Series of glycosylated hemoglobin specific removal systems, and preparation method and application thereof

Abstract

The invention discloses a series of glycosylated hemoglobin specific removal systems as well as a preparation method and application thereof. According to the system, an AIE fluorescence positioning group is used as a skeleton anchor point, and ordered polymerization of the AIE fluorescence positioning group with stimulation response groups such as a disulfide bond, a diselenide bond and a tellurium bond is realized through a Schiff base reaction; a series of novel oxidative stress response covalent organic framework materials are constructed, and the glycosylated protein capture potential is recognized by utilizing the excellent self-assembly performance of a hydrazide bond PEG group. The series of glycosylated hemoglobin specific removal systems have the advantages that the glycosylated hemoglobin self-capture systems are high in myocardial targeting property, long in residence time and remarkable in regulation and control effect, and organic combination of stable and long-acting removal of disease course marker glycosylated hemoglobin and myocarditis microenvironment macrophage specific targeting regulation and control is realized; the invention provides a new idea and a new tool for targeted treatment of complex pathogenesis of diabetic cardiomyopathy, and has good research significance and excellent clinical transformation value.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a series of glycated hemoglobin specific removal systems, preparation methods and uses thereof. Background Art

[0002] Covalent Organic Frameworks (COFs), as a porous material composed entirely of organic structural units, have attracted extensive attention in the fields of materials science and chemistry due to their unique pore structure, large specific surface area, low density, high stability, and easy-to-regulate functions. They have been listed as one of the hot research directions in the field of chemistry by the American Chemical Society. Since the first report of COF-1 by Omar M. Yaghi's research group at the University of California, Berkeley in 2005, the preparation and application research of COFs materials has entered a stage of rapid development and has become a highly anticipated research hotspot.

[0003] Since COFs are constructed from organic raw materials, they have a series of unique characteristics. First, COFs have unique designability, which is one of the most significant differences from other porous materials. Through the combination of different building blocks, materials with expected structures can be obtained, which provides unlimited possibilities for the customization and functionalization of COFs. Researchers can design and synthesize COFs materials with specific structures and functions according to actual needs to meet the application needs of different fields. Secondly, COFs are chemically unique. Through thermodynamically controlled reversible covalent bond connection, materials with crystalline structures can be obtained. This crystalline structure makes COFs significantly different from other porous materials in structure and properties, giving them unique physical and chemical properties. In addition, COFs also have the characteristics of regular pore structure, structural diversity and easy functionalization. These characteristics make COFs have broad application prospects in gas adsorption and separation, catalysis, optoelectronics and other fields.

[0004] The dynamic covalent bonds in the COF structure are different from traditional covalent bonds and coordination bonds. The dynamic covalent bonds in COF have dynamic functionality, which makes it stable under normal conditions and responsively degrades in acid, alkali, redox and other environments. That is, it can achieve local dynamic treatment under changes in environmental stimulus factors. This dynamic response type has become one of the research hotspots in the field of smart responsive materials. The stimulus responsiveness of dynamic covalent bonds provides more potential for COF itself as a drug delivery carrier. Disulfide bonds, as a redox dual responsive group, have been widely used in the field of drug controlled release. The bond energy of disulfide bonds is 240 kJ·mol -1, and its responsiveness in a reducing environment makes related materials containing disulfide bonds widely used in the research of prodrugs and drug carriers. Diselenide bonds have been reported to have dual redox responsiveness, and their bond energy is 172 kJ·mol -1 , which is lower than that of disulfide bonds. Therefore, when the diselenide bond is placed in an oxidizing or reducing environment, its structural response speed is faster than that of the disulfide bond. Compared with selenium atoms, tellurium atoms have a larger atomic radius, which also makes the bond energy of the chemical bond formed by tellurium atoms lower than that of selenium atoms under the same conditions. Among them, the bond energy of the ditelluride bond is relatively low, only 126 kJ·mol -1 Therefore, from theoretical analysis, it can be seen that the ditellurium bond has a stronger redox sensitivity than the diselenium bond. At present, the research on tellurium in the field of biomedicine mainly focuses on the development of tellurium-related drugs and the research of tellurium-responsive materials. As for tellurium-responsive materials, it is mainly based on the dynamic responsiveness and reduction responsiveness of tellurium covalent bonds. At present, there are few studies on tellurium-containing polymer materials. Based on the lower bond energy of the ditellurium bond and the characteristics of the GPx enzyme similar to the diselenium bond in a reducing environment, it can be inferred that the ditellurium bond should have a higher catalytic NO release rate than the diselenium bond. In addition, the hydrazide enrichment method is a common strategy for the enrichment of N-glycopeptides. Its principle is that the cis-vicinal dihydroxyl group in the sugar chain can be oxidized to an aldehyde group by sodium periodate, and the hydrazone reaction formed by the covalent connection of the hydrazide and the aldehyde group is further specifically separated from the complex biological system. Then, the peptide N-glycosidase F (PNGase F) is used to release the glycoprotein or glycopeptide and enter the mass spectrometry detection. Therefore, we expect that through the design of molecular structure and by introducing stimulus-responsive functional groups such as disulfide bonds, diselenide bonds, and ditelluride bonds into the structure of COF materials, we can achieve responsiveness to the inflammatory microenvironment and expand the types of in situ catalytic response materials, and improve their synergistic enhancement properties in the biomedical field.

[0005] Diabetic cardiomyopathy is a myocardial disease caused by diabetes, and inflammation plays a key role in diabetic cardiomyopathy, among which macrophages are the main participants in the inflammatory response. At present, the treatment of diabetes and its complications is usually limited to controlling blood sugar and rescuing necrotic cells, and there is a lack of strategies to improve inflammatory responses and inhibit the progression of diabetic heart disease. In addition, advanced glycation end products are products of high-sugar environments, which can aggravate myocardial damage in diabetic patients. Among them, glycated hemoglobin (HbA1c) is not only an important indicator of chronic hyperglycemia, but also a key risk factor for cardiovascular complications of diabetes. How to specifically remove excess HbA1c in the blood circulation of diabetic patients and ensure circulatory homeostasis is an unprecedented task. Therefore, designing a new strategy to organically combine the specific regulation of myocardial macrophages and the stable removal of HbA1c can achieve a "dilemma" in the treatment of diabetic cardiomyopathy. The present invention aims to break through the limitations of traditional nanomaterials as drug carriers, construct a series of COF carrier cores with potential for the treatment of diabetic cardiomyopathy to further exert the immunomodulatory and disease treatment effects of stimulus-responsive bonds, and utilize hydrazide bond PEG groups to realize the HbA1c self-capture system to achieve active myocardial macrophage targeting function. Summary of the invention

[0006] Based on the above, the purpose of the present invention is to provide a series of glycated hemoglobin specific removal systems, preparation methods and uses thereof. Through the present invention, a series of porous carrier cores with potential for treating diabetic cardiomyopathy are constructed to further exert the immunomodulatory and disease therapeutic effects of stimulus-responsive bonds, and the hydrazide bond polyethylene glycol group is used to realize the glycated hemoglobin HbA1c self-capture system to achieve active myocardial macrophage targeting function. Specifically, the present invention adopts the following technical solutions:

[0007] First, a series of glycated hemoglobin specific removal systems described in the present invention are Y-COF@PEG composite materials, wherein Y is at least one of S, Se, and Te, the hydrazide bond PEG is hydrazide polyethylene glycol hydrazide (HZ-PEG-HZ), and Y-COF is obtained by reacting a Y-substituted diphenylamine monomer with a tetraaldehyde tetraphenylethylene monomer through a Schiff base, and the Y-substituted diphenylamine monomer is at least one of 4,4'-disulfide diphenylamine, 4,4'-diselenide diphenylamine, and 4,4'-ditelluride diphenylamine.

[0008] Secondly, the preparation method of a series of glycated hemoglobin specific removal systems of the present invention may include the following steps:

[0009] (1) Y-COF material is prepared by reacting Y-substituted diphenylamine monomer with tetraaldehyde tetraphenylethylene through Schiff base reaction;

[0010] (2) Y-COF material and hydrazide bond PEG were used to prepare Y-COF@PEG composite material by acid-catalyzed polymerization.

[0011] In the above-mentioned preparation method, preferably, the step (1) is to react tetraaldehyde tetraphenylethylene with Y-substituted diphenylamine monomer at 100-140° C. in the presence of 1,4-dioxane, mesitylene and 4-8M acetic acid for 36-96 hours.

[0012] In the above-described preparation method, preferably, the molar ratio of the tetraaldehyde tetraphenylethylene to the Y-substituted diphenylamine monomer is 1:3.6-4.5.

[0013] In the above-described preparation method, preferably, the volume ratio of 1,4-dioxane, mesitylene and acetic acid is 5-20: 5-20: 2-5.

[0014] In the preparation method described above, preferably, the step (2) is to mix and dissolve the Y-COF material and the hydrazide bond PEG in a mixed solution of mesitylene and 1,4-dioxane, and then add 4-8M acetic acid for reaction.

[0015] In the preparation method described above, preferably, the mass ratio of the Y-COF material to the hydrazide bond PEG is 1:2, and the molecular weight of the hydrazide bond PEG is 500-8000.

[0016] In the above-described preparation method, preferably, the volume ratio of 1,4-dioxane, mesitylene and acetic acid is 8-12: 8-12: 5-8, preferably 10:10:6.

[0017] The preparation method of a series of glycated hemoglobin specific removal systems of the present invention is firstly to obtain COFs material by Schiff base reaction of disulfide diphenylamine, diselenide diphenylamine, ditelluride diphenylamine monomers and tetraaldehyde tetraphenylethylene, and then to polymerize the obtained COFs material containing disulfide bond, diselenide bond, and ditelluride bond oxidative stress response groups on the surface by acid catalysis to realize the polymerization self-assembly of hydrazide bond PEG with different molecular weights to form a series of functionalized systems with different PEG molecular weights, and to obtain hydrazide bond PEG glycosylated protein self-capture systems with different molecular sizes and based on different stimulus response groups after dialysis freeze-drying separation and purification. The main peak of the X-ray diffraction spectrum of the novel aggregated luminescent degradable COFs material obtained by the present invention in the range of 2Theta (2θ) angle 1~20° is before 12°. The removal system obtained by the present invention has high stability and uniform dispersibility in aqueous solution, which lays a foundation for subsequent biological applications.

[0018] This invention uses the aggregation-induced emission (AIE) fluorescent positioning group as the skeleton anchor point, and realizes the orderly polymerization of it with disulfide bonds, diselenide bonds, ditelluride bonds and other stimulus response groups through the classic Schiff base reaction, and constructs a series of new covalent organic framework materials that respond to oxidative stress. On the premise of ensuring good biocompatibility, the biomedical application potential of COF materials is deeply explored, which not only gives COF materials excellent fluorescence traceability and inflammatory microenvironment-specific responsiveness, but also realizes the organic combination of material degradation and active oxygen scavenging functions, breaking through the limitations of traditional nanomaterials, enriching the application and connotation of COF materials, and creating a bright prospect for the development of COF materials in biomedicine.

[0019] Thirdly, the series of glycated hemoglobin specific removal systems described in the present invention can be used to capture or remove glycated hemoglobin in the blood.

[0020] Furthermore, the series of glycated hemoglobin specific clearance systems described in the present invention can also be used to prepare drugs for preventing, improving or treating diabetic cardiomyopathy.

[0021] In addition, the series of glycated hemoglobin specific clearance systems described in the present invention can also be used to prepare drugs for preventing, improving or treating diabetes.

[0022] The series of glycated hemoglobin specific removal systems of the present invention are a system for capturing glycated hemoglobin using a porous composite material, and the structural features thereof are as follows:

[0023] Backbone groups: The stimulus responsiveness of dynamic covalent bonds provides more potential for COF itself as a drug delivery carrier. Disulfide bonds, diselenide bonds, and ditelluride bonds as redox dual responsive groups can provide the basis, tools, and strategies for the innovative design and applicable development of oxidative stress stimulus responsive materials. Tetraaldehyde tetraphenylethylene as an AIE fluorescent excitation group is helpful for in vivo and in vitro monitoring and tracking.

[0024] Glycated hemoglobin scavenging group: A series of hydrazide-bonded PEG groups with different molecular weights are self-assembled and polymerized on the COF surface. Based on the characteristics brought by different PEG lengths, a system with good biocompatibility, system stability, excellent glycosylated protein capture ability, coordinated ratio of protein corona glycosylated hemoglobin, and significant macrophage uptake is screened out in the blood samples of diabetic patients in vitro.

[0025] The present invention constructs a new type of aggregated luminescent degradable covalent organic framework (COF) material, and self-assembles hydrazide-bonded PEG groups with glycated hemoglobin self-capture function on its surface to achieve targeted regulation of myocardial macrophages and stable clearance of damaging hemoglobin, thereby providing new ideas and tools for the treatment of diabetes and its complications.

[0026] The beneficial effects of the present invention are as follows:

[0027] Fast and stable: The glycosylated protein self-capture system can specifically capture glycated hemoglobin and achieve effective removal of glycated hemoglobin in the blood. At the same time, the stability of the system ensures long-term effects in complex biological environments.

[0028] Biocompatibility and monitoring: The glycosylated protein self-capture system has AIE properties, which makes the system easy to track and monitor in vivo or in vitro experiments, helping to evaluate the clearance effect and adjust the treatment plan.

[0029] Potential clinical applications: The progressive design, the organic combination of fluorescence traceability, inflammatory microenvironment-specific response and anti-oxidative stress effect enrich the new applications and connotations of COF materials. Organically combining the self-capture of glycosylated hemoglobin with targeted regulation of myocardial macrophages - high glycosylated hemoglobin (HbA1c) levels and pro-inflammatory macrophage infiltration are important risk factors for the onset of cardiomyopathy in diabetic patients. Previous studies have found that HbA1c in the blood of diabetic patients has a high affinity for macrophages, and macrophages recruited by the heart are the key factors that cause inflammation and lead to myocardial damage. Therefore, the self-capture of glycosylated hemoglobin is organically combined with the targeted regulation of myocardial macrophages, thereby providing a dual-effect strategy for the complex pathogenesis of diabetic cardiomyopathy.

[0030] The present invention utilizes the excellent self-assembly performance and glycosylated protein capture potential of the hydrazide-bonded PEG group to construct a series of glycosylated protein self-capture systems of different sizes and structures based on stimulus-responsive COF surface polymerized hydrazide-bonded PEG. On the basis of fully verifying its in vitro and in vivo stability and biocompatibility, the structure and corresponding function of the protein corona formed in the high-glucose blood environment of diabetic patients are qualitatively and quantitatively analyzed, and the HbA1 self-capture system with strong myocardial targeting, long residence time and significant regulation effect is further screened out, achieving an organic combination of stable and long-term clearance of the disease course marker glycosylated hemoglobin and specific targeted regulation of macrophages in the myocardial inflammatory microenvironment, providing new ideas and new tools for targeted treatment of the complex pathogenesis of diabetic cardiomyopathy, which has good research significance and excellent clinical transformation value. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 These are COFs materials based on oxidative stress response groups containing disulfide bonds, diselenide bonds, and ditellurium bonds: X-ray diffraction (XRD) crystal structure characterization diagrams of S-COF (a), Se-COF (b), and Te-COF (c).

[0032] Figure 2These are the FT-IR images of S-COF (d), Se-COF (e) and Te-COF (f) before and after polymerization of polyethylene glycol hydrazide bond groups with different molecular weights.

[0033] Figure 3 The relative levels of total glycosylated protein in the plasma of diabetic patients were detected by NBT method after incubation with capture systems with different concentrations of S-COF (a), Se-COF (b) and Te-COF (c) cores for 12 h; the relative levels of glycosylated hemoglobin in the plasma of diabetic patients were detected by TBA method after incubation with capture systems with different concentrations of S-COF (d), Se-COF (e) and Te-COF (f) cores for 12 h; the relative levels of blood glucose in diabetic patients were detected by hexokinase method after incubation with capture systems with different concentrations of S-COF (g), Se-COF (h) and Te-COF (i) cores for 12 h, n=5, *p < 0.05, **p < 0.01, ***p < 0.001and ****p < 0.0001.

[0034] Figure 4 The changes in the levels of plasma total protein (a), albumin (b), apolipoprotein A1 (c), apolipoprotein B (d), high-density lipoprotein cholesterol (e), low-density lipoprotein cholesterol (f), total cholesterol (g) and triglycerides (h) were detected after the plasma of diabetic patients was incubated with different glycosylated protein capture systems for 12 hours, n=5 (5 parallel experiments, the same below).

[0035] Figure 5 After constructing the STZ-induced diabetic mouse model, the mouse serum was collected on the 9th day after injection of different glycosylated proteins to detect glycosylated protein (a), glycosylated hemoglobin (b), and the levels of inflammatory factors such as IL-6 (c), TNF-α (d), IL-1β (e) and myocardial injury marker cTn I (f), and the blood glucose changes of each group of mice were dynamically monitored, n=5.

[0036] Figure 6 Reflecting the improvement effect of different COF glycosylated protein capture systems on myocardial function and ejection capacity of diabetic mice, n=5.

[0037] Figure 7 It is a preparation process of a series of porous composite materials for capturing glycated hemoglobin system of the present invention and a schematic diagram of capturing glycated hemoglobin. DETAILED DESCRIPTION

[0038] The following embodiments are further descriptions of the content of the present invention as an explanation of the technical content of the present invention, but the essential content of the present invention is not limited to the following embodiments. Ordinary technicians in this field can and should know that any simple changes or replacements based on the essential spirit of the present invention should fall within the scope of protection required by the present invention.

[0039] Example 1

[0040] The molar ratio of tetraaldehyde tetraphenylene to 4,4'-dithiodiphenylamine, 4,4'-diselenediphenylamine, and 4,4'-ditellurized diphenylamine was 1:4. 7.28 mg (0.016 mmol) of tetraaldehyde tetraphenylene, 0.064 mmol of 4,4'-dithiodiphenylamine, 0.064 mmol of 4,4'-diselenediphenylamine, 0.064 mmol of 4,4'-ditellurized diphenylamine, and 1,4-dioxane, mesitylene, and 6 M acetic acid aqueous solution (10:10:3, v / v / v) were loaded into a glass tube, and then a freeze-pump-thaw cycle was used for 3 degassing procedures. The glass vial was then flame-sealed, and the mixture was reacted at 120°C for 3 days. After the precipitate was collected by filtration, it was washed at least 3 times with tetrahydrofuran and purified overnight with tetrahydrofuran Soxhlet extraction. Finally, the solid is subjected to supercritical CO 2 Drying gave the products (S-COF, Se-COF, Te-COF) in the form of yellow powder (yield: 90.0%). Figure 1 As shown in the powder X-ray diffraction (PXRD) spectra, S-COF, Se-COF, and Te-COF based on AIEgen exhibit crystalline characteristics. The PXRD spectra show strong diffraction peaks, indicating the existence of a long-range ordered structure.

[0041] Example 2

[0042] 10 mg of the three COF materials synthesized above were added to 20 mg of hydrazide-bonded PEG with different molecular weights (MW=600, 2000, 6000), 1 ml of mesitylene, and 1 ml of 1,4-dioxane in a sealed tube. After being fully dispersed by ultrasonication for 3 hours, 0.6 ml of 6M acetic acid aqueous solution was added, and ultrasonication was continued for 30 minutes. After three cycles of liquid nitrogen freezing, dialysis and freeze-drying, 9 glycated hemoglobin (HbA1c) self-capture systems based on stimulus-responsive COF surface polymerized hydrazide-bonded PEG were finally obtained, namely S-COF@PEG600, S-COF@PEG2000, S-COF@PEG6000, Se-COF@PEG600, SeCOF@PEG2000, Se-COF@PEG6000, Te-COF@PEG600, TeCOF@PEG2000, and Te-COF@PEG6000. Figure 2 As shown in the infrared spectra, the SS COF, Se-Se COF, and Te-Te COF based on AIEgen show a strong C=N absorption peak near 1625 cm-1, while the NH absorption peak at 3300-3400 cm-1 has disappeared. At the same time, the strong absorption peak C=O near 1200~1000 cm-1 has weakened (no longer a characteristic absorption peak of C=O), indicating that the aldehyde group and the amino group have undergone a Schiff base reaction. The 9 glycated hemoglobin (HbA1c) self-capture systems based on the stimuli-responsive COF surface polymerized hydrazide bond PEG show a strong C=O absorption peak at 1200~1000 cm-1, indicating that the three COF materials and three different molecular weight hydrazide bond PEGs have been successfully polymerized.

[0043] Experimental Example 3

[0044] The in vitro performance evaluation methods of a series of HbA1c self-capture systems based on stimuli-responsive COF surface polymerized hydrazide-bonded PEG are as follows:

[0045] (1) In accordance with clinical ethics requirements, after signing the relevant informed consent documents, blood samples with high glycated hemoglobin were obtained from diabetic patients. After coagulation, the samples were centrifuged at 3000 rpm / min for 15 minutes, and the supernatant was collected to obtain the patient serum samples.

[0046] (2) Add 200 μl of blood sample and 0.4 mg of a series of COFs materials to a centrifuge tube to make the material concentration 2 mg / ml. No material is added to the control group. After thorough mixing, incubate at 37 °C for 12 h, then centrifuge at 14,000 rpm / min for 10 min to separate the material precipitate and collect the supernatant.

[0047] (3) If Figure 3As shown, the NBT method was used to detect the changes in the relative levels of serum glycated protein (GSP) in diabetic patients after incubation with the capture systems with different concentrations of S-COF (a), Se-COF (b) and Te-COF (c) cores for 12 h; the TBA method was used to detect the changes in the relative levels of serum glycated hemoglobin (GHB) in diabetic patients after incubation with the capture systems with different concentrations of S-COF (d), Se-COF (e) and Te-COF (f) cores for 12 h; the hexokinase method was used to detect the changes in the relative levels of blood glucose (Glu) in diabetic patients after incubation with the capture systems with different concentrations of S-COF (g), Se-COF (h) and Te-COF (i) cores for 12 h. It was found that a series of glycosylated hemoglobin HbA1c self-capture systems based on stimulus-responsive COF surface polymerized hydrazide-bonded PEG can significantly reduce the levels of GSP, GHB, and Glu in the serum of diabetic patients. In this series of glycosylated hemoglobin self-capture systems, the self-assembly effect of COFs material and PEG2000 polymerization was the best, namely S-COF@PEG2000, SeCOF@PEG2000, and Te-COF@PEG2000.

[0048] Experimental Example 4

[0049] like Figure 4 As shown, the plasma of diabetic patients was incubated with different glycosylated protein capture systems in the same manner as in Experimental Example 3 for 12 hours, and then the changes in the content of plasma total protein (a), albumin (b), apolipoprotein A1 (c), apolipoprotein B (d), high-density lipoprotein cholesterol (e), low-density lipoprotein cholesterol (f), total cholesterol (g) and triglycerides (h) were detected. It was found that a series of glycosylated protein capture systems had little effect on these indicators. Figure 4 This can better illustrate the specific capture of glycated hemoglobin by this series of glycosylated protein self-capture systems.

[0050] Experimental Example 5

[0051] After screening in Experimental Examples 3 and 4, we found that S-COF@PEG2000, SeCOF@PEG2000, and Te-COF@PEG2000 had better effects, and thus continued to verify the in vivo experiments. Five experimental groups were set up (6-8 cases in each group: normal group (Con), model group (DCM), S-COF@PEG2000, SeCOF@PEG2000, and Te-COF@PEG2000 groups). Figure 5As shown, a mouse model of diabetes induced by tetrafluoropyrimidine was constructed. After the same dose of different glycosylated protein capture was injected into the tail vein once every two days, the mouse serum was collected on the 9th day to detect glycosylated protein (a), glycosylated hemoglobin (b), and the content of inflammatory factors such as IL-6 (c), TNF-α (d), IL-1β (e) and myocardial injury marker cTn I (f), and the blood glucose changes of each group of mice were dynamically monitored (g). The results show that the glycosylated hemoglobin self-capture system we constructed can also have a good hypoglycemic effect in vivo, and can better clear GSP and GHB, and can reduce inflammatory factors such as IL-6, TNF-α, IL-1β, and cTn I.

[0052] Experimental Example 6

[0053] Five experimental groups (6-8 cases in each group: normal group, model group, S-COF@PEG2000, SeCOF@PEG2000, Te-COF@PEG2000 group) were set up to construct a diabetic mouse model induced by tetrafluoropyrimidine. The same dose of glycosylated protein self-capture system was injected into the tail vein once every two days for two weeks. After two weeks, the cardiac function index of the mice was detected by B-ultrasound. Figure 6 . The left ventricular ejection fraction LVEF (Figure a) and left ventricular short axis shortening fraction LVFS (Figure b) of the treated mice were significantly improved. Compared with the control group, the left ventricular ejection fraction and shortening fraction were enhanced by S-COF@PEG2000, SeCOF@PEG2000, and Te-COF@PEG2000, respectively, and significantly improved after four weeks, and the cardiac function was further improved. These beneficial effects were accompanied by reduced cardiomyocyte apoptosis and improved cardiac function and survival rate.

[0054] Based on the above, the glycosylated hemoglobin self-capture system of the present invention is not only innovative in design, but also shows great potential in biological applications, providing new ideas and methods for the treatment of related diseases.

[0055] It is particularly worth emphasizing that the series of glycated hemoglobin (HbA1c) self-capture systems based on stimulus-responsive COF surface polymerized hydrazide-bonded PEG described in this application are the first to directly target the high concentration of glycated hemoglobin in the blood of diabetic patients, a potential risk factor, for scavenging treatment strategies, which is of great significance in the biomedical field. Its therapeutic effectiveness has not only been fully verified in in vitro experiments at the cellular or molecular level, but also demonstrated actual therapeutic effects in complex in vivo environments (such as mouse models), further confirming its wide application and reliability.

[0056] In addition, the system is designed with full consideration of cost-effectiveness and ease of preparation to ensure its feasibility in large-scale applications. More importantly, the system demonstrates rapid, efficient and specific clearance of glycated hemoglobin and targeted regulation of myocardial macrophages, while maintaining excellent biosafety, which is crucial to ensuring the safety of patients during treatment. Therefore, the organic combination of glycated hemoglobin self-capture and targeted regulation of myocardial macrophages provides a dual-effect strategy for the complex pathogenesis of diabetic cardiomyopathy, bringing revolutionary changes to research and clinical practice in related fields.

[0057] It should be noted that the above-mentioned technical contents of the present invention are only for explanation and clarification to enable those skilled in the art to understand the technical essence of the present invention, so the technical contents are not used to limit the substantial protection scope of the present invention. The substantial protection scope of the present invention shall be subject to the claims. Those skilled in the art should know that any modification, equivalent substitution and improvement based on the substantial spirit of the present invention shall be within the substantial protection scope of the present invention.

Claims

1. A series of glycated hemoglobin specific removal systems, which are Y-COF@PEG composite materials, which are obtained by acid-catalyzed polymerization of Y-COF material and hydrazide bond PEG, wherein Y is at least one of S, Se, and Te, and the hydrazide bond PEG is hydrazide polyethylene glycol hydrazide, and the Y-COF material is obtained by Schiff base reaction of Y-substituted diphenylamine monomer and tetraaldehyde tetraphenylethylene monomer, and the Y-substituted diphenylamine monomer is at least one of 4,4'-dithiodiphenylamine, 4,4'-diselendiphenylamine, and 4,4'-ditelluride diphenylamine.

2. The method for preparing the system according to claim 1, comprising the following steps: (1) Y-COF material is prepared by reacting Y-substituted diphenylamine monomer with tetraaldehyde tetraphenylethylene through Schiff base reaction; (2) Y-COF material and hydrazide bond PEG were used to prepare Y-COF@PEG composite material by acid-catalyzed polymerization.

3. The preparation method according to claim 2, characterized in that: The step (1) is to react tetraaldehyde tetraphenylethylene with Y-substituted diphenylamine monomer at 100-140° C. in the presence of 1,4-dioxane, mesitylene and 4-8M acetic acid for 36-96 hours.

4. The preparation method according to claim 3, characterized in that: The molar ratio of the tetraaldehyde tetraphenylethylene to the Y-substituted diphenylamine monomer is 1:3.6-4.

5.

5. The preparation method according to claim 3, characterized in that: The volume ratio of the 1,4-dioxane, mesitylene and acetic acid is 5-20: 5-20: 2-5.

6. The preparation method according to claim 2, characterized in that: The step (2) is to mix and dissolve the Y-COF material and the hydrazide bond PEG in a mixed solution of mesitylene and 1,4-dioxane, and then add 4-8M acetic acid for reaction.

7. The preparation method according to claim 6, characterized in that: The mass ratio of the Y-COF material to the hydrazide bond PEG is 1:

2.

8. The preparation method according to claim 6, characterized in that: The volume ratio of 1,4-dioxane, mesitylene and acetic acid is 8-12: 8-12: 5-8, preferably 10:10:

6.

9. Use of the system according to claim 1 or the system obtained by the preparation method according to any one of claims 2 to 8 in capturing or removing glycated protein and / or glycated hemoglobin in blood.

10. Use of the system according to claim 1 or the system obtained by the preparation method according to any one of claims 2 to 8 in the preparation of a drug for preventing, improving or treating diabetic cardiomyopathy.

11. Use of the system according to claim 1 or the system obtained by the preparation method according to any one of claims 2 to 8 in the preparation of a drug for preventing, improving or treating diabetes.

12. Use of the system according to claim 1 or the system obtained by the preparation method according to any one of claims 2 to 8 in the preparation of a drug for lowering blood sugar.

13. Use of the system according to claim 1 or the system obtained by the preparation method according to any one of claims 2 to 8 in the preparation of drugs for reducing inflammatory factors such as IL-6, TNF-α, IL-1β, cTn I, etc.

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