Compositions containing metal-organic structures for inducing polarization of macrophages and their applications

Abstract

This invention relates to a composition for inducing macrophageous cell polarization, comprising a metal-organic framework (MOF), and its applications. The composition of this invention has been confirmed to effectively induce polarization of M2 macrophages. Therefore, it can be applied to disease treatment methods related to mechanisms for suppressing M1 macrophageous cell polarization or inducing M2 macrophageous cell polarization.

Description

[Technical Field]

[0001] This invention relates to a composition for inducing macrophageous cell polarization, comprising a metal-organic framework (MOF), and its applications. [Background technology]

[0002] Innate immune response is a primary defense mechanism that prioritizes protecting our bodies from invading pathogens, and is also called nonspecific immunity. Neutrophils, mononuclear cells, macrophages, etc., are involved in innate immune response, and it reacts rapidly to the invasion and infection of pathogens, regardless of the type of pathogen or whether or not there has been a history of infection.

[0003] In particular, macrophages are cells distributed throughout all tissues in the body that are responsible for immunity, and are involved in the elimination of invading pathogens, the removal of virus-infected self cells and cancer cells, and the induction of inflammatory responses. Macrophages can be classified into tissue-resident macrophages, which are derived from tissue cells differentiated from the yolk sac or fetal liver during development, and monocyte-derived macrophages, which are derived from mononuclear cells (differentiated from bone marrow cells) in the blood that differentiate due to inflammatory responses or the invasion of pathogens.

[0004] Macrophagocytes derived from tissue cells and mononuclear cells can differentiate into M1 and M2 macrophagocytes, which act on different immune responses depending on the type of cytokines used. Cytokines are proteins involved in intercellular communication, secreted in a chain reaction of immune responses from pathogens or cells that recognize infection, and promote the differentiation and proliferation of cells dedicated to immune responses, such as helper T cells (Th cells), B cells, and macrophagocytes. M1 macrophagocytes are induced by Th1 cell cytokines such as IFN-γ and TNF-α, and act on inducing the Th1 response, inducing inflammatory responses, and suppressing cancer growth. M2 macrophagocytes are induced by Th2 cell cytokines such as IL-4 and IL-10, and act on inducing the Th2 response, suppressing inflammatory responses, and repairing damaged tissue. Thus, macrophagocytes derived from bone marrow and mononuclear cells can differentiate into M1 or M2 macrophagocytes, which act on different aspects depending on the type of cytokine used.

[0005] It takes time for macrophages to differentiate, proliferate, and become activated by cytokines. Recently, there has been active research into methods to shorten the differentiation, proliferation, and activation time of macrophages without inducing hypersensitive reactions or anaphylaxis in the human body.

[0006] Against this backdrop, we developed a technology to induce polarization in M2 macrophages using metal-organic structures, thereby completing the present invention. [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] One aspect of the present invention provides a composition for inducing macrophageous cell polarization, comprising a metal-organic framework (MOF).

[0008] Another aspect of the present invention provides a method for inducing intracellular polarization, comprising the step of administering the macrophageous cell polarization-inducing composition to an organism.

[0009] A further aspect of the present invention provides a method for inducing polarization of macrophages, comprising the step of treating isolated cells with the macrophages polarization-inducing composition. [Means for solving the problem]

[0010] One aspect of the present invention provides a composition for inducing macrophageous cell polarization, comprising a metal-organic framework (MOF).

[0011] In this specification, the term "metal-organic framework (MOF)" refers to a porous material in which metal clusters and organic linkers (organic bridging ligands) are linked by coordination bonds to form a three-dimensional structure. A variety of MOFs can be produced by selecting metal ions and organic ligands. MOFs are characterized by their porosity, meaning that empty spaces exist within their structure. The size of the pores, porosity, three-dimensional structure, and surface area can be designed in diverse ways depending on the type of metal ions and organic ligands that make up the MOF and the bonding method. Due to this porosity, MOFs have a very large surface area and an open pore structure, allowing for the movement of large amounts of molecules or solvents compared to other known porous materials. When used as a catalyst or gas storage material, they have the advantage of having many active sites, maximizing efficiency. Furthermore, MOFs do not deform well at high temperatures and have a rigid framework, resulting in excellent chemical and thermal stability.

[0012] The aforementioned metal-organic structure is made of aluminum (Al, Al 2+ , Al 3+ ), iron (Fe, Fe 2+ Fe 3+ ) and zirconium (Zr, Zr 2+ , Zr 3+ , Zr 4+One or more metals selected from the group consisting of ) or metal ions thereof, synthesized using the selected metal or metal ions, and specifically including the metal or metal ions and an organic ligand coordinated thereto. Specifically, the metal part of the metal-organic structure is composed of one or more metals selected from the group consisting of aluminum (Al, Al 2+ 、Al 3+ ), iron (Fe, Fe 2+ 、Fe 3+ ) and zirconium (Zr, Zr 2+ 、Zr 3+ 、Zr 4+ ) or metal ions thereof.

[0013] In one embodiment, the metal-organic structure is an aluminum-based MOF, an iron-based MOF, and / or a zirconium-based MOF.

[0014] The metal-organic structure is aluminum (Al, Al 2+ 、Al 3+ ), iron (Fe, Fe 2+ 、Fe 3+ ) and zirconium (Zr, Zr 2+ 、Zr 3+ 、Zr 4+One or more metals or metal ions selected from the group consisting of ) and 4,4'-biphenyldicarboxilic acid, benzene-1,4-dicarboxylic acid, 9,10-anthracenedicarboxylic acid, biphenyl-3,3,5,5'-tetracarboxylic acid, biphenyl-3,4',5-tricarboxylic acid, 5-bromoisophthalic acid, 5-cyano-1,3-benzenedicarboxylic acid, 2,2-diamino-4,4'-stilbenedicarboxylic acid, terephthalic acid 2-aminoterephthalic acid, 2,5-diaminoterephthalic acid, 1,1,2,2-tetra(4-carboxylphenyl)ethylene, 2,5-dihydroxyterephthalic acid, 2,2-dinitro-4,4-stilbenedicarboxylic acid, 5-ethynyl-1,3-benzenedicarboxylic acid, 2-hydroxyterephthalic acid, 2,6-naphthalenedicarboxylic acid acid), 1,2,4,5-tetrakis(4-carboxyphenyl)benzene, 4,4,4,4,41 / 2-s-triazine-2,4,6-triyl-tribenzoic acid, 1,3,5-tricarboxybenzene, 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid It may contain one or more organic ligands selected from the group consisting of acid, 1,3,5-tris(4-carboxy[1,1'-biphenyl]-4-yl)benzene, 1,3,5-tris(4-carboxyphenyl)benzene, 1,3,5-triscarboxyphenylethynylbenzene, and 2-methylimidazole.

[0015] The metal-organic framework is UIO-66[C 48 H 28 O 32 Zr6], UIO-66-NH2[C 48 H 34 N6O 32 Zr6], UIO-67[C 84 H 52 O 32 Zr6], UIO-67-NH2[C 84 H 58 N6O 32 Zr6], PCN-128[C 108 H 76 O 30 Zr6], MOF-801[C 24 H 16 O 32 Zr6], MOF-808[C 24 H 16 O 32 Zr6], MOF-867[C 72 H 40 N 12 O32 Zr6], Al-MIL-53[C8H5AlO5], Al-MIL-53-NH2[C8H6NO5Al], Al-MIL-88[C 24 H 12 Al3O 13 ], Al-MIL-88-NH2[C 24 H 15 La3N3O 13 ], Al-MIL-100[C9H6O6Al], Al-MIL-100-NH2[C9H7NO6Al], Al-MIL-101[C 24 H 12 ClAl3O 13 ], Al-MIL-101-NH2[C 24 H 19 Al3ClN3O 15 ], Al-MIL-125[C 48 H 28 O 36 Al8], Al-MIL-125-NH2[C 48 H 34 N6O 36 Al8], Fe-MIL-53[C8H5FeO5], Fe-MIL-53-NH2[C8H6FeNO5], Fe-MIL-88[C 24 H 12 Fe3O 13 ], Fe-MIL-88-NH2[C 24 H 15 Fe3N3O 13 ], Fe-MIL-100[C9H6O6Fe], Fe-MIL-100-NH2[C9H7NO6Fe], Fe-MIL-101[C 24 H 12 ClFe3O 13 ], Fe-MIL-101-NH2[C 24 H 19 Fe3ClN3O 15 ], Fe-MIL-125[C 48 H 28 O 36 Fe8, Fe-MIL-125-NH2[C 48 H 34 N6O 36 Fe8] and ZIF-8[C8H 10 It includes, but is not limited to, one or more selected from the group consisting of [N4Zn].

[0016] In one embodiment, the aluminum-based MOF includes, but is not limited to, one or more selected from the group consisting of Al-MIL-53, Al-MIL-53-NH2, Al-MIL-88, Al-MIL-88-NH2, Al-MIL-100, Al-MIL-100-NH2, Al-MIL-101, Al-MIL-101-NH2, Al-MIL-125, and Al-MIL-125-NH2. According to one embodiment, as a representative example of an aluminum-based MOF, Al-MIL-101-NH2 was confirmed to effectively induce macrophagocyte polarization (polarization to M2 macrophages).

[0017] In one embodiment, the iron-based MOF includes, but is not limited to, one or more selected from the group consisting of Fe-MIL-53, Fe-MIL-53-NH2, Fe-MIL-88, Fe-MIL-88-NH2, Fe-MIL-100, Fe-MIL-100-NH2, Fe-MIL-101, Fe-MIL-101-NH2, Fe-MIL-125, and Fe-MIL-125-NH2. According to one embodiment, as a representative example of an iron-based MOF, Fe-MIL-101-NH2 was confirmed to effectively induce macrophagocyte polarization (polarization to M2 macrophages).

[0018] In one embodiment, the zirconium-based MOF includes, but is not limited to, one or more selected from the group consisting of UIO-66, UIO-66-NH2, UIO-67, UIO-67-NH2, PCN-128, MOF-801, MOF-808, and MOF-867. According to one embodiment, as a representative example of a zirconium-based MOF, UIO-66 was confirmed to effectively induce macrophagocyte polarization (polarization to M2 macrophages).

[0019] In this specification, the term "macrophage" refers to a representative plague cell derived from bone marrow cells that plays a major role in innate immunity. Initially, it leaves the bone marrow via the bloodstream as an immature mononuclear cell (monocyte). The mononuclear cell's activity increases during the process of recognizing by-products and pathogens derived from infected cells, and it differentiates into a mature macrophage. Macrophages play an important role in removing invading pathogens and inducing adaptive immunity to maintain tissue homeostasis, and they are crucial in the initial stages of inflammatory responses in the human body. Depending on their differentiation method, they specifically mature into two forms: M1 macrophages (classically activated macrophages) and M2 macrophages (alternatively activated macrophages). Of these, M2 macrophages are known to reduce inflammation and promote tissue repair.

[0020] The aforementioned macrophagocyte polarization-inducing composition means a composition for inducing polarization into macrophages, and specifically, a composition that modulates or induces polarization, differentiation, and / or activation of M2 macrophages (M2 type).

[0021] The composition induces the polarization of cells that have the potential to polarize into M2 macrophages, or are known to polarize, into M2 macrophages, specifically by regulating or inducing the polarization, differentiation, and / or activation of one or more cells selected from the group consisting of undifferentiated macrophages, monocytes, M0 macrophages, and M1 macrophages into M2 macrophages.

[0022] The aforementioned M2 macrophages are CD11b + CD45 + and Arginase 1 + Having one or more phenotypes selected from the group consisting of, specifically, the M2 macrophages are CD11b + CD45 + and Arginase 1 + Phenotype.

[0023] In the above composition, the metal-organic structure further comprises a macrophageocyte polarization inducer, and more specifically, the metal-organic structure is equipped with a macrophageocyte polarization inducer.

[0024] The macrophagocyte polarization inducer is an active substance that induces polarization in M2 macrophages, specifically an active substance that induces the polarization, differentiation, and / or activation of undifferentiated macrophages, M0 macrophages, and / or M1 macrophages into M2 macrophages.

[0025] The macrophagey cell polarization inducer comprises one or more selected from the group consisting of artemisinin, IL (Interleukin)-4, IL-6, IL-10, IL-13, TGF-beta, and adenosine.

[0026] In one embodiment, the metal-organic structure is 0.001 to 500 μg / ml, specifically 0.001 to 500 μg / ml, 0.001 to 300 μg / ml, 0.001 to 200 μg / ml, 0.001 to 100 μg / ml, 0.001 to 80 μg / ml, 0.001 to 50 μg / ml, 0.001 to 30 μg / ml, 0.001 to 20 μg / ml, 0.0 0.1 to 10 μg / ml, 0.01 to 500 μg / ml, 0.01 to 300 μg / ml, 0.01 to 200 μg / ml, 0.01 to 100 μg / ml, 0.01 to 80 μg / ml, 0.01 to 50 μg / ml, 0.01 to 30 μg / ml, 0.01 to 20 μg / ml, 0.01 to 10 μg / ml, 0.1 to 500 μg / ml, 0.1 to 300 μg / ml l, 0.1 to 200 μg / ml, 0.1 to 100 μg / ml, 0.1 to 80 μg / ml, 0.1 to 50 μg / ml, 0.1 to 30 μg / ml, 0.1 to 20 μg / ml, 0.1 to 10 μg / ml, 0.51 to 500 μg / ml, 0.5 to 300 μg / ml, 0.5 to 200 μg / ml, 0.5 to 100 μg / ml, 0.5 to 80 μg / ml, 0.5 The concentrations are, but are not limited to, 1 to 50 μg / ml, 0.5 to 30 μg / ml, 0.5 to 20 μg / ml, 0.5 to 10 μg / ml, 1 to 500 μg / ml, 1 to 300 μg / ml, 1 to 200 μg / ml, 1 to 100 μg / ml, 1 to 80 μg / ml, 1 to 50 μg / ml, 1 to 30 μg / ml, 1 to 20 μg / ml, and 1 to 10 μg / ml.

[0027] In one example, the metal-organic structure is included in 0.001 to 100% by weight of the total weight of the composition, specifically 0.001 to 100% by weight, 0.001 to 80% by weight, 0.001 to 50% by weight, 0.001 to 30% by weight, 0.001 to 20% by weight, 0.001 to 10% by weight, 0.01 to 100% by weight, 0.01 to 80% by weight, 0.01 to 50% by weight, 0.01 to 30% by weight, 0.01 to 20% by weight, 0.01 to 10% by weight, The amounts are 0.1 to 100% by weight, 0.1 to 80% by weight, 0.1 to 50% by weight, 0.1 to 30% by weight, 0.1 to 20% by weight, 0.1 to 10% by weight, 0.5 to 100% by weight, 0.5 to 80% by weight, 0.5 to 50% by weight, 0.5 to 30% by weight, 0.5 to 20% by weight, 0.5 to 10% by weight, 1 to 100% by weight, 1 to 80% by weight, 1 to 50% by weight, 1 to 30% by weight, 1 to 20% by weight, and 1 to 10% by weight, but are not limited to these.

[0028] The aforementioned composition is a pharmaceutical composition.

[0029] The pharmaceutical composition may include a pharmaceutically acceptable carrier. A "pharmaceutically acceptable carrier" means a carrier or diluent that does not irritate living organisms and does not inhibit the biological activity and properties of the injected compound. Here, "pharmaceutically acceptable" means that it does not suppress the activity of the active ingredient and does not impair the toxicity of the target organism beyond what is appropriate for the application (prescription). Any type of carrier that is commonly used in the art and is pharmaceutically acceptable may be used in the pharmaceutical composition. Non-limiting examples of the carrier include lactose, dextrose, maltodextrin, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, glycerol, ethanol, starch, acacia gum, alginic acid, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, saline solution, sterile water, Ringer's solution, buffered saline, albumin injection solution, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, or mineral oil. These may be used alone or in combination of two or more. The pharmaceutical composition, in addition to the active ingredient, comprises a pharmaceutically acceptable carrier and may be prepared in oral or parenteral dosage forms by a conventional route of administration known to the art. Each of the aforementioned pharmaceutical compositions can be formulated by conventional methods into oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, as well as topical preparations, suppositories, or sterile injection solutions for use.

[0030] When formulating the aforementioned pharmaceutical composition, it is generally prepared using fillers, bulking agents, binders, wetting agents, disintegrants, or diluents or excipients such as surfactants, but is not limited to these.

[0031] When the aforementioned pharmaceutical composition is manufactured in oral dosage form, it may be produced in powder, granule, tablet, pill, sugar-coated tablet, capsule, liquid, gel, syrup, suspension, wafer, or other dosage form by methods known in the art, together with a suitable carrier. Examples of pharmaceutically acceptable suitable carriers include sugars such as lactose, glucose, sucrose, dextrose, sorbitol, mannitol, and xylitol; starches such as corn starch, potato starch, and wheat starch; celluloses such as cellulose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, and hydroxypropyl methylcellulose; polyvinylpyrrolidone; water; methyl hydroxybenzoate; propyl hydroxybenzoate; magnesium stearate; mineral oil; malt; gelatin; talc; polyol; and vegetable oil. When formulation, the composition may be formulated with fillers, bulking agents, binders, wetting agents, disintegrants, diluents such as surfactants, and / or excipients as needed.

[0032] When the aforementioned pharmaceutical composition is manufactured in parenteral dosage form, it can be formulated in the form of injections, transdermal administrations, nasal inhalants, and suppositories by methods known in the art, together with a suitable carrier. When formulated as an injection, suitable carriers include sterile water, ethanol, polyols such as glycerol and propylene glycol, or mixtures thereof. Preferably, Ringer's solution, triethanolamine-containing PBS (phosphate buffered saline), sterile water for injection, or isotonic solutions such as 5% dextrose can be used. When formulated as a transdermal administration agent, it can be formulated in the form of ointments, creams, lotions, gels, topical solutions, pastes, liniments, air rolls, etc. In the case of nasal inhalants, the formulation is made into an aerosol spray using a suitable propellant such as dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, or carbon dioxide. When formulated into suppositories, the base may include witepsol, tween 61, polyethylene glycols, cocoa butter, lauric acid butter, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, or sorbitan fatty acid esters.

[0033] The pharmaceutical composition may be administered in a pharmaceutically effective amount. The term “pharmaceutically effective amount” means an amount sufficient to treat or prevent a disease with a reasonable benefit / risk ratio applicable to medical treatment or prevention, and the level of the effective dose may be determined by the severity of the disease, the activity of the drug, the patient’s age, weight, health, sex, the patient’s sensitivity to the drug, the time of administration, route of administration and excretion rate of the composition of the present invention used, the duration of treatment, elements including drugs compounded or co-administered with the composition of the present invention used, and other elements known in the medical field. The pharmaceutical composition of the present invention may be administered alone or in combination with components known to exhibit therapeutic effects against known inflammation, allergic diseases, atopic dermatitis, or asthma. Taking all of the above elements into consideration, it is important to administer an amount that provides the maximum effect with the minimum amount without side effects.

[0034] The dosage of the pharmaceutical composition can be determined by a person skilled in the art, taking into consideration the intended use, the degree of toxicity of the disease, the patient's age, weight, sex, medical history, or the type of substance used as the active ingredient. For example, the pharmaceutical composition of the present invention is administered to an adult at a dose of about 0.1 ng to about 1,000 mg / kg, preferably 1 ng to about 100 mg / kg, and the frequency of administration of the composition of the present invention is not particularly limited thereto, but can be administered once a day or divided into several doses. Neither the dosage nor the number of doses limits the scope of the present invention.

[0035] Another aspect of the present invention provides a method for inducing intracellular polarization, comprising the step of administering the macrophageous cell polarization-inducing composition to an organism. The same parts as described above also apply to the above method.

[0036] As used herein, the term "individual" includes, without limitation, mammals such as dogs, cats, mice, livestock, and humans, as well as birds, reptiles, farmed fish, etc., excluding humans.

[0037] The aforementioned cells are cells that are polarized, differentiated, and / or activated into M2 macrophages, and specifically include one or more selected from the group consisting of undifferentiated macrophages, mononuclear cells (monocytes), M0 macrophages, and M1 macrophages.

[0038] The method described above induces polarization, differentiation, and / or activation of M2 macrophages, specifically regulating or inducing the polarization, differentiation, and / or activation of undifferentiated macrophages, monocytes, M0 macrophages, and / or M1 macrophages into M2 macrophages.

[0039] The aforementioned pharmaceutical composition may be administered in single or multiple doses in pharmaceutically effective amounts. In this case, the composition may be administered in dosage forms such as liquids, powders, aerosols, injections, intravenous solutions (Ringer's solution), capsules, pills, tablets, suppositories, or patches. The pharmaceutical composition may be administered via any common route, as long as it can reach the target tissue.

[0040] The aforementioned pharmaceutical composition may be administered via routes such as intraperitoneal, intravenous, intramuscular, subcutaneous, intradermal, transdermal patch, oral, intranasal, intrapulmonary, or rectal administration, depending on the purpose, although this is not particularly limited. However, when administered orally, since the active ingredient of the pharmaceutical composition may be denatured or degraded by stomach acid, the oral composition may be administered orally in a dosage form or oral patch that is coated with the active agent or protected from degradation in the stomach. Furthermore, the composition may be administered by any device that allows the active substance to move to target cells.

[0041] A further aspect of the present invention provides a method for inducing polarization of macrophages, comprising the step of treating isolated cells with the macrophageous cell polarization-inducing composition. The same portions described above also apply to the method.

[0042] The isolated cells are cells that are polarized, differentiated, and / or activated into M2 macrophages, and specifically include one or more selected from the group consisting of undifferentiated macrophages, monocytes, M0 macrophages, and M1 macrophages.

[0043] It includes one or more cells selected from the group consisting of M0 macrophages and M1 macrophages.

[0044] The method described above induces polarization, differentiation, and / or activation of M2 macrophages, specifically regulating or inducing the polarization, differentiation, and / or activation of undifferentiated macrophages, monocytes, M0 macrophages, and / or M1 macrophages into M2 macrophages.

[0045] Yet another aspect of the present invention is to provide applications for inducing macrophages' polarization using metal-organic frameworks (MOFs) or compositions containing them. The same portions described above also apply to these applications.

[0046] UIO-66 [C 48 H 28 THEIR 32 Zr6]、UIO-66-NH2[C 48 H 34 N6O 32 Zr6]、UIO-67[C 84 H 52 THEIR 32 Zr6]、UIO-67-NH2[C 84 H 58 N6O 32 Zr6]、PCN-128[C 108 H 76 THEIR 30 Zr6]、MOF-801[C 24 H 16 THEIR 32 Zr6]、MOF-808[C 24 H 16 THEIR 32 Zr6]、MOF-867[C 72 H 40 N 12 THEIR 32 Zr6]、Al-MIL-53[C8H5AlO5]、Al-MIL-53-NH2[C8H6NO5Al]、Al-MIL-88[C 24 H 12 Al3O 13 ]、Al-MIL-88-NH2[C 24 H 15 Al3N3O 13 ]、Al-MIL-100[C9H6O6Al]、Al-MIL-100-NH2[C9H7NO6Al]、Al-MIL-101[C 24 H 12 ClAl3O 13 ]、Al-MIL-101-NH2[C 24 H 19 Al3ClN3O 15 ]、Al-MIL-125[C 48 H 28 THEIR 36 Al8]、Al-MIL-125-NH2[C 48 H 34 N6O 36Al8], Fe-MIL-53[C8H5FeO5], Fe-MIL-53-NH2[C8H6FeNO5], Fe-MIL-88[C 24 H 12 Fe3O 13 ], Fe-MIL-88-NH2[C 24 H 15 Fe3N3O 13 ], Fe-MIL-100[C9H6O6Fe], Fe-MIL-100-NH2[C9H7NO6Fe], Fe-MIL-101[C 24 H 12 ClFe3O 13 ], Fe-MIL-101-NH2[C 24 H 19 Fe3ClN3O 15 ], Fe-MIL-125[C 48 H 28 O 36 Fe8, Fe-MIL-125-NH2[C 48 H 34 N6O 36 It includes one or more selected from the group consisting of Fe8. [Effects of the Invention]

[0047] The composition of the present invention has been confirmed to effectively induce polarization of M2 macrophages. Therefore, it can be used to suppress the polarization of M1 macrophages or to induce the polarization of M2 macrophages in disease treatment methods related to this mechanism. [Brief explanation of the drawing]

[0048] [Figure 1] This is a diagram showing the results of scanning electron microscopy observations of Al-MIL-101-NH2. [Figure 2] This is a diagram showing the results of X-ray diffraction analysis of Al-MIL-101-NH2. [Figure 3] This diagram shows the adsorption / desorption isotherm and specific surface area / pore size measurement results for Al-MIL-101-NH2. [Figure 4] This is a diagram showing the results of scanning electron microscopy observations of Mg-MOF-74. [Figure 5]This is a diagram showing the results of X-ray diffraction analysis of Mg-MOF-74. [Figure 6] This diagram shows the adsorption / desorption isotherm and specific surface area / pore size measurement results for Mg-MOF-74. [Figure 7] This is a diagram showing the results of scanning electron microscopy observations of ZIF-8. [Figure 8] This is a diagram showing the results of the X-ray diffraction analysis of ZIF-8. [Figure 9] This diagram shows the adsorption / desorption isotherm and specific surface area / pore size measurement results for ZIF-8. [Figure 10] This is a diagram showing the results of scanning electron microscopy observations of Fe-MIL-101-NH2. [Figure 11] This is a diagram showing the results of X-ray diffraction analysis of Fe-MIL-101-NH2. [Figure 12] This diagram shows the adsorption / desorption isotherm and specific surface area / pore size measurement results for Fe-MIL-101-NH2. [Figure 13] This is a diagram showing the observation results of the UIO-66 using a scanning electron microscope. [Figure 14] This is a diagram showing the results of the X-ray diffraction analysis of UIO-66. [Figure 15] This diagram shows the adsorption / desorption isotherm and specific surface area / pore size measurement results for UIO-66. [Figure 16] This diagram shows the results of the cytotoxicity evaluation of Al-MIL-101-NH2. [Figure 17] This diagram shows the results of the cytotoxicity evaluation of Mg-MOF-74. [Figure 18] This diagram shows the results of the cytotoxicity evaluation of ZIF-8. [Figure 19] This diagram shows the results of the cytotoxicity evaluation of Fe-MIL-101-NH2. [Figure 20] This diagram shows the results of the cytotoxicity evaluation of UIO-66. [Figure 21] This diagram shows the results of the evaluation of the polarization-inducing ability of metal ions and metal-organic structures in M2 macrophages. [Figure 22]This diagram shows a schematic representation of the process of incorporating a macrophageic cell polarization inducer (artemisinin) into a metal-organic structure. [Figure 23] This is a diagram showing the results of scanning electron microscopy observations of ART@Al-MIL-101-NH2. [Figure 24] This is a diagram showing the X-ray diffraction analysis results of ART@Al-MIL-101-NH2. [Figure 25] This diagram shows the adsorption / desorption isotherms and specific surface area / pore size measurement results for ART@Al-MIL-101-NH2. [Figure 26] This is a diagram showing the FT-IR measurement results for ART@Al-MIL-101-NH2. [Figure 27] This diagram shows the results of the evaluation of the polarization-inducing ability of ART@Al-MIL-101-NH2 in M2 macrophages. [Modes for carrying out the invention]

[0049] The invention will be further explained below through the examples provided. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.

[0050] (Example 1: Synthesis of metal-organic structures) Various types of metal-organic frameworks (MOFs) were fabricated / synthesized using the following methods.

[0051] 1-1:Al-MIL-101-NH 2 synthesis To synthesize an aluminum (Al)-based metal-organic structure, Al-MIL-101-NH2 was synthesized as a representative example.

[0052] First, 724 mg of aluminum chloride (AlCl3) and 272 mg of 2-aminoterephthalic acid were added to 60 ml of N,N-dimethylformamide and stirred. Once all the reagents were dissolved, the container was sealed and the mixture was reacted at 110°C for 16 hours. Next, the synthesized particles were washed three times each with dimethylformamide and ethanol, and then dried in an oven at 80°C to obtain Al-MIL-101-NH2 powder.

[0053] 1-2: Synthesis of Mg-MOF-74 To synthesize magnesium (Mg)-based metal-organic structures, we synthesized Mg-MOF-74 as a representative example.

[0054] First, 155 mg of 2,5-dihydroxyterephthalic acid and 665 mg of magnesium nitrate hexahydrate (MgNO3) were dissolved in 62 ml of dimethylformaldehyde. Next, 4 ml each of ethanol and distilled water were added to the solution, the container was sealed, and the mixture was reacted at 125°C for 24 hours. Then, the synthesized particles were washed three times each with dimethylformaldehyde and ethanol, and after washing, methanol was added 50 ml once a day for three times to replace the mixture. The mixture was then dried in an oven at 80°C to obtain Mg-MOF-74 powder.

[0055] 1-3: Synthesis of ZIF-8 To synthesize zinc (Zn)-based metal-organic structures, we synthesized ZIF-8 as a representative example.

[0056] First, 1.2 g of zinc acetate (Zn(CH3CO2)2) was dissolved in 20 ml of distilled water, and 4.48 g of 2-methylimidazole was also dissolved in a separate 20 ml of distilled water. While gradually stirring the 2-methylimidazole solution, the zinc acetate solution was added little by little to mix the two solutions, and the mixture was stirred at room temperature for 24 hours. Next, the synthesized particles were washed three times each using distilled water and ethanol, and then dried in an oven at 80°C to obtain ZIF-8 powder.

[0057] 1-4:Fe-MIL-101-NH 2 synthesis To synthesize iron (Fe)-based metal-organic structures, Fe-MIL-101-NH2 was synthesized as a representative example.

[0058] First, 203 mg of iron chloride hexahydrate (FeCl3) and 102 mg of 2-aminoterephthalic acid were added to 30 ml of N,N-dimethylformaldehyde and stirred. 450 μl of acetic acid was added to the solution, the container was sealed, and the mixture was reacted at 120°C for 6 hours. Next, the synthesized particles were washed three times each with N,N-dimethylformaldehyde and ethanol, and then dried in an oven at 80°C to obtain Fe-MIL-101-NH2 powder.

[0059] 1-5: Synthesis of UIO-66 To synthesize zirconium (Zr)-based metal-organic structures, we synthesized UIO-66 as a representative example.

[0060] First, 93.22 mg of zirconium chloride (ZrCl4) and 132.9 mg of terephthalic acid were added to 50 ml of dimethylformamide (DMF) and stirred. 33.38 μl of hydrochloric acid (HCl) was added to the solution, the container was sealed, and the mixture was reacted at 130°C for 24 hours. Next, the synthesized particles were washed three times each with N,N-dimethylformaldehyde and ethanol, and then dried in an oven at 80°C to obtain UIO-66 powder.

[0061] (Example 2: Confirmation of the physicochemical properties of metal-organic structures) To confirm the physicochemical properties of the metal-organic structure fabricated / synthesized in Example 1, the following experiment was conducted.

[0062] First, to prepare for measurement with a scanning electron microscope (SEM), 2-3 mg of the powder sample was placed in an Eppendorf tube, 100 μl of ethanol was added, and bath sonification was performed. Subsequently, 10 μl was dropped onto a silicon wafer and dried in an 80°C oven. The dried silicon wafer was then attached to the SEM mount using carbon tape, and the wafer was moved to the SEM equipment for image measurement (Company name: Zeiss / Model: ULTRA PLUS).

[0063] Next, for X-ray diffraction (XRD) measurement, the powder sample was carefully placed in the XRD sample holder, and the sample was compressed with appropriate force using a glass slide. After carefully removing all the powder scattered around the sample holder, the sample holder was transferred to the equipment and set up, and measurements were taken in the 2-30°C range (Company name: Bruker / Model: D2 phaser).

[0064] Next, approximately 40 mg of a completely dried sample was prepared for N2 adsorption isotherm and BET specific surface area-pore measurement. This sample was carefully placed into a glass sampler using a glass funnel, and all powder adhering to the glass tube outside the lower sample container was removed. Subsequently, the upper filter cap was attached, and degassing was carried out using the pretreatment equipment under vacuum and heat treatment at 120°C for 12 hours. The weight of the pretreated sample was measured using a microbalance, and the weight of the complete sample was calculated by subtracting the weight of the previously measured empty cell. The glass sampler was attached to the N2 adsorption-desorption equipment, and the measurement was carried out (Company name: MICROTAAC / Model: BELSORP MINI X).

[0065] Based on the measurement results, it was confirmed that the metal-organic skeletons prepared / synthesized in Example 1 were properly synthesized (Al-MIL-101-NH2: Figures 1 to 3, Mg-MOF-74: Figures 4 to 6, ZIF-8: Figures 7 to 9, Fe-MIL-101-NH2: Figures 10 to 12, UIO-66: Figures 13 to 15).

[0066] (Example 3: Evaluation of cytotoxicity of metal-organic structures) To evaluate the cytotoxicity of metal-organic structures, the following experiments were conducted.

[0067] Specifically, in order to evaluate the cytotoxicity of the metal-organic structure prepared / synthesized in Example 1, first, mouse fibroblasts (L929) were placed in a 96-well plate in a 1 × 10⁶ solution. 5Cells were placed in each well and incubated at 37°C in a 5% CO2 incubator for 24 hours. After 24 hours, the existing medium was removed from each well, and the metal-organic structure particles to be tested were suspended in medium at concentrations of 100, 50, 25, 10, or 1 μg / ml to prepare the test solution. 100 μl of this solution was added to each well and incubated at 37°C in a 5% CO2 incubator for 24 hours, after which the medium was removed. The plates and cell surfaces were then washed three times with PBS to remove any particles adhering to them. Next, 10% EZ-cytox medium was added to each well and incubated at 37°C for 1 hour. Absorbance at 450 nm and 600 nm was measured, and cell viability was compared with the control group.

[0068] The experimental results for cytotoxicity showed that Al-MIL-101-NH2 showed no cytotoxicity at all concentrations (Figure 16), Mg-MOF-74 showed no cytotoxicity at all concentrations (Figure 17), ZIF-8 showed less than 50% cell viability at concentrations of 100 μg / ml or higher (Figure 18), Fe-MIL-101-NH2 showed no cytotoxicity at all concentrations (Figure 19), and UIO-66 showed no cytotoxicity at all concentrations (Figure 20).

[0069] (Example 4: Evaluation of the macrophageocyte polarization-inducing ability of metal-organic structures) To evaluate the ability of metal-organic structures to induce polarization in macrophages, the following experiments were conducted.

[0070] Specifically, as an example of a metal-organic structure, in order to evaluate the macrophageocyte polarization-inducing ability of the metal-organic structure manufactured / synthesized in Example 1, the femur and pelvic bone of a mouse were first separated, the epiphyses were cut, PBS was flowed into the bone marrow cavity, and bone marrow cells were collected to obtain macrophages derived from undifferentiated bone marrow. ACK buffer was used to remove erythrocytes from the collected bone marrow cells. Next, 10 ml of DMEM medium and 1 ml of L929 culture supernatant were placed in a cell culture dish, and the obtained bone marrow cells were cultured for 6 days, with 10 ml of DMEM medium added on the 3rd day of culture. 1 × 10⁶ macrophages differentiated through the culture were obtained. 5Cells were separated into 96-well plates at a concentration of cells / well and cultured for 24 hours. Test samples (10 μg / ml each) were added to the cultured cells and incubated for 24 hours. Subsequently, unpolarized macrophages (M0) and M2 polarized macrophages were quantitatively analyzed using flow cytometry and fluorescent antibodies. As a control group for the metal-organic structures, the underlying metal ions of each metal-organic structure were used.

[0071] In the evaluation of the macrophageous cell polarization-inducing ability, no M0→M2 polarization of macrophages was observed in the case of the metal samples (AlCl3, FeCl3, MgNO3, Zn(CH3CO2)2, ZrCl4) used as control groups for each metal-organic structure.

[0072] Next, as representative examples of metal-organic structures based on aluminum, iron, and zirconium, M2-polarized macrophages were meaningfully observed in Al-MIL-101-NH2, Fe-MIL-101-NH2, and UIO-66. However, in the case of zinc and magnesium-based metal-organic structures ZIF-8 and Mg-MOF-74, M2-polarized macrophages did not significantly increase (Figure 21).

[0073] Based on the above results, it was found that even if the metal ions themselves do not have the ability to induce macrophagocyte polarization, the metal-organic structures synthesized based on the metal ions do have the ability to induce macrophagocyte polarization, and in particular, in the case of aluminum, iron, and zirconium-based metal-organic structures, it was found that they effectively induce polarization of M2 macrophages.

[0074] (Example 5: Evaluation of the properties and macrophageous polarization-inducing ability of metal-organic structures equipped with macrophageous cell polarization inducers) To evaluate the properties of metal-organic structures loaded with macrophagocyte polarization inducers and to assess their macrophagocyte polarization-inducing ability, the following experiments were conducted.

[0075] Specifically, as a representative example of a metal-organic structure, we synthesized a metal-organic structure (ART@Al-MIL-101-NH2) in which artemisinin (ART), known to induce macrophagocyte polarization, was mounted on Al-MIL-101-NH2, whose macrophagocyte polarization-inducing ability was confirmed in Example 4 (Figure 22).

[0076] Next, using the method described in Example 2, we confirmed the SEM image, X-ray diffraction analysis results, adsorption / desorption isotherm and specific surface area / pore size measurement results, and FT-IR analysis results of the metal-organic structure containing artemisinin (Figures 23 to 26).

[0077] Next, using the method described in Example 4, we confirmed the macrophageous polarization-inducing ability of the metal-organic structure carrying artemisinin. The results showed that the rapid-acting organic skeleton (ART@Al-MIL-101-NH2) carrying artemisinin, a macrophageous polarization-inducing agent, exhibited superior polarization efficiency compared to treatment with Al-MIL-101-NH2 (Figure 27).

[0078] Based on the above results, it can be seen that when a macrophageous cell polarization inducer is incorporated into a metal-organic structure, the macrophageous cell polarization efficiency is significantly improved.

[0079] The above description of the present invention is illustrative, and a person with ordinary skill in the art will understand that it can be easily modified into other specific forms without altering the technical idea or essential features of the invention. Therefore, the above-described embodiments should be understood to be illustrative and not limiting in all respects.

Claims

1. A composition for inducing macrophage polarization, comprising a metal-organic framework (MOF).

2. The composition according to claim 1, wherein the metal-organic structure comprises one or more metals or metal ions selected from the group consisting of aluminum (Al), iron (Fe), and zirconium (Zr).

3. The metal-organic framework is one or more selected from the group consisting of UIO-66, UIO-66-NH ２ , UIO-67, UIO-67-NH ２ , PCN-128, MOF-801, MOF-808, MOF-867, Al-MIL-53, Al-MIL-53-NH ２ , Al-MIL-88, Al-MIL-88-NH ２ , Al-MIL-100, Al-MIL-100-NH ２ , Al-MIL-101, Al-MIL-101-NH ２ , Al-MIL-125, Al-MIL-125-NH ２ , Fe-MIL-53, Fe-MIL-53-NH ２ , Fe-MIL-88, Fe-MIL-88-NH ２ , Fe-MIL-100, Fe-MIL-100-NH ２ , Fe-MIL-101, Fe-MIL-101-NH ２ , Fe-MIL-125, Fe-MIL-125-NH ２ The composition according to claim 1, comprising one or more selected from the group consisting of

4. The composition according to claim 1, wherein the composition induces polarization in M2 macrophages.

5. The aforementioned M2 macrophages are CD11b ＋ CD45 ＋ and Arginase 1 ＋ The composition according to claim 4, having one or more phenotypes selected from the group consisting of the following.

6. The composition according to claim 1, wherein the metal-organic structure further comprises a macrophageoplasmic cell polarization inducer.

7. The composition according to claim 6, wherein the macrophagey cell polarization inducer comprises one or more selected from the group consisting of artemisinin, IL-4, IL-6, IL-10, IL-13, TGF-beta (Transforming growth factor-beta), and adenosine.

8. A method for inducing polarization of macrophages, comprising the step of treating isolated cells with a composition according to any one of claims 1 to 7.

9. The method according to claim 8, wherein the isolated cells include one or more selected from the group consisting of undifferentiated macrophages, monocytes, M0 macrophages, and M1 macrophages.

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