A cerium-based metal-organic framework material, its preparation method and applications

Abstract

This invention belongs to the field of supramolecular chemistry, specifically relating to a cerium-based metal-organic framework (Ce-MOF) material, its preparation method, and its applications. The ultrasound-assisted soft template synthesis method of this invention accelerates the reaction of metal ions and organic ligands on the surface of a soft template in a short time, synthesizing core-shell structured Ce-MOF spheres in one step. The method of this invention is simple, quick, and efficient, requiring only 5-10 minutes for the entire synthesis process, which can be completed at room temperature under mild reaction conditions. Furthermore, the hollow Ce-MOF material synthesized by this method retains the antioxidant enzyme activity of Ce-MOF, effectively scavenging reactive oxygen species. Its hollow structure also provides the potential for highly efficient drug delivery, showing broad application prospects in the treatment of neurological injuries.

Description

Technical Field

[0001] This invention belongs to the field of supramolecular chemistry technology, specifically relating to a cerium-based metal-organic framework (Ce-MOF) material, its preparation method, and its applications. Background Technology

[0002] In recent years, metal-organic frameworks (MOFs) have attracted much attention due to their diverse structures and functions, high specific surface area, high catalytic activity, and good biocompatibility, and have been widely used in various fields such as catalysis, energy storage, adsorption and separation, disease diagnosis, and biomedical therapy. By adjusting the type or ratio of metal salts and organic compounds, introducing hybrids, introducing templates, etching, and calcination, MOF materials and their derivatives with various morphologies, including crystals, sheets, core-shell structures, and nanoflowers, can be prepared. Among these, the core-shell structure has high mass transfer efficiency and can be used for drug loading, making it one of the most widely studied structures in the biomedical field.

[0003] Currently, the mainstream methods for synthesizing hollow MOF materials include the template method, the interface method, and the etching method. Each of these methods has its own advantages and limitations in preparing ideal hollow MOFs. (1) The template method precisely controls the morphology of MOFs through templates, but the complex multi-step operation, such as the controllability of MOF growth on the template and the suitability of template removal conditions, limits its widespread application. (2) The interface method utilizes the reaction of metal ions and organic ligands at the interface to form a thin MOF layer. This method is convenient and fast, but the control of morphology needs to be improved. (3) The etching method selectively etches the core inside the MOF, retaining only its MOF shell. However, since most MOF materials are pH sensitive, the etching process has extremely high requirements and is difficult to apply on a large scale.

[0004] To address the challenges of synthesizing hollow MOFs, the inventors have proposed an ultrasound-assisted soft template synthesis method. This method accelerates the reaction of metal ions and organic ligands on the soft template surface using ultrasound within a short time, enabling the one-step synthesis of core-shell structured Ce-MOF spheres. Compared to common hydrothermal, etching, and calcination methods, this invention is simpler, faster, and requires only 5-10 minutes for the entire synthesis process. Furthermore, the reaction conditions are mild, allowing completion at room temperature without the need for prolonged high-temperature and high-pressure reactions. This method is of great significance for the mass production of hollow MOF materials.

[0005] Furthermore, the hollow Ce-MOF material synthesized by the method of this invention retains the antioxidant enzyme activity of Ce-MOF, which can effectively scavenge reactive oxygen species. At the same time, its hollow structure provides the potential for efficient drug loading, and it has broad application prospects in the treatment of diseases such as nerve injury. Summary of the Invention

[0006] In order to overcome the defects and shortcomings of the existing technology, the inventors provide a cerium-based metal-organic framework (Ce-MOF) material, its preparation method and uses.

[0007] To achieve the objectives of this invention, the following technical solution is adopted: In a first aspect, the present invention provides a method for preparing a cerium-based metal-organic framework (Ce-MOF) material, the method comprising the following steps: (1) Add acetic acid, Prönnicke F127 (F127), 1,3,5-trimethylbenzene (TMB) and 1,4-terephthalic acid (H2BDC) to a mixed solution of deionized water and anhydrous ethanol, and shake to dissolve completely; (2) Use an ultrasonic disruptor to intermittently sonicate the solution in step (1) until it becomes an emulsion, with a sonication time of 10 to 30 seconds; (3) Add Ce salt to the emulsion in step (2) and continue sonication for 5-10 minutes; (4) Stop the sonication, centrifuge to collect the precipitate, wash with organic solvent and dry to obtain hollow spherical Ce-MOF nanoparticles.

[0008] As an optional method, in the above preparation method, in step (1), the volume ratio of deionized water to anhydrous ethanol is 1:1, and in the mixture prepared in step (1), the concentration of acetic acid is 5% by volume, the concentration of F127 is 25~40 mg / mL, the concentration of TMB is 10~25 mg / mL, and the concentration of H2BDC is 0.0125 mol / L.

[0009] As an optional method, in the above preparation method, in step (2), the ultrasonic power of the intermittent ultrasound is 270W, and the ultrasound is turned on for 1 second and turned off for 2 seconds as one cycle, lasting for 20-30 seconds.

[0010] As an optional approach, in the above preparation method, in step (3), the molar ratio of Ce salt to H2BDC is 1:1, and the Ce salt is selected from one or more of the following: cerium ammonium nitrate, cerium nitrate hexahydrate, cerium acetate or cerium chloride, and the ultrasonic conditions are the same as in step (2).

[0011] Preferably, the Ce salt is cerium ammonium nitrate.

[0012] As an optional method, in the above preparation method, in step (4), the sonication is stopped, the reaction solution is centrifuged at 4°C and 8000 rpm, the precipitate is taken, washed with an organic solvent, and then dried in an oven at 50°C. The organic solvent is selected from one or more of the following: ethanol, acetone or dimethyl sulfoxide.

[0013] Preferably, in step (4), acetone and anhydrous ethanol are used for alternating washing.

[0014] In a second aspect, the present invention provides a method for preparing Ce-MOF drug-loaded materials, wherein hollow spherical Ce-MOF nanoparticles prepared by the preparation method described in the first aspect are ultrasonically dispersed with a drug in an appropriate amount of organic solvent, mixed uniformly in a shaker, centrifuged to collect the precipitate, and washed to obtain drug-loaded Ce-MOF particles.

[0015] Alternatively, in the above preparation method, the organic solvent is anhydrous ethanol, the centrifugation conditions are 4°C and 8000 rpm, and the drug is a drug or active factor with neuroprotective effects, such as curcumin, rapamycin, puerarin, ginsenosides, neurotrophic factors, etc.

[0016] Preferably, the drug is curcumin.

[0017] Preferably, in step (4), anhydrous ethanol and deionized water are used for washing.

[0018] In a third aspect, the present invention provides hollow Ce-MOF materials prepared by the preparation method described in the first aspect above, or drug-loaded Ce-MOF materials prepared by the preparation method described in the second aspect above.

[0019] In a fourth aspect, the present invention provides the use of the hollow Ce-MOF material or drug-loaded Ce-MOF material described in the fourth aspect above in the preparation of medicaments for treating nerve injury diseases.

[0020] Preferably, the neurological injury disease is selected from one or more of the following: traumatic brain injury, traumatic spinal cord injury, ischemic stroke, Alzheimer's disease, or Parkinson's disease.

[0021] Compared with the prior art, the present invention has the following advantages: (1) The ultrasound-assisted soft template synthesis method proposed by the inventors can accelerate the reaction of metal ions and organic ligands on the surface of a soft template in a short time, and synthesize core-shell structured Ce-MOF spheres in one step. Compared with common hydrothermal, etching and calcination methods, the method of the present invention is simple and easy to implement, and takes only 5 to 10 minutes for the entire synthesis process. Moreover, the reaction conditions are mild and can be completed at room temperature without long-term high-temperature and high-pressure reaction, which is of great significance for the mass production of hollow MOF materials.

[0022] (2) The hollow Ce-MOF material synthesized by the method of the present invention retains the antioxidant enzyme activity of Ce-MOF and can effectively scavenge reactive oxygen species. At the same time, its hollow structure provides the potential for efficient drug loading. It has been verified that the loading rate of the neuroprotective drug curcumin is 27.42%. The Ce-MOF loaded with the drug achieved good therapeutic effects in the nerve injury cell model and has broad application prospects in the treatment of nerve injury and other diseases. Attached Figure Description

[0023] The accompanying drawings are provided to further illustrate the invention and form part of the specification. They are used in conjunction with embodiments of the invention to explain the invention and do not constitute a limitation thereof. In the drawings: Figure 1 TEM image of hollow spherical Ce-MOF nanoparticles prepared in Example 1.

[0024] Figure 2 FTIR spectra of hollow spherical Ce-MOF nanoparticles prepared in Example 1.

[0025] Figure 3 XRD patterns of hollow spherical Ce-MOF nanoparticles prepared in Example 1.

[0026] Figure 4 Ce-MOF SEM images were synthesized using a soft template method without ultrasound assistance at room temperature.

[0027] Figure 5 Peroxidase-like (POD) activity of hollow Ce-MOF.

[0028] Figure 6 JC-1 staining images of HT22 cells under oxidative stress incubated with hollow Ce-MOF and Cur@Ce-MOF.

[0029] Figure 7 Quantitative analysis of red fluorescence in JC-1 HT22 cells under oxidative stress incubated with hollow Ce-MOF and Cur@Ce-MOF.

[0030] Figure 8 Cytotoxicity results of hollow Ce-MOF. Detailed Implementation

[0031] The present invention will be further described below with reference to specific embodiments. It should be understood that the specific embodiments described herein are for illustrative purposes only and are not intended to limit the scope of the invention.

[0032] Where specific techniques or conditions are not specified in the examples, they shall be performed in accordance with the techniques or conditions described in the literature in this field, or in accordance with the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased through legitimate channels.

[0033] Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods. Unless otherwise specified, the experimental materials used in the following embodiments are commercially available products.

[0034] Preparation Example: Preparation Example 1: Preparation of Hollow Spherical Ce-MOF Nanoparticles (1) In a 20 mL mixture of deionized water and anhydrous ethanol (volume ratio 1:1), add 1 mL of acetic acid, 600 mg of F127, 400 μL of TMB and 41.5 mg of H2BDC, and shake to dissolve completely; (2) Place the solution in step (1) in an ice-water bath and use an ultrasonic disruptor to intermittently sonicate it until it becomes an emulsion. The ultrasonic power is 270W, and the ultrasonic cycle is 1 second on and 2 seconds off, with a duration of 30 seconds. (3) Add cerium ammonium nitrate with a molar ratio of 1:1 to H2BDC to the emulsion in step (2), and continue sonication for 5 to 10 minutes under the above ultrasonic conditions; (4) Stop the sonication, centrifuge the reaction solution at 4℃ and 8000 rpm, take the precipitate, wash it alternately with acetone and anhydrous ethanol, and then dry it in an oven at 50℃. The product obtained is hollow spherical Ce-MOF nanoparticles.

[0035] Subsequently, the inventors characterized the hollow spherical Ce-MOF nanoparticles synthesized using the method described in Preparation Example 1. The hollow spherical Ce-MOF nanoparticles synthesized using the method described in Preparation Example 1 were uniformly dispersed in anhydrous ethanol and diluted to a suitable concentration. They were then dropped onto a copper grid covered with a carbon film, dried at room temperature, and observed and photographed using a transmission electron microscope (TEM).

[0036] The results are as follows Figure 1 As shown, the Ce-MOF nanoparticles synthesized using the method described in Example 1 exhibit a complete hollow spherical structure with a particle size between 300 and 400 nm. Qualitative analysis of the above samples was performed using Fourier transform infrared spectroscopy (FTIR), and the results are as follows. Figure 2 As shown, compared with H2BDC, the stretching vibration frequency of the carbonyl group in the synthesized Ce-MOF is reduced from 1682 cm⁻¹. -1 It became 1560 cm -1 This confirmed the influence of coordination covalent bonds in Ce-MOF. X-ray diffraction (XRD) analysis was performed on the above samples using an X-ray diffractometer, scanning within the range of 5° to 40°. The results are as follows: Figure 3 As shown, the synthesized Ce-MOF exhibits distinct diffraction peaks at 7.1°, 8.2°, and 24.8°, with sharp characteristic peaks, demonstrating good crystallinity.

[0037] The FTIR and XRD spectra are as follows: Figures 1 to 3 As shown.

[0038] Preparation Example 2: Preparation of Cur@Ce-MOF drug-loaded particles (1) In a 20 mL mixture of deionized water and anhydrous ethanol (volume ratio 1:1), add 1 mL of acetic acid, 600 mg of F127, 400 μL of TMB and 41.5 mg of H2BDC, and shake to dissolve completely; (2) Place the solution in step (1) in an ice-water bath and use an ultrasonic disruptor to intermittently sonicate it until it becomes an emulsion. The ultrasonic power is 270W, and the ultrasonic cycle is 1 second on and 2 seconds off, with a duration of 30 seconds. (3) Add cerium ammonium nitrate with a molar ratio of 1:1 to H2BDC to the emulsion in step (2), and continue sonication for 5 to 10 minutes under the above ultrasonic conditions; (4) Stop the sonication, centrifuge the reaction solution at 4℃ and 8000 rpm, take the precipitate, wash it alternately with acetone and anhydrous ethanol, and then dry it in an oven at 50℃. The product obtained is hollow spherical Ce-MOF nanoparticles. (5) Take 20 mg of the hollow spherical Ce-MOF nanoparticles synthesized in step (4), and disperse them with 20 mg of curcumin (Cur) in 5 mL of anhydrous ethanol by ultrasonication. Mix them on a shaker for 24 hours, then centrifuge at 4℃ and 8000 rpm, take the precipitate, wash it alternately with anhydrous ethanol and deionized water, and freeze-dry it. The product obtained is Cur@Ce-MOF drug-loaded particles.

[0039] Comparative Example: Products synthesized using soft templates without ultrasound assistance at room temperature In a 1:1 mixture of 20 mL deionized water and anhydrous ethanol, add 1 mL acetic acid, 600 mg F127, 400 μL TMB, and 41.5 mg H2BDC. Stir magnetically until an emulsion is formed. Then add 137 mg cerium ammonium nitrate and stir at 700 rpm for 3 hours at room temperature. Centrifuge the reaction solution at 4°C, collect the precipitate, wash alternately with acetone and anhydrous ethanol, and then dry in a 50°C oven. The resulting product is shown below. Figure 4 As shown, it presents as uneven lumps, with significant agglomeration.

[0040] Example of effect: Example 1: POD activity of hollow Ce-MOF Ce-MOF (prepared in Preparation Example 1) dispersions with concentrations of 25, 50, 100, 150, 200, 500, 800, and 1000 μg / mL were prepared using PBS (pH=7.4) as the solvent. 50 μM of 3,3',5,5'-tetramethylbenzidine and 100 μM of hydrogen peroxide were added to each dispersion. The mixtures were reacted at room temperature (25°C) for 30 minutes, then centrifuged at 8000 rpm to remove insoluble matter. 100 μL of the supernatant was transferred to an ELISA plate, and the absorbance at 652 nm was measured. The absorbance value was directly proportional to the enzyme activity. The experimental results are as follows: Figure 5 As shown.

[0041] Example 2: Protective effect of hollow Ce-MOF and Cur@Ce-MOF on HT22 cells in mouse hippocampal neurons HT22 cells (purchased from Savill Biotechnology Co., Ltd.) were cultured in an incubator at 37°C and 5% CO2 to construct an oxidative stress injury model of neuronal cell lines, simulating the peroxidative microenvironment following nerve injury. Specifically, HT22 cells were divided into three groups: control group (Ctrl), model group (H2O2), curcumin group (Cur, purchased from Maclean Biotechnology Co., Ltd.), Ce-MOF group (prepared from Preparation Example 1), and Cur@Ce-MOF group (prepared from Preparation Example 2). The control group was cultured in DMEM complete medium, the model group in DMEM complete medium containing 400 μM hydrogen peroxide, the curcumin group in DMEM complete medium containing 400 μM hydrogen peroxide and 27 μg / mL Cur, the Ce-MOF group in DMEM complete medium containing 400 μM hydrogen peroxide and 100 μg / mL Ce-MOF, and the Cur@Ce-MOF group in DMEM complete medium containing 400 μM hydrogen peroxide and 100 μg / mL Cur@Ce-MOF. After 24 hours, the conditioned medium was removed and the cells were washed with PBS (pH=7.4). A 20 μg / mL JC-1 working solution was prepared using DMEM and added to the cells. The cells were incubated at 37°C for 20 minutes, the staining solution was washed off, DMEM was added again, and bright-field, red fluorescence (Ex=585 nm, Em=590 nm), and green fluorescence (Ex=514 nm, Em=529 nm) imaging was performed. Red fluorescence is positively correlated with the health of cellular mitochondria.

[0042] JC-1 staining images of HT22 cells under oxidative stress incubated with hollow Ce-MOF and Cur@Ce-MOF are shown below. Figure 6 As shown, the quantitative analysis results of red fluorescence in JC-1 HT22 cells under oxidative stress incubated with hollow Ce-MOF and Cur@Ce-MOF are as follows: Figure 7As shown in the figure. Experimental results indicated that the control group cells exhibited significant red fluorescence, representing good cell viability and mitochondrial health. In contrast, the model group treated with hydrogen peroxide showed reduced red fluorescence, indicating mitochondrial damage, thus successfully establishing the oxidative stress model. Cells incubated with curcumin, Ce-MOF, and Cur@Ce-MOF all showed enhanced red fluorescence, with the Cur@Ce-MOF group exhibiting significantly higher red fluorescence intensity than the curcumin group, demonstrating the good synergistic therapeutic potential of Cur@Ce-MOF.

[0043] Example 3: Biocompatibility of Hollow Ce-MOF HT22 cells were cultured in an incubator at 37°C and 5% CO2. DMEM medium containing Ce-MOF (prepared in Preparation Example 1) with concentrations of 25, 50, 75, and 100 μg / mL were prepared and the cells were incubated. MTT assay was performed after 24 hours to determine their cytotoxicity.

[0044] Cytotoxicity results of hollow Ce-MOFs are as follows Figure 8 As shown, compared with the blank control group, the cell viability after incubation with Ce-MOF at concentrations of 25, 50, 75, and 100 μg / mL was 87.11%, 87.05%, 82.33%, and 89.35%, respectively. The results indicate that Ce-MOF has low cytotoxicity to neurons, and cell growth was not significantly affected even at higher concentrations.

[0045] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. A method for preparing a cerium-based metal-organic framework (Ce-MOF) material, characterized in that: The preparation method comprises the following steps: (1) In a 1:1 mixture of 20 mL of deionized water and anhydrous ethanol, add 1 mL of acetic acid, 600 mg of Pranic F127 (F127), 400 μL of 1,3,5-trimethylbenzene (TMB) and 41.5 mg of 1,4-terephthalic acid (H2BDC), and shake to dissolve completely; (2) Place the solution in step (1) in an ice-water bath and use an ultrasonic disruptor to intermittently sonicate it until it becomes an emulsion. The ultrasonic power is 270W, and the ultrasonic cycle is 1 second on and 2 seconds off, with a duration of 30 seconds. (3) Add cerium ammonium nitrate with a molar ratio of 1:1 to H2BDC to the emulsion in step (2), and continue sonication for 5 to 10 minutes under the above ultrasonic conditions; (4) Stop the sonication, centrifuge the reaction solution at 4℃ and 8000 rpm, take the precipitate, wash it alternately with acetone and anhydrous ethanol, and then dry it in an oven at 50℃. The product obtained is hollow spherical Ce-MOF nanoparticles.

2. A method for preparing a Ce-MOF drug-loaded material, characterized in that: Hollow spherical Ce-MOF nanoparticles prepared by the preparation method described in claim 1 are ultrasonically dispersed with a drug in an appropriate amount of organic solvent, placed on a shaker for uniform mixing, centrifuged to collect the precipitate, and washed to obtain drug-loaded Ce-MOF particles. The organic solvent is anhydrous ethanol, the centrifugation conditions are 4°C and 8000 rpm, and the drug is curcumin.

3. Hollow Ce-MOF material prepared by the preparation method of claim 1 or drug-loaded Ce-MOF material prepared by the preparation method of claim 2.

4. Use of the hollow Ce-MOF material or drug-loaded Ce-MOF material according to claim 3 in the preparation of medicaments for treating nerve injury diseases.

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