A series of glycated hemoglobin-specific scavenging systems, methods of making and uses thereof

Abstract

The application discloses a series of glycated hemoglobin specific elimination systems, a preparation method and application thereof. The system is an AIE fluorescent positioning group as a skeleton anchor point, and orderly polymerization of the system with a disulfide bond, a diselenide bond, a ditelluride bond and other stimulus response groups is realized through a Schiff base reaction, so that a series of novel oxidative stress response covalent organic framework materials are constructed, and the excellent self-assembly performance of a hydrazine bond PEG group is utilized to identify the glycated protein capture potential. The series of glycated hemoglobin specific elimination systems have a myocardial targeting property, a long residence time, a significant glycated hemoglobin self-capture system, realize stable and long-acting elimination of a disease course marker glycated hemoglobin and specific targeting regulation of myocarditis inflammatory microenvironment macrophages, provide a new idea and a new tool for targeted treatment of a complex pathogenesis of diabetic cardiomyopathy, and have good research significance and excellent clinical transformation value.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a series of glycated hemoglobin specific elimination systems, a preparation method and use thereof. BACKGROUND

[0002] Covalent organic framework materials (COFs) are a kind of porous materials composed entirely of organic structural units. Due to their unique pore structure, large specific surface area, low density, high stability, and easy-to-control function, they have attracted widespread attention in the fields of materials science and chemistry, and have been listed by the American Chemical Society as one of the hottest research directions in the field of chemistry. Since the first report of COF-1 by Omar M. Yaghi's group at the University of California, Berkeley in 2005, the preparation and application of COFs have entered a stage of rapid development and have become a research hotspot.

[0003] Because 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 between them and other porous materials. Through the combination of different building blocks, materials with desired structures can be obtained, which provides unlimited possibilities for the customization and functionalization of COFs. Researchers can design and synthesize COFs with specific structures and functions according to actual needs to meet the application requirements of different fields. Second, COFs have chemical uniqueness. Through thermodynamically controlled reversible covalent bonds, 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 regular pore structures, structural diversity, and easy functionalization. These characteristics make COFs have wide application prospects in the fields of gas adsorption and separation, catalysis, and optoelectronics.

[0004] For the dynamic covalent bonds in COF structures, unlike traditional covalent bonds and coordination bonds, the dynamic covalent bonds in COFs have dynamic functionality, which makes them stable under normal conditions and responsive to degradation in acidic, basic, and redox environments. That is, they can achieve local dynamic therapy under changes in surrounding environmental stimuli. This dynamic response has become one of the hotspots in the field of intelligent response materials. The stimulus responsiveness of dynamic covalent bonds provides more potential for COFs as drug delivery carriers. Disulfide bonds, as a redox-responsive group, have been widely used in drug controlled release. The bond energy of disulfide bond is 240 kJ·mol -1and the response ability in the reducing environment, so that the related materials containing disulfide bond are widely used in the research of prodrugs and drug carriers. Diselenide bond has been reported to have redox dual response ability, and its bond energy is 172 kJ·mol -1 , which is lower than that of disulfide bond. Therefore, when diselenide bond is placed in an oxidizing or reducing environment, its structural response speed is more rapid than that of disulfide bond. The atomic radius of tellurium atom is larger than that of selenium atom, which also makes the bond energy of tellurium atom lower than that of selenium atom under the same conditions. Among them, the bond energy of ditellurium bond is relatively low, only 126 kJ·mol -1 Therefore, from the theoretical analysis, it can be seen that the ditellurium bond has stronger redox sensitivity than the diselenide bond. At present, the research of tellurium element in the field of biological medicine mainly focuses on the research and development of tellurium-containing drugs and the research of tellurium-containing responsive materials. The tellurium-containing responsive materials are mainly based on the dynamic responsiveness and reduction responsiveness of tellurium-containing covalent bond. At present, the research on tellurium-containing polymer materials is still less. Based on the low bond energy of ditellurium bond and the GPx enzyme-like characteristics of diselenide bond in the reducing environment, it can be speculated that the ditellurium bond should have a higher catalytic release rate of NO than the diselenide bond. In addition, the hydrazide enrichment method for N-glycopeptide enrichment is a common strategy. Its principle is based on the fact that the cis-adjacent dihydroxyl group in the sugar chain can be oxidized to aldehyde group by sodium periodate, and further covalently connected with hydrazine and aldehyde group to form hydrazone. The reaction specifically separates glycoprotein or sugar chain from complex biological system, and then uses peptide N-glycosidase F (PNGase F) to release glycoprotein or glycopeptide into mass spectrometry detection. Therefore, we expect that by designing the molecular structure and introducing stimulus-responsive functional groups such as disulfide bond, diselenide bond and ditellurium bond into the structure of COF material, the response to inflammatory microenvironment and the type of in-situ catalytic response material can be realized, and the synergistic effect in the field of biological medicine can be improved.

[0005] Diabetic cardiomyopathy is a myocardial disease caused by diabetes, and inflammation plays a key role in diabetic cardiomyopathy, in which macrophages are the main participants of inflammatory response. At present, the treatment of diabetes and its complications is usually limited to controlling blood glucose and salvaging necrotic cells, and there is a lack of strategies for improving inflammatory response and inhibiting the progression of diabetic cardiomyopathy. In addition, advanced glycation end products are products in a high glucose environment, which can aggravate myocardial injury in diabetic patients. Among them, glycated hemoglobin (HbA1c) is not only an important indicator of chronic hyperglycemia, but also a key risk factor for diabetic cardiovascular complications. How to specifically remove excess HbA1c in the blood circulation of diabetic patients while ensuring the stability of the circulation is a unprecedented work. Therefore, designing a new strategy to organically combine the specific regulation of myocardial macrophages and the stable removal of HbA1c can realize the "dilemma self-solution" in the field of diabetic cardiomyopathy treatment. The purpose of the present application is to break through the limitation of traditional nanomaterials as drug carriers, construct a series of COF carrier cores with potential for the treatment of diabetic cardiomyopathy, further play the immune regulation and disease treatment role of the stimulus-responsive bond site, and realize the active myocardial macrophage targeting function by using the hydrazine bond PEG group to realize the HbA1c self-capture system. SUMMARY

[0006] Based on the above, the purpose of the present application is to provide a series of glycated hemoglobin specific removal systems, preparation methods and uses thereof. A series of porous carrier cores with potential for the treatment of diabetic cardiomyopathy are constructed by the present application to further play the immune regulation and disease treatment role of the stimulus-responsive bond site, and the hydrazine bond polyethylene glycol group is used to realize the HbA1c self-capture system to realize the active myocardial macrophage targeting function. Specifically, the technical scheme adopted by the present application is as follows:

[0007] Firstly, the series of glycated hemoglobin specific removal systems according to the present application are Y-COF@PEG composite materials, wherein Y is at least one of S, Se and Te, the hydrazine bond PEG is hydrazine polyethylene glycol hydrazine (HZ-PEG-HZ), and the Y-COF is obtained by Schiff base reaction of Y-substituted diphenylamine monomer and tetraaldehyde-based tetraphenyl ethylene monomer. The Y-substituted diphenylamine monomer is at least one of 4,4'-dithiodiphenylamine, 4,4'-diseleno diphenylamine and 4,4'-ditellurium diphenylamine.

[0008] Secondly, the preparation method of the series of glycated hemoglobin specific removal systems according to the present application can include the following steps:

[0009] (1) preparing Y-COF material by Schiff base reaction of Y-substituted diphenylamine monomer and tetraaldehyde-based tetraphenyl ethylene;

[0010] (2) Y-COF material is polymerized with hydrazine bond PEG by acid catalysis to prepare Y-COF@PEG composite material.

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

[0012] In the preparation method, preferably, the molar ratio of the tetraaldehyde tetraphenyl ethylene and Y-substituted diphenylamine monomer is 1:3.6-4.5.

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

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

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

[0016] In the preparation method, preferably, the volume ratio of the 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 glycosylated hemoglobin specific removal systems comprises the following steps: first, obtaining COFs material by Schiff base reaction of dithiodiphenylamine, diseleno diphenylamine, ditelluride diphenylamine monomer and tetraaldehyde tetraphenyl ethylene; second, polymerizing and self-assembling different molecular weight hydrazine bond PEG by acid catalysis polymerization on the surface of the obtained COFs material containing dithio bond, diseleno bond and ditelluride bond oxidative stress response group to obtain a series of functional systems with different PEG molecular weights; and third, obtaining different molecular size, hydrazine bond PEG glycosylated protein self-capturing systems based on different stimulus response groups after dialysis and freeze-drying separation and purification. The X-ray diffraction pattern 2Theta (2θ) angle of the novel aggregated luminescent degradable COFs material obtained in the application is 1-20°, and the main peak value is before 12°. The removal system obtained in the application has high stability and uniform dispersibility in aqueous solution, which lays a foundation for subsequent biological applications.

[0018] The application takes an induced light-emitting (AIE) fluorescent positioning group as a skeleton anchor point, realizes orderly polymerization of the group with a disulfide bond, a diselenide bond, a ditelluride bond and the like through a classic Schiff base reaction, and constructs a series of novel oxidative stress response covalent organic framework materials. Under the premise of ensuring good biocompatibility, biomedical application potential of the COF material is deeply mined, the COF material is not only endowed with excellent fluorescent traceability, inflammation microenvironment specificity responsiveness, but also realizes organic combination of material degradation and active oxygen scavenging function, breaks through the action limitation of traditional nanomaterials, enriches the application and connotation of the COF material, and creates a bright prospect for development of the COF material in biomedicine.

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

[0020] Further, the series of glycated hemoglobin specific removal systems can also be applied to prepare a medicine for preventing or improving or treating diabetic cardiomyopathy.

[0021] In addition, the series of glycated hemoglobin specific removal systems can also be applied to prepare a medicine for preventing or improving or treating diabetes.

[0022] The series of glycated hemoglobin specific removal systems is a porous composite material system for capturing glycated hemoglobin, and has the following structural characteristics:

[0023] The skeleton group: the stimulus responsiveness of the dynamic covalent bond provides more potential for the COF itself as a drug delivery carrier. The disulfide bond, the diselenide bond and the ditelluride bond serve as a redox double-responsive group, which can provide a basis, a tool and a strategy for innovative design and application development of oxidative stress stimulus-responsive materials. The tetraaldehyde group tetraphenyl ethylene serves as an AIE fluorescent excitation group, which is helpful for in vitro and in vivo monitoring and tracking.

[0024] The glycated hemoglobin removal group: a series of hydrazine bond PEG groups with different molecular weights are self-assembled and polymerized on the surface of the COF, and according to the characteristics brought by different PEG lengths, a system with good biocompatibility, system stability, excellent glycated protein capture ability, coordinated protein crown glycated hemoglobin ratio and significant macrophage uptake is screened in the blood samples of diabetic patients in vitro.

[0025] The application constructs a new type of aggregation-emitting degradable covalent organic framework (COF) material, and self-assembles a hydrazine bond PEG group with a glycated hemoglobin self-capturing function on the surface of the COF, so as to realize targeted regulation and stable removal of myocardial macrophages and harmful hemoglobin, thereby providing a new idea and tool for treatment of diabetes and its complications.

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

[0027] Fast stabilization: the glycosylated protein self-capture system can specifically capture glycated hemoglobin, effectively removing glycated hemoglobin in the blood, and the stability of the system ensures long-term effect in complex biological environment.

[0028] Biocompatibility and monitoring: the glycosylated protein self-capture system has AIE characteristics, making it easy to track and monitor in vivo or in vitro experiments, which helps to evaluate the removal effect and adjust the treatment plan.

[0029] Potential clinical applications: the organic combination of layer-by-layer progressive design, fluorescence traceability, inflammation microenvironment-specific response and antioxidant stress effect enriches the new applications and new connotations of COF materials. The organic combination of glycosylated hemoglobin self-capture and myocardial macrophage targeting regulation - high glycated hemoglobin (HbA1c) level and pro-inflammatory macrophage infiltration are important risk factors for myocardial disease in diabetic state. Previous studies have found that HbA1c in the blood of diabetic patients has high affinity for macrophages, and the macrophages recruited by the heart are the key factors that cause inflammation and lead to myocardial damage. Therefore, the organic combination of glycosylated hemoglobin self-capture and myocardial macrophage targeting regulation provides a double-effect strategy for the complex pathogenesis of diabetic cardiomyopathy.

[0030] The present application utilizes the excellent self-assembly performance of hydrazine bond PEG groups and the potential of glycosylated protein capture to construct a series of glycosylated protein self-capture systems based on stimulus-responsive COF surface polyhydrazine bond PEG with different sizes and structures. On the basis of fully verifying its in vitro and in vivo stability and biocompatibility, the structure of the protein crown formed in the high-sugar blood environment of diabetic patients and the corresponding function 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, realizing the organic combination of stable and long-acting removal of disease marker glycated hemoglobin and specific targeting regulation of myocardial inflammatory microenvironment macrophages, providing new ideas and new tools for targeted treatment of the complex pathogenesis of diabetic cardiomyopathy, which has good research significance and excellent clinical translation value. BRIEF DESCRIPTION OF DRAWINGS

[0031] Figure 1 X-ray diffraction (XRD) crystal structure characterization of COFs materials containing disulfide bond, diselenide bond, ditelluride bond oxidative stress response group: S-COF (a), Se-COF (b) and Te-COF (c).

[0032] Figure 2are FT-IR spectra of S-COF (d), Se-COF (e) and Te-COF (f) before and after polymerization of different molecular weight polyethylene glycol hydrazine bond groups.

[0033] Figure 3 are the relative level changes of total glycated proteins in the plasma of diabetic patients after incubation with different concentrations of S-COF (a), Se-COF (b) and Te-COF (c) core capture systems for 12 h; the relative level changes of glycated hemoglobin in the plasma of diabetic patients after incubation with different concentrations of S-COF (d), Se-COF (e) and Te-COF (f) core capture systems for 12 h; the relative level changes of blood glucose in diabetic patients after incubation with different concentrations of S-COF (g), Se-COF (h) and Te-COF (i) core capture systems for 12 h, n = 5, * p < 0.05, ** p < 0.01, *** p < 0.001 and **** p < 0.0001.

[0034] Figure 4 are the content changes of total proteins (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) in the plasma of diabetic patients after incubation with different glycosylated protein capture systems for 12 h, n = 5 (5 parallel experiments, the same below).

[0035] Figure 5 are the contents of glycated proteins (a), glycated hemoglobin (b), inflammatory factors IL-6 (c), TNF-α (d), IL-1β (e) and myocardial injury marker cTn I (f) in the serum of STZ-induced diabetic mice after injection of different glycosylated protein capture systems for 9 days, and the dynamic monitoring of blood glucose changes in mice in each group, n = 5.

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

[0037] Figure 7 is the preparation process of a series of porous composite material capture glycated hemoglobin systems and a schematic diagram of capturing glycated hemoglobin. DETAILED DESCRIPTION

[0038] The following examples are further illustrations of the present application and are not intended to limit the present application in any way. Those skilled in the art will readily understand any variations or modifications of the present application that fall within the scope of the application.

[0039] Example 1

[0040] The molar ratio of tetraaldehyde tetraphenyl ethylene to 4,4'-dithiodianiline, 4,4'- diseleno dianiline, 4,4'-ditelluro dianiline was 1:4. Take 7.28 mg (0.016 mmol) of tetraaldehyde tetraphenyl ethylene, take 0.064 mmol of 4,4'-dithiodianiline, 0.064 mmol of 4,4'-diseleno dianiline, 0.064 mmol of 4,4'-ditelluro dianiline, and take 1,4 dioxane, mesitylene and 6 M aqueous acetic acid (10:10:3, v / v / v) into a glass tube, then use a freeze-pump-thaw cycle for 3 times of degassing procedure. Then flame seal the glass vial and allow the mixture to react at 120 °C for 3 days. After filtration, the precipitate was washed with tetrahydrofuran at least 3 times and purified by Soxhlet extraction with tetrahydrofuran overnight. Finally, the solid was supercritical CO2 dried to produce the product (S-COF, Se-COF, Te-COF) in the form of yellow powder (yield: 90.0%). As shown in the powder X-ray diffraction (PXRD) spectra, the S-COF, Se-COF, Te-COF based on AIEgen exhibited crystalline properties. The PXRD spectra showed strong diffraction peaks, indicating the presence of long-range ordered structure. Figure 1

[0041] Example 2

[0042] Take 10 mg of the three COF materials synthesized above and 20 mg of hydrazone-PEG with different molecular weights (MW = 600, 2000, 6000), 1 ml of mesitylene, 1 ml of 1,4-dioxane into a sealed tube, ultrasonic for 3 h to disperse uniformly, then add 0.6 ml of 6 M aqueous acetic acid, continue to ultrasonic for 30 min, freeze by 3 times of liquid nitrogen cycle, then dialysis and freeze-drying to obtain 9 kinds of glycosylated hemoglobin (HbA1c) self-capture systems based on stimulus-responsive COF surface polymerization hydrazone-PEG, namely S-COF@PEG600, S-COF@PEG2000, S-COF@PEG6000, Se-COF@PEG600, SeCOF@PEG2000, Se-COF@PEG6000, Te-COF@PEG600, TeCOF@PEG2000, Te-COF@PEG6000. As shown in the powder X-ray diffraction (PXRD) spectra, the S-COF, Se-COF, Te-COF based on AIEgen exhibited crystalline properties. The PXRD spectra showed strong diffraction peaks, indicating the presence of long-range ordered structure.​Figure 2 The S-S COF, Se-Se COF, and Te-Te COF based on AIEgen shown in the infrared spectrum show a strong C=N absorption peak near the 1625 cm-1 position, while the N-H absorption peak at 3300-3400 cm-1 has disappeared, and the strong absorption peak C=O near the 1200~1000 cm-1 position has been weakened (not belonging to the characteristic absorption peak of C=O), indicating that the Schiff base reaction between aldehyde group and amino group has occurred. The nine kinds of glycosylated hemoglobin (HbA1c) self-capturing systems based on stimulus-responsive COF surface polymerization of hydrazine bond PEG show strong C=O absorption peaks at 1200~1000 cm-1, indicating that the three kinds of COF materials and three kinds of different molecular weight hydrazine bond PEG polymerization are successful.

[0043] Experimental Example 3

[0044] The in vitro performance evaluation method of a series of HbA1c self-capturing systems based on stimulus-responsive COF surface polymerization of hydrazine bond PEG is as follows:

[0045] (1) According to the requirements of clinical ethics, after signing the relevant informed consent documents, obtain the high glycosylated hemoglobin blood samples of diabetic patients, centrifuge at 3000 rpm / min for 15 minutes after coagulation, and collect the supernatant to obtain the patient serum sample.

[0046] (2) Add 200 μl of blood sample and 0.4 mg of a series of COF materials to the centrifuge tube, so that the material concentration is 2 mg / ml, and the control group does not add materials. After fully mixing, incubate at 37 ℃ for 12 hours, then centrifuge at 14000 rpm / min for 10 minutes, separate the material precipitate and collect the supernatant.

[0047] (3) If Figure 3As shown, the NBT method was used to detect the relative changes in serum glycated protein (GSP) levels in diabetic patients after co-incubation for 12 h with capture systems containing different concentrations of S-COF(a), Se-COF(b), and Te-COF(c) cores; the TBA method was used to detect the relative changes in serum glycated hemoglobin (GHB) levels in diabetic patients after co-incubation for 12 h with capture systems containing different concentrations of S-COF(d), Se-COF(e), and Te-COF(f) cores; and the hexokinase method was used to detect the relative changes in blood glucose (Glu) levels in diabetic patients after co-incubation for 12 h with capture systems containing different concentrations of S-COF(g), Se-COF(h), and Te-COF(i) cores. A series of glycosylated hemoglobin (HbA1c) self-capture systems based on the surface polymerization of PEG with hydrazide bonds on COFs were discovered to significantly reduce the levels of GSP, GHB, and Glu in the serum of diabetic patients. Among these glycosylated hemoglobin self-capture systems, the self-assembly of COFs with PEG2000 showed the best results, namely S-COF@PEG2000, SeCOF@PEG2000, and Te-COF@PEG2000.

[0048] Experiment Example 4

[0049] like Figure 4 As shown, after incubating the plasma of diabetic patients with different glycosylated protein capture systems for 12 hours using the same method as in Experiment 3, the changes in the levels of 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 measured. It was found that a series of glycosylated protein capture systems had virtually no effect on these indicators. Further comparison... Figure 4 This further demonstrates the specific capture of glycated hemoglobin by this series of glycosylated protein self-capture systems.

[0050] Experimental Example 5

[0051] Following screening in Experiments 3 and 4, we identified S-COF@PEG2000, SeCOF@PEG2000, and Te-COF@PEG2000 as having better effects, thus necessitating further in vivo validation experiments. Five experimental groups were set up (6-8 cases per group: normal group (Con), model group (DCM), and S-COF@PEG2000, SeCOF@PEG2000, and Te-COF@PEG2000 groups). Figure 5The mice were injected with the same dose of different glycosylated protein capture system once every two days, and the serum of the mice was taken on the 9th day after injection for detection of glycosylated protein (a), glycosylated hemoglobin (b), and the contents of inflammatory factors IL-6 (c), TNF-α (d), IL-1β (e), and myocardial injury marker cTn I (f). The blood glucose change of the mice in each group was dynamically monitored (g). The results show that the glycosylated hemoglobin self-capture system constructed by us has good blood glucose lowering effect in vivo, and can better remove GSP, GHB, and reduce IL-6, TNF-α, IL-1β, cTn I and other inflammatory factors.

[0052] Experimental Example 6

[0053] Five experimental groups were set up (6-8 cases per group: normal group, model group, S-COF@PEG2000, SeCOF@PEG2000, Te-COF@PEG2000 group). The mice were injected with the same dose of glycosylated protein self-capture system once every two days for two weeks. After two weeks, the cardiac function index of the mice was detected by B-ultrasound, such as Figure 6 The left ventricular ejection fraction LVEF (Figure a) and left ventricular short axis shortening fraction LVFS (Figure b) of the mice in the treatment group were significantly improved. Compared with the Control group, the left ventricular ejection fraction and shortening fraction of the mice treated with S-COF@PEG2000, SeCOF@PEG2000 and Te-COF@PEG2000 were enhanced, and after four weeks, the cardiac function was significantly improved, and the cardiac function was greatly improved. These beneficial effects are accompanied by reduced myocardial cell apoptosis and improved cardiac function and survival rate.

[0054] Based on the above, the glycosylated hemoglobin self-capture system of the present application not only has innovation in design, but also has great potential in biological application, and provides a new idea and method for the treatment of related diseases.

[0055] It is particularly emphasized that the glycosylated hemoglobin (HbA1c) self-capture system based on the stimulus-responsive COF surface polyhydrazide bond PEG described in the present application directly targets the removal of high-concentration glycosylated hemoglobin in the blood of diabetic patients, which is a potential dangerous factor, which has important significance in the field of biomedicine. The treatment effectiveness is not only fully verified in in vitro experiments at the cellular or molecular level, but also shows actual treatment effect in complex in vivo environment (such as mouse model), further confirming the universality and reliability of its application.

[0056] In addition, the system fully considers cost-effectiveness and preparation convenience in design, ensuring its feasibility in large-scale application. More importantly, the system exhibits rapid, efficient and specific glycated hemoglobin clearance effect and targeted regulation of myocardial macrophages, while maintaining excellent biological safety, which is crucial to ensure patient safety during treatment. Therefore, the combination of glycosylated hemoglobin self-capture and myocardial macrophage targeted regulation provides a double-effect strategy for the complex pathogenesis of diabetic cardiomyopathy, bringing revolutionary changes to related research and clinical practice.

[0057] It should be noted that the above technical content of the present application is only an explanation and clarification to enable those skilled in the art to understand the essence of the present application, so the technical content is not used to limit the essential protection scope of the present application. The essential protection scope of the present application shall be subject to the description in the claims. Those skilled in the art should know that any modification, equivalent replacement and improvement made on the basis of the essential spirit of the present application shall be within the essential protection scope of the present application.

Claims

1. A glycated hemoglobin specific scavenging material, which is Y-COF@PEG composite material, and is obtained by polymerization of Y-COF material and hydrazine bond PEG through acid catalysis, wherein Y is at least one of S, Se and Te, the hydrazine bond PEG is hydrazine polyethylene glycol hydrazine with a molecular weight of 500-8000, the Y-COF material is obtained by Schiff base reaction of Y-substituted diphenylamine monomer and tetraaldehyde-based tetraphenyl ethylene monomer, and the Y-substituted diphenylamine monomer is at least one of 4, 4'-dithiodiphenylamine, 4, 4'-diseleno diphenylamine and 4, 4'-ditellurium diphenylamine. 2.A preparation method of the scavenging material of claim 1, comprising the following steps: (1) preparing Y-COF material by Schiff base reaction of Y-substituted diphenylamine monomer and tetraaldehyde-based tetraphenyl ethylene; (2) preparing Y-COF@PEG composite material by polymerization of Y-COF material and hydrazine bond PEG through acid catalysis.

3. The production method according to claim 2, wherein In the step (1), the tetraaldehyde-based tetraphenyl ethylene and Y-substituted diphenylamine monomer are reacted at 100-140℃ in 1, 4-dioxane, mesitylene and 4-8M acetic acid for 36-96 hours.

4. The production method according to claim 3, wherein The molar ratio of the tetraaldehyde-based tetraphenyl ethylene to the Y-substituted diphenylamine monomer is 1:3.6-4.

5.

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

6. The production method according to claim 2, wherein In the step (2), the Y-COF material and hydrazine bond PEG are mixed and dissolved into a mixed solution of mesitylene and 1, 4-dioxane, and then 4-8M acetic acid is added for reaction.

7. The production method according to claim 6, wherein The mass ratio of the Y-COF material to the hydrazine bond PEG is 1:

2.

8. The production method according to claim 6, wherein The volume ratio of the 1, 4-dioxane, mesitylene and acetic acid is 8-12: 8-12: 5-8.

9. The production method according to claim 8, wherein The volume ratio of the 1, 4-dioxane, mesitylene and acetic acid is 10:10:

6. 10.Use of the scavenging material of claim 1 or the scavenging material obtained by the preparation method of any one of claims 2-8 in preparation of a system for capturing or scavenging glycated protein and / or glycated hemoglobin in blood. 11.Use of the scavenging material of claim 1 or the scavenging material obtained by the preparation method of any one of claims 2-8 in preparation of a drug for preventing or improving or treating diabetic cardiomyopathy. 12.Use of the scavenging material of claim 1 or the scavenging material obtained by the preparation method of any one of claims 2-8 in preparation of a drug for preventing or improving or treating diabetes. 13.Use of the scavenging material of claim 1 or the scavenging material obtained by the preparation method of any one of claims 2-8 in preparation of a drug for reducing blood glucose. 14.Use of the scavenging material of claim 1 or the scavenging material obtained by the preparation method of any one of claims 2-8 in preparation of a drug for reducing at least one of IL-6, TNF-α, IL-1β and cTn I.

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