KR20130122585A - Magnetic resonance imaging contrast agent using graphene quantum dot or graphene oxide quantum dot, and manufacturing method of the same - Google Patents

Abstract

The present application relates to a magnetic resonance image (MRI) contrast agent which is water-soluble, has biodegradation property, and stability without toxicity to human body and a method for manufacturing the same. The MRI contrast agent contains ^13C-containing graphene quantum dots or ^13C-containing graphene oxide quantum dots with long relation time. [Reference numerals] (AA) Normalized intensity;(BB) Chemical Shift, ppm

Description

FIELD OF THE INVENTION [0001] The present invention relates to an MRI contrast agent including a graphene quantum dot or an oxidized graphene quantum dot, and a method of manufacturing the same. BACKGROUND ART [0002]

The present invention relates to a magnetic resonance imaging (MRI) contrast agent comprising a ¹³ C-containing graphene quantum dot or a ¹³ C-containing oxidative graphene quantum dot and a method of producing the contrast agent.

Low-dimensional nanomaterials composed of carbon atoms include fullerene, carbon nanotube, graphene, and graphite. That is, when the carbon atoms form a hexagonal shape and become a ball, fullerene as a zero-dimensional structure, carbon nanotubes as a one-dimensional dried material, graphene as a two-dimensional atom, and graphite as a three- Can be distinguished. Among them, graphene is very stable not only structurally and chemically, but also as an excellent conductor, and exhibits excellent conductivity due to its structural characteristics, which have a thickness of one atom and relatively few surface defects. For example, graphene can move electrons 100 times faster than silicon, and theoretically can carry about 100 times more current than copper.

Recently, as the elderly population increases, cerebrovascular diseases and cancer diseases are increasing, and the age of onset of adult diseases due to changes in the living environment is gradually lowered, thereby increasing interest in health. Various diagnostic methods for the early detection of diseases have been developed and the use of magnetic resonance images (MRI) as the most advanced diagnostic method is increasing rapidly.

MRI basically measures the signal from a proton. MRI was initially aimed at noninvasive diagnostic methods, but it has been shown that the first MRI contrast agent in 1988 can be used in combination with contrast agents to improve diagnostic sensitivity and specificity. In recent years, MRI The area of use of MRI contrast agent is gradually increasing from angiography to perfusion imaging.

The MRI contrast agent penetrates into sites (vessels, stomach, intestines, etc.) that were unrecognizable during X-ray imaging and allows the images to be clearly or positively distinguished during MRI imaging As a substance, it is possible to make an early diagnosis such as angina pectoris and myocardial infarction, thereby enabling treatment before the disease worsens, and also providing a clear image for early detection and treatment of cancer. The contrast agent market is about 25% of the anticancer drug market, which is expected to grow into a bigger market in the future.

As a result of nanoparticle technology development, nanoparticles composed of various materials (organic, inorganic, or organic hybrids) are being produced, and biocompatible nanoparticles, diagnostic simultaneous treatment nanoparticles and the like are being studied. For example, there have been related studies such as "MRI contrast agent containing manganese oxide nanoparticles (Korean Patent Publication No. 2008-0071463) ". Based on these research results, multiple images such as NIRF / MRI, NIRF / PET, and NIRF / CT using nanoparticle technology and near infrared fluorescence image are introduced. The development of multifunctional nanoparticles using nanoparticle technology is closely related to the development of contrast agents for biospecific and multiple imaging. In particular, nanoparticles as drug delivery materials have been proven as a biocompatible material for several decades, and the development of target-oriented drug delivery systems has been advanced to increase the specificity for diseases. The properties of these drug delivery vehicles have recently been used to develop contrast agents for molecular imaging.

Conventionally, ¹ H has been generally used as a nucleus of nuclear magnetic resonance in MRI. The contrast agent using this technique uses the principle of indirectly visualizing the presence of ¹ H of water molecules in the body by shortening the relaxation time of the water. However, in MRI using ¹ H as the nucleus of nuclear magnetic resonance, since the linearity of the magnetic resonance signal and contrast due to ¹ H is not complete and only 0.001% of the proton is detected and the relative sensitivity is low, There is a drawback that acquisition of an image enabling analysis is difficult. In addition, ¹⁹ F nuclei with sensitivity similar to those of protons have been studied as targets for application to molecular imaging by MRI, but they have not been put to practical use because of difficulty in synthesis of fluorine atom-containing compounds and the like . In contrast, contrast agents using iron oxide or gadolinium or contrast agents using atoms such as fluorine should be considered to some degree of toxicity when they are used, and they should be used by attaching a ligand or the like to improve physical properties.

Accordingly, research has been conducted on contrast agents containing fullerenes or carbon nanotubes containing ¹³ C that are harmless to the human body and usable as contrast agents. However, since fullerene and carbon nanotubes are not soluble in water, they must be used in combination with a substrate that is well soluble in water in order to be used as a contrast agent. In the case of fullerenes and carbon nanotubes, the dynamic nuclear polarization (DNP) process enhances the ¹³ C MRI signal by 10 ³ times. In order to efficiently use the contrast agent as a contrast agent, it must be used through a dynamic nuclear polarization process. There was a limit.

Accordingly, the present invention provides a magnetic resonance imaging (MRI) system comprising a ¹³ C-containing graphene quantum dot or a ¹³ C-containing oxidative graphene quantum dot having no harmful effect on the human body, water-soluble, biodegradable, stable, MRI) contrast agent, and a method for producing such a MRI contrast agent.

However, the problems to be solved by the present invention are not limited to the above-mentioned problems, and other problems not mentioned can be clearly understood by those skilled in the art from the following description.

A first aspect of the invention provides a magnetic resonance imaging (MRI) contrast agent comprising a ¹³ C-containing graphene quantum dot or a ¹³ C-containing oxidized graphene quantum dot.

A second aspect of the present invention provides a method for preparing a magnetic resonance imaging (MRI) contrast agent comprising ¹³ C-containing oxidative graphene quantum dots.

A third aspect of the invention provides a method for preparing a magnetic resonance imaging (MRI) contrast agent comprising ¹³ C-containing graphene quantum dots.

The present disclosure provides a magnetic resonance imaging (MRI) contrast agent that can be used as an MRI contrast agent without any specific pretreatment and includes biocompatible ¹³ C-containing graphene quantum dots or ¹³ C-containing oxidative graphene quantum dots. The MRI contrast agent is efficient and has a long relaxation time, so that it has an advantageous effect on imaging of a magnetic resonance imaging image. In addition, the ¹³ C-containing graphene quantum dot or ¹³ C-containing oxidized graphene quantum dot itself generates a magnetic resonance signal and is water-soluble and free from harm to the human body, so that a magnetic resonance imaging agent can be simply and economically manufactured without any special pretreatment .

FIG. 1 is a graph showing the fluorescence characteristics of ¹³ C-containing graphene quantum dots according to an embodiment of the present invention.
2A is a structural diagram of a functionalized ¹³ C-containing graphene quantum dot according to an embodiment of the present invention, and FIGS. 2B and 2C are nuclear magnetic resonance (NMR) spectra of a ¹³ C-containing graphene quantum dot according to an embodiment of the present invention. Graph.
3 is a nuclear magnetic resonance (NMR) graph of ¹³ C-containing graphene quanta according to one embodiment of the present invention.

Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings so that those skilled in the art can easily carry out the present invention. It should be understood, however, that the present invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. In the drawings, the same reference numbers are used throughout the specification to refer to the same or like parts.

Throughout this specification, when an element is referred to as "including " an element, it is understood that the element may include other elements as well, without departing from the other elements unless specifically stated otherwise.

The terms "about "," substantially ", etc. used to the extent that they are used herein are intended to be taken as a reference to either the numerical value or to the numerical value when the manufacturing and material tolerance inherent in the stated meaning is presented, Accurate or absolute numbers are used to prevent unauthorized exploitation by unauthorized intruders of the mentioned disclosure. Also, throughout the present specification, the phrase " step "or" step "does not mean" step for.

Throughout this specification, when a member is " on " another member, it includes not only when the member is in contact with the other member, but also when there is another member between the two members.

Throughout this specification, the term " combination thereof " included in the expression of the machine form means one or more combinations or combinations selected from the group consisting of the constituents described in the expression of the machine form, And the like.

Throughout this specification, the description of "A and / or B" means "A or B, or A and B".

Throughout this specification, the term "quantum dot" refers to a nanosized material having a bandgap due to the quantum confinement effect.

Hereinafter, embodiments and examples of the present invention will be described in detail with reference to the accompanying drawings.

A first aspect of the invention provides a magnetic resonance imaging (MRI) contrast agent comprising a ¹³ C-containing graphene quantum dot or a ¹³ C-containing oxidized graphene quantum dot. ^When a molecule containing ¹³ C is present in the subject, magnetic resonance imaging of the subject can be performed by measuring the magnetic resonance signal by ¹³ C, so that a molecule containing ¹³ C is used as a contrast agent for MRI But may not be limited thereto.

For example, a magnetic resonance signal by ¹³ C is useful for the acquisition of images used for quantitative evaluation because the background value in the subject is lower than ¹ H, but may not be limited thereto. For example, the ¹³ C-containing graphene quantum dot or the ¹³ C-containing oxidized graphene quantum dot may contain no harmful, water-soluble, biodegradable, stable, and long relaxation time, But may not be limited thereto. For example, the ¹³ C-containing graphene quantum dot or the ¹³ C-containing oxidized graphene quantum dot may include, but not limited to, those subjected to a dynamic nuclear polarization (DNP) process. For example, the magnetic resonance imaging contrast agent may include exhibiting high sensitivity even at low concentrations, and the magnetic resonance imaging contrast agent may include, but is not limited to, used as a positive contrast agent. For example, the ¹³ C-containing graphene quantum dot or ¹³ C-containing oxidized graphene quantum dot may include, but is not limited to, those that need not be pretreated or functionalized prior to use as a contrast agent. For example, the ¹³ C-containing graphene quantum dot or the ¹³ C-containing oxidized graphene quantum dot may include, but not limited to, those containing ¹³ C in a ratio of at least a natural abundance ratio. For example, ¹³ C may include, but is not limited to, those that have magnetic properties per se and do not require the addition of magnetic functional groups prior to use as contrast agents. For example, the graphene quantum dot or the oxidized graphene quantum dot may include, but not limited to, those whose size can be controlled during manufacture.

For example, the graphene oxide may include, but is not limited to, a functional group such as oxygen, hydrogen, a carboxyl group, a hydroxyl group, an alcohol group, and / or an epoxy group in addition to carbon.

According to one embodiment of the invention, the MRI contrast agent wherein the ¹³ C- containing graphene quantum dot or the ^13, the proportion of ¹³ C containing the graphene quantum dot C- containing oxidized about 5% to about 100 of the total carbon atoms %, Although the present invention is not limited thereto. For example, the C- ¹³ containing Yes ratio of the quantum dot or the pin ¹³ a ¹³ C containing the graphene C- quantum dot-containing oxide is from about 5% to about 100% of the total carbon atoms and about 10% to about 100%, From about 20% to about 100%, from about 30% to about 100%, from about 40% to about 100%, from about 50% to about 100%, from about 60% to about 100% About 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% , About 50%, about 10% to about 40%, about 10% to about 30%, or about 10% to about 20%. For example, the higher the C- ¹³ containing graphene quantum dots, or ^{13 13} C content of the C- containing graphene oxide quantum dots, but can include the detection sensitivity of the magnetic resonance signal high, may not be limited thereto.

According to an embodiment of the present invention, the magnetic resonance imaging contrast agent may include, but is not limited to, the graphene quantum dot or the oxidized graphene quantum dot having a size of about 0.1 nm to about 100 nm. For example, the size of the graphene quantum dot or the graphene graphene quantum dot can be from about 0.1 nm to about 100 nm, from about 0.5 nm to about 100 nm, from about 1 nm to about 100 nm, from about 4 nm to about 100 nm, From about 5 nm to about 100 nm, from about 6 nm to about 100 nm, from about 10 nm to about 100 nm, from about 15 nm to about 100 nm, from about 20 nm to about 100 nm, from about 50 nm to about 100 nm, From about 0.1 nm to about 10 nm, from about 2 nm to about 10 nm, or from about 4 nm to about 100 nm, from about 0.1 nm to about 70 nm, from about 0.1 nm to about 50 nm, from about 0.1 nm to about 20 nm, About 6 nm, but may not be limited thereto. For example, when the size of the ¹³ C-containing graphene quantum dot or the ¹³ C-containing oxidized graphene quantum dot is smaller than 50 nm, the retention time of the blood vessel is relatively longer than that of superparamagnetic iron oxide (SPIO) Localized lymph node imaging, neovascularization of cancer cells, or atherosclerotic images, which may be readily obtained by way of non-limiting examples of nuclear magnetic resonance tomography, . For example, when the size of the ¹³ C-containing graphene quantum dot or the ¹³ C-containing oxidized graphene quantum dot is larger than 50 nm, the size of the ¹³ C-containing graphene quantum dot or the ¹³ C- system to acquire their magnetic resonance images, but it may not be limited thereto.

According to one embodiment of the present invention, the MRI contrast agent may include, but is not limited to, those used to acquire images of the liver or spinal epithelium including the spleen. For example, when the size of the ¹³ C-containing graphene quantum dot or the ¹³ C-containing oxidized graphene quantum dot is larger than 50 nm, it may accumulate within a short period of time by the reticuloendothelial system after in vivo injection, Including, but not limited to, obtaining magnetic resonance imaging of an organ.

According to one embodiment of the present disclosure, the MRI contrast agent may include, but is not limited to, those used to obtain images of blood vessels, lymph nodes, angiogenesis, or atherosclerosis plaques . For example, when the size of the ¹³ C-containing graphene quantum dot or the ¹³ C-containing oxidized graphene quantum dot is smaller than 50 nm, the size of the ¹³ C-containing graphene quantum dot or the ¹³ C- But it may include, but is not limited to, local lymph node imaging with long residence time, imaging with respect to neovascularization of cancer cells, or imaging with atherosclerosis.

According to one embodiment of the present invention, the MRI contrast agent may be a magnetic resonance imaging (MRI) image, an image including Raman imaging, positron emission tomography (PET), or fluorescence imaging But may also be, but not limited to, a multi-imaging contrast agent that is also used to obtain contrast agents. Multiregional imaging agents capable of multiple imaging with other imaging devices based on magnetic resonance imaging enable faster and more accurate diagnosis of the desired disease and enable precise recognition of the disease prior to entering the treatment phase. For example, by performing both MRI-based and PET-based molecular imaging simultaneously, multiple images can be used to obtain various information about the lesion, and to complement each other's disadvantages, But may not be so limited.

According to one embodiment of the invention, the ¹³ C-containing graphene quantum dot or The ¹³ C-containing oxidized graphene quantum dots may include those coated with a biocompatible material, but the present invention is not limited thereto. For example, the biocompatible material may include a substance that stabilizes the ¹³ C-containing graphene quantum dot or a ¹³ C-containing oxidized graphene quantum dot in a water-soluble environment and / or a substance that is not toxic in vivo But may not be limited thereto. Any material known to those of ordinary skill in the art as a material exhibiting blood compatibility or biocompatibility can be used as the coating material of the ¹³ C-containing graphene quantum dot or ¹³ C-containing oxidized graphene quantum dot of the present invention.

According to one embodiment of the present disclosure, the biocompatible material is selected from the group consisting of polyvinyl alcohol, polylactide, polyglycolide, poly (lactide-co-glycolide) , Polyanhydride, polyester, polyetherester, polycaprolactone, polyesteramide, polyacrylate, polyurethane, polyetherketone, polyetherketone, But are not limited to, polyvinyl fluoride, polyvinyl imidazole, chlorosulphonate polyolefin, polyethylene oxide, polyethyleneglycol, dextran, mixtures thereof, and mixtures thereof. But are not limited to, those selected from the group consisting of copolymers of these.

According to one embodiment of the present invention, the MRI contrast agent may include a bioactive substance bound to the outer surface of the ¹³ C-containing graphene quantum dot or the ¹³ C-containing oxidative graphene quantum dot, . For example, the bioactive substance may be an antibody that recognizes and selectively binds to a specific antigen by immunological activation in vivo; A monoclonal antibody or a polyclonal antibody prepared based thereon; Variable or constant regions of the antibody; Chimeric antibodies in which some or all of them are artificially altered; Humanized antibodies; A nucleic acid such as DNA or RNA capable of complementary binding to DNA or RNA having a specific base sequence; A biochemical substance capable of binding with a specific chemical group through a hydrogen bond or the like under a predetermined condition, and the like; Various pharmacologically active substances having therapeutic, prophylactic, or palliative effects on various disease sites; Toxic active substances such as genes or toxic proteins that induce apoptosis; Electromagnetic, magnetic, electric, light, or heat sensitive chemicals; A fluorescent material that generates fluorescence; A biologically active substance such as an isotope that generates radiation; Or glucose tracer, but the present invention is not limited thereto.

In addition, the bioactive material includes all of the in vivo active materials already known in the related art, and more specifically, all bioactive materials that can be bound by methods known in the related art. For example, the ¹³ C-containing graphene quantum dot or the ¹³ C-containing oxidized graphene quantum dot may be an active ingredient having activity as a medicine; Or substances capable of binding to an active component capable of responding to radiation, electric fields, magnetic fields, various electromagnetic waves, heat, or light, and capable of diagnosing and / or treating tumors, specific proteins, etc. . For example, the ¹³ C-containing graphene quantum dots or the ¹³ C-containing oxidized graphene quantum dots combined with the bioactive substance can be used for the treatment of gastric cancer, lung cancer, breast cancer, liver cancer, laryngeal cancer, cervical cancer, ovarian cancer, But are not limited to, various diseases related to various tumors such as pancreatic cancer, bladder cancer, or colon cancer, and various diseases associated with specific proteins such as Alzheimer's disease, Parkinson's disease, or mad cow disease have.

According to one embodiment of the present invention, the bioactive substance is a target-directed substance selected from the group consisting of proteins, RNA, DNA, antibodies, and combinations thereof, which selectively bind to a target substance in a living body; A cell suicide inducing gene or toxic protein; Fluorescent material; Isotope; Light, electromagnetic waves, radiation, or heat sensitive material; Substances exhibiting pharmacological activity; And combinations thereof. However, the present invention is not limited thereto.

In one embodiment herein, the ¹³ C-containing graphene or the ¹³ C-containing oxidized graphene may be prepared using any method commonly used to produce graphene or oxide graphenes in the art without limitation . For example, the ¹³ C-containing graphene or the ¹³ C-containing oxidized graphene may be formed by a chemical vapor deposition (CVD) method or a modified hummer's method, but the present invention is not limited thereto.

The second aspect of the present invention comprises a process for producing a catalyst comprising the steps of: growing a ¹³ C -containing oxidized graphene on a support by providing a support comprising a metal catalyst thin film with a reaction gas and heat comprising a ¹³ C-containing carbon source and reacting; Obtaining the ¹³ C-containing oxidized graphene; And, magnetic, comprising the step of forming the oxide-containing C- ¹³ Yes to give a ¹³ C- containing graphene oxide quantum dots from the pin ^13, the magnetic resonance imaging comprising a C- containing graphene oxide quantum dots (MRI) contrast agents (MRI) contrast agent.

For example, the metal catalyst thin film may be formed of one selected from the group consisting of Ni, Co, Fe, Pt, Au, Al, Cr, Cu, Mg, Mn, Mo, Rh, Si, Ta, Ti, W, U, V, Zr, brass But is not limited to, a metal catalyst thin film comprising at least one metal or alloy selected from the group consisting of aluminum, copper, aluminum, copper, copper, aluminum,

For example, the carbon source can be a carbon source such as carbon monoxide, carbon dioxide, methane, ethane, ethylene, ethanol, acetylene, propane, butane, butadiene, pentane, pentene, cyclopentadiene, hexane, cyclohexane, benzene, But is not limited thereto. For example, the step of growing the ¹³ C-containing oxidized graphene may be performed at a temperature of from about 300 캜 to about 2000 캜, from about 500 캜 to about 2000 캜, from about 1000 캜 to about 2000 캜, from about 300 캜 to about 1500 캜, The method may include, but is not limited to, growing the ¹³ C-containing oxidized graphene by providing heat at a temperature of from about 300 ° C to about 1000 ° C, or from about 300 ° C to about 500 ° C.

The step of producing the ¹³ C-containing oxidized graphene can be carried out by a method known in the art. The step ¹³ of generating the ¹³ C- containing graphene oxide quantum dots from the C- containing oxidized graphene may be performed by the quantum dot generation method known in the art.

According to a third aspect of the present invention, there is provided a method for preparing a metal catalyst, comprising: growing a ¹³ C -containing oxide graphene on the support by providing a support comprising a metal catalyst thin film and a reaction gas comprising a ¹³ C- Obtaining the ¹³ C-containing oxidized graphene; The ¹³ by reducing the C- containing oxidized graphene ¹³ to produce a C- containing graphene; And the ¹³ C - containing yes to give a ¹³ C- containing graphene quantum dot pins from the ¹³ C- containing yes comprises forming a magnetic resonance imaging (MRI) contrast agent comprising a pin quantum dots, magnetic resonance imaging (MRI ) Contrast agent.

For example, the metal catalyst thin film may be formed of one selected from the group consisting of Ni, Co, Fe, Pt, Au, Al, Cr, Cu, Mg, Mn, Mo, Rh, Si, Ta, Ti, W, U, V, Zr, brass But is not limited to, a metal catalyst thin film comprising at least one metal or alloy selected from the group consisting of aluminum, copper, aluminum, copper, copper, aluminum,

For example, the carbon source can be a carbon source such as carbon monoxide, carbon dioxide, methane, ethane, ethylene, ethanol, acetylene, propane, butane, butadiene, pentane, pentene, cyclopentadiene, hexane, cyclohexane, benzene, But is not limited thereto. For example, the step of growing the ¹³ C-containing oxidized graphene may be performed at a temperature of from about 300 캜 to about 2000 캜, from about 500 캜 to about 2000 캜, from about 1000 캜 to about 2000 캜, from about 300 캜 to about 1500 캜, The method may include, but is not limited to, growing the ¹³ C-containing oxidized graphene by providing heat at a temperature of from about 300 ° C to about 1000 ° C, or from about 300 ° C to about 500 ° C.

For example, the step of reducing the ¹³ C-containing oxidized graphene to generate the ¹³ C-containing graphene may be performed by heat reduction, but the present invention is not limited thereto. For example, the step ¹³ of generating the ¹³ C- containing graphene quantum dots from the C- containing graphene may be performed by the quantum dot generation method known in the art.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

[ Example ]

[ Example  One]

¹³ C-containing oxidized graphene Quantum dot  synthesis

In this embodiment, a nickel film was inserted into the CVD chamber and vacuum was formed (up to 10 ^-4 torr) using a pump. After the pump was turned off, the furnace was heated to 1,000 ° C., and argon gas and hydrogen gas were flowed at a constant rate, and the chamber was filled with argon gas and hydrogen gas near to normal pressure. Next, methane gas containing ¹³ C was introduced into the chamber to reach the atmospheric pressure, and ¹³ C-containing graphite was grown for about 30 minutes to 60 minutes in this state. The ratio of ¹³ C of carbon in the methane gas used was 10%, 30%, or 100%. After the reaction was completed, the chamber was rapidly cooled to cause the ¹³ C-containing graphite melted in the nickel thin film to diffuse outward, and then the nickel was removed by etching with FeCl ₃ . Thereafter, washing was performed _three to four times to remove FeCl ₃ , thereby obtaining ¹³ C-containing oxidized graphene.

The obtained ¹³ C-containing oxidized graphene was mixed with sulfuric acid and nitric acid, and subjected to ultrasonic treatment, followed by filtering using a Millipore membrane to remove the acid. The filtered material was dispersed in water and neutralized with a base. The material thus obtained was placed in an autoclave and then overnight. After that, the process of filtering, the process of neutralizing with the base, and the process of over-nipping by high-pressure sterilization are repeated.

The solution obtained by the repeated procedure was dialyzed using a dialysis bag to obtain ¹³ C-containing oxide graphene quantum dots.

[ Example  2]

¹³ C - content Grapina Quantum dot  synthesis

In this embodiment, a nickel film was inserted into the CVD chamber and vacuum was formed (up to 10 ^-4 torr) using a pump. After the pump was turned off, the furnace was heated to 1,000 ° C, and argon gas and hydrogen gas were supplied at a constant rate, and the inside of the chamber was filled with argon gas and hydrogen gas near the normal pressure. Next, methane gas containing ¹³ C was introduced into the chamber to reach atmospheric pressure, and ¹³ C-containing graphite was grown for about 30 minutes to 60 minutes in this state. The ratio of ¹³ C of carbon in the methane gas used was 10%, 30%, or 100%. After the reaction was completed, the chamber was rapidly cooled to cause the ¹³ C-containing graphite melted in the nickel thin film to diffuse outward, and then the nickel was removed by etching with FeCl ₃ . Thereafter, washing was performed _three to four times to remove FeCl ₃ , thereby obtaining ¹³ C-containing oxidized graphene.

The ¹³ C-containing oxidized graphene is thermally reduced in a nitrogen gas atmosphere at a temperature of 200 to 300 degrees to prepare a ¹³ C-containing graphene sheet.

The thus-obtained ¹³ C-containing graphene sheet was mixed with sulfuric acid and nitric acid, subjected to ultrasonic treatment, and then filtered using a Millipore membrane to remove the acid. The filtered material was dispersed in water, neutralized with a base, and the obtained material was over-kneaded in a high-pressure autoclave. Thereafter, the process of filtering, the process of neutralizing with the base, and the process of over-kneading in the high-pressure sterilizer are repeated.

The solution obtained by the repeated procedure was dialyzed using a dialysis bag to obtain ¹³ C-containing graphene quantum dots.

[ Example  3]

The obtained ¹³ C-containing graphite, ¹³ C-content Grapina , And ¹³ C-content Graphene oxide  Character analysis

¹³ C-bearing graphite was analyzed using Raman spectroscopy (CRM200, Witech) and NMR (chemagnetics CMX-400 spectrometer).

¹³ C-containing graphene, and ¹³ C-containing oxide graphene, CRM200, Witech, NMR, chemagnetics CMX-400 spectrometer, FTIR, Nicolef 710 spectrometer, (TEM, JEM3010, Jeol), atomic force microscope (AFM, XE-100, park system), XPS, Kratos Axis ultra DLD x-ray photoelectron spectrometer and XRD, Rigaku D / max-2500 wing Cu Kx radiation).

[ Example  4]

¹³ C-content Grapina Quantum dot  Fluorescence Characterization

In this example, the fluorescence of ¹³ C-containing graphene quantum dots synthesized according to the above examples was measured and shown in a graph (see FIG. As a result, it was confirmed that the ¹³ C-containing graphene quantum dot emitted blue fluorescence at a wavelength of about 441 nm (see FIG. 1 b). Thus, it was confirmed that the contrast agent containing the ¹³ C-containing graphene quantum dot of the present invention can also be used to obtain fluorescence images.

[ Example  5]

¹³ C-content Grapina Quantum dot  Nuclear magnetic resonance NMR ) Measure

In this example, the nuclear magnetic resonance (NMR) of the ¹³ C-containing graphene quantum dots synthesized according to the above examples was measured using a chemagnetics CMX-400 spectrometer. For measurement of nuclear magnetic resonance, the ¹³ C-containing graphene quantum dots (represented by GQDs (Graphene Quantum Dots) in FIG. 2A) were first functionalized with hexylamine as shown in FIG. Respectively. As a result, peaks of functionalized ¹³ C-containing graphene quantum dots were confirmed by H-NMR as shown in Figs. 2B and 2C.

The ¹³ C-NMR of the functionalized ¹³ C-containing graphene quantum dots was measured and shown in FIG. According to the shown in Figure 3 the functionalized C- ¹³ containing yes been identified in the pin ¹³ C-NMR peak of the quantum dot, wherein the small amount of functionalized therefrom containing ¹³ C- Yes in a short time using a pin QD ¹³ It was confirmed that C-peak can be confirmed and thus can be used as an MRI contrast agent.

It will be understood by those of ordinary skill in the art that the foregoing description of the embodiments is for illustrative purposes and that those skilled in the art can easily modify the invention without departing from the spirit or essential characteristics thereof. It is therefore to be understood that the above-described embodiments are illustrative in all aspects and not restrictive. For example, each component described as a single entity may be distributed and implemented, and components described as being distributed may also be implemented in a combined form.

The scope of the present invention is defined by the appended claims rather than the detailed description, and all changes or modifications derived from the meaning and scope of the claims and their equivalents should be construed as being included within the scope of the present invention.

Claims (12)

¹³ C-containing graphene quantum dot or ¹³ C-containing oxidative graphene quantum dot.
The method of claim 1,
Wherein the ratio of ¹³ C contained in the graphene quantum dot or the graphene oxide graphene is 5% to 100% of the total carbon atoms.
The method of claim 1,
Wherein the graphene quantum dot or the graphene graphene quantum dot has a size of 0.1 nm to 100 nm.
The method of claim 1,
Wherein the magnetic resonance imaging (MRI) contrast agent is used to acquire an image thereof accumulated in the retinal endothelial system including liver or spleen.
The method of claim 1,
Wherein the magnetic resonance imaging (MRI) contrast agent is used to obtain an image of angiogenesis, or atheroschlerosis plaque of blood vessels, lymph nodes, cancer cells.
The method of claim 1,
The magnetic resonance imaging (MRI) contrast agent may be used to obtain images including Raman imaging, Positron Emission Tomography (PET), or Fluorescence Imaging in addition to magnetic resonance imaging (MRI) contrast agent, a multi-imaging contrast agent.
The method of claim 1,
The graphene quantum dot or Wherein the graphene oxide quantum dots include those coated with a biocompatible material.
The method of claim 7, wherein
The biocompatible material may be selected from the group consisting of polyvinyl alcohol, polylactide, polyglycolide, poly (lactide-co-glycolide), polyanhydride ), Polyester, polyetherester, polycaprolactone, polyesteramide, polyacrylate, polyurethane, polyvinylfluoride, polyvinylidene fluoride, A group consisting of polyvinylimidazole, chlorosulphonate polyolefin, polyethylene oxide, polyethyleneglycol, dextran, mixtures thereof, and copolymers thereof. (MRI) contrast agent.
The method of claim 1,
Wherein the graphene quantum dot or the oxidized graphene quantum dot has a bioactive substance bound to an outer surface thereof.
The method of claim 9,
The bioactive substance is a target-directed substance selected from the group consisting of proteins, RNA, DNA, antibodies, and combinations thereof, which selectively binds to a target substance in a living body, or is a cell suicide inducing gene or toxic protein; Fluorescent material; Isotope; Light, electromagnetic waves, radiation, or heat sensitive material; Substances exhibiting pharmacological activity; And combinations thereof. ≪ RTI ID = 0.0 > 11. < / RTI >
Growing a ¹³ C -containing oxide graphene on the support by reacting and reacting a support comprising a metal catalyst thin film with a reaction gas and heat comprising a ¹³ C-containing carbon source;
Obtaining the ¹³ C-containing oxidized graphene; And
The ¹³ C-containing oxide yes ¹³ from the pin C - forming a magnetic resonance imaging (MRI) contrast agent comprising the oxide-containing graphene quantum dot-containing oxide yes the ¹³ C to give the pin QD
(MRI) contrast agent.
Growing a ¹³ C -containing oxide graphene on the support by providing a reaction gas and a heat comprising a ¹³ C-containing carbon source to the support comprising the metal catalyst thin film and reacting;
Obtaining the ¹³ C-containing oxidized graphene;
Reducing the ¹³ C - containing oxidized graphene to produce ¹³ C - containing graphene; And
The ¹³ C-containing yes ¹³ from the pin C - forming a magnetic resonance imaging (MRI) contrast agent comprising a quantum dot-containing graphene-containing yes the ¹³ C to give the pin QD
(MRI) contrast agent.

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