KR101345097B1 - Novel manganese oxide nanopaticle and contrast agent comprising the same - Google Patents

Novel manganese oxide nanopaticle and contrast agent comprising the same Download PDF

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KR101345097B1
KR101345097B1 KR1020100077392A KR20100077392A KR101345097B1 KR 101345097 B1 KR101345097 B1 KR 101345097B1 KR 1020100077392 A KR1020100077392 A KR 1020100077392A KR 20100077392 A KR20100077392 A KR 20100077392A KR 101345097 B1 KR101345097 B1 KR 101345097B1
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manganese
manganese oxide
oxide nanoparticles
nanoparticles
needle
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KR1020100077392A
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KR20120021632A (en
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이광렬
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고려대학교 산학협력단
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Priority to PCT/KR2011/003946 priority patent/WO2012020911A2/en
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    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01G—COMPOUNDS CONTAINING METALS NOT COVERED BY SUBCLASSES C01D OR C01F
    • C01G45/00—Compounds of manganese
    • C01G45/02—Oxides; Hydroxides
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2002/00—Crystal-structural characteristics
    • C01P2002/70—Crystal-structural characteristics defined by measured X-ray, neutron or electron diffraction data
    • C01P2002/72—Crystal-structural characteristics defined by measured X-ray, neutron or electron diffraction data by d-values or two theta-values, e.g. as X-ray diagram
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2002/00—Crystal-structural characteristics
    • C01P2002/80—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70
    • C01P2002/85—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70 by XPS, EDX or EDAX data
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2004/00—Particle morphology
    • C01P2004/01—Particle morphology depicted by an image
    • C01P2004/04—Particle morphology depicted by an image obtained by TEM, STEM, STM or AFM
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2004/00—Particle morphology
    • C01P2004/60—Particles characterised by their size
    • C01P2004/64—Nanometer sized, i.e. from 1-100 nanometer

Abstract

The present invention is a novel type of manganese oxide nanoparticles that can be used as a contrast agent in magnetic resonance imaging and terahertz wave imaging, a method for preparing the same, a contrast agent composition comprising the manganese oxide nanoparticles, and terahertz wave imaging using manganese ions. It's about the law. Manganese oxide nanoparticles having a needle-like surface according to the present invention when Mn2 + ions are melted from MnO inside the nanoparticles when they come close to the cancer cells exhibiting acidity, the surface maintains the sea urchin shape and the inside has a hollow shape. This structure maximizes the surface area, amplifies the T1 contrast effect, and also has a double amplification effect in which the T1 contrast effect is amplified once more by the released Mn2 + ions. Indicates. In addition, the manganese oxide nanoparticles according to the present invention is a multifunctional contrast agent that can also be used as a terahertz contrast agent that can overcome the limitations of MRI that is difficult to diagnose the organs containing air such as stomach, lungs, intestines As it is, utilization is very good.

Description

Novel manganese oxide nanopaticle and contrast agent comprising the same

The present invention is a novel type of manganese oxide nanoparticles that can be used as a contrast agent in magnetic resonance imaging and terahertz wave imaging, a method for preparing the same, a contrast agent composition comprising the manganese oxide nanoparticles, and terahertz wave imaging using manganese ions. It's about the law.

Currently, studies on early diagnosis of cancer using magnetic resonance imaging (MRI), the most efficient and most widely used cancer diagnosis, are in progress. Contrast agents that have been used in MRI to date are contrast agents using metal ions and organic ligands. However, due to the toxicity of metal ions and ligands, there is a need for the development of a contrast agent with a relatively low toxicity and a high contrast effect. Therefore, MRI contrast agents using nanoparticles are being actively researched.

More than 80% of the ongoing MRI contrast agents research is focused on T2 MRI contrast agents using ferrite nanoparticles of iron oxide or ferrite structure. However, contrast imaging agents that give dark images on MRIs are difficult to diagnose correctly when the cancers of the organs in the body are relatively entangled or located underneath other organs.

Several early papers have recently been published on the study of T1 MRI contrast agents using nanoparticles, a typical example being T1 MRI contrast agents using MnO nanoparticles (Angew. Chem. Int. Ed. 2007, 46, 5397-5401). However, the paper is simply based on the theory that T1 contrast is performed by Mn ions on the surface of manganese oxide nanoparticles, and it provides only a passive T1 MRI contrast agent. Therefore, it is necessary to develop an efficient MRI contrast agent using active T1 MRI contrast agent. In addition, it is necessary to develop a contrast agent capable of selectively exerting a higher efficiency on cancer cells.

On the other hand, optical studies on cancer diagnosis are relatively insignificant compared to MRI. The terahertz (THz; 10 12 Hz) electromagnetic wave is located between the millimeter wave and the far infrared ray in the frequency domain, and the frequency range is 0.3 to 10 THz and the wavelength is 30 µm to 1 mm. For electromagnetic waves in this THz region, chemicals have unique fingerprint-like absorption characteristics that are not seen at other wavelengths. In addition, the electromagnetic wave in the THz region is transparent like most X-rays because of its high transmittance with respect to most materials, which is superior to any wavelength region for non-invasive inspection and imaging. In particular, THz electromagnetic waves have a very high water absorption rate, which is useful for characterizing and imaging biomaterials. In particular, in the case of cancer cells, since the amount of water contained in the cancer cells is different from that of normal cells, there is a possibility that they can be precisely detected by the THz wave.

For example, in cases where a cancer resection is performed for the purpose of treating breast cancer in general, cancer tissues that are cut off after the radical resection and still remain unobserved by the naked eye may remain. These residual cancerous tissues can be an opportunity to spread throughout the body, and also carry the risk of having to retreat a wider area. From this point of view, three-dimensional mapping of local lesions in real-time using THz waves during surgery allows for more complete curative resection. In other words, even lesions that are not visible to the naked eye, in particular, carcinoma in Situ (CIS) can be accurately and easily identified immediately during surgery. This is different from conventional ultrasound, where early stage CIS lesions cannot be detected. In addition, conventional imaging techniques using magnetic resonance imaging (MRI) have many difficulties in diagnosing diseases of human organs containing air, such as the stomach, lungs, and intestines, and thus have problems such as terahertz / optical imaging techniques. The development of new imaging methods that can overcome is urgently needed. If terahertz waves can be used to develop non-destructive biopsy methods that outperform or exceed magnetic resonance imaging (MRI) in terms of price and resolution, they can add value in two areas: instrumentation and new contrast agents. have. According to a recently published paper, the best ions that can absorb terahertz waves are ionic forms of K, Na and Ca. However, these ions tend to be poisons in the body.

The present invention is to provide a new type of manganese oxide nanoparticles that can be used as a contrast agent in magnetic resonance imaging and terahertz wave imaging, a preparation method thereof, and a contrast agent composition comprising the manganese oxide nanoparticles. The present invention also provides a terahertz wave imaging method using manganese ions.

The present invention provides a method for producing a new type of manganese oxide nanoparticles that can be used as a contrast agent in magnetic resonance imaging and terahertz wave imaging.

More specifically, the present invention is a needle comprising the synthesis of manganese oxide nanoparticles by pyrolyzing a mixture comprising a manganese precursor, a surfactant and an organic solvent, and etching the manganese oxide nanoparticles by adding an etchant to the reactant Provided are methods for producing manganese oxide nanoparticles having a surface.

In the present invention, the "manganese oxide nanoparticle" is 1nm to 1000nm in diameter, including manganese oxide (Manganese (II) oxide, MnO) or trimanganese tetraoxide (Manganese (II, III) oxide, Mn 3 O 4 ), preferably Means nanoparticles having a diameter of 40 nm to 400 nm.

In addition, "manganese oxide nanoparticles having a needle-like surface" means that the surface of the manganese oxide nanoparticles has a needle-like protrusion extending radially outward as if the surface of the sea urchin.

Manganese oxide nanoparticles having a needle-like surface according to the present invention is prepared by first synthesizing conventional spherical or octahedral manganese oxide nanoparticles by pyrolysis and etching the manganese oxide nanoparticles.

Synthesis of conventional spherical or octahedral manganese oxide nanoparticles can be synthesized using pyrolysis methods known in the art.

The "manganese precursor" used in the pyrolysis reaction can be used as long as manganese oxide nanoparticles can be prepared using the above, but is not limited thereto, manganese (II) acetate (manganese (II) acetate), Manganese (II) acetylacetonate, manganese (II) bromide, manganese (II) carbonate, manganese (II) chloride ) chloride), manganese (II) fluoride, manganese (II) iodide, manganese (II) nitrate, manganese (II) ) Manganese (II) sulfate, hydrates thereof, mixtures thereof, and the like.

In addition, the surfactant used in the pyrolysis process may be an alkyl carboxylic acid (RCOOH, such as oleic acid, lauric acid, stearic acid, mysteric acid or hexadecanoic acid, wherein R is 4 to 24 carbon atoms, preferably carbon number). 6 to 19 alkyl); Alkyl amines such as oleyl amine, lauryl amine, hexadecyl amine, trioctyl amine, dioctyl amine and the like (RNH 2 , wherein R represents alkyl having 4 to 24 carbon atoms, preferably 6 to 19 carbon atoms); Or mixtures thereof. As the alkyl amine, preferably, a primary alkyl amine such as oleyl amine, lauryl amine, hexadecyl amine can be used.

On the other hand, the type of organic solvent that can be used in the pyrolysis process is not particularly limited, but preferably has a boiling point higher than the temperature at which the pyrolysis reaction occurs. Such solvents include hydrocarbon-based compounds such as alkanes, alkenes, alkynes, cycloalkanes or alkadienes having 5 to 24 carbon atoms; Ether compounds such as butyl ether, hexyl ether, octyl ether, decyl ether, heterocyclic compounds such as pyridine, tetrahydrofuran, aromatic compounds such as toluene, xylene, mesitylene, benzene, trioctylamine, oleylamine, etc. Amines and the like.

The pyrolysis reaction may be performed by heating a mixture including manganese precursor, surfactant, and an organic solvent at about 210 ° C. to 340 ° C., which may be performed for about 10 minutes to 24 hours. Although not limited thereto, the pyrolysis reaction may be performed under inert conditions. Control of conditions such as the amount of surfactant, reaction time, and reaction temperature in the pyrolysis process can control the size and shape of the manganese oxide nanoparticles formed. For example, as the amount of surfactant increases, the size of the manganese oxide nanoparticles produced may be smaller. On the other hand, as the synthesis temperature increases, the size of the produced manganese oxide nanoparticles may increase. Manganese oxide nanoparticles formed through this process may have, for example, a spherical or octahedral structure.

The process of etching the manganese oxide nanoparticles with manganese oxide nanoparticles having a needle-like surface by adding an etchant to the manganese oxide nanoparticles, or adding an etchant to the manganese oxide nanoparticles separated from the reactant By addition.

As the "etchant" used in the above process, an organic acid, a solvent containing an organic acid or water may be used. For example, organic acids such as alkyl carboxylic acids (RCOOH, where R means alkyl having 4 to 24 carbon atoms, preferably 6 to 19 carbon atoms), uric acid, and the like, organic solvents containing organic acids or solvents such as water Can be used.

Etching of the manganese oxide nanoparticles can be performed by adding such an etchant to the manganese oxide nanoparticles or a reactant comprising the same and reacting at about 240 ° C. to 340 ° C., preferably 250 ° C. to 340 ° C., the etching being about 10 It may be performed for minutes to 24 hours. Below 240 ° C., the time required for etching may be too long, and since the boiling point of the solvent is limited, it is not necessary to exceed 340 ° C. Conditioning such as the amount of etchant, reaction time, reaction temperature, etc. in the etching process can control the size and shape of the manganese oxide nanoparticles formed on the needle surface. For example, as the amount of etchant increases, the size of the manganese oxide nanoparticles having the needle surface produced may be smaller. Increasing the reaction time can also make the nanoparticles smaller. In addition, the higher the temperature at the time of injection of the etchant, the larger the size of the particles before etching, so that the resulting sea urchin-shaped particles may be larger. .

Manganese oxide nanoparticles having a needle-shaped surface formed through the above process can be easily separated and obtained by centrifuging the reactant or by adding another solvent to the reactant to precipitate the nanoparticles.

Manganese oxide nanoparticles having a needle surface prepared as described above include manganese (II) oxide (MnO) in the core, and manganese (II, III) oxide, in a shell having a needle surface. Mn 3 O 4 ) has a core-shell structure (core-shell) structure.

Thus, the present invention also includes manganese (II) oxide (MnO) in the core and manganese (II, III) oxide, Mn 3 O 4 in a shell having a needle surface. To provide manganese oxide nanoparticles (hereinafter referred to as 'MnO @ Mn 3 O 4 manganese oxide nanoparticles').

As can be seen in the following examples, the manganese oxide nanoparticles having such a core-shell structure has a very large specific surface area compared to the previously reported manganese oxide nanoparticles because the shell containing manganese tetraoxide has a needle surface. This can significantly amplify the T1 contrast effect. In addition, unlike the normal tissue, when the manganese oxide nanoparticles are located in the cancer cells exhibiting an acidic pH of about 5.5, Mn2 + ions exhibiting the T1 contrast effect are released from the manganese nitrous oxide corresponding to the core, and thus, manganese oxide nano As the particles gradually become hollow, the surface area becomes wider, which further amplifies the T1 contrast effect. In addition, the manganese oxide nanoparticles according to the present invention have been found to absorb terahertz waves Mn 2+ ions released from the core of the manganese oxide nanoparticles. Therefore, by measuring the difference in the absorption of terahertz waves between the Mn2 + ions emitted from the manganese oxide nanoparticles and the water according to the present invention and imaging them, it is possible to perform biocontrast using terahertz waves. Therefore, the manganese oxide nanoparticles according to the present invention have the advantage that can be used as a contrast agent of terahertz wave imaging as well as MRI.

Meanwhile, manganese oxide nano containing manganese oxide (Manganese (II) oxide, MnO) in the core and trimanganese tetraoxide (Manganese (II, III) oxide, Mn 3 O 4 ) in a shell having a needle surface Particles (MnO @ Mn 3 O 4 manganese oxide nanoparticles) can be prepared to have a hollow through an additional process. For example, MnO @ Mn 3 O 4 manganese oxide nanoparticles can escape Mn 2+ ions present in the core at low pH conditions, so that MnO @ Mn 3 O 4 manganese oxide nanoparticles can easily form hollow structures by treating acid. Can be. In addition, when an organic acid such as oleic acid is added at a temperature of 200 ° C to 300 ° C, preferably 230 ° C to 260 ° C, and reacted, only manganese tetraoxide on the surface remains, and the inner manganese oxide melts.

Accordingly, the present invention also provides manganese oxide nanoparticles comprising manganese (II, III) oxide (Mn 3 O 4 ) in a shell having a needle surface and having a hollow in the core. Manganese oxide nanoparticles having a hollow structure not only exhibits an improved T1 contrast effect due to the expansion of the specific surface area, but can also carry a drug in the hollow, thereby having an advantage of enabling diagnosis and treatment at the same time.

On the other hand, manganese oxide nanoparticles according to the present invention may be coated with a biocompatible material. The biocompatible material can be used as long as it is known in the art as a biocompatible material. In one embodiment, the biocompatible material may include a material selected from the group consisting of polymers, lipids, peptides, silicas and dextran. In addition, the biocompatible materials can be further modified to provide better biocompatibility. For example, it is possible to use lipids or peptides in combination with polymers. Specific examples of the biocompatible polymer include biopolymers such as chitosan, elastin, hyaluronic acid, alginate, gelatin, collagen and cellulose, polyethylene glycol (PEG), polyethylene oxide (PEO), polycaprolactone (PCL), polylactic acid PLGA), poly [(3-hydroxybutyrate) -co- (3-hydroxyvalerate) (PHBV), poly (L-lactide) -co- (D-lactide) -Poly (L-lactide) -co- (caprolactone) (PVA), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), polystyrene (PS), polyaniline (PAN), and the like, such as poly [ethylene-co- (vinyl alcohol)] (PVOH), polyacrylic acid Chemical polymers can be used. In one embodiment, the biocompatible material may be a polymer such as polyethylene glycol.

In addition, such biocompatible materials may be associated with target directed ligands. The target directional ligand refers to a ligand that can be introduced into a tissue or cell to be contrasted using the manganese oxide nanoparticles according to the present invention. As the target directional ligand, not only antibodies and aptamers but also compound ligands known to bind to specific receptors on the cell surface may be usefully used. Specific kinds of such antibodies, aptamers, and compound ligands are well known in the art.

Bonding between the target directional ligand and the coating layer comprising the biocompatible material may be achieved through physical bonding or covalent linkage between the functional group present on the coating layer and the functional group present on the target directional ligand. These functional groups may be inherently present on the coating layer or the ligand, but may be modified to have a functional group capable of cross-linking if necessary. The functional groups present on the coating layer and the functional groups present on the ligand can be selected from known functional group binding examples so that they can form bonds with each other. Representative examples of these known functional group binding examples are shown in Table 1 below.

I II III R-NH 2 R'-COOH R-NHCO-R ' R-SH R'-SH R-SS-R R-OH R '-(epoxy) R-OCH 2 C (OH) CH 2 -R ' RH-NH 2 R '-(epoxy) R-NHCH 2 C (OH) CH 2 -R ' R-SH R '-(epoxy) R-SCH 2 C (OH) CH 2 -R ' R-NH 2 R'-COH R-N = CH-R ' R-NH 2 R'-NCO R-NHCONH-R ' R-NH 2 R'-NCS R-NHCSNH-R ' R-SH R'-COCH 2 R'-COCH 2 SR R-SH R'-O (C = O) X R-OCH 2 (C = O) O-R ' R- (aziridine group) R'-SH R-CH 2 CH (NH 2 ) CH 2 S-R ' R-CH = CH 2 R'-SH R-CH 2 CHS-R ' R-OH R'-NCO R'-NHCOO-R R-SH R'-COCH 2 X R-SCH 2 CO-R ' R-NH 2 R'-CON 3 R-NHCO-R ' R-COOH R'-COOH R- (C = O) O (C = O) -R '+ H 2 O R-SH R'-X R-S-R ' R-NH 2 R'CH 2 C (NH 2 + ) OCH 3 R-NHC (NH 2 + ) CH 2 -R ' R-OP (O 2 -) OH R'-NH 2 R-OP (O 2 -) -NH-R ' R-CONHNH 2 R'-COH R-CONHN = CH-R ' R-NH 2 R'-SH R-NHCO (CH 2 ) 2 SS-R ' I or II: functional group present on the coating layer or functional group present on the ligand
III: binding example according to reaction of I and II
R or R ': any functional group

When the manganese oxide nanoparticles according to the present invention are introduced into a living body, they may be introduced into cells by endocytosis. As can be seen in the following examples, the manganese oxide nanoparticles having a hollow structure in which Mn2 + ions have already escaped are mainly attached to the outer surface of blood vessels or cancer tissues, whereas the manganese oxide nanoparticles according to the present invention are bound to cancer tissues. Mn2 + ions are then dissolved and spread between the cancer cells to brighten the entire cancer tissue.

Meanwhile, when introducing another diagnostic probe into the manganese oxide nanoparticles according to the present invention, it may be used as a multiple diagnostic probe. For example, when an optical diagnostic probe such as a fluorescent material is attached to a manganese oxide nanoparticle according to the present invention or mounted on a hollow structure in which manganese ions are released, other methods of optical imaging besides magnetic resonance images and terahertz wave images Simultaneously, the combination of CT diagnostic probes or manganese ions can be mounted on the hollow structure out of the magnetic resonance image, terahertz wave image and CT diagnosis can be performed at the same time. In addition, combined with radioisotopes, PET and SPECT can be diagnosed simultaneously with magnetic resonance imaging and terahertz wave imaging.

Accordingly, the present invention also provides manganese oxide nanoparticles further comprising one or more probes selected from the group consisting of optical diagnostic probes, CT diagnostic probes, and radioisotopes. These probes may be used by binding to the manganese oxide nanoparticles according to the present invention or encapsulated in a coating layer depending on the functional groups and hydrophobic / hydrophilic characteristics of the probes used.

For example, optical diagnostic probes include quantum dots, CT diagnostic probes include I (iodine) compounds, gold nanoparticles, and radioisotopes include In, Tc, F, and the like.

In addition, the present invention is an oxidation comprising a manganese oxide (Manganese (II) oxide, MnO) in the core, and a manganese tetraoxide (Manganese (II, III) oxide, Mn 3 O 4 ) in a shell having a needle surface It provides a contrast agent for magnetic resonance imaging containing manganese nanoparticles. As described above, the manganese oxide nanoparticles according to the present invention exhibit a very significant T1 contrast effect unlike the previously reported T1 contrast agents due to the large surface area and the release of Mn 2+ ions with pH.

The present invention also includes a contrast agent for magnetic resonance imaging comprising manganese (II, III) oxide, Mn 3 O 4 , in a shell having a needle-like surface, and containing manganese oxide nanoparticles having a hollow core. To provide. Since the manganese oxide nanoparticles have a large specific surface area, they not only show a remarkable T1 contrast effect, but also can carry a drug in a hollow existing therein. Thus, a contrast agent for magnetic resonance imaging including these manganese oxide nanoparticles is treated together with a diagnosis. To make it possible.

In addition, the present invention includes a manganese oxide (Manganese (II) oxide, MnO) in the core, and a manganese tetraoxide (Manganese (II, III) oxide, Mn 3 O 4 ) in the shell having a needle surface It provides a contrast agent for terahertz wave imaging containing manganese oxide nanoparticles. As described above, the manganese oxide nanoparticles according to the present invention release Mn 2+ ions in a low pH environment in which cancer cells are present, and cancer cells contain such Mn 2+ ions within the cell. Therefore, it is possible to distinguish between cancer tissue and normal tissue by imaging the difference in terahertz wave absorption between Mn2 + ions in cancer tissue and water in normal tissue, which is very useful for the treatment of cancer through terahertz endoscopy. Can be used.

The present invention also administers the manganese oxide nanoparticles or manganese ions to a living body, exposes the living body to terahertz waves, and then measures the difference in the absorbance of terahertz waves between manganese ions and water in vivo, and imaging these differences. It provides a terahertz wave imaging method that includes. In the present invention, the manganese ions absorb terahertz waves, and by using the difference between the terahertz wave absorption of water and the terahertz wave absorption of manganese ions, it is possible to image cancer tissue by detecting manganese ions present in cancer tissue. Revealed for the first time. As long as manganese ions are introduced into cancer cells, the terahertz wave imaging method can be applied, so that the manganese ion precursor used for the implantation of manganese ions in vivo is not particularly limited, and any manganese ions can be released in vivo. Anything is available. However, in consideration of the advantage that the magnetic resonance imaging contrast agent and the terahertz contrast agent can be used multiplely, it would be preferable to use the manganese oxide nanoparticles according to the present invention.

The contrast agent for magnetic resonance imaging or the contrast agent for terahertz wave imaging according to the present invention may include a carrier and a vehicle commonly used in the pharmaceutical field. Particularly preferred are ion exchange resins, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as various phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids ), Water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose based substrates, polyethylene glycol, sodium carboxy Methyl cellulose, polyarylate, wax, polyethylene glycol or wool, and the like. Contrast agents according to the invention may also further comprise lubricants, wetting agents, emulsifiers, suspending agents, preservatives and the like in addition to the above components.

In one embodiment, the contrast agent according to the present invention may be prepared as an aqueous solution for parenteral administration, preferably a buffered solution such as Hanks' solution, Ringer's solution or physically buffered saline. Can be used. Aqueous injection suspensions may contain a substrate capable of increasing the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran.

Another preferred embodiment of the contrast agent of the invention may be in the form of sterile injectable preparations of sterile injectable aqueous or oily suspensions. Such suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents (e. G., Tween 80) and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions (eg solutions in 1,3-butanediol) in nontoxic parenterally acceptable diluents or solvents. Vehicles and solvents that may be used include mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, nonvolatile oils are conventionally used as a solvent or suspending medium. For this purpose, any non-volatile oil including synthetic mono or diglycerides and less irritant may be used.

The step of administering the contrast agent to the living body may be administered via a route conventionally used in the pharmaceutical field, and parenteral administration is preferable and may be administered through, for example, an intravenous, intraperitoneal, intramuscular, subcutaneous or topical route. Can be.

Manganese oxide nanoparticles having a needle-like surface according to the present invention when Mn2 + ions are melted from MnO inside the nanoparticles when they come close to the cancer cells exhibiting acidity, the surface maintains the sea urchin shape and the inside has a hollow shape. This structure maximizes the surface area, amplifies the T1 contrast effect, and also has a double amplification effect in which the T1 contrast effect is amplified once more by the released Mn2 + ions. Indicates. In addition, the manganese oxide nanoparticles according to the present invention is a multifunctional contrast agent that can also be used as a terahertz contrast agent that can overcome the limitations of MRI that is difficult to diagnose the organs containing air such as stomach, lungs, intestines It is very useful because of that.

FIG. 1A is a TEM photograph showing octahedral manganese oxide nanoparticles formed through pyrolysis, and FIG. 1B is a diagram of manganese oxide nanoparticles having a needle-shaped surface formed by etching such manganese oxide nanoparticles.
FIG. 2A is XRD data showing the composition change of manganese oxide nanoparticles with time, and FIG. 2B is XPS data showing the composition of manganese oxide nanoparticles after 3 days of synthesis.
Figure 3 is a TEM photograph showing the shape change of the manganese oxide nanoparticles with the control of the temperature and time of the etching process.
4 is a TEM photograph showing the shape change of the manganese oxide nanoparticles according to the ratio of the organic acid used in the etching process.
5 is a TEM photograph showing the size change of manganese oxide nanoparticles according to the amount of amine used in the pyrolysis process.
Figure 6 is a TEM photograph showing the change in size and shape of the manganese oxide nanoparticles with a change in etching time.
7 and 8 are TEM images showing the shape change of manganese oxide nanoparticles with time and pH.
Figure 9 is a photograph showing the color change of the buffer containing manganese oxide nanoparticles with time and pH.
10 shows the results of ICP analysis of manganese oxide nanoparticles with time and pH.
FIG. 11 shows MRI data over time using Mn 2+ ions dissolved from manganese oxide nanoparticles at different pHs.
12 is an ICP analysis showing the release of Mn 2+ ions and thereby the T1 contrast effect.
FIG. 13 is an MRI analysis showing the release of Mn 2+ ions and thereby the T1 contrast effect.
14 shows the results of comparing the T1 contrast effect of octahedral manganese oxide nanoparticles and acicular manganese oxide nanoparticles.
FIG. 15 is a TEM photograph showing morphological changes of MnO @ Mn 3 O 4 nanoparticles in RAW 264.7 cells. FIG.
FIG. 16 is a TEM photograph showing morphological changes of MnO @ Mn 3 O 4 nanoparticles in NIH3T6.7 cells. FIG.
17 shows the T1 contrast effect of MnO @ Mn 3 O 4 nanoparticles and hollow structured Mn 3 O 4 nanoparticles in NIH3T6.7 cells.
FIG. 18 shows the results of comparing the T1 contrast effect in rat cancer cells using needle-shaped MnO @ Mn 3 O 4 nanoparticles and hollow needle-shaped Mn 3 O 4 nanoparticles.
19 shows the terahertz absorption results of manganese ions using the direct transmission method.
Figure 20 shows the transmission spectrum results of the ion release in the pH4 solution of the needle-shaped MnO @ Mn 3 O 4 nanoparticles using a direct transmission method.
Figure 21 shows the results of the terahertz transmission spectrum in accordance with the concentration of Mn + 2 ions with wave guide transmission methods.

Advantages and features of the present invention and methods of achieving them will become apparent with reference to the embodiments described in detail below. However, the present invention is not limited to the embodiments disclosed below, but will be implemented in various forms, and only the embodiments are intended to complete the disclosure of the present invention, and the general knowledge in the technical field to which the present invention pertains. It is provided to fully convey the scope of the invention to those skilled in the art, and the present invention is defined only by the scope of the claims.

[ Example ]

Example  1: Preparation of Manganese Oxide Nanoparticles with Needle Surface-1

1.4 mmol (0.24916 g) of Mn (II) acetate, 1.5 mmol (0.4264 g) of oleic acid, 3.0 mmol (0.8043 g) of oleylamine, and 5 g of trioctylamine were added to a reaction tube. Pyrolysis was carried out by heating argon gas at a volume of 10-40 cc / min in a reaction vessel for 50 minutes from room temperature to 270 ° C. for 5-10 minutes. As a result, as can be seen in FIG. 1A, octahedral manganese oxide nanoparticles of about 100 to 200 nm were produced. A mixture of oleic acid (1.6 mmol, 0.45 g) and trioctylamine (2 g) was injected into a reaction vessel containing manganese oxide nanoparticles, and the reaction was terminated after etching for 1 hour. As a result, as can be seen in Figure 1B, manganese oxide nanoparticles having a sea urchin-shaped acicular surface were produced. To confirm the composition of the manganese oxide nanoparticles prepared as described above, XRD analysis was performed. As a result, as can be seen in the XRD data of FIG. 2A, the manganese oxide nanoparticles immediately after synthesis were composed of MnO, but Mn 3 O 4 was also observed with time. After 3 days of synthesis, the manganese oxide nanoparticles were confirmed to be mixed with MnO and Mn 3 O 4 , as can be seen from the XPS data of FIG. 2B. That is, the manganese oxide nanoparticles immediately after the synthesis is made of MnO, it can be seen that the surface of the manganese oxide nanoparticles are converted to Mn 3 O 4 when exposed to air.

Comparative Example  1: Preparation of Manganese Oxide Nanoparticles

1.4 mmol (0.24916 g) of Mn (II) acetate, 1.5 mmol (0.4264 g) of oleic acid, 3.0 mmol (0.8043 g) of oleylamine, and 5 g of trioctylamine were added to a shlenk tube. Pyrolysis was carried out by heating argon gas at a volume of 10-40 cc / min in a reaction vessel for 50 minutes from room temperature to 270 ° C. for 5-10 minutes. As a result, octahedral manganese oxide nanoparticles were produced. After the temperature of the reactants including the manganese oxide nanoparticles was lowered to 210 ° C. and 240 ° C., respectively, 1.6 mmol (0.45 g) of oleic acid and 2 g of trioctylamine were added thereto. The mixture was poured into a heating vessel, etched for 1 hour and the reaction ended. As a result, as can be seen in Figure 3, the etching phenomenon does not occur, the octahedral-shaped manganese oxide nanoparticles are maintained and the size is increased as the temperature is lowered.

Example  2: Preparation of Manganese Oxide Nanoparticles with Needle Surface-2

In Example 1, etching was performed by varying the ratio of oleic acid to the reactant including the octahedral manganese oxide nanoparticles formed through the pyrolysis reaction. 0.8 mmol (0.23 g) of oleic acid and 2 g of trioctylamine were added, 2.4 mmol (0.68 g) of oleic acid, 2 g of trioctylamine, 5.3 mmol (1.5 g) of oleic acid, and 2 g of trioctylamine were added thereto. The mixture was poured into a heating vessel, etched for 1 hour and the reaction ended. As a result, as can be seen in Figure 4, the shape of the manganese oxide nanoparticles having a sea urchin-shaped needle-shaped surface according to the ratio of oleic acid was changed. When the ratio of oleic acid is small, the etching is small and when the ratio is large, small nanoparticles are made.

Example  3: Preparation of Manganese Oxide Nanoparticles with Needle Surface-3

1.4 mmol (0.24916 g) of Mn (II) acetate, 1.5 mmol (0.4264 g) of oleic acid, 7.0 mmol (1.8724 g) of oleylamine, and 5 g of trioctylamine were added to a reaction tube (shlenk tube). Pyrolysis was carried out by heating argon gas at a volume of 10-40 cc / min in a reaction vessel for 50 minutes from room temperature to 270 ° C. for 5-10 minutes. As a result, when the amount of oleylamine was increased during the initial reaction, as shown in FIG. 5A, smaller octahedral manganese oxide nanoparticles were produced. 0.8 mmol (0.23 g) of oleic acid, 2 g of trioctylamine, and 2 g of trioctylamine of oleic acid were added to the reaction product containing the manganese oxide nanoparticles. The mixture was poured into a heating vessel, etched for 1 hour and the reaction ended. As a result, as can be seen in Figure 5B, it can be seen that the size of the octahedral manganese oxide nanoparticles decreases as the amount of oleylamine increases during the initial reaction, and the etching process does not occur when the oleic acid is added. It can be seen.

Example  4: Preparation of Manganese Oxide Nanoparticles with Needle Surface-4

In Example 1, a mixture of 1.6 mmol (0.45 g) of oleic acid and 2 g of trioctylamine was injected into a reaction vessel containing octahedral manganese oxide nanoparticles formed through pyrolysis, and then etched for 3 hours to terminate the reaction. It was. As a result, as can be seen in Figure 6, the etching process is long, manganese oxide nanoparticles having a small sea urchin-shaped needle surface was produced.

Example  5: Preparation of Manganese Oxide Nanoparticles with Acicular Surface Coated with Biocompatible Materials

10 mg (0.14 mmol) of manganese oxide particles prepared in Examples and Comparative Examples were dissolved in 4 ml of an organic solvent (hexane or chloroform). Ultrasonic wave was applied at 500rpm to 1000rpm with stirring, and 100mg (0.058mmol) of carboxypolyed solvate-80 (carboxylated polysorbate-80 or carboxylated Tween-80) was dissolved in 20 ml of water. Reacted. The water temperature of the ultrasonicator was maintained at 4 o C to prevent the temperature of the reaction vessel from rising during the reaction. The mixture was stirred in air to volatilize the organic solvent present in the reaction solution. The above method is a modification of the commonly used micro-emulsion method according to the present invention, the amount of nanoparticles, polysorbate, organic solvent, distilled water is not very important, but the amount of distilled water should be more than the organic solvent and It is important to use an impeller to stir while maintaining a low temperature to prevent structural collapse.

Example  6: Targeting Ligand Combined  Preparation of Manganese Oxide Nanoparticles with Needle Surfaces

Prepared according to the method disclosed in Example 5, Herceptin was bound as a targeting ligand to MnO @ Mn 3 O 4 manganese oxide nanoparticles having a needle-like surface coated with a biocompatible material. Here's how to bind Herceptin: 5 equivalents of 1-ethyl-3- [3-dimethylaminopropyl] carbodiimide hydrochloride and 5 equivalents of N -hydroxy based on the amount of T-80 of the acicular manganese oxide nanoparticles in the aqueous solution prepared in Example 5 Sulfosuccinimide and 0.001 equivalent of Herceptin were dissolved in 10 ml of PBS buffer and allowed to react, followed by centrifugation to separate needle-shaped manganese oxide nanoparticles bound to the targeting ligand.

Example  7: Preparation of Manganese Oxide Nanoparticles with Needle Surface and Hollow Structure in Core

It shows the MnO of manganese oxide nanoparticles both melt was prepared swelman Mn 3 O 4 nanoparticles remaining hollow of Mn 3 O 4. Acicular manganese oxide nanoparticles on the aqueous solution prepared according to Example 5 were separated by precipitation by centrifugation. Then, 20 ml of PBS buffer solution having a pH of 6 or less was added thereto. After 48 hours at pH 4, more than 95% of the particles will be punctured. Thereafter, the targeting ligand was bound as required according to the method of Example 6.

Experimental Example  1: of manganese oxide nanoparticles with needle surface pH Change of manganese ion emission

In order to confirm the change in the release of manganese ions with pH and time, MnO @ Mn 3 O 4 manganese oxide nanoparticles having a needle-like surface coated with a biocompatible material prepared according to Examples 1 and 5 were prepared at different pH. In a buffer having pH 3, pH 4, pH 5, pH 6 and pH 7.4, and after a predetermined time, the buffer was centrifuged to observe the morphological changes of the manganese oxide nanoparticles by TEM, and then not dissolved in the buffer. The amount of manganese present in the manganese oxide nanoparticles and the amount of manganese ions dissolved in the buffer were measured by IPC (Inductively Coupled Plasma) and MRI, respectively.

7 is a TEM image showing the change in shape of manganese oxide nanoparticles with time and pH. As can be seen in Figure 7, it can be seen that the hollow gradually forms inside the manganese oxide nanoparticles over time under acidic conditions of pH 4 to 6. On the other hand, as can be seen in Figure 8, the manganese oxide nanoparticles disintegrate at a rapid rate at pH 3, at pH 7.4 it can be confirmed that no hollow is formed because it does not affect the manganese oxide nanoparticles over time. have. Figure 9 is a photograph showing the color change of the buffer containing manganese oxide nanoparticles with time and pH. As can be seen in Figure 9, at pH 3, Mn 3 O 4 part corresponding to the shell of the manganese oxide nanoparticles also melted, it was confirmed that the solution becomes clear over time.

On the other hand, Figure 10 shows the results of ICP analysis of manganese oxide nanoparticles with time and pH. As can be seen in FIG. 10, at pH 7.4, almost no manganese ions are released from the manganese oxide nanoparticles over time, while at pH 6 or less, the pH is lowered and the release of manganese ions increases with time, resulting in increased manganese oxide. It can be seen that the amount of manganese remaining in the nanoparticles gradually decreased. In addition, FIG. 11 shows MRI data over time using Mn 2+ ions dissolved from manganese oxide nanoparticles for each pH. As can be seen from FIG. 11, it can be seen that at pH 6 or lower, as the pH is lower, the release of manganese ions increases with time, thereby significantly increasing the T1 contrast effect. Therefore, it is expected that in cancer cells exhibiting a pH of about 5.5, manganese ions may be released from the manganese oxide nanoparticles according to the present invention to be distinguished from normal tissues through the T1 contrast effect.

On the other hand, to compare the release of the Mn2 + ions and the resulting improvement in the T1 contrast effect, using the Mn 3 O 4 nanoparticles of hollow structure prepared according to the method of Example 7 as a comparison group, respectively, ICP (Inductively Coupled Plasma) ) And MRI analysis. As a result, as shown in the ICP results of FIG. 12, the hollow structure of Mn 3 O 4 having a stable structure at a relatively low pH condition did not melt except in a strong acidity condition such as pH 3, so that at pH 6 to pH 4 It can be seen that almost no Mn2 + ions can be released. In addition, as can be seen in the results of the MRI analysis of FIG. 13, it can be seen that Mn 2+ ions hardly dissolve over time at low pH conditions, and thus there is no improvement in the T1 MR contrast effect according to Mn 2+. Compared to Mn 3 O 4 nanoparticles of the hollow structure from the result of the T1 contrast effect of MnO @ Mn 3 O 4 nanoparticles can be found far excellent.

In addition, to compare the T1 contrast effect between the manganese oxide having a needle-like structure and the general octahedral manganese oxide was tested as follows. First, 10 mg of manganese oxide having a needle-like structure prepared in Example 1 was used to make manganese oxide (urchin closed) having a stable needle-like structure in water. 10 mg of manganese oxide having a needle structure made in this manner was prepared in the manner described in Example 7 to prepare a manganese oxide having a hollow structure (urchin hollow). As a comparative control, a typical octahedral nanoparticle (Octahedral closed) was synthesized octahedral manganese oxide nanoparticles synthesized through the pyrolysis reaction of Example 1 to synthesize 10 mg of octahedral manganese oxide nanoparticles stable in aqueous solution using the method described in Example 5. It was. In addition, 10 mg of octahedral manganese oxide nanoparticles prepared by the same method was used to form octahedral nanoparticles (Octahedral hollow) having a hollow structure through the method of Example 7. FIG. 14 is a solution MR image of a solution obtained by diluting a stock solution at a concentration of 1/2 from the leftmost side. As can be seen in Figure 14a it can be seen that when using the same amount of manganese oxide of a broad surface acicular structure shows a higher T1 contrast effect. In addition, as shown in FIG. 14B, the T1 image of the hollow structure also shows higher T1 contrast efficiency due to the larger surface area of the manganese oxide of the acicular structure.

Experimental Example  2: Confirmation of Morphological Changes in Cells of Manganese Oxide Nanoparticles with Needle Surfaces

MnO @ Mn 3 O 4 nanoparticles prepared according to the above example were introduced into cells, and morphological changes of the nanoparticles were observed in the cells.

2- (1). Morphological Changes of MnO @ Mn 3 O 4 Nanoparticles in RAW 264.7 Cells

MnO @ Mn 3 O 4 nanoparticles prepared according to Example 1 and coated with a biocompatible material according to the method of Example 5 were dissolved in water and added to the culture medium of RAW 264.7 cells, which are macrophages. As a result, as shown in FIG. 15, it was confirmed that MnO @ Mn 3 O 4 nanoparticles were introduced into macrophages by pagocytosis after 30 minutes of culture through TEM observation, and the cells gradually increased with time. It was observed that MnO @ Mn 3 O 4 nanoparticles introduced into the MnO part melted due to the low pH inside the macrophage, forming a hollow inside.

2- (2). Morphological Changes of MnO @ Mn 3 O 4 Nanoparticles in NIH3T6.7 Cells

Herceptin-bound MnO @ Mn 3 O 4 nanoparticles prepared according to Examples 1, 5, and 6 were added to a culture of NIH3T6.7 cells, breast cancer cells overexpressed with Her2 / neu. As a result, as shown in FIG. 16, it was confirmed that MnO @ Mn 3 O 4 nanoparticles were introduced into cancer cells by endocytosis after 30 minutes of culture, and gradually introduced into cancer cells over time. The low pH of the MnO @ Mn 3 O 4 nanoparticles, which is a characteristic of cancer cells, resulted in the formation of a hollow inside the relatively weak MnO moiety to Mn 2+.

Experimental Example  3: in vitro of manganese oxide nanoparticles with needle surface T1  Check the contrast effect

MnO @ Mn 3 O 4 nanoparticles prepared according to the above example were introduced into breast cancer cells, and the T1 contrast effect of the nanoparticles was investigated.

3- (1). T1 Contrast Effect of MnO @ Mn 3 O 4 Nanoparticles in NIH3T6.7 Cells

Herceptin-coupled MnO @ Mn 3 O 4 nanoparticles prepared according to Examples 1, 5, and 6 were treated by concentration to NIH3T6.7 cells, which are breast cancer cells overexpressed with Her2 / neu, and MRI contrast was performed. In order to confirm the release of Mn2 + ions of the MnO @ Mn 3 O 4 nanoparticles according to the present invention and the improvement of the resulting T1 contrast effect, Herceptin-coupled hollow structures prepared according to Examples 1, 5, 6, and 7 The same experiment was performed using Mn 3 O 4 nanoparticles. As a result, as can be seen in Figure 17, the NIH3T6.7 cells untreated with a magnetic resonance imaging signal is black, while in the group treated with MnO @ Mn 3 O 4 nanoparticles according to the treatment concentration It was confirmed that the resonance image signal changed from gray to white indicating high T1 contrast effect. In addition, in the group treated with hollow structured Mn 3 O 4 nanoparticles, the surface area of MnO @ Mn 3 O 4 was initially larger than that of MnO @ Mn 3 O 4. As the Mn2 + ions were etched over time, the T1 magnetic resonance imaging signal became stronger than the conventional Mn3O4.

Experimental Example  3: In vivo of manganese oxide nanoparticles with needle surface T1  Check the contrast effect

MnO @ Mn 3 O 4 nanoparticles prepared according to Examples 1, 5 and 6 were intravenously administered to nude mice transplanted with breast cancer cells and MRI was performed to investigate the in vivo T1 contrast effect of the nanoparticles. In order to confirm the release of Mn2 + ions of the MnO @ Mn 3 O 4 nanoparticles according to the present invention and the resulting improvement in T1 contrast effect, the Herceptin-coupled hollow structure prepared according to Examples 1, 5, 6 and 7 The same experiment was performed using Mn 3 O 4 nanoparticles as a comparison group. As a result, as can be seen in Figure 18, the perforated nanoparticles (Fig. 18A) is mainly attached to the blood vessels show a limit to contrast the entire cancer cells, but the closed structure MnO @ Mn 3 O 4 nanoparticles (Fig. 18B) In the case of binding around the cancer cells after the melting of manganese ions spread out between the cells it was confirmed that the entire cancer cells can be brightly contrasted.

Experimental Example  4: of manganese ions using direct transmission Terahertzpa  Check the contrast effect

The permeation spectrum of 1M manganese ion and water was compared by using the terahertz transmission spectrum by directly transmitting the terahertz wave. In general, light in the terahertz region has the highest absorption of water. Therefore, the practical medical application is difficult because more than 70% of the human body consists of water, there is currently no applicable substance of the contrast agent in the internal tissues of the body. Therefore, only medical applications of near-organs such as skin cancer or breast cancer are being studied. Therefore, there is a need for the development of a material that can show the difference between water and permeation moisture spectrum.

First, manganese chloride dissolved in water with the concentration of Mn + 2 solution using an absorption spectrum is seen to check whether or not the manganese ion used as a terahertz contrast agent. In addition, the bioavailability was also confirmed through the concentration of manganese ions dissolved in PBS buffer, which is the best for the cell growth environment. As can be seen in Figure 19, the absorption of water and PBS buffer was found to have a very similar absorption of about 4%. As a result of preliminary experiments, the transmission spectrum of Mn 2 + sample dissolved in PBS buffer and PBS buffer at a concentration of 1M was confirmed that the transmittance of Mn 2 + of 1M was higher than that of PBS buffer. The formation of clusters of Mn 2+ ions and ions on the PBS buffer can be expected. In this case, the transmittance of the generated cluster was about 20% higher than that of the PBS buffer. In the case of water, the transmission spectrum of water and 1M of manganese ions was confirmed to be about 10% more absorption of manganese ions than water, showing the possibility of terahertz contrast agent of manganese ions.

Experimental Example  5: of Manganese Oxide Nanoparticles with Needle Surface Using Direct Transmission Terahertzpa  Check the contrast effect

The needle-shaped manganese oxide nanoparticles prepared by the methods of Examples 1 and 5 were etched using a PBS buffer of pH 4 and an aqueous hydrochloric acid solution adjusted to pH 4. The application of terahertz contrast agent was measured by absorption spectrum analysis when manganese ions were etched after exposure to buffer and hydrochloric acid solution with little manganese ions and after 18 hours. As can be seen in FIG. 20, when exposed to PBS buffer, the absorption rate of up to 5% was shown to be higher when starting and when manganese ions increased over time. It has been shown that there is applicability of nanoparticles as terahertz contrast agents. In the case of aqueous hydrochloric acid, the difference was greater than that of PBS buffer. After 18 hours, manganese ions in the aqueous hydrochloric acid solution showed good absorption of more than about 15%, further increasing the applicability of terahertz contrast agents.

Experimental Example  6: of manganese ions using waveguide method Terahertzpa  Check the contrast effect

Preliminary experiments were carried out through the terahertz transmission spectrum to determine whether Mn2 + ion could be used as a terahertz contrast agent using the waveguide method. In general, the most absorbing material in the terahertz wavelength is known as water. Therefore, to use in the human body must satisfy two things. First, it should have absorbance that is roughly different from water in aqueous solution, and also show different absorbance depending on concentration. FIG. 21 shows that the terahertz absorption spectrum differs by up to about 20% or more depending on the change in Mn2 + concentration (1M of Mn2 + and 415 uM of Mn2 +). This is a result that can be seen as a terahertz contrast agent.

Claims (21)

Pyrolysis reaction of a mixture comprising a manganese precursor, a surfactant and an organic solvent to synthesize manganese oxide nanoparticles,
A method for producing manganese oxide nanoparticles having a needle-like surface comprising etching the manganese oxide nanoparticles by adding an etchant to the reactant.
The method of claim 1,
The manganese precursor is manganese (II) acetate, manganese (II) acetylacetonate, manganese (II) bromide, manganese (II) carbonate (manganese (II) carbonate), manganese (II) chloride, manganese (II) fluoride, manganese (II) iodide, Process for preparing manganese oxide nanoparticles having needle-like surfaces that are manganese (II) nitrate, manganese (II) sulfate, hydrates thereof, or mixtures thereof .
The method of claim 1,
The surfactant is a method for producing manganese oxide nanoparticles having a needle-like surface which is alkyl carboxylic acid, alkyl amine or a mixture thereof.
The method of claim 1,
The pyrolysis reaction is a method for producing manganese oxide nanoparticles having a needle-like surface is carried out by heating a mixture containing a manganese precursor, a surfactant and an organic solvent at 210 ℃ to 340 ℃.
The method of claim 1,
The etchant is a method for producing manganese oxide nanoparticles having a needle-like surface is an organic acid, an organic solvent containing an organic acid or water containing an organic acid.
The method of claim 1,
Wherein said etching is carried out by adding an etchant to the reactants and reacting at 240 ° C. to 340 ° C. 10.
Manganese oxide nanoparticles containing manganese (II) oxide (MnO) in the core and trimanganese tetraoxide (Manganese (II, III) oxide, Mn 3 O 4 ) in a shell having a needle surface.
The method of claim 7, wherein
The manganese oxide nanoparticles are coated with a biocompatible material.
9. The method of claim 8,
The biocompatible material is manganese oxide nanoparticles comprising a material selected from the group consisting of polymers, lipids, peptides, silica and dextran.
9. The method of claim 8,
Manganese oxide nanoparticles in which a target directional ligand is bound to the biocompatible material.
The method of claim 10,
The target directional ligand is manganese oxide nanoparticles that are an antibody, aptamer or compound ligand.
The contrast medium for magnetic resonance imaging comprising the manganese oxide nanoparticles of claim 7.
A manganese oxide nanoparticle comprising manganese (II, III) oxide, Mn 3 O 4 , in a shell having a needle surface, and having a hollow in the core.
The method of claim 13,
Manganese oxide nanoparticles in which a drug is carried in the hollow of the manganese oxide nanoparticles.
15. The method of claim 14,
The manganese oxide nanoparticles are coated with a biocompatible material.
16. The method of claim 15,
The biocompatible material is manganese oxide nanoparticles comprising a material selected from the group consisting of polymers, lipids, peptides, silica and dextran.
17. The method of claim 16,
Manganese oxide nanoparticles in which a target directional ligand is bound to the biocompatible material.
18. The method of claim 17,
The target directional ligand is manganese oxide nanoparticles that are an antibody, aptamer or compound ligand.
Contrast agent for magnetic resonance imaging comprising the manganese oxide nanoparticles of claim 13.
Terahertz wave imaging contrast agent comprising the manganese oxide nanoparticles of claim 7.
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