Nanoplatform for targeting inflammatory macrophages and composition for preventing or treating inflammatory diseases comprising the same

Abstract

The present invention relates to a nanoplatform for targeting inflammatory macrophages and a composition for preventing or treating inflammatory diseases using the same. The nanoplatform for targeting inflammatory macrophages according to the present invention is not only capable of selectively targeting inflammatory macrophages by binding a glucosyl group as a delivery substance, but also has the effect of suppressing inflammatory responses in damaged cells or tissues and restoring mitochondrial function to suppress cell death, and therefore can be provided as an effective composition for preventing or treating inflammatory diseases, particularly kidney diseases.

Description

[Technical Field]

[0001] The present invention relates to a nanoplatform for targeting inflammatory macrophages and a composition for preventing or treating inflammatory diseases using the same.

[0002] Inflammation is a defense mechanism of the body against various internal and external stimuli, such as external infections and metabolic products, and involves various intracellular inflammatory regulatory factors as mediators, leading to a variety of diseases, including allergies, atopy, arthritis, kidney disease, brain disease, and cardiovascular disorders, as well as cancer.

[0003] In general, the inflammatory response is a biological defense process that repairs and regenerates damage caused by invasion, which causes matrix changes in the cells and tissues of the body. This process involves the action of local blood vessels, various tissue cells in body fluids, and immune cells. The inflammatory response normally induced by foreign invading bacteria is a defense system that protects the body, but on the other hand, if an abnormally excessive inflammatory response is induced, it can manifest as various diseases, and such diseases are called inflammatory diseases.

[0004] The onset of many inflammatory diseases is associated with the activation of macrophages and the resulting excessive production of inflammation-related factors, such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and nitric oxide (NO).

[0005] The kidneys are organs that excrete waste products and maintain homeostasis within the body. Kidney disease occurs when the filtering function of the glomeruli, the main components of the kidney, decreases. Depending on the rate of kidney damage, kidney disease can be broadly categorized into acute kidney injury (AKI) and chronic kidney disease (CKD).

[0006] Acute kidney injury (AKI) is a condition in which kidney function declines suddenly over a short period of hours or days. Its prevalence is increasing every year, regardless of gender or age, and it occurs in approximately 10% of hospitalized patients. Even if patients recover from AKI, they may progress to chronic kidney disease or end-stage renal failure. Failure to recover increases the risk of permanent kidney damage and death. Chronic kidney disease is a condition in which glomerular filtration function gradually declines, ultimately leading to permanent kidney function recovery. A study conducted by the US National Institutes of Health (NIH) in 2008 found that the risk of developing AKI increases in patients with other conditions, with 1 in 3 diabetics and 1 in 5 hypertensive patients experiencing AKI.

[0007] The number of patients with end-stage renal disease has also increased dramatically over the past 20 years, with the number of dialysis patients in South Korea soaring from 64,679 in 2014 to 87,720 in 2019. Patients with end-stage renal disease are a medical and socioeconomic burden due to their high mortality rate and medical costs.

[0008] Renal fibrosis, a type of kidney disease, is the final common pathway. If the cause of kidney disease is discovered early, it may be possible to recover through appropriate treatment. However, if patients suffer from moderate or severe chronic kidney disease, it will progress to end-stage renal failure or lead to death due to cardiovascular complications.

[0009] Proximal tubular epithelial cells, the primary site of renal function, are characterized by a high density of mitochondria, and mitochondrial deformation, damage, and dysfunction have been proposed as the pathophysiological background of acute kidney injury and chronic kidney disease. In particular, inflammatory responses caused by excessive macrophage activation can cause mitochondrial damage, and if this mitochondrial damage persists, oxidative stress can damage kidney cell proteins, lipids, and DNA, leading to apoptosis.

[0010] Thus, the importance of mitochondria in kidney diseases has been noted, and there is a need to develop a fundamental therapeutic agent that can regulate the progression of kidney diseases through the maintenance and improvement of mitochondrial function. DETAILED DESCRIPTION OF THE INVENTION

[0011] TECHNICAL PROBLEM An object of the present invention is to provide an albumin-based nanopatform that selectively targets inflammatory macrophages.

[0012] Another object of the present invention is to provide a composition for preventing or treating an inflammatory disease, containing the nanopatform for targeting inflammatory macrophages as an active ingredient.

[0013] Still another object of the present invention is to provide a composition for preventing or treating a kidney disease, containing the nanopatform for targeting inflammatory macrophages as an active ingredient.

[0014] SOLUTION TO THE PROBLEM To achieve the above object, the present invention provides a nanopatform obtained by a click chemistry reaction between albumin bound with an azide (N3) or cyclooctyne functional group and a delivery substance bound with an azide (N3) or cyclooctyne functional group, wherein the delivery substance contains a glucosyl group, and when the albumin binds with an azide functional group, the delivery substance binds with a cyclooctyne functional group, and when the albumin binds with a cyclooctyne functional group, the delivery substance binds with an azide functional group, for targeting inflammatory macrophages. L In the present invention, the number of azide or cyclooctyne functional groups introduced into the albumin can be 1 to 14.

[0015]

[0016] ​In the present invention, the nanoplatform is L It may contain 4 to 8 glucosyl groups.

[0017] In the present invention, L An azide or cyclooctyne functional group can be attached to the carbon 6 of the cosyl group.

[0018] In the present invention, the delivery substance further comprises a radioisotope, and the radioisotope is 3 H, 11 C. 18 F, 14 Cl, 32 P, 35 S, 36 Cl, 45 Ca, 51 Cr, 57 Co, 58 Co, 59 F, 6 64 Cu, 67 Ga, 68 Ga, 89 Zr, 90 Y, 99 Mo, 99m Tc, 111 In, 131 I, 125 I, 124 I, 123 I, 186 Re, 188 Re, 225 Ac, 212 Pb, 117m Sn, and 177 Lu.

[0019] In the present invention, the radioisotope is labeled with a chelating agent, and the chelating agent is not particularly limited, and examples thereof include NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DFO (3-[6,17-dihydroxy-7,10,18,21-tetraoxo-27-[N-acetylhydroxylamino]-6,11,17,22-tetraazaheptaeicosane]thiourea), DTPA (diethylenetriaminepentaacetic acid), N2S2 (diaminodithiol), p-SCN-Bn-NOTA (2-(4'-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid), and the like. acid), NODAGA(1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid), p-SCN-Bn-DOTA(2-(4'-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic TETA(1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid), p-SCN-Bn-DTPA(2-(4-isothiocyanatobenzyl)-diethylenetriaminepentaacetic acid), p-SCN-Bn-DFO (1-(4-Isothiocyanatophenyl)-3-[6,17-dihydroxy-7,10,18,21-tetraoxo-27-[N-acetylhydroxylamino]-6,11,17,22-tetraazaheptaeicosane]thiourea), and HYNIC (hydrazinonicotinic acid).

[0020] In the present invention, the delivery substance further includes a fluorescent substance, and the fluorescent substance may be one or more selected from the group consisting of FNR (Ferrodoxin NADP(+) reductase), cyanine fluorescent substances, TAMRA (tetramethylrhodamine-5-maleimide), Flamma (registered trademark) fluorescent substance, and ICG (indocyanine green).

[0021] In the present invention, the nano-platform can selectively target macrophages that overexpress GLUT (Glucose Transporter).

[0022] The present invention also provides a pharmaceutical composition for preventing or treating inflammatory diseases, which comprises the nanoplatform for targeting inflammatory macrophages as an active ingredient.

[0023] The pharmaceutical composition for preventing or treating an inflammatory disease according to the present invention can selectively target damaged tissues.

[0024] The pharmaceutical composition for preventing or treating inflammatory diseases according to the present invention can restore mitochondrial function and suppress cell death in damaged tissues.

[0025] In the present invention, the inflammatory disease may be one or more selected from the group consisting of sepsis, septic shock, inflammatory bowel disease (IBD), peritonitis, inflammatory kidney disease, acute bronchitis, chronic bronchitis, osteoarthritis, enteropathic spondylitis, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, acute lung injury, and bronchopulmonary dysplasia.

[0026] The present invention also provides a pharmaceutical composition for preventing or treating kidney diseases, comprising the nanoplatform for targeting inflammatory macrophages as an active ingredient.

[0027] In the present invention, the kidney disease may be one or more selected from the group consisting of nephritis, pyelonephritis, renal syndrome, kidney cancer, acute pyelonephritis, chronic pyelonephritis, renal tuberculosis, urinary tract infection, urinary tract stones, ureteral stones, acute renal failure, chronic renal failure, diabetic nephropathy, renal fibrosis, chronic glomerulonephritis, acute progressive nephritis, nephrotic syndrome, focal glomerulosclerosis, membranous nephropathy, and membranoproliferative glomerulonephritis.

[0028] Effect of the invention The nanoplatform for targeting inflammatory macrophages according to the present invention uses globulin as a delivery substance. L This albumin-based nanoplatform with cosyl groups attached can selectively target inflammatory macrophages, suppress inflammatory responses in damaged cells or tissues, restore mitochondrial function, and inhibit cell death, and therefore can be provided as an effective composition for the prevention or treatment of inflammatory diseases, particularly inflammatory kidney diseases. [Brief explanation of the drawings]

[0029] FIG. 1 is a diagram illustrating a graph according to one embodiment of the present invention. L The results confirmed the targeting ability of cosylated albumin and mannosylated albumin against M0, M1, and M2 types of macrophages.

[0030] FIG. 2 shows the results of confirming the targeting ability of GLUT-overexpressing cells by albumin binding at carbons 1, 2, and 6 of glucose according to one embodiment of the present invention.

[38] Figure 3 shows a graph of a cell model of acute kidney injury according to one embodiment of the present invention. L These are the results of confirming the cytotoxicity of albumin with a cosyl group (Alb_Glu).

[0031] FIG. 4 shows a graph of a cell model of acute kidney injury according to one embodiment of the present invention. L These results confirm the effect of cosylated albumin (Glu_Alb) in improving apoptosis / necrosis.

[0032] FIG. 5 shows a graph of the results of a cell model of acute kidney injury according to one embodiment of the present invention. L 1 shows fluorescence microscopic analysis images confirming the effect of cosylated albumin (Glu_Alb) in restoring mitochondrial morphology.

[0033] FIG. 6 shows a graph of the results of a cell model of acute kidney injury according to one embodiment of the present invention. L 1 shows fluorescence microscopic analysis images confirming the effect of cosylated albumin (Glu_Alb) in restoring mitochondrial morphology.

[0034] FIG. 7 shows a graph of the results of a cell model of acute kidney injury according to one embodiment of the present invention. L This shows the results of confirming the intracellular expression of cosylated albumin (Glu_Alb).

[0035] FIG. 8 shows a graph of the results of a kidney injury in an animal model of ischemia-reperfusion (IRI) kidney damage according to one embodiment of the present invention. L 1 is a graph confirming the effect of administering cosylated albumin (Glu_Alb) on improving renal function.

[0036] FIG. 9 shows a graph of the results of a kidney injury animal model according to one embodiment of the present invention. L These results confirm the effect of administering cosylated albumin (Glu_Alb) on improving renal tissue and mitochondrial function.

[0037] FIG. 10 is a diagram illustrating a graph according to one embodiment of the present invention. L 1 shows the results of confirming kidney damage and mitochondrial recovery levels in an animal model of kidney damage administered with cosylated albumin (Glu_Alb).

[0038] FIG. 11 shows a radioisotope-labeled group in a bilateral ischemia-reperfusion (IRI) kidney injury animal model according to one embodiment of the present invention. L This is the result of confirming the targeting ability of cosylated albumin to kidney tissue and kidney diseases.

[0039] FIG. 12 shows a graph of the results of a unilateral ischemia-reperfusion (IRI) kidney injury animal model according to one embodiment of the present invention. L The results confirm the ability of cosylated albumin to selectively target kidney diseases.

[0040] Specific embodiments of the present invention will be described in more detail below. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by skilled artisans in the art to which the present invention belongs. Generally, the nomenclature used herein is that which is well known and commonly used in the art.

[0041] The present invention relates to an albumin-based nanoplatform that selectively targets inflammatory macrophages and a composition for preventing or treating kidney disease using the same.

[0042] Macrophages are broadly divided into pro-inflammatory M1 and anti-inflammatory M2 types, but they can change type by repolarization in response to stimuli in the surrounding environment, and this change in macrophage type can directly contribute to the pathogenesis of the disease. In particular, as inflammation progresses, the initial immune response is induced by M1, which induces inflammation in other immune cells and triggers additional inflammatory responses. Therefore, targeting M1 macrophages can be used to treat various autoimmune diseases or other inflammatory diseases.

[0043] In the present invention, glucose is bound to albumin. L We discovered that the cosylated albumin nanoplatform can not only selectively target inflammatory macrophages but also improve macrophage function and kidney function, preventing or treating inflammatory diseases.

[0044] One aspect of the present invention is a nanoplatform obtained by a click chemistry reaction between albumin bound with an azide (N3) or cyclooctyne functional group and a delivery substance bound with an azide (N3) or cyclooctyne functional group, wherein the delivery substance is a group L The nanoplatform for targeting inflammatory macrophages is provided, which contains a glucosyl group, and when the albumin binds with the azide functional group, the delivery substance binds with the cyclooctyne functional group, and when the albumin binds with the cyclooctyne functional group, the delivery substance binds with the azide functional group.

[0045] In the present invention, albumin refers to a protein that is one of the proteins that constitute the basic substances of cells, is present in large amounts in blood, and is produced in the liver. Albumin has the lowest molecular weight among simple proteins present in nature. Serum albumin in blood maintains and restores plasma volume, prevents shock caused by excessive bleeding, and is used in surgery and burn treatment. It is also known to have oxygen delivery capacity similar to that of hemoglobin.

[0046] The albumin may include any albumin that can be formulated, but is preferably, but not limited to, albumin derived from human plasma or recombinant human serum albumin produced by genetic engineering. Genetic information for the albumin of the present invention can be obtained from publicly known databases such as NCBI GenBank.

[0047] In the present invention, the number of amino groups (-NH2) exposed on the surface of albumin can be 15 to 30.

[0048] In one specific example of the present invention, a representative human serum albumin (HSA) was used to fabricate a biocompatible albumin-based nanoplatform that targets in vivo inflammatory macrophages and exhibits therapeutic effects against diseases induced by inflammatory macrophages. A cyclooctyne or azide (N3) group, which is a functional group on one side of click chemistry, was introduced onto the surface of the human serum albumin under reaction conditions that minimized denaturation of HSA.

[0049] In the present invention, azide (N3) has high reactivity in a reactor consisting of three nitrogen atoms, and is known to act as an electron donor in 1,3-dipolar cycloaddition, a type of Cu-free cluck chemistry, to form a triaza-5-membered ring.

[0050] The cyclooctyne functional group is an eight-membered aliphatic ring containing a triple bond under ring strain. It is known to act as an electron acceptor in 1,3-dipolar cycloaddition reactions, a type of Cu-free click chemistry, and to form a triaza-5-membered ring. The structural feature of cyclooctyne, i.e., the triple bond structure under ring strain, enables click chemistry without the need for a Cu(I) catalyst.

[0051] The cyclooctyne functional group is 4-cyclooctyn-1-yl ( JPEG0007777381000001.jpg3829), 3-cyclooctyn-1-yl( JPEG0007777381000002.jpg3736), 2-cyclooctyn-1-yl( JPEG0007777381000003.jpg3436), monofluorinated cyclooctyne (MOFO) ( JPEG0007777381000004.jpg3135), difluorinated cyclooctyne (DIFO) ( JPEG0007777381000005.jpg3438), Dimethoxyazacyclooctyne (DIMAC) ( JPEG0007777381000006.jpg3546), Dibenzocyclooctyne (DIBO) ( JPEG0007777381000007.jpg3360), azadibenzocyclooctyne (ADIBO) group ( JPEG0007777381000008.jpg3452), and biarylazacyclooctynone (BARAC) ( JPEG0007777381000009.jpg3559), but is not necessarily limited thereto.

[0052] Albumin conjugated with an azide (N3) or cyclooctyne functional group can be obtained by (a) dissolving albumin in phosphate-buffered saline (PBS), (b) dissolving azide-NHS or cyclooctyne-NHS in DMSO, and (c) mixing the resulting solutions and then reacting them at 20 to 37°C for 30 minutes to 1 hour.

[0053] In step (a), the phosphate buffer solution (PBS) may have a pH of 6.8 to 7.6, preferably 7.0 to 7.4.

[0054] In step (b), the amount of DMSO used to prepare the azide-NHS solution or the cyclooctyne-NHS solution may be 2% (v / v) or less of the total reaction solution.

[0055] In step (c), the mixing molar ratio of albumin to azide-NHS or cyclooctyne-NHS can be 1:1 to 1:25.

[0056] In step (c), when the albumin solution and the azide-NHS solution are mixed, the functional group bound to the albumin may be an azide functional group, and when the albumin solution and the cyclooctyne-NHS solution are mixed in step (c), the functional group bound to the albumin may be a cyclooctyne functional group.

[0057] In one example of the present invention, a human serum albumin (HSA) solution and an ADIBO-NHS solution were mixed and reacted at 37°C for 30 minutes to prepare HSA-ADIBO.

[0058] The number of click functional groups (azide or cyclooctyne functional groups) introduced onto the albumin surface is preferably 1 to 14, and more preferably 10 to 12. In this case, when injected into the human body, the albumin remains in the blood for a long time, increasing the possibility of uptake into the target site. In contrast, if the number of click functional groups is excessive, the albumin is quickly taken up by the liver upon injection into the body, which may limit uptake into other target disease sites. The number of click functional groups introduced onto the albumin surface can be adjusted depending on the reaction ratio of albumin to azide-NHS or cyclooctyne-NHS.

[0059] The nanoplatform for targeting inflammatory macrophages, which is one embodiment of the present invention, is obtained by a click chemistry reaction by mixing a solution containing albumin to which the above-mentioned azide (N3) or cyclooctyne functional group is bound with a solution containing a delivery substance to which the azide (N3) or cyclooctyne functional group is bound, and the click chemistry reaction may be a copper-catalyzed (Cu-free) click chemistry reaction.

[0060] In one embodiment of the present invention, the azide functional group used as the click chemistry functional group is an electron donor, and the cyclooctyne functional group is an electron acceptor. Therefore, when the functional group bound to albumin is an azide functional group, the functional group bound to the delivery substance is preferably a cyclooctyne functional group, and when the functional group bound to albumin is a cyclooctyne functional group, the functional group bound to the delivery substance is preferably an azide functional group.

[0061] The nanoplatform for targeting inflammatory macrophages of the present invention has a large number of click-reactive functional groups, allowing various delivery substances to be bound to the large number of reactive groups.

[0062] In the present invention, the delivery substance refers to a substance that is bound to albumin and delivered into the body. L Contains a glucosyl group. L The structure of a cosyl group is shown in Formula 1 below.

[0063] [Formula 1] JPEG0007777381000010.jpg5966

[0064] Macrophages, which are diverse and flexible, can redifferentiate in response to stimuli in the surrounding environment, transforming into the pro-inflammatory M1 type, which defends against bacteria that invade our bodies, and the M2 type, which is associated with the repair of damaged tissues and anti-inflammatory responses. This transformation of macrophage type can sometimes be a direct pathogenic mechanism in the development of disease.

[0065] Among these, the M1 type, which is an inflammatory macrophage, has excessive expression of GLUT (Glucose Transporter) on its surface and mainly utilizes glycolysis for energy metabolism.

[0066] This allows for the use of Glycogen as a delivery agent. L The albumin-based macrophage-targeting nanoplatform of the present invention, to which a cosyl group is attached, has the ability to target inflammatory macrophages, and can be used as a nanoplatform that can be selectively taken up by inflammatory macrophages in damaged tissues, suppress the inflammatory response and ROS generation induced by inflammatory macrophages, restore the function of damaged mitochondria, and suppress cell death in damaged tissues, thereby preventing or treating the progression of serious diseases.

[0067] In particular, in the present invention, it was confirmed that the type of macrophage targeted differs depending on the type of sugar attached to albumin. L Albumin with a cosyl group attached thereto can selectively target M1 type macrophages. L As a result of an experiment comparing albumin with cosyl groups and albumin with mannosyl groups, L It was confirmed that cosylated albumin showed high uptake efficiency in M1-type macrophages, while mannosylated albumin showed high uptake efficiency in M2-type macrophages.

[0068] In the present invention, the albumin-based nanoplatform for targeting inflammatory macrophages is LThe number of glucosyl groups may be 4 to 8, more preferably 5 to 7. In this case, the nano-platform injected into the body can remain in the blood for a long time, increasing the target site targeting potential. L If the number of cosyl groups exceeds 8, the compound may be rapidly taken up by the liver when injected into the body, resulting in a significant reduction in the initial blood circulation volume, which may limit targeting to the target disease site.

[0069] In the present invention, the delivery substance L The cosyl group is linked to the azide or cyclooctyne functional group attached to albumin. L It can be conjugated to a nanoplatform for inflammatory macrophage targeting through a click chemistry reaction with an azide or cyclooctyne functional group attached to the cosyl group.

[0070] In this case, GLUT overexpressed on the surface of M1 type cells obtains glucose for use as an energy source by recognizing the OH functional groups at positions 1, 3, and 5 of glucose. In the present invention, albumin can be bound to carbon positions 1, 2, and 6 of glucose to more effectively target M1 type macrophages, with position 6 being the most preferred.

[0071] For example, azides attached to carbons 1, 2, or 6 are L The cosyl group has the same chemical structure as shown in Formula 2, Formula 3, and Formula 4 below, respectively.

[0072] [Formula 2] JPEG0007777381000011.jpg59104

[0073] [Formula 3] JPEG0007777381000012.jpg6267

[0074] [Formula 4] JPEG0007777381000013.jpg6469

[0075] According to one embodiment of the present invention, albumin was bound to the 1st, 2nd, and 6th carbon positions of glucose, and then the targeting ability of GLUT-overexpressing cells was confirmed. As a result, it was confirmed that the nanoplatform with albumin bound to the 6th carbon position of glucose exhibited GLUT targeting ability that was three times and two times higher, respectively, than the nanoplatform with albumin bound to the 1st and 2nd carbon positions of glucose.

[0076] The albumin-based nanoplatform of the present invention is a L In addition to the cosyl group, one or more other substances may be further included. In this case, multiple substances can be simultaneously subjected to a click chemistry reaction with albumin having an azide or cyclooctyne functional group bound thereto, or multiple substances can be sequentially subjected to a click chemistry reaction.

[0077] In the present invention, the delivery substance is L In addition to the cosyl group, a radioisotope may be further included, and the radioisotope may be displayed by a chelating agent.

[0078] A radioisotope is an element with the same atomic number but a different atomic mass, and an isotope that has radioactivity is called a radioisotope. Such radioisotopes can be used as important markers for diagnosing diseases and confirming pharmacokinetics by utilizing their property of emitting gamma rays and other subatomic particles to decay radioactivity. Radioisotopes that can be used as markers in the present invention can be any radioisotope known in the art without limitation. 3 H, 11 C. 18 F, 14 Cl, 32 P, 35 S, 36 Cl, 45 Ca, 51 Cr, 57 Co, 58 Co, 59 F, 64 Cu, 67 Ga,68 Ga, 89 Zr, 90 Y, 99 Mo, 99m Tc, 111 In, 131 I, 125 I, 124 I, 123 I, 186 Re, 188 Re, 225 Ac, 212 Pb, 117m Sn, and 177 Lu, and preferably 11 C. 18 F, 64 Cu, 67 Ga, 68 Ga, 89 Zr, 99m Tc, 111 In and 123 I, etc., but is not necessarily limited to this.

[0079] The chelating agent serves to link the radioisotope to albumin, and examples thereof include NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DFO (3-[6,17-dihydroxy-7,10,18,21-tetraoxo-27-[N-acetylhydroxylamino)-6,11,17,22-tetraazaheptaeicosane]thiourea), DTPA (diethylenetriaminepentaacetic acid), N2S2 (diaminedithiol), p-SCN-Bn-NOTA (2-(4'-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid), and the like. acid), NODAGA(1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid), p-SCN-Bn-DOTA(2-(4'-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic TETA(1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid), p-SCN-Bn-DTPA(2-(4-isothiocyanatobenzyl)-diethylenetriaminepentaacetic The hydroxybenzoate may be one or more selected from the group consisting of p-SCN-Bn-DFO (1-(4-Isothiocyanatophenyl)-3-[6,17-dihydroxy-7,10,18,21-tetraoxo-27-[Nacetylhydroxylamino]-6,11,17,22-tetraazaheptaeicosane]thiourea), and HYNIC (hydrazinonicotinic acid), but is not necessarily limited thereto.

[0080] A fluorescent substance refers to a substance that emits a specific wavelength of visible light at a specific wavelength, and in the present invention, includes all fluorescent substances that can be bound to an albumin-based macrophage targeting nanoplatform and used to confirm the location of the nanoplatform.

[0081] Specifically, fluorescent substances that can be used as markers in the present invention can be any fluorescent substance known in the art, and include, but are not limited to, rhodamine-based substances such as rhodamine, TAMRA, etc.; fluorescein-based substances such as fluorescein, FITC (fluorescein isothiocyanate), and FAM (fluoreceinamidite); bodipy (borondipyrromethene); alexa fluor; and cyanine-based substances such as Cy3, Cy5, Cy7, and indocyanine green.

[0082] In the present invention, the delivery substance may further include a fluorescent substance.

[0083] A fluorescent substance refers to a substance that emits a specific wavelength of visible light at a specific wavelength, and in the present invention, includes all fluorescent substances that can be bound to an albumin-based macrophage targeting nanoplatform and used to confirm the location of the nanoplatform.

[0084] Specifically, fluorescent substances that can be used as markers in the present invention can be any fluorescent substance known in the art and can be used without limitation, including, but not limited to, rhodamine-based substances such as rhodamine, TAMRA, etc.; fluorescein-based substances such as fluorescein, FITC (fluorescein isothiocyanate), and FAM (fluorescein amidite); bodipy (boron-dipyrromethene); Alexa Fluor-based substances; and cyanine-based substances such as Cy3, Cy5, Cy7, and indocyanine green.

[0085] Another aspect of the present invention relates to a pharmaceutical composition for preventing or treating inflammatory diseases, which comprises the nano-platform for targeting inflammatory macrophages as an active ingredient.

[0086] In the present invention, L We discovered that a cosyl-conjugated albumin-based nanoplatform can not only target inflammatory macrophages but also suppress inflammatory responses in tissues and restore mitochondrial function, thereby preventing or treating inflammatory diseases.

[0087] Specifically, the nanoplatform for targeting inflammatory macrophages according to the present invention can selectively target damaged tissues and be taken up into the tissues. The nanoplatform delivered into the damaged tissues in this manner can be selectively taken up by inflammatory macrophages, thereby suppressing inflammatory responses in the tissues and restoring mitochondrial function, thereby suppressing cell death in the damaged tissues.

[0088] According to one embodiment of the present invention, LThe cosylated albumin-based nanoplatform not only showed no cytotoxicity even at high concentrations, but also showed a significant improvement in apoptosis / necrosis compared to cells treated with albumin alone, and demonstrated superior efficacy in restoring mitochondrial morphology.

[0089] Therefore, the nanoplatform of the present invention can be used for the prevention or treatment of inflammatory diseases, and the inflammatory disease can be one or more selected from the group consisting of sepsis, septic shock, inflammatory bowel disease (IBD), peritonitis, inflammatory kidney disease, acute bronchitis, chronic bronchitis, osteoarthritis, enteropathic spondylitis, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, acute lung injury, and bronchopulmonary dysplasia.

[0090] The nanoplatform of the present invention can also be utilized to improve kidney disease.

[0091] The present invention L The cosylated albumin-based nanoplatform has excellent targeting ability to damaged kidney tissue and can significantly improve kidney function.

[0092] According to one embodiment of the present invention, L A mouse model administered with the cosylated albumin-based nanoplatform demonstrated improved kidney function, with decreased expression of NGAL, cytochrome C, and p21, and increased expression of Sod-1 and E-cadherin.

[0093] In particular, the nanoplatform of the present invention can remain in the body for a long period of time without being completely excreted even after 24 hours, and is expected to have a significant impact on disease treatment, such as administration before surgery.

[0094] In the present invention, the kidney disease may be one or more kidney diseases selected from the group consisting of nephritis, pyelonephritis, renal syndrome, kidney cancer, acute pyelonephritis, chronic pyelonephritis, kidney tuberculosis, urinary tract infection, urinary tract stones, ureteral stones, acute renal failure, chronic renal failure, diabetic nephropathy, renal fibrosis, chronic glomerulonephritis, acute progressive nephritis, nephrotic syndrome, focal glomerulosclerosis, membranous nephropathy, and membranoproliferative glomerulonephritis, but is not limited thereto.

[0095] The pharmaceutical composition may further contain a suitable pharmaceutically acceptable carrier, excipient, or diluent according to a conventional method. The pharmaceutically acceptable carrier is one commonly used in pharmaceutical formulations, including, but not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil.

[0096] In addition to the above ingredients, the pharmaceutical composition of the present invention may additionally contain lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, etc. Suitable pharmaceutically acceptable carriers and formulations can be suitably formulated according to each ingredient using the methods disclosed in Remington's Pharmaceutical Sciences (19th ed., 1995).

[0097] The pharmaceutical composition of the present invention can be administered either orally or parenterally. Parenteral administration includes intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, and the like.

[0098] Oral dosage forms include tablets, pills, hard and soft capsules, liquids, suspensions, emulsions, syrups, and granules. These formulations may contain, in addition to the active ingredient, diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine) and glidants (e.g., silica, talc, stearic acid and its magnesium or calcium salts, and / or polyethylene glycol). The tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidine, and may optionally contain disintegrants or boiling mixtures such as starch, agar, alginic acid, or its sodium salt, and / or absorbents, colorants, flavorings, and sweeteners. The formulations may be prepared by conventional mixing, granulating, or coating methods.

[0099] A typical example of a formulation for parenteral administration is an injection formulation, and examples of solvents for the injection formulation include water, Ringer's solution, isotonic saline, and suspensions.

[0100] Sterile fixed oils can be used as a solvent or suspending medium for the injectable preparations, and any non-irritating fixed oils including mono- and diglycerides can be used for this purpose.Furthermore, fatty acids such as oleic acid can be used for the injectable preparations.

[0101] The compositions of the present invention are administered in a pharmaceutically effective amount. In the present invention, the term "pharmaceutically effective amount" refers to an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to any medical treatment. The effective dose level can be determined based on factors including the type and severity of the patient's disease, the activity of the drug, its sensitivity, the time of administration, the route of administration and excretion rate, the duration of treatment, concurrently used drugs, and other factors well known in the medical field. The compositions of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with conventional therapeutic agents, and can be administered singly or in multiple doses. Taking all of the above factors into consideration, it is important to administer an amount that can achieve maximum effect with the minimum amount without side effects, which can be easily determined by a skilled artisan.

[0102] Specifically, the effective amount of the composition according to the present invention may vary depending on the age, sex, and weight of the patient, but is generally 0.001 to 150 mg per kg of body weight, preferably 0.01 to 100 mg, administered daily or every other day, or in 1 to 3 divided doses per day. However, since this amount may increase or decrease depending on the route of administration, sex, weight, age, etc., the scope of the present invention is not limited by any method of administration of the above-mentioned amount.

[0103] The present invention will be described in more detail through the following examples, but these examples are merely illustrative of some experimental methods and configurations for the purpose of illustrating the present invention, and the scope of the present invention is not limited to these examples.

[0104] Preparation Example 1: Preparation of an albumin-based nanoplatform for macrophage targeting 1-1. Production of glucosyl-conjugated albumin Albumin was dissolved in phosphate-buffered saline (PBS, pH 7.4) at a concentration of 40 mg / mL, and the albumin solution was dispensed at 20 mg / 0.5 mL per vial. ADIBO-NHS was dissolved in DMSO (10 mg / 50 μL) and added to the albumin solution to prepare a 500 μL solution.

[0105] Albumin and ADIBO-NHS were reacted at a ratio of 1:14 at room temperature for 6 hours and purified using an Amicon Ultra-0.5 centrifugal filter tube. For glucose-albumin synthesis, 6-azido-glucose was dissolved in distilled water at a concentration of 3 mg / mL, and then added to the ADIBO-albumin (AD-Alb) solution (4 mg / 0.5 mL). The mixture was incubated at room temperature for 1 hour and then purified using a centrifugal filter tube.

[0106] Next, we used UV-Vis spectroscopy to confirm the absorbance at 280 nm and 309 nm to confirm the trend of Glucose-AD-Alb (Glc-AD-Alb). To measure the absorbance of albumin, each albumin sample was diluted to 2 mg / mL and used. MALDI-TOF MS was performed to determine the number of ADIBO and glucose bound to albumin (degree of functionalization = DOF).

[0107] The number of ADIBO molecules on the albumin surface and the number of glucose molecules introduced via the click reaction were then measured using UV and MALDI-TOF analysis. To prepare AD11-Alb-FL and Glc6-AD11-Alb-FL, N3-FNR648 (10 nmol / 1 μL, dissolved in DMSO) was added to AD-Alb and Glc-AD-Alb (30 nmol / 500 μL), incubated at 4°C for 30 minutes, and then purified using a centrifugal filter.

[0108] The number of ADIBO functional groups introduced into HSA-ADIBO was quantified using UV-Vis spectrophotometric analysis, and was found to be 12.8-13.1. MALDI-TOF quantification revealed that the number was 11.1-11.5. The number of glucose molecules bound to the ADIBO functional groups was found to be 5.4-7.8.

[0109] [Table 1] JPEG0007777381000014.jpg48147

[0110] 1-2. Production of mannosyl-conjugated albumin HSA-ADIBO was dissolved in PBS and mixed with Man-N3 (1-O-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)-α-D-mannopyranoside) at a molar ratio of 1:8 HSA-ADIBO:Man-N3, followed by reaction at 37°C for 1 hour to prepare albumin conjugated with mannosyl groups. The conjugation of mannosyl groups was then confirmed using the method of Preparation Example 1-1.

[0111] 1-3. Fluorescent or radioisotope binding 64 The vial containing Cu was dried with N gas in a hood for 30 min, then 200 μL of 1 M sodium acetate buffer (pH 5) was added to the vial to adjust the pH to 5, and NOTA-N3 (1 mg / mL in DW, 10 μL) was added and heated at 70 °C for 5 min.

[0146] To measure the radiolabeling efficiency, thin-layer chromatography (TLC) was performed using ITLC-SG paper (Radio-TLC, 0.1 M citric acid as the mobile phase). After confirming the radiolabeling efficiency, the NOTA-N3 solution radiolabeled with Glc6-AD11-Alb or AD11-Alb ([ 64 10 μL (9 nmole, 0.5 mCi) of [Cu]Cu-NOTA-N3, 10 mCi / 200 μL) was added.

[0112] Alb was placed in PBS (500 μg / 0.5 mL, 15 nmole / 0.5 mL) and incubated at room temperature (RT) for 30 min. Finally, unlabeled 64 Cu, [ 64 The Rf values ​​of radiolabeled Glc6-AD11-Alb or AD11-Alb (Glc6-AD11-Alb- 64 Cu or AD11-Alb- 64 Radio-TLC was performed to confirm the generation of Cu. 64 Cu-NOTA-N3 and Glc6-AD11-Alb- 64 Cu or AD11-Alb- 64 Cu was 1.0, 0.5-0.6, and 0.0-0.1, respectively.

[0113] Experimental Example 1: Confirmation of macrophage targeting ability of albumin-based nanoplatform The graph obtained in Production Example 1 L An experiment was conducted to confirm whether HAS-ADIBO conjugated with cosyl or mannosyl groups could target macrophages.

[0114] Referring to Figure 1, L Cosylated albumin showed a high uptake rate in M1 macrophages, while mannosylated albumin showed a high uptake effect in M2 macrophages. L We confirmed that both cosylated and mannosylated albumin were hardly taken up by M0 macrophages.

[0115] These results suggest that the targeting ability of albumin to macrophages varies depending on the type of sugar attached to the albumin surface. L We confirmed that the cosylated albumin-based nanoplatform is capable of selectively targeting inflammatory macrophages M1.

[0116] Experimental Example 2: Confirmation of targeting ability by glucose carbon position We decided to confirm the macrophage targeting ability depending on the carbon position of glucose and to identify the carbon position suitable for albumin binding.

[0117] As a result, the expression of SPARC, which is the albumin uptake mechanism, was low, and GLUT was overexpressed in the cancer cell line MDA-MB231, where albumin was bound to the 1st, 2nd, and 6th carbons of glucose. L Cosylated albumin was treated to confirm targeting ability.

[0118] As shown in Figure 2, the targeting ability of GLUT-overexpressing cells differed significantly depending on the glucose carbon position. In particular, the nanoplatform with albumin conjugated to glucose position 6 exhibited the highest GLUT targeting ability, demonstrating three-fold higher targeting ability than the nanoplatform with albumin conjugated to glucose position 1 and two-fold higher targeting ability than the nanoplatform with albumin conjugated to glucose position 2.

[0119] Experimental Example 3: Confirmation of the in vitro kidney function improving effect of albumin-based nanoplatform In a cell model of acute kidney injury using primary cultured human renal proximal tubular epithelial cells, L The effect of the albumin nanoplatform (glucose-albumin) conjugated with a cosyl group on improving kidney function was confirmed.

[0120] A cell model of acute kidney injury was prepared by inducing oxidative stress in primary cultured human renal proximal tubular epithelial cells by treating them with hydrogen peroxide (H2O2, 1mM). The cell model was divided into an albumin-only group and a glucose-albumin group, and treated with albumin and glucose-albumin at 1000 nM each.

[0121] First, the results of confirming cytotoxicity by MTS analysis are shown in Figure 3. From Figure 3, it was confirmed that no cytotoxicity was observed even when high concentrations of glucose-albumin were administered.

[0122] Next, flow cytometry was performed on the acute kidney injury cell model treated with albumin and glucose-albumin. The results are shown in Figure 4. It was confirmed that apoptosis / necrosis was significantly reduced in the glucose-albumin group compared to the albumin-only group.

[0123] In addition, using cells cultured under H2O2 stress conditions, we examined using fluorescence microscopy whether glucose-albumin could be effective in restoring and maintaining the function of damaged mitochondria.

[0124] Referring to Figure 5, which shows the results of fluorescence microscopy, mitochondrial fragmentation was observed in the presence of H2O2, whereas the glucose-albumin administration group showed recovery of mitochondrial morphology in the form of droplets or dilated mitochondrial structures.

[0125] As shown in Figure 6, cells with damaged mitochondria were confirmed in the presence of H2O2, but the shape of damaged mitochondria in cells treated with glucose and albumin was confirmed to have recovered.

[0126] This confirmed that glucose-albumin had a significant effect on restoring mitochondrial morphology.

[0127] 7 shows the results of fluorescence microscopy analysis confirming the intracellular expression of glucose-albumin in the acute kidney injury cell model. From FIG. 7, it was confirmed that intracellular glucose-albumin was stably expressed.

[0128] These results confirmed that glucose-albumin is involved in the restoration of mitochondrial morphology and the recovery of damaged cells in the kidney.

[0129] Experimental Example 4: Confirmation of the in vivo kidney function improving effect of the albumin-based nanoplatform bIRI (bilateral ischemia reperfusion injury) mouse model L A cosyl-conjugated albumin-based nanoplatform (glucose-albumin) was administered at 40 μg / mice via the tail vein one hour before surgery, and its effects on kidney function and mitochondria were examined.

[0130] First, the BUN (blood urea nitrogen) and creatine levels of the model were confirmed and shown in Figure 8. Compared with the untreated control group, decreased BUN and creatine levels were observed in the serum of mice treated with glucose-albumin, confirming that glucose-albumin is effective in improving kidney function.

[0131] Next, the effects of glucose-albumin on kidney tissue damage and mitochondrial function improvement were confirmed, as shown in Figures 9 and 10. The expression of NGAL, a diagnostic marker for kidney damage, and cytochrome C and p21, which induce mitochondrial apoptosis, was reduced by glucose-albumin treatment, while the expression of Sod-1 and E-cadherin, which regulate kidney function, was increased. This confirmed that glucose-albumin has the effect of restoring damaged kidney tissue and mitochondrial function.

[0132] Experimental Example 5: Confirmation of in vivo targeting ability of albumin-based nanoplatform G L The albumin nanoplatform with cosyl groups attached was isotope-labeled, and the disease and tissue targeting ability of the albumin nanoplatform was confirmed in a mouse model, as shown in Figures 11 and 12.

[0133] After introducing glucose into albumin in the same manner as in Preparation Example 1, the isotopes were successively introduced in the same manner to obtain the isotope ( 64 Cu) labeled group L A cosylated albumin nanoplatform (glucose-albumin) was obtained and administered IP to a bIRI mouse model with albumin as a control. Fluorescence expression was then confirmed using an isotope to confirm whether the albumin nanoplatform could selectively target disease and tissue.

[0134] Referring to Figure 11, which confirmed the targeting ability of glucose-albumin and albumin, fluorescence was observed in the red box representing the kidney in the glucose-albumin administration group, clearly confirming that glucose-albumin was taken up by the damaged kidney.

[0135] In particular, the glucose-albumin group showed higher kidney uptake than the albumin group, while the albumin-only group showed increased blood flow at existing inflammation sites.

[0136] This allows L It was confirmed that cosylated albumin exhibits high targeting efficiency to damaged kidney tissue, and thus the present invention L The possibility of using cosylated albumin as a therapeutic agent for kidney diseases was confirmed.

[0137] Next, mice that underwent uIRI (unilateral ischemia-reperfusion injury) surgery were treated with isotopes ( 64 Cu)-labeled glucose-albumin nanoplatform was intravenously administered, and the fluorescence expression level was confirmed and shown in Figure 12.

[0138] As shown in Figure 12, isotopes ( 64 We were able to confirm that Cu-labeled glucose-albumin was selectively taken up by the injured kidney and was still stored in the body even after 24 hours.

[0139] Based on the above results, we confirmed that intravenous (IV) administration of glucose-albumin is also an effective administration method for targeting kidney disease, since albumin is not excreted through normal kidneys.

[0140] Although some embodiments of the present invention have been described above, the present invention is not limited to the above-described embodiments, and can be implemented with modifications and variations within the scope of the gist of the present invention, and such modified and varied forms should also be understood as belonging to the technical spirit of the present invention.

Claims

1. Azide (N ３ ) or cyclooctyne functional group-bound albumin, and azide (N ３ ) or a cyclooctyne functional group-conjugated delivery substance, the delivery agent comprises a glucosyl group; A nanoplatform for targeting inflammatory M1 macrophages, wherein when the albumin is conjugated with an azide functional group, the delivery substance is conjugated with a cyclooctyne functional group, and when the albumin is conjugated with a cyclooctyne functional group, the delivery substance is conjugated with an azide functional group.

2. The nanoplatform for targeting inflammatory M1 macrophages according to claim 1, wherein the number of azide or cyclooctyne functional groups introduced into the albumin is 1 to 14.

3. The nanoplatform for targeting inflammatory M1 macrophages according to claim 1, wherein the nanoplatform comprises 4 to 8 glucosyl groups.

4. The nanoplatform for targeting inflammatory M1 macrophages according to claim 1, wherein an azide or cyclooctyne functional group is attached to the 6th carbon of the glucosyl group.

5. The delivery agent further comprises a radioisotope, the radioisotope comprising: ３ H, １１ C. １８ F, １４ Cl, ３２ P, ３５ S, ３６ Cl, ４５ Ca, ５１ Cr, ５７ Co, ５８ Co, ５９ F, ６４ Cu, ６７ Ga, ６８ Ga, ８９ Zr, ９０ Y, ９９ Mo, ９９ｍ Tc, １１１ In, １３１ I, １２５ I, １２４ I, １２３ I, １８６ Re, １８８ Re, ２２５ Ac, ２１２ Pb, １１７ｍ Sn, and １７７ The nanoplatform for targeting inflammatory M1 macrophages according to claim 1, wherein the nanoplatform is one or more selected from the group consisting of:

6. The radioisotope is labeled with a chelating agent, and the chelating agent is not particularly limited, and examples of the chelating agent include NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DFO (3-[6,17-dihydroxy-7,10,18,21-tetraoxo-27-[N-acetylhydroxylamino]-6,11,17,22-tetraazaheptaeicosane]thiourea), DTPA (diethylenetriaminepentaacetic acid), N2S2 (diaminodithiol), p-SCN-Bn-NOTA (2-(4'-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid), and NODAGA (1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid). p-SCN-Bn-DOTA (2-(4'-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid), p-SCN-Bn-DTPA (2-(4-isothiocyanatobenzyl)-diethylenetriaminepentaacetic hydrazinonicotinic The nanoplatform for targeting inflammatory M1 macrophages according to claim 5, wherein the nanoplatform is one or more selected from the group consisting of:

7. 2. The nanoplatform for targeting inflammatory M1 macrophages according to claim 1, wherein the delivery substance further comprises a fluorescent substance, and the fluorescent substance is one or more selected from the group consisting of FNR (Ferrodoxin NADP(+) reductase), cyanine fluorescent substances, TAMRA (tetramethylrhodamine-5-maleimide), Flamma® fluorescent substance, and ICG (indocyanine green).

8. The nanoplatform for targeting inflammatory M1 macrophages according to claim 1 , wherein the nanoplatform selectively targets macrophages that overexpress GLUT (Glucose Transporter).

9. A pharmaceutical composition for preventing or treating an inflammatory disease, comprising the nanoplatform for targeting inflammatory M1 macrophages according to any one of claims 1 to 8 as an active ingredient.

10. The pharmaceutical composition for preventing or treating an inflammatory disease according to claim 9, wherein the nano-platform for targeting inflammatory M1 macrophages selectively targets damaged tissues.

11. The pharmaceutical composition for preventing or treating an inflammatory disease according to claim 9, wherein the nano-platform for targeting inflammatory M1 macrophages restores mitochondrial function and suppresses cell death in damaged tissues.

12. 10. The pharmaceutical composition for the prevention or treatment of an inflammatory disease according to claim 9, wherein the inflammatory disease is one or more selected from the group consisting of sepsis, septic shock, inflammatory bowel disease (IBD), peritonitis, inflammatory kidney disease, acute bronchitis, chronic bronchitis, osteoarthritis, enteropathic spondylitis, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, acute lung injury, and bronchopulmonary dysplasia.

13. A pharmaceutical composition for preventing or treating kidney disease, comprising the nanoplatform for targeting inflammatory macrophages according to any one of claims 1 to 8 as an active ingredient. The pharmaceutical composition for preventing or treating kidney disease, wherein the kidney disease is one or more kidney diseases selected from the group consisting of nephritis, pyelonephritis, renal syndrome, kidney cancer, acute pyelonephritis, chronic pyelonephritis, renal tuberculosis, urinary tract infection, urinary tract stones, ureteral stones, acute renal failure, chronic renal failure, diabetic nephropathy, renal fibrosis, chronic glomerulonephritis, acute progressive nephritis, nephrotic syndrome, focal glomerulosclerosis, membranous nephropathy, and membranoproliferative glomerulonephritis.

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