Drug-loading metal organic framework material as well as preparation method and application thereof

Abstract

The invention discloses a drug-loading metal organic framework material, a preparation method thereof and an application of the drug-loading metal organic framework material in drug entrapment. According to the metal organic framework material, 4, 4 ', 5, 5'-tetrabenzoic acid dibenzo-18-crown-6 serves as an organic ligand, potassium ions serve as a metal center, and 4, 4 ', 5, 5'-tetrabenzoic acid dibenzo-18-crown-6 is coordinated with K < + > through carboxylic acid groups in molecules of 4, 4 ', 5, 5'-tetrabenzoic acid dibenzo-18-crown-6. The preparation method comprises the following step: carrying out solvothermal reaction on 4, 4 ', 5, 5'-tetrabenzoic acid dibenzo-18-crown-6 and a potassium source in a solvent to obtain the metal organic framework material. The metal organic framework material capable of loading the medicine is a good medicine carrier, the preparation method is simple and convenient, vancomycin and other medicines can be loaded through a simple soaking method, and good medicine loading efficiency and biological medicine application prospects are shown.

Description

Technical Field

[0001] The present invention relates to the technical field of metal organic framework materials, and in particular to a metal organic framework material capable of carrying drugs, and a preparation method and application thereof. Background Art

[0002] Metal-organic frameworks (MOFs) are organic-inorganic hybrid materials with periodic network structures formed by the self-assembly of metal ions or metal clusters and organic ligands. This unique structure endows MOFs with a range of excellent properties, giving them great application potential in a wide range of fields.

[0003] In recent years, MOFs have demonstrated revolutionary potential in biomedicine, particularly in drug delivery systems. Their high surface area and porous structure enable efficient loading of drug molecules, including small molecules, proteins, and nucleic acids. Their pore size can be precisely controlled at the nanometer scale, enabling drug entrapment and slow release, thereby prolonging the duration of drug action and reducing dosing frequency. Furthermore, MOFs can be designed to be sensitive to specific physiological conditions (such as pH, temperature, and reducing agents), enabling intelligent controlled drug release. Despite their numerous advantages, most MOFs are based on transition metals, and their potential toxicity limits their biomedical applications. Therefore, developing highly biocompatible MOFs is a key research focus.

[0004] Potassium (K + As the second most abundant metal element in organisms, potassium possesses excellent biocompatibility. The design and synthesis of MOFs using potassium can effectively address the metal toxicity issues of traditional MOFs. The development of potassium-based MOFs with potassium ions as the metal core not only overcomes the limitations of traditional MOFs in terms of pore structure and biocompatibility, but also provides a safe and efficient new carrier platform for drug delivery systems.

[0005] After searching, the following prior art is available: Patent specification CN110025592A discloses cyclodextrin-metal-organic framework (CD-MOF) composite microspheres and their preparation method. The composite microspheres are prepared by encapsulating a drug-loaded metal-organic framework (MOF) complex with ethyl cellulose as a protective agent. The preparation method involves uniformly mixing and dispersing the drug-loaded CD-MOF with a predetermined proportion of ethyl cellulose solution. The microspheres are then prepared in a single step using high-speed rotation and solvent evaporation in an ultrafine particle preparation system. The CD-MOF is an organic framework material composed of β-cyclodextrin as an organic ligand and potassium ions as inorganic metal centers.

[0006] Patent specification CN117224702A discloses a cross-linked cyclodextrin metal-organic framework (CMMF) capable of loading ibuprofen and a method for its preparation. The preparation method comprises the following steps: ibuprofen and gamma-cyclodextrin are mixed and dissolved in potassium hydroxide, filtered, and methanol evaporated and diffused into the solution for a first crystallization. A certain volume of the reaction solution is then taken and cetyltrimethylammonium bromide and methanol are added for a second crystallization to produce ibuprofen-loaded CDMOFs. The ibuprofen-loaded CDMOFs are then dissolved in DMF solvent and the crosslinker isophorone diisocyanate is added to produce ibuprofen-loaded CLCDMOFs. This cross-linked cyclodextrin metal-organic framework can load ibuprofen, is stable in water, and delays drug release, providing a reference for the preparation of oral liquid ibuprofen preparations with sustained-release properties. Summary of the Invention

[0007] The present invention provides a drug-carrying metal organic framework material and a preparation method and application thereof.

[0008] The specific technical solutions are as follows: In the first aspect, the present invention provides a drug-carrying metal organic framework material, wherein the metal organic framework material uses 4,4',5,5'-tetrabenzoic acid dibenzo-18-crown-6 as an organic ligand and potassium ion as a metal center, and 4,4',5,5'-tetrabenzoic acid dibenzo-18-crown-6 binds to K through the carboxylic acid group in its molecule. + coordination.

[0009] The 4,4',5,5'-tetrabenzoic acid dibenzo-18-crown-6 described in the present invention is a prior art, for example, see the literature Adv. Sci. 2024, 11 , 2308663 (DOI: 10.1002 / advs.202308663), etc., which has the following molecular structure: .

[0010] Furthermore, the drug-loaded metal-organic framework material has the following single crystal structure data:

[0011] Furthermore, the drug-loaded metal organic framework material is c There are two different sized pores in the axial direction, and the diameters of the two different sized pores are 3.3 nm and 1.2 nm respectively.

[0012] Furthermore, the specific surface area of ​​the drug-loaded metal organic framework material is greater than 1000 m 2 / g, for example, up to 1034 m 2 / g.

[0013] In a second aspect, the present invention provides a method for preparing the drug-loaded metal organic framework material described in the first aspect, comprising: subjecting 4,4',5,5'-tetrabenzoic acid dibenzo-18-crown-6 and a potassium source to a solvothermal reaction in a solvent to obtain the metal organic framework material.

[0014] In the method for preparing the drug-loaded metal-organic framework material, the potassium source is preferably potassium chloride.

[0015] In the method for preparing the drug-loaded metal-organic framework material, the molar ratio of the 4,4',5,5'-tetrabenzoic acid dibenzo-18-crown-6 to the potassium in the potassium source is preferably 1:1.

[0016] In the method for preparing the drug-loaded metal-organic framework material, the solvent is preferably N,N-dimethylformamide (DMF) and ethanol. Furthermore, the volume ratio of the N,N-dimethylformamide to the ethanol is preferably 4:1.

[0017] In the method for preparing the drug-loaded metal-organic framework material, the usage ratio of the solvent to the 4,4',5,5'-tetrabenzoic acid dibenzo-18-crown-6 is preferably 10 mL:20 mg.

[0018] In the method for preparing the drug-loaded metal-organic framework material, the temperature of the solvent thermal reaction is preferably 70-90°C, such as 85°C.

[0019] In the method for preparing the drug-loaded metal-organic framework material, the solvent thermal reaction time is preferably 24 hours.

[0020] In the method for preparing the drug-loaded metal-organic framework material, the solvent thermal reaction is preferably an open reaction.

[0021] In the method for preparing the drug-loaded metal-organic framework material, the solvothermal reaction is preferably carried out under acidic conditions. Furthermore, the acidic conditions are preferably at a pH of 2 to 4. The acidic conditions are preferably achieved by adding hydrochloric acid.

[0022] Preferably, the method for preparing the drug-loaded metal-organic framework material further comprises: after the solvothermal reaction is completed, cooling and collecting the crystals, washing, and drying to obtain the metal-organic framework material. The crystals are preferably washed with N,N-dimethylformamide and / or water. The drying temperature is preferably 35-45°C, for example, 40°C. The drying time is preferably 12 hours.

[0023] In a third aspect, the present invention provides the use of the drug-loaded metal organic framework material described in the first aspect in drug encapsulation, wherein the drug may be vancomycin or the like.

[0024] In a fourth aspect, the present invention provides a drug-loaded metal-organic framework composite, comprising the drug-loaded metal-organic framework described in the first aspect and a drug loaded within the drug-loaded metal-organic framework. The drug may be vancomycin, for example.

[0025] In a fifth aspect, the present invention provides a method for preparing the drug-entrapped metal-organic framework composite described in the fourth aspect, comprising: thoroughly stirring the drug-entrapped metal-organic framework and the drug in a mixture of water and ethanol to allow the drug-entrapped metal-organic framework to entrap the drug; then performing solid-liquid separation, washing the solid to remove any unentrapped drug residue, and drying to obtain the drug-entrapped metal-organic framework composite. Furthermore, the volume ratio of water to ethanol in the water-ethanol mixture can be, for example, 2:1. Furthermore, the stirring can be performed in the dark, at a speed of 500 rpm, for a duration of 12 hours, for example. Furthermore, the solid-liquid separation method can be centrifugation, at a speed of 5000 rpm, for a duration of 10 minutes, for example. Furthermore, the solid can be washed with N,N-dimethylformamide and / or water and / or ethanol to remove any unentrapped drug residue. Furthermore, the drying temperature may be 35-45° C., for example, 40° C., and the drying time may be 12 hours.

[0026] Compared with the prior art, the present invention has the following beneficial effects: The drug-loaded metal-organic framework material of the present invention is a good drug carrier with a simple preparation method. It can load drugs such as vancomycin by a simple immersion method, showing good drug loading efficiency and biomedical application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 The diagram shows the one-dimensional pore structure of the drug-carrying metal organic framework material of the present invention, and the coordination binding mode of the potassium ion metal center and 4,4'5,5'-tetrabenzoic acid dibenzo-18-crown-6.

[0028] Figure 2 This is a scanning electron microscope photograph of the metal organic framework material prepared in Example 1. The scale in the figure is 10 μm.

[0029] Figure 3 This is a scanning electron microscope element distribution diagram of the metal organic framework material prepared in Example 1. The scale in the figure is 5 μm.

[0030] Figure 4This is a nitrogen adsorption-desorption curve of the metal organic framework material prepared in Example 1.

[0031] Figure 5 This is the UV absorption standard curve of vancomycin.

[0032] Figure 6 This is a diagram showing the drug loading efficiency of vancomycin by the metal organic framework material prepared in Example 1. DETAILED DESCRIPTION

[0033] The present invention will be further described below with reference to the accompanying drawings and specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0034] Example 1: 20 mg of dibenzo-18-crown-6-4,4',5,5'-tetrabenzoate and 1.77 mg of potassium chloride were weighed and dissolved in 10 mL of a mixed solvent consisting of N,N-dimethylformamide and ethanol in a 4:1 volume ratio. Dilute hydrochloric acid was added to adjust the pH to 2-4. The mixture was magnetically stirred at room temperature until completely dissolved. The mixed solution was transferred to a glass bottle and placed in an open oven at 85°C for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, and the resulting colorless crystals were collected by filtration, washed sequentially with DMF and water, and finally dried at 40°C for 12 hours to obtain a drug-loaded metal-organic framework. Figure 1 The one-dimensional pore structure of the drug-loaded metal-organic framework material, the coordination binding mode of the potassium ion metal center and 4,4'5,5'-tetrabenzoic acid dibenzo-18-crown-6 were demonstrated. The results showed that the potassium ion metal center formed a 6-coordination mode with four carboxyl groups and two water molecules, and presented an ordered pore structure, showing certain drug encapsulation potential. Figure 2 and Figure 3 The scanning electron microscope photograph and scanning electron microscope element distribution map of the metal organic framework material prepared in Example 1 respectively indicate that the synthesized metal organic framework material has a regular and uniform morphology. Elemental analysis shows that the synthesized metal organic framework material contains C, O, and K elements, further supporting the above-mentioned coordination mode analysis with potassium ions as the metal center and carboxyl groups as the coordinating functional groups.

[0035] The metal organic framework material prepared in Example 1 has the following single crystal structure data:

[0036] The undried metal-organic framework material from Example 1 was washed with ether and then immersed in ether overnight, ensuring that the sample settled to the bottom. The sample was then subjected to conventional solvent exchange with liquid carbon dioxide. After activation with supercritical carbon dioxide, the treated metal-organic framework sample was placed in a vacuum desiccator to remove moisture and organic solvent from the sample. The sample was then transferred to a sample tube near a Quantachrome Autosorb-IQ2 adsorption instrument. Before the adsorption test, the sample was degassed to remove surface-adsorbed impurities. The degassing temperature was set to 120°C and the degassing time was set to at least 6 hours, until the sample weight change stabilized. After degassing, the nitrogen adsorption test was initiated. Using liquid nitrogen as a cooling bath, liquid nitrogen was injected into the adsorption instrument's Dewar flask to the specified liquid nitrogen level. Under a nitrogen atmosphere, the nitrogen pressure was gradually increased in 10 kPa increments, and the amount of nitrogen adsorbed at each pressure point was recorded. After each pressure point was increased, the system was allowed to reach equilibrium and the data was recorded. After adsorption, the desorption test was performed. Slowly reduce the nitrogen pressure and record the amount of nitrogen desorbed at different pressures. Calculate the specific surface area of ​​the metal-organic framework using the Brunauer-Emmett-Teller (BET) method using the data processing software provided with the adsorption instrument. Figure 4 This is a nitrogen adsorption-desorption curve of the metal-organic framework material prepared in Example 1. The results show that the synthesized metal-organic framework material has a good pore structure and exhibits a large specific surface area, further supporting its application as a drug carrier.

[0037] Example 2: 10 mg of the metal-organic framework material synthesized in Example 1 and 20 mg of vancomycin were weighed separately and added to a 10 mL reaction flask. 6 mL of a mixed solution of water and ethanol with a volume ratio of 2:1 was then added. The reaction flask was placed in a dark place and stirred at 500 rpm for 12 hours at room temperature. After stirring, the mixture was centrifuged at 5000 rpm for 10 minutes, and the precipitate was collected. The precipitate was washed three times with deionized water and ethanol respectively to remove unloaded vancomycin. Finally, the obtained drug-loaded metal-organic framework material was vacuum-dried at 40°C for 12 hours to obtain a metal-organic framework material complex loaded with the drug, i.e., a vancomycin-loaded metal-organic framework material.

[0038] Accurately weigh an appropriate amount of vancomycin hydrochloride standard, dissolve it in ultrapure water, and dilute to a desired volume to prepare a 1 mg / mL vancomycin stock solution. Store at -20°C. Take appropriate amounts of the stock solution and dilute it with ultrapure water to prepare standard solutions of varying concentrations, such as 10 μg / mL, 20 μg / mL, 50 μg / mL, 100 μg / mL, and 200 μg / mL. Store in brown bottles protected from light. Scan the UV absorption spectrum of the vancomycin solution in the wavelength range of 200–400 nm using a UV-visible spectrophotometer, and determine its maximum absorption wavelength at approximately 230 nm. Take each of the above vancomycin standard solutions of varying concentrations and place them in a cuvette. Measure the absorbance at the wavelength of maximum absorption. Use data processing software to construct a standard curve, with the vancomycin concentration (μg / mL) plotted on the abscissa (X) and the corresponding absorbance value plotted on the ordinate (Y). The linear regression equation was calculated using the least squares method, and the correlation coefficient R was calculated. 2 =0.9949, indicating that the absorbance value of vancomycin has a good linear relationship with the concentration within the selected concentration range. Figure 5 shown.

[0039] The sample to be tested (vancomycin-loaded metal-organic framework) is diluted appropriately with ultrapure water and placed in a cuvette. Measure the absorbance of the sample solution at the selected maximum absorption wavelength. Substitute the measured absorbance value into the linear regression equation of the standard curve to calculate the vancomycin concentration in the sample. Figure 6 The drug loading capacity of the synthesized metal-organic framework material for vancomycin hydrochloride is shown in Figure 2. The results show that the synthesized metal-organic framework material can achieve good drug loading, with a drug loading capacity of up to 40wt% (based on the mass of the metal-organic framework material).

[0040] In addition, it should be understood that after reading the above description of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A drug-loaded metal-organic framework material, characterized in that: The metal organic framework material uses 4,4',5,5'-tetrabenzoic acid dibenzo-18-crown-6 as an organic ligand and potassium ion as a metal center. 4,4',5,5'-tetrabenzoic acid dibenzo-18-crown-6 binds to K through the carboxylic acid group in its molecule. + coordination.

2. The drug-loaded metal-organic framework material according to claim 1, characterized in that: The metal organic framework material has the following single crystal structure data: 。 3. The drug-loaded metal-organic framework material according to claim 1 or 2, characterized in that: The metal organic framework material c There are two different sized pores in the axial direction, with diameters of 3.3 nm and 1.2 nm respectively; The specific surface area of ​​the metal organic framework material is greater than 1000 m 2 / g.

4. The method for preparing a drug-loaded metal-organic framework material according to any one of claims 1 to 3, characterized in that: include: The metal organic framework material is obtained by subjecting 4,4',5,5'-tetrabenzoic acid dibenzo-18-crown-6 and a potassium source to a solvothermal reaction in a solvent.

5. The method for preparing a drug-loaded metal-organic framework material according to claim 4, characterized in that: The potassium source is potassium chloride; The molar ratio of the 4,4',5,5'-tetrabenzoic acid dibenzo-18-crown-6 to the potassium in the potassium source is 1:1; The solvent is N,N-dimethylformamide and ethanol; the volume ratio of the N,N-dimethylformamide to the ethanol is 4:1; The ratio of the solvent to the dibenzo-18-crown-6-tetrabenzoate is 10 mL:20 mg; The temperature of the solvent thermal reaction is 70-90°C; The solvent thermal reaction time is 24 hours; The solvent thermal reaction is an open reaction; The solvent thermal reaction is carried out under acidic conditions; the acidic conditions are pH=2~4; The acidic condition is achieved by adding hydrochloric acid; The method for preparing the drug-loaded metal organic framework material further comprises: after the solvothermal reaction is completed, cooling and collecting crystals, washing, and drying to obtain the metal organic framework material; washing the crystals with N,N-dimethylformamide and / or water; The drying temperature is 35-45°C; The drying time is 12 hours.

6. Use of the drug-loaded metal-organic framework material according to any one of claims 1 to 3 in drug encapsulation.

7. The use according to claim 6, characterized in that The drug is vancomycin.

8. A drug-loaded metal-organic framework composite, characterized in that: The invention comprises the drug-loaded metal-organic framework material according to any one of claims 1 to 3 and a drug contained in the drug-loaded metal-organic framework material.

9. The drug-loaded metal-organic framework composite according to claim 8, characterized in that: The drug is vancomycin.

10. The method for preparing a drug-loaded metal-organic framework composite according to claim 8 or 9, characterized in that: include: The drug-loaded metal-organic framework material and the drug are fully stirred in a mixture of water and ethanol to allow the drug-loaded metal-organic framework material to encapsulate the drug, and then the solid-liquid separation is performed to remove the residual drug that is not encapsulated, and the solid is washed and dried to obtain the drug-encapsulated metal-organic framework material complex.

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