KR20090004374A - Method for preparing nanoparticles containing iron oxide and nanoparticles containing iron oxide thereby - Google Patents

Abstract

A manufacturing method of iron oxide nano particle is provided to manufacture easily iron oxide nano particle at a low temperature by simple reaction, to be applied practically and to heighten effectiveness of the manufacturing process. A manufacturing method of iron oxide nano particle comprises steps of: reacting di-valent iron salt and tri-valent iron salt and into solvent of the chemical formula CnH2n+1 OH and forming an iron oxide nano particle precursor; and forming the iron oxide system nano particle by reacting a precursor with a base. The di-valent iron salt is one or more materials selected from a group consisting of iron(II) acetate, iron(II) nitrate and iron(II) halide. The tri-valent iron salt is one or more materials selected from a group consisting of iron(III) acetate, iron(III) nitrate and iron(III) halide.

Description

METHOD FOR PREPARING NANOPARTICLES CONTAINING IRON OXIDE AND NANOPARTICLES CONTAINING IRON OXIDE THEREBY}

The present invention relates to iron oxide-based nanoparticles and a method for manufacturing the same, and more particularly, one-pot synthesis without undergoing a surface modification process required for in vivo and ex vivo applications in molecular imaging medicine. synthesis) and a method for producing iron oxide-based nanoparticles and iron oxide-based nanoparticles prepared accordingly.

Recently, researches using various kinds of nanoparticles have been actively conducted in biomedical fields such as cell staining, cell separation, in vivo drug delivery, gene transfer, diagnosis and treatment of diseases or abnormalities, and molecular imaging. In order for the medical application of such nanoparticles to have a practical meaning, it is necessary to be able to produce satisfactory results both in-vitro and in-vivo. In other words, by performing animal experiments on nanoparticles whose effects have been demonstrated first through cell experiments, medical applications can be finally made possible. In general, cell experiments confirm the effect by fluorescence microscopy observation of nanoparticles using phosphors, and in animal experiments, magnetic nanoparticles are used for in vivo application through nuclear magnetic resonance imaging (MRI). Will be confirmed.

Therefore, in the biomedical field, nanoparticles having both magnetic and fluorescence properties that can be applied both in vivo and in vitro are required for practical application of nanoparticles. In this regard, research on multilayer nanoparticles in which magnetic nanoparticles and organic / inorganic phosphors are hybridized is being activated. As magnetic nanoparticles, gadolinium nanoparticles, which are paramagnetic materials, are currently widely used in clinical practice, and superparamagnetic iron oxide nanoparticles are known to be used as liver specific contrast agents using MRI.

However, since most of the materials constituting the core of the multilayer nanoparticles are heavy metals, a process of enhancing biocompatibility by introducing a silica layer on the surface of the nanoparticles is essential for biomedical applications. The most common method used to introduce a silica layer on the surface of nanoparticles is mixing tetraethyl orthosilicate (TEOS), a silica raw material, with a catalyst such as NH ₄ OH in an alcoholic solvent such as methanol, ethanol, propanol, etc. The Stober method which synthesize | combines a silica by the sol-gel method is mentioned. In other words, in order to introduce the silica layer into the paramagnetic iron oxide nanoparticles, the prepared iron oxide nanoparticles must be dispersed in ethanol.

However, the co-precipitation method is synthesized in an aqueous solution of about 100 ° C., which is the most common method of manufacturing iron oxide nanoparticles, which is widely used, or a hot organic solution that is synthesized in a non-aqueous solution about 300 ° C. Iron oxide-based nanoparticles prepared according to the method can not be immediately dispersed in ethanol because the charge or organic matter present on the surface. Therefore, in order to introduce a silica layer on the surface of the iron oxide-based nanoparticles prepared by the conventional method, a surface modification process is required. In addition, the conventional method for producing iron oxide-based nanoparticles have a disadvantage that the synthesis is not easy because it is made at a high temperature.

As such, the iron oxide nanoparticles, which can be efficiently used in the field of molecular imaging, can be used for one-pot synthesis at low temperature without the need for a separate surface modification process for in vivo and ex vivo application. There is a need for a method that can be produced by the present invention.

On the other hand, myocarditis is a disease characterized by the inflammatory response of the heart muscle, it can be seen that the autoimmune response proceeds as the inflammatory response of the myocardium is activated. As a diagnostic method for myocarditis, non-invasive tests such as serum factor measurement, virus antibody test, nuclear medicine test, and imaging test and invasive tests that are histologically confirmed by myocardial biopsy are clinically used. The tests only play a supporting role, and there are no tests to confirm myocarditis.

Therefore, in the diagnosis of myocarditis, non-invasive anatomical and functional information can be provided in a high resolution image, does not require radioisotopes, and myocarditis using MRI has the advantage of being able to image deep biological tissues. There is a need for a way to confirm this.

Therefore, the present inventors have conducted research to overcome the above-mentioned problems, and do not have to undergo a separate surface modification process for applying the iron oxide-based nanoparticles in vivo and in vitro, and the synthesis reaction is performed at a low temperature. It can be prepared by a one-port synthesis method that can be easily made, and the iron oxide-based nanoparticles prepared as described above can be usefully used as MRI contrast agent, especially by confirming that it can be applied to the diagnosis of myocarditis using MRI The invention has been completed.

That is, an object of the present invention is to provide a method for producing iron oxide-based nanoparticles that can produce iron oxide-based nanoparticles by one-pot synthesis and iron oxide-based nanoparticles prepared according to the above method.

The present invention also provides an MRI contrast agent comprising iron oxide-based nanoparticles prepared by the above method.

The present invention also provides an MRI contrast agent for diagnosing myocarditis comprising iron oxide-based nanoparticles prepared by the above method.

The objects of the present invention are not limited to the above-mentioned objects, and other objects and advantages of the present invention which are not mentioned above can be understood by the following description, and will be more clearly understood by the embodiments of the present invention. It will also be appreciated that the objects and advantages of the present invention may be realized by the means and combinations thereof indicated in the claims.

The present invention comprises the steps of reacting a divalent iron salt and a trivalent iron salt in a solvent of the formula C _n H _{2n +1} OH (wherein n is an integer of 1 to 6) to form an iron oxide-based nanoparticle precursor; And it provides a method for producing iron oxide-based nanoparticles comprising the step of reacting the precursor with a base to form iron oxide-based nanoparticles and iron oxide-based nanoparticles prepared according to the method.

The present invention also provides an MRI contrast agent comprising iron oxide-based nanoparticles prepared according to the above method.

The present invention also provides an MRI contrast agent for diagnosing myocarditis comprising iron oxide-based nanoparticles prepared according to the above method.

According to the present invention, iron oxide-based nanoparticles can be prepared by one-pot synthesis without the need for a separate surface modification process for in vivo and ex vivo applications. According to the production method of the present invention, iron oxide-based nanoparticles can be easily produced by a simple reaction at a low temperature as compared with the conventional method, the practical applicability is high and the efficiency of the manufacturing process can be improved.

In addition, the iron oxide-based nanoparticles according to the present invention can be prepared as a multi-layer nanoparticles having both magnetic and fluorescent properties, it can be used for various applications in vivo and in vitro molecular imaging in the biomedical field.

Iron oxide-based nanoparticles according to the present invention, when used as an MRI contrast agent, can exhibit excellent efficiency, in particular can be effectively used as a diagnostic method specific to myocarditis, it can be usefully applied as a method of confirming myocarditis.

The above objects, features, and advantages will become more apparent from the detailed description given hereinafter with reference to the accompanying drawings, and accordingly, those skilled in the art to which the present invention pertains may share the technical idea of the present invention. It will be easy to implement. In addition, in describing the present invention, when it is determined that the detailed description of the known technology related to the present invention may unnecessarily obscure the gist of the present invention, the detailed description thereof will be omitted. Hereinafter, exemplary embodiments of the present invention will be described in detail with reference to the accompanying drawings.

Iron oxide nanoparticles according to the present invention is a method for producing iron oxide-based nanoparticles iron oxide by reacting a divalent iron salt and a trivalent iron salt in a solvent of formula C _n H _{2n +1} OH (wherein n is an integer of 1 to 6) Forming a system nanoparticle precursor; And reacting the precursor with a base to form iron oxide nanoparticles.

Salts that can be used to form iron oxide-based nanoparticle precursors of the present invention are not limited as long as they include divalent iron and trivalent iron, and particularly preferably iron (II) acetate, iron (II) nitrate and At least one divalent iron salt and iron (III) acetate, iron (III) nitrate selected from the group consisting of iron (II) halides (the halides are selected from the group consisting of fluorides, chlorides, bromides and iodides) And at least one trivalent iron salt selected from the group consisting of iron (III) halides, wherein the halides are selected from the group consisting of fluoride, chloride, bromide and iodide.

In the precursor forming step of the iron oxide nanoparticles, divalent iron and trivalent iron react at a molar ratio of 2: 3 regardless of the mixing ratio.

The precursor of the iron oxide-based nanoparticles is prepared by reacting the mixed divalent iron salt and trivalent iron salt in a solvent of the formula C _n H _{2n +1} OH (wherein n is an integer of 1 to 6). The solvent of the formula C _n H _{2n +1} OH (wherein n is an integer of 1 to 6) includes methanol, ethanol, propanol, butanol, pentanol, and hexanol, preferably ethanol. When ethanol is used as a solvent in the preparation of the iron oxide nanoparticle precursor, efficient operation of the prepared precursor can be expected, synthesis can be performed at a significantly lower temperature than the conventional method, and the uniformity of the finally prepared nanoparticles can be achieved. Size distribution can be obtained.

In addition, by forming a precursor of iron oxide-based nanoparticles using a solvent of the formula C _n H _{2n +1} OH (wherein n is an integer of 1 to 6), forming a silica layer for in vivo application of nanoparticles The surface modification process, which is required at the time, can be omitted, thereby enabling one-port synthesis.

The reaction temperature during the reaction of the divalent iron salt and the trivalent iron salt with a solvent of the formula C _n H _{2n +1} OH (wherein n is an integer of 1 to 6) is 50 to 100 ° C, preferably 70 to 90 ° C. Most preferably, it is 78-85 degreeC. If the reaction temperature is less than 50 ℃ does not cause a sufficient reaction to generate the precursor of the iron oxide-based nanoparticles, if the temperature exceeds 100 ℃ the size of the nanoparticle precursor produced is very large, the non-uniformity is also increased and is not suitable.

The reaction time may vary depending on the reaction temperature, but the precursor of the iron oxide nanoparticles is prepared by reacting for 1 to 5 hours, preferably for 2 to 4 hours, and most preferably for 3 hours. If the reaction time is less than 1 hour, a sufficient reaction does not occur and the product cannot effectively act as a precursor. If the reaction time exceeds 5 hours, the size of the precursor becomes very unevenly large and is not suitable.

The iron oxide-based nanoparticle precursor prepared as described above is in a solution state, brownish, and clear and transparent. Iron oxide nanoparticles are prepared by reacting the iron oxide nanoparticle precursor prepared as described above with a base.

Bases that can be used in the present invention are not limited, but lithium hydroxide or sodium hydroxide may be suitably used. Iron oxide nanoparticles may be prepared by mixing the precursor and the base in a molar ratio of 1: 1 to 1:10. When the temperature is increased during the reaction with the precursor, there is a fear that the crystal size of the nanoparticles may increase, so that the crystal size of the nanoparticles may be treated in an ultrasonic bath (Ultrasonic (120W, 35 kW)) for about 10-30 minutes.

In general, since the precursor and the reacting base are all in solution, the iron oxide-based nanoparticles prepared according to the above method may be separated and washed according to a known method, for example, after centrifugation, such as ethanol. It can be washed with a suitable solvent.

Iron oxide-based nanoparticles prepared according to the present invention is prepared by forming a precursor using ethanol or the like as a solvent, silica layer or organic fluorescent material on the surface of the nanoparticles required as an essential process for use in molecular imaging medicine in the biomedical field In order to form the silica layer, the silica layer may be immediately dispersed in ethanol without a separate surface modification process. In addition, the iron oxide nanoparticle manufacturing method according to the present invention is synthesized at a significantly lower temperature than the conventional method, not only easy synthesis process itself, but also because the uniformity of the size of the resulting nanoparticles increases efficiently Applicable in the biomedical field.

In order to apply the iron oxide-based nanoparticles prepared as described above in vivo and in vitro molecular imaging medicine, it is preferable to form a silica layer containing an organic fluorescent material on the surface of the nanoparticles. Specifically, the organic fluorescent material is reacted with a material having both -NH ₂ group and a silane group to introduce a silane group, and then the organic fluorescent material, tetraethylorthosilicate (TEOS) and NH ₄ OH to which the silane group is introduced are iron oxide nanoparticles. In addition, the silica layer containing the organic fluorescent substance may be formed on the surface of the nanoparticles by reacting with the resin.

The organic fluorescent material that can be used in the present invention is not limited, but particularly preferably Rhodamine B isothiocyanate (RITC) or Fluoresceine isothiocyanate (FITC). In addition, the material having both a -NH ₂ group and a silane group used to introduce a silane group into the organic fluorescent substance may include 3-aminopropyltriethoxysilane or (3-trimethoxysilyl) propyldiethylenetriamine. However, the present invention is not limited thereto.

For example, when using Rhodamine B isothiocyanate (RITC) as an organic fluorescent material and 3-aminopropyltriethoxysilane (APS) as a material having both -NH ₂ and silane groups, RITC: APS is 1: 0.5 to At a molar ratio of 1: 1, the reaction may be carried out while stirring at a temperature of 0 ° C. or higher for 1 hour or more to introduce a silane group into RITC which is an organic fluorescent substance. Since, TEOS: iron oxide-based nanoparticles: the organic fluorescent substance introduced into the silane group is 1: 10 at a molar ratio of ^2: 1: 1 to 1:10 ⁴ After mixing 1 vol% or more of NH ₄ OH as a catalyst to the mixed mixture and reacting with stirring at a temperature of 0 ° C. or more for 1 hour or more, a silica layer containing an organic fluorescent substance may be formed on the surface of the iron oxide nanoparticles.

The iron oxide-based multilayer nanoparticles formed as described above are magnetic due to iron oxide contained in the core portion, and the organic silica material is contained in the surface silica layer, so that they can be used for both in vitro fluorescence microscopy and in vivo MRI imaging. Effective application in the field of radiology is possible.

In particular, the iron oxide-based nanoparticles according to the present invention is easily lost to the myocardial microvascular vessels in the heart during intravenous administration, and gradually disappears as they are absorbed. Thus, the nanoparticles that escape the blood vessels may be able to devour these immune cells and stay in the myocardium over time. That is, the iron oxide-based nanoparticles of the present invention are discharged immediately without being absorbed in healthy heart tissues, but accumulate in myocarditis tissues for a long time, and are characterized by a difference in contrast level in MRI according to the degree of myocarditis.

As described above, the iron oxide-based nanoparticles according to the present invention may be usefully used as an MRI contrast agent having high efficiency. In particular, iron oxide-based nanoparticles according to the present invention can be used as MRI contrast agent specific for the diagnosis of myocarditis. When the iron oxide-based nanoparticles according to the present invention is used as MRI contrast agent, it can be administered by intravenous injection mainly in the form of an injection. When preparing the iron oxide-based nanoparticles according to the present invention as an injection can be prepared by dissolving in conventional saline, deionized water, distilled water and the like.

In addition, in order to be used as an MRI contrast agent, the iron oxide nanoparticles not only have to have a uniform size distribution, but also preferably have a size of 100 nm or less. If the size of the iron oxide-based nanoparticles exceeds 100nm, a large amount of nanoparticles from the myocardial tissue over time during MRI imaging is not suitable for diagnosis. In the case of MRI imaging of myocarditis using iron oxide nanoparticles of 100 nm or less, a considerable amount of nanoparticles may accumulate in myocardial tissues after a certain time and may be used for diagnosis of myocarditis.

Specifically, when the iron oxide-based nanoparticles of 100nm or less according to the present invention are injected in vivo to an individual suffering from myocarditis, more than 10% of the injected amount remains in the myocardial tissue even after 48 hours after the injection. Therefore, it is possible to observe a significant difference from normal tissue by MRI imaging, so it can be applied as a new method for diagnosis of myocarditis, which has not been confirmed.

According to the present invention, iron oxides of 100 nm or less that can be used as MRI contrast agents through selection of specific iron-containing salts and solvents, control of reaction times and temperatures of precursor formation, control of reaction conditions in the formation of silica layers, and the like System-based nanoparticles can be provided. In addition, the iron oxide-based nanoparticles according to the present invention can be usefully used for MRI imaging for the diagnosis of myocarditis.

Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited to the following examples.

Example 1 Preparation of the iron oxide-based nanoparticles

To a 250 ml round bottom flask with a condenser was added a solution of 0.02 mol of iron (II) acetate and 0.01 mol of iron (III) acetate in 100 ml ethanol. The solution was refluxed at 78-85 ° C. for about 3 hours until 100 ml of solution became 40 ml. The final precursor obtained should be brown, clear and transparent. 60 mL of a solution of 0.04 mol lithium hydroxide dissolved in ethanol was added to the 40 mL precursor obtained after the reaction, and then the reaction mixture was placed in an ice bath and treated with an ultrasonicator (Ultrasonic, 120 W, 35 kHz) for about 20 minutes. The synthesized iron oxide nanoparticles were centrifuged at 23,000 rpm for 20 minutes and washed twice with ethanol.

The synthesized iron oxide nanoparticles were added to 250 ml of ethanol (concentration 25 mg / ml). RITC (Rhodamine B isothiocyanate) was reacted with (3-trimethoxysilyl) propyl diethylene triamine for 24 hours to introduce a silane group into RITC. Thus, 2 ml of RITC incorporating a silane group was mixed with 30 ml of an ethanol solution of the prepared iron oxide-based nanoparticles, 0.2 mol of tetraethylorthosilicate (TEOS), and 1.5 ml of NH ₄ OH, followed by reaction under vigorous stirring for 6 hours. In this way, an organic fluorescent substance-containing silica layer was formed on the surface of the iron oxide nanoparticles. After the reaction, centrifuged for 20 minutes at 20,000rpm using a high-speed centrifuge, and then precipitates were purified by washing with ethanol and water to prepare iron oxide nanoparticles having a silica layer containing an organic fluorescent material. A transmission electron micrograph of the nanoparticles (SiO ₂ (RITC) @MNP) thus prepared is shown in FIG. 1.

[Example 2] A test taken after injection of the iron oxide-based nano-particles of a less 100㎚ prepared in Example 1 in the early myocarditis rat heart in MRI

      MRI was performed at 0, 10 minutes, 1 hour, 24 hours and 48 hours after intravenous injection of 50 mg / kg of iron oxide nanoparticles of 100 nm or less prepared in Example 1 in early myocarditis rats. In the 10-minute image, the nanoparticles accumulate in the cardiac tissue, which peaks in one hour, and some of the nanoparticles are released in 48 hours. The results are shown in FIG.

Example 3 Severe myocarditis mice in Example 1 taken by injection of the iron oxide-based nanoparticles manufactured 100㎚ less size after cardiac MRI in experiments in

      MRI was performed at 0, 10 minutes, 1 hour, 24 hours, and 48 hours after intravenous injection of 50 mg / kg of iron oxide nanoparticles of 100 nm or less prepared in Example 1 in severe myocarditis rats. In the 10-minute image, the nanoparticles accumulate in the cardiac tissue, which peaks in one hour, but shows an image in which a certain amount of nanoparticles remain in 48 hours. The results are shown in FIG. 4.

[Comparative Example 1] Myocarditis is not healthy mice that in Example 1 an experiment photographing the iron oxide-based nano-particles and then inject a heart prepared by the MRI

      MRI was performed at 0, 10 minutes, 1 hour, 24 hours and 48 hours after intravenous injection of 50 mg / kg of the iron oxide nanoparticles prepared in Example 1 in healthy rats without myocarditis. In 10 minutes, the nanoparticles accumulate in the heart tissue, peaking at 1 hour, and most of the nanoparticles are released at 48 hours, showing an image similar to the heart before nanoparticle administration. The results are shown in FIG.

[ Comparative Example 2] Experiments in which the heart was taken by MRI after injection of iron oxide nanoparticles having a size exceeding 100 nm into severe myocarditis rats

      Heart disease at 0, 10 minutes, 1 hour, and 48 hours after intravenous injection of 50 mg / kg of iron oxide-based nanoparticles prepared by the same method as Example 1 except that the size of myocarditis rats exceeded 100 nm. MRI was performed on the stomach. At 10 minutes, nanoparticles accumulate in the heart tissue, peaking at 1 hour, and at 48 hours, a large amount of nanoparticles are released and imaged similarly to the heart before nanoparticle administration. In addition, the peak 1 hour image shows that the degree of contrast is significantly reduced compared to the image administered with nanoparticles of 100 nm or less. The results are shown in FIG.

[ Test Example 1] Fluorescence microscopy observation experiment of the heart tissue obtained after the iron oxide-based nanoparticle injection according to Example 1 in normal rats and myocardial rats.

Severe myocarditis rats were sacrificed 48 hours after intravenous injection of 50 mg / kg of iron oxide-based nanoparticles according to Example 1, and the result was observed by confocal fluorescence microscopy. 6 is compared with the result obtained after the injection. As shown in FIG. 6, after 48 hours, no nanoparticles remained in normal rats, but it was confirmed that a considerable number of nanoparticles were deposited even at 48 hours in myocardial tissues of myocarditis rats.

As confirmed in Examples 2 and 3 and Comparative Example 1, when the iron oxide-based nanoparticles according to the present invention is used for MRI imaging, in the normal rat nanoparticles accumulated in the heart tissue at the peak of 1 hour after injection in the peak After that, most of the nanoparticles were released after 48 hours (Comparative Example 1). However, when injected into rats with early myocarditis and severe myocarditis, peaking at 1 hour after injection was similar to that of normal rats, but after 48 hours, a certain amount or a considerable amount of nanoparticles accumulated in myocardial tissue. (Examples 2 and 3).

That is, the iron oxide-based nanoparticles according to the present invention are accumulated in myocardial tissues suffering from myocarditis even after a certain period of time after the in vivo injection, and can be confirmed by MRI contrast. can confirm.

In addition, as clearly seen from the comparison of Example 3 and Comparative Example 2, when MRI contrast using the 100 nm or less iron oxide-based nanoparticles prepared according to Example 1 nanoparticles 1 hour after the nanoparticle injection The amount of accumulation in cardiac tissue was highest, and even after 48 hours, a considerable amount of nanoparticles were accumulated in cardiac tissue (Example 3), whereas MRI imaging was performed using iron oxide nanoparticles exceeding 100 nm. In the case of 1 hour after the injection of nanoparticles, the degree of contrast was reduced compared to Example 3, and after 48 hours of injection, a considerable amount of nanoparticles escaped and showed a level of contrast almost similar to that before the administration of nanoparticles.

From such an embodiment, according to the present invention, it is possible to efficiently produce iron oxide-based nanoparticles by an easy method by one-port synthesis without the need for surface modification for in vivo application, and thus manufactured iron oxide-based Nanoparticles can be usefully applied as an MRI contrast agent, in particular, it can be seen that it can be used as an MRI contrast agent useful for diagnosing myocarditis.

The present invention described above can be variously substituted, modified and changed within the scope without departing from the spirit of the present invention for those of ordinary skill in the art to which the present invention belongs, the above-described embodiment and the accompanying drawings It is not limited by.

1 is a view of the iron oxide-based nanoparticles prepared in Example 1.

FIG. 2 is a diagram taken by MRI after injecting the nanoparticles prepared in Example 1 into a control rat not suffering from myocarditis according to Comparative Example 1. FIG.

3 is a diagram taken by MRI after injection of the iron oxide-based nanoparticles prepared in Example 1 to the initial myocarditis rat according to Example 2.

4 is a diagram taken by MRI after injecting the iron oxide-based nanoparticles prepared in Example 1 in the myocarditis mice in severe myocarditis mice according to Example 3.

5 is a diagram taken by MRI after injection of iron oxide-based nanoparticles of 100nm or more in severe myocarditis rats according to Comparative Example 2.

FIG. 6 is a fluorescence microscope observation diagram of heart tissue obtained after injecting iron oxide-based nanoparticles according to Example 1 into normal rats and myocarditis rats.

Claims (15)

Reacting the divalent iron salt with the trivalent iron salt in a solvent of the formula C _n H _{2n +1} OH, wherein n is an integer of 1 to 6, to form an iron oxide nanoparticle precursor; And Reacting the precursor with a base to form iron oxide nanoparticles Method for producing iron oxide nanoparticles. The method of claim 1, The divalent iron salt is at least one substance selected from the group consisting of iron (II) acetate, iron (II) nitrate and iron (II) halide, The trivalent iron salt is at least one substance selected from the group consisting of iron (III) acetate, iron (III) nitrate and iron (III) halide Method for producing iron oxide nanoparticles. The method of claim 1, In the forming of the iron oxide nanoparticle precursor, the divalent iron and the trivalent iron react at a molar ratio of 2: 3. Method for producing iron oxide nanoparticles. The method of claim 1, The iron oxide-based nanoparticle precursor is reacted with divalent iron salt and trivalent iron salt at 50-100 ° C. for 1-5 hours in a solvent of formula C _n H _{2n + 1} OH (wherein n is an integer of 1-6). Formed by Method for producing iron oxide nanoparticles. The method of claim 1, The solvent of the formula C _n H _{2n +1} OH (in the formula n = 1 to 6) is ethanol Method for producing iron oxide nanoparticles. The method of claim 1, The base is lithium hydroxide or sodium hydroxide Method for producing iron oxide nanoparticles. The method of claim 1, The iron oxide-based nanoparticle forming step is made by mixing the precursor and the base, and then treating the mixture for 10-30 minutes with an ultrasonic wave in an ice bath. Method for producing iron oxide nanoparticles. The method of claim 1, The method may further include forming a silica layer containing an organic fluorescent material on the surface of the formed iron oxide nanoparticles. Method for producing iron oxide nanoparticles. The method of claim 2, Forming a silica shell containing an organic fluorescent material on the surface of the iron oxide-based nanoparticles, the organic fluorescent material is reacted with a material having both -NH ₂ group and a silane group to introduce a silane group, and then the organic fluorescence material introduced the silane group, Tetraethylorthosilicate (TEOS) and NH ₄ OH are added to the iron oxide nanoparticles to react Method for producing iron oxide nanoparticles. The method of claim 9, The organic phosphor is rhodamine B isothiocyanate (RITC) or fluorescein isocyanate (FITC) Method for producing iron oxide nanoparticles. The method of claim 9, The material having both the —NH ₂ group and the silane group is 3-aminopropyltriethoxysilane or (3-trimethoxysilyl) propyldiethylenetriamine. Method for producing iron oxide nanoparticles. Iron oxide-based nanoparticles prepared according to the method of any one of claims 1 to 11. MRI contrast agent comprising iron oxide-based nanoparticles according to claim 12. The method of claim 13, Characterized in that it is used to diagnose myocarditis MRI contrast agent. The method of claim 14, The iron oxide nanoparticles have a size of 100 nm or less, and at least 10% of the injected amount remains in the myocardial tissue 48 hours after the in vivo injection of the individual suffering from myocarditis. MRI contrast agent.

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