particles growth is low.
This situation corresponds to a rapid addition and a vigorous
mixing of reagents in the reaction.
[0054] Slow addition of reagents in the coprecipitation reaction
leads to the formation of bigger nuclei than rapid addition. It
must be also taken into account that in the case of slow addition
of the base to solution of metal salts, a separate precipitation
takes place due to the different pH of precipitation pH.sub.pr, for
different metals. Separate precipitation may increase the chemical
inhomogenity in the particles. To obtain ferrite particles of a
smaller size, less dispersed in size and more chemically
homogeneous the mixing of reagents must be performed as fast as
possible.
[0055] An increase in temperature (in the range 20-100.degree. C.)
significantly accelerates formation of ferrite particles. The
activation energy for formation of ferrites of different metals is
not equal. The heating at temperatures close to 100.degree. C. is
preferable for an easier and more rapid formation of the Mn--Zn
ferrite particles.
[0056] Non-limiting, exemplary embodiments of co-precipitation
processes are described below in Example 5 and in Example 3,
wherein Mn.sub.0.5Zn.sub.0.5Gd.sub.xFe.sub.(2-x)O.sub.4
nanoparticles having a low Curie temperature and a moderately high
value of magnetization and a high pyromagnetic coefficient were
made using a chemical coprecipitation method. The pyromagnetic
co-efficient of a material can be enhanced by gadolinium
substitution.
[0057] In one embodiment for making nanoparticles, liquid polyols
such as ethylene glycol or diethylene are used both as a solvent
and as a reducing agent for the chemical preparation of metallic
powders from various inorganic precursors. The basic reaction
scheme for the synthesis of these metal powders by the polyol
process involves: (a) dissolution of the solid precursor; (b)
reduction of the dissolved metallic species by the polyol itself;
(c) nucleation of the metallic phase; and (d) growth of the nuclei.
To obtain metallic powders with a narrow size distribution, it is
desirable that two conditions be fulfilled: (1) a complete
separation of the nucleation and growth steps; and (2) avoidance of
aggregation of the metal particles during the nucleation and growth
steps. The general procedure for the synthesis of different
metallic powders and films involved suspending the corresponding
metal precursors in ethylene glycol or tetraethylene glycol and
subsequently bringing the resulting mixture to refluxing
temperature (generally between 120 to 200.degree. C.) for one to
three hours. During this reaction time, the metallic moieties are
precipitated out of the mixture. The metal-glycol mixture is then
cooled to room temperature, filtered, and the collected precipitate
is dried in air. For film deposition, substrates are immersed in
the reaction mixture. Compared to aqueous methods, the polyol
approach results in synthesis of metallic nanoparticles protected
by surface adsorbed glycol, thus minimizing unwanted oxidation.
Methods of Using the Composition
[0058] Generally, the method includes placing the magnetic material
having a selected Curie temperature (or selected Curie temperature
range) at a site intended for heating, and then exposing the
magnetic material to an alternating magnetic field to generate
hysteresis heat for a period of time effective for a particular
result. While the site often would be in a patient for medical
applications, the material optional could be used in industrial or
other non-medical applications.
[0059] In one embodiment, a method of hyperthermia treatment of a
patient in need thereof is provided which comprises: administering
to the patient a composition comprising magnetic nanoparticles
having a Curie temperature of between 40 and 46.degree. C.; and
exposing the magnetic nanoparticles in the patient to an
alternating magnetic field effective to generate hysteresis heat in
the nanoparticles. In a preferred embodiment, the heating method is
used for site-specific treatment of diseased tissue in a patient.
For example, the method can include the steps of: (i) providing a
biocompatible composition comprising magnetic nanoparticles with
Curie temperature of between 40 and 46.degree. C., more preferably
between 42 and 44.degree. C.; (ii) delivering the biocompatible
composition to diseased tissue in a patient; and (iii) exposing the
biocompatible composition in the patient to an alternating magnetic
field to generate hysteresis heat in the diseased tissue,
preferably until the diseased tissue has been destroyed or treated
sufficiently to ameliorate the disease. The diseased tissue can,
for example, be a tumor.
[0060] In an optional embodiment, the magnetic nanoparticles are
administered to a cancerous tissue site in a patient and the
cancerous tissue is further treated with one or more therapeutic
drugs, one or more therapeutic radiation treatments, or a
combination thereof. For instance, the method of treatment
optionally can further include delivering to the diseased tissue
radiation, a radiosensitizing agent, and/or a chemotherapeutic
agent, as known in the art. The radiosensitizing or
chemotherapeutic agent can be delivered as part of the magnetic
particle composition or separately (simultaneously to, or before or
after administration of the magnetic particles) from the magnetic
nanoparticles.
[0061] In another embodiment, the method comprises the steps of:
(i) providing a biocompatible composition comprising (a) magnetic
nanoparticles with Curie temperature between 40 and 46.degree. C.,
more preferably between 42 and 44.degree. C., (b) a matrix
material, and (c) a drug; (ii) delivering the biocompatible
composition to a site in vivo in a patient; and (iii) exposing the
biocompatible composition in the patient to an alternating magnetic
field to generate hysteresis heat to facilitate release of the drug
from the composition, and to aid in destroying diseased tissue, if
any, present at the site.
[0062] In one embodiment, the microcapsules comprising the magnetic
particles further comprise one or more drugs for release. In one
embodiment, the drug is encapsulated in the same matrix material
encapsulating the magnetic particles. In one method, release of the
drug is essentially independent of the heating of the magnetic
particles. In another method, release of drug is increased or
facilitated by heating of the magnetic particles. The heating may
operate to (1) increase the porosity of the matrix material, (2)
increase the rate of molecular diffusion through the matrix
material, (3) enhance the biodegradation or dissolution of matrix
material, or (4) effect combinations of these mechanisms. For
example, in one embodiment, the composition comprises magnetic
nanoparticles that are coated by or dispersed in a biocompatible
polymeric matrix material (e.g., in the form of larger micro- or
nano-particles) that contains the drug, and magnetic heating
expands the polymer to allow for the drug to diffuse out at the
tumor site.
[0063] The compositions and methods also may be used in other
hyperthermia treatments besides cancer treatment. For example,
magnetic hyperthermia can be used in pain relief, controlling
bleeding, or in the treatment of prostatic hypertrophy or
psoriasis.
[0064] The biocompatible composition may be delivered to the
diseased tissue in a patient by any means known in the art.
Representative examples of suitable routes of administration
include intratumoral, peritumoral and intravascular administrations
(e.g., intra-arterial, intraperitoneal, subcutaneous, or
intrathecal injection). In one embodiment, the biocompatible
composition is delivered to the diseased tissue via the arterial or
venous blood supply.
[0065] The magnetic field can be induced using simple magnets or
other equipment well known in the art. The magnetic filed strength
needed for effective alignment of the nanotubes can vary depending,
for example, upon the amount of magnetic material attached to the
nanotubes, the viscosity of the fluid medium, and the distance
between the magnetic field and the fluid medium. The basic
principle that allows this method to work is a balance between the
magnetic force generated by the applied field (which is a function
of the magnetic susceptibility, the volume of the magnetic
material, the magnetic field, and the magnetic field gradient) and
the resistance force (which is directly proportional to the viscous
resistance of the fluid medium). In one embodiment, the strength of
the magnetic field is between about 0.5 and about 1 T, inclusive of
these end points.
[0066] The methods and compositions can be further understood with
the following non-limiting examples.
Example 1
Physically Synthesized Nickel-Copper Nanoparticles for Magnetic
Hyperthermia
[0067] Nanoparticles, which consisted of a binary alloy of
copper-nickel, having a preselected Curie temperature, were
made.
[0068] The phase equilibria system for copper-nickel shows a linear
progression for the Curie temperature, which starts at a
composition of 67% nickel and 33% copper (by weight) for a
temperature of 0.degree. C. (Chakrabarti et al., Binary alloy phase
diagrams, Materials Park, Ohio, 1990 Massalski et al. (editors)).
From the Cu--Ni alloy phase diagram, the optimum amount of nickel
in the alloy was selected to be 71-71.4% by weight, in order to
yield an alloy having a Curie temperature in the range of 41 to
46.degree. C.
[0069] The nanoparticles were made by process that combined melting
and ball milling of bulk materials. The nickel-copper alloy was
obtained via physical melting, in which nickel powder (AlfaAesar,
325 mesh, 99%) and copper powder (AlfaAesar, 500 mesh, 99%) were
mixed in the desired composition (71% nickel, 29% copper; w/w). In
order to obtain a highly homogenous composition over the resulting
bulk alloy, the mixture was ball milled for 2 hours, before it was
placed into an alumina crucible. The mixture was heated to
1465.degree. C. for 3 hours, under nitrogen to prevent oxidation.
(While the liquid temperature of the alloy is 1365.degree. C., a
higher temperature was used to avoid inaccuracies due to
differences between actual and set temperature.) The liquid mixture
was cooled to form a bulk chunk of the alloy. The resulting alloy
was then processed in two steps to convert the bulk into particles
of a desired size. First, a mechanical abrasion step was carried
out to produce a powder texture that enables the second step, which
includes the use of continuous grinding media. The first step
included a simple and automated grinding process, and the second
step included additional grinding in a ceramic ball mill for at
least 3 to 7 days. The grinding was carried out in a wet
environment using acetone in order to enhance the mixing of the
materials being milled and to prevent oxidation of the materials
and to prevent the formation of a toxic and uncollectible metallic
particle gas. Ten ceramic (alumina) balls were used for 5 g of
starting material. The ball weight to content weight ratio was 6.
The rotation speed of a jar (40 mm in diameter) was 120 min.sup.-1.
After decanting from the jar, the dispersion was dried in vacuum. A
highly dispersed grayish-metallic suspension was obtained after the
first day of ball milling.
[0070] A JEOL 2010 transmission electron microscope was used to
determine the particle morphology. A ZetaPALS Particle Size
Analyzer (Brookhaven Instrument Corp.) was used to determine the
particle size. Magnetic properties were measured using an MPMS 5
Superconducting Quantum Interference Device (SQUID) magnetometer.
Wide angle X-ray diffraction pattern was taken in a Siemens 500
X-ray diffractogram with CuK.alpha. (.lamda.=0.154 nm)
radiation.
[0071] FIG. 1 shows the magnetization of the as-produced bulk
alloy, as well as the ground powder and ball-milled powder in a
magnetic field of 100 Oe. It indicates for the as-produced powder a
complete phase transition from ferromagnetic to paramagnetic
behavior at 97.degree. C. (370 K), which does not fall into our
target temperature range. From FIG. 1, one can see a shift towards
the target temperatures for the ground and ball-milled powders. The
coarse sand-grinded powder (particle diameter<150 .mu.m) shows a
Curie temperature of about 72.degree. C. (345 K) and the fine
ball-milled powder (effective particle diameter: 436 nm) shows a
temperature of about 46 to 47.degree. C. (319 to 320 K).
[0072] Curie temperature also is related to the lattice constants.
The Curie temperature increases with an increase in lattice
constant (Gilleo, Ferromagnetic Materials, p. 34 (eds., E. P.
Wohlfharth) (North Holland Physics Publishing 1986). Based on the
electron diffraction (ED) pattern and the wide-angle X-ray
diffraction pattern (XRD), the d-spacing value (between the 111
planes) was calculated and the result is shown in Table 1.
TABLE-US-00001 TABLE 1 Comparison of XRD on sand ground powder and
Electron Diffraction on ball-milled powder 2.theta. - angle
(.degree.) d-spacing (.ANG.) XRD (111) (1.sup.st peak) 44.24 2.045
ED (111) Inner ring 44.44 2.036
[0073] It was observed that the d-spacing changes from 2.045 in the
sand-ground bulk alloy to 2.036 in the ball-milled Cu--Ni alloy
particles. While not being bound to any theory, it is believed that
this might be the reason for decrease in the Tc value observed in
the ball-milled powder. That is, by ball milling, the nanostructure
is obtained by repeated mechanical deformation using a number of
milling balls, and the internal strain in the crystalline structure
caused the change in the d-spacing. FIG. 2 shows the hysteresis
plot of the ball-milled fine powder. There is no remanent magnetic
moment at room temperature indicating the superparamagnetic
behavior of the Cu--Ni ball milled powder.
[0074] Transmission electron microscopy (TEM) analysis and particle
size analysis verified that sub-micron particles were obtained by
the mechanical alloying method used. The particle size was measured
after ultrasonication of an aqueous dispersion for a few minutes
and resulted in an effective diameter of 436 nm with a half width
distribution of 218 nm. The particles that were found during TEM
analysis ranged from around 100 nm to a few micrometers. The
population of spherical particles (.about.100 nm) was very low
compared to particles with flake-like geometry. In these flake-like
particles, submicron grains and boundaries also were observed along
with little contrast. Since copper and nickel have almost the same
density (Cu 8920 kg/m.sup.3, Ni 8908 kg/m.sup.3) and similar
face-centered cubic lattices with nearly the same lattice
constants, changes in contrasts are only due to different particle
thicknesses. The texture of the particles reflects the abrasive
nature of the ball milling process. Highly magnified
(.times.200000) micrographs of the solid texture of a single
(micron sized) particle showed clearly a polycrystalline structure
with its grains and boundaries. The grains have submicron
dimensions.
[0075] Nanomagnetic particles with desired Curie temperature were
made, and the desired range of Curie temperatures was obtained by
selection of the weight percentage of nickel and copper based on
the phase diagram. Generating particles in submicron size appears
to be important to vary the Curie temperature. Ball milling was
found effective to generate submicron particles, and the
combination of melting and ball milling was effective to produce
alloy particles in large quantity, in what would appear to be a
commercially viable process.
Example 2
Synthesis of Nickel-Chromium (Ni.sub.1-xCr.sub.x) Nanoparticles
[0076] A series of Ni.sub.1-xCr.sub.x alloys were prepared to find
the specific composition that has a Curie temperature around
316-317 K. Magnetic properties of the samples were investigated,
including Curie temperature, saturation magnetization and
hysteresis. The Curie temperatures of the alloys were decreased
from 401 K to 289 K, while increasing the Cr concentration from
x=4.54 wt % to x=5.90 wt %. The results showed that
(Ni.sub.1-xCr.sub.x) alloys are good candidates for self regulating
magnetic hyperthermia applications, because the Curie temperature
of the alloys decreases almost linearly with increasing Cr
concentration.
[0077] A series of NiCr binary alloys were prepared from nickel and
chromium metals with 99.9% purity under a argon gas atmosphere by a
standard arc melting technique. The samples were turned over and
re-melted three times to ensure homogeneity. Finally the samples
were annealed in argon gas filled and sealed quartz tubes at
850.degree. C. for 5 hours.
[0078] Powder X-ray diffraction profiles were collected using a
Siemens diffractometer with Cu K.alpha. radiation. Data were
collected at room temperature over the two ranges of 43.degree. and
85.degree. in 0.02.degree. steps with an integration time of 2
seconds. Vibrating Sample Magnetometer (Lake Shore) and SQUID
Magnetometer (Quantum Design) were used for magnetic
characterization of the samples. The solubility of chromium in
nickel is above 45% at the eutectic point, 1343.degree. C. However,
chromium-rich secondary .beta. phase forms at lower temperatures
when the chromium atomic percentage exceeds 30%. Magnetic
transition temperature of the alloys also decreases with increasing
atomic percentage of chromium in nickel. FIG. 3 shows an X-ray
diffraction pattern obtained from a 5.63 wt % Cr and 94.37 wt % Ni
sample which has 317 K Curie temperature. The XRD pattern is
similar to the XRD pattern of pure Ni, and no extras or split peaks
which correspond to the individual Cr or Cr.sub.2O.sub.3 phases are
seen. This indicates that single phase solid solutions were
obtained with the processing conditions over the range of chromium
wt %.
[0079] Magnetizations versus temperature experiments were conducted
to measure the ordering temperature (Curie temperature (Tc)) of the
samples. The Tc values of the samples were obtained using the
relation of the spontaneous magnetization M .alpha.
(Tc-T).sup..beta. with .beta.=1/3. The Curie temperatures of the
samples were determined by M.sup.3 versus T plots by extrapolating
M.sup.3 to zero and by the Arrot's plot. FIG. 4 shows the
magnetization versus temperature of NiCr alloys in a magnetic field
of 100 Oe. The samples showed sharp transition from ferromagnetic
to paramagnetic properties while the temperature was increasing.
FIG. 5 shows the Arrot's plots of Ni-5.63 wt % Cr. The Tc value of
Ni-5.63 wt % Cr was obtained as 317 K from both graphs. The Tc
values of the samples are also in good agreement with reported
values. FIG. 6 shows Curie temperature versus Cr wt % concentration
graph. Curie temperature of the samples decreased almost linearly
with increasing Cr wt % concentration in nickel, which indicates
that Ni.sub.1-xCr.sub.x alloys with desired Curie temperature can
be processed by adjusting Cr concentration.
[0080] FIG. 7 shows field dependent mass magnetizations of
Ni.sub.1-xCr.sub.x samples with 5.16, 5.63, and 5.90 wt % Cr. The
measurements were conducted at 300 K. The maximum applied magnetic
field was 50 kOe, in order to obtain the saturation magnetization.
The samples were not saturated with applied 50 kOe at 300 K, as
they are not purely in the ferromagnetic state at 300 K.
Magnetizations (M) of the samples were increased with increasing
applied magnetic field. Magnetization of the samples also decreased
with increasing wt % Cr concentration in Ni.sub.1-xCr.sub.x alloys.
The complete magnetization loops of the three samples show small
hysteric losses.
Example 3
Gadolinium Substitution on Mn--Zn-Ferrite Nanoparticles
[0081] Mn--Zn ferrite and Gd substituted Mn--Zn ferrite
nanoparticles were synthesized using a chemical co-precipitation
method to obtain low Curie temperature magnetic particles with a
moderately high value of magnetization and a high pyromagnetic
coefficient. The magnetic properties and temperature dependence of
these particles, and the effect of varying Gd proportions, were
studied. The particles exhibited properties that make would make
them worth considering for hyperthermia applications.
[0082] Mn--Zn-ferrite particles and Gd substituted Mn--Zn-Ferrite
particles were obtained via chemical co-precipitation and
ferritization. First, the metal salts were co-precipitated into
hydroxides. This was done by addition of aqueous solution of metal
salts in water to the coprecipitating base (e.g. NaOH,
CH.sub.3NH.sub.3OH etc.). For the case of Mn--Zn Ferrite particles
the reaction occurs as follows:
##STR00003##
Then this precipitate is transformed into ferrite by heating in the
precipitation alkaline solution (ferritization). The reaction for
Mn--Zn ferrite particles is as follows:
##STR00004##
FeCl.sub.3 6H.sub.2O, GdCl.sub.3 6H.sub.2O, MnCl.sub.2 4H.sub.2O
and ZnSO.sub.4 7H.sub.2O were used to obtain Fe.sup.3+, Gd.sup.3+,
Mn.sup.2+ and Zn.sup.2+ ions in the aqueous solution. This salt
solution at 90.degree. C. was added to 8M NaOH solution at
90.degree. C. followed by vigorous stirring. The stirring and
heating at 90.degree. C. was continued for a minimum of 40 minutes.
The product was then filtered, washed with distilled water, and
finally washed and dried with acetone. Six samples were made of
Mn.sub.0.5Zn.sub.0.5Gd.sub.xFe.sub.(2-x)O.sub.4, where x, the
proportion of Gd, was equal to one of the following proportions 0,
0.2, 0.5, 0.7, 1.0, and 1.5. These samples were labeled S, T, U, V,
W, and X, respectively.
[0083] All the samples were examined by X-ray powder diffraction
(XRD). Hysteresis curves were obtained by using vibration sample
magnetometer (VSM) by subjecting the samples to a field in the
range of 0 to 5,000 G. A Quantum Design SQUID was used to study the
temperature dependence of the magnetization, where a constant field
of 100 G was applied to the sample and the moment was measured by
varying the temperature from 0 K to 450 K.
[0084] XRD diagrams for the samples are shown in FIG. 8, and
demonstrate a spinel crystalline structure, which is typical for
ferrites. The hysteresis curves for Samples S, U, W and X were
observed to be soft-magnetic as shown in FIG. 9.
[0085] The variation in saturation magnetization with increasing Gd
proportion is plotted in FIG. 10. It can be seen that the addition
of gadolinium results in an increase in saturation magnetization,
from 24 EMU/g for Sample S (x=0) to 29 EMU/g for Sample U (x=0.5).
But addition of gadolinium beyond x=1.0 results in reduction of
saturation magnetization the value being 24 EMU/g for Sample W
(x=1.0) and 9.5 EMU/g for Sample X (x=1.5) (see Table 1). The
initial increase in the saturation magnetization can be explained
by considering that the Gd.sup.3+ ions have a large spin only
magnetic moment per atom (7 .mu.B) as compared to that of Fe.sup.3+
ion (5 .mu.B). As a result, the net moment of the octahedral sites
increases resulting in a corresponding increase in the saturation
magnetization. Addition of Gd.sup.3+ ions results in their
occupancy of the octahedral sites, an occurrence attributable to
their large ionic radii. Since the ionic radii of the Gd.sup.3+
ions is large, there is a decrease in the distance between these
and the oxygen ions when adding Gd ions consequently strengthening
the B--B interaction (Smit & Wijn, Ferrites, John Wiley &
Sons, NY, 1959, p 139-42). As a result the ions at the octahedral
sites no longer have their moments parallel to each other. A part
of these ions have moments aligned antiparallel to the other atoms
on these octahedral sites. This results in a reduction in the net
magnetic moment of the octahedral atoms. As the Gd substitution is
increased, more and more octahedral atoms have their moments
antiparallel. As a result, the saturation magnetization drops. In
addition, Gd shows magnetic order at low temperatures. At room
temperature, its magnetic moment is small--thus the decrease in the
magnetization when increasing the Gd fraction.
[0086] The variation in coercivity with increasing Gd proportion is
plotted in FIG. 11. The coercivity values show some fluctuations
with an average value of 1.1 G.
[0087] Retentivity, which also is called Remanence, is the strength
of the magnetic field that remains in the magnetic particles after
it is exposed to a strong magnetic field and the external field is
removed. The variation of retentivity with increasing Gd proportion
is plotted in FIG. 12. There is a steady increase in retentivity up
to x=1.0 (Sample W), yet further addition of Gd results in a drop
in retentivity (Sample X: x=1.5).
[0088] FIG. 13 shows the superimposed temperature dependence plots
for all the samples. The Curie temperature was calculated by
extrapolation of the linear sections of the temperature dependence
plots. The variation in Curie temperature with increasing Gd
proportion is plotted in FIG. 14, where an increase in Curie
temperature with Gd substitution can be observed. The Curie
temperature increases from 320 K for Sample S (x=0) to about an
average of 410 K for sample T (409 K), U (412 K), V (406 K) and W
(414 K). Thus, the Curie temperature remains almost constant for
x=0.2 until x=1.0. However, further addition of Gd results in a
decrease in Curie temperature (Sample X: x=1.5: Tc=382 K). This
variation in the Curie temperatures can be attributed to the
changes in the B--B interaction due to addition of Gd.sup.3+
ions.
[0089] The nanosize Mn--Zn ferrite and Gd substituted Mn--Zn
ferrite particles were observed to be soft-magnetic. Addition of
Gd.sup.3+ ions up to proportions of x.ltoreq.0.5 results in an
increase in the net moment. Further addition of the Gd.sup.3+ ions
resulted in a decrease in the net moment. The saturation
magnetization increases then decreased with increasing proportion
of gadolinium. Coercivity did not show any clear trend, while the
Retentivity increased until x=1.0 and decreased thereafter. The
Curie temperature increased with addition of gadolinium, but
addition of Gd beyond x=1.0 resulted in a decrease in Curie
temperature.
TABLE-US-00002 TABLE 2 Magnetic Properties of the Samples
Saturation Curie Sample Magnetization Retentivity Temperature Name
(EMU/g) Coercivity (G) (EMU/g) (K) S 20 1.5233 0.0179 320 T -- --
-- 409 U 29 0.8268 0.1011 412 V -- -- -- 406 W 24 1.6617 0.1796 414
X 9.5 0.5448 0.0256 382
Example 4
Borohydride Reduction
[0090] Fe--Nd--B particles are usually synthesized using
borohydride reduction, but have a very high Curie temperature of
310.degree. C., well beyond the required optimum range of
42-43.degree. C. So an attempt was made to replace Nd with Gd with
an aim of lowering the Curie temperature. Fe--Gd--B nanoparticles
were synthesized using borohydride reduction. Salts of the required
metallic elements were reduced by sodium borohydride (NaBH.sub.4).
The procedure involved a dropwise addition of aqueous solution of
metallic salts to NaBH.sub.4 solution along with a vigorous
stirring. The pH of the salt solution was maintained at 6, whereas
that of the NaBH.sub.4 was maintained at 12. NaOH can be added to
the NaBH.sub.4 solution to increase the pH to this level.
[0091] A 0.04 M solution of salts GdCl.sub.3 and FeSO.sub.4 mixed
in the required stoichiometric proportions was added to a 1 M
NaBH.sub.4 solution kept in a round bottom flask. The resultant
mixture was vigorously stirred. The reaction was carried out in an
argon atmosphere by passing argon into the flask during the
reaction. After complete addition of the salt solution, the
reaction and stirring was allowed to continue for 40 minutes more.
The reaction may be represented by the following chemical
reaction:
##STR00005##
Three samples were made with Gd:Fe ratios of 80:20, 60:40 and
95:5.
Example 5
Chemical Co-Precipitation
[0092] Chemical co-precipitation was used to make nanoparticles of
Mn--Zn ferrite, Gd-substituted Mn--Zn ferrite, Fe--Zn ferrite, Zn
ferrite, and Gd-substituted Zn ferrite. Salt solutions of the
appropriate metallic elements were reduced by NaOH solution. The
reactants when mixed were at temperatures of 90.degree. C. After
the mixing, the reaction was continued for 40 minutes along with
heating at 90.degree. C. The nanoparticles were synthesized with
and compositions varied with the objective of making nanoparticles
in the desired Curie temperature range of about 315.degree. K.
(42.degree. C.). The results were as follows:
1. Mn--Zn ferrite nanoparticles with curie temperatures in the
desired range were made by changing the Zn proportions. 2.
Gd-substituted Mn--Zn ferrite nanoparticles with Mn:Zn ratio other
than 1:1 were made. 3. Fe--Zn ferrite particles of the form
Zn.sub.xFe.sub.1-xFe.sub.2O.sub.4 with x=0.5 to x=0.7 were made,
and Fe--Zn ferrite nanoparticles were synthesized with x>=0.7
with an aim of getting the Curie temperature down to the desired
range of 315 K. 4. From the trend of Curie temperature of the
Fe--Zn ferrite nanoparticles, it was observed that the Curie
temperature of the nanoparticles decreased with increasing Zn
proportions. 5. On comparing the characterization data of the
Gd-substituted Mn--Zn ferrite particles with that of the Mn--Zn
ferrite particles, it was noticed that addition of Gd in small
amounts leads to an increase in the Curie temperature as well as
the pyromagnetic co-efficient of the nanoparticles. Since the Curie
temperature of the Zn ferrite was measured to be below the desired
range, Gd-substituted Zn ferrite particles were synthesized to
increase its Curie temperature.
Example 6
Refluxing in Polyol Method
[0093] Ni--Cu nanoparticles were synthesized using the polyol
process. The salts NiCl.sub.2 and CuSO.sub.4 were dissolved in
ethylene glycol and refluxed at 195.degree. C. for 11-12 hrs.
[0094] Publications cited herein and the materials for which they
are cited are specifically incorporated by reference. Modifications
and variations of the methods and devices described herein will be
obvious to those skilled in the art from the foregoing detailed
description. Such modifications and variations are intended to come
within the scope of the appended claims.
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