KR20190010509A - Iron Oxide Nanoparticle doped with alkali metal or alkali earth metal capable of huge self-heating in the biocompatible magnetic field and Preparation Method therof - Google Patents

Abstract

Iron oxide nanoparticles of the present invention are synthesized through pyrolysis of Fe^(3+) precursors and M^+ or M^(2+) precursors (M = Li, Na, K, Mg, or Ca) under atmosphere in the presence of oxygen, wherein Fe^(3+) vacancy sites are doped with alkali metal ions or alkali earth metal ions. The iron oxide nanoparticles generate explosive heat even in biodegradable magnetic fields. In both in vitro and in vivo experiments, it was verified that cancer cells can be killed by hyperthermia using the iron oxide nanoparticles of the present invention.

Description

FIELD OF THE INVENTION The present invention relates to an iron oxide nanoparticle doped with an alkali metal or an alkaline earth metal capable of generating a giant magnetism in a biocompatible magnetic field and a method for manufacturing the same. Method therof}

The present invention relates to iron oxide nanoparticles capable of self-heating in an alternating magnetic field, and can be used for hyperthermia treatment.

Hyperthermia treatment is a cancer treatment using the characteristic that cancer cells are more sensitive to heat than abnormal cells due to abnormal environment around cancer cells. Unlike conventional chemotherapy or radiotherapy, this treatment technique maintains the surrounding temperature of the cancer cells in the warm range (41 to 45 ° C), thereby locally locating the cancer cells without harming them, or forming very small cancer cells Can also be selectively killed.

Development of heat therapy technology in vivo is required for the realization of thermal therapy for effective cancer therapy. Recently, research on development of self-heating technology using magnetic nanoparticles has been attempted. In the treatment of warm cancer by magnetic nanoparticles, heat is induced by using the characteristics of self-heating magnetic nanoparticles by frequency and magnetic field control coils to kill cancer cells.

In addition, magnetic nanoparticles showing superparamagnetic properties have no aggregation of particles during the inflow of the living body. However, if an AC or DC magnetic field is applied from the outside, the magnetic field can be easily controlled by the applied magnetic field. It is possible to enter and move the body.

However, in recent years, there have been limitations in practical applications due to limitations of the continuous increase of the heating temperature and difficulty in the inflow into the living body. Recently, the National University of Singapore and the Yokohama National University of Japan The research results of the magnetic nanoparticles, which effectively heat up in the nanoparticles, have been published by the research team, and the exothermic effect between the cells has been shown to be effective enough to be practically applied, so that a new cancer treatment method can be realized.

Applied Physics Letters, Vol. 89, 252503 (2006), "Applications of NiFe ₂ O ₄ nanoparticles for a hyperthermia agent in biomedicine", have shown that magnetic nanoparticles have self-heating and temperature retention It is said that there is an advantage in that.

In addition, U.S. Patent Publication No. 2005-0090732 discloses a target-oriented high temperature treatment using iron oxide. However, most of the prior art relates to iron oxide nanoparticles having a heat radiation effect at high frequencies.

However, in the case of high-frequency warm cancer treatment, red spots may appear around the skin, and some burns, wounds, inflammation, necrosis, etc. may occur in areas with high fat. Above all, side effects due to harmful effects of high frequency electric fields can not be avoided. Therefore, it is prohibited to use in pregnant women, patients with severe inflammation, patients with heart pacemakers, pleural effusion and patients with severe ascites.

In addition, since heat is applied to the cancer tissue for a long time, there is a problem that the human body is exposed to electromagnetic waves of a high frequency and a high frequency for a long time, thereby causing damage to normal tissues in addition to cancer tissues.

To solve these problems, it is required to develop magnetic nanoparticles capable of self-heating in a biocompatible low frequency magnetic field.

An object of the present invention is to provide iron oxide nanoparticles which can sufficiently self-heat even under a biomedical magnetic field.

The iron oxide nanoparticles of the present invention are those in which γ-Fe ₂ O ₃ is doped with an alkali metal or an alkaline earth metal, specifically, a Fe ^{3 +} vacancy site of γ-Fe ₂ O ₃ ) Is doped with an alkali metal ion or an alkaline earth metal ion.

Preferably, the alkali metal may be lithium (Li), sodium (Na) or potassium (K), and the alkaline earth metal may be magnesium (Mg) or calcium (Ca).

The doped metal ion may be at least one alkali metal ion or alkaline earth metal ion, and preferably at least one selected from the group consisting of Li ⁺ , Na ⁺ , K ⁺ , Mg ^{2 +,} or Ca ^{2 +} have.

The iron oxide nanoparticles, f _{appl ·} H _appl is 3.0 x 10 ⁹ Am ^-1 s ^-1 in biocompatible low-frequency magnetic field, the following can radiate a large amount of _{heat, f appl · H appl <1.8} x 10 9 Am _{^{-1 s -1 (f appl <120}} KHZ, H appl <15.12 KA / m) is a ^{13.5 ~ 14.5 nHm 2 / Kg ILP} (Intrinsic Loss Power) in the alternating magnetic field below.

The iron oxide nanoparticles are preferably M _x -yFe ₂ O ₃ (M = Li, Na, K, Mg, and Ca), and X is 0.00 <X ≦ 0.30, preferably 0.10 ≦ X ≦ 0.25 , And most preferably 0.10? X? 0.20.

The size of the iron oxide nanoparticles of the present invention is not limited to about 7 nm to 13 nm.

The method for producing iron oxide nanoparticles of the present invention is a method for producing nanoparticles capable of generating heat even in a biocompatible low frequency alternating magnetic field, wherein Fe ^{3 +} precursor and M ⁺ or M ²⁺ (M = Li, Na, K, Mg, and Ca) precursors are mixed with a surfactant and a solvent and pyrolyzed at a high temperature.

The Fe ^{3 +} precursor and the M ⁺ or M ²⁺ (M = Li, Na, K, Mg, and Ca) precursors are metal nitrate compounds, metal sulfate compounds, metal acetylacetonate compounds, At least one of an acetoacetate-based compound, a metal halide-based compound, a metal perchlorate-based compound, a metal alkyloxide-based compound, a metal sphalamate-based compound, a metal styrate- But is not limited thereto. For example, Mg _x -yFe ₂ O ₃ For the nanoparticles, Mg acetate tetrahydrate and iron acetylacetonate were used.

Examples of the reaction solvent include benzene solvents, hydrocarbon solvents, ether solvents, polymer solvents, ionic liquid solvents, halogen hydrocarbons, alcohols, sulphoxide solvents, water and the like, preferably benzene, toluene, halo At least one of benzene, octane, nonane, decane, benzyl ether, phenyl ether, hydrocarbon ether, polymer solvent, DEG (diethylene glycol), water and ionic liquid solvent may be used. For example, Mg _x -yFe ₂ O ₃ For nanoparticles, benzyl ether was used.

Surfactants are used to stabilize the nanoparticles in the process of the present invention. Such surfactants include oleic acid, lauric acid, stearic acid, mysteric acid, At least one of organic acids including hexadecanoic acid (C _n COOH, C _n : hydrocarbon, 7? _{N? 30} ) may be used but is not limited thereto. For example, Mg _x -yFe ₂ O ₃ In the case of nanoparticles, oleic acid was used.

(A) an Fe ³⁺ precursor, M ⁺ or M ²⁺ (M = Li, Na, K, Mg, and Ca) precursor, a surfactant, and a solvent (B) the mixed solution is reheated to a point at which the solvent is broken in a mixed atmosphere of oxygen and argon and maintained for a predetermined time, (c) the heating source is removed And cooling the mixed solution to room temperature. (D) adding a polar solvent to the mixed solution and centrifuging to precipitate and separate the nanoparticle powder.

The method for producing iron oxide nanoparticles of the present invention is characterized in that the Fe ³⁺ precursor Or the amount of M ⁺ or M ²⁺ (M = Li, Na, K, Mg, and Ca) precursors.

The iron oxide nanoparticles of the present invention can sufficiently self-emit under a biocompatible low frequency magnetic field. Therefore, the iron oxide nanoparticles of the present invention can be utilized for the treatment of low-frequency and hyperthermal cancer.

1 is Mg _x -γFe according to one embodiment of the present invention ₂ O ₃ And a method of synthesizing nanoparticles.
FIG. 2 is a graph showing the results of the measurement of Mg &lt; RTI ID = _0.0 &gt; _{0. 13-} γFe ₂ O ₃ It is a transmission electron microscope photograph of nanoparticles.
FIGS. 3 and 4 are views for explaining a lattice structure of magnetic nanoparticles according to an embodiment of the present invention.
Figure 5 is a graph showing the change in temperature was added to the low frequency alternating magnetic field in an embodiment Mg _{0 .13} -γFe ₂ O ₃ of the present invention.
FIG. 6 is a graph showing a change in temperature under a low frequency alternating magnetic field with respect to a nanoparticle electron microscope photograph synthesized by a conventional technique and a photomicrograph thereof.
7 is a graph showing the X-ray absorption spectroscopy measurement result.
8 is a diagram showing the results of EDS mapping.
Figure 9 shows a DC hysteresis loop, and Figure 10 is a graph showing magnetization with temperature.
Figure 11 shows an AC hysteresis loop.
12 is a graph showing the magnetization (magnetization) and the degree of anisotropy energy (anisotropy energy) according to the doping level of Mg ^{2 +} in accordance with one embodiment of the present invention.
FIG. 13 is a graph showing a temperature change with time after the magnetic nanoparticles according to an embodiment of the present invention are transferred to an aqueous solution layer.
FIG. 14 is a graph comparing ILP values of magnetic nanoparticles according to an embodiment of the present invention with typical known materials.
FIG. 15 is a graph showing the relationship between the? -Fe ₂ O ₃ The ^{Li +, Na +, K +} , a graph showing the temperature changes in the low-frequency alternating magnetic field for a single nanoparticle doped with Ca ^{+ 2.}
16 to 18 are results of in vitro hyperthermia testing using magnetic nanoparticles according to an embodiment of the present invention.
19 is a result of performing in vivo hyperthermia test using magnetic nanoparticles according to an embodiment of the present invention.
20 is a graph showing the results of toxicity tests of magnetic nanoparticles according to an embodiment of the present invention in U87MG cells and Hep3B cells.

Hereinafter, preferred embodiments of the present invention will be described in detail with reference to the accompanying drawings. However, the present invention is not limited to the embodiments described herein but may be embodied in other forms. Rather, the embodiments disclosed herein are provided so that this disclosure will be thorough and complete, and will fully convey the concept of the invention to those skilled in the art.

The iron oxide nanoparticles of the present invention are obtained by doping an Fe ^{3 +} vacancy site of γ-Fe ₂ O ₃ with an alkali metal ion or an alkaline earth metal ion, Explosive heat is generated even in a low frequency magnetic field. In general, biocompatible magnetic field in a heat treatment (hyperthermia) is _{appl ·} f H _appl is 5.0 x 10 ⁹ Am ^-1 s ^-1 in the range of, more preferably at most f _{appl ·} H _appl is 3.0 x 10 ⁹ Am ^{- 1} s &lt; ^{-1 &} gt ;. However, the iron oxide nanoparticles of the present invention may generate explosive heat even at such biocompatible low frequency (less than 120 Hz) magnetic field.

In the present invention, the fact that metal ions are doped means that metal atoms are doped and ion-bonded to peripheral atoms. Therefore, in the description of the present invention, 'metal ions are doped', 'metal atoms are doped ',' Metal doped 'should be interpreted as the same concept.

The iron oxide nanoparticles of the present invention can be used in a biocompatible low frequency alternating magnetic field, as well as self-heating in both direct current and alternating magnetic fields.

Hereinafter, Mg _{x -?} Fe ₂ O ₃ will be described as an example of the iron oxide nanoparticles of the present invention.

Mg _x -Fe ₂ O ₃ is synthesized by pyrolysis of Fe ^{3 +} precursor and Mg ^{2 +} precursor at high temperature in the presence of oxygen, and Mg ^{2 +} is synthesized in Fe ^{3 +} vacancy site of γ-Fe ₂ O ₃ Doped structure and also generates explosive heat in a biocompatible low frequency alternating magnetic field.

Hereinafter, a synthesis process of Mg _{x -?} Fe ₂ O ₃ (x = 0.13) will be described (see FIG. 1).

To synthesize Mg _{0 .13} -γFe ₂ O _3, magnesium acetate tetrahydrate (Mg acetate tetrahydrate) 0.13 mmol, iron acetyl la Seto carbonate (Fe acetylacetonate) 2.0 mmol, oleic acid (oleic acid) and 1.2 mmol of benzyl ether ( benzyl ether) are mixed in a 50 mL round bottom flask and magnetically stirred. The mixed reaction solution is heated to 200 ° C for 30 minutes (~ 8 ° C / min, the first ramping up rate) and maintained for 50 minutes in an oxygen and argon mixed atmosphere (flow rate of ~ 100 mL / min) Generation step). The mixed reaction solution is reheated (5 ° C / min, the second ramping rate) to 296 ° C (boiling point of benzyl ether) for 20 minutes and maintained for 60 minutes (growth phase).

Thereafter, the heating source is removed and the mixed reaction solution is cooled to room temperature.

A polar solvent such as ethanol is added and centrifuged to precipitate and separate the black powder. The separated nanoparticles are dispersed in a non-polar solvent such as toluene.

Mg _{0 .13} -γFe ₂ O ₃ In order to adjust the doping level (X) of the Mg ^{+ 2} and different from the amount of Fe ^{3 +} or Mg ^{2 +} precursors under the same conditions. For example, Mg _{0 .10 -}粒 Fe ₂ O ₃ To synthesize nanoparticles, 0.10 mmol of Mg acetate tetrahydrate and 2.0 mmol of Fe acetylacetonate are used under the same conditions.

Mg _{0 .13} of 7nm size synthesized by the process -γFe ₂ O ₃ A transmission electron microscope image of the nanoparticles is shown in FIG. In the right photograph, the crystal growth direction 400 is observed. The lattice distance is 2.09 Å, the crystal growth direction 200 is observed, and the lattice distance is 2.95 Å. These values γFe ₂ O ₃ Of the reference bulk material. Therefore, it can be proved that the nanoparticles synthesized through the above process are Mg _{x -?} Fe ₂ O ₃ .

Applying the conventional synthesis method of nanoparticles, MgFe ₂ O ₄ Nanoparticles (Mg ^{2 +} ions are doped into Fe ₃ O ₄ nanoparticles) are synthesized.

1.0 mmol of MgCl _{2 and} 2.0 mmol of Fe (acac) ₃ are added to a 100 mL 3-neck round bottom flask containing a surfactant (oleic acid and oleylamine) in dibenzyl ether. 10.0 mmol of 1,2-hexadecandiol is used as the reducing agent.

The mixed solution is heated to 200 DEG C for 25 minutes in an argon atmosphere and held for 60 minutes (nucleation step).

The mixed solution is then heated again to 296 ° C (boiling point of the benzyl ether) for 30 minutes and held for 60 minutes. After removing the heating source, cool the reaction to room temperature.

Ethanol is added and the black powder precipitated through centrifugation is obtained, and the obtained MgFe ₂ O ₄ nanoparticles are dispersed in a non-polar solvent such as toluene.

In the synthesis of existing nanoparticles, oleic acid and oleylamine are used as size control factors. In the case of oleylamine, there is a reducing power, and γFe ₂ O ₃ can be changed to Fe ₃ O ₄ .

Since oleylamine is widely used to synthesize iron oxide nanoparticles, we have conducted experiments with oleylamine instead of oleic acid and investigated its function as a surfactant. However, the nanoparticles synthesized using the Olay lamin were to self-heating phenomenon _{MFe 2 O 4 (M = Fe} 3+, Co 2 +, Ni 2 +, Mg 2 +) similar to the nanoparticles. It is envisaged that the Fe ^{+ 3} is reduced to Fe ^{+ 2} made of Fe ₃ O ₄ lattice.

The iron oxide nanoparticles of the present invention, Mg _{x -?} Fe ₂ O ₃ Is γFe ₂ O ₃ In which Fe ^{3 +} vacancy site is doped with Mg ^{2 +} .

Unlike Fe ₃ O ₄ , γFe ₂ O ₃ has a vacancy site of about 11% of metal vacancies (see FIG. 3). This is because when Fe ₃ O ₄ is synthesized in an oxygen atmosphere, Fe ₂ O ₃ changes into Fe ₂ O _{3. In} this case, the Fe ^{2 +} ion existing in Fe ₃ O ₄ is oxidized to Fe ^{3 +} This is because the vacant space formed is present in the oxidized material Fe ₂ O ₃ . In order to synthesize the iron oxide nanoparticles according to the present invention, oxidation is required, and therefore, they can be synthesized in an oxygen-containing atmosphere or an oxidizing agent can be used. In actual synthesis, it is preferable that the reaction is performed in a mixed atmosphere of oxygen and argon for the stability of the reaction.

When such an empty space is doped with an alkali metal or an alkaline earth metal, the magnetic properties are changed. Especially, when the magnetic susceptibility is changed and the AC magnetic softness is changed, the low frequency alternating magnetic field (See FIG. 4).

On the other hand, the transition metal (transition metal, Zn, Fe, Mn, Co, Ni , etc.) Alternatively an empty space (vacancy site) situated octahedral space next (octahedral site, O _h) For the tetrahedral space (tetrahedral site, It is thermodynamically and energetically advantageous to substitute Fe ^{3 +} in the T _h ) site, which in turn reduces net magnetic properties and does not respond to low frequency alternating magnetic fields (FIGS. 3 and 4 Reference).

The iron oxide nanoparticles of the present invention are such that alkali metal (alkali metal) or alkali earth metal is doped in Fe ^{3 +} vacancy site to? Fe ₂ O ₃ . Preferably, the alkali metal is lithium (Li), sodium (Na), or potassium (K), and the alkaline earth metal is magnesium (Mg) Or calcium (Ca).

The iron oxide nanoparticles of the present invention may also be doped with at least one alkali metal or alkaline earth metal. Preferably, the metal ions to be doped are Li ⁺ , Na ⁺ , K ⁺ , Mg ^{2 +} or Ca ²⁺ May be selected.

Iron oxide nanoparticles of the present invention, f _{appl ·} H _appl is 3.0 x 10 ⁹ Am ^-1 s ^-1 in the alternating magnetic field of biocompatible or less and can radiate a large amount of _{heat, f appl · H appl <1.8} x 10 _{^{9 Am -1 s -1 (f appl}} <120 KHZ, H appl <15.12 KA / m) is a ^{13.5 ~ 14.5 nHm 2 / Kg ILP} (Intrinsic Loss Power) in the alternating magnetic field below.

In addition, the iron oxide nanoparticles of the present invention can be obtained by using M _{x -?} Fe ₂ O ₃ (M = Li, Na, K, Mg, and Ca), and the value of X may vary depending on the doping amount of the metal. The value of X is 0.00 <X? 0.30, preferably 0.10? X? 0.25, Preferably, 0.10? X? 0.20.

The iron oxide nanoparticles of the present invention have a size of about 7 nm to 13 nm, but the present invention is not limited thereto. The nanoparticles can be produced in various sizes in a nanoscale.

5 is added to the low frequency alternating magnetic field _(appi f = 110 kHz, _appi H = 140 Oe) in the embodiment of Mg _{0 .13} -γFe ₂ O ₃ of the present invention illustrating a temperature change with time. As shown, it can be seen that the temperature rises, the amount of doping of Mg ^{2 +} ions in the case of 0.13 Mg _{0 .13} -γFe ₂ O ₃ at low frequency alternating magnetic field to about 180 ℃. On the other hand, MgFe ₂ O ₄ nanoparticles (Mg ^{2 +} doped with Fe ₃ O ₄ ) synthesized in the conventional argon (Ar) atmosphere have almost no heat release effect at low frequencies.

6 shows temperature changes with time in a low frequency alternating magnetic field (f _appi = 110 kHz, H _appi = 140 Oe) under the same conditions for the nanoparticles synthesized in the prior art. It can be seen that CoFe ₂ O ₄ , Fe ₃ O ₄ , MnFe ₂ O ₄ , and NiFe ₂ O ₄ nanoparticles synthesized in a conventionally known argon (Ar) atmosphere have almost no heat release effect. CoFe ₂ O ₄ , Fe ₃ O ₄ , MnFe ₂ O ₄ , NiFe ₂ O ₄ Is a structure in which Co ^{2 +} , Fe ^{2 +} , Mn ^{2 +} , and Ni ^{2 +} ions are doped in Fe ₃ O ₄ rather than γ-Fe ₂ O ₃ .

FIG. 7 shows the X-ray absorption spectroscopy measurement result. The right graph of the Fourier transform shows that peaks of MgFe ₂ O ₄ nanoparticles and bulk Fe ₃ O ₄ are similar, and Mg _{0 .13 -}粒 Fe ₂ O ₃ For the nanoparticles can be seen that, similar to the γFe ₂ O ₃ peaks. Therefore, from the above results, MgFe ₂ O ₄ nanoparticles synthesized according to the prior art are Mg ^{2 +} -doped in the magnetite (Fe ₃ O ₄ ) structure, and Mg _{0 .13} -γ Fe ₂ O ₃ nanoparticles can be seen Marg H. mite _{(maghemite (γFe 2 O 3)} ) in the structure that the Mg ²⁺ doping.

8 is a mapping result of Mg _{0.13 -?} Fe ₂ O ₃ nanoparticles using an energy dispersive spectroscopy (EDS) method, and γFe ₂ O ₃ Around It can be seen that Mg ^{2 +} is dispersed.

Figure 9 shows a DC hysteresis loop, and Figure 10 is a graph showing magnetization with temperature. Thus, it can be proved that Mg _{x -?} Fe ₂ O ₃ according to the present invention has a superparamagnetic property.

Figure 11 shows an AC hysteresis loop. As the area of the hysteresis curve increases, a large AC magnetic softness can be generated in the alternating magnetic field, and Mg _x -γ Fe ₂ O ₃ (x = 0.13) nanoparticles have a larger area than MgFe ₂ O ₄ nanoparticles or Fe ₃ O ₄ . Thus, it can be proved that the Mg _{x -?} Fe ₂ O ₃ nanoparticles according to the present invention exhibit a high heat emission phenomenon.

12 is a graph showing the magnetization (magnetization) and the degree of magnetic anisotropy energy (magnetic anisotropy energy) according to the doping level of Mg ^{+ 2.} Mg _{x -?} Fe ₂ O ₃ X = 0 in the nanoparticles. 0.05, 0.10, 0.13, and 0.15, respectively. According to this, it is shown that there is a lot of heat emission effect at 0.05 ≤ X ≤ 0.15, and theoretically, when X = 0.13, it emits the greatest heat, which is consistent with experimental results.

FIG. 13 shows the results of temperature changes with time after the iron oxide nanoparticles of the present invention were transferred to an aqueous solution layer. 13, intrinsic loss power (ILP) values of about 14 nHm ² / Kg are obtained in toluene, ethanol, and water.

Figure 14 is a graph comparing ILP values with representative known materials. FIG. 14 shows that the ILP value is increased by about 100 times as compared with the conventional Fe ₃ O ₄ nanoparticles.

15 is γFe ₂ O ₃ The ^{Li +, Na +, Ka +} , a graph showing the temperature changes in the low-frequency alternating magnetic field _{(f appl = 110 kHz, H} appl = 140 Oe) for the iron oxide nano-particles doped with Ca ^{2 +.} _{.20 Li 0 .15 -γFe 2 O 3} , Na 0 -γFe 2 O 3, K 0.18 -γFe 2 O 3, Ca 0 .18 -γFe 2 O 3 It can be confirmed that the temperature rises to a high temperature in all cases. Therefore, the iron oxide nanoparticles according to the present invention are not limited to γFe ₂ O ₃ It can be confirmed that even when Mg is doped with other alkali metal or alkaline earth metal, it exerts high self heating at low frequency alternating magnetic field.

Figure 16 Mg _{0 .13} -γFe ₂ O ₃ The result of in vitro hyperthermia testing of the nanoparticles in U87MG cells.

U87MG cells Mg _{0 .13} -γFe ₂ O ₃ for cell influx Nanofluids and the contrast medium resovist (700 ㎍ / mL). The magnetic field was applied to the cells in an alternating magnetic coil for 1500 s at f _appl = 99 kHz and H _appl = 155 Oe (H _{appl appl appl} = 1.22 × 10 ⁹ Am ^-1 s ^{- 1} ). In the right graph of Fig. _{16, Mg 0 .13 -γFe 2 O} 3 It can be seen that the nanofluid is elevated to a temperature (63.5 ° C) which is much higher than the contrast agent temperature (37.5 ° C).

17 showing the test results, it can be seen that all the cancer cells are necrotic in the right photograph. More specifically, 75% of the cells were necrosed at a temperature of 48 ° C and completely necrosed at 63.5 ° C. Thus, the bioavailability of the nanoparticles according to the present invention has been demonstrated.

Figure 18, on the other hand, is a photograph showing the results of a test on cells treated with the contrast agent resovist alone, but no deformed or atrophied cells were observed. Thus, it can be seen that the viability of the cells depends entirely on the hyperthermia treatment.

Figure 19 shows hyperthermia results in vivo.

For bioluminescence imaging (BLI), Hep3B cells infected with luciferase were grown under the cancer-xenograft model.

11.5 ㎍ / ㎕ on cancer cells of the rat Mg _{0 .13} -γFe ₂ O ₃ 100 μl of nanofluid (~ 1000 mm ³ ) was injected and temperature was monitored by mounting optical thermometers on cancer cells and intestines.

For comparison, rats were injected with Resorvist and saline, respectively.

Alternating magnetic field to the magnetic coil from the AC rat ^- were exposed for 900 seconds to _{(f appl = 99 kHz, H} appl = 155 Oe, H appl f appl = 1.22 x 10 9 Am -1 s 1).

Hep3B the intestines of rats and resorcinol Beast injection but at 34 ℃ to 36.37 and 37.14 ^o C ^o C the temperature is slightly increased, respectively, Mg _{0 .13} -γFe ₂ O ₃ The nanofluid injected Hep3B rapidly increased in temperature to ~ 50.2 ^° C (thermoablation temperature).

Comparison of the initial and 2 days after and 7 days after the image, two days after Mg _{0 .13} -γFe ₂ O ₃ BL-intensity did not appear in the nanofluid-injected model, but BL-intensity was still present in the model with saline and resorubist injection.

The absence of BL-intensity means that due to the Mg _{0 .13} -γFe ₂ O ₃ is a cancer cell apoptosis was completely necrotic.

20 is a graph showing the results of toxicity test on U87MG cells and Hep3B cells. Toxicity tests in both cells showed little toxicity to 300 ㎍ / mL.

As described above, both in vitro and in vivo experiments have demonstrated that cancer cell therapy is possible. Therefore, the iron oxide nanoparticles of the present invention can be clinically applied.

As described above, an optimal embodiment has been disclosed in the drawings and specification. Although specific terms have been employed herein, they are used for purposes of illustration only and are not intended to limit the scope of the invention as defined in the claims or the claims. Therefore, those skilled in the art will appreciate that various modifications and equivalent embodiments are possible without departing from the scope of the present invention. Accordingly, the true scope of the present invention should be determined by the technical idea of the appended claims.

Claims (1)

Wherein self-heating occurs in the magnetic field through doping of metal ions.

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