Copper-based supramolecular organic framework material, application and preparation method
By preparing Cu-SOF materials, the problems of low copper loading and slow release rate of existing copper-based materials have been solved, and rapid release of copper ions in a weakly acidic environment has been achieved, which promotes the healing of diabetic ulcers and has good biosafety and industrialization potential.
Patent Information
- Application Number
- CN202610145099.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-02-02
- Publication Date
- 2026-05-01
AI Technical Summary
Existing copper-based materials have low copper loading and slow copper ion release rates when treating diabetic ulcers, making them difficult to respond to weakly acidic microenvironments. Furthermore, their high cost and poor stability limit their widespread application.
Cu-SOF materials were prepared by hydrothermal reaction using melamine and adipic acid as raw materials. These materials have atomically dispersed ortho-copper sites and a rich hydrogen bond network, enabling them to rapidly release copper ions in a weakly acidic environment, thereby increasing the copper loading and simplifying the preparation process.
The study achieved rapid copper ion release from Cu-SOF materials with high copper loading in a weakly acidic environment, significantly induced copper death in macrophages, and promoted the healing of diabetic ulcers. It has good biosafety and industrialization potential.
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Figure CN121949815A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of metal-organic supramolecular materials technology, and in particular to a copper-based supramolecular organic framework material, its applications, and preparation methods. Background Technology
[0002] Diabetic ulcers (DUs) are a common complication of diabetes. Of the approximately 460 million people with diabetes worldwide, about 25% will develop DUs; of these, about 65% will relapse within 3-5 years, and about 20% will eventually require amputation. The 5-year mortality rate for amputees is 50%-70%, significantly higher than that of most common cancers. Current treatments for diabetic ulcers (such as negative pressure therapy, surgical debridement, antibiotic treatment, topical medications, and wound dressings) primarily target symptoms and cannot eradicate the underlying pathological mechanisms.
[0003] Macrophage polarization imbalance has been proven to be a key factor in the chronic and difficult-to-heal nature of diabetic ulcers, with the persistent dominance of M1 macrophages contributing to prolonged tissue inflammation. In recent years, some drugs that regulate macrophage polarization (such as ON101 / FESPIXON® cream) have entered clinical use, promoting healing by inhibiting M1 polarization and enriching M2 macrophages. However, these drugs often suffer from high cost, demanding storage conditions, and poor stability, limiting their widespread application.
[0004] Research has revealed that copper death is a novel form of cell death, with ferroredoxin 1 (FDX1) playing a crucial role. Pro-inflammatory M1 macrophages in the inflammatory microenvironment highly express FDX1 and exhibit greater sensitivity to copper death. This finding offers a new approach to the treatment of diabetic ulcers: by inducing copper death in pro-inflammatory M1 macrophages, the ulcer microenvironment can be remodeled, promoting the healing process. However, existing copper-based materials (such as Cu-MOF, Cu-HOF, and Cu-COF) suffer from the following problems: 1) relatively low copper loading; 2) slow copper ion release rate, making it difficult to reach the concentration threshold for inducing cell copper death; and 3) lack of responsive release to the weakly acidic microenvironment of diabetic ulcers (DUs). Summary of the Invention
[0005] In view of this, the purpose of this invention is to provide a method for preparing a copper-based supramolecular organic framework (Cu-SOF) material and its application. This Cu-SOF possesses atomically dispersed ortho-copper sites and a rich hydrogen bond network, enabling it to rapidly release copper ions in response to a weakly acidic environment; it exhibits a high copper loading capacity, far exceeding that of existing copper-based MOF and HOF materials; simultaneously, the preparation process is simple, low-cost, and uses readily available raw materials, facilitating large-scale industrial production; it demonstrates significant therapeutic effects, effectively inducing copper death in dysfunctional macrophages, while also exhibiting good biocompatibility.
[0006] This invention provides a method for preparing copper-based supramolecular organic framework materials, comprising the following steps:
[0007] Melamine and adipic acid are mixed and ground thoroughly to obtain a mixture, wherein the molar ratio between melamine and adipic acid is 1:(1-2);
[0008] Deionized water was added to the mixture, and Cu-SOF precursor was obtained under preset hydrothermal conditions;
[0009] Copper acetate was added to the Cu-SOF precursor, and the reaction was continued under preset hydrothermal conditions.
[0010] The reaction system is cooled and then subjected to final processing to obtain Cu-SOF material.
[0011] In one embodiment, the preset hydrothermal conditions are a temperature of 100-140°C and a reaction time of 24-72 hours.
[0012] In one embodiment, the cooling reaction system and final processing to obtain Cu-SOF material further include:
[0013] Cool the reaction system to room temperature;
[0014] Crystal products were collected by centrifugation;
[0015] The crystalline product was washed with water and dried at 60°C to obtain Cu-SOF material.
[0016] In one embodiment, the Cu-SOF material rapidly releases copper ions under weakly acidic conditions through a synergistic dissociation-recombination mechanism.
[0017] In one embodiment, copper is uniformly distributed within the framework of the Cu-SOF material and has an atomically dispersed state.
[0018] The present invention also provides a copper-based supramolecular organic framework material, obtained by any of the preparation methods described above, comprising melamine, adipic acid and copper acetate, wherein the molar ratio of melamine, adipic acid and copper acetate is 1:(1-2):(1-2).
[0019] In one embodiment, it is used to treat one or more of diabetic foot ulcers, diabetic skin ulcers, diabetic corneal ulcers, diabetic gastric ulcers, and diabetic oral ulcers.
[0020] The copper-based supramolecular organic framework material, its application, and its preparation method provided by this invention have atomically dispersed ortho-copper sites and a rich hydrogen bond network, enabling them to rapidly release copper ions in response to a weakly acidic environment. They exhibit high copper loading, far exceeding that of existing copper-based MOF and HOF materials. Furthermore, the preparation process is simple, low-cost, and uses readily available raw materials, facilitating large-scale industrial production. The therapeutic effects are significant, effectively inducing copper death in dysfunctional macrophages, while also demonstrating good biocompatibility. Attached Figure Description
[0021] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.
[0022] Figure 1 This is a schematic diagram of the synthesis route of the Cu-SOF material provided in Embodiment 1 of the present invention.
[0023] Figure 2 Here is a crystal structure diagram of the Cu-SOF material in Embodiment 2 of the present invention: (A) is the coordination environment centered on Cu; (B) is the basic building block of Cu-SOF; (C) is the hydrogen bond network between melamine and adipic acid molecules; and (D) is the hydrogen bond network of water molecules.
[0024] Figure 3 This is the X-ray diffraction (XRD) pattern of the Cu-SOF material in Embodiment 2 of the present invention.
[0025] Figure 4 These are scanning electron microscope (SEM) images of the Cu-SOF material in Embodiment 2 of the present invention, where (a) is 2 μm and (b) is 1 μm.
[0026] Figure 5 This is a transmission electron microscope (TEM) image of the Cu-SOF material in Embodiment 2 of the present invention;
[0027] Figure 6 This is the elemental distribution diagram of the Cu-SOF material in Embodiment 2 of the present invention.
[0028] Figure 7 The copper ion release characteristics of Cu-SOF material in Embodiment 2 of the present invention are as follows: (A) is the copper ion release curve of Cu-SOF under different pH conditions; (B) is a comparison of the copper ion release curves of Cu-SOF with MOF-199 and HOF-21-Cu.
[0029] Figure 8This describes the effect of the Cu-SOF material in Example 2 of the present invention on macrophage activity and the expression of copper death-related proteins.
[0030] Figure 9 This refers to the changes in the levels of inflammatory factors in macrophages after treatment with Cu-SOF material in Embodiment 2 of the present invention.
[0031] Figure 10 These are photographs showing the wound healing of the Cu-SOF material in Embodiment 2 of the present invention at different times after treatment of diabetic mice.
[0032] Figure 11 This is a photograph of the Cu-SOF material of Embodiment 2 of the present invention after hematoxylin-eosin (H&E) staining of wounds in diabetic mice.
[0033] Figure 12 The second embodiment of this invention describes the immunofluorescence staining of M1 and M2 macrophages and the M2 / M1 ratio analysis of Cu-SOF material after wound treatment in diabetic mice. Detailed Implementation
[0034] The specific embodiments of the present invention will now be described in detail with reference to the accompanying drawings. Obviously, the described embodiments are merely some, not all, of the embodiments of the present invention. Based on the description of the present invention, all other embodiments obtained by those skilled in the art without inventive effort are within the scope of protection of the present invention.
[0035] In the description of this invention, unless otherwise explicitly specified and limited, the terms "set," "install," "connect," etc., should be interpreted broadly. For example, they can refer to a fixed connection, a detachable connection, or an integral connection; they can refer to a mechanical connection or an electrical connection; they can refer to a direct connection or an indirect connection through an intermediate medium. Those skilled in the art can understand the specific meaning of the above terms according to the specific circumstances.
[0036] The terms “upper,” “lower,” “left,” “right,” “front,” “back,” “top,” “bottom,” “inner,” and “outer,” etc., indicate the orientation or positional relationship based on the orientation or positional relationship shown in the accompanying drawings, or the orientation or positional relationship commonly used when the product of the invention is in use. They are only for the convenience of description and simplification, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation. Therefore, they should not be construed as limitations on the present invention.
[0037] The terms “first,” “second,” “third,” etc., are used merely to distinguish elements with similar attributes, not to indicate or imply relative importance or a specific order.
[0038] The terms “include,” “comprising,” or any other variation thereof are intended to cover non-exclusive inclusion, which includes not only the elements listed but also other elements not expressly listed.
[0039] Example 1
[0040] Please see Figure 1 The method for preparing copper-based supramolecular organic framework materials provided by the present invention includes the following steps:
[0041] S1, melamine (0.126 g, 1.0 mmol) and adipic acid (0.219 g, 1.5 mmol) are mixed and ground to obtain a mixture;
[0042] S2, the mixture from step S1 above is transferred to a hydrothermal reactor, and 10 mL of deionized water is added to the mixture. The mixture is reacted at 120°C for 48 hours, and then cooled to room temperature to obtain the Cu-SOF precursor.
[0043] S3, copper acetate monohydrate (0.199 g, 1.0 mmol) was added to the obtained Cu-SOF precursor, and the mixture was hydrothermally reacted again at 120 °C for 48 hours.
[0044] S4. The material obtained from the reaction in step S3 is cooled, and the crystals are collected by centrifugation. The crystals are washed three times with deionized water and dried at 60°C for 24 hours to obtain a dark blue crystal product, namely Cu-SOF material.
[0045] Example 2
[0046] Please see Figure 2 This embodiment provides a copper-based supramolecular organic framework material, obtained by the preparation method described above, comprising melamine, adipic acid and copper acetate, wherein the molar ratio of melamine, adipic acid and copper acetate is 1:1.5:1.
[0047] The basic characteristics of the Cu-SOF material prepared in Example 1 above are as follows:
[0048] The copper loading was determined to be 25.2 wt% by inductively coupled plasma mass spectrometry (ICP-MS).
[0049] Please see Figure 3 The image shows the single-crystal X-ray diffraction (XRD) pattern of Cu-SOF material.
[0050] The Cu-SOF prepared in Example 1 was subjected to X-ray diffraction (XRD), and single-crystal data were collected and analyzed. The results are as follows: Figure 2As shown: (A) Cu-SOF has atomically dispersed copper sites, and the copper center presents an approximately pyramidal geometric configuration, with the nitrogen atom of the melamine heterocycle occupying the vertices coordinated with the oxygen atoms of different adipic acid molecules occupying the four bases; (B) Adjacent copper centers are connected by coordination condensation with melamine to form a helical building unit; the basic building unit of Cu-SOF forms a two-dimensional layered structure through the multiple hydrogen bond interactions of (C) melamine-adipic acid and (D) melamine-water-adipic acid.
[0051] X-ray diffraction (XRD pattern) of Cu-SOF material;
[0052] The Cu-SOF prepared in Example 1 was subjected to X-ray diffraction (XRD), and the results are as follows: Figure 3 As shown, the powder XRD pattern of Cu-SOF is in perfect agreement with the simulated XRD pattern, indicating that it has good crystal integrity.
[0053] Scanning electron microscope (SEM) image of Cu-SOF material;
[0054] The Cu-SOF prepared in Example 1 was scanned under a electron microscope (SEM). The results are as follows: Figure 4 As shown, Cu-SOF exhibits a layered structure composed of nanorods.
[0055] Transmission electron microscopy (TEM) images and elemental distribution of Cu-SOF materials:
[0056] The Cu-SOF prepared in Example 1 was placed under a transmission electron microscope (TEM). The results are as follows: Figure 5 As shown, Cu-SOF exhibits a layered structure consistent with that observed in scanning electron microscopy (SEM), such as... Figure 6 As shown in the elemental mapping image, C, N, O, and Cu elements are uniformly distributed in Cu-SOF, indicating the successful introduction of Cu element.
[0057] Test of copper ion release performance of Cu-SOF materials:
[0058] 10 mg of the Cu-SOF material sample prepared in Example 1 was weighed and dispersed in 10 mL of PBS solution with pH values of 7.4 and 6.5, and the solution was shaken at 37 °C. Samples were taken at 0.5 h, 2 h, 4 h, 8 h, 12 h, 24 h, 48 h, and 72 h, respectively. After centrifugation and filtration, the Cu concentration in the supernatant was determined (ICP-MS method). The results are as follows. Figure 7As shown in Figure A, under pH 6.5 conditions, the cumulative release rate was approximately 66.4% after 12 hours and reached 95.1% after 72 hours; however, under pH 7.4 conditions, only 39.5% was released after 72 hours. Comparing Cu-MOF (MOF-199) and Cu-HOF (HOF-21-Cu), the Cu release rate of Cu-SOF was approximately 5.3 times and 1.3 times higher, respectively. Figure 7 (See Figure B). This demonstrates that its Cu-SOF framework exhibits rapid copper ion release characteristics and excellent weak acid responsiveness.
[0059] Cu-SOF material-induced copper death in macrophages:
[0060] Human THP-1 cells were activated into the M1 form using LPS / IFN-γ (100 ng / mL / 20 ng / mL). Subsequently, different concentrations of Cu-SOF (0 μg / mL, 50 μg / mL, 100 μg / mL, 200 μg / mL, 500 μg / mL, 1000 μg / mL) were added and incubated for 24 hours. Cell viability and the expression level of the copper death marker protein FDX1 were then measured. Results are as follows: Figure 8 As shown in Figure A, when the Cu-SOF concentration was ≥200 μg / mL, cell viability decreased by approximately 60%, and FDX1 was significantly downregulated. Figure 8 B) indicates that Cu-SOF can effectively induce copper death in pro-inflammatory M1 macrophages.
[0061] Changes in the expression levels of macrophage inflammatory factors after treatment with Cu-SOF material:
[0062] Macrophages were treated with 200 μg / mL Cu-SOF, and then quantitative real-time polymerase chain reaction (qRT-PCR) analysis was performed. The results are as follows: Figure 9 As shown, the mRNA levels of pro-inflammatory cytokines interleukin-6 (IL-6) and interleukin-1β (IL-1β) were significantly downregulated, indicating a significant reduction in inflammation levels.
[0063] The therapeutic effect of Cu-SOF in a diabetic mouse ulcer model:
[0064] An ulcer model was established using db / db diabetic mice.
[0065] Mice were randomly divided into four groups: control group (non-diabetic ulcer mice, PBS intervention), diabetic group (db / db), experimental group (Cu-SOF intervention), and clinical control group (rb-bFGF intervention).
[0066] The drug was administered continuously for 9 days, and wound changes were recorded and hematoxylin-eosin (H&E) staining was performed.
[0067] The results are as follows Figure 10 As shown, the wound closure rate of the Cu-SOF group on day 9 was 78.4±5.3%, which was significantly higher than that of the rb-bFGF group (63.2±4.7%). Figure 11 The results showed that the Cu-SOF group had improved granulation tissue formation quality and reduced inflammatory cell infiltration, indicating that Cu-SOF treatment effectively alleviated the inflammatory response in diabetic ulcer tissue and promoted wound healing.
[0068] Cu-SOF promotes macrophage phenotypic remodeling:
[0069] In the aforementioned diabetic mouse ulcer model, the M1 type (iNOS) was further tested. + ) and M2 type (CD206) + Macrophage ratio. Immunofluorescence results ( Figure 12 The results showed that the number of M1 cells in the Cu-SOF group decreased significantly, while the number of M2 cells increased significantly, and the M2 / M1 ratio increased by 7.4 times. This indicates that the material of the present invention promotes the repair of diabetic ulcers by inducing copper death of macrophages to achieve inflammation regulation and immune remodeling.
[0070] Example 3
[0071] This embodiment provides a copper-based supramolecular organic framework material, obtained by the preparation method described above, characterized in that it comprises melamine, adipic acid, and copper acetate, wherein the molar ratio of melamine, adipic acid, and copper acetate is 1:1:1.
[0072] Example 4
[0073] This embodiment provides a copper-based supramolecular organic framework material, obtained by the preparation method described above, characterized in that it comprises melamine, adipic acid, and copper acetate, wherein the molar ratio of melamine, adipic acid, and copper acetate is 1:2:2.
[0074] As described above, the copper-based supramolecular organic framework material provided by this invention has atomically dispersed ortho-copper sites and a rich hydrogen bond network, enabling it to rapidly release copper ions in response to a weakly acidic environment; it has a high copper loading capacity, far exceeding that of existing copper-based MOF and HOF materials; at the same time, the preparation process is simple, the cost is low, the raw materials are readily available, and it is easy to scale up for industrial production; it has significant therapeutic effects, effectively inducing copper death in dysfunctional macrophages, while also exhibiting good biocompatibility.
[0075] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the appended claims.
Claims
1. A copper-based supramolecular organic framework material, characterized in that, It includes melamine, adipic acid and copper acetate, wherein the molar ratio of melamine, adipic acid and copper acetate is 1:(1-2):(1-2).
2. The copper-based supramolecular organic framework material as described in claim 1, characterized in that, The copper-based supramolecular organic framework material is used to treat one or more of diabetic foot ulcers, diabetic skin ulcers, diabetic corneal ulcers, diabetic gastric ulcers, and diabetic oral ulcers.
3. A method for preparing a copper-based supramolecular organic framework material, characterized in that, The preparation of the copper-based supramolecular organic framework material as described in claim 1 or 2 comprises the following steps: Melamine and adipic acid are mixed and ground thoroughly to obtain a mixture, wherein the molar ratio between melamine and adipic acid is 1:(1-2); Deionized water was added to the mixture, and Cu-SOF precursor was obtained under preset hydrothermal conditions; Copper acetate was added to the Cu-SOF precursor, and the reaction was continued under preset hydrothermal conditions. The reaction system is cooled and then subjected to final processing to obtain Cu-SOF material.
4. The method for preparing copper-based supramolecular organic framework materials as described in claim 3, characterized in that, The preset hydrothermal conditions are a temperature of 100-140℃ and a reaction time of 24-72 hours.
5. The method for preparing copper-based supramolecular organic framework materials as described in claim 3, characterized in that, The cooling reaction system is then subjected to final processing to obtain Cu-SOF material, further comprising: Cool the reaction system to room temperature; Crystal products were collected by centrifugation; The crystalline product was washed with water and dried at 60°C to obtain Cu-SOF material.
6. The method for preparing copper-based supramolecular organic framework materials as described in claim 3, characterized in that, The Cu-SOF material rapidly releases copper ions under weakly acidic conditions through a synergistic dissociation-recombination mechanism.
7. The method for preparing copper-based supramolecular organic framework materials as described in claim 3, characterized in that, The copper element is uniformly distributed and has an atomically dispersed state within the framework of the Cu-SOF material.