KR102020870B1

KR102020870B1 - Magnetic resonance imaging contrast agent using graphene quantum dot or graphene oxide quantum dot, and manufacturing method of the same

Info

Publication number: KR102020870B1
Application number: KR1020130048447A
Authority: KR
Inventors: 홍병희; 정철; 이동수; 최승홍
Original assignee: 바이오그래핀 주식회사; 서울대학교산학협력단
Priority date: 2012-04-30
Filing date: 2013-04-30
Publication date: 2019-09-16
Also published as: KR20130122585A

Abstract

^A magnetic resonance imaging (MRI) contrast agent comprising ¹³ C-containing graphene quantum dots or ¹³ C-containing graphene oxide quantum dots and a method of preparing the contrast agent.

Description

MRI contrast agent comprising graphene quantum dots or graphene oxide quantum dots, and a method for manufacturing the same

The present application relates to a magnetic resonance imaging (MRI) contrast agent comprising ¹³ C-containing graphene quantum dots or ¹³ C-containing graphene oxide quantum dots and a method of preparing the contrast agent.

Low-dimensional nanomaterials composed of carbon atoms include fullerene, carbon nanotube, graphene, and graphite. That is, when carbon atoms form a hexagonal array and become a ball, fullerene, which is a 0-dimensional structure, carbon nanotubes that are dried in one dimension, graphene when a layer is formed in one layer in two dimensions, and graphite when stacked in three dimensions Can be distinguished. Of these, graphene is not only structurally and chemically stable but also an excellent conductor, and exhibits excellent conductivity due to its structural characteristics with a single layer of atomic thickness and relatively low surface defects. For example, graphene can move electrons 100 times faster than silicon, and theoretically can carry about 100 times more current than copper.

As the elderly population increases, cerebrovascular disease and cancer disease increase, and the age of onset of adult disease gradually decreases due to changes in living environment, and interest in health increases. Accordingly, various diagnostic methods for early detection of disease have been developed, and the use of magnetic resonance image (MRI), a state-of-the-art diagnostic method, is rapidly increasing.

MRI basically measures the signal from the protons. MRI was initially targeted at non-invasive diagnostic methods, but since the first MRI contrast agent was marketed in 1988, it has been found that use with contrast agents can improve diagnostic sensitivity and specificity, and recently MRI. From angiography to perfusion imaging, the area of use of MRI contrast agents is gradually increasing.

The MRI contrast agent penetrates into areas that were unidentifiable during X-ray imaging (vascular organs, such as blood vessels, stomach, or intestines), thereby brightening or darkening the image during MRI imaging so that images can be clearly distinguished. As a substance, it enables the early diagnosis of angina pectoris, myocardial infarction, etc., through which the treatment can be treated before the disease worsens, and also provides a clear image for early detection and treatment of cancer, The size of the contrast agent market is expected to grow to about 25% of the anticancer drug market.

In addition, as a result of the development of nanoparticle technology, nanoparticles made of various materials (organic, inorganic, or organic-inorganic hybrids) are being produced, and researches on biocompatible nanoparticles, diagnostic simultaneous treatment nanoparticles, and the like have been made. For example, there has been a related study such as "MRI containing magnetic manganese oxide nanoparticles (Korean Patent Publication No. 2008-0071463)". Based on these research results, recently, multiple images such as NIRF / MRI, NIRF / PET, and NIRF / CT using nanoparticle technology and near infrared fluorescence images have been introduced. The development of multifunctional nanoparticles using nanoparticle technology is closely related to the development of contrast media for biospecific and multiple imaging. In particular, nanoparticles as drug carriers have been proven to be safe as biocompatible materials for decades, and development of target-oriented drug carriers has been progressed in order to increase specificity for diseases. The properties of such drug carriers have recently been used to develop contrast agents for molecular imaging.

Conventionally, ¹ H has been generally used as an object of nuclear magnetic resonance in MRI. The contrast agent using the same utilizes the principle of indirectly visualizing the existence of the H by shortening the relaxation time of ¹ H of water molecules present in the surroundings. However, in MRI using ¹ H as the target nucleus of nuclear magnetic resonance, the linearity of the magnetic resonance signal and contrast agent concentration by ¹ H is not perfect, and only 0.001% of protons are detected and the relative sensitivity is low. There is a drawback that acquisition of an image that enables analysis is difficult. In addition, the non-proton-nuclides are not reached until in but a few of similar sensitivity ¹⁹ F nucleus and a proton been studied to as an application target for the molecular imaging by the MRI, the cause of the synthetic difficulty of fluorine atoms compound practical . In addition, in contrast agents using iron oxide or gadolinium, or contrast agents using atoms such as fluorine, some degree of toxicity should be considered in using them, and the physical properties should be improved by attaching ligands or the like.

Accordingly, there has been a study on contrast agents containing fullerenes or carbon nanotubes containing ¹³ C which are harmless to humans and can be used as contrast agents. However, fullerenes and carbon nanotubes are not soluble in water, so in order to be used as a contrast agent, they must be used in combination with a substrate soluble in water. In addition, if the fullerene or carbon nanotube geochimyeon dynamic nuclear polarization (DNP) process the MRI signal of ¹³ C 10 there is enhanced ^3-fold, to be used through the dynamic nuclear polarization process in order to efficiently use as a contrast medium for use as contrast agents There was a limit.

Accordingly, the present application provides a magnetic resonance image including ¹³ C-containing graphene quantum dots or ¹³ C-containing graphene oxide quantum dots that are harmless to the human body, are water-soluble, biodegradable, stable, and have a long relaxation time. MRI) contrast medium, and a method for preparing such a magnetic resonance imaging contrast medium.

However, the problem to be solved by the present invention is not limited to the above-mentioned problem, another task that is not mentioned will be clearly understood by those skilled in the art from the following description.

A first aspect of the present disclosure provides a magnetic resonance imaging (MRI) contrast agent comprising ¹³ C-containing graphene quantum dots or ¹³ C-containing graphene oxide quantum dots.

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

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

The present application provides a magnetic resonance imaging (MRI) contrast agent, which can be used as an MRI contrast agent without special pretreatment and comprises biocompatible ¹³ C-containing graphene quantum dots or ¹³ C-containing graphene oxide quantum dots. The magnetic resonance imaging contrast agent has good efficiency and has a long relaxation time, and thus has an advantageous effect on the imaging of the magnetic resonance image. In addition, the ¹³ C-containing graphene quantum dot or ¹³ C-containing graphene oxide quantum dot itself generates a magnetic resonance signal, water-soluble and harmless to the human body can be produced economically simple magnetic resonance imaging contrast agent without special pretreatment Can be.

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

DETAILED DESCRIPTION Hereinafter, exemplary embodiments of the present disclosure will be described in detail with reference to the accompanying drawings so that those skilled in the art may easily implement the present disclosure. As those skilled in the art would realize, the described embodiments may be modified in various different ways, all without departing from the spirit or scope of the present invention. In the drawings, parts irrelevant to the description are omitted for simplicity of explanation, and like reference numerals designate like parts throughout the specification.

Throughout this specification, when a part is said to "include" a certain component, it means that it can further include other components, without excluding the other components unless specifically stated otherwise.

As used herein, the terms "about", "substantially", and the like, are used at, or in close proximity to, numerical values when manufacturing and material tolerances inherent in the meanings indicated are provided to aid the understanding herein. In order to prevent the unfair use of unscrupulous infringers. In addition, throughout this specification, "step to" or "step of" does not mean "step for."

Throughout this specification, when a member is located “on” another member, this includes not only when one member is in contact with another member but also when another member exists between the two members.

Throughout this specification, the term “combination of these” included in the expression of the makushi form means one or more mixtures or combinations selected from the group consisting of the constituents described in the expression of the makushi form, wherein the constituents It means to include one or more selected from the group consisting of.

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 by quantum confinement effect.

Hereinafter, with reference to the accompanying drawings will be described embodiments and embodiments of the present application;

A first aspect of the present disclosure provides a magnetic resonance imaging (MRI) contrast agent comprising ¹³ C-containing graphene quantum dots or ¹³ C-containing graphene oxide quantum dots. The case of the presence of molecules containing the ¹³ C in a subject, by measuring the magnetic resonance signal by the ¹³ C because the MRI imaging of the subject can be, using the molecules containing ¹³ C as a contrast medium for MRI It may be, but may not be limited thereto.

For example, the magnetic resonance signal at ¹³ C is useful for acquiring an image used for quantitative evaluation because the background value in the subject is lower than that of ¹ H, but may not be limited thereto. For example, the ¹³ C-containing graphene quantum dots or ¹³ C-containing graphene oxide quantum dots may include a harmless, water-soluble, biodegradable, stable, long relaxation time to the human body, This may not be limited. For example, the ¹³ C-containing graphene quantum dots or ¹³ C-containing graphene oxide quantum dots may include a dynamic nuclear polarization (DNP) process, but may not be limited thereto. For example, the magnetic resonance imaging contrast agent may include a high sensitivity even at low concentrations, and the magnetic resonance imaging contrast agent may be used as a positive contrast agent, but may not be limited thereto. For example, the ¹³ C-containing graphene quantum dots or ¹³ C-containing graphene oxide quantum dots may include, but may not be limited to those that do not need to be pretreated or functionalized before being used as a contrast agent. For example, the ¹³ C-containing graphene quantum dots or ¹³ C-containing graphene oxide quantum dots may include those containing ¹³ C in a ratio of more than natural abundance, but may not be limited thereto. For example, ¹³ C may include, but is not limited to, being magnetic in itself and not requiring the addition of a magnetic functional group prior to use as a contrast agent. For example, the graphene quantum dots or the graphene oxide quantum dots may include, but may not be limited to those that can be adjusted in size during manufacture.

For example, the graphene oxide may include functional groups such as oxygen, hydrogen, carboxyl group, hydroxy group, alcohol group, and / or epoxy group in addition to carbon, but may not be limited thereto.

According to one embodiment of the invention, the MRI contrast agent wherein the ¹³ C- or the quantum dot-containing graphene ^13. The ratio of the ¹³ C-containing quantum dots to the graphene-containing C- oxide about 5% to about 100 of the total carbon atoms It may be to include a%, but may not be 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%, About 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80 % To about 100%, about 90% 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% to About 50%, about 10% to about 40%, about 10% to about 30%, or about 10% to about 20%, but may not be limited thereto. 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 the exemplary embodiment of the present disclosure, the magnetic resonance imaging contrast agent may include, but is not limited to, the graphene quantum dot or the graphene oxide quantum dot having a size of about 0.1 nm to about 100 nm. For example, the size of the graphene quantum dots or the graphene oxide quantum dots is about 0.1 nm to about 100 nm, about 0.5 nm to about 100 nm, about 1 nm to about 100 nm, about 4 nm to about 100 nm, about 5 nm to about 100 nm, about 6 nm to about 100 nm, about 10 nm to about 100 nm, about 15 nm to about 100 nm, about 20 nm to about 100 nm, about 50 nm to about 100 nm, about 70 nm To about 100 nm, about 0.1 nm to about 70 nm, about 0.1 nm to about 50 nm, about 0.1 nm to about 20 nm, about 0.1 nm to about 10 nm, about 2 nm to about 10 nm, or about 4 nm to It may include about 6 nm, but may not be limited thereto. For example, when the size of the ¹³ C-containing graphene quantum dots or ¹³ C-containing graphene oxide quantum dots is smaller than 50 nm, the small size of the ¹³ C-containing graphene quantum dots is relatively long compared to superparamagnetic iron oxide (SPIO). Non-limiting examples of nuclear magnetic resonance tomography images that can be easily obtained thereby include, but are not limited to, regional lymph node images, images of neovascularization of cancer cells, or images of atherosclerotic plaques. . For example, when the size of the ¹³ C-containing graphene quantum dots or ¹³ C-containing graphene oxide quantum dots is larger than 50 nm, the size of the reticuloendothelial, such as the liver cells Cooper cells or spleen after injection in vivo The magnetic resonance image can be obtained by accumulating at a rapid time in a system), but may not be limited thereto.

According to the exemplary embodiment of the present application, the magnetic resonance imaging contrast agent may be included in the reticulum endothelial system including the liver or the spleen and used to obtain an image thereof, but may not be limited thereto. For example, when the size of the ¹³ C-containing graphene quantum dots or ¹³ C-containing graphene oxide quantum dots is larger than 50 nm, the liver, spleen, or other accumulated in a rapid time by the retinal endothelial system after in vivo injection Magnetic resonance imaging of the organ may include, but may not be limited thereto.

According to one embodiment of the present application, the magnetic resonance imaging contrast agent may be to include those used to obtain an image of blood vessels, lymph nodes, angiogenesis, or atherosclerosis (atheroschlerosis plaque), but is not limited thereto. You may not. For example, when the size of the ¹³ C-containing graphene quantum dots or ¹³ C-containing graphene oxide quantum dots is smaller than 50 nm, the size of the ¹³ C-containing graphene quantum dots is smaller than 50 nm. The long residence time may include, but may not be limited to, local lymph node imaging, images of neovascularization of cancer cells, or images of atherosclerotic plaques.

According to the exemplary embodiment of the present application, the magnetic resonance imaging contrast agent is an image including Raman imaging, Positron Emission Tomography (PET), or fluorescence imaging in addition to magnetic resonance imaging (MRI). It may be to include a multi-image contrast agent that is also used to obtain, but may not be limited thereto. In the case of a multi-image contrast agent capable of multiple imaging with other imaging devices based on magnetic resonance imaging, it is possible to diagnose a desired disease more quickly and accurately, and to accurately recognize the disease before entering the treatment stage. For example, by performing MRI tomography and PET imaging at the same time, it is possible to obtain various information about lesions through multiple images and to recognize the state of the lesion more reliably by compensating each other's shortcomings. It may include but is not limited to showing the results.

According to an embodiment of the present application, the ¹³ C-containing graphene quantum dots or The ¹³ C-containing graphene oxide quantum dots may be coated with a biocompatible material, but may not be limited thereto. For example, the biocompatible material includes the ¹³ C-containing graphene quantum dot or the ¹³ C-containing graphene oxide quantum dot to stabilize the dispersion state in a water-soluble environment and / or a material that does not show toxicity in vivo However, this may not be limited. Any material known to those skilled in the art as a material showing blood compatibility or biocompatibility may be used as the coating material for the ¹³ C-containing graphene quantum dots or ¹³ C-containing graphene oxide quantum dots of the present invention.

According to one embodiment of the present application, the biocompatible material is polyvinyl alcohol, polylactide, polyglycolide, poly (lactide-glycolide) copolymer [poly (lactide-co-glycolide) ], Polyanhydrides, polyesters, polyetheresters, polycaprolactones, polyesteramides, polyacrylates, polyurethanes, Polyvinylfluoride, polyvinylimidazole, chlorosulphonate polyolefin, polyethylene oxide, polyethyleneglycol, dextran, mixtures thereof, and It may be to include those selected from the group consisting of copolymers, but may not be limited thereto.

According to the exemplary embodiment of the present application, the magnetic resonance imaging contrast agent may include a bioactive material coupled to an outer surface of the ¹³ C-containing graphene quantum dot or the ¹³ C-containing graphene oxide quantum dot, but is not limited thereto. It may not be. For example, the bioactive substance may include an antibody that recognizes and selectively binds to a specific antigen by immunoactivation in vivo; Monoclonal antibodies or polyclonal antibodies prepared based on these; Variable or constant regions of antibodies; Chimeric antibodies which have been artificially changed in part or in whole; Humanized antibodies; Nucleic acids such as DNA or RNA capable of complementary binding to DNA or RNA having a specific base sequence; Target-oriented substances including non-biological chemicals that can be bonded to specific chemical groups through hydrogen bonding or the like under certain conditions; Various pharmacologically active substances having a therapeutic, prophylactic, or symptomatic effect on various disease sites; Toxic actives such as genes or toxic proteins that induce cell death; Chemicals sensitive to electromagnetic waves, magnetic fields, electric fields, light, or heat; Fluorescent material for generating fluorescence; Active substances in vivo, such as isotopes that generate radiation; Or a glucose tracer (glucose tracer) may be included, but may not be limited thereto.

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

According to an embodiment of the present disclosure, the bioactive material may include a target-oriented material selected from the group consisting of proteins, RNA, DNA, antibodies, and combinations thereof that selectively bind to a target material in vivo; Cell suicide inducing gene or toxic protein; Fluorescent material; Isotopes; Materials that are sensitive to light, electromagnetic waves, radiation, or heat; Substances exhibiting pharmacological activity; And combinations thereof may be selected from the group consisting of, but may not be limited thereto.

In one embodiment of the present application, the ¹³ C-containing graphene or the ¹³ C-containing graphene oxide may be prepared using, without limitation, methods generally used in the art to prepare graphene or graphene oxide. Can be. For example, the ¹³ C-containing graphene or the ¹³ C-containing graphene oxide may be generated by chemical vapor deposition (CVD) or modified hummer's method, but may not be limited thereto.

According to a second aspect of the present invention, there is provided a method including growing a ¹³ C-containing graphene oxide on a support by providing a reaction gas including a ¹³ C-containing carbon source and heat to a support including a metal catalyst thin film; Obtaining the ¹³ C-containing graphene oxide; 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 It provides a method for preparing a resonance imaging (MRI) contrast agent.

For example, the metal catalyst thin film is Ni, Co, Fe, Pt, Au, Al, Cr, Cu, Mg, Mn, Mo, Rh, Si, Ta, Ti, W, U, V, Zr, brass (brass ), A metal catalyst thin film including one or more metals or alloys selected from the group consisting of bronze, stainless steel, and Ge, but may not be limited thereto.

For example, the carbon source may be a carbon source such as carbon monoxide, carbon dioxide, methane, ethane, ethylene, ethanol, acetylene, propane, butane, butadiene, pentane, pentene, cyclopentadiene, hexane, cyclohexane, benzene, or toluene. It may be included, but may not be limited thereto. For example, the step of growing the ¹³ C-containing graphene oxide is about 300 ℃ to about 2000 ℃, about 500 ℃ to about 2000 ℃, about 1000 ℃ to about 2000 ℃, about 300 ℃ to about 1500 ℃, about It may include, but is not limited to, growing the ¹³ C-containing graphene oxide by providing heat at a temperature of about 300 ° C. to about 1000 ° C., or about 300 ° C. to about 500 ° C. for reaction.

Producing the ¹³ C-containing graphene oxide may be performed 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 including growing a ¹³ C-containing graphene oxide on a support by providing a reaction gas including a ¹³ C-containing carbon source and heat to a support including a metal catalyst thin film; Obtaining the ¹³ C-containing graphene oxide; ¹³ by reducing the graphene oxide containing C- 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 ) Provides a method for preparing the contrast agent.

For example, the C- ¹³ by reducing the graphene-containing oxide to produce the ¹³ C- contain graphene, but may be performed by heat reduction, it may not be limited thereto. For example, generating the ¹³ C-containing graphene quantum dots from the ¹³ C-containing graphene may be performed by a quantum dot generation method known in the art.

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

[ Example ]

[ Example One]

¹³ C-containing graphene oxide Quantum dots synthesis

In this embodiment, after the nickel thin film was inserted into the CVD chamber, a vacuum state (up to 10 ^-4 torr) was formed by using a pump. After the pump was turned off, the furnace was heated up to 1,000 ° C., and argon gas and hydrogen gas were flowed at a predetermined rate to fill the chamber with argon gas and hydrogen gas near to atmospheric pressure. Next, methane gas containing ¹³ C was introduced into the chamber to reach atmospheric pressure, and ¹³ C-containing graphite was grown in this state for about 30 to 60 minutes. The proportion of ¹³ C in carbon of methane gas used at this time was 10%, 30%, or 100%. After the reaction was completed, the chamber was rapidly cooled to allow diffusion of ¹³ C-containing graphite dissolved in the nickel thin film to the outside, and then nickel was removed by etching with FeCl ₃ . After washing 3 to 4 times to remove FeCl ₃ to obtain a ¹³ C-containing graphene oxide.

The obtained ¹³ C-containing graphene oxide was mixed with sulfuric acid and nitric acid, sonicated, and filtered using a Millipore membrane to remove acid. The filtered material was dispersed in water and neutralized with a base, and the obtained material was overnight in an autoclave. Thereafter, the filtering, the neutralizing with the base, and the autoclaving are repeated.

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

[ Example 2]

¹³ C-containing Graphene Quantum dots synthesis

The ¹³ C-containing graphene oxide is heat-reduced in a nitrogen gas atmosphere at 200 to 300 degrees to prepare a ¹³ C-containing graphene sheet.

The obtained ¹³ C-containing graphene sheet was mixed with sulfuric acid and nitric acid, sonicated, and filtered using a Millipore membrane to remove acid. The filtered material was dispersed in water, neutralized with base, and the resulting material was put in an autoclave and overnight. Thereafter, the filtering, the neutralizing with the base, and the overnight put into the autoclave are repeated.

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

[ Example 3]

Obtained ¹³ C-containing graphite, ¹³ C-containing Graphene , And ¹³ C-containing Graphene oxide Characterization

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

¹³ C-containing graphene and ¹³ C-containing graphene oxide, Raman spectroscopy (CRM200, Witech), nuclear magnetic resonance (NMR, chemagnetics CMX-400 spectrometer), Fourier transform spectrometer (FTIR, Nicolef 710 spectrometer), transmission Electron microscopy (TEM, JEM3010, Jeol), internuclear microscope (AFM, XE-100, park system), photoelectron spectroscopy (XPS, Kratos Axis ultra DLD x-ray photoelectron spectrometer), and X-ray diffraction (XRD, Rigaku) D / max-2500 wing Cu Kx radiation).

[ Example 4]

¹³ C-containing Graphene Quantum dots Fluorescence Characterization

In this example, the fluorescence of the ¹³ C-containing graphene quantum dots synthesized according to the above example was measured and shown as a graph (see FIG. 1A). As a result, it was confirmed that the ¹³ C-containing graphene quantum dots emit blue fluorescence at a wavelength of about 441 nm (see FIG. 1B). Therefore, it was confirmed that the contrast agent including the ¹³ C-containing graphene quantum dots of the present application can also be used to obtain a fluorescence image.

[ Example 5]

¹³ C-containing Graphene Quantum dots Nuclear magnetic resonance ( NMR ) Measure

In this example, nuclear magnetic resonance (NMR) of ¹³ C-containing graphene quantum dots synthesized according to the above example was measured using a chemagnetics CMX-400 spectrometer. For the measurement of nuclear magnetic resonance, the ¹³ C-containing graphene quantum dots (denoted as GQDs (GQDs) in FIG. 2A in FIG. 2A) were first functionalized with hexylamine as shown in FIG. 2A, and then H-NMR Measured. As a result, the peaks of the functionalized ¹³ C-containing graphene quantum dots in the H-NMR results as shown in Figure 2b and 2c it could be confirmed.

In addition, ¹³ C-NMR of the functionalized ¹³ C-containing graphene quantum dots were measured and shown in FIG. 3. 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 Since C-peaks can be identified, it has been confirmed that it can be used as an MRI contrast agent.

The above description of the present application is intended for illustration, and it will be understood by those skilled in the art that the present invention may be easily modified in other specific forms without changing the technical spirit or essential features of the present application. Therefore, it should be understood that the embodiments described above are exemplary in all respects and not restrictive. For example, each component described as a single type may be implemented in a distributed manner, and similarly, components described as distributed may be implemented in a combined form.

The scope of the present application is indicated by the following claims rather than the above description, and it should be construed that all changes or modifications derived from the meaning and scope of the claims and their equivalents are included in the scope of the present application.

Claims

^A magnetic resonance imaging (MRI) contrast agent comprising ¹³ C-containing graphene quantum dots or ¹³ C-containing graphene oxide quantum dots.

The method of claim 1,
Magnetic resonance imaging (MRI) contrast agent, the ratio of ¹³ C contained in the graphene quantum dots or graphene oxide quantum dots is 5% to 100% of the total carbon atoms.

The method of claim 1,
Magnetic resonance imaging (MRI) contrast agent, the size of the graphene quantum dot or the graphene oxide quantum dot is 0.1 nm to 100 nm.

The method of claim 1,
The magnetic resonance imaging (MRI) contrast agent is accumulated in the reticulum endothelial system including the liver or spleen and is used to obtain the image, magnetic resonance imaging (MRI) contrast agent.

The method of claim 1,
The magnetic resonance imaging (MRI) contrast agent, which is used to obtain angiogenesis (angiogenesis) of the blood vessels, lymph nodes, cancer cells, or atherosclerosis (atheroschlerosis plaque), magnetic resonance imaging (MRI) contrast agent.

The method of claim 1,
The magnetic resonance imaging (MRI) contrast agent is used to obtain an image including Raman imaging, Positron Emission Tomography (PET), or fluorescence imaging in addition to the magnetic resonance imaging. Magnetic resonance imaging (MRI) contrast agent.

The method of claim 1,
The graphene quantum dots or The graphene oxide quantum dot is to be covered with a biocompatible material, magnetic resonance imaging (MRI) contrast agent.

The method of claim 7, wherein
The biocompatible material is polyvinyl alcohol, polylactide, polyglycolide, poly (lactide-glycolide) copolymer [poly (lactide-co-glycolide)], polyanhydride ), Polyesters, polyetheresters, polycaprolactones, polyesteramides, polyacrylates, polyurethanes, polyvinylfluorides, Polyvinylimidazole, chlorosulphonate polyolefin, polyethylene oxide, polyethyleneglycol, dextran, mixtures thereof, and copolymers thereof Magnetic resonance imaging (MRI) contrast agent, including those selected.

The method of claim 1,
Magnetic resonance imaging (MRI) contrast agent is a biologically active material is coupled to the outer surface of the graphene quantum dots or the graphene oxide quantum dots.

The method of claim 9,
The bioactive material may be a target-oriented material selected from the group consisting of proteins, RNA, DNA, antibodies, and combinations thereof that selectively bind to a target material in vivo, or a cell suicide inducing gene or toxic protein; Fluorescent material; Isotopes; Materials that are sensitive to light, electromagnetic waves, radiation, or heat; Substances exhibiting pharmacological activity; And it comprises one selected from the group consisting of, magnetic resonance imaging (MRI) contrast agent.

Growing ¹³ C-containing graphene oxide on the support by providing a reaction gas comprising a ¹³ C-containing carbon source and heat to a support comprising a metal catalyst thin film;
Obtaining the ¹³ C-containing graphene oxide; 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
Including, Magnetic resonance imaging (MRI) contrast agent manufacturing method.

Growing ¹³ C-containing graphene oxide on the support by providing a reactant comprising a ¹³ C-containing carbon source and heat to a support comprising a metal catalyst thin film;
Obtaining the ¹³ C-containing graphene oxide;
The ¹³ C - by reducing the graphene oxide containing ¹³ C - generating a graphene-containing; 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
Including, Magnetic resonance imaging (MRI) contrast agent manufacturing method.