Synthesis method for NANO drug for treating rheumatoid arthritis

Abstract

The present invention relates to the technical field of nano drug synthesis. Disclosed is a synthesis method for a nano drug for treating rheumatoid arthritis, comprising the following steps: S10: acquiring or preparing CaO2 nanoparticles having high purity and a small particle size; S20: wrapping the CaO2 nanoparticles in a ZIF67 system to obtain CaO2@ZIF67; and S30: dissolving methotrexate in methanol to obtain an MTX additive solution, dissolving CaO2@ZIF67 in methanol, then dropwise adding the MTX additive solution, fully stirring, and finally purifying, washing and drying the obtained product to obtain CaO2@MTX@ZIF67. For two main pathological features, i.e., inflammation and an anoxic microenvironment, of rheumatoid arthritis, calcium peroxide loaded by ZIF67 is combined with methotrexate to jointly treat the inflammatory part of rheumatoid arthritis, so that a construct can inhibit expression of a tumor necrosis factor -α / interleukin-6 and overcome the anoxic property of rheumatoid arthritis, thereby achieving the technical characteristics of mitigating an inflammatory symptom, changing a disease process, being low in cost, less in side effect and used for long-term treatment, and the like.

Description

A method for synthesizing nanomedicine for treating rheumatoid arthritis Technical Field

[0001] The present invention relates to the technical field of nano drug synthesis, and in particular to a method for synthesizing a nano drug for treating rheumatoid arthritis. Background Art

[0002] Rheumatoid arthritis is a chronic inflammatory joint disease characterized by inflammatory proliferation of synovial cells, pannus formation, and erosion and destruction of cartilage and bone. Clinically, it primarily manifests as symmetrical involvement of the small joints of the hands and feet, although some patients may also experience synovitis of larger joints. In the later stages of the disease, erosive destruction of articular cartilage and bone leads to deformity and dysfunction in the affected joints, resulting in a high disability rate. Its key pathological features include synovial inflammation caused by the overexpression of multiple proinflammatory cytokines and a hypoxic state that contributes to the chronic inflammatory environment, the rheumatoid arthritis microenvironment. Synovial inflammation is the most fundamental and crucial pathological feature of rheumatoid arthritis. Within the inflamed synovial tissue, the normal 2–3 layers of synovial lining transform into a highly proliferative 10–20 layers of synovial cells, forming pannus structures. Pannus tissue contains numerous activated fibroblast-like synoviocytes (FLS) and macrophages. Pannus adheres to the surface of articular cartilage, forming cartilage-pannus junctions, eroding and degrading the cartilage matrix, ultimately leading to joint structural destruction. The hypoxic microenvironment is mainly due to synovial intimal hyperplasia and increased immune cell infiltration, which together enhance the synovial demand for oxygen. The induction of angiogenesis may be the result of synovial hypoxia in rheumatoid arthritis.

[0003] In the existing technology, drug treatments for rheumatoid arthritis are currently divided into four categories, including anti-rheumatic drugs (DMARDs), glucocorticoids (GCs), non-steroidal anti-inflammatory drugs (NSAIDs) and biological agents that have become popular in recent years.

[0004] Methotrexate (MTX) is the most representative DMARD. As the cornerstone of rheumatoid arthritis treatment, it is still widely used in clinical treatment. It can effectively inhibit the secretion of inflammatory factors, thereby alleviating local inflammatory responses. However, due to severe systemic side effects such as immunosuppression, bone marrow suppression, liver and kidney damage, and gastrointestinal dysfunction, MTX is not suitable for the long-term treatment of rheumatoid arthritis. The use of GCs to treat rheumatoid arthritis patients can also achieve good therapeutic effects, but serious side effects such as cardiovascular disease, infection, and osteoporosis also limit the long-term systemic use of GCs. NSAIDs are cyclooxygenase inhibitors. Although the use of NSAIDs can quickly relieve patients' pain, it cannot fundamentally change the progression of the disease and is limited to symptom relief. In recent years, biologics have been widely developed and applied. For example, interleukin-6 (IL-6) receptor inhibitors, interleukin-1 inhibitors, B and T cell-related agents have also shown good therapeutic effects in the treatment of rheumatoid arthritis. However, the high cost of long-term use of biologics, as well as systemic infections such as tuberculosis, and local infections and even malignant tumors at the injection site, still limit the clinical application of biologics.

[0005] The prior art lacks a method for preparing a drug targeting the two main pathological characteristics of rheumatoid arthritis, namely inflammation and hypoxic microenvironment. Technical issues

[0006] The purpose of the present invention is to provide a method for synthesizing nanomedicines for the treatment of rheumatoid arthritis, aiming to solve the problem in the prior art that there is a lack of preparation methods for drugs targeting the two pathological characteristics of rheumatoid arthritis, inflammation and hypoxia microenvironment. Technical Solutions

[0007] The present invention is achieved by a method for synthesizing a nanomedicine for treating rheumatoid arthritis, comprising the following steps:

[0008] S10: Obtain or prepare high-purity CaO2 nanoparticles, wherein the particle size of the CaO2 nanoparticles is ≤300 nm;

[0009] S20: Encapsulating CaO2 nanoparticles in the ZIF67 system to obtain CaO2@ZIF67;

[0010] S30: dissolving methotrexate in methanol to obtain an MTX additive solution; dissolving CaO2@ZIF67 in methanol, then dropwise adding the MTX additive solution and stirring thoroughly; and finally purifying, washing, and drying the obtained product to obtain CaO2@MTX@ZIF67.

[0011] Optionally, in step S10, preparing high-purity CaO2 nanoparticles includes the following steps:

[0012] S11: Dissolve anhydrous CaCl2 in a certain amount of methanol and stir thoroughly to completely dissolve it;

[0013] S12: Add a certain amount of H2O2 solution and stir thoroughly;

[0014] S13: A certain amount of NH3·H2O solution is then added dropwise and stirred thoroughly to allow the solution to precipitate completely. The precipitate is collected to obtain CaO2 nanoparticles.

[0015] Optionally, in step S13, the mixture is centrifuged at 12000 rpm for 10 min to collect the resulting precipitate; the resulting precipitate is then washed 2-3 times with methanol, and finally dried, crushed, and collected to obtain high-purity CaO2 nanoparticles.

[0016] Optionally, the concentration of the H2O2 solution in S12 is 30%, and the concentration of the NH3·H2O solution in S13 is 25%.

[0017] Optionally, in step S20, obtaining CaO2@ZIF67 includes the following steps:

[0018] S21: dissolving Co(NO3)2·6H2O in methanol to form a Co(NO3)2·6H2O droplet; dissolving CaO2 nanoparticles in methanol and ultrasonically stirring for a set time to form a CaO2 methanol solution;

[0019] S22: Add the Co(NO3)2·6H2O solution dropwise to the CaO2 methanol solution and stir for more than 20 minutes to obtain a first intermediate solution;

[0020] S23: dissolving 2-methylimidazole in methanol to obtain a 2-methylimidazole methanol solution, then adding the 2-methylimidazole methanol solution dropwise to the first intermediate solution, stirring thoroughly for a certain period of time, and obtaining CaO2@ZIF67.

[0021] Optionally, the CaO2@ZIF67 obtained in step S23 is washed with methanol 2-3 times, dried, and crushed for collection.

[0022] Optionally, in step S21, the set time is 3-5 minutes; in step S23, the mixture is fully stirred for 4-6 hours.

[0023] Optionally, in step S30, when dissolving methotrexate in methanol, 10% DMSO solution is added to aid dissolution.

[0024] Optionally, during the thorough stirring process, the stirred solution is shielded from light.

[0025] The CaO2@MTX@ZIF67 nanodrug was prepared based on the above-mentioned nanodrug synthesis method for the treatment of rheumatoid arthritis. Beneficial effects

[0026] And has the following beneficial effects:

[0027] (1) Targeting the two main pathological characteristics of rheumatoid arthritis, namely inflammation and hypoxic microenvironment, ZIF67-loaded calcium peroxide was combined with methotrexate to treat the inflammatory sites of rheumatoid arthritis.

[0028] (2) ZIF67 has good stability and biocompatibility, and using it as a carrier can reduce the side effects of the drug itself on humans.

[0029] (3) ZIF67 decomposes in an acidic environment, which matches the weak acid environment of the inflammatory microenvironment of rheumatoid arthritis. Its loading with MTX and CaO2 can give it a passive targeting function.

[0030] (4) CaO2 can not only release oxygen at the site of inflammation to improve the inflammatory microenvironment, but also 2+ It also has the function of promoting the regeneration of articular cartilage, Ca 2+ It can also promote related apoptosis and immunogenic cell death. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] FIG1 is a schematic flow diagram of a method for synthesizing a nanomedicine for treating rheumatoid arthritis provided by the present invention;

[0032] FIG2 is a schematic diagram of the particle size of CaO2, an intermediate product in a method for synthesizing nanomedicine for treating rheumatoid arthritis provided by the present invention;

[0033] FIG3 is a schematic diagram of the particle size of CaO2@MTX@ZIF67, the final product of a nanomedicine synthesis method for treating rheumatoid arthritis provided by the present invention;

[0034] FIG4a is a TEM diagram of CaO2, an intermediate product of a nanomedicine synthesis method for treating rheumatoid arthritis provided by the present invention;

[0035] FIG4 b is a TEM schematic diagram of CaO2@MTX@ZIF67, the final product of a nanomedicine synthesis method for treating rheumatoid arthritis provided by the present invention;

[0036] FIG5 is a material absorption spectrum characterization diagram of CaO2, MTX, and CaO2@MTX@ZIF67 in a nanomedicine synthesis method for treating rheumatoid arthritis provided by the present invention;

[0037] FIG6 is a material element spectrum of CaO2@MTX@ZIF67, the final product of a nanomedicine synthesis method for treating rheumatoid arthritis provided by the present invention;

[0038] FIG7 is a comparison of O2 release amounts of CaO2@MTX@ZIF67 under different pH conditions according to a nanomedicine synthesis method for treating rheumatoid arthritis provided by the present invention;

[0039] FIG8 is a material characterization EDS graph of CaO2@MTX@ZIF67 of a nanomedicine synthesis method for treating rheumatoid arthritis provided by the present invention;

[0040] FIG9 is a comparison chart of the oxygen release of CaO2 and water in a method for synthesizing a nanomedicine for treating rheumatoid arthritis provided by the present invention;

[0041] FIG10 is an absorption spectrum of three groups of substances: titanium sulfate, titanium sulfate + H2O2, and titanium sulfate + CaO2;

[0042] 11 is a CaO2 absorption spectrum of hydroxyl radicals detected under different pH conditions according to a method for synthesizing nanomedicines for treating rheumatoid arthritis provided by the present invention;

[0043] FIG12 is an absorption spectrum of CaO2@MTX@ZIF67 for detecting hydroxyl radicals under different pH conditions according to a method for synthesizing nanomedicines for treating rheumatoid arthritis provided by the present invention. Best Mode for Carrying Out the Invention

[0044] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0045] The implementation of the present invention is described in detail below with reference to specific embodiments.

[0046] The same or similar numbers in the drawings of this embodiment correspond to the same or similar parts; in the description of the present invention, it should be understood that if the terms "up", "down", "left", "right", etc. indicate directions or positional relationships, they are based on the directions or positional relationships shown in the drawings. This is only for the convenience of describing the present invention and simplifying the description, and does not indicate or imply that the device or element referred to must have a specific direction, be constructed and operated in a specific direction. Therefore, the terms describing the positional relationship in the drawings are only used for illustrative purposes and cannot be understood as limiting the present invention. For ordinary technicians in this field, the specific meanings of the above terms can be understood according to specific circumstances.

[0047] 1-12 , which are preferred embodiments of the present invention.

[0048] A method for synthesizing a nanomedicine for treating rheumatoid arthritis comprises the following steps:

[0049] S10: obtaining or preparing high-purity CaO2 nanoparticles, wherein the CaO2 nanoparticles are small-sized nanoparticles with a particle size of ≤300 nm, so as to be easily encapsulated by the ZIF67 system;

[0050] S20: Encapsulating CaO2 nanoparticles in the ZIF67 system to obtain CaO2@ZIF67;

[0051] S30: dissolving methotrexate in methanol to obtain an MTX additive solution; dissolving CaO2@ZIF67 in methanol, then dropwise adding the MTX additive solution and stirring thoroughly; and finally purifying, washing, and drying the obtained product to obtain CaO2@MTX@ZIF67.

[0052] Among them, ZIF67, the full name of which is Zeolitic Imidazolate Framework 67, is a porous material obtained by the reaction of 2-methylimidazole and Co(NO3)2·6H2O. It has an ultra-high specific surface area of ​​about 1500m 2 / g. 2-Methylimidazole crosslinks with transition metal cobalt to form a tetrahedral framework. Metal ions are located at the corners of the tetrahedron, while N atoms are located in the center. The resulting tetrahedral structural units are then connected to adjacent metal or organic ligands to form an h-dimensional framework material. This results in high thermal and chemical stability in aqueous media. The unique properties imparted by this novel nanoscale oriented structure make ZIF67 suitable for the preparation of nanomedicines.

[0053] This example provides a method for synthesizing a nanodrug for the treatment of rheumatoid arthritis. Anhydrous CaCl2 is dissolved in a certain amount of methanol solution, followed by a 30% H2O2 solution and a 25% NH3·H2O solution, followed by thorough stirring to produce high-purity, small-diameter CaO2 nanoparticles. ZIF67 is then synthesized, and the CaO2 nanoparticles are encapsulated within the ZIF67 system. Finally, methotrexate (MTX) is adsorbed and encapsulated within the ZIF67 system, resulting in ZIF67-loaded CaO2 and methotrexate nanoparticles.

[0054] It has the following beneficial effects:

[0055] (1) Targeting the two main pathological characteristics of rheumatoid arthritis, namely inflammation and hypoxic microenvironment, ZIF67-loaded calcium peroxide was combined with methotrexate to treat the inflammatory sites of rheumatoid arthritis.

[0056] (2) ZIF67 has good stability and biocompatibility, and using it as a carrier can reduce the side effects of the drug itself on humans.

[0057] (3) ZIF67 decomposes in an acidic environment, which matches the weak acid environment of the inflammatory microenvironment of rheumatoid arthritis. Its loading with MTX and CaO2 can give it a passive targeting function.

[0058] (4) CaO2 can not only release oxygen at the site of inflammation to improve the inflammatory microenvironment, but also 2+ It also has the function of promoting the regeneration of articular cartilage, Ca 2+ It can also promote related apoptosis and immunogenic cell death.

[0059] Specifically, in step S10, preparing high-purity CaO2 nanoparticles includes the following steps:

[0060] S11: Dissolve anhydrous CaCl2 in a certain amount of methanol and stir thoroughly to completely dissolve it;

[0061] S12: Add a certain amount of H2O2 solution and stir thoroughly;

[0062] S13: A certain amount of NH3·H2O solution is then added dropwise and stirred thoroughly to allow complete precipitation. The resulting precipitate is collected to obtain small-sized CaO2 nanoparticles, with a particle size of ≤300 nm, preferably 20-100 nm, to facilitate encapsulation by the ZIF67 system in subsequent steps. If the obtained CaO2 nanoparticles are too large, they can be reduced to less than 100 nm by ultrasound.

[0063] Optionally, in step S13, the mixture is centrifuged at 12000 rpm for 10 min to collect the resulting precipitate; the resulting precipitate is then washed 2-3 times with methanol, and finally dried, crushed, and collected to obtain high-purity CaO2 nanoparticles.

[0064] Optionally, the concentration of the H2O2 solution in S12 is 30%, and the concentration of the NH3·H2O solution in S13 is 25%.

[0065] Specifically, in step S20, obtaining CaO2@ZIF67 includes the following steps:

[0066] S21: Dissolve Co(NO3)2·6H2O in methanol to form a Co(NO3)2·6H2O droplet; dissolve CaO2 nanoparticles in methanol and ultrasonically stir for a set time to form a CaO2 methanol solution; ultrasonic stirring can disperse and deagglomerate the solids in the liquid to achieve the purpose of stirring, stir evenly, shorten the reaction time, and improve the reaction yield.

[0067] S22: Add the Co(NO3)2·6H2O solution dropwise to the CaO2 methanol solution and stir for more than 20 minutes to obtain a first intermediate solution;

[0068] S23: dissolving 2-methylimidazole in methanol to obtain a 2-methylimidazole methanol solution, then adding the 2-methylimidazole methanol solution dropwise to the first intermediate solution, stirring thoroughly for a certain period of time, and obtaining CaO2@ZIF67.

[0069] Optionally, the CaO2@ZIF67 obtained in step S23 is washed with methanol 2-3 times, dried, and crushed for collection.

[0070] Optionally, in step S21, the set time is 3-5 minutes; in step S23, the mixture is fully stirred for 4-6 hours.

[0071] Specifically, in step S30, when dissolving methotrexate in methanol, 10% DMSO solution is added to aid dissolution. DMSO is dimethyl sulfoxide, with a molecular formula of C2H6OS, which can be used as an organic solvent, reaction medium, and organic synthesis intermediate.

[0072] During the stirring process, the stirred solution was shielded from light to prevent light from affecting the formation of CaO2@MTX@ZIF67.

[0073] The stirring time is 10 to 15 hours, preferably 12 hours.

[0074] In the following specific embodiment, a method for synthesizing a nanomedicine for treating rheumatoid arthritis includes the following specific steps:

[0075] S10: Obtain or prepare high-purity small-size CaO2 nanoparticles.

[0076] Specifically, 0.444g of anhydrous CaCl2 was placed in 60ml of methanol and stirred thoroughly for 10 minutes to completely dissolve it. 1ml of 30% H2O2 solution was then added and stirred thoroughly for about 10 minutes. Finally, 1ml of 25% NH3·H2O was added dropwise to the system and stirred thoroughly to allow complete precipitation. Finally, the system was centrifuged at 12,000 rpm for 10 minutes, and the resulting precipitate was collected. CaO2 nanoparticles were obtained. The entire reaction system was in methanol. Generally, the obtained precipitate needs to be washed with methanol 2-3 times to ensure its purity. Finally, it was dried, ground in a mortar, and collected to obtain high-purity small-particle CaO2 nanoparticles.

[0077] As shown in Figure 2, the CaO2 nanoparticles obtained in the above steps have a particle size of approximately 80 nanometers, making them suitable for subsequent loading and encapsulation in the ZIF67 system. If the resulting CaO2 nanoparticles are too large, for example, larger than the ZIF67 particle size (approximately 500 nanometers), they can be reduced to less than 100 nanometers using ultrasound.

[0078] S20: Encapsulate CaO2 nanoparticles in the ZIF67 system to obtain CaO2@ZIF67.

[0079] Specifically, 50 mg of CaO2 was dissolved in 40 ml of methanol and sonicated for 3-5 minutes. 200 mg of Co(NO3)2·6H2O was then dissolved in 5 ml of methanol and added dropwise to the solution, stirring for 30 minutes. 200 mg of 2-methylimidazole was then dissolved in 5 ml of methanol and added dropwise to the solution, stirring for 5 hours. This yielded CaO2@ZIF67. Finally, the solution was washed with methanol two or three times to ensure purity. Finally, it was dried, ground in a mortar, and collected to obtain high-purity CaO2@ZIF67 nanoparticles. Co(NO3)2·6H2O and 2-methylimidazole are the raw materials for preparing ZIF67. Through these steps, CaO2 was loaded and encapsulated within ZIF67.

[0080] S30: dissolving methotrexate in methanol to obtain an MTX additive solution; dissolving CaO2@ZIF67 in methanol, then dropwise adding the MTX additive solution and stirring thoroughly; and finally purifying, washing, and drying the obtained product to obtain CaO2@MTX@ZIF67.

[0081] Specifically, 30 mg of methotrexate (MTX) was dissolved in 20 ml of methanol (using 10% DMSO for solubilization) and added dropwise to 30 mg of CaO2@ZIF67 in 20 ml of methanol. The mixture was stirred thoroughly for 12 hours (wrapped in tin foil to protect from light, as MTX needs to be stored away from light). This yielded CaO2@MTX@ZIF67. Finally, the mixture was washed twice with methanol and once with neutral distilled water to ensure purity. Finally, the mixture was dried, ground in a mortar, and collected to obtain high-purity CaO2@MTX@ZIF67 nanoparticles.

[0082] ZIF67 is a novel crystalline porous material with an ultra-high specific surface area and large pore volume. While it readily decomposes in weakly acidic environments, it exhibits excellent stability in neutral and alkaline environments. ZIF67 exhibits excellent biocompatibility and can be used to encapsulate materials, adsorb MTX, or load MTX through the pores of the ZIF67 material.

[0083] As shown in Figure 3, the CaO2@MTX@ZIF67 nanoparticles obtained in the above steps have a particle size of approximately 600nm-800nm, with a maximum of approximately 700nm. The particle size of ZIF67 itself is approximately 500nm, and its volume increases after CaO2 is added to the center and MTX is adsorbed on the outside.

[0084] See Figures 4a and 4b, which are transmission electron microscope images of CaO2 and CaO2@MTX@ZIF67, respectively. Since the transmission electron microscope images represent the situation of a single particle, their particle size distribution is somewhat random, but they can still be used as a reference.

[0085] See Figure 5, which is the absorption spectra of CaO2, MTX, and CaO2@MTX@ZIF67, where ZCMNPs in Figure 5 represents CaO2@MTX@ZIF67.

[0086] See Figure 6, which is the elemental spectrum of CaO2@MTX@ZIF67, which was obtained by detecting CaO2@MTX@ZIF67 using an energy spectrometer. The principle is to use the different characteristic energies of X-ray photons of different elements to perform composition analysis.

[0087] Figure 7 shows a comparison of O2 release from CaO2@MTX@ZIF67 at different pH values. At pH 7.4, O2 release from CaO2@MTX@ZIF67 approaches zero, indicating that CaO2@MTX@ZIF67 is relatively stable in neutral and alkaline environments. In acidic environments, O2 release from CaO2@MTX@ZIF67 increases rapidly over time. Furthermore, under the same time conditions, the lower the pH, the greater the O2 release from CaO2@MTX@ZIF67.

[0088] See Figure 8, the material characterization EDS diagram of CaO2@MTX@ZIF67; the EDS diagram is obtained by energy dispersive spectroscopy (EDS), and the composition analysis is performed using the different characteristic energies of X-ray photons of different elements.

[0089] Referring to FIG9 , which shows the change in oxygen release of CaO 2 and water over time, CaO 2 releases more oxygen to overcome the hypoxic nature of rheumatoid arthritis.

[0090] Referring to FIG10 , which shows the absorption spectra of three groups of substances, titanium sulfate, titanium sulfate + H2O2, and titanium sulfate + CaO2, titanium sulfate has no absorption peak, corresponding to the substantially horizontal curve in FIG10 . The absorption curves of the other two groups of substances are relatively close, both having characteristic absorption peaks at 415 nm. This is because H2O2 reacts with titanium sulfate to produce a yellow peroxide-titanium complex precipitate. The H2O2 content can be quantitatively detected by changes in the absorbance value. The close absorption curves of the latter two groups of substances also indicate that CaO2 also produces H2O2 in an acidic environment.

[0091] H2O2 and cobalt ions in ZIF67 raw materials can produce hydroxyl radicals (i.e., reactive oxygen species), which are important components of the final product CaO2@MTX@ZIF67 that have anti-inflammatory effects.

[0092] As shown in Figure 11, experiments show that CaO2 does not contain hydroxyl radicals at different pH values, even in an acidic environment. This shows that hydroxyl radicals cannot be generated without the participation of cobalt ions.

[0093] Referring to Figure 12, experiments have shown that CaO2@MTX@ZIF67 does not contain hydroxyl radicals at pH = 7.4, corresponding to the slightly downward-sloping, straight-line-like curve in Figure 12; in an acidic environment (pH less than 7), CaO2@MTX@ZIF67 was detected to contain hydroxyl radicals (i.e., reactive oxygen species), so that CaO2@MTX@ZIF67 can inhibit the proliferation of fibroblast-like synoviocytes (FLS), which correspond to inflammatory cells, that is, the product has an anti-inflammatory effect.

[0094] Recognizing the limitations of existing drugs, this invention addresses the two key pathological hallmarks of rheumatoid arthritis: inflammation and a hypoxic microenvironment. This approach utilizes ZIF67-loaded calcium peroxide in combination with methotrexate to treat the inflamed areas of rheumatoid arthritis. The construct inhibits the expression of tumor necrosis factor-α and interleukin-6, overcoming the hypoxic nature of rheumatoid arthritis. This approach alleviates inflammatory symptoms and modifies the disease progression, while offering low cost, minimal side effects, and long-term therapeutic potential. This approach provides new insights and approaches for the development of rheumatoid arthritis treatments.

[0095] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for synthesizing nanomedicine for treating rheumatoid arthritis, characterized in that: The following steps are involved: S10: obtaining or preparing high-purity CaO2 nanoparticles, wherein the particle size of the CaO2 nanoparticles is ≤300 nm; S20: Encapsulating CaO2 nanoparticles in the ZIF67 system to obtain CaO2@ZIF67; S30: dissolving methotrexate in methanol to obtain MTX additive solution; dissolving CaO2@ZIF67 in methanol, then dropping the MTX additive solution, and stirring sufficiently, and finally purifying, washing, and drying the obtained product to obtain CaO2@MTX@ZIF67.

2. A method for synthesizing a nano drug for treating rheumatoid arthritis as claimed in claim 1, characterized in that: In step S10, preparing high-purity CaO2 nanoparticles includes the following steps: S11: dissolving anhydrous CaCl2 in a certain amount of methanol and stirring thoroughly to make it completely dissolved; S12: adding a certain amount of H2O2 solution and stirring thoroughly; S13: Add a certain amount of NH3·H2O solution and stir thoroughly to make it precipitate completely, collect the precipitate, and obtain CaO2 nanoparticles.

3. A method for synthesizing a nano drug for treating rheumatoid arthritis as claimed in claim 2, characterized in that: In step S13, centrifuge at 12000 rpm for 10 min to collect the generated precipitate; then wash the generated precipitate with methanol for 2-3 times, and finally dry it, grind it and collect it to obtain high-purity CaO2 nanoparticles.

4. A method for synthesizing a nano drug for treating rheumatoid arthritis as claimed in claim 2, characterized in that: The concentration of H2O2 solution in S12 is 30%, and the concentration of NH3·H2O solution in S13 is 25%.

5. A method for synthesizing a nano drug for treating rheumatoid arthritis according to any one of claims 1 to 4, characterized in that: In step S20, obtaining CaO2@ZIF67 includes the following steps: S21: dissolving Co(NO3)2·6H2O in methanol to form a Co(NO3)2·6H2O drop solution; dissolving CaO2 nanoparticles in methanol, and ultrasonically stirring for a set time to form a CaO2 methanol solution; S22: Add the Co(NO3)2·6H2O dropwise solution to the CaO2 methanol solution and stir for more than 20 minutes to obtain a first intermediate solution; S23: dissolving 2-methylimidazole in methanol to obtain a 2-methylimidazole methanol solution, then dropping the 2-methylimidazole methanol solution into the first intermediate solution, stirring sufficiently for a certain period of time, and obtaining CaO2@ZIF67.

6. A method for synthesizing a nano drug for treating rheumatoid arthritis as claimed in claim 5, characterized in that: The CaO2@ZIF67 obtained in step S23 is washed with methanol 2-3 times, dried, and crushed for collection.

7. A method for synthesizing a nano drug for treating rheumatoid arthritis as claimed in claim 5, characterized in that: In step S21, the set time is 3-5 minutes; in step S23, the mixture is fully stirred for 4-6 hours.

8. A method for synthesizing a nano drug for treating rheumatoid arthritis according to any one of claims 1 to 4, characterized in that: In step S30, when dissolving methotrexate in methanol, 10% DMSO solution is added to aid dissolution.

9. A method for synthesizing a nano drug for treating rheumatoid arthritis as claimed in claim 7, characterized in that: During the thorough stirring, the stirred solution was shielded from light.

10. The CaO2@MTX@ZIF67 nanomedicine prepared by the nanomedicine synthesis method for treating rheumatoid arthritis according to any one of claims 1 to 9.

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