Preparation method of two-dimensional metal organic framework nanosheet and application of two-dimensional metal organic framework nanosheet in tumor photothermal-photodynamic combined therapy

Abstract

The invention discloses a preparation method of a two-dimensional metal organic framework nanosheet and application of the two-dimensional metal organic framework nanosheet in photothermal-photodynamic combined therapy of tumors. The two-dimensional metal organic framework nanosheet is a metal-organic framework material composed of X metal ions and Y organic ligands, has a strong absorption peak from red light to near-infrared regions, can penetrate deeper tissues, overcomes the limitation of insufficient penetration due to ultraviolet / visible light absorption of a traditional photosensitizer, and can be applied to the field of photosensitizers. Meanwhile, the two-dimensional nanosheet structure can increase the specific surface area and improve the surface activity, metal ions can promote generation of reactive oxygen free radicals through electron gain and loss, the high photoexcitation reactive oxygen free radical generation capacity is achieved, and the phototherapy effect on tumors is enhanced. Tumor targeted molecular modification is further performed on the surface of the material, and the tumor phototherapy effect can be remarkably improved after drug loading.

Description

Technical Field

[0001] The present invention belongs to the technical field of photosensitizers, and particularly relates to a preparation method of two-dimensional metal-organic framework nanosheets and their application in the combined photothermal-photodynamic therapy of tumors. Background Art

[0002] Phototherapy is a minimally invasive treatment technology. Its principle is to guide laser light to the lesion site through interventional techniques such as optical fibers and endoscopes, irradiate the lesion site, and convert light energy into heat energy. Through local high temperature at the lesion site, the cancer tissue undergoes coagulative necrosis to achieve the effect of tumor treatment. According to different treatment principles, phototherapy can be divided into photothermal therapy (PTT) and photodynamic therapy (PDT). Among them, photothermal therapy refers to a treatment method that uses a photosensitizer to absorb light of a specific wavelength and convert it into heat energy, and kills tumor cells by local heating. Photothermal therapy has advantages such as small trauma, low toxicity, good selectivity, and repeatable treatment, and is widely used in the treatment of solid tumors such as skin cancer, prostate cancer, liver cancer, and esophageal cancer that are not suitable for surgery on the surface or have clear local lesions. However, in the clinical application process of phototherapy, due to the limited penetrability of light and the limitation of accurate identification of tumor boundaries by imaging equipment, photothermal therapy currently has its limitations. For example, the treatment effect on deep tumors is not good, or the ablation of tumor tissues outside the irradiation range is not thorough and there are residues, thus increasing the risk of tumor recurrence. Therefore, it is necessary to sensitize photothermal therapy to improve light absorption and enhance the photothermal conversion efficiency.

[0003] A photosensitizer refers to a material that can improve the treatment effect of tumor phototherapy. According to different sensitization principles, it can be divided into photothermal sensitization and photodynamic sensitization. Photothermal sensitization is achieved by a photothermal sensitizer absorbing light energy of a specific wavelength, usually near-infrared light. Subsequently, it causes its electrons to transition from the ground state to the excited state, and converts the absorbed light energy into heat energy through a non-radiative relaxation process. This process usually does not involve changes in the chemical structure of the photosensitizer, but releases energy in the form of heat through vibration and rotation. Commonly used photothermal sensitizers include metal nanoparticles, ICG (indocyanine green), and metal-organic frameworks, etc., all of which enhance the absorption of light of a specific wavelength by the material, thereby increasing the tissue temperature. Photodynamic sensitization refers to that under the excitation of light of a specific wavelength, a photodynamic sensitizer (such as porphyrin nanoparticles, upconversion nanoparticles, etc.) undergoes an electron transition to activate type I and type II reactions to generate reactive oxygen species such as singlet oxygen and hydroxyl radicals, and then undergoes an oxidation reaction with tumor cells and induces their apoptosis or necrosis.

[0004] Existing phototherapy sensitizers mainly achieve tumor ablation sensitization by improving the photothermal conversion efficiency or photoexciting cytotoxic reactive oxygen species. The sensitization mode is single, and the sensitization effect needs to be improved. Therefore, designing and constructing a new type of sensitizing material that simultaneously enhances photothermal conversion and the generation of cytotoxic reactive oxygen species will help improve the effect of phototherapy for treating tumors. SUMMARY OF THE INVENTION

[0005] The primary object of the present invention is to overcome the disadvantages and deficiencies of the prior art and provide a metal-organic framework material.

[0006] Another object of the present invention is to provide a method for preparing the metal-organic framework material.

[0007] A further object of the present invention is to provide the application of the metal-organic framework material.

[0008] The object of the present invention is achieved by the following technical solutions:

[0009] A metal-organic framework material, which is a metal-organic framework material composed of X metal ions and Y organic ligands;

[0010] The X metal includes one or more of rare earth metals, alkaline earth metals, main group metals, and transition element metals;

[0011] The Y organic ligands include one or more of porphyrin ligands, carboxylic acid ligands, phthalic acid, terephthalic acid, phthalic acid, aminoterephthalic acid, 1,4-benzenedicarboxylic acid, p-hydroxybenzoic acid, pyridine and its derivatives, 1,4-benzenedicarboxylic acid, benzenetricarboxylic acid, benzotetracarboxylic acid, benzodicarboxylic acid, benzohexacarboxylic acid, 1,3,5-benzenetricarboxylic acid, glycine, lysine, valine, phenylglycine, phenylalanine, phenylalanine, aromatic diol ligands, non-aromatic diol ligands, and aromatic diamine ligands.

[0012] The metal-organic framework material has a nanosheet structure with a particle size of 50 - 1000 nm in length and width (preferably 100 - 300 nm).

[0013] Preferably, the rare earth metals include one or more of Ce, Er, and Yb.

[0014] Preferably, the alkaline earth metals include one or two of Mg and Ca.

[0015] Preferably, the main group metals include one or more of Sn, Ge, Al, and In.

[0016] Preferably, the transition element metals include one or more of Zn, Cu, Co, Fe, Cr, Mn, Ti, Zr, Cd, Ni, Mo, Sc, Hf, V, VTi (vanadium-titanium), Os, Ir, Ag, Ru, and Nb.

[0017] More preferably, the X metal is one or more of Co, Ni, Mn, Zn, Ti, Cu, Zr, and Al.

[0018] More preferably, the X metal is one or more of Co, Ni, Mn, and Zn.

[0019] Further preferably, the Y organic ligand is one or more of tetrakis(4-carboxyphenyl)porphine, 4,4'-bipyridine, phenylalanine, aminoterephthalic acid, and pyridine.

[0020] More preferably, the Y organic ligand is tetrakis(4-carboxyphenyl)porphine and 4,4'-bipyridine. When the X metal is Co, due to the relatively special coordination conditions of Co, two organic ligands are required for coordination. Among them, 4,4'-bipyridine is easy to coordinate with Co ions, and its addition is more likely to form a stable framework structure.

[0021] The preparation method of the metal-organic framework material includes the following steps: Dissolve the compound containing X metal and the Y organic ligand in an organic solvent, and after ultrasonic assistance and stirring, carry out the reaction at 50-250 °C to obtain the metal-organic framework material.

[0022] Preferably, the compound containing X metal (core metal compound) includes cobalt nitrate, magnesium nitrate, aluminum nitrate, iron(III) nitrate nonahydrate, cobalt nitrate hexahydrate, cobalt chloride, nickel(II) nitrate hexahydrate, copper(II) nitrate trihydrate, scandium nitrate, tetrabutyl titanate, titanium tetrachloride, titanium trichloride, hexameric titanium oxo cluster, titanium isopropoxide, vanadium nitrate, chromium nitrate, manganese nitrate, manganese chloride tetrahydrate, iron chloride, nickel nitrate, copper nitrate, copper-oxygen metal cluster, zinc nitrate, gallium nitrate hydrate, germanium oxide, Zr6O8 metal cluster, zirconium chloride, niobium chloride tetrahydrofuran complex, indium trichloride, indium nitride, erbium trichloride, erbium carbonate, molybdenum trioxide, ruthenium chloride, silver nitrate, cadmium acetate, stannous chloride, ammonium cerium nitrate, hafnium tetrachloride, ytterbium nitrate, dodecacarbonyltriosmium, and iridium chloride, etc.

[0023] Further preferably, the compound containing X metal (core metal compound) is one or more of cobalt nitrate, nickel nitrate, manganese chloride tetrahydrate, and zinc nitrate.

[0024] Preferably, the molar ratio of the compound containing X metal to the Y organic ligand is 1:1-5.

[0025] Further preferably, the molar ratio of the compound containing X metal to the Y organic ligand is 1:2.5-5.

[0026] The organic solvent is a solvent obtained by mixing N,N-dimethylformamide and an alcohol compound; preferably a solvent obtained by mixing N,N-dimethylformamide and an alcohol compound in a volume ratio of 7.5-12.5:2.5, where the alcohol compound is methanol or ethanol; the amount of the organic solvent is added as needed to dissolve the raw materials and enable the reaction to proceed smoothly.

[0027] Preferably, the conditions for ultrasonic-assisted dissolution are as follows: ultrasonic frequency 40 KHz, ultrasonic power 360 W, and ultrasonic time 10 - 30 min.

[0028] More preferably, the conditions for ultrasonic-assisted dissolution are as follows: ultrasonic frequency 40 KHz, ultrasonic power 360 W, and ultrasonic time 15 min.

[0029] Preferably, the conditions for stirring are as follows: stirring at 500 - 1500 revolutions per minute for 1 - 3 hours.

[0030] More preferably, the conditions for stirring are as follows: stirring at 1000 revolutions per minute for 1 hour.

[0031] Preferably, the reaction is carried out in a high-temperature reaction kettle.

[0032] Preferably, the temperature of the reaction is 50 - 130 °C.

[0033] More preferably, the temperature of the reaction is 80 - 100 °C.

[0034] Preferably, the time of the reaction is 1 - 48 h.

[0035] More preferably, the time of the reaction is 12 - 24 h.

[0036] For the preparation method of the metal-organic framework material described above, after the reaction is completed, the product can be further washed with an organic solvent, and then the product is dried to obtain the required metal-organic framework material.

[0037] A surface-defect metal-organic framework material is prepared by heating and reacting the above metal-organic framework material under the action of a reducing agent in a protective gas atmosphere.

[0038] Preferably, the reducing agent includes one or more of sodium borohydride, potassium borohydride, sodium citrate, and vitamin C.

[0039] Preferably, the dosage of the reducing agent is 10 - 60% of the mass of the metal-organic framework material.

[0040] More preferably, the dosage of the reducing agent is 50% of the mass of the metal-organic framework material.

[0041] Preferably, the temperature of the heating reaction is 220 - 350 °C.

[0042] More preferably, the temperature of the heating reaction is 300 - 350 °C.

[0043] More preferably, the temperature of the heating reaction is 300 °C.

[0044] Preferably, the protective gas includes one or both of argon and nitrogen.

[0045] The method for preparing the surface-defective metal-organic framework material includes the following steps: After mixing the metal-organic framework material and the reducing agent, heating to 220-350 °C for reaction under a protective gas atmosphere. After the reaction is completed, dispersing the reaction product in absolute ethanol, centrifuging and washing, and finally drying the reactant to obtain the surface-defective metal-organic framework material.

[0046] Preferably, the conditions for centrifuging and washing are: centrifuging at 8000-12000 revolutions per minute for 20-40 minutes.

[0047] More preferably, the conditions for centrifuging and washing are: centrifuging at 12000 revolutions per minute for 30 minutes.

[0048] Preferably, the number of times of centrifuging and washing is more than three.

[0049] A metal-organic framework material with surface-modified polymer, which modifies the polymer on the surface of the above metal-organic framework material and / or surface-defective metal-organic framework material.

[0050] Preferably, the polymer includes one or more of polyethylene glycol, chitosan, soluble pectin, plant polysaccharide compound, maltodextrin, amino polyethylene glycol, carboxyl polyethylene glycol, phospholipid polyethylene glycol carboxyl, dextran, carboxymethyl dextran, carboxymethyl chitosan, carboxymethyl starch, polyacrylic acid, polystyrene-b-polyacrylic acid, polymaleic acid, polylactic acid, polylactic acid-glycolic acid, polyvinylpyrrolidone, polysorbate, poly(lactide), polycaprolactone, polyglycolic acid, polyamino acid, polyacrylic acid, polymethacrylic acid, polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, poly(oxyethylene)-poly(oxypropylene) block copolymer, carbomer copolymer, glycolide-lactide copolymer, lauroyl polyoxyethylene glycerol ester, ethyl acrylate-methyl methacrylate copolymer, polyethylene glycol-distearoyl phosphatidylethanolamine, polydopamine, polyethyleneimine, polyvinylamine, liposome, albumin nanosphere.

[0051] More preferably, the polymer is polyethylene glycol 2000 (i.e., the molecular weight of polyethylene glycol is 2000).

[0052] The preparation method of the metal-organic framework material with surface-modified polymer includes the following steps: dispersing the above metal-organic framework material and / or surface-defective metal-organic framework material into a solvent, then adding a polymer and stirring for reaction. After the reaction is completed, centrifugation is carried out to obtain the metal-organic framework material with surface-modified polymer.

[0053] Preferably, the molar ratio of the metal-organic framework material (or surface-defective metal-organic framework material) to the polymer is 1:1.5 - 3.

[0054] Preferably, the solvent is water.

[0055] More preferably, the solvent is deionized water.

[0056] Preferably, the dispersion can be assisted by ultrasonic dispersion.

[0057] Preferably, the conditions of the ultrasonic treatment are: ultrasonic frequency 40KHz, ultrasonic power 360W, and ultrasonic time 0.5 - 1.5 hours.

[0058] More preferably, the conditions of the ultrasonic treatment are: ultrasonic frequency 40KHz, ultrasonic power 360W, and ultrasonic time 1 hour.

[0059] Preferably, the reaction time is 1 - 48h.

[0060] More preferably, the reaction time is 24h.

[0061] Preferably, the conditions of the centrifugal washing are: centrifuging at 8000 - 12000 revolutions per minute for 20 - 40 minutes.

[0062] More preferably, the conditions of the centrifugal washing are: centrifuging at 12000 revolutions per minute for 30 minutes.

[0063] A metal-organic framework material (composite material) conjugated with a tumor-targeting molecule conjugates the tumor-targeting molecule on the surface of the above metal-organic framework material, and / or surface-defective metal-organic framework material, and / or metal-organic framework material with surface-modified polymer.

[0064] Preferably, the tumor-targeting molecule includes one or more of folic acid, RGD peptide (arginyl-glycyl-aspartic acid), vascular endothelial growth factor, neuropeptide, tumor-specific antibody or polypeptide.

[0065] The preparation method of the metal-organic framework material conjugated with a tumor-targeting molecule comprises the following steps: dispersing at least one of the above metal-organic framework materials, surface-defective metal-organic framework materials, and metal-organic framework materials modified with a surface-modifying polymer into a buffer solution, then adding 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and N-hydroxysulfosuccinimide to activate the carboxyl group, and then adding the tumor-targeting molecule, followed by stirring for reaction. After the reaction is completed, centrifugation is carried out to obtain the metal-organic framework material conjugated with the tumor-targeting molecule.

[0066] Preferably, the mass ratio of the metal-organic framework material (or surface-defective metal-organic framework material, or metal-organic framework material modified with a surface-modifying polymer), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, and N-hydroxysulfosuccinimide is 100:10-20:5-10.

[0067] More preferably, the mass ratio of the metal-organic framework material (or surface-defective metal-organic framework material, or metal-organic framework material modified with a surface-modifying polymer), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, and N-hydroxysulfosuccinimide is 100:10:5.

[0068] Preferably, the mass ratio of the metal-organic framework material (or surface-defective metal-organic framework material, or metal-organic framework material modified with a surface-modifying polymer) to the tumor-targeting molecule is 100:3-7.

[0069] More preferably, the mass ratio of the metal-organic framework material (or surface-defective metal-organic framework material, or metal-organic framework material modified with a surface-modifying polymer) to the tumor-targeting molecule is 100:5.

[0070] Preferably, the buffer solution is one or more of phosphate buffer solution (PBS), tris(hydroxymethyl)aminomethane (Tris) buffer solution, Hanks balanced salt solution, and a mixture of Hanks balanced salt solution and TAE buffer solution.

[0071] Preferably, the reaction time is 1-24 h.

[0072] More preferably, the reaction time is 16 h.

[0073] Preferably, the conditions for centrifugal washing are: centrifuging at 8000-12000 revolutions per minute for 20-40 minutes.

[0074] More preferably, the conditions for centrifugal washing are: centrifuging at 12000 revolutions per minute for 30 minutes.

[0075] A metal-organic framework material loaded with an anti-tumor drug, wherein the anti-tumor drug is loaded on the surface of the above-mentioned metal-organic framework material, and / or surface-defective metal-organic framework material, and / or metal-organic framework material modified with a polymer on the surface, and / or metal-organic framework material conjugated with a tumor-targeting molecule.

[0076] Preferably, the anti-tumor drug includes one or more of doxorubicin, paclitaxel, and cisplatin.

[0077] The preparation method of the metal-organic framework material loaded with an anti-tumor drug includes the following steps: dispersing at least one of the above-mentioned metal-organic framework material, surface-defective metal-organic framework material, metal-organic framework material modified with a polymer on the surface, and metal-organic framework material conjugated with a tumor-targeting molecule into a buffer solution, then adding the anti-tumor drug, stirring and reacting in the dark, and after the reaction ends, centrifuging to obtain the metal-organic framework material loaded with an anti-tumor drug.

[0078] Preferably, the mass ratio of the metal-organic framework material (or surface-defective metal-organic framework material, or metal-organic framework material modified with a polymer on the surface, or metal-organic framework material conjugated with a tumor-targeting molecule) to the anti-tumor drug is 100:5 to 15.

[0079] More preferably, the mass ratio of the metal-organic framework material (or surface-defective metal-organic framework material, or metal-organic framework material modified with a polymer on the surface, or metal-organic framework material conjugated with a tumor-targeting molecule) to the anti-tumor drug is 100:10.

[0080] Preferably, the buffer solution is one or more of phosphate buffer solution (PBS), tris(hydroxymethyl)aminomethane (Tris) buffer solution, Hanks balanced salt solution, and the mixture of Hanks balanced salt solution and TAE buffer solution.

[0081] Preferably, the reaction time is 1 to 48 h.

[0082] More preferably, the reaction time is 24 h.

[0083] Preferably, the conditions for centrifugal washing are: centrifuging at 8000 to 12000 revolutions per minute for 20 to 40 minutes.

[0084] More preferably, the conditions for centrifugal washing are: centrifuging at 12000 revolutions per minute for 30 minutes.

[0085] A metal-organic framework material loaded with an immune activator, which loads the immune activator on the surface of the above metal-organic framework material, and / or surface-defective metal-organic framework material, and / or metal-organic framework material modified with a surface polymer, and / or metal-organic framework material conjugated with a tumor-targeting molecule, and / or metal-organic framework material loaded with an anti-tumor drug.

[0086] Preferably, the immune activator is R848.

[0087] The metal-organic framework material loaded with an immune activator includes the following steps: dispersing at least one of the above metal-organic framework material, surface-defective metal-organic framework material, metal-organic framework material modified with a surface polymer, metal-organic framework material conjugated with a tumor-targeting molecule, and metal-organic framework material loaded with an anti-tumor drug into a buffer solution, then adding the immune activator, stirring and reacting, and after the reaction is completed, centrifuging to obtain the metal-organic framework material loaded with the immune activator.

[0088] Preferably, the mass ratio of the metal-organic framework material (or surface-defective metal-organic framework material, or metal-organic framework material modified with a surface polymer, or metal-organic framework material conjugated with a tumor-targeting molecule, or metal-organic framework material loaded with an anti-tumor drug) to the immune activator is 100:5 to 15.

[0089] More preferably, the mass ratio of the metal-organic framework material (or surface-defective metal-organic framework material, or metal-organic framework material modified with a surface polymer, or metal-organic framework material conjugated with a tumor-targeting molecule, or metal-organic framework material loaded with an anti-tumor drug) to the immune activator is 100:10.

[0090] Preferably, the buffer solution is one or more of phosphate buffer (PBS), tris(hydroxymethyl)aminomethane (Tris) buffer, Hanks balanced salt solution, and a mixture of Hanks balanced salt solution and TAE buffer.

[0091] Preferably, the reaction time is 1 to 48 h.

[0092] More preferably, the reaction time is 24 h.

[0093] Preferably, the conditions for centrifugal washing are: centrifuging at 8000 to 12000 revolutions per minute for 20 to 40 minutes.

[0094] More preferably, the conditions for centrifugal washing are: centrifuging at 12000 revolutions per minute for 30 minutes.

[0095] Use of at least one of the metal-organic framework material, surface defect metal-organic framework material, metal-organic framework material modified with surface polymer, metal-organic framework material conjugated with tumor targeting molecule, metal-organic framework material loaded with anti-tumor drug, and metal-organic framework material loaded with immune activator in the preparation of a photosensitizer for phototherapy, a product for tumor microwave dynamic therapy, a product for tumor sonodynamic therapy, and / or a product for combined tumor photothermal-photodynamic therapy.

[0096] Preferably, the photosensitizer for phototherapy is a photosensitizer for tumor phototherapy.

[0097] Preferably, the tumor is a malignant tumor, including liver cancer, etc.

[0098] Preferably, the product includes drugs, etc.

[0099] A photosensitizer for phototherapy, which comprises one or more of a metal-organic framework material, a surface defect metal-organic framework material, a metal-organic framework material modified with surface polymer, a metal-organic framework material conjugated with tumor targeting molecule, a metal-organic framework material loaded with anti-tumor drug, and a metal-organic framework material loaded with immune activator.

[0100] Preferably, the photosensitizer for phototherapy is a photosensitizer for tumor phototherapy.

[0101] Preferably, the tumor is a malignant tumor, including liver cancer, etc.

[0102] The present invention has the following advantages and effects compared with the prior art:

[0103] 1. The metal-organic framework material in the present invention has a strong absorption peak in the red to near-infrared region (600 - 800 nm), can penetrate deeper tissues, and overcomes the limitation of insufficient penetration of traditional photosensitizers due to ultraviolet / visible light absorption.

[0104] 2. The metal-organic framework material in the present invention has a nano-sheet structure, with an increased specific surface area and surface activity. The metal ions therein can promote the generation of reactive oxygen species through electron gain and loss, and have a high ability to generate cytotoxic reactive oxygen species under light excitation. Therefore, the phototherapy effect of tumors can be enhanced.

[0105] 3. The surface defect treatment of the metal-organic framework material in the present invention will further promote the electron transfer effect under light excitation and improve the generation of reactive oxygen species.

[0106] 4. In the present invention, the surface of the metal-organic framework material is hydrophilically modified, which will improve the stability of the metal-organic framework material in the physiological solution environment. After coupling with tumor-targeting molecules, the recognition ability of the metal-organic framework material for tumor cells will be improved. After loading anti-tumor drugs, the killing effect of the metal-organic framework material on tumor cells will be enhanced. After loading immune activators, the anti-tumor immunity of the body will be activated.

[0107] 5. The photosensitizer for photodynamic therapy of the present invention can also effectively increase the yield of reactive oxygen species during microwave dynamic therapy and sonodynamic therapy, and can also be used for the photosensitization application of tumor microwave dynamic therapy and sonodynamic therapy. BRIEF DESCRIPTION OF THE DRAWINGS

[0108] Figure 1 It is the TEM image of the porous metal-organic framework material Co-TCPP in Example 1 of the present invention.

[0109] Figure 2 It is the DLS image of the porous metal-organic framework material Co-TCPP in Example 1 of the present invention.

[0110] Figure 3 It is the Zeta potential image of the porous metal-organic framework material Co-TCPP in Example 1 of the present invention and Co-TCPP@PEG in Example 6.

[0111] Figure 4 It is the XRD image of the porous metal-organic framework material Co-TCPP in Example 1 of the present invention.

[0112] Figure 5 It is the TEM image of the porous metal-organic framework material Co-BDC in Comparative Example 1 of the present invention.

[0113] Figure 6 It is the temperature rise curve image of Co-TCPP in Example 1 of the present invention and Co-BDC in Comparative Example 1 under light irradiation.

[0114] Figure 7 It is the photodynamic sensitization performance image of Co-TCPP in Example 1 of the present invention and Co-BDC in Comparative Example 1 compared with the reactive oxygen radical probe DPBF under light irradiation.

[0115] Figure 8 It is the cell survival rate result image of Co-TCPP@PEG in Example 6 of the present invention and HepG2 cells after culturing for 12 h at different experimental concentrations.

[0116] Figure 9 It is the fluorescence images of Co-TCPP@PEG modified with rhodamine B (Rh B) in Example 7 of the present invention and HepG2 cells after culturing for 0, 2, and 4 h.

[0117] Figure 10 The fluorescence images of HepG2 cells co-incubated with Co-TCPP@PEG and ROS probe in Example 6 of the present invention after being treated with light or without light.

[0118] Figure 11 The cell survival rate results of Co-TCPP in Example 1 of the present invention after incubating with HepG2 cells at different concentrations and being treated with light.

[0119] Figure 12 The cell survival rate results of Co-TCPP@PEG in Example 6 of the present invention after incubating with HepG2 cells at different concentrations and being treated with light. Detailed implementation manners

[0120] The present invention will be further described in detail below in conjunction with embodiments, but the implementation manners of the present invention are not limited thereto. Unless otherwise specified, the raw materials, reagents, methods and equipment used in the present invention are conventional raw materials, reagents, methods and equipment in the technical field. The test methods of the following examples without specific experimental conditions are usually carried out according to conventional experimental conditions or according to the experimental conditions recommended by the manufacturer. Unless otherwise specified, the reagents and raw materials used in the present invention can be obtained commercially.

[0121] Example 1

[0122] Weigh 8 mg of tetra(4-carboxyphenyl)porphine (CAS No.: 14609-54-2; TCPP), 16 mg of 4,4'-bipyridine, and 21 mg of cobalt nitrate, and dissolve them in a mixed solution formed by 7.5 mL of N,N-dimethylformamide and 2.5 mL of absolute ethanol. Sonicate (frequency 40 KHz, power 360 W) for 15 minutes at room temperature and stir at 1000 revolutions per minute for 1 hour. Then transfer the solution to a high-temperature reaction kettle and react at 80 °C for 12 hours. After the reaction is completed, wait for the reaction kettle to cool to room temperature, wash it three times with N,N-dimethylformamide and absolute ethanol respectively, and finally dry the sample to obtain the porous metal-organic framework material Co-TCPP.

[0123] The transmission electron microscope (TEM) detection, hydrodynamic diameter (DLS) detection, Zeta potential detection, and X-ray diffraction spectrum (XRD) detection results of the porous metal-organic framework material Co-TCPP prepared in this example are respectively as Figure 1 , 2, as shown in Figures 3 and 4. As shown in the TEM image, the Co-TCPP sample exhibits a regular rectangular two-dimensional nanosheet structure with a length and width in the range of 100 - 300 nm. As shown in the DLS image, the hydrodynamic diameter of the Co-TCPP sample is 210 nm, which is consistent with the observation under the electron microscope. As shown in the Zeta potential image, compared with TCPP, the Zeta potential of the Co-TCPP sample decreases, indicating that the Co-TCPP sample is more stable in the physiological environment. As Figure 4 shown in the X-ray diffraction spectrum of the sample, it matches the simulated peaks of the Co-TCPP single crystal sample, demonstrating the successful synthesis of the Co-TCPP sample.

[0124] Example 2

[0125] Weigh 20 mg of phenylalanine and 8.93 mg of nickel nitrate and dissolve them in a mixed solution formed by 7.5 mL of N,N-dimethylformamide and 2.5 mL of absolute ethanol. Sonicate (frequency 40 KHz, power 360 W) for 15 minutes at room temperature to assist dissolution, and then stir at 1000 revolutions per minute for 1 hour. Then transfer the solution to a high-temperature reaction kettle and react at 90 °C for 24 hours. After the reaction is completed, wait for the reaction kettle to cool to room temperature, wash it three times with N,N-dimethylformamide and absolute ethanol respectively, and finally dry the sample to obtain the porous metal-organic framework material Ni MOFs.

[0126] Example 3

[0127] Weigh 32 mg of 2-aminoterephthalic acid (CAS No.: 10312-55-7) and 12 mg of manganese chloride tetrahydrate and dissolve them in a mixed solution formed by 7.5 mL of N,N-dimethylformamide and 2.5 mL of absolute ethanol. Sonicate (frequency 40 KHz, power 360 W) for 15 minutes at room temperature to assist dissolution, and then stir at 1000 revolutions per minute for 1 hour. Then transfer the solution to a high-temperature reaction kettle and react at 100 °C for 12 hours. After the reaction is completed, wait for the reaction kettle to cool to room temperature, wash it three times with N,N-dimethylformamide and absolute ethanol respectively, and finally dry the sample to obtain the porous metal-organic framework material Mn MOFs.

[0128] Example 4

[0129] Weigh 23 mg of pyridine and 18.94 mg of zinc nitrate and dissolve them in a mixed solution formed by 7.5 mL of N,N-dimethylformamide and 2.5 mL of absolute ethanol. Sonicate (frequency 40 KHz, power 360 W) for 15 minutes at room temperature to assist dissolution, and then stir at 1000 revolutions per minute for 1 hour. Then transfer the solution to a high-temperature reaction kettle and react at 90 °C for 24 hours. After the reaction is completed, wait for the reaction kettle to cool to room temperature, wash it three times with N,N-dimethylformamide and absolute ethanol respectively, and finally dry the sample to obtain the porous metal-organic framework material Zn MOFs.

[0130] Comparative Example 1

[0131] Weigh 543 mg of p-hydroxybenzoic acid and 130 mg of cobalt(II) nitrate hexahydrate, and dissolve them in a mixed solution formed by 13.5 mL of N,N-dimethylformamide and 1.5 mL of anhydrous methanol. Sonicate (frequency 40 kHz, power 360 W) to assist dissolution for 30 minutes at room temperature, and stir at 1000 revolutions per minute for 1 hour. Then transfer the solution to a high-temperature reaction kettle and react at 80 °C for 12 hours. After the reaction, wash three times with N,N-dimethylformamide and anhydrous methanol respectively, and finally dry the sample to obtain the porous metal-organic framework material Co-BDC.

[0132] The transmission electron microscope test results of the porous metal-organic framework material Co-BDC prepared in this comparative example are as Figure 5 shown: The Co-BDC sample presents a regular rhombic two-dimensional nanostructure with a length and width in the range of 100 - 600 nm.

[0133] Example 5

[0134] Take 600 mg of the porous metal-organic framework material Co-TCPP powder prepared in Example 1 and 300 mg of sodium borohydride powder, and mix them evenly. Place the powder in a tubular furnace and heat and react at 300 °C for 6 hours under argon protection. After the reaction, disperse the mixed powder in anhydrous ethanol and centrifuge at 12000 revolutions per minute for 30 minutes, repeat 3 times, then disperse in deionized water and centrifuge at 12000 revolutions per minute for 30 minutes. Dry the obtained reactant to obtain the surface-defected Co-TCPP metal-organic framework material.

[0135] Example 6

[0136] Take 15 mg of the porous metal-organic framework material Co-TCPP powder in Example 1 and disperse it in 20 mL of deionized water, and sonicate (frequency 40 kHz, power 360 W) to assist dissolution for 1 hour. Then add 10 mg of polyethylene glycol (molecular weight 2000) to the solution and continue to stir and react for 24 hours. After the reaction, centrifuge the reactant at 12000 revolutions per minute for 30 minutes to obtain the polyethylene glycol-modified metal-organic framework nanosheet Co-TCPP@PEG.

[0137] Example 7

[0138] First, weigh 5 mg of Co-TCPP@PEG prepared in Example 6 and place it in a 20 mL round-bottom flask. Then add 5 mL of deionized water to the round-bottom flask to disperse it, obtaining an aqueous solution of Co-TCPP@PEG. Subsequently, weigh 10 mg of rhodamine B (Rh B), disperse it with 5 mL of deionized water, place it in a constant-pressure funnel, and drop it into the Co-TCPP@PEG aqueous solution at a constant flow rate (1 mL / min) under light-shielded conditions, and stir at room temperature for 12 h. After the reaction, wash the Rh B-modified Co-TCPP@PEG complex with deionized water multiple times.

[0139] Example 8

[0140] Take 100 mg of the polyethylene glycol-modified metal-organic framework nanosheet Co-TCPP@PEG powder prepared in Example 6, disperse it in 5 mL of PBS buffer solution with a pH of 7.5, add 10 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 5 mg of N-hydroxysulfosuccinimide, stir to activate the carboxyl group for 1 h, add 5 mg of RGD short peptide (arginyl-glycyl-aspartic acid; CAS No.: 99896-85-2), and stir for reaction for 16 h. After the reaction, centrifuge at 12,000 rpm for 30 min to remove the excess reactants, obtaining the metal-organic framework material Co-TCPP@PEG@RGD conjugated with RGD short peptide.

[0141] Example 9

[0142] Take 100 mg of the metal-organic framework material Co-TCPP@PEG@RGD conjugated with RGD short peptide prepared in Example 8, disperse it in 5 mL of PBS buffer solution with a pH of 7.5, add 10 mg of doxorubicin, and stir for reaction for 24 h under light-shielded conditions. After the reaction, centrifuge at 12,000 rpm for 30 min to remove the excess reactants, obtaining the metal-organic framework material Co-TCPP@PEG@RGD@ADM loaded with doxorubicin.

[0143] Example 10

[0144] Take 100 mg of the metal-organic framework material Co-TCPP@PEG@RGD@ADM loaded with doxorubicin prepared in Example 9, disperse it in 5 mL of PBS buffer solution with a pH of 7.5, add 10 mg of the immune activator R848 (Resiquimod), and stir for reaction for 24 h. After the reaction, centrifuge at 12,000 rpm for 30 min to remove the excess reactants, obtaining the metal-organic framework composite material Co-TCPP@PEG@RGD@ADM@R848 loaded with the immune activator R848.

[0145] Example 11

[0146] Disperse Co-TCPP prepared in Example 1 and Co-BDC prepared in Comparative Example 1 separately in deionized water to obtain homogeneous solutions with a concentration of 100 μg / mL as the experimental groups. Set a separate deionized water group as the control group. Use an 808 nm laser emitter with a power density of 5 W / cm 2 (power range 0.1 - 100 W / cm 2 ) to irradiate the metal-organic framework materials for 5 min, and use an infrared thermal imager to record the temperature in real time. The experiment is set up with three replicates.

[0147] The results are as Figure 6 shown: As Figure 6 can be seen, after 5 min of light irradiation, the temperature of the deionized water group (H2O) only increased by 1.8 °C. Compared with the control group, the solution temperature in the experimental groups all increased significantly after 5 min of light irradiation, proving that both Co-BDC and Co-TCPP have photothermal sensitization performance; among them, the temperature of the Co-BDC group increased by 7.2 °C after 5 min of light irradiation, while the temperature of the Co-TCPP group increased by 23.8 °C after 5 min of light irradiation. The results prove that Co-TCPP has good photothermal sensitization performance. At the same time, the laser in the near-infrared region has good tissue penetration, which proves that Co-TCPP can penetrate deeper tissues and overcome the limitation of insufficient penetration of traditional photosensitizers due to ultraviolet / visible light absorption.

[0148] Example 12

[0149] Test the in vitro microwave dynamic sensitization effect of the porous metal-organic framework material Co-TCPP prepared in Example 1 with the active oxygen free radical probe 1,3-diphenylisobenzofuran (DPBF). The specific steps are as follows:

[0150] Disperse the porous metal-organic framework material Co-TCPP in deionized water to obtain a Co-TCPP solution with a concentration of 100 μg / mL; then take 1 mL of the Co-TCPP solution, add DPBF and mix well. Use an 808 nm light emitter with a power density of 5 W / cm 2 (power range 0.1 - 100 W / cm 2 ) to irradiate the Co-TCPP metal-organic framework material for 0, 1, 2, 3, 4, 5 minutes. After the irradiation, use a UV-visible spectrometer to detect the absorption peak of DPBF. Since DPBF can react with the generated active oxygen, its characteristic absorption in the UV-visible spectrum around 420 nm decreases. The experiment is set up with three replicates.

[0151] The test results are as Figure 7As shown, in the solution containing DPBF and two-dimensional metal-organic framework, with the increase of microwave irradiation time, the characteristic absorption value of DPBF decreases, which proves that the Co-TCPP metal-organic framework material can generate reactive oxygen free radicals under light excitation, so it has a photodynamic sensitization effect.

[0152] Example 13

[0153] The Co-TCPP@PEG prepared in Example 6 was used to prepare a high-concentration stock solution of 2 mg / mL with PBS buffer as the solvent, and then diluted with complete medium (DMEM + fetal bovine serum FBS at a volume ratio of 10% + 1% penicillin-streptomycin double antibody) to prepare experimental concentrations of 0, 10, 20, 40, 60, 80, and 100 μg / mL respectively. HepG2 cells (Procell) were digested with trypsin, and after counting, a HepG2 cell suspension of 2×10 5 cells / mL was prepared and inoculated into a 96-well plate at 100 μL / well, and then cultured in a cell incubator for 12 h until the cells adhered. After the cells adhered, the 96-well plate was taken out of the cell incubator. After removing the original medium, the experimental groups were added with complete medium containing different concentrations (0, 5, 10, 20, 40, 60, 80, 100 μg / mL) of Co-TCPP@PEG to the 96-well plates of different cells, and 5 replicates were set for each concentration. It was transferred to the cell incubator and cultured for 12 h.

[0154] The results are as Figure 8 shown: At all experimental concentrations of the present invention, HepG2 cells have good activity. Even when the concentration reaches 100 μg / mL, the survival rate of HepG2 cells is still above 90%. The results show that the Co-TCPP@PEG nanosheets have low dark toxicity to HepG2 cells and good biosafety; the 100 μg / mL Co-TCPP@PEG nanosheets are a safe dose that can be further applied in vivo.

[0155] Example 14

[0156] The Rh B-modified Co-TCPP@PEG complex in Example 7 was used to prepare a high-concentration stock solution of 2 mg / mL with PBS buffer as the solvent, and then diluted with complete medium (DMEM + fetal bovine serum FBS at a volume ratio of 10% + 1% penicillin-streptomycin double antibody) to prepare an experimental concentration of 100 μg / mL. The cells in the culture flask were digested with trypsin, and the cell suspension was centrifuged and collected into a centrifuge tube, re-suspended with fresh medium, counted, and prepared into a concentration of 3×10 4cells / mL HepG2 cell suspension was inoculated into a confocal culture dish at a density of 1 mL of cell suspension per dish. Subsequently, the confocal dish was transferred to a cell culture incubator and cultured for 12 h until the cells adhered. Complete medium containing the diluted Co-TCPP@PEG complex modified with Rh B was added and co-cultured with HepG2 cells for 2 h and 4 h. Subsequently, the cell uptake was observed under a fluorescence microscope. The experiment was set up with three replicates.

[0157] The results were as Figure 9 shown. At 2 h of co-incubation, the Co-TCPP@PEG nanosheets had been phagocytosed by HepG2 cells and emitted red fluorescence in the cells. As the incubation time increased, it could be more clearly seen that the Co-TCPP@PEG nanosheets were enriched in the cells, demonstrating the effectiveness of HepG2 cell uptake of the Co-TCPP@PEG nanosheets.

[0158] Example 15

[0159] First, prepare the DCFH-DA working solution (reactive oxygen species ROS fluorescent probe, 2,7-dichlorofluorescein diacetate) according to the instructions. Add 1 μL of 1000×DCFH-DA to 1 mL of DMEM basal medium and shake evenly in a vortex mixer to obtain the DCFH-DA working solution. The HepG2 cells digested with trypsin were counted and prepared into a cell suspension with a cell density of 6×10 4 cell / mL. Add 1 mL of cell suspension to each well of a 12-well plate and place it in a cell culture incubator to culture overnight for the cells to adhere and grow. After the incubation, discard the old culture medium, and co-incubate the HepG2 cells with complete medium (DMEM + fetal bovine serum FBS at a volume ratio of 10% + 1% penicillin-streptomycin double antibody) containing the Co-TCPP@PEG nanosheets (100 μg / mL) prepared in Example 6 for 3 h; at the same time, use tetrakis(4-carboxyphenyl)porphine (TCPP), Co-TCPP prepared in Example 1 as a control, and an equal volume of PBS as a blank control. After the incubation, wash several times with PBS to wash away the Co-TCPP@PEG nanosheets that did not enter the cells. Subsequently, add 0.5 mL of the DCFH-DA working solution to each well and continue co-incubating for 30 min. After the incubation, irradiate the cells with an 808 nm light emitter with a power density of 5 W / cm 2 or not, and then incubate in the dark for 1 h. Finally, wash with PBS to remove the basal medium containing the dye and make there be 1 mL of PBS buffer in the final well plate. Use an inverted fluorescence microscope with an excitation wavelength of 488 nm to observe the generation of reactive oxygen species in the cells by observing the green fluorescence of DCF. The experiment was set up with three replicates.

[0160] The experimental results were as Figure 10As shown, it can be observed that basically no green fluorescence was observed under the fluorescence microscope in all groups without laser irradiation, indicating that PBS, TCPP, Co-TCPP, and Co-TCPP@PEG produce very little ROS at the cellular level. After laser irradiation, no generation of green fluorescence was still observed in the PBS group under the fluorescence microscope, indicating that single laser irradiation does not induce cells to produce ROS. A very weak fluorescence generation was observed in the TCPP group under the fluorescence microscope, indicating that the ability of the combination of TCPP and laser to induce ROS production in HepG2 cells is weak. Green fluorescence generation was observed in both Co-TCPP and Co-TCPP@PEG nanosheets under the fluorescence microscope after laser excitation, indicating that they have the ability to induce ROS production in HepG2 cells under laser excitation. In addition, it can be observed that the green fluorescence generated by Co-TCPP@PEG nanosheets after laser excitation is significantly stronger than that of Co-TCPP, indicating that Co-TCPP@PEG has the best photodynamic sensitization performance.

[0161] Example 16

[0162] The Co-TCPP prepared in Example 1 and the Co-TCPP@PEG prepared in Example 6 were respectively formulated into high-concentration mother liquors of 2 mg / mL with PBS as the solvent, and then diluted with complete medium (DMEM + fetal bovine serum FBS with a volume ratio of 10% + 1% penicillin-streptomycin double antibody) to prepare experimental concentrations of 0, 10, 20, 40, 60, 80, and 100 μg / mL respectively. HepG2 cells (Procell) were digested with trypsin, and after counting, a HepG2 cell suspension of 2×10 5 cells / mL was prepared and inoculated into a 96-well plate at 100 μL / well, and then cultured in a cell incubator for 12 h until the cells adhered. After the cells adhered, the 96-well plate was taken out of the cell incubator. After removing the original medium, complete medium containing different concentrations (0, 5, 10, 20, 40, 60, 80, 100 μg / mL) of Co-TCPP@PEG or Co-TCPP was added to the 96-well plates of different cells. Five replicates were set for each concentration. It was transferred to the cell incubator and cultured for 2 h. After the cells took up the materials, the unabsorbed materials were washed away with PBS, and then laser irradiation treatment was carried out with an 808 nm light emitter with a power density of 5 W / cm 2 to quantitatively evaluate cell damage by CCK8 reagent. The experiment was set up with three replicates.

[0163] The experimental results are as Figure 11 and Figure 12As shown, with the increase in the material concentration, the survival rate of HepG2 cells gradually decreases. When the concentration of Co-TCPP@PEG is 100 μg / mL, after laser treatment, the survival rate of HepG2 is only 14.65%. In the group of Co-TCPP combined with laser treated in the same way, when the concentration of Co-TCPP is 100 μg / mL, the survival rate of HepG2 is 45.54%. The results show that Co-TCPP@PEG nanosheets can enhance the phototherapeutic performance at the cellular level and can be further used for in vivo phototherapy.

[0164] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

Claims

1. A metal-organic framework material, characterized in that: The material described is a metal-organic framework material composed of X metal ions and Y organic ligands; The X metal described includes one or more of rare earth metals, alkaline earth metals, main group metals, and transition element metals; The Y organic ligands described include one or more of porphyrin ligands, carboxylic acid ligands, phthalic acid, terephthalic acid, phthalic acid, aminoterephthalic acid, 1,4-benzenedicarboxylic acid, p-hydroxybenzoic acid, pyridine and its derivatives, 1,4-benzenedicarboxylic acid, benzenetricarboxylic acid, benzophenetetracarboxylic acid, benzodicarboxylic acid, benzophenhexacarboxylic acid, 1,3,5-benzenetricarboxylic acid, glycine, lysine, valine, phenylglycine, phenylalanine, phenylalanine, aromatic diol ligands, non-aromatic diol ligands, and aromatic diamine ligands.

2. The metal-organic framework material according to claim 1, characterized in that: The rare earth metals described include one or more of Ce, Er, and Yb; The alkaline earth metals described include one or two of Mg and Ca; The main group metals described include one or more of Sn, Ge, Al, and In; The transition element metals described include one or more of Zn, Cu, Co, Fe, Cr, Mn, Ti, Zr, Cd, Ni, Mo, Sc, Hf, V, VTi, Os, Ir, Ag, Ru, and Nb; The Y organic ligand is one or more of tetrakis(4-carboxyphenyl)porphine, 4,4'-bipyridine, phenylalanine, aminoterephthalic acid, and pyridine.

3. A metal-organic framework material with surface defects, characterized in that: It is prepared by heating and reacting the metal-organic framework material according to any one of claims 1 to 2 under the action of a reducing agent in a protective gas atmosphere; Furthermore, the reducing agent described includes one or more of sodium borohydride, potassium borohydride, sodium citrate, and vitamin C.

4. A metal-organic framework material with surface-modified polymer, characterized in that: Surface-modified polymer of the metal-organic framework material according to any one of claims 1 to 2 and / or the surface-defect metal-organic framework material according to claim 3; Furthermore, the polymers described include one or more of polyethylene glycol, chitosan, soluble pectin, plant polysaccharide compounds, maltodextrin, amino polyethylene glycol, carboxyl polyethylene glycol, phospholipid polyethylene glycol carboxyl, dextran, carboxymethyl dextran, carboxymethyl chitosan, carboxymethyl starch, polyacrylic acid, polystyrene-b-polyacrylic acid, polymaleic acid, polylactic acid, polylactic acid-glycolic acid, polyvinylpyrrolidone, polysorbate, poly(lactide), polycaprolactone, polyglycolic acid, polyamino acids, polyacrylic acid, polymethacrylic acid, polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, poly(oxyethylene)-poly(oxypropylene) block copolymer, carbomer copolymer, glycolide-lactide copolymer, lauroyl polyoxyethylene glycerol ester, ethyl acrylate-methyl methacrylate copolymer, polyethylene glycol-distearoyl phosphatidylethanolamine, polydopamine, polyethyleneimine, polyvinylamine, liposomes, albumin nanospheres.

5. The preparation method of the metal-organic framework material of the surface-modified polymer according to claim 4, characterized in that: It includes the following steps: dispersing the metal-organic framework material and / or the surface-defect metal-organic framework material into a solvent, then adding the polymer and stirring for reaction, and after the reaction is completed, centrifuging to obtain the metal-organic framework material with a surface-modified polymer; Further, the molar ratio of the metal-organic framework material or the surface-defective metal-organic framework material to the polymer is 1:1.5 - 3.

6. A metal-organic framework material conjugated with a tumor-targeting molecule, characterized in that: Couple a tumor targeting molecule to the surface of the metal-organic framework material according to any one of claims 1 - 2, and / or the surface-defective metal-organic framework material according to claim 3, and / or the metal-organic framework material with surface-modified polymer according to claim 4; Further, the tumor targeting molecule includes one or more of folic acid, RGD peptide, vascular endothelial growth factor, neuropeptide, tumor-specific antibody or polypeptide.

7. A metal-organic framework material loaded with an anti-tumor drug, characterized in that: Load an anti-tumor drug on the surface of the metal-organic framework material according to any one of claims 1 - 2, and / or the surface-defective metal-organic framework material according to claim 3, and / or the metal-organic framework material with surface-modified polymer according to claim 4, and / or the metal-organic framework material coupled with a tumor targeting molecule according to claim 6; Further, the anti-tumor drug includes one or more of doxorubicin, paclitaxel and cisplatin.

8. A metal-organic framework material loaded with an immune activator, characterized in that: Load an immune activator on the surface of the metal-organic framework material according to any one of claims 1 - 2, and / or the surface-defective metal-organic framework material according to claim 3, and / or the metal-organic framework material with surface-modified polymer according to claim 4, and / or the metal-organic framework material coupled with a tumor targeting molecule according to claim 6, and / or the metal-organic framework material loaded with an anti-tumor drug according to claim 7; Further, the immune activator is R848.

9. Use of at least one of the metal-organic framework material according to any one of claims 1 - 2, the surface-defective metal-organic framework material according to claim 3, the metal-organic framework material with surface-modified polymer according to claim 4, the metal-organic framework material coupled with a tumor targeting molecule according to claim 6, the metal-organic framework material loaded with an anti-tumor drug according to claim 7, and the metal-organic framework material loaded with an immune activator according to claim 8 in the preparation of a product for phototherapy sensitizer, tumor microwave dynamic therapy, tumor sonodynamic therapy and / or tumor photothermal-photodynamic combined therapy.

10. A photosensitizer for photodynamic therapy, characterized in that: Include one or more of the metal-organic framework material according to any one of claims 1 - 2, the surface-defective metal-organic framework material according to claim 3, the metal-organic framework material with surface-modified polymer according to claim 4, the metal-organic framework material coupled with a tumor targeting molecule according to claim 6, the metal-organic framework material loaded with an anti-tumor drug according to claim 7, and the metal-organic framework material loaded with an immune activator according to claim 8.

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