CN114230803A - Metal organic framework composite nano material and preparation method and application thereof - Google Patents

Metal organic framework composite nano material and preparation method and application thereof Download PDF

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CN114230803A
CN114230803A CN202010941636.1A CN202010941636A CN114230803A CN 114230803 A CN114230803 A CN 114230803A CN 202010941636 A CN202010941636 A CN 202010941636A CN 114230803 A CN114230803 A CN 114230803A
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solution
organic framework
acid
metal
metal organic
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马雪华
陈天翔
林杰
吴爱国
刘闯
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Ningbo Institute of Material Technology and Engineering of CAS
Cixi Institute of Biomedical Engineering CNITECH of CAS
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Ningbo Institute of Material Technology and Engineering of CAS
Cixi Institute of Biomedical Engineering CNITECH of CAS
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/34—Copper; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0076—PDT with expanded (metallo)porphyrins, i.e. having more than 20 ring atoms, e.g. texaphyrins, sapphyrins, hexaphyrins, pentaphyrins, porphocyanines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0036—Porphyrins
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Abstract

The application discloses a metal organic framework composite nano material and a preparation method and application thereof. The metal organic framework composite nano material comprises a functional material and a copper metal organic framework carrying the functional material; wherein the functional material comprises small organic molecules. The metal organic framework composite nano material has good chemical stability and tumor microenvironment responsiveness, and can realize noninvasive, in-situ and efficient treatment and real-time monitoring of tumor parts.

Description

Metal organic framework composite nano material and preparation method and application thereof
Technical Field
The application relates to a metal organic framework composite nano material and a preparation method and application thereof, belonging to the field of biological medicine.
Background
It is known that chemotherapy for cancer requires the use of highly toxic chemotherapeutic drugs. However, due to the non-specificity of the drug, normal cells are killed at the same time as cancer cells, so that normal tissues and organs are damaged, and in addition, the toxicity of the chemotherapeutic drug is increased due to the sudden release of the chemotherapeutic drug. In recent years, the nano material not only serves as a drug carrier, but also serves as the diagnosis and treatment performance of the nano drug, so that people have attracted extensive attention. Based on non-toxic/low-toxicity nano materials, the method selectively catalyzes/triggers specific chemical reactions in tumor tissues, locally generates a considerable amount of specific reaction products, can realize the specific chemokinetic treatment of the tumor without generating obvious side effects on normal tissues, and improves the cure rate of the tumor.
The metal organic framework material is an organic-inorganic hybrid material with intramolecular pores formed by self-assembly of metal ions and organic ligands through coordination bonds. The nano-drug has the characteristics of high porosity, adjustable chemical components and crystal morphology, and easy-to-change metal-coordination bonds, so that the nano-drug has certain biodegradability and the like, and becomes a high-quality candidate material for constructing nano-drugs at present.
Disclosure of Invention
According to an aspect of the application, a metal organic framework composite nanomaterial is provided, the metal organic framework structure has good chemical stability and tumor microenvironment responsiveness, and noninvasive, in-situ, efficient treatment and real-time monitoring of tumor parts can be realized.
A metal organic framework composite nano material comprises a functional material and a copper metal organic framework carrying the functional material; wherein the functional material comprises small organic molecules.
Alternatively, the copper metal organic framework is obtained by reacting a compound containing copper metal ions and an organic ligand.
Optionally, the particle size of the copper metal organic framework is 40-300 nm.
Optionally, the copper metal organic framework has a porosity of 50-600m2/g。
The copper metal organic framework has high porosity, can carry various micromolecules or cluster imaging agents or medicines, and has good clinical application potential.
The copper metal organic framework is a therapeutic copper metal organic framework with tumor microenvironment responsiveness.
Alternatively, the copper metal organic framework is prepared by at least one method selected from a liquid-solid solution method, a hydrothermal synthesis method, a solvothermal method, a stirring reaction, or a vapor deposition method.
Optionally, the preparation method of the copper metal organic framework comprises the following steps: and (3) reacting the solution I containing the compound containing the copper metal ions and the organic ligand at the temperature of 0-200 ℃ for 1-48 h to obtain the copper metal organic framework.
Alternatively, the reaction is carried out under basic conditions.
Alternatively, the alkaline conditions are provided by NaOH.
Alternatively, the upper reaction temperature limit of the solution I is selected from 25, 40, 70, 80, 100, 150, 200 ℃; the lower limit is selected from 0, 25, 40, 70, 80, 100, 150 ℃.
Alternatively, the upper reaction time limit of the solution I is selected from 6, 8, 25, 36, 48 h; the lower limit is selected from 1, 2, 6, 8, 25, 36 h.
Optionally, the solvent of the solution I is at least one selected from water, methanol, ethanol, propanol, ethylene glycol, glycerol, N-hexane, cyclohexane, chloroform, N-dimethylformamide, acetonitrile, tetrahydrofuran, pyridine, and oleic acid.
Alternatively, the solvent of solution I comprises: oleic acid, ethanol, n-hexane and water.
Optionally, the compound containing copper metal ions is selected from at least one of nitrate, chloride, acetate, nitrate hydrate, chloride hydrate and acetate hydrate of metal copper.
Optionally, the compound containing copper metal ions is selected from Cu (NO)3)2·3H2O、Cu(CH3COO)2·H2O、Cu(CH3COOH)2、Cu(NO3)2、Cu(NO3)2、CuCl2·2H2O、CuCl2·3H2O、CuCl2At least one of (1).
Optionally, the organic ligand is selected from at least one of o-m-benzoic acid, phthalic acid, m-benzenetricarboxylic acid, 3-acetylbenzoic acid, 3-mercaptobenzoic acid, 4-hydroxymethylbenzoic acid, 4-tert-butylbenzoic acid, 4-ethoxybenzoic acid, p-cyclohexylbenzoic acid, 4- (aminomethyl) benzoic acid, 4-aminobenzoic acid, 5-aminoisophthalic acid, o-carboxyphenylacetic acid.
Optionally, the mass ratio (mg/mg) of the copper ion-containing compound to the organic ligand is (40-50): (2.5-50).
Optionally, the mass ratio (mg/mg) of the copper ion-containing compound to the organic ligand is (40-50): (10-50).
Optionally, the mass ratio (mg/mg) of the copper ion-containing compound to the organic ligand is (40-50): (2.5-10).
Optionally, the mass ratio (mg/mg) of the copper ion-containing compound to the organic ligand is (40-50): (45-50).
Optionally, in the solution I, the concentration of the compound containing copper metal ions is 1-5 mg/mL.
Optionally, in the solution I, the concentration of the compound containing copper metal ions is 2-3 mg/mL.
Optionally, the concentration of the organic ligand is 0.1-5 mg/mL.
Optionally, the upper concentration limit of the organic ligand is selected from 0.5, 1, 2, 3, 4, 5 mg/mL; the lower limit is selected from 0.1, 1, 2, 3, 4 mg/mL.
Optionally, the small organic molecule is a small organic molecule photosensitizer.
Optionally, the small organic molecule is selected from at least one of protoporphyrin and its derivatives, tetraphenylporphyrin tetrasulfonic acid and its derivatives, 5, 10, 15, 20-tetrakis (4-pyridyl) porphyrin and its derivatives, 5, 10, 15, 20-tetrakis (4-methoxyphenyl) porphyrin and its derivatives, 5- (4-carboxyphenyl) -10, 15, 2-triphenylporphyrin and its derivatives, m-tetraphenylporphyrin and its derivatives, and m-tetraphenylporphyrin-4, 4 ', 4 ", 4' -tetracarboxylic acid and its derivatives.
Optionally, the small organic molecule has the following structure:
Figure BDA0002673847230000031
Figure BDA0002673847230000041
optionally, the small organic molecule is immobilized on the copper metal organic framework by a coordination bond.
Optionally, the loading amount of the small organic molecules in the metal-organic framework composite nanomaterial is 10-80 wt%.
The invention creatively selects the small organic molecules, coordinates the small organic molecules with the copper metal organic framework to generate fluorescence quenching, and gradually releases the small organic molecules and recovers the fluorescence after the copper organic framework structure at the tumor part is dissociated, thereby realizing the real-time monitoring of the tumor part.
Optionally, the metal-organic framework composite nanomaterial further comprises an amphiphilic polymer; wherein the amphiphilic polymer is coated on the outermost layer.
Optionally, the amphiphilic polymer is selected from at least one of phospholipid-polyethylene glycol, carboxylated phospholipid polyethylene glycol, aminated phospholipid polyethylene glycol, hydroxylated phospholipid polyethylene glycol, sulfhydrylated phospholipid polyethylene glycol, and polyoxyethylene polyoxypropylene ether.
Optionally, the content of amphiphilic polymer in the metal-organic framework composite material is 20-60 wt%. Optionally, the particle size of the metal organic framework composite nanomaterial is 40-300 nm.
According to another aspect of the present application, there is provided a method for preparing a metal organic framework composite nanomaterial as described in any one of the above, the method comprising the steps of: reacting a raw material I containing a copper metal organic framework and small organic molecules to obtain the metal organic framework composite nano material.
Optionally, the mass ratio of the copper metal organic framework to the organic small molecules is 2-8: 1.
optionally, the mass ratio of the copper metal organic framework to the organic micromolecules is 6-8: 1.
optionally, the mass ratio of the copper metal organic framework to the organic small molecules is 2-4: 1.
optionally, the mass ratio of the copper metal organic framework to the organic small molecules is 4-8: 1.
optionally, the upper limit of the mass ratio of the copper metal organic framework to the organic small molecule is selected from 2:1, 3:1, 4:1 and 5:1, and the lower limit is selected from 5:1, 6:1, 7:1 and 8: 1.
Optionally, the method comprises the steps of:
(S1) reacting the solution M containing the copper metal organic framework and the organic micromolecules for 4-48 hours at 10-30 ℃ to obtain an intermediate product I;
(S2) carrying out ultrasonic dispersion on the solution N containing the intermediate product I and the amphiphilic polymer to obtain the metal-organic framework composite nanomaterial.
Alternatively, the solvent of the solution M and the solution N is independently selected from at least one of methanol, chloroform, acetone ethanol, propanol, ethylene glycol, glycerol, N-hexane, cyclohexane, N-dimethylformamide, acetonitrile, tetrahydrofuran, and pyridine.
Optionally, the concentration of the copper metal organic framework in the solution M is 2-40 mg/mL.
Optionally, the upper concentration limit of the copper metal organic framework in the solution M is selected from 3, 4, 10, 15, 20, 30, 40 mg/mL; the lower limit is selected from 4, 10, 15, 20, 30 mg/mL.
Optionally, the concentration of the small organic molecules in the solution M is 1-5 mg/mL.
Optionally, the concentration of the small organic molecules in the solution M is 1-2 mg/mL.
Optionally, the concentration of the small organic molecules in the solution M is 3-5 mg/mL.
Optionally, the concentration of the intermediate product I in the solution N is 2-8 mg/mL.
Optionally, the upper concentration limit of the intermediate product I in the solution N is selected from 1, 2, 3, 4 mg/mL; the lower limit is selected from 1, 2, 3, 4 mg/mL.
Optionally, the concentration of the amphiphilic polymer in the solution N is 2-8 mg/mL.
Alternatively, the upper limit of the concentration of the amphiphilic polymer in the solution N is selected from 1, 2, 3, 4 mg/mL; the lower limit is selected from 1, 2, 3, 4 mg/mL.
Optionally, in the step (S2), the mass ratio of the intermediate product I to the amphiphilic polymer is 0.5-8: 1.
Optionally, in the step (S2), the mass ratio of the intermediate product I to the amphiphilic polymer is 0.5-2: 1.
Optionally, in the step (S2), the mass ratio of the intermediate product I to the amphiphilic polymer is 0.5-1: 1.
Optionally, in the step (S2), the mass ratio of the intermediate product I to the amphiphilic polymer is 1-2: 1.
The preparation method of the metal organic framework composite nanomaterial realizes preparation of the diagnosis and treatment integrated metal organic framework composite nanomaterial with tumor microenvironment responsiveness, and the obtained metal organic framework composite nanomaterial is good in biocompatibility and small in toxicity to normal cells. The preparation method has the advantages of mild reaction conditions, simple steps and easy operation.
According to another aspect of the application, there is provided a use of the metal-organic framework composite nanomaterial or the metal-organic framework composite nanomaterial prepared by the preparation method according to any one of the above as a tumor microenvironment-responsive drug or a tumor fluorescence imaging agent. The metal organic framework composite nano material is dissociated under the stimulation of a tumor microenvironment to generate a specific chemical reaction, so that a large number of active oxygen species are generated, a series of oxidative damages of tumor cells are triggered, and the fixed-point release of the composite nano material at the tumor tissue is realized; meanwhile, the carried small organic molecules are released, and the in-vivo tissue distribution and aggregation conditions of the composite nano material and the real-time monitoring of tumor parts are realized.
By adopting the technical scheme, the technical principle is as follows: the organic ligand and copper ions form a copper metal organic framework, under the reductive condition of weak acid, hypoxia or glutathione at the tumor part, the structure of the copper metal organic framework is dissociated to release divalent copper ions which can trigger/catalyze H in the tumor tissue2O2Generating active oxygen species (such as. OH) by Fenton-like reaction, thereby killing tumor cells; organic micromolecules carried in the copper metal organic framework are gradually released, the fluorescence imaging effect of the tumor part is enhanced, and noninvasive, in-situ and efficient chemodynamics diagnosis and treatment of the tumor part are realized. The metal organic framework composite nano material is not only beneficial to enhancing the uptake of tumor cells to nano particles, but also beneficial to clearing the nano particles in vivo.
The beneficial effects that this application can produce include:
1) the metal organic framework composite nanomaterial provided by the application can be used for specific response of a tumor microenvironment. In the internal circulation, the copper metal organic framework structure has good chemical stability and tumor microenvironment responsiveness, and can be disintegrated only in the tumor microacid, hypoxic and glutathione reducing environments to release copper ions and organic micromolecules, so that noninvasive, in-situ and efficient treatment and real-time monitoring of tumor parts are realized.
2) In the metal organic framework composite nanomaterial provided by the application, the carried small organic molecules are fixed on the metal organic framework through coordination bonds, so that the leakage of the small organic molecules can be effectively reduced, and the imaging effect is enhanced.
3) The metal organic framework composite nano material provided by the application also has the property of photodynamic therapy, enhances the treatment effect by cooperating with the chemodynamic therapy, and further improves the treatment effect by consuming glutathione.
4) In the application, the metal organic framework composite nano material can be used as a conveying carrier, is stable, non-toxic and harmless under a normal tissue environment, dissociates in a tumor reductive environment to release a large amount of copper ions, further generates a specific chemical reaction, generates a large amount of active oxygen species, initiates a series of oxidative damage of tumor cells, and can effectively reduce the toxicity to normal cells. In the invention, the combination of the copper metal organic framework structure material and the organic micromolecular photosensitizer not only enables the organic micromolecular photosensitizer to be more stable in the in vivo circulation process, but also endows the imaging agent with tumor targeting performance. Meanwhile, the copper metal organic framework carrier has high porosity, and can carry various micromolecules or cluster imaging agents, so that the metal organic framework composite nano material has better clinical application potential.
5) The technical scheme provides a copper metal organic framework composite nano material, and the preparation process is mild in condition, simple in steps and easy to operate.
Drawings
FIG. 1 is a TEM image of the copper metal organic framework material Cu-MOF obtained in example 2, wherein a is a TEM image of the copper metal organic framework material Cu-MOF at a magnification of 38000 times; b is TEM image of Cu-MOF of copper metal organic framework material at 71000 times.
FIG. 2 is an XRD diagram of Cu-MOF of the Cu metal organic framework material obtained in example 2 and Cu-MOF/TCPP-PEG-COOH of the metal organic framework composite nano material obtained in example 18 (Cu-MOF/TCPP in the corresponding diagram).
FIG. 3 is an IR chart of Cu-MOF obtained from example 2 and Cu-MOF/TCPP-PEG-COOH (Cu-MOF/TCPP in the corresponding figure) obtained from example 18.
FIG. 4 is a graph showing fluorescence emission of meso-tetraphenylporphyrin-4, 4' -tetracarboxylic acid (TCPP) and the metal-organic framework composite nanomaterial Cu-MOF/TCPP-PEG-COOH of example 18 (Cu-MOF/TCPP in the corresponding graph).
FIG. 5 is a graph of fluorescence images of the metal organic framework composite nanomaterial Cu-MOF/TCPP-PEG-COOH obtained in example 18 reacted with glutathione for different times.
Detailed Description
The present application will be described in detail with reference to examples, but the present application is not limited to these examples.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.
Unless otherwise specified, all materials used in this application are commercially available.
Without specific reference, the general test conditions of the present application are as follows:
(1) transmission Electron microscopy characterization (TEM)
Performed on a FEITecnai F20 transmission electron microscope, test conditions: 200Kv, 101. mu.A.
(2) Characterization by X-ray diffractometer (XRD)
Performed on an X-ray diffractometer model brueck D8Advance, testing conditions: cu K α target, 5 °/min, 40kV,40 mA.
(3) Intelligent Fourier infrared spectrum characterization (FT-IR)
Performed on a Thermo NICOLET 6700 intelligent fourier infrared spectrometer.
(4) Fluorospectro photometer characterization
The method is carried out on a HITACHI F-4600 fluorescence spectrophotometer, and the test conditions are as follows: ex: 526 nm.
(5) Small animal fluorescence imager characterization
Performed on a PerkinElmer IVIS luminea XRMS, test conditions: ex: 530 nm.
The room temperature described herein is 25 ℃.
EXAMPLE 1 Synthesis of Cu-MOF, a copper Metal organic framework Material
(1) Measuring volume ratio 2: 1: 3, stirring the mixture of oleic acid, ethanol and normal hexane at 50 ℃ for 10 minutes to obtain a solution A for later use;
(2) weighing 40mgNaOH, dissolving into 4mL of water, adding into 10mL of A solution, and stirring at 50 ℃ for 10 minutes to obtain B solution for later use;
(3) 50mg of Cu (NO) are weighed out3)2·3H2Dissolving the O in 1mL of water, adding the solution into the solution B, and stirring for 15 minutes at 50 ℃ to obtain a solution C for later use;
(4) weighing 50mg of m-benzenetricarboxylic acid, dissolving the m-benzenetricarboxylic acid into 1.5mL of ethanol/water (V/V is 1.5:1), adding the solution into the solution C to obtain a solution I, and stirring the solution I at 70 ℃ for 2 hours to obtain copper metal organic framework Cu-MOF;
(5) at the rotating speed of 11000 r/min, the mixture is centrifuged for 5 min by cyclohexane/ethanol (V/V is 1:1), centrifuged for 3 times, and finally dissolved in N, N-dimethylformamide solution for standby.
EXAMPLE 2 Synthesis of Cu-MOF, a copper Metal organic framework Material
(1) Measuring volume ratio 1: 1: 3, stirring the mixture of oleic acid, ethanol and normal hexane at 50 ℃ for 10 minutes to obtain a solution A for later use;
(2) weighing 40mgNaOH, dissolving into 4mL of water, adding into 10mL of A solution, and stirring at 50 ℃ for 10 minutes to obtain B solution for later use;
(3) 50mg of Cu (NO) are weighed out3)2·3H2Dissolving the O in 1mL of water, adding the solution into the solution B, and stirring for 15 minutes at 50 ℃ to obtain a solution C for later use;
(4) weighing 50mg of m-benzenetricarboxylic acid, dissolving the m-benzenetricarboxylic acid into 1.5mL of ethanol/water (V/V is 1.5:1), adding the solution into the solution C to obtain a solution I, and stirring the solution I at 70 ℃ for 2 hours to obtain copper metal organic framework Cu-MOF;
(5) at the rotating speed of 11000 r/min, the mixture is centrifuged for 5 min by cyclohexane/ethanol (V/V is 1:1), centrifuged for 3 times, and finally dissolved in N, N-dimethylformamide solution for standby.
EXAMPLE 3 Synthesis of Cu-MOF, a copper Metal organic framework Material
(1) Measuring volume ratio 1: 3, stirring the mixture of the ethanol and the normal hexane at 50 ℃ for 10 minutes to obtain a solution A for later use;
(2) weighing 40mgNaOH, dissolving into 4mL of water, adding into 10mL of A solution, and stirring at 50 ℃ for 10 minutes to obtain B solution for later use;
(3) 50mg of Cu (NO) are weighed out3)2·3H2Dissolving the O in 1mL of water, adding the solution into the solution B, and stirring for 15 minutes at 50 ℃ to obtain a solution C for later use;
(4) weighing 50mg of m-benzenetricarboxylic acid, dissolving the m-benzenetricarboxylic acid into 1.5mL of ethanol/water (V/V is 1.5:1), adding the solution into the solution C to obtain a solution I, and stirring the solution I at 70 ℃ for 6 hours to obtain metal organic framework Cu-MOF;
(5) at the rotating speed of 11000 r/min, the mixture is centrifuged for 5 min by cyclohexane/ethanol (V/V is 1:1), centrifuged for 3 times, and finally dissolved in N, N-dimethylformamide solution for standby.
EXAMPLE 4 Synthesis of Cu-MOF, a copper Metal organic framework Material
(1) Measuring volume ratio 1: 1: 3, stirring the mixture of oleic acid, ethanol and normal hexane at 50 ℃ for 10 minutes to obtain a solution A for later use;
(2) weighing 40mgNaOH, dissolving into 4mL of water, adding into 10mL of A solution, and stirring at 50 ℃ for 10 minutes to obtain B solution for later use;
(3) 50mg of Cu (NO) are weighed out3)2·3H2Dissolving the O in 1mL of water, adding the solution into the solution B, and stirring for 15 minutes at 50 ℃ to obtain a solution C for later use;
(4) weighing 25mg of m-benzenetricarboxylic acid, dissolving the m-benzenetricarboxylic acid into 1.5mL of ethanol/water (V/V is 1.5:1), adding the solution into the solution C to obtain a solution I, and stirring the solution I at 70 ℃ for 8 hours to obtain copper metal organic framework Cu-MOF;
(5) at the rotating speed of 11000 r/min, the mixture is centrifuged for 5 min by cyclohexane/ethanol (V/V is 1:1), centrifuged for 3 times, and finally dissolved in N, N-dimethylformamide solution for standby.
EXAMPLE 5 Synthesis of Cu-MOF, a copper Metal organic framework Material
(1) Measuring volume ratio 1: 1: 3, stirring the mixture of oleic acid, ethanol and normal hexane at 50 ℃ for 10 minutes to obtain a solution A for later use;
(2) weighing 40mgNaOH, dissolving into 4mL of water, adding into 10mL of A solution, and stirring at 50 ℃ for 10 minutes to obtain B solution for later use;
(3) 50mg of CuCl was weighed out2.2H2Dissolving the O in 1mL of water, adding the solution into the solution B, and stirring for 15 minutes at 50 ℃ to obtain a solution C for later use;
(4) weighing 10mg of m-benzenetricarboxylic acid, dissolving the m-benzenetricarboxylic acid into 1.5mL of ethanol/water (V/V is 1.5:1), adding the solution into the solution C to obtain a solution I, and stirring the solution I at 70 ℃ for 36 hours to obtain copper metal organic framework Cu-MOF;
(5) at the rotating speed of 11000 r/min, the mixture is centrifuged for 5 min by cyclohexane/ethanol (V/V is 1:1), centrifuged for 3 times, and finally dissolved in N, N-dimethylformamide solution for standby.
EXAMPLE 6 Synthesis of Cu-MOF, a copper Metal organic framework Material
(1) Measuring volume ratio 1: 1: 3, stirring the mixture of oleic acid, ethanol and normal hexane at 50 ℃ for 10 minutes to obtain a solution A for later use;
(2) weighing 40mgNaOH, dissolving into 4mL of water, adding into 10mL of A solution, and stirring at 50 ℃ for 10 minutes to obtain B solution for later use;
(3) 50mg of Cu (NO) are weighed out3)2·3H2Dissolving the O in 1mL of water, adding the solution into the solution B, and stirring for 15 minutes at 50 ℃ to obtain a solution C for later use;
(4) weighing 10mg of m-benzenetricarboxylic acid, dissolving the m-benzenetricarboxylic acid into 1.5mL of ethanol/water (V/V is 1.5:1), adding the solution into the solution C to obtain a solution I, and stirring the solution I at 100 ℃ for 2 hours to obtain copper metal organic framework Cu-MOF;
(5) at the rotating speed of 11000 r/min, the mixture is centrifuged for 5 min by cyclohexane/ethanol (V/V is 1:1), centrifuged for 3 times, and finally dissolved in N, N-dimethylformamide solution for standby.
EXAMPLE 7 Synthesis of Cu-MOF, a copper Metal organic framework Material
(1) Measuring volume ratio 1: 1: 3, stirring the mixture of oleic acid, ethanol and normal hexane at 50 ℃ for 10 minutes to obtain a solution A for later use;
(2) weighing 40mgNaOH, dissolving into 4mL of water, adding into 10mL of A solution, and stirring at 50 ℃ for 10 minutes to obtain B solution for later use;
(3) 50mg of Cu (NO) are weighed out3)2·3H2Dissolving the O in 1mL of water, adding the solution into the solution B, and stirring for 15 minutes at 50 ℃ to obtain a solution C for later use;
(4) weighing 10mg of m-benzenetricarboxylic acid, dissolving the m-benzenetricarboxylic acid into 1.5mL of ethanol/water (V/V is 1.5:1), adding the solution into the solution C to obtain a solution I, and stirring the solution I at 200 ℃ for 2 hours to obtain copper metal organic framework Cu-MOF;
(5) at the rotating speed of 11000 r/min, the mixture is centrifuged for 5 min by cyclohexane/ethanol (V/V is 1:1), centrifuged for 3 times, and finally dissolved in N, N-dimethylformamide solution for standby.
EXAMPLE 8 Synthesis of Cu-MOF, a copper Metal organic framework Material
(1) Measuring volume ratio 1: 1: 3, stirring the mixture of oleic acid, ethanol and normal hexane at 50 ℃ for 10 minutes to obtain a solution A for later use;
(2) weighing 40mgNaOH, dissolving into 4mL of water, adding into 10mL of A solution, and stirring at 50 ℃ for 10 minutes to obtain B solution for later use;
(3) 50mg of Cu (NO) are weighed out3)2·3H2Dissolving the O in 1mL of water, adding the solution into the solution B, and stirring for 15 minutes at 50 ℃ to obtain a solution C for later use;
(4) weighing 10mg of m-benzenetricarboxylic acid, dissolving the m-benzenetricarboxylic acid into 1.5mL of ethanol/water (V/V is 1.5:1), adding the solution into the solution C to obtain a solution I, and stirring the solution I at 150 ℃ for 2 hours to obtain copper metal organic framework Cu-MOF;
(5) at the rotating speed of 11000 r/min, the mixture is centrifuged for 5 min by cyclohexane/ethanol (V/V is 1:1), centrifuged for 3 times, and finally dissolved in N, N-dimethylformamide solution for standby.
EXAMPLE 9 Synthesis of Cu-MOF, a copper Metal organic framework Material
(1) Measuring volume ratio 1: 1: 3, stirring the mixture of oleic acid, ethanol and normal hexane at 50 ℃ for 10 minutes to obtain a solution A for later use;
(2) weighing 40mgNaOH, dissolving into 4mL of water, adding into 10mL of A solution, and stirring at 50 ℃ for 10 minutes to obtain B solution for later use;
(3) 50mg of CuCl was weighed out2·3H2O, dissolving the mixture into 1mL of water, adding the mixture into the solution B,stirring for 15 minutes at 50 ℃ to obtain a solution C for later use;
(4) weighing 2.5mg of m-benzenetricarboxylic acid, dissolving the m-benzenetricarboxylic acid into 1.5mL of ethanol/water (V/V is 1.5:1), adding the solution into the solution C to obtain a solution I, and stirring the solution I at 150 ℃ for 48 hours to obtain copper metal organic framework Cu-MOF;
(5) at the rotating speed of 11000 r/min, the mixture is centrifuged for 5 min by cyclohexane/ethanol (V/V is 1:1), centrifuged for 3 times, and finally dissolved in N, N-dimethylformamide solution for standby.
EXAMPLE 10 Synthesis of Cu-MOF, a copper Metal organic framework Material
(1) Measuring volume ratio 1: 1: 3, stirring the mixture of oleic acid, ethanol and normal hexane at 50 ℃ for 10 minutes to obtain a solution A for later use;
(2) weighing 40mgNaOH, dissolving into 4mL of water, adding into 10mL of A solution, and stirring at 50 ℃ for 10 minutes to obtain B solution for later use;
(3) 50mg of Cu (NO) are weighed out3)2Dissolving the mixed solution into 1mL of water, adding the mixed solution into the solution B, and stirring the mixed solution at 50 ℃ for 15 minutes to obtain a solution C for later use;
(4) weighing 50mg of o-carboxyphenylacetic acid, dissolving the o-carboxyphenylacetic acid into 1.5mL of ethanol/water (V/V is 1.5:1), adding the o-carboxyphenylacetic acid into the solution C to obtain a solution I, and stirring the solution I at 100 ℃ for 2 hours to obtain copper metal organic framework Cu-MOF;
(5) at the rotating speed of 11000 r/min, the mixture is centrifuged for 5 min by cyclohexane/ethanol (V/V is 1:1), centrifuged for 3 times, and finally dissolved in N, N-dimethylformamide solution for standby.
EXAMPLE 11 Synthesis of Cu Metal organic framework Material Cu-MOF
(1) Measuring volume ratio 1: 1: 3, stirring the mixture of oleic acid, ethanol and normal hexane at 50 ℃ for 10 minutes to obtain a solution A for later use;
(2) weighing 40mgNaOH, dissolving into 4mL of water, adding into 10mL of A solution, and stirring at 50 ℃ for 10 minutes to obtain B solution for later use;
(3) 50mg of Cu (CH) was weighed3COO)2·H2Dissolving the O in 1mL of water, adding the solution into the solution B, and stirring for 15 minutes at 50 ℃ to obtain a solution C for later use;
(4) weighing 2.5mg of o-carboxyphenylacetic acid, dissolving the o-carboxyphenylacetic acid into 1.5mL of ethanol/water (V/V is 1.5:1), adding the o-carboxyphenylacetic acid into the solution C to obtain a solution I, and stirring the solution I at 150 ℃ for 2 hours to obtain copper metal organic framework Cu-MOF;
(5) at the rotating speed of 11000 r/min, the mixture is centrifuged for 5 min by cyclohexane/ethanol (V/V is 1:1), centrifuged for 3 times, and finally dissolved in N, N-dimethylformamide solution for standby.
EXAMPLE 12 Synthesis of Cu-MOF, a copper Metal organic framework Material
(1) Measuring volume ratio 1: 1: 3, stirring the mixture of oleic acid, ethanol and normal hexane at 50 ℃ for 10 minutes to obtain a solution A for later use;
(2) weighing 40mgNaOH, dissolving into 4mL of water, adding into 10mL of A solution, and stirring at 50 ℃ for 10 minutes to obtain B solution for later use;
(3) 50mg of Cu (CH) was weighed3COOH)2Dissolving the mixed solution into 1mL of water, adding the mixed solution into the solution B, and stirring the mixed solution at 50 ℃ for 15 minutes to obtain a solution C for later use;
(4) weighing 2.5mg of o-carboxyphenylacetic acid, dissolving the o-carboxyphenylacetic acid into 1.5mL of ethanol/water (V/V is 1.5:1), adding the o-carboxyphenylacetic acid into the solution C to obtain a solution I, and stirring the solution I at 150 ℃ for 2 hours to obtain copper metal organic framework Cu-MOF;
(5) at the rotating speed of 11000 r/min, the mixture is centrifuged for 5 min by cyclohexane/ethanol (V/V is 1:1), centrifuged for 3 times, and finally dissolved in N, N-dimethylformamide solution for standby.
EXAMPLE 13 Synthesis of Cu-MOF, a copper Metal organic framework Material
(1) Measuring volume ratio 1: 1: 3, stirring the mixture of oleic acid, ethanol and normal hexane at 50 ℃ for 10 minutes to obtain a solution A for later use;
(2) weighing 40mgNaOH, dissolving into 4mL of water, adding into 10mL of A solution, and stirring at 50 ℃ for 10 minutes to obtain B solution for later use;
(3) 50mg of Cu (NO) are weighed out3)2·3H2Dissolving the O in 1mL of water, adding the solution into the solution B, and stirring for 15 minutes at 50 ℃ to obtain a solution C for later use;
(4) weighing 10mg of benzoic acid, dissolving the benzoic acid into 1.5mL of ethanol/water (V/V is 1.5:1), adding the benzoic acid into the solution C to obtain a solution I, and stirring the solution I at 200 ℃ for 2 hours to obtain copper metal organic framework Cu-MOF;
(5) at the rotating speed of 11000 r/min, the mixture is centrifuged for 5 min by cyclohexane/ethanol (V/V is 1:1), centrifuged for 3 times, and finally dissolved in N, N-dimethylformamide solution for standby.
Example 14 Synthesis of Metal organic framework composite nanomaterial Cu-MOF/TCPP-PEG
(1) The Cu-MOF solution obtained in example 2 was mixed with meso-tetraphenylporphyrin-4, 4 ', 4 ", 4"' -tetracarboxylic acid (TCPP) to obtain a solution M with a mass ratio of Cu-MOF to meso-tetraphenylporphyrin-4, 4 ', 4 ", 4"' -tetracarboxylic acid (TCPP) of 2:1, wherein the concentration of Cu-MOF is 4mg/mL and the concentration of meso-tetraphenylporphyrin-4, 4 ', 4 ", 4"' -tetracarboxylic acid (TCPP) is 2 mg/mL. Stirring the solution M at room temperature for 16 hours, centrifuging, collecting precipitate to obtain an intermediate product I, and dissolving the intermediate product I in a methanol solution for later use;
(2) putting the intermediate product I obtained in the step (1) and amphiphilic polymer phospholipid-polyethylene glycol (DSPE-PEG) into a single-neck flask filled with 50mL of methanol to obtain a solution N, wherein the mass ratio of the intermediate product I to the amphiphilic polymer phospholipid-polyethylene glycol (DSPE-PEG) in the solution N is 2:1, wherein the concentration of the intermediate product I is 4mg/mL, and the concentration of the amphiphilic polymer phospholipid-polyethylene glycol (DSPE-PEG) is 2 mg/mL. After the solution N is dispersed uniformly by ultrasound, the solution N is subjected to rotary evaporation at 40 ℃ to obtain a product Cu-MOF/TCPP-PEG.
Example 15 Synthesis of Metal organic framework composite nanomaterial Cu-MOF/TCPP-PEG
(1) The Cu-MOF solution obtained in example 2 was mixed with meso-tetraphenylporphyrin-4, 4 ', 4 ", 4"' -tetracarboxylic acid (TCPP) to obtain a solution M with a mass ratio of Cu-MOF to meso-tetraphenylporphyrin-4, 4 ', 4 ", 4"' -tetracarboxylic acid (TCPP) of 2:1, wherein the concentration of Cu-MOF is 4mg/mL and the concentration of meso-tetraphenylporphyrin-4, 4 ', 4 ", 4"' -tetracarboxylic acid (TCPP) is 2 mg/mL. Stirring the solution M at room temperature for 16 hours, centrifuging and collecting precipitates to obtain an intermediate product I, and dissolving the intermediate product I in a methanol solution;
(2) putting the intermediate product I obtained in the step (1) and amphiphilic polymer phospholipid-polyethylene glycol (DSPE-PEG) into a single-neck flask filled with 50mL of methanol to obtain a solution N, wherein the mass ratio of the intermediate product I to the amphiphilic polymer phospholipid-polyethylene glycol (DSPE-PEG) in the solution N is 0.5:1, wherein the concentration of the intermediate product I is 4mg/mL, and the concentration of the amphiphilic polymer phospholipid-polyethylene glycol (DSPE-PEG) is 8 mg/mL. After the solution N is dispersed uniformly by ultrasound, the solution N is subjected to rotary evaporation at 40 ℃ to obtain a product Cu-MOF/TCPP-PEG.
Example 16 Synthesis of Metal organic framework composite nanomaterial Cu-MOF/TCPP-PEG
(1) The Cu-MOF solution obtained in example 2 was mixed with meso-tetraphenylporphyrin-4, 4 ', 4 ", 4"' -tetracarboxylic acid (TCPP) to obtain a solution M having a mass ratio of Cu-MOF to meso-tetraphenylporphyrin-4, 4 ', 4 ", 4"' -tetracarboxylic acid (TCPP) of 1:1, wherein the concentration of Cu-MOF is 4mg/mL and the concentration of meso-tetraphenylporphyrin-4, 4 ', 4 ", 4"' -tetracarboxylic acid (TCPP) is 4 mg/mL. Stirring the solution M at room temperature for 16 hours, centrifuging and collecting precipitates to obtain an intermediate product I, and dissolving the intermediate product I in a methanol solution;
(2) putting the intermediate product I obtained in the step (1) and amphiphilic polymer phospholipid-polyethylene glycol (DSPE-PEG) into a single-neck flask filled with 50mL of methanol to obtain a solution N, wherein the mass ratio of the intermediate product I to the amphiphilic polymer phospholipid-polyethylene glycol (DSPE-PEG) in the solution N is 0.5:1, wherein the concentration of the intermediate product I is 4mg/mL, and the concentration of the amphiphilic polymer phospholipid-polyethylene glycol (DSPE-PEG) is 8 mg/mL. After the solution N is dispersed uniformly by ultrasound, the solution N is subjected to rotary evaporation at 40 ℃ to obtain a product Cu-MOF/TCPP-PEG.
Example 17 Synthesis of Metal organic framework composite nanomaterial Cu-MOF/TCPP-PEG
(1) The Cu-MOF solution obtained in example 2 was mixed with meso-tetraphenylporphyrin-4, 4 ', 4 ", 4"' -tetracarboxylic acid (TCPP) to obtain a solution M with a mass ratio of Cu-MOF to meso-tetraphenylporphyrin-4, 4 ', 4 ", 4"' -tetracarboxylic acid (TCPP) of 2:1, wherein the concentration of Cu-MOF is 4mg/mL and the concentration of meso-tetraphenylporphyrin-4, 4 ', 4 ", 4"' -tetracarboxylic acid (TCPP) is 2 mg/mL. Stirring the solution M at room temperature for 4 hours, centrifuging and collecting precipitates to obtain an intermediate product I, and dissolving the intermediate product I in a methanol solution;
(2) putting the intermediate product I obtained in the step (1) and amphiphilic polymer phospholipid-polyethylene glycol (DSPE-PEG) into a single-neck flask filled with 50mL of methanol to obtain a solution N, wherein the mass ratio of the intermediate product I to the amphiphilic polymer phospholipid-polyethylene glycol (DSPE-PEG) in the solution N is 1:1, wherein the concentration of the intermediate product I is 4mg/mL, and the concentration of the amphiphilic polymer phospholipid-polyethylene glycol (DSPE-PEG) is 4 mg/mL. After the solution N is dispersed uniformly by ultrasound, the solution N is subjected to rotary evaporation at 40 ℃ to obtain a product Cu-MOF/TCPP-PEG.
Example 18 Synthesis of Metal organic framework composite nanomaterial Cu-MOF/TCPP-PEG-COOH
(1) The Cu-MOF solution obtained in example 2 was mixed with meso-tetraphenylporphyrin-4, 4 ', 4 ", 4"' -tetracarboxylic acid (TCPP) to obtain a solution M with a mass ratio of Cu-MOF to meso-tetraphenylporphyrin-4, 4 ', 4 ", 4"' -tetracarboxylic acid (TCPP) of 2:1, wherein the concentration of Cu-MOF is 4mg/mL and the concentration of meso-tetraphenylporphyrin-4, 4 ', 4 ", 4"' -tetracarboxylic acid (TCPP) is 2 mg/mL. Stirring the solution M at room temperature for 4 hours, centrifuging and collecting precipitates to obtain an intermediate product I, and dissolving the intermediate product I in a methanol solution;
(2) putting the intermediate product I obtained in the step (1) and amphiphilic polymer carboxylated phospholipid-polyethylene glycol (DSPE-PEG-COOH) into a single-neck flask filled with 50mL of methanol to obtain a solution N, wherein the mass ratio of the intermediate product I to the polymer carboxylated phospholipid-polyethylene glycol (DSPE-PEG-COOH) in the solution N is 0.5:1, wherein the concentration of the intermediate product I is 4mg/mL, and the concentration of the amphiphilic polymer carboxylated phospholipid-polyethylene glycol (DSPE-PEG-COOH) is 8 mg/mL. After the solution N is dispersed uniformly by ultrasound, the solution N is subjected to rotary evaporation at 40 ℃ to obtain a product Cu-MOF/TCPP-PEG-COOH.
Example 19 Metal organic framework composite nanomaterial Cu-MOF/TCPP-PEG-NH2Synthesis of (2)
(1) The Cu-MOF solution obtained in example 2 was mixed with meso-tetraphenylporphyrin-4, 4 ', 4 ", 4"' -tetracarboxylic acid (TCPP) to obtain a solution M with a mass ratio of Cu-MOF to meso-tetraphenylporphyrin-4, 4 ', 4 ", 4"' -tetracarboxylic acid (TCPP) of 4:1, wherein the concentration of Cu-MOF is 4mg/mL and the concentration of meso-tetraphenylporphyrin-4, 4 ', 4 ", 4"' -tetracarboxylic acid (TCPP) is 1 mg/mL. Stirring the solution M at room temperature for 36 hours, centrifuging and collecting precipitates to obtain an intermediate product I, and dissolving the intermediate product I in a chloroform solution;
(2) taking the intermediate product I obtained in the step (1) and amphiphilic polymer amination phospholipid-polyethylene glycol (DSPE-PEG-NH)2) In a single-neck flask containing 50mL of chloroform, a solution N was obtained in which intermediate I was reacted with amphiphilic polymer aminated phospholipid-polyethylene glycol (DSPE-PEG-NH)2) Is 0.5:1, wherein the concentration of the intermediate product I is 5mg/mL, and the amphiphilic polymer aminated phospholipid-polyethylene glycol (DSPE-PEG-NH)2) The concentration of (B) was 2.5mg/mL solution. After the solution N is dispersed uniformly by ultrasound, the solution N is rotated and evaporated at 40 ℃ to obtain a product Cu-MOF/TCPP-PEG-NH2。
Example 20 Synthesis of Metal organic framework composite nanomaterial Cu-MOF/TCPP-PEG
(1) The Cu-MOF solution obtained in example 2 was mixed with meso-tetraphenylporphyrin-4, 4 ', 4 ", 4"' -tetracarboxylic acid (TCPP) to obtain a solution M with a mass ratio of Cu-MOF to meso-tetraphenylporphyrin-4, 4 ', 4 ", 4"' -tetracarboxylic acid (TCPP) of 8:1, wherein the concentration of Cu-MOF is 40mg/mL and the concentration of meso-tetraphenylporphyrin-4, 4 ', 4 ", 4"' -tetracarboxylic acid (TCPP) is 5 mg/mL. Stirring the solution M at room temperature for 48 hours, centrifuging, collecting precipitate, and dissolving in acetone solution;
(2) and (2) dissolving the intermediate product I obtained in the step (1) and amphiphilic polymer phospholipid-polyethylene glycol (DSPE-PEG) in a single-neck flask filled with 50mL of acetone to obtain a solution N, wherein the mass ratio of the intermediate product I to the amphiphilic polymer phospholipid-polyethylene glycol (DSPE-PEG) in the solution N is 0.5:1, the concentration of the intermediate product I is 5mg/mL, the concentration of the amphiphilic polymer phospholipid-polyethylene glycol (DSPE-PEG is 5mg/mL, the solution N is subjected to ultrasonic dispersion uniformly, and then rotary evaporation is carried out at 40 ℃ to obtain a product Cu-MOF/TCPP-PEG.
Example 21 morphology and Structure characterization
The metal organic framework Cu-MOF prepared in the examples is subjected to morphology and structure characterization.
(1) Transmission Electron microscopy characterization (TEM)
Performed on a FEITecnai F20 transmission electron microscope, test conditions: 200Kv, 101. mu.A.
FIG. 1 shows a TEM image of the copper metal organic framework Cu-MOF obtained in example 2.
As can be seen from fig. 1: the grain size of the Cu-MOF with the copper metal organic framework obtained in the embodiment 2 is 70-100 nm. The size meets the requirement of long circulation in vivo, greatly increases the circulation time of the material in blood, and enables the material to realize effective enrichment in tumor tissues through high permeability and retention Effect (EPR) of solid tumors. Meanwhile, as can be seen from the pictures, the copper metal organic framework Cu-MOF obtained in example 2 has high porosity. The test results for other copper metal organic frameworks Cu-MOFs were similar to those of example 2.
(2) Characterization by X-ray diffractometer (XRD)
Performed on an X-ray diffractometer model brueck D8Advance, testing conditions: cu K α target, 5 °/min, 40kV,40 mA.
FIG. 2 shows XRD patterns of Cu-MOF of the Cu metal organic framework obtained in example 2 and Cu-MOF/TCPP-PEG-COOH of the composite nano material with the metal organic framework structure obtained in example 18.
As can be seen from fig. 2: XRD characteristic peaks of the Cu-MOF with the copper metal organic framework obtained in the example 2 and the Cu-MOF/TCPP-PEG-COOH with the metal organic framework composite nano material obtained in the example 18 are consistent, the characteristic peaks are obvious, and the crystal structure is stable.
(3) Meter Intelligent Fourier Infrared Spectroscopy characterization (FT-IR)
Performed on a Thermo NICOLET 6700 intelligent fourier infrared spectrometer.
FIG. 3 shows IR diagrams of the metal-organic framework Cu-MOF obtained in example 2 and the metal-organic framework composite nanomaterial Cu-MOF/TCPP-PEG-COOH obtained in example 18.
As can be seen from FIG. 3, after loading meso-tetraphenylporphyrin-4, 4 '-tetracarboxylic acid, the Cu-MOF/TCPP-PEG-COOH composite nanomaterial of metal-organic framework structure obtained in example 18 showed a Cu-N peak at 999nm, indicating that Cu in the metal-organic framework structure Cu-MOF forms a coordination bond with N in meso-tetraphenylporphyrin-4, 4' -tetracarboxylic acid.
(4) Fluorospectro photometer characterization
The method is carried out on a HITACHI F-4600 fluorescence spectrophotometer, and the test conditions are as follows: ex: 526 nm.
FIG. 4 shows fluorescence emission diagrams of meso-tetraphenylporphyrin-4, 4' -tetracarboxylic acid (TCPP) and the metal-organic framework structure composite nanomaterial Cu-MOF/TCPP-PEG-COOH obtained in example 18.
The fluorescence emission pattern of meso-tetraphenylporphyrin-4, 4 ', 4 ", 4'" -tetracarboxylic acid and the Cu-MOF/TCPP-PEG-COOH synthesized in example 18 under 526nm excitation is shown in FIG. 4. From FIG. 4, it can be seen that meso-tetraphenylporphyrin-4, 4' -tetracarboxylic acid is carried on a metal-organic framework, and fluorescence quenching occurs, and no fluorescence emission occurs.
Example 22 Small animal fluorescence imager characterization
Performed on a PerkinElmer IVIS luminea XRMS, test conditions: ex: 530 nm.
FIG. 5 shows the fluorescence imaging of the metal organic framework composite nanomaterial Cu-MOF/TCPP-PEG obtained in example 18 reacted with glutathione for different times.
The Cu-MOF/TCPP-PEG-COOH synthesized in example 18 was dispersed in PBS and Glutathione (GSH) environment (1M, pH5.5), and the in vitro fluorescence signal of the material was measured by a small animal fluorescence imager, and the result is shown in FIG. 5. As can be seen from fig. 5, after the Cu-MOF/TCPP-PEG-COOH synthesized in example 18 is loaded with meso-tetraphenylporphyrin-4, 4 ', 4 ", 4"' -tetracarboxylic acid, the organic small molecule photosensitizer undergoes fluorescence quenching, and after GSH is added, the organic small molecule photosensitizer recovers fluorescence properties, so that the site-specific release of the organic small molecule photosensitizer at tumor tissue can be realized, and the imaging effect is improved.
Although the present application has been described with reference to a few embodiments, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the application as defined by the appended claims.

Claims (10)

1. The metal-organic framework composite nanomaterial is characterized in that the metal-organic framework composite nanomaterial comprises a functional material and a copper metal organic framework carrying the functional material; wherein the functional material comprises small organic molecules.
2. The metal-organic framework composite nanomaterial according to claim 1, characterized in that the copper metal-organic framework is obtained by reacting a compound containing copper metal ions with an organic ligand;
preferably, the particle size of the copper metal organic framework is 40-300 nm; the porosity of the copper metal organic frame is 50-600m2/g；
Preferably, the method for preparing the copper metal organic framework comprises the following steps: reacting a compound containing copper metal ions and a solution I of an organic ligand for 1-48 hours at the temperature of 0-200 ℃ to obtain the copper metal organic framework;
preferably, the solvent of the solution I is at least one selected from water, methanol, ethanol, propanol, ethylene glycol, glycerol, N-hexane, cyclohexane, chloroform, N-dimethylformamide, acetonitrile, tetrahydrofuran, pyridine, and oleic acid;
preferably, the compound containing copper metal ions is selected from at least one of nitrate, chloride, acetate, nitrate hydrate, chloride hydrate and acetate hydrate of metal copper;
preferably, the organic ligand is selected from at least one of o-m-benzoic acid, o-phthalic acid, m-benzenetricarboxylic acid, 3-acetylbenzoic acid, 3-mercaptobenzoic acid, 4-hydroxymethylbenzoic acid, 4-tert-butylbenzoic acid, 4-ethoxybenzoic acid, p-cyclohexylbenzoic acid, 4- (aminomethyl) benzoic acid, 4-aminobenzoic acid, 5-aminoisophthalic acid, o-carboxyphenylacetic acid;
preferably, the mass ratio (mg/mg) of the copper ion-containing compound to the organic ligand is (40-50): (2.5-50);
preferably, in the solution I, the concentration of the compound containing copper metal ions is 1-5 mg/mL; the concentration of the organic ligand is 0.1-5 mg/mL.
3. The metal-organic framework composite nanomaterial according to claim 1, characterized in that the small organic molecules are selected from at least one of protoporphyrin and its derivatives, tetraphenylporphyrin tetrasulfonic acid and its derivatives, 5, 10, 15, 20-tetrakis (4-pyridyl) porphyrin and its derivatives, 5, 10, 15, 20-tetrakis (4-methoxyphenyl) porphyrin and its derivatives, 5- (4-carboxyphenyl) -10, 15, 2-triphenylporphyrin and its derivatives, m-tetraphenylporphyrin and its derivatives, meso-tetraphenylporphyrin-4, 4 ', 4 ", 4"' -tetracarboxylic acid and its derivatives;
preferably, the organic small molecule is fixed on the copper metal organic framework through a coordination bond;
preferably, the loading amount of the organic micromolecules in the metal-organic framework composite nanometer material is 10-80 wt%.
4. The metal-organic framework composite nanomaterial of claim 1, further comprising an amphiphilic polymer; wherein the content of the first and second substances,
the amphiphilic polymer is coated on the outermost layer;
preferably, the amphiphilic polymer is selected from at least one of phospholipid-polyethylene glycol, carboxylated phospholipid polyethylene glycol, aminated phospholipid polyethylene glycol, hydroxylated phospholipid polyethylene glycol, sulfhydrylated phospholipid polyethylene glycol and polyoxyethylene polyoxypropylene ether;
preferably, the content of the amphiphilic polymer in the metal-organic framework composite material is 20-60 wt%.
5. The metal-organic framework composite nanomaterial according to claim 1, wherein the particle size of the metal-organic framework composite nanomaterial is 40-300 nm.
6. A preparation method of the metal organic framework composite nano material as claimed in any one of claims 1 to 5, characterized by comprising the following steps: reacting a raw material I containing a copper metal organic framework and small organic molecules to obtain the metal organic framework composite nano material.
7. The preparation method of the metal organic framework composite nanomaterial according to claim 6, wherein the mass ratio of the copper metal organic framework to the small organic molecules is 2-8: 1.
8. the method for preparing metal organic framework composite nanomaterial according to claim 6, characterized in that the method comprises the following steps:
(S1) reacting the solution M containing the copper metal organic framework and the organic micromolecules for 4-48 hours at 10-30 ℃ to obtain an intermediate product I;
(S2) carrying out ultrasonic dispersion on the solution N containing the intermediate product I and the amphiphilic polymer to obtain the metal-organic framework composite nano material;
preferably, the solvent of the solution M and the solution N is at least one selected from methanol, chloroform, acetone ethanol, propanol, ethylene glycol, glycerol, N-hexane, cyclohexane, N-dimethylformamide, acetonitrile, tetrahydrofuran and pyridine;
preferably, the concentration of the copper metal organic framework in the solution M is 2-40 mg/mL;
preferably, the concentration of the small organic molecules in the solution M is 1-5 mg/mL;
preferably, the concentration of the intermediate product I in the solution N is 2-8 mg/mL.
9. The preparation method of the metal-organic framework composite nanomaterial according to claim 6, wherein the concentration of the amphiphilic polymer in the solution N is 2-8 mg/mL.
10. The application of the metal organic framework composite nano material as defined in any one of claims 1 to 5 and/or the metal organic framework composite nano material prepared by the preparation method as defined in any one of claims 6 to 9 as a tumor microenvironment responsive drug or a tumor fluorescence imaging agent.
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