Porphyrin-based metal-organic framework-containing composition for inducing macrophage polarization and use thereof

Abstract

The present invention relates to: a porphyrin-based metal-organic framework (MOF)-containing composition for inducing macrophage polarization; and a use thereof. The composition according to the present invention was found to effectively induce polarization into M2 macrophages and can thus be applied to methods for treating diseases related to mechanisms for inhibiting M1 macrophage polarization or inducing M2 macrophage polarization.

Description

Composition for inducing macrophage polarization comprising porphyrin-based metal-organic framework and use thereof

[0001] The present invention relates to a composition for inducing macrophage polarization, comprising a porphyrin-based metal-organic framework (MOF), and its use.

[0002] The innate immune response is the body's first line of defense against invading pathogens, also known as nonspecific immunity. Neutrophils, monocytes, and macrophages are involved in the innate immune response, and it responds rapidly to pathogen invasion or infection, regardless of the type of pathogen or prior infection experience.

[0003] In particular, macrophages are cells distributed throughout all tissues in the body and are responsible for immunity, and are involved in the removal of invading pathogens, the removal of virus-infected autologous cells and cancer cells, and the induction of inflammatory responses. Macrophages can be divided into tissue-resident macrophages that differentiate from yolk sacs or fetal livers during development, and monocyte-derived macrophages that differentiate from monocytes in the blood (differentiated from bone marrow cells) in response to inflammatory responses or pathogen invasion.

[0004] Tissue-derived macrophages and monocyte-derived macrophages can differentiate into M1 macrophages and M2 macrophages, which act on different immune responses by cytokines. Cytokines are proteins involved in the transmission of information between cells, and are secreted by a chain of immune responses from cells that recognize pathogens or infections, and promote the differentiation and proliferation of cells that are responsible for the immune response, such as helper T cells (Th cells), B cells, and macrophages. M1 macrophages are induced by Th1 cell cytokines such as IFN-γ and TNF-α, and act to induce Th1 responses, induce inflammation, and suppress cancer growth. M2 macrophages are induced by Th2 cell cytokines such as IL-4 and IL-10, and act to induce Th2 responses, suppress inflammation, and repair damaged tissue. In this way, bone marrow-derived macrophages and monocyte-derived macrophages can differentiate into M1 or M2 macrophages, which have different functions depending on the type of cytokine.

[0005] These macrophages require time to differentiate, proliferate, and become activated by cytokines. Recently, active research has been conducted on methods to shorten the time required for macrophage differentiation, proliferation, and activation without inducing hypersensitive reactions or anaphylaxis in the human body.

[0006] Against this backdrop, the present invention was completed by developing a technique for inducing polarization toward M2 macrophages using a porphyrin-based metal-organic framework.

[0007] One aspect provides a composition for inducing macrophage polarization, comprising a porphyrin-based metal-organic framework (MOF).

[0008] Another aspect provides a method of inducing polarization of cells in a subject, comprising administering to the subject a composition for inducing macrophage polarization.

[0009] Another aspect provides a method for inducing polarization of macrophages, comprising the step of treating isolated cells with the composition for inducing macrophage polarization.

[0010] One aspect is to provide a composition for inducing macrophage polarization, comprising a porphyrin-based metal-organic framework (MOF).

[0011] The term "metal-organic framework (MOF)" as used herein refers to a porous material in which metal clusters and organic linkers, or organic bridging ligands, are linked by coordination bonds to form a three-dimensional structure, and various MOFs can be created depending on the selection of metal ions and organic ligands. The MOF is characterized by porosity in which empty spaces exist within the structure, and the pore size, porosity, three-dimensional structure, surface area, etc. can be designed in various ways depending on the type and bonding method of the metal ions and organic ligands that make up the MOF. Due to this porosity, MOFs not only have a very large surface area but also have an open pore structure, so they can transport a large amount of molecules or solvents compared to other porous materials known in the art, and when used as a catalyst or gas storage medium, they have the advantage of having many active sites, which can maximize efficiency. In addition, the MOF does not easily deform at high temperatures and has a rigid skeleton, so it has excellent chemical and thermal stability.

[0012] The above metal-organic framework may include a porphyrin-based compound as an organic ligand, and specifically, the porphyrin-based compound may include a compound represented by the following chemical formula 1.

[0013] [Chemical Formula 1]

[0014]

[0015] (Here, R 1 Inland R 4 Silver, respectively, hydrogen, hydroxyl group (-OH), halogen, C1~C 20 Alkyl group of C2~C 20　 Alkenyl group, C2~C 20 Alkynyl group and C1~C 20 Selected from alkoxy, R 5 Inland R 6 Silver, respectively, hydrogen, halogen, C1~C 20 Alkyl group of C2~C 20　 Alkenyl group and C2~C 20 Selected from an alkynyl group, and the above C1~C 20 Alkoxy groups are represented by -O-R', where R' is C1~C 20 Alkyl group of C2~C 20　 Alkenyl group and C2~C 20 (selected from alkynyl groups)

[0016] In one embodiment, R in the chemical formula 1 1 Inland R 4 Silver, respectively, hydrogen, hydroxyl group (-OH), halogen, C1~C 20 Alkyl group of C2~C 20　 Alkenyl group, C2~C 20 Alkynyl group and C1~C 20 Selected from alkoxy, specifically R 1 Inland R 4 Silver, respectively, hydrogen, hydroxyl group (-OH), halogen, C1~C 10 Alkyl group of C2~C 10　 Alkenyl group, C2~C 10 Alkynyl group and C1~C 10It is selected from alkoxy groups, more specifically R 1 Inland R 4 Silver, each can be selected from hydrogen, halogen and C1~C5 alkyl group. The C1~C 20 An alkoxy group is an alkyloxy group represented by -O-R', where R' is C1~C 20 Alkyl group of C2~C 20　 Alkenyl group and C2~C 20 It can be selected from an alkynyl group.

[0017] In one embodiment, R in the chemical formula 1 5 Inland R 6 Silver, respectively, hydrogen, halogen, C2~C 20 Alkyl group of C2~C 20　 Alkenyl group and C2~C 20 Selected from an alkynyl group, specifically, R 5 Inland R 6 are respectively hydrogen, halogen, C1~C 10 Alkyl group of C2~C 10　 Alkenyl group and C2~C 10 Selected from an alkynyl group, more specifically, R 5 Inland R 6 Each can be selected from hydrogen and halogen.

[0018] In one embodiment, at least one of the four carboxyl groups (-COOH) present at the terminal of the compound in the above chemical formula 1 is in an ionized form (-COO - ) may exist.

[0019] In one embodiment, the porphyrin compound may include tetrakis(4-carboxyphenyl)porphyrin [Tetrakis(4-carboxyphenyl)porphyrin (TCPP)] or an ionized form thereof.

[0020] The above metal-organic framework is made of aluminum (Al, Al 2+ , Al 3+ ), iron (Fe, Fe 2+ , Fe3+ ), zinc (Zn, Zn 2+ , Zn 3+ ), magnesium (Mg, Mg 2+ , Mg 3+ ) and zirconium (Zr, Zr 2+ , Zr 3+ , Zr 4+ ) may be selected from the group consisting of one or more metals or metal ions thereof, and may be synthesized using the selected metal or metal ion, and specifically may be comprised of the metal or metal ion and an organic ligand coordinated thereto. Specifically, the metal part of the metal-organic framework is aluminum (Al, Al 3+ ), iron (Fe, Fe 3+ ), zinc (Zn, Zn 2+ , Zn 3+ ), magnesium (Mg, Mg 2+ , Mg 3+ ) and zirconium (Zr, Zr 4+ ) may be composed of one or more metals or metal ions thereof selected from the group consisting of:

[0021] In one embodiment, the metal-organic framework comprises zirconium (Zr, Zr 2+ , Zr 3+ , Zr 4+ ) may contain a metal or its metal ion. The metal-organic framework is MOF-525 [Zr6(OH)4O4(C 48 H 28 N4O8)3], MOF-545 (PCN-222) [Zr6O8(C 48 H 28 N4O8)2(H2O)8], PCN-221 [Zr8O6(C 48 H 26 N4O8)3], PCN-223 [Zr6O4(OH)4(C 48 H 26 N4O8)3 and PCN-224 [Zr6O4(OH)4(C48 H 26 N4O8) 1.5 ] may include one or more selected from the group consisting of.

[0022] In one embodiment, it was confirmed that porphyrin-based MOFs, MOF-525 or MOF-545, can effectively induce macrophage polarization (polarization toward M2 macrophages).

[0023] The term "macrophage" in this specification refers to a representative immune cell that originates from bone marrow cells and plays a major role in innate immunity. Initially, it leaves the bone marrow through the bloodstream in the form of an immature monocyte. Monocytes recognize by-products or pathogens derived from infected cells, and their activity increases, differentiating into mature macrophages. Macrophages have an important function in maintaining tissue homeostasis by removing pathogens that have invaded from the outside, inducing adaptive immunity, and playing a very important role in the initial stage of inflammatory responses in the human body. Depending on the method of differentiation, they specifically mature into two forms: M1 macrophages (classically activated macrophages) and M2 macrophages (alternatively activated macrophages). Among these, M2 macrophages are known to reduce inflammation and promote tissue repair.

[0024] The composition for inducing macrophage polarization refers to a composition for inducing polarization into macrophages, and specifically, may be a composition capable of controlling or inducing polarization, polarization, differentiation and / or activation into M2 macrophages (M2 type).

[0025] The composition may be capable of inducing polarization of a cell known to be capable of polarizing or is polarized into an M2 macrophage, specifically, regulating or inducing polarization, polarization, differentiation and / or activation of one or more selected from the group consisting of undifferentiated macrophages, monocytes, MO macrophages and M1 macrophages into an M2 macrophage.

[0026] The above M2 macrophages may have one or more phenotypes selected from the group consisting of CD11b+, CD45+, and Arginase 1+, and specifically, the above M2 macrophages may have a CD11b+, CD45+, and Arginase 1+ phenotype.

[0027] In the above composition, the metal-organic framework may additionally include a macrophage polarization inducer, and specifically, the metal-organic framework may be loaded with a macrophage polarization inducer.

[0028] The above macrophage polarization inducer may be an active substance that induces polarization into M2 macrophages, and specifically, may be an active substance that induces polarization, polarization, differentiation and / or activation of undifferentiated macrophages, MO macrophages and / or M1 macrophages into M2 macrophages.

[0029] The above macrophage polarization inducer may include at least one selected from the group consisting of artemisinin, IL (Interleukin)-4, IL-6, IL-10, IL-13, TGF-beta, and adenosine.

[0030] In one embodiment, the metal-organic framework may be 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, 0.001 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, 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 It may be 80 μg / ml, 0.5 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, 1 to 10 μg / ml, but is not limited thereto.

[0031] In one embodiment, the metal-organic framework may be included in an amount of 0.001 to 100 wt% based on the total weight of the composition, specifically 0.001 to 100 wt%, 0.001 to 80 wt%, 0.001 to 50 wt%, 0.001 to 30 wt%, 0.001 to 20 wt%, 0.001 to 10 wt%, 0.01 to 100 wt%, 0.01 to 80 wt%, 0.01 to 50 wt%, 0.01 to 30 wt%, 0.01 to 20 wt%, 0.01 to 10 wt%, 0.1 to 100 wt%, 0.1 to 80 wt%, 0.1 to 50 wt%, 0.1 to 30 wt%, 0.1 to 20 The weight %, 0.1 to 10 wt %, 0.5 to 100 wt %, 0.5 to 80 wt %, 0.5 to 50 wt %, 0.5 to 30 wt %, 0.5 to 20 wt %, 0.5 to 10 wt %, 1 to 100 wt %, 1 to 80 wt %, 1 to 50 wt %, 1 to 30 wt %, 1 to 20 wt %, 1 to 10 wt % may be, but is not limited thereto.

[0032] The above composition may be a pharmaceutical composition.

[0033] The pharmaceutical composition may include a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" may refer to a carrier or diluent that does not stimulate a living organism and does not inhibit the biological activity or properties of the injected compound. Here, "pharmaceutically acceptable" means that the carrier does not inhibit the activity of the active ingredient and does not exhibit toxicity exceeding the adaptability of the subject of application (prescription). Any carrier commonly used in the art and pharmaceutically acceptable for the pharmaceutical composition may be used. Non-limiting examples of the above carriers include lactose, dextrose, maltodextrin, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, glycerol, ethanol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, saline solution, sterile water, Ringer's solution, buffered saline, albumin injection solution, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil. These may be used alone or in combination of two or more. The pharmaceutical composition may be prepared as an oral formulation or a parenteral formulation according to the route of administration by a conventional method known in the art, including a pharmaceutically acceptable carrier in addition to the active ingredient. The above pharmaceutical composition can be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, or sterile injection solutions, each according to a conventional method.

[0034] When formulating the above pharmaceutical composition, it may be prepared using a diluent or excipient such as a generally used filler, bulking agent, binder, wetting agent, disintegrant, or surfactant, but may not be limited thereto.

[0035] When the above pharmaceutical composition is manufactured into an oral dosage form, it can be manufactured into a dosage form such as powder, granules, tablets, pills, dragees, capsules, liquids, gels, syrups, suspensions, wafers, etc., using a suitable carrier according to a method known in the art. At this time, examples of suitable pharmaceutically acceptable carriers include sugars such as lactose, glucose, sucrose, dextrose, sorbitol, mannitol, xylitol, etc.; starches such as corn starch, potato starch, and wheat starch; celluloses such as cellulose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, and hydroxypropylmethylcellulose; polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, magnesium stearate, mineral oil, malt, gelatin, talc, polyols, and vegetable oils. In case of formulation, the formulation may include diluents and / or excipients such as fillers, bulking agents, binders, wetting agents, disintegrants, and surfactants, as needed.

[0036] When the above pharmaceutical composition is prepared as a parenteral dosage form, it can be formulated in the form of injections, transdermal administration, nasal inhalation, and suppositories using a suitable carrier according to a method known in the art. When formulated as an injection, suitable carriers include sterile water, ethanol, polyols such as glycerol or propylene glycol, or mixtures thereof, and preferably, Ringer's solution, phosphate buffered saline (PBS) containing triethanolamine, sterile water for injection, and isotonic solutions such as 5% dextrose can be used. When formulated as a transdermal dosage form, it can be formulated in the form of ointments, creams, lotions, gels, external solutions, pastes, liniments, aerosols, etc. In the case of nasal inhalation, it can be formulated in the form of an aerosol spray using a suitable propellant such as dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, or carbon dioxide, and in the case of formulating it as a suppository, the base can be witepsol, tween 61, polyethylene glycol, cacao butter, laurin butter, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene stearate, sorbitan fatty acid ester, etc.

[0037] The pharmaceutical composition may be administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" refers to an amount sufficient to treat or prevent a disease at a reasonable benefit / risk ratio applicable to medical treatment or prevention, and the effective dosage level may be determined based on 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 of the composition of the present invention used, the route of administration and the excretion rate, the treatment period, the drug used in combination or simultaneously with the composition of the present invention used, and other factors well known in the medical field. The pharmaceutical composition of the present invention may be administered alone or in combination with a component known to exhibit a therapeutic effect on known inflammation, allergic diseases, atopic dermatitis, or asthma. Taking all of the above factors into consideration, it is important to administer an amount that can achieve the maximum effect with the minimum amount without side effects.

[0038] The dosage of the pharmaceutical composition may be determined by a person skilled in the art in consideration of 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 may be administered at about 0.1 ng to about 1,000 mg / kg, preferably 1 ng to about 100 mg / kg, per adult, and the frequency of administration of the composition of the present disclosure is not particularly limited thereto, but may be administered once a day or administered in divided doses several times. The dosage or frequency of administration does not limit the scope of the present disclosure in any way.

[0039]

[0040] Another aspect provides a method for inducing polarization of cells in a subject, comprising administering to the subject a composition for inducing macrophage polarization. The same portions described above also apply to the method.

[0041] The term "subject" as used herein may include, without limitation, mammals, birds, reptiles, farmed fish, etc., including dogs, cats, rats, livestock, humans, etc., and the subject may exclude humans.

[0042] The above cells may be cells capable of polarization, differentiation and / or activation into M2 macrophages, and specifically may include one or more selected from the group consisting of undifferentiated macrophages, monocytes, MO macrophages and M1 macrophages.

[0043] The above method may be for inducing polarization, differentiation and / or activation into M2 macrophages, and specifically may be for regulating or inducing polarization, polarization, differentiation and / or activation of undifferentiated macrophages, monocytes, MO macrophages and / or M1 macrophages into M2 macrophages.

[0044] The composition may be administered in single or multiple doses in a pharmaceutically effective amount. The composition may be formulated and administered in the form of a liquid, powder, aerosol, injection, infusion (Ringel), capsule, pill, tablet, suppository, or patch. The pharmaceutical composition may be administered via any conventional route, as long as it can reach the target tissue.

[0045] The above composition is not particularly limited thereto, but may be administered via routes such as intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, transdermal patch administration, oral administration, intranasal administration, intrapulmonary administration, and rectal administration depending on the purpose. However, when administered orally, it may be administered in an unformulated form, and since the active ingredient of the composition may be denatured or decomposed by gastric acid, the oral composition may be administered orally in a form that coats the active agent or is formulated to protect it from decomposition in the stomach, or in the form of an oral patch. In addition, the composition may be administered by any device that allows the active ingredient to move to the target cell.

[0046]

[0047] Another aspect provides a method for inducing polarization of macrophages, comprising the step of treating isolated cells with the composition for inducing macrophage polarization. The same portions described above also apply to the method.

[0048] The above separated cells may be cells capable of polarization, differentiation and / or activation into M2 macrophages, and specifically may include one or more selected from the group consisting of undifferentiated macrophages, monocytes, MO macrophages and M1 macrophages.

[0049] It may include one or more selected from the group consisting of MO macrophages and M1 macrophages.

[0050] The above method may be for inducing polarization, differentiation and / or activation into M2 macrophages, and specifically may be for regulating or inducing polarization, polarization, differentiation and / or activation of undifferentiated macrophages, monocytes, MO macrophages and / or M1 macrophages into M2 macrophages.

[0051]

[0052] Another aspect provides a use of a porphyrin-based metal-organic framework (MOF) or a composition comprising the same for inducing macrophage polarization. The same aspects described above also apply to the above use.

[0053] The above metal-organic framework is MOF-525 [Zr6(OH)4O4(C 48 H 28 N4O8)3], MOF-545(PCN-222) [Zr6O8(C 48 H 28 N4O8)2(H2O)8], PCN-221 [Zr8O6(C 48 H 26 N4O8)3], PCN-223 [Zr6O4(OH)4(C 48 H 26 N4O8)3 and PCN-224 [Zr6O4(OH)4(C 48 H 26 N4O8) 1.5 ] may include one or more selected from the group consisting of.

[0054] It has been confirmed that the composition of the present invention can effectively induce polarization toward M2 macrophages, and thus the composition can be applied to a method for treating diseases related to a mechanism for inhibiting polarization of M1 macrophages or inducing polarization of M2 macrophages.

[0055] Figure 1 is a drawing showing a frontal structural image of a MOF-525 particle.

[0056] Figure 2 is a drawing showing a side structural image of a MOF-525 particle.

[0057] Figure 3 is a drawing showing the results of scanning electron microscope observation of MOF-525.

[0058] Figure 4 is a drawing showing the results of X-ray diffraction analysis of MOF-525.

[0059] Figure 5 is a diagram showing the adsorption / desorption isotherm and specific surface area / pore measurement results of MOF-525.

[0060] Figure 6 is a diagram showing the results of zeta potential measurement of MOF-525.

[0061] Figure 7 is a drawing showing the FT-IR measurement results of MOF-525.

[0062] Figure 8 is a drawing showing a frontal structural image of a MOF-545 particle.

[0063] Figure 9 is a drawing showing a side structural image of a MOF-545 particle.

[0064] Figure 10 is a drawing showing the results of scanning electron microscope observation of MOF-545.

[0065] Figure 11 is a drawing showing the results of X-ray diffraction analysis of MOF-545.

[0066] Figure 12 is a diagram showing the adsorption / desorption isotherm and specific surface area / pore measurement results of MOF-545.

[0067] Figure 13 is a diagram showing the results of zeta potential measurement of MOF-545.

[0068] Figure 14 is a diagram showing the FT-IR measurement results of MOF-545.

[0069] Figure 15 is a drawing showing the results of the cytotoxicity evaluation of MOF-525.

[0070] Figure 16 is a drawing showing the results of the cytotoxicity evaluation of MOF-545.

[0071] Figure 17 is a diagram showing the results of evaluating the M2 macrophage polarization induction ability of MOF-525 and MOF-545.

[0072] The present invention will be described in more detail through the following examples. However, these examples are provided for illustrative purposes only and the scope of the present invention is not limited to these examples.

[0073]

[0074] Example 1: Synthesis of porphyrin-based metal-organic frameworks

[0075] MOF-525 and MOF-545, porphyrin-based metal-organic frameworks (MOFs), were prepared / synthesized using the following method.

[0076]

[0077] 1-1: Synthesis of MOF-525

[0078] MOF-525, a porphyrin-based metal-organic framework, was synthesized as follows.

[0079] First, 130 mg of tetrakis(4-carboxyphenyl)porphyrin (TCPP) and 1.75 g of benzoic acid were added to 110 ml of N,N-dimethylformamide (DMF) and stirred to prepare a TCPP mixed solution. Next, 120 mg of zirconyl chloride (ZrOCl2) was added to the TCPP mixed solution and stirred. Afterwards, the mixture was reacted in an oven at 100 °C for 24 hours. After the reaction, the reactant was obtained and centrifuged at 15,000 rpm for 10 minutes and the supernatant was removed. Next, 30 ml of DMF was added to the lower layer fraction and resuspended to wash the obtained product. Afterwards, the same washing process was repeated three times, 30 ml of ethanol was treated three times, and the upper layer of ethanol was discarded in the final centrifugation process. The lower layer of MOF-525 particles was then dried in an oven at 80°C for 8 hours to obtain the particles.

[0080]

[0081] 1-2: Synthesis of MOF-545

[0082] MOF-545, a porphyrin-based metal-organic framework, was synthesized as follows.

[0083] First, 32 mg of tetrakis(4-carboxyphenyl)porphyrin (TCPP) and 87 mg of zirconyl chloride (ZrOCl2) were dissolved in 60 ml of N,N-dimethylformamide (DMF) by stirring. Next, 5 ml of dichloroacetic acid was added and the mixture was reacted at 110°C for 18 hours. Next, the mixture was washed three times each with DMF and ethanol as described above, and then dried to obtain the product.

[0084]

[0085] Example 2: Identification of physicochemical properties of metal-organic frameworks

[0086] In order to confirm the physicochemical properties of the metal-organic framework manufactured / synthesized in Example 1, the following experiments were performed.

[0087] First, to measure with a scanning electron microscope (SEM), a 2-3 mg powder sample was placed in an Eppen tube, 100 μl of ethanol was added, and bath sonication was performed. After that, 10 μl was spotted on a silicon wafer and dried in an oven at 80°C. The dried silicon wafer was attached to an SEM mount using carbon tape, and then moved to the SEM equipment to measure images (Company name: Zeiss / Model name: ULTRA PLUS).

[0088] Next, for X-ray diffraction (XRD) measurement, the powder sample was carefully placed on the XRD sample holder, and the sample was compressed by pressing it with an appropriate force using a glass slide glass. After that, all powder scattered around the sample holder was carefully removed, and the sample holder was moved to the equipment, set up, and measurements were performed in the 2-30℃ range (Company name: Bruker / Model name: D2 phaser).

[0089] Next, for N2 adsorption isotherm and BET specific surface area-pore measurement, about 40 mg of completely dried sample was prepared and carefully placed in a glass sampler using a glass funnel, and all powder adhering around the glass tube except for the lower sample container was removed. After that, the upper filter cap was attached, and degas was performed by vacuum and heat treatment at 120 ℃ for 12 hours in a pretreatment device. The weight of the pretreated sample was measured using a microbalance, and the weight of the empty cell that was measured in advance was subtracted to calculate the weight of the intact sample. The glass sampler was attached to the N2 adsorption-desorption device and the measurement was performed (Company name: MICROTAAC / Model name: BELSORP MINI X).

[0090] As a result of the above measurement, it was confirmed that the metal-organic framework manufactured / synthesized in Example 1 was properly synthesized (MOF-525: FIGS. 3 to 7, MOF-545: FIGS. 10 to 14).

[0091]

[0092] Example 3: Cytotoxicity Evaluation of Porphyrin-Based Metal-Organic Frameworks

[0093] To evaluate the cytotoxicity of porphyrin-based metal-organic frameworks, the following experiments were performed.

[0094] Specifically, to evaluate the cytotoxicity of the metal-organic framework manufactured / synthesized in Example 1, mouse fibroblasts (L929) were first seeded in a 96-well plate at 1X10 per well.5 Cells were added and cultured for 24 hours in a 37℃, 5% CO2 incubator. After 24 hours, the existing medium in each well was removed, and the metal-organic framework particles to be tested were suspended in the medium at a concentration of 50, 25, 10, or 1 ug / ml to make a test solution, and 100 ul was added to each well. The solution was cultured for 24 hours in a 37℃, 5% CO2 incubator, and the medium was removed. Next, the plate was washed three times with PBS to remove particles attached to the cell surface. Next, 10% EZ-cytox medium was added to each well and reacted in a 37℃ incubator for 1 hour, and the absorbance at 450 nm and 600 nm was measured to compare the cell viability with the control group.

[0095] As a result of the above cytotoxicity test, it was confirmed that MOF-525 and MOF-545 did not exhibit cytotoxicity at any concentration (Figs. 15 and 16).

[0096]

[0097] Example 4: Evaluation of the ability of porphyrin-based metal-organic frameworks to induce macrophage polarization.

[0098] To evaluate the ability of porphyrin-based metal-organic frameworks to induce macrophage polarization, the following experiments were performed.

[0099] Specifically, in order to evaluate the macrophage polarization induction ability of MOF-525 and MOF-545, which are metal-organic frameworks manufactured / synthesized in Example 1, first, mouse femurs and pelvic bones were separated, the epiphyseal portion was cut, and PBS was poured into the medullary cavity to collect bone marrow cells, thereby obtaining undifferentiated bone marrow-derived macrophages. ACK buffer was used to remove red blood cells from the collected bone marrow cells. Next, 10 mL of DMEM medium and 1 mL of L929 culture supernatant were added to a cell culture dish, and the bone marrow cells obtained above were cultured for 6 days, and on the third day of culture, 10 mL of DMEM medium was added. Through the culture, the differentiated macrophages were cultured at 10 5 The cells were seeded into 96-well plates at a concentration of 10 cells / well and cultured for 24 hours. Test samples (50 or 100 ug / mL for each sample) were added to the cultured cells and incubated for 24 hours. Afterwards, unpolarized macrophages (M0) and M2 polarized macrophages were quantitatively analyzed using a flow cytometer and fluorescent antibodies. For the quantitative analysis of the M2 polarized macrophages, the number of cells with CD11b+, CD45+, and Arginase 1+ phenotypes was counted.

[0100] As a result of the evaluation of the ability to induce macrophage polarization, M2 polarized macrophages were significantly confirmed for MOF-525 and MOF-545 synthesized / manufactured in Example 1 (Fig. 17). Therefore, it can be seen that MOF-525 and MOF-545 can effectively induce polarization toward M2 macrophages, and based on this, it can be seen that porphyrin-based metal-organic frameworks can effectively induce polarization toward M2 macrophages.

[0101]

[0102] The foregoing description of the present invention is provided for illustrative purposes only. Those skilled in the art will readily appreciate that the present invention can be readily modified into other specific forms without altering the technical spirit or essential characteristics of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

Claims

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

2. A composition according to claim 1, wherein the porphyrin-based metal-organic framework comprises a porphyrin compound as a ligand.

3. In claim 2, the composition comprises a compound represented by the following chemical formula 1: [Chemical Formula 1] (Here, R 1 Inland R 4 Silver, respectively, hydrogen, hydroxyl group (-OH), halogen, C1~C 20 Alkyl group of C2~C 20　 Alkenyl group, C2~C 20 Alkynyl group and C1~C 20 Selected from alkoxy, R 5 Inland R 6 Silver, respectively, hydrogen, halogen, C1~C 20 Alkyl group of C2~C 20　 Alkenyl group and C2~C 20 Selected from an alkynyl group, and the above C1~C 20 Alkoxy groups are represented as -O-R', where R' is C1~C 20 Alkyl group of C2~C 20　 Alkenyl group and C2~C 20 (selected from alkynyl groups).

4. A composition according to claim 1, wherein the porphyrin-based metal-organic framework comprises one or more metals or metal ions selected from the group consisting of aluminum (Al), iron (Fe), zinc (Zn), magnesium (Mg), and zirconium (Zr).

5. A composition according to claim 1, wherein the porphyrin-based metal-organic framework comprises at least one selected from the group consisting of MOF-525, MOF-545 (PCN-222), PCN-221, PCN-223, and PCN-224.

6. A composition according to claim 1, wherein the composition induces polarization into M2 macrophages.

7. A composition according to claim 6, wherein the M2 macrophages have at least one phenotype selected from the group consisting of CD11b+, CD45+, and Arginase 1+.

8. A composition according to claim 1, wherein the porphyrin-based metal-organic framework further comprises a macrophage polarization inducer.

9. A composition according to claim 8, wherein the macrophage polarization inducer comprises at least one selected from the group consisting of artemisinin, IL-4, IL-6, IL-10, IL-13, TGF-beta (Transforming growth factor-beta), and adenosine.

10. 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 9.

11. A method according to claim 10, wherein the separated cells comprise at least one selected from the group consisting of undifferentiated macrophages, monocytes, MO macrophages, and M1 macrophages.

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