WO2019009607A1 - Chelate complex, preparation method therefor, and composition containing same for diagnosis and treatment of cancer - Google Patents

Abstract

The present invention relates to a chelate complex comprising melanoidin, a paramagnetic metal ion, and a platinum-based drug, to a preparation method therefor, and to a composition containing the same for diagnosis and treatment. A chelate complex according to an aspect has an in-vivo residence time that can be controlled by adjusting the molecular weight through reaction time control, can be safely used without toxicity problems, and can perform the contrasts for disease diagnosis and therapy simultaneously, so that anticancer therapy can be performed while the progress of cancer can be monitored. Furthermore, the chelate complex can be used as a T1 and T2 double functional contrast medium, and thus has high tissue resolution and high lesion detectability.

Description

Chelate complex, a method for producing the same, and a diagnostic and cancer therapeutic composition containing the same

This application claims priority from Korean Patent Application No. 10-2018-0077316, filed on July 3, 2018, the entire contents of which are incorporated herein by reference.

A chelate complex comprising melanoidin, a paramagnetic metal ion, and a platinum-based drug, a method for producing the chelate complex, and a diagnostic and therapeutic composition comprising the chelate complex.

Magnetic resonance imaging (MRI) is a technique for irradiating a sample with low electromagnetic energy and then detecting a magnetic resonance image signal from a water molecule. Magnetic resonance imaging (MRI) is known to be the most suitable method for the diagnosis of diseases and drug treatment of patients because it is possible to obtain 0 high resolution tissue dissolving ability and non-invasive magnetic resonance imaging that can be repeated several times in a short time. The magnetic resonance imaging signal is determined by the two time parameters T1 and T2, the relaxation time, and the amount of protons in the water molecules resulting from the spin density. The contrast of magnetic resonance imaging is controlled by MRI contrast agents. MRI contrast agents enhance the contrast between normal and abnormal tissues by detecting the difference in T1 / T2 relaxation time caused by strong external magnetic field and high frequency energy after in vivo implantation, MRI contrast agents are generally classified into paramagnetic contrast agents and superparamagnetic contrast agents and are classified into T1 contrast agent and TGFR agent by spin relaxation of nuclear magnetic resonance T2 contrast agent. The paramagnetic metal ions used as T1 contrast agents accelerate T1 relaxation and form a bright contrast in T1-weighted images. On the other hand, superparamagnetic iron oxides (SPIOs) used as T2 contrast agents increase the T2 relaxation rate to form dark contrast.

Since the contrast of magnetic resonance imaging is controlled by the contrast agent, the development of contrast contrast agents in recent effective magnetic resonance imaging attracts much attention, but only the contrast agent used in clinical practice is T1 contrast agent, Are all gadolinium (Gd) formulations. Gadolinium (Gd) itself is highly toxic and can cause anaphylactoid reaction, and it has been pointed out that it can cause serious nephrogenic systemic fibrosis (NSF). In addition, gadolinium preparations have been reported to be toxic to about 1% of gadolinium in infusion through the blood-brain barrier in healthy subjects. Therefore, in order to overcome the adverse effects of this gadolinium preparation, a new low- Research is underway to develop. Although most of the T1 contrast media including Gd-DTPA occupy the majority of the contrast media for imaging of the blood vessels of each tissue, there is insufficient time to acquire images due to the short residence time in the body, and the use of metal nanoparticles such as iron oxide nanoparticles T1 and T2 dual-mode contrast agents are difficult to release in vivo. Currently, there is no research that successfully implemented a dual contrast agent because it did not effectively control the signal quenching of the T1 contrast agent by the T2 contrast agent.

Accordingly, the present inventors confirmed that chelating a paramagnetic metal ion and a platinum-based drug in the manufacture of melanoid can be used as a dual-function contrast agent for T1 and T2, and can be used as a contrast agent and a therapeutic agent, and completed the Theragnosis System Respectively.

One aspect is melanoidin; Paramagnetic metal ion; And a chelate complex comprising a platinum-based drug.

Other aspects include melanoidin; Paramagnetic metal ion; And a chelate complex comprising a platinum-based drug.

Other aspects include melanoidin; Paramagnetic metal ion; And a chelate complex comprising a platinum-based drug. The present invention also provides a composition for diagnosing and treating diseases comprising the chelate complex.

Other aspects include; amino acid; Paramagnetic metal ion; And a platinum-based drug at a pH of from 6.5 to 8.5 and at a temperature of from 35 to 40 ° C.

One aspect is melanoidin; Paramagnetic metal ion; And a chelate complex comprising a platinum-based drug.

As used herein, the term " Melanoidin " is the final product of the Maillard reaction in which the sugar and amino acid are reacted. The Mailard reaction is a non-enzymatic browning reaction that can occur in almost all foods. Melanoidine refers to a polymer formed by stabilization and rearrangement of a Schiff base adduct formed by bonding of a carbonyl group of a sugar and an amine group of an amino acid.

The melanoidins can be produced by extraction in the natural world or by chemical synthesis. The melanoid may be one obtained by the maillard reaction of sugars and amino acids.

The Mailard reaction may be carried out under pH conditions of pH 6.5 to 8.5, pH 7 to 8, or pH 7.3 to 7.5, or 35 to 40 캜, 36 캜 to 38 캜, or 37 캜.

The chelate complex may have a weight average molecular weight of 2,000 Da to 20,000 Da, 3,000 Da to 19,000 Da, 4,000 Da to 18,000 Da, 5,000 Da to 17,000 Da, 5,000 Da to 16,000 Da, or 5,000 Da to 15,000 Da, It is not. In the present invention, the weight average molecular weight of the chelate complex can be controlled to a desired molecular weight by controlling the reaction time. When the chelate complex has a weight average molecular weight within this range, it can be used as a T1 contrast agent, a T2 contrast agent, or a T1-T2 dual function contrast agent.

The sugar may comprise a monosaccharide, a disaccharide or a mixture thereof. Specifically, the monosaccharide may include glucose, galactose, mannose, or fructose, The disaccharide may include sucrose, lactulose, lactose, maltose, trehalose, or cellobiose. The disaccharide may include sucrose, lactose, maltose, trehalose, or cellobiose.

Wherein the amino acid is selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, cysteine, proline, serine, threonine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, . ≪ / RTI >

The term " paramagnetic metal ion " refers to a material representing nuclear magnetic resonance imaging. Unpaired spins present in the interior usually exhibit an irregular spin arrangement due to thermal motion. When an external magnetic field is applied As a result of the spin alignment in a certain direction due to the influence, it means a material which is not normally magnetized but is magnetized in the magnetic field direction when an external magnetic field is applied.

The paramagnetic metal ion is selected from the group consisting of iron (Fe), manganese (Mn), nickel (Ni), copper (Cu), erbium (Er), europium (Eu), holmium (Ho) Or more, but is not limited thereto.

The paramagnetic metal ion may be coordinately bound to melanoid. When the paramagnetic metal ion is chelated with melanoid, an excellent MR imaging effect can be exerted on T1-weighted images and T2-weighted images compared with conventionally used contrast agents such as Gd.

The term " platinum drug " may also be referred to as a platinum-based drug, and may include, without limitation, platinum-containing drugs.

The platinum-based drug may include a platinum-based anticancer drug. Specifically, the platinum-based anticancer agent may be selected from the group consisting of cisplatin, Carboplatin, ornaplastatin, oxaliplatin, znipratin, enoloplatin, rovaplatin or spiroplatin, tetraplatin, ≪ / RTI > galactosyltransferase, meflatin, eplluclatin, or a combination thereof.

When the platinum-based drug is chelated with melanoidin, the platinum-based drug may be coordinately bound to melanoidin, and the platinum-based drug may be released from the chelate complex by irradiating a laser to the tissue diagnosed as cancer, . The platinum-based drug can be released specifically to the cancer-diagnosed tissue, so that the toxicity of the platinum-based drug can be minimized. Therefore, when the platinum-based drug is chelated with melanoid, it is possible to minimize side effects on organs other than the target due to drug resistance and toxicity of the platinum-based drug.

In one embodiment of the present invention, the platinum-based drug may have the general structural formula cis- [PtX ₂ (Am)] ₂ , where Am has a NH moiety as a stable group, X is a group Lt; / RTI >

The platinum-based drug may be specifically released from the chelate complex to cancer tissues by laser irradiation to have an effect of treating cancer.

Other aspects include melanoidin; Paramagnetic metal ion; And a chelate complex comprising a platinum-based drug.

The pharmaceutical composition may be for cancer treatment.

In the present invention, " cancer treatment " means any action that improves or alleviates the symptoms of cancer by administering a composition comprising the chelate complex of the present invention into the body. The cancer or carcinoma that can be treated with the pharmaceutical composition is not particularly limited, and includes solid cancer and blood cancer. More specifically, the present invention relates to a pharmaceutical composition for preventing or treating cancer, lung cancer, breast cancer, ovarian cancer, liver cancer, bronchial cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, colon cancer, colon cancer, But are not limited to, renal cancer, esophageal cancer, biliary cancer, testicular cancer, rectal cancer, head and neck cancer, cervical cancer, ureter cancer, osteosarcoma, neuronal cell subtype, melanoma, fibrosarcoma, rhabdomyosarcoma, astrocytoma, neuroblastoma, But is not limited thereto.

In the above pharmaceutical composition, the platinum-based drug can be released from the chelate complex to the target tissue by laser irradiation. In one embodiment of the present invention, the platinum-based drug can be chelated with melanoids and exhibit a therapeutic effect of diseases by being specifically released into a target tissue, for example, cancer tissue by laser irradiation.

The pharmaceutical composition may be capable of simultaneously performing treatment and magnetic resonance imaging (MRI).

When performing MRI imaging with the pharmaceutical composition, the pharmaceutical composition can be used as a T1 contrast agent or a T2 contrast agent and can be used as a T1 contrast agent and a T2 contrast agent, i.e., a T1-T2 dual function contrast agent.

The term " MRI (Magnetic Resonance Image) " refers to a phenomenon in which an external energy specific to a magnetic moment of an atomic nucleus acts in a magnetic field, absorbing the energy and transitioning to another energy level Quot;

The pharmaceutical composition may contain 1 to 99 parts by weight, 1 to 50 parts by weight, 1 to 40 parts by weight, 1 to 30 parts by weight, 1 to 20 parts by weight, for example, 1 to 20 parts by weight of the chelate complex based on 100 parts by weight of the total composition. To 10 parts by weight.

The pharmaceutical composition is characterized in being capable of monitoring the progress of cancer through MRI contrast while performing chemotherapy with an anticancer agent. Since the progress of cancer can be monitored at the same time as performing the chemotherapy, an appropriate amount of the cancer drug can be administered at an appropriate time. In addition, it is possible to monitor whether or not the effect of the anticancer drug used in the chemotherapy is effective. Therefore, there is an advantage that patient-specific treatment is possible.

Other aspects include melanoidin; Paramagnetic metal ion; And a chelate complex comprising a platinum-based drug.

In the present invention, " diagnosis and treatment of disease " can be used in combination with " theragnosis ". The term teraginosis, which includes both therapy and diagnosis, is used to monitor changes in enzymes, biomarkers, and genes in the body through molecular imaging and medical techniques to determine the presence and progress of the disease. And at the same time provide the progress of customized treatment.

Diagnosis of the disease may include cancer diagnosis or angiography.

Treatment of the disease may include cancer therapy. The cancer or the carcinoma is not particularly limited, and includes solid cancer and blood cancer. More specifically, the present invention relates to a pharmaceutical composition for preventing or treating cancer, lung cancer, breast cancer, ovarian cancer, liver cancer, bronchial cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, colon cancer, colon cancer, But are not limited to, renal cancer, esophageal cancer, biliary cancer, testicular cancer, rectal cancer, head and neck cancer, cervical cancer, ureter cancer, osteosarcoma, neuronal cell subtype, melanoma, fibrosarcoma, rhabdomyosarcoma, astrocytoma, neuroblastoma, But is not limited thereto.

In one embodiment of the invention, the chelate complex comprises a paramagnetic metal ion, platinum-based drug, chelated with melanoid. The chelate complex can contain a paramagnetic metal ion and can be used as a contrast agent for diagnosis of diseases, specifically cancer diagnosis or angiography.

The term " contrast agent " refers to a substance used for diagnostic purposes to artificially create a difference in contrast and display it as an image. The most important reason for using contrast agents is to understand the overall range of lesions that are more accurate for all lesions.

The chelate complex may be used as a T1 contrast agent, a T2 contrast agent, or a T1-T2 dual-mode MRI contrast agent. The term " T1 contrast agent " refers to a substance that increases signal intensity in a T1 weighted image through a decrease in T1 relaxation time. The term " T2 contrast agent " refers to a substance that increases signal intensity in T2-weighted images by decreasing T2 relaxation time. When T1 contrast is used, the desired site appears bright (positive contrast) and dark when T2 contrast is used (negative contrast). The term " T1-T2 dual-function contrast agent " refers to a substance that can be used as a T1 contrast agent and a T2 contrast agent.

The chelate complex may increase the molecular weight or decrease the molecular weight depending on the reaction time of the melanoid, the paramagnetic metal ion, and the platinum-based drug. In one embodiment of the invention, increasing the reaction time increases the molecular weight of the chelate complex, thereby increasing the function of the T2 contrast agent and reducing the molecular weight of the chelate complex, thereby increasing T1 contrast agent function. That is, it can be used as a T1-T2 dual-function contrast agent by controlling the molecular weight by controlling the reaction time. The molecular weight of the chelate complex that can be used as a T1-T2 dual function contrast agent can be from 5000 Da to 15000 Da, and the reaction time can be from about 3 days to 20 days, but is not limited thereto.

T1 and T2 dual-function MRI contrast agents can provide more accurate and detailed information about the disease than a single-function MRI contrast agent. Specifically, T1 and T2 dual-function MRI contrast agents can enhance diagnostic accuracy due to the high tissue resolution of T1-weighted images and high lesion detection capabilities of T2-weighted images. Since the composition for teragnosia can obtain a contrast effect for a long time, it has a remarkably excellent effect over conventional MRI contrast agents that can obtain a contrast effect only for a short time. In addition, the composition for teraginosis is extremely cytotoxic and specifically acts on target tissues, and thus can be safely used in the body.

In one embodiment of the present invention, by increasing the reaction time of the chelate complex, the molecular weight is increased and the molecular weight is increased, so that the circulation time in the blood is increased and sufficient image acquisition time can be secured. An EPR effect (Enhanced Permeability Retention effect) appears at a sufficiently secured image acquisition time and the chelate complex can accumulate in a target tissue, such as cancer tissue. When the laser is irradiated to the chelate complex accumulated in the target tissue as described above, the platinum-based drug may be released from the chelate complex to the target tissue. Since the released platinum-based drug acts specifically on the target tissue and exhibits the therapeutic effect of the disease, the disease treatment effect can be obtained without side effects on tissues other than the target tissue.

The composition for teraginosis comprises 1 to 99 parts by weight, 1 to 50 parts by weight, 1 to 40 parts by weight, 1 to 30 parts by weight and 1 to 20 parts by weight of the chelate complex based on 100 parts by weight of the total composition, But it is not limited thereto.

The composition for teraginosis may further comprise a pharmaceutically acceptable carrier. In the case of oral administration, a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersant, a stabilizer, a suspending agent, a pigment and a flavoring agent may be used. , A stabilizer, and the like. In case of topical administration, a base, an excipient, a lubricant, a preservative, etc. may be used.

The formulation of the composition for teraginosis may be variously prepared by mixing with a pharmaceutically acceptable carrier as described above. For example, it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like in the case of oral administration, and in the case of injections, unit dosage ampoules or a plurality of dosage forms. When the contrast agent composition is formulated as an injectable preparation, it may contain a non-toxic buffer solution which appears as blood, as a diluent, for example, a phosphate buffer solution of pH 7.4. The composition may include other diluents or additives in addition to the buffer solution. Excipients and additives that may be added to such injections are well known to those skilled in the art.

The composition for teraginosus may typically comprise a surfactant that facilitates migration through the membrane. Such surfactants are those derived from steroids or cationic lipids such as N- [1- (2,3-dioloyl) propyl-N, N, N-trimethylammonium chloride (DOTMA), or cholesterol hemi- , Phosphatidylglycerol, and the like.

Another aspect provides a method of diagnosing, monitoring, and treating cancer comprising administering to said individual said chelate complex.

The chelate complex can be used for MRI imaging for diagnosis and treatment of cancer, so that cancer progression can be performed and cancer progress can be monitored. It may also be helpful to choose the treatment plan and treatment medication of the patient because the patient can know in advance what the effect of the specific drug will be.

A suitable dose of a composition comprising the chelate complex of the present invention will depend on factors such as the formulation method, the mode of administration, the age, weight, sex, pathological condition, food, time of administration, route of administration, excretion rate and responsiveness of the patient And the ordinarily skilled physician can readily determine and prescribe dosages effective for the desired treatment or prophylaxis.

Other aspects include; amino acid; Paramagnetic metal ion; And a platinum-based drug at a pH of from 6.5 to 8.5 and at a temperature of from 35 占 폚 to 40 占 폚.

The sugar, amino acid, paramagnetic metal ion, platinum-based drug, and chelate complex are as described above.

When a sugar, an amino acid, a paramagnetic metal ion, and a platinum-based drug are all mixed and reacted at a pH of 6.5 to 8.5 and at a temperature of 35 to 40 ° C, melanoidin is produced by a mailard reaction between sugar and amino acid The chelate complex can be obtained by chelating both the paramagnetic metal ion and the platinum-based drug in melanoidin.

Specifically, the mailard reaction is carried out under pH conditions of pH 6.5 to 8.5, pH 7 to 8, or pH 7.3 to 7.5, or 35 to 40 ° C, 36 to 38 ° C, or 37 ° C Lt; / RTI > When the Mailard reaction is carried out at too high a temperature and at a non-physiological pH, the saccharide and amino acids may be degraded or synthesized into substances capable of causing cytotoxicity and genotoxicity, for example, 5-hydroxymethylpurine But are not limited to, 5-hydroxymethyl furfural, 4-methylimidazole, formaldehyde, acetaldehyde, glyoxal, 2-furaldehyde, Since methylglyoxal or an unknown bioreactive compound may occur, the sugar and amino acid are reacted at a physiological pH and temperature so as to react in an environment similar to a mailrad reaction occurring in vivo to prevent it, It can be prevented from being decomposed or synthesized into substances that can cause toxicity and genotoxicity.

In addition, in the method for preparing the chelate complex of the present invention, the molecular weight of the chelate complex can be controlled by controlling the reaction time. Specifically, the reaction time of the step of reacting is 1 to 56 days, 1 to 30 days, 1 to 14 days, 1 to 10 days, 1 to 7 days, 2 to 56 days, 2 to 30 days, 2 to 14 days, 2 to 10 days, 2 to 7 days, but is not limited thereto. In one embodiment of the present invention, the reaction time of the step of reacting may be adjusted to 1 day to 10 days, and the molecular weight of the chelate complex may increase as the reaction time increases.

The chelate complex according to one aspect can control the residence time in the body by controlling the molecular weight by controlling the reaction time, can be safely used without toxicity problem, can simultaneously perform diagnosis and diagnosis of disease, You can monitor the progress of the cancer. It can also be used as a dual-function contrast agent for T1 and T2, and has high tissue resolution and high lesion detection capability.

Figure 1 is an illustration of one embodiment in the manufacture of chelate complexes.

FIG. 2 is a graph showing the T1-weighted MRI image of the chelate complex according to an embodiment.

FIG. 3 is a graph showing the results of a T2-weighted MRI image of a chelate complex according to an embodiment.

Figure 4 is a graph showing cell viability by treatment of a chelate complex according to one embodiment.

Figure 5 is an MR image of a liver cancer mouse model treated with a chelate complex according to one embodiment.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these embodiments are intended to illustrate one or more embodiments, and the scope of the present invention is not limited to these embodiments.

Example  1. Platinum-based drug - Melanoidin - Synthesis of paramagnetic metal ion chelate complex and confirmation of molecular weight control

In order to synthesize a platinum-based drug-melanoidine-paramagnetic metal ion complex (hereinafter referred to as "chelate complex"), cisplatin was used as a platinum-based drug and iron ion (Fe ^{3 +} ) as a paramagnetic metal ion. Melanoid (melanoidin) was prepared by reacting glucose with glycine. A schematic diagram of manufacture is shown in Fig.

Specifically, melranoyidin order to chelating the during cisplatin and iron ions produced, glucose 1g, Glycine _{1g, FeCl 3 · 6H 2 O} 0.2 g, and cisplatin 0.06 g the same time mixed in distilled water to 20 mL, at 37 ℃ and pH 7.4 conditions Lt; / RTI > After 2 days, 4 days, and 8 days of reaction, each reaction product was put into a dialysis tube (MWCO 7000 Da) and unreacted by-products were removed from distilled water and stored at -4 ° C. The molecular weight was analyzed by Gel Filtration Chromatography (GFC) and PEG / PEO was used as a standard of GFC. As a result of molecular weight analysis, it was confirmed that the molecular weights of the chelate complexes produced by the reaction for 2 days, 4 days, and 7 days were about 3500 Da, 4800 Da, and 6900 Da, respectively.

Therefore, it was confirmed that the molecular weight of the chelate complex can be controlled by controlling the reaction time because the molecular weight of the chelate complex is increased as the reaction time of the MAlard reaction is increased.

Example 2. Analysis of content of chelate complex

The contents and components of Fe ^{3 +} and cisplatin in the chelate complex prepared in Example 1 were analyzed.

First, the chelate complex solution was lyophilized to obtain a powder form. 1 mL of aqua regia was added to 1 mg of the chelate complex, and the solution was boiled at 200 ° C until all the solution was blown. The solution was redissolved in 10% HCl solution and analyzed by inductively coupled plasma-atomic emission spectroscopy (ICP-AES). The atomic concentration of C, N, O, Fe, and Pt was analyzed by X-ray photoelectron spectroscopy (XPS) analysis of the chelate complex in the form of a lyophilized powder, Respectively.

Reaction time (days)	Amount of metal ion (mg) / Chelate complex (mg)		Atomic concentration (at.%)
	Fe	Pt	C	N	O	Fe		Pt
2	0.20	0.46	34.2	1.3	44.1	12.4	8
4	0. 19	0.40	40.5	2	41.3	10.2	6
7	0. 18	0. 19	51.3	3.7	36.3	6.7	2

As shown in Table 1, it was confirmed that Fe ^{3 +} and cisplatin were chelated to melanoidin simultaneously during the mailard reaction. In addition, it was confirmed that the amount of Fe ^{3 +} and cisplatin (Pt) chelated with melanoid was decreased as the molecular weight increased with increasing reaction time. This is because the -OH and -COOH functional groups present at the edge of the melanoid are participating in the polymerization and the coordination site is reduced, thereby allowing Fe ^{3 +} and cisplatin to be stably coordinated inside the molecule of melanoid Respectively.

Example 3. MRI analysis of chelate complex

The T1 and T2 magnetic resonance images and the relaxation rates of r1 and r2 of the complex prepared by the reaction for 4 days in Example 2 were analyzed using a 3T clinical MRI scanner. The results for T2 are shown in Fig.

As shown in FIG. 2 and FIG. 3, it was confirmed that the chelate complex of the present invention had r1 = 1.96 mM ^-1 s ^-1 and r2 = 10.04 mM ^-1 s ^-1 .

Therefore, since the chelate complex has similar relaxivity to r ₁ = 3.5 mM ^-1 s ^-1 and r ₂ = 5.4 mM ^-1 s ^-1 of Gd-DTPA, which is one of the MRI contrast agents used in clinical practice, It can be used as a contrast agent.

Example 4. Cytotoxicity evaluation of chelate complex

In order to evaluate the toxicity of the chelate complex of the present invention, it was carried out as follows. B16F1 cells were treated with 1 mg / mL of the chelate complex, which was reacted for 4 days, and cultured for 24 hours. Thereafter, a laser with a wavelength of 800 nm was irradiated for 10 minutes. The cell viability after the irradiation was measured and the results are shown in Fig.

As shown in Fig. 4, it was confirmed that the treatment of the chelate complex of the present invention (melanoidin-Fe3 +, cisplatin) hardly affected the cell survival rate when compared with the control group without any treatment, Melanoidin-Fe3 +, cisplatin / laser), approximately 50% of the cells were killed.

Therefore, it was confirmed that the chelate complex of the present invention can be safely used in the body since it is not toxic.

Example 5. In vivo MRI assay of chelate complex

In order to assess liver MRI efficacy of the chelate complex according to one aspect in in vivo, the following procedure was performed. The chelate complex synthesized according to Example 1 was intravenously injected intraperitoneally into a mouse liver cancer model at 10 mg / mL and MR images were obtained at 30 minutes, 1 hour, 2 hours, 24 hours and 48 hours. The image is shown in Fig.

As shown in Fig. 5, in the T1 image when the chelate complex is not injected, it is hard to distinguish the cancer tissue because the liver cancer tissue and the normal liver tissue have almost the same MR intensity. However, after the intravenous injection of the chelate complex, And the normal liver tissue became dark. After 2 hours, there was a clear difference between liver cancer tissue and normal liver tissue. After 48 hours, the difference in MR intensity between liver cancer tissue and normal liver tissue was reduced again.

In T2 images, the hepatic cancer tissues grew brighter and the normal liver tissues grew darker after the intravenous injection of the chelate complex, confirming that cancer tissues were clearly distinguished after 2 hours of injection.

This is probably due to the difference in uptake of the chelate complex between liver cancer tissue and normal liver tissue. Thus, the chelate complex of the present invention confirmed that MRI for liver cancer tissue is possible as a T1-T2 dual-function contrast agent in In vivo.

Claims (20)

1. Melanoidin; Paramagnetic metal ion; And a chelate complex comprising a platinum-based drug.
2. The chelate complex according to claim 1, wherein the melanoid is obtained by a maillard reaction of a sugar and an amino acid.
3. The chelate complex of claim 1, wherein the weight average molecular weight is from 5,000 Da to 15,000 Da.
4. 3. The chelate complex of claim 2, wherein the sugar is a monosaccharide, a disaccharide, or a mixture thereof.
5. [Claim 4] The method according to claim 4, wherein the monosaccharide is at least one selected from the group consisting of glucose, galactose, mannose, and fructose, and the disaccharide is sucrose, Wherein the chelate complex is at least one selected from the group consisting of lactulose, lactose, maltose, trehalose and cellobiose.
6. The method of claim 2, wherein the amino acid is selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, cysteine, proline, serine, threonine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, ≪ / RTI > histidine, and derivatives thereof.
7. The method of claim 1, wherein the paramagnetic metal ions are selected from the group consisting of Gd, Fe, Mn, Ni, Cu, Er, Eu, And chromium (Cr).
8. The chelate complex according to claim 1, wherein the platinum-based drug is a platinum-based anticancer drug.
9. The pharmaceutical composition according to claim 1, wherein the platinum-based drug is selected from the group consisting of Cisplatin, Carboplatin, Ormaplatin, Oxaliplatin, Zeniplatin, Enoplatatin, Lobaplatin, Spiroplatin, , ≪ / RTI > orthophyllatin and < RTI ID = 0.0 > iiproplatin. ≪ / RTI >
10. Melanoidin; Paramagnetic metal ion; And a chelate complex comprising a platinum-based drug.
11. The pharmaceutical composition according to claim 10, which is for treating cancer.
12. The pharmaceutical composition according to claim 11, wherein the platinum-based drug is released from the chelate complex to the target tissue by laser irradiation.
13. The pharmaceutical composition according to claim 11, wherein cancer treatment and MRI (magnetic resonance imaging) imaging can be performed simultaneously.
14. 14. The pharmaceutical composition according to claim 13, which is used as a T1-T2 dual-mode MRI contrast agent.
15. [Claim 12] The pharmaceutical composition according to claim 11, which is capable of performing chemotherapy with a platinum-based drug and monitoring the progress of cancer.
16. Melanoidin; Paramagnetic metal ion; And a chelate complex comprising a platinum-based drug.
17. 17. The composition according to claim 16, wherein the diagnosis of the disease is cancer diagnosis or angiography.
18. 17. The composition of claim 16, wherein the treatment of the disease is cancer therapy.
19. Party; amino acid; Paramagnetic metal ion; And a platinum-based drug at a pH of from 6.5 to 8.5 and at a temperature of from 35 占 폚 to 40 占 폚.
20. 21. The method of claim 19, wherein the reaction time is adjusted to adjust the molecular weight of the chelate complex.

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