WO2019018004A1 - Iron oxide nanoparticles doped with alkali metals or alkali earth metals - Google Patents

Iron oxide nanoparticles doped with alkali metals or alkali earth metals Download PDF

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WO2019018004A1
WO2019018004A1 PCT/US2018/015926 US2018015926W WO2019018004A1 WO 2019018004 A1 WO2019018004 A1 WO 2019018004A1 US 2018015926 W US2018015926 W US 2018015926W WO 2019018004 A1 WO2019018004 A1 WO 2019018004A1
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iron oxide
oxide nanoparticles
metal
app
nanoparticles
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Seong Tae Bae
Jung Tak Jang
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Neo Nanomedics Inc
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Neo Nanomedics Inc
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Priority to EP18716084.1A priority Critical patent/EP3655042B1/en
Priority to CN201880000592.3A priority patent/CN109475647B/en
Priority to ES18716084T priority patent/ES2955867T3/en
Priority to JP2018557017A priority patent/JP6781422B2/en
Publication of WO2019018004A1 publication Critical patent/WO2019018004A1/en
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y10S977/811—Of specified metal oxide composition, e.g. conducting or semiconducting compositions such as ITO, ZnOx
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Definitions

  • the present invention relates to iron oxide nanoparticles capable of gigantic AC self-heating characteristics in a biocompatible AC magnetic field and application to hyperthermia treatment.
  • Hyperthermia is a cancer treatment modality using characteristics of cancer cells, which are more sensitive to heat than normal cells due to abnormal environments around the cancer cells.
  • This treatment modality maintains the surrounding temperature around the cancer cells in a warm range (41°C to 45°C) compared to conventional chemotherapy or radiotherapy, so that this treatment modality has medical advantages in that even extremely small cancer cells localized or deeply seated in living tissue can be selectively killed by heat without damage to normal cells.
  • iron oxide nanoparticles are prepared by doping an Fe + vacancy site of Y-Fe 2 0 3 with an alkali metal ion or alkali earth metal ion, and generate gigantic heat even in a biocompatible low AC magnetic field.
  • a biocompatible AC magnetic field generally has f a ppi H ap pi of 5.0 ⁇ 10 9 ArrfV 1 or less, preferably 3.0 x 10 9 ArrfV 1 or less.
  • the iron oxide nanoparticles according to the present invention can generate gigantic heat even in such a biocompatible low AC magnetic field.
  • the expression “doped with ... metal ion” means that a metal atom is doped and ion-bonded to surrounding atoms, and thus all of expressions “doped with ... metal ion”, “doped with ... metal atom”, and “doped with ... metal” should be interpreted as having the same meaning.
  • Mg x -yFe 2 03 is prepared by high-temperature thermal decomposition of an Fe + precursor and an Mg 2+ precursor in an oxygen atmosphere, has a crystal structure in which an Fe + vacancy site of Y-Fe 2 0 3 is doped with Mg 2+ , and generates gigantic heat even in a biocompatible low AC magnetic field.
  • Mg 0.13 -yFe 2 O 3 0.13 mmol of magnesium (Mg) acetate tetrahydrate, 2.0 mmol of iron (Fe) acetyl acetonate, 1.2 mmol of oleic acid, and 20 mL of benzyl ether are mixed in a 50 mL round bottom flask and are magnetically stirred.
  • Fig. 2 shows transmission electron microscope images of 7 nm Mg 0.13 -yFe 2 O 3 nanoparticles prepared through the above processes. Referring to the right-side image, it can be seen that a crystal growth orientation (400) is observed and the corresponding lattice distance is 2.09 A, and that a crystal growth orientation (200) is observed and the corresponding lattice distance is 2.95 A. These values are the same as those of a reference bulk material of Y-Fe 2 0 3 . Therefore, it can be proven that the crystal structure of nanoparticles prepared through the above processes has a typical spinel structure of Y-Fe 2 0 3 .
  • the mixed solution is heated again to 296°C (boiling point of benzyl ether) for 30 minutes and maintained for 60 minutes. A heat source is removed and a reaction mixture is cooled to room temperature.
  • the crystal structure may be change Y-Fe 2 0 into Fe 0 4 during synthesis process thereof.
  • y-Fe 2 0 has spaces (vacancy sites), which occupy about 12% of the total volume thereof (see Fig. 3). Since Fe 0 4 is gradually changed into y-Fe 2 0 upon preparation in an oxygen atmosphere, Fe 2+ ions present in Fe 0 4 are oxidized to Fe + ions, diffused out, and vacancy sites was formed in y-Fe 2 0 . Since oxidation is required to prepare the iron oxide nanoparticles according to the present invention, preparation may be performed in an oxygen atmosphere, or an oxidant may be used. Actual preparation is preferably performed in a mixed atmosphere of oxygen and argon for stability of reaction.
  • doped y-Fe 2 03 exhibits reduced net magnetic properties and respond negligibly to a low AC magnetic field (see Figs. 3 and 4).
  • the iron oxide nanoparticles according to the present invention are doped with at least one alkali metal or alkali earth metal, preferably at least one metal ion selected from the group consisting of Li + , Na + , K + , Mg 2+ , and Ca 2+ .
  • the iron oxide nanoparticles according to the present invention may emit gigantic heat even in a biocompatible low AC magnetic field of f a pprH ap pi of 3.0 ⁇ 10 9 ArrfV 1 or less, and have an intrinsic loss power (ILP) of 13.5 nHm 2 /Kg to 14.5 nHm 2 /Kg in an AC magnetic field of fapprHappi ⁇ 1.8 10 9 Arn ' V 1 (f app i ⁇ 120 KHz, H app i ⁇ 15.12 KA/m).
  • IPP intrinsic loss power
  • CoFe 2 C>4 Fe 3 04, MnFe 2 04, and NiFe 2 04 have a structure in which Co 2+ , Fe 2+ , Mn 2+ , and Ni 2+ ions are doped into Fe 3 04 instead of y-Fe 2 0 3 , respectively.
  • MgFe 2 04 nanoparticles have a typical local Fe coordination of Fe 3 04 while, according to the EXAFS analyzed results (right-side graph in Fig. 7), it was confirmed that go.i3-YFe 2 0 3 nanoparticles has a typical y-Fe 2 0 3 (maghemite).
  • conventionally synthesized MgFe 2 04 nanoparticles are obtained by doping Mg 2+ into a magnetite (Fe 3 04) structure, and that the Mg 0 .i 3 -YFe 2 O 3 nanoparticles according to the present invention are obtained by doping Mg 2+ into a maghemite (y-Fe 2 0 3 ) structure.
  • Fig. 12 shows graphs depicting the dependence of M s , P to tai, Preiaxation ioss, and x" m on the Mg 2+ cation doping concentration (x) of Mg x -yFe 2 0 3 nanoparticles.
  • the ⁇ " ⁇ (and Preiaxation-ioss) was dramatically increased from 2.51 x 10 "3 emu-g ⁇ Oe "1 (6.84 x 10 6 W/m 3 ) to
  • the Mg x -yFe 2 0 3 nanoparticles emit a large amount of heat when x satisfies 0.05 ⁇ x ⁇ 0.15.
  • Fig. 13 shows graphs depicting the dependence of anisotropy energy and calculated
  • the physical reason for the obvious increase of ⁇ " ⁇ (PNeei-reiaxation-ioss) depending on the Mg 2+ cation doping concentration is thought to be primarily due to the enhanced TN (faster TN) that is resulted from the change of AC magnetic softness or magnetic anisotropy caused by the modification of Mg 2+ doping concentration in Fe vacancy sites of y-Fe 2 0 3 .
  • a f app i 110 KHz
  • H app i ⁇ 140 Oe with a concentration of 3 mg/mL
  • the Mg 0 .i 3 -YFe 2 O 3 iron oxide nanoparticles according to the present invention have an intrinsic loss power (ILP) value of about 13.9 nHm 2 kg _1 (in toluene), a 14.5 nHm 2 kg “1 (in ethanol), and a 14.0 nHm 2 kg _1 (in water), respectively.
  • IPP intrinsic loss power
  • Fig. 15 is a graph for comparison of ILP values between iron oxide nanoparticles according to the present invention and previously reported superparamagnetic nanoparticles known in the art. Referring to Fig. 15, it can be confirmed that the iron oxide nanoparticles according to the present invention have an ILP value that is about 100 times higher than that of commercial Fe C>4 (Feridex) nanoparticles.
  • Fig. 17 show results obtained by an in-vitro hyperthermia test using U87MG cells after treating Mg 0 .i -YFe 2 O magnetic nanoparticles and Resovist.
  • the U87MG cells were incubated with 700 ⁇ g/mL of Mgo.i -yFe 2 0 nanofluids and Resovist, as a control group, for cellular uptake.
  • T A c,max 63.5 °Q than Resovist (37.5 °Q.
  • Fig. 20 shows results obtained by an in-vivo hyperthermia test using Mg 0.13 -yFe 2 O 3 magnetic nanoparticles.
  • Hep3B cells transfected with luciferase (for bioluminescence imaging, BLI) grew subcutaneously in mice (cancer-xenograft model)
  • a 100 ⁇ _, of Mgo.i3-YFe 2 03 nanofluids (100 ⁇ ., 11.5 ⁇ g/ ⁇ L) was intratumorally injected into cancer cells of the mice ( ⁇ 1000 mm 3 ) through soft tissue using a bent needle and optical thermometers were mounted in the cancer cells and rectum area to monitor the temperature.
  • Resovist 100 ⁇ ., 11.5 ⁇ g/ ⁇ L
  • normal saline 100 ⁇ ., 11.5 ⁇ g ⁇ L
  • the temperature of the rectum and Hep3B injected with Resovist were slightly increased from 34 °C to 36.37 °C and 37.14 °C, respectively.
  • the temperature of the Hep3B cells injected with the Mg 0.13 -YFe 2 O 3 nanofluids was rapidly increased up to 50.2 °C (thermoablation temperature).
  • the activity of the Hep3B was analyzed by employing a bioluminescence imaging (BLI) technique.
  • the Hep3B treated with Mg 0.13 -yFe 2 O 3 nanofluids did not exhibit any BL- intensity from day 2 after magnetic nanofluid hyperthermia, while the control groups still exhibited strong BL-intensity after magnetic nanofluid hyperthermia. No BL-intensity means that the cancer cells was completely necrotized by magnetic nanofluid hyperthermia.
  • Fig. 21 shows graphs depicting results obtained by a toxicity test
  • Mg 0.13 -yFe 2 O 3 nanoparticles showed a high biocompatibility (non-toxicity) even at a higher concentration (300 ⁇ g/mL).
  • Fe 3 0 the Fenton reaction is likely to occur and produce a toxic effect to the cells during cellular internalization due to the Fe 2+ ions in Fe 3 0 lattice.
  • Mg 0 .i 3 -yFe 2 O 3 nanoparticles which is fully oxidized forms from Fe 3 0 4 , has only Fe + ions in y-Fe 2 0 3 lattice crystal.
  • Fenton reaction is readily expected to be an extremely low during cellular internalization.

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Abstract

Disclosed herein are iron oxide nanoparticles prepared through high-temperature thermal decomposition of an Fe3+ precursor and an M+ or M2+ (M = Li, Na, K, Mg, and Ca) precursor in an oxygen atmosphere. The iron oxide nanoparticles are nanoparticles, in which an alkali metal or alkali earth metal is doped into an Fe3+ vacancy site of Y-Fe2O3, and generate explosive heat even in a biocompatible low AC magnetic field. Through both in vitro and in vivo tests, it was proven that cancer cells could be killed by performing low- frequency hyperthermia using the iron oxide nanoparticles set forth above.

Description

IRON OXIDE NANOPARTICLES DOPED WITH ALKALI METALS OR
ALKALI EARTH METALS
BACKGROUND
1. Technical Field
The present invention relates to iron oxide nanoparticles capable of gigantic AC self-heating characteristics in a biocompatible AC magnetic field and application to hyperthermia treatment.
2. Description of the Related Art
Hyperthermia is a cancer treatment modality using characteristics of cancer cells, which are more sensitive to heat than normal cells due to abnormal environments around the cancer cells. This treatment modality maintains the surrounding temperature around the cancer cells in a warm range (41°C to 45°C) compared to conventional chemotherapy or radiotherapy, so that this treatment modality has medical advantages in that even extremely small cancer cells localized or deeply seated in living tissue can be selectively killed by heat without damage to normal cells.
Development of AC magnetic self-heating technique in in-vivo environments is required for realizing effective cancer treatment, and recently a great deal of research efforts have been paid to develop AC magnetic self-heating magnetic nanoparticles. In the cancer treatment of hyperthermia using magnetic nanoparticles, the cancer cells were killed by heat generated by magnetic nanoparticles in the AC magnetic field.
In addition, magnetic nanoparticles with superparamagnetism have no aggregation of particle when they are introduced into a living body. When an AC magnetic field is applied to the magnetic nanoparticles, it is possible to easily control heat generated by the applied AC magnetic field and magnetic nanoparticles can be introduced into a living body only by simple injection treatment without a surgery.
Although only bulk sized magnetic materials showed a self-heating effect, there are limitations for their practical application due to difficulty in continuously increasing the self- heating temperature and difficulty in introduction of the magnetic materials into a living body. However, recently, a collaborative research team of the National University of Singapore and the Yokohama National University of Japan has published a study on a new type of self-heating magnetic nanoparticles, and their heating effect in the cells is effective enough for practical application, thus it is possible to expect the realization of a new cancer treatment.
A paper entitled "Applications of NiFe204 nanoparticles for a hyperthermia agent in biomedicine" in Applied Physics Letters, Vol. 89, 252503 (2006) discloses the effectiveness of NiFe204 magnetic nanoparticles as an in vivo hyperthermia agent.
In addition, US Patent Publication No. 2005-0090732 discloses target-oriented hyperthermia treatment using iron oxide. However, most conventional hyperthermia treatment relate to iron oxide nanoparticles showing a heat emission effect at high frequencies and high magnetic field (or high AC magnetic field).
However, in the cancer treatment of high-frequency hyperthermia, red spots may appear around the skin, and area with high fat, some burns, wounds, inflammations, and cell necrosis may occur. Above all, side effects due to harmfulness of high-frequency electric fields to humans are unavoidable. Therefore, this treatment is prohibited for pregnant women, patients with severe inflammation, patients with implanted cardiac pacemakers, and patients with severe pleural effusion and ascites.
In addition, since heat needs to be irradiated to cancer tissues for a long, human bodies are exposed to high-frequency electromagnetic waves for a long time, and thus, there is a problem in that normal tissues can also be damaged.
To solve the aforementioned problems, it is required to develop the magnetic nanoparticles capable of self-heating in a biocompatible low AC magnetic field (or a safe AC magnetic field). BRIEF SUMMARY
It is an object of the present invention to provide iron oxide nanoparticles capable of sufficient self-heating even in a biocompatible low (or safe) AC magnetic field.
In accordance with one aspect of the present invention, iron oxide nanoparticles are nanoparticles in which Y-Fe203 (maghemite) is doped with an alkali metal ion or alkali earth metal ion, specifically nanoparticles in which an Fe vacancy site of y-Fe203 is doped with an alkali metal ion or alkali earth metal ion.
The alkali metal ion may include lithium (Li), sodium (Na) and potassium (K), and the alkali earth metal ion may include magnesium (Mg) or calcium (Ca).
The doping metal ion may include at least one alkali metal ion or alkali earth metal ion, preferably at least one selected from the group consisting of Li+, Na+, K+, Mg2+, and Ca2+.
The iron oxide nanoparticles may generate a gigantic heat even in a biocompatible low AC magnetic field of fappi Happi of 3.0 x 109 ArrfV1 or less, and may have an intrinsic loss power (ILP) of 13.5 nHm2/Kg to 14.5 nHm2/Kg in an AC magnetic field of fappi Happi < 1.8 x 109 Am V1 (fappi < 120 kHz, Happi < 15.12 kA/m).
The iron oxide nanoparticles may be represented by Mx-yFe203 (M = Li, Na, K, Mg, and Ca), and x may satisfy 0.00 < x < 0.30, preferably 0.10 < x < 0.25, more preferably 0.10 < x < 0.20.
The iron oxide nanoparticles may have an average particle diameter of about 7 nm to about 13 nm, without being limited thereto.
In accordance with another aspect of the present invention, a method of preparing iron oxide nanoparticles is applied to preparation of nanoparticles capable of being heated even in a biocompatible low AC magnetic field, and includes preparing iron oxide nanoparticles by mixing an Fe + precursor, an M+ or M2+ (M = Li, Na, K, Mg, and Ca) precursor, a surfactant, and a solvent in an oxygen atmosphere caused by high temperature thermal decomposition (HTTD).
The Fe + precursor and the M+ or M2+ (M = Li, Na, K, Mg, and Ca) precursor may include at least one selected from among metal nitrate, metal sulfate, metal acetylacetonate, metal fluoroacetoacetate, metal halide, metal perchlorate, metal alkyl oxide, metal sulfamate, metal stearate, and organic metal compounds, without being limited thereto. For example, for Mgx-yFe203 nanoparticles, magnesium (Mg) acetate tetrahydrate and iron (Fe) acetylacetonate was used.
The solvent may include benzene solvents, hydrocarbon solvents, ether solvents, polymer solvents, ionic liquid solvents, halogen hydrocarbons, alcohols, sulfoxide solvents, water, and the like, preferably at least one of benzene, toluene, halobenzene, octane, nonane, decane, benzyl ether, phenyl ether, hydrocarbon ethers, polymer solvents, diethylene glycol (DEG), water, and ionic liquid solvents, without being limited thereto. For example, for Mgx- YFe203 nanoparticles, benzyl ether was used.
In the method according to the present invention, the surfactant may be used to stabilize nanoparticles and may include at least one of organic acids (CnCOOH, Cn: hydrocarbon, 7<n<30) including oleic acid, lauric acid, stearic acid, myristic acid, and hexadecanoic acid, without being limited thereto. For example, for Mgx-YFe203 nanoparticles, oleic acid was used.
According to the present invention, the method of preparing iron oxide nanoparticles includes: (a) heating a mixed solution of an Fe + precursor, an M+ or M2+ (M = Li, Na, K, Mg, and Ca) precursor, a surfactant, and a solvent to a temperature less than a boiling point of the solvent in a mixed atmosphere of oxygen and argon, followed by maintaining the mixed solution at the temperature for a certain period of time; (b) heating the mixed solution again to the boiling point of the solvent in a mixed atmosphere of oxygen and argon, followed by maintaining the mixed solution at the boiling point for a certain period of time; (c) removing a heating source and cooling the mixed solution to room temperature; and (d) performing precipitation and separation of nanoparticle powder by adding a polar solvent to the mixed solution and then performing centrifugation.
In the method of preparing iron oxide nanoparticles according to the present invention, a doping level can be adjusted by adjusting an amount of the Fe + precursor or the M+ or M2+ (M = Li, Na, K, Mg, and Ca) precursor.
According to the present invention, the iron oxide nanoparticles can perform sufficient self-heating even in a biocompatible low AC magnetic field. Therefore, the iron oxide nanoparticles can be used for hyperthermia cancer treatment in a low AC magnetic field.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a diagram illustrating a method of preparing Mx-yFe203 (M = Li, Na, K, Mg, and Ca) nanoparticles according to an embodiment of the present invention.
Fig. 2 shows transmission electron microscopy (TEM) images of Mg0.13-yFe2O3 nanoparticles prepared according to an embodiment of the present invention.
Figs. 3 are diagrams illustrating atomic structure models describing the spin configuration of y-Fe203 (maghemite) and Fe304 (magnetite) magnetic nanoparticles according to an embodiment of the present invention.
Figs. 4 are diagrams illustrating crystal structure of Mg0.i3-YFe2O3 (maghemite) magnetic nanoparticles according to an embodiment of the present invention. An enlarged image indicates that face-centered cubic lattices of oxygen (white sphere). The Fe + (blue sphere) spins at Td sites aligns in antiparallel with Fe + spins at Oh sites under external magnetic field. The Mg2+ (red sphere) ions predominantly occupy the Fe vacancy sites existing in the Oh sites of y-Fe203.
Fig. 5 is a graph depicting AC magnetically-induced heating characteristics of Mgo.i3-YFe203, MgFe204, and Fe304 measured at a fappi = 110 KHz and Happi = ±140 Oe according to an embodiment of the present invention.
Fig. 6 shows transmission electron microscopy (TEM) images of MFe204 (M = Mn, Co, Ni, Fe) nanoparticles prepared by a conventional method and a graph depicting AC magnetically-induced heating characteristics thereof in a low AC magnetic field.
Fig. 7 shows graphs depicting X-ray absorption spectroscopy (left: X-ray absorption near edge structure, right: extended X-ray absorption fine structure) measurement results of Mg0.i3-YFe2O3, MgFe204, and bulk Fe304.
Fig. 8 is a diagram showing composition determination of Mg0.i3-YFe2O3 by energy dispersive X-ray spectroscopy (EDS).
Fig. 9 shows DC minor hysteresis loops measured at a sweeping field of Happi = ±140 Oe (= 11.14 KAm"1) of Mg0.i3-YFe2O , MgFe204, and Fe304, and Fig. 10 is a graph depicting a temperature dependent magnetization of Mg0.i -YFe2O nanoparticles measured at an excitation magnetic field of 100 Oe.
Fig. 11 shows AC hysteresis loops measured at a fappi = 110 KHz and Happi = ±140 Oe of Mgo.i -YFe20 , MgFe204, and Fe 04.
Fig. 12 shows graphs depicting the dependence of Ms, Ptotai, Preiaxation loss, and χ" on the Mg2+ cation doping concentration (level) (x) of Mgx-yFe20 according to an embodiment of the present invention.
Fig. 13 shows graphs depicting the dependence of anisotropy energy and calculated Neel relaxation time on Mg2+ cation doping concentration (x) in Mgx-yFe20 according to an embodiment of the present invention.
Fig. 14 shows characteristics of AC magnetically-induced heating temperature rise of Mgo.i -YFe20 nanofluids dispersed in toluene, ethanol, and D.I water measured at a fappi = 110 KHz and Happi = ±140 Oe with a concentration of 3 mg/mL according to an embodiment of the present invention are moved to an aqueous solution layer.
Fig. 15 is a graph for comparison of ILP values between previously reported superparamagnetic nanoparticles and Mg0.i -YFe2O superparamagnetic nanoparticles according to an embodiment of the present invention and existing representative materials known in the art.
Fig. 16 shows graphs depicting characteristics of AC magnetically-induced heating temperature rise of Li0.i5-YFe2O , Nao.2o-yFe20 , K0. i8-YFe2O , and Cao.i8-yFe20 nanoparticles according to an embodiment of the present invention with Li+, Na+, K+, and Ca2+, respectively, in a low AC magnetic field.
Figs. 17 to 19 show results obtained by an in-vitro hyperthermia test using Mg0.i - yFe20 magnetic nanoparticles according to an embodiment of the present invention.
Fig. 20 shows results obtained by an in-vivo hyperthermia test using Mg0.i -YFe2O magnetic nanoparticles according to an embodiment of the present invention.
Fig. 21 shows graphs depicting results obtained by a toxicity test of Mg0.i -YFe2O magnetic nanoparticles according to an embodiment of the present invention on U87MG cells and Hep3B cells. Fig. 22 shows graphs depicting cell survival rate of Mg0.i3-yFe2O3 nanoparticles and reported superparamagnetic nanoparticles determined using U87MG cell lines.
DETAILED DESCRIPTION
Hereinafter, exemplary embodiments of the present invention will be described in detail with reference to the accompanying drawings. It should be understood that the present invention is not limited to the following embodiments and may be embodied in different ways, and that the embodiments are provided for complete disclosure and thorough understanding of the invention by those skilled in the art.
According to the present invention, iron oxide nanoparticles are prepared by doping an Fe + vacancy site of Y-Fe203 with an alkali metal ion or alkali earth metal ion, and generate gigantic heat even in a biocompatible low AC magnetic field. In hyperthermia, a biocompatible AC magnetic field generally has fappi Happi of 5.0 χ 109 ArrfV1 or less, preferably 3.0 x 109 ArrfV1 or less. The iron oxide nanoparticles according to the present invention can generate gigantic heat even in such a biocompatible low AC magnetic field.
As used herein, the expression "doped with ... metal ion" means that a metal atom is doped and ion-bonded to surrounding atoms, and thus all of expressions "doped with ... metal ion", "doped with ... metal atom", and "doped with ... metal" should be interpreted as having the same meaning.
The iron oxide nanoparticles according to the present invention generate heat in AC magnetic fields, and are preferably used in a biocompatible low AC magnetic field.
Hereinafter, as an example of the iron oxide nanoparticles according to the present invention, Mgx-YFe203 will be described.
Mgx-yFe203 is prepared by high-temperature thermal decomposition of an Fe + precursor and an Mg2+ precursor in an oxygen atmosphere, has a crystal structure in which an Fe + vacancy site of Y-Fe203 is doped with Mg2+, and generates gigantic heat even in a biocompatible low AC magnetic field.
A process of preparing Mgx-yFe203 (x = 0.13) will be described in more detail (see Fig. 1). To prepare Mg0.13-yFe2O3, 0.13 mmol of magnesium (Mg) acetate tetrahydrate, 2.0 mmol of iron (Fe) acetyl acetonate, 1.2 mmol of oleic acid, and 20 mL of benzyl ether are mixed in a 50 mL round bottom flask and are magnetically stirred. The mixed solution is heated to 200 °C for 30 minutes (~8 °C/min, first ramping up rate) in a mixed atmosphere of oxygen and argon (flow rate of -100 mL/min) and is then maintained for 50 minutes (nucleation step). Next, the mixed solution is heated again to 296°C (boiling point of benzyl ether) for 20 minutes (5°C/min, second ramping rate) and is then maintained for 60 minutes (growth step).
Next, a heating source is removed and the mixed solution is cooled to room temperature.
A polar solvent such as ethanol is added to the mixed solution, followed by centrifugation, thereby precipitating and separating black powder. Separated products (nanoparticles) are dispersed in a nonpolar solvent such as toluene.
To control the Mg2+ doping concentration (x) of Mgx-YFe203, the different amount of Mg2+/Fe + metal precursor are used under identical experimental conditions. For example, to synthesize the Mg0.io-YFe203 nanoparticles, 0.10 mmol of Mg acetate tetrahydrate and 2.0 mmol of Fe acetyl acetonate are used under the identical experimental conditions.
Fig. 2 shows transmission electron microscope images of 7 nm Mg0.13-yFe2O3 nanoparticles prepared through the above processes. Referring to the right-side image, it can be seen that a crystal growth orientation (400) is observed and the corresponding lattice distance is 2.09 A, and that a crystal growth orientation (200) is observed and the corresponding lattice distance is 2.95 A. These values are the same as those of a reference bulk material of Y-Fe203. Therefore, it can be proven that the crystal structure of nanoparticles prepared through the above processes has a typical spinel structure of Y-Fe203.
In a conventionally synthesized nanoparticles, MgFe204 nanoparticles (Mg2+ doped
Fe304 structure) are prepared.
To prepare MgFe204 nanoparticles, 1.0 mmol of MgCl2 and 2.0 mmol of Fe(acac)3 are placed in a 100 mL round bottom flask containing dibenzyl ether and a surfactant (oleic acid and oleylamine). 10.0 mmol of 1,2-hexadecandiol is used as a reductant.
The mixed solution is heated to 200°C for 25 minutes in an argon atmosphere and maintained for 60 minutes (nucleation step).
Next, the mixed solution is heated again to 296°C (boiling point of benzyl ether) for 30 minutes and maintained for 60 minutes. A heat source is removed and a reaction mixture is cooled to room temperature.
Ethanol is added to the reaction product, followed by centrifugation, thereby obtaining precipitated black powder. The obtained MgFe204 nanoparticles are dispersed in a nonpolar solvent such as toluene.
Upon preparation of existing nanoparticles, two chemical reagents, that is, oleic acid and oleylamine are used as size control factors, and oleylamine can be used as reducing agent. The crystal structure may be change Y-Fe20 into Fe 04 during synthesis process thereof.
Oleylamine is mainly used in preparation of iron oxide nanoparticles. In order to investigate the role of surfactant, a control experiments were carried out with oleylamine instead of oleic acid. The nanoparticles synthesized with oleylamine showed a similar AC self-heating behavior to MFe204 (M = Fe , Co , Ni , Mg ) nanoparticles due to the reduction of Fe + into Fe2+ that leads to the Fe 04 lattice in the presence of oleylamine. This result confirms that Mg2+ ion doped Fe 04 lattice has no contribution to the AC heating properties.
Mgx-yFe20 , which corresponds to the iron oxide nanoparticles according to the present invention, is obtained by doping Fe + vacancy sites of Y-Fe20 with Mg2+.
Unlike Fe 04, y-Fe20 has spaces (vacancy sites), which occupy about 12% of the total volume thereof (see Fig. 3). Since Fe 04 is gradually changed into y-Fe20 upon preparation in an oxygen atmosphere, Fe2+ ions present in Fe 04 are oxidized to Fe + ions, diffused out, and vacancy sites was formed in y-Fe20 . Since oxidation is required to prepare the iron oxide nanoparticles according to the present invention, preparation may be performed in an oxygen atmosphere, or an oxidant may be used. Actual preparation is preferably performed in a mixed atmosphere of oxygen and argon for stability of reaction.
When such vacancy sites of y-Fe20 is doped with an alkali metal or alkali earth metal, the doped y-Fe20 demonstrate change in DC/ AC magnetic softness and magnetic properties, specifically magnetic susceptibility, and thus responds to a low AC magnetic field, thereby generating heat (see Fig. 4).
On the other hand, unlike the above case, in the case of a transition metal (Zn, Fe, Mn, Co, Ni, and the like), since it is energetically favorable in terms of thermodynamics that the transition metal is predominantly substituted with Fe + ions at an octahedral site (Oh) and a tetrahedral site (Th), not in vacancy site, doped y-Fe203 exhibits reduced net magnetic properties and respond negligibly to a low AC magnetic field (see Figs. 3 and 4).
The iron oxide nanoparticles according to the present invention are nanoparticles in which Fe + vacancy sites of y-Fe203 are doped with an alkali metal or alkali earth metal. According to the present invention, a doping metal includes any alkali metal or alkali earth metal without limitation. Preferably, the alkali metal is lithium (Li), sodium (Na), or potassium (K), and the alkali earth metal is magnesium (Mg) or calcium (Ca).
In addition, the iron oxide nanoparticles according to the present invention are doped with at least one alkali metal or alkali earth metal, preferably at least one metal ion selected from the group consisting of Li+, Na+, K+, Mg2+, and Ca2+.
The iron oxide nanoparticles according to the present invention may emit gigantic heat even in a biocompatible low AC magnetic field of fapprHappi of 3.0 χ 109 ArrfV1 or less, and have an intrinsic loss power (ILP) of 13.5 nHm2/Kg to 14.5 nHm2/Kg in an AC magnetic field of fapprHappi < 1.8 109 Arn'V1 (fappi < 120 KHz, Happi < 15.12 KA/m).
Further, the iron oxide nanoparticles according to the present invention may be represented by Mx-yFe203 (M = Li, Na, K, Mg, and Ca), and x may vary with a doping concentration of a metal, x satisfies 0.00 < x < 0.30, preferably 0.10 < x < 0.25, more preferably 0.10 < x < 0.20.
The iron oxide nanoparticles according to the present invention have an average particle diameter of about 7 nm to about 13 nm, without being limited thereto, and may have various nanometer scale sizes.
Fig. 5 is a graph depicting AC magnetically-induced heating characteristics of go.i3-YFe203, MgFe204, and Fe304 measured at a low AC magnetic field (fappi = 110 kHz, Happi = ±140 Oe) according to an embodiment of the present invention. As shown in Fig. 5, go.i3-YFe203 nanoparticles exhibits an exceptionally high TaC;max of 180 °C. While, conventionally prepared MgFe204 (Mg2+ ion doped Fe304) nanoparticles exhibits a low Tac,max of 22 °C under same AC magnetic field. According to an conventional method have almost no effect of heat emission at a low AC magnetic field.
Fig. 6 shows a graph depicting transmission electron microscopy images and AC magnetically-induced heating characteristics of MFe204 (M = Co , Fe , Mn , and Ni ) nanoparticles, which are prepared by a conventional method under the same AC magnetic conditions (fappi = 110 kHz, Happi = ±140 Oe). It can be seen that conventionally synthesized nanoparticles (CoFe204, Fe304, MnFe204, and NiFe204) have almost no effect of heat emission. CoFe2C>4, Fe304, MnFe204, and NiFe204 have a structure in which Co2+, Fe2+, Mn2+, and Ni2+ ions are doped into Fe304 instead of y-Fe203, respectively.
Fig. 7 shows X-ray absorption near edge structure (XANES) and extended X-ray absorption fine structure (EXAFS) measurement results of Mg0.i3-YFe2O3 nanoparticles. For comparison, conventional MgFe204 nanoparticles and bulk Fe304 was prepared. The Fe K- edge XANES spectra (left-side graph in Fig. 7) showed that Mg0.i3-YFe2O3, and MgFe204 nanoparticles have average iron oxidation states of +3, and +2.75, respectively. Comparing to bulk Fe304, MgFe204 nanoparticles have a typical local Fe coordination of Fe304 while, according to the EXAFS analyzed results (right-side graph in Fig. 7), it was confirmed that go.i3-YFe203 nanoparticles has a typical y-Fe203 (maghemite). In contrast, conventionally synthesized MgFe204 nanoparticles are obtained by doping Mg2+ into a magnetite (Fe304) structure, and that the Mg0.i3-YFe2O3 nanoparticles according to the present invention are obtained by doping Mg2+ into a maghemite (y-Fe203) structure.
Fig. 8 shows composition determination results of Mg0.i3-YFe2O3 nanoparticles using an energy dispersive X-ray spectroscopy (EDS), and it can be seen that Mg2+ ions is well presented in y-Fe203 nanoparticles.
Fig. 9 shows DC minor hysteresis loops and Fig. 10 shows the temperature dependent magnetization of Mg0.i3-YFe2O3 nanoparticles. Referring to Figs. 9 and 10, it can be proven that Mg0.i3-YFe2O3 according to the present invention exhibits superparamagneti sm .
Fig. 11 shows the area of AC hysteresis loops measured at a fappi = 110 KHz and Happi = ±140 Oe of Mgo.i3-YFe203, MgFe204, and Fe304. Mg0.i3-YFe2O3 nanoparticles had the much larger area than those of MgFe204 and Fe304. The larger AC hysteresis loss area of Mgo.i3-YFe203 indicates that it has a higher AC magnetic softness (or faster AC magnetic response). Thus, it can be proven that the Mg0.13-yFe2O3 nanoparticles according to the present invention exhibit gigantic (or exceptionally high) heat emission.
Fig. 12 shows graphs depicting the dependence of Ms, Ptotai, Preiaxation ioss, and x"m on the Mg2+ cation doping concentration (x) of Mgx-yFe203 nanoparticles. The χ"ω (and Preiaxation-ioss) was dramatically increased from 2.51 x 10"3 emu-g^Oe"1 (6.84 x 106 W/m3) to
7.574 10" 3 1 1 6 7 2~l~ x emu-g" Oe" (3.42 x 10 W/m ) by increasing the doping concentration of Mg ion up to 0.13 and Ptotai was correspondingly increased from 7.82 x 106 W/m3 to 4 x 107 W/m3. However, the further increase the doping concentration of Mg2+ ion up to 0.15 led to severe reduction of χ"ω (PNeei-reiaxation-ioss), Ms, and Ptotai- The increase of Mg2+ ion doping concentration from 0 to 0.13 during the synthesis leads to the acceleration of occupation of Fe vacancy sites by Mg2+ ions in y-Fe203 lattice so that results in the increase of Mg2+ doping concentration that would be mainly responsible for the significant enhancement of Ms (%"m). On the contrary, the sudden decrease of χ"ω, Ptotai, and Ms at x = 0.15 can be supposed to be due to the reduction of Mg2+ doping concentration in Fe vacancy sites in y-Fe203 resulted from the substitution of Fe + in the Oh site by Mg2+ cations. Referring to Fig. 12, it can be seen that the Mgx-yFe203 nanoparticles emit a large amount of heat when x satisfies 0.05 < x < 0.15. The Mgx-yFe203 nanoparticles theoretically emit the largest amount of heat in the case of x = 0.13, and it can be seen that this coincides with the experimental results.
Fig. 13 shows graphs depicting the dependence of anisotropy energy and calculated
Neel relaxation time on Mg2+ cation doping concentration (x) in Mgx-yFe203 nanoparticles. The physical reason for the obvious increase of χ"ω (PNeei-reiaxation-ioss) depending on the Mg2+ cation doping concentration is thought to be primarily due to the enhanced TN (faster TN) that is resulted from the change of AC magnetic softness or magnetic anisotropy caused by the modification of Mg2+ doping concentration in Fe vacancy sites of y-Fe203.
Fig. 14 shows characteristics of AC magnetically-induced heating temperature rise of Mgo.i3-YFe203 nanofluids dispersed in toluene, ethanol, and D.I water measured at a fappi = 110 KHz and Happi = ±140 Oe with a concentration of 3 mg/mL Referring to Fig. 14, it can be confirmed that the Mg0.i3-YFe2O3 iron oxide nanoparticles according to the present invention have an intrinsic loss power (ILP) value of about 13.9 nHm2kg_1 (in toluene), a 14.5 nHm2kg"1 (in ethanol), and a 14.0 nHm2kg_1 (in water), respectively.
Fig. 15 is a graph for comparison of ILP values between iron oxide nanoparticles according to the present invention and previously reported superparamagnetic nanoparticles known in the art. Referring to Fig. 15, it can be confirmed that the iron oxide nanoparticles according to the present invention have an ILP value that is about 100 times higher than that of commercial Fe C>4 (Feridex) nanoparticles.
Fig. 16 shows graphs depicting characteristics of AC magnetically-induced heating temperature rise of Li0.i5-YFe2O , Nao.2o-yFe20 , K0.i8-YFe2O , and Cao.i8-yFe20 nanoparticles, respectively, in a low AC magnetic field (fappi = 110 kHz, Happi = ±140 Oe). It can be confirmed that all the nanoparticles (Li0.i5-YFe2O , Nao.2o-yFe20 , K0.i8-YFe2O , and Cao.i8-yFe20 ) exhibited an exceptionally high TAc,max above 100 °C. Therefore, it can be seen that all of the Mx-yFe20 (M = Li, Mg, K, Na, and Ca) nanoparticles according to the present invention, which are obtained by doping y-Fe20 with Mg or by doping yFe20 with a different alkali metal or alkali earth metal from Mg, exhibit high AC self-heating in a low AC magnetic field.
Fig. 17 show results obtained by an in-vitro hyperthermia test using U87MG cells after treating Mg0.i -YFe2O magnetic nanoparticles and Resovist.
The U87MG cells were incubated with 700 μg/mL of Mgo.i -yFe20 nanofluids and Resovist, as a control group, for cellular uptake. The cells were placed in the center of an AC magnetic coil, and a magnetic field of fappi = 99 kHz and Happi = ±155 Oe (Happrfappi = 1.22 109 Am'V1) was applied to the cells for 1500 seconds. Referring to the right-side graph of Fig. 17, it can be confirmed that the cells treated with Mgo.i -yFe20 nanofluids showed the much higher TAc,max (63.5 °Q than Resovist (37.5 °Q.
Referring to Fig. 18 showing the optical microscope images of U87MG cells before and after magnetic nanofluid hyperthermia with Mgo.i -yFe20 nanofluids, it can be confirmed that the cell necrosis of U87MG resulted from severe deformation and shrinkage of the cell morphology caused by the applied thermal energy was clearly observed after magnetic nanofluid hyperthermia, all cancer cells were killed by heat. In more detail, it was confirmed that 75% of the cancer cells were killed at 48°C and all of the cancer cells were completely necrotized at 63.5°C. Thus, bioavailability of the nanoparticles according to the present invention was proven.
On the other hand, Fig. 19 is an image showing the optical microscope image of U87MG cells after magnetic nanofluid hyperthermia with Resovist (control group), and cells suffering from deformation or shrinkage were not observed. Thus, it can be seen that cell viability was strongly dependent on AC heating temperature.
Fig. 20 shows results obtained by an in-vivo hyperthermia test using Mg0.13-yFe2O3 magnetic nanoparticles.
Hep3B cells transfected with luciferase (for bioluminescence imaging, BLI) grew subcutaneously in mice (cancer-xenograft model)
A 100 μΙ_, of Mgo.i3-YFe203 nanofluids (100 μΐ., 11.5 μg/μL) was intratumorally injected into cancer cells of the mice (~ 1000 mm3) through soft tissue using a bent needle and optical thermometers were mounted in the cancer cells and rectum area to monitor the temperature.
For comparison, Resovist (100 μΐ., 11.5 μg/μL) and normal saline (100 μΐ., 11.5 μg μL) were also intratumorally injected into the mice, respectively.
The mice were placed in the center of an AC magnetic coil and exposed to an AC magnetic field (fappi = 99 kHz, Happi = ±155 Oe, Happi fappi = 1.22 χ 109 Am"V') for 900 seconds.
The temperature of the rectum and Hep3B injected with Resovist were slightly increased from 34 °C to 36.37 °C and 37.14 °C, respectively. However, the temperature of the Hep3B cells injected with the Mg0.13-YFe2O3 nanofluids was rapidly increased up to 50.2 °C (thermoablation temperature).
The activity of the Hep3B was analyzed by employing a bioluminescence imaging (BLI) technique. The Hep3B treated with Mg0.13-yFe2O3 nanofluids did not exhibit any BL- intensity from day 2 after magnetic nanofluid hyperthermia, while the control groups still exhibited strong BL-intensity after magnetic nanofluid hyperthermia. No BL-intensity means that the cancer cells was completely necrotized by magnetic nanofluid hyperthermia.
Fig. 21 shows graphs depicting results obtained by a toxicity test
Figure imgf000016_0001
magnetic nanoparticles according to the present invention on U87MG cells and Hep3B cells. From the this result, it was confirmed that Mg0.13-yFe2O3 nanoparticles showed a high biocompatibility (non-toxicity) even at a higher concentration (300 μg/mL).
Fig. 22 shows graphs depicting cell survival rate of Mg0.i3-yFe2O3 nanoparticles and reported superparamagnetic nanoparticles determined using U87MG cell lines. Mg0.i3-yFe2O3 nanoparticles had a higher biocompatibility (non-toxicity) with U87Mg cell lines compared to all other reported superparamagnetic nanoparticles even at a higher concentration (300 μg/mL). The reported nanoparticles (Fe30 , CoFe204, CoFe204@MnFe204) have a Fe30 crystal structure. In the case of Fe30 , the Fenton reaction is likely to occur and produce a toxic effect to the cells during cellular internalization due to the Fe2+ ions in Fe30 lattice. However, Mg0.i3-yFe2O3 nanoparticles, which is fully oxidized forms from Fe304, has only Fe + ions in y-Fe203 lattice crystal. Hence the possibility to occur Fenton reaction is readily expected to be an extremely low during cellular internalization.
As described above, it was proven through both of the in-vitro and in-vivo tests that cancer cells could be completely killed using magnetic nanoparticles according to the present invention. Therefore, the iron oxide nanoparticles according to the present invention can be clinically used.
Heretofore, the present invention has been described with reference to some embodiments in conjunction with the accompanying drawings. Although specific terms are used herein, it should be understood that the terms are only for the purpose of describing the embodiments of the present invention and are not intended to limit the present invention. In addition, it should be understood that various modifications, changes, alterations, and equivalent embodiments can be made by those skilled in the art without departing from the spirit and scope of the present invention. Therefore, the scope of the present invention should be defined only by the accompanying claims and equivalents thereof.

Claims

WHAT IS CLAIMED IS:
1. Iron oxide nanoparticles in which Y-Fe203 is doped with an alkali metal or alkali earth metal.
2. The iron oxide nanoparticles according to claim 1, wherein an Fe vacancy site of γ- Fe203 is doped with the alkali metal or alkali earth metal.
3. The iron oxide nanoparticles according to claim 1, wherein the alkali metal comprise lithium (Li), sodium (Na), and potassium (K).
4. The iron oxide nanoparticles according to claim 1, wherein the alkali earth metal comprise magnesium (Mg) and calcium (Ca).
5. The iron oxide nanoparticles according to claim 1, wherein the doping metal comprises at least one selected from the group consisting of Li+, Na+, K+, Mg2+, and Ca2+.
6. The iron oxide nanoparticles according to claim 1, wherein the iron oxide nanoparticles generate gigantic heat in a biocompatible AC magnetic field of fappi Happi of 3.0 x 109 Am^s"1 or less.
7. The iron oxide nanoparticles according to claim 1, wherein the iron oxide nanoparticles generate gigantic heat in an biocompatible AC magnetic field of fappi Happi of 1.8 x lO' Am'V1 (fappi < 120 kHz, Happi < 15.12 kA/m) or less.
8. The iron oxide nanoparticles according to claim 1, wherein the iron oxide nanoparticles have an intrinsic loss power (ILP) of 13.5 nHm2/Kg to 14.5 nHm2/Kg in an AC magnetic field of fapprHappi of 1.8 x 109 Am V1 (fappi < 120 kHz, Happi < 15.12 kA/m) or less.
9. The iron oxide nanoparticles according to claim 1, wherein the iron oxide nanoparticles are represented by Mx-j¥e2 3 (M = Li, Na, K, Mg, and Ca), and x satisfies 0.00 < x < 0.30.
10. A method of preparing iron oxide nanoparticles capable of heating even in a biocompatible low AC magnetic field, the method comprising: preparing iron oxide nanoparticles by mixing an Fe + precursor, an M+ or M2+ (M = Li, Na, K, Mg, and Ca) precursor, a surfactant, and a solvent in an oxygen atmosphere to be thermally decomposed at high temperature.
11. The method according to claim 10, wherein the Fe + precursor and the M+ or M2+ (M = Li, Na, K, Mg, and Ca) precursor comprises at least one selected from among metal nitrate, metal sulfate, metal acetylacetonate, metal fluoroacetoacetate, metal halide, metal perchlorate, metal alkyl oxide, metal sulfamate, metal stearate, and organic metal compounds.
12. The method according to claim 10, wherein the surfactant comprises at least one of organic acids (CnCOOH, Cn: hydrocarbon, 7 < n < 30) comprising oleic acid, lauric acid, stearic acid, myristic acid, and hexadecanoic acid.
13. The method according to claim 10, comprising:
(a) heating a mixed solution of an Fe + precursor, an M+ or M2+ (M = Li, Na, K, Mg, and Ca) precursor, a surfactant, and a solvent to a temperature less than a boiling point of the solvent in a mixed atmosphere of oxygen and argon, followed by maintaining the mixed solution at the temperature for a certain period of time;
(b) heating the mixed solution again to the boiling point of the solvent in a mixed atmosphere of oxygen and argon, followed by maintaining the mixed solution at the boiling point for a certain period of time;
(c) removing a heat source and cooling the mixed solution to room temperature; and
(d) performing precipitation and separation of nanoparticle powder by adding a polar solvent to the mixed solution and then performing centrifugation.
14. The method according to claim 10, wherein a doping level is adjusted by adjusting an amount of the Fe + precursor or the M+ or M2+ (M = Li, Na, K, Mg, and Ca) precursor.
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