Self-crosslinking hydrogel with tertiary amine group as well as preparation and application of self-crosslinking hydrogel

Abstract

The invention discloses a self-crosslinking hydrogel with a tertiary amine group and preparation and application thereof, and belongs to the field of biomedical polymer materials, the self-crosslinking hydrogel comprises aminophenylboronic acid modified oxidized glucan, tertiary amine compound modified oxidized glucan and a solvent medium; the preparation method comprises the following steps: dissolving amino phenylboronic acid modified oxidized dextran and tertiary amine compound modified oxidized dextran in a solvent medium, mixing, standing for a certain time, and carrying out self-crosslinking to obtain the self-crosslinking hydrogel with tertiary amine groups. A cross-linking point (phenylboronic acid) of the gel network is a response unit of glucose. In addition, the hydrogel can effectively avoid uncontrollable drug release caused by non-responsive factors, and the response release efficiency of the drug is improved; by loading the hypoglycemic drug insulin to be applied to the treatment research process of diabetes, the occurrence of hypoglycemia can be avoided, and meanwhile, the possibility is provided for realizing intelligent controlled release of insulin through blood glucose response.

Description

Technical Field

[0001] The present application relates to the field of biomedical polymer materials, and in particular to a self-crosslinking hydrogel having tertiary amine groups and its preparation and application. Background Art

[0002] Hydrogels have been widely used in the treatment of different types of diseases in recent years as a new type of drug sustained-release material due to their good biosafety and physiological tissue-like advantages. Most of them are constructed by high molecular polymers with good biosafety (such as polyethylene glycol, chitosan, ester polymers, etc.). Among them, dextran, as a polysaccharide polymer with good biocompatibility and degradability, has been widely used in plasma substitutes, drug delivery carriers, tissue engineering, etc. It is also a common basic material for constructing biomedical hydrogels.

[0003] The continuous blood sugar fluctuation in diabetic patients is a key physiological characteristic of their microenvironment and an important basis for determining the insulin injection dose. Accurately controlling the release of insulin based on blood sugar fluctuations can not only improve the accuracy and effectiveness of diabetes treatment, but also significantly improve the quality of life of patients, which has important clinical significance and application prospects.

[0004] In view of this, the development of a hydrogel carrier material that can respond to changes in blood sugar levels in patients for a long time and intelligently control the release of insulin is of great significance for maintaining normal blood sugar in patients for a long time and reducing the psychological and life burden of patients caused by frequent insulin injections. Summary of the invention

[0005] The purpose of the present application is to provide a self-crosslinking hydrogel with a tertiary amine group and its preparation and application. The preparation method provided by the present invention has the characteristics of mild conditions, simple operation, and easy implementation. It can be applied to the treatment research of diabetes by loading insulin, but is not limited to loading insulin drugs. Compared with the existing hydrogel system, the drug is often directly loaded in the hydrogel in the form of physical coating and distributed in the pores and cavities of the hydrogel; however, the lack of interaction between the hydrogel and the drug often leads to the uncontrolled free release of some drugs in the pores, thereby bringing undesirable treatment risks. The hydrogel of the present invention can bind the drug in the gel network through the electrostatic interaction between the positively charged tertiary amine group and the negatively charged insulin, reduce its uncontrolled release caused by free diffusion behavior, avoid the occurrence of hypoglycemia, and provide the possibility of realizing a more intelligent release of insulin through blood glucose response.

[0006] To achieve the above-mentioned purpose, the present application provides a self-crosslinking hydrogel comprising aminophenylboronic acid-modified oxidized dextran, tertiary amine compound-modified oxidized dextran and a solvent medium; the aminophenylboronic acid-modified oxidized dextran and the tertiary amine compound-modified oxidized dextran are dissolved in a solvent medium, mixed and allowed to stand, and self-crosslinked to form a gel, thereby obtaining a self-crosslinking hydrogel having tertiary amine groups.

[0007] Preferably, the tertiary amine compound is a positively charged molecule that is protonated in a physiological environment of pH 6.5-7.5, and the oxidized dextran modified with the tertiary amine compound includes one or more of oxidized dextran modified with 1-(2-aminoethyl)piperidine, oxidized dextran modified with piperazine-1-amine, and oxidized dextran modified with N-(2-azidoethyl)-pyrrolidine.

[0008] Preferably, the oxidized dextran is prepared by reacting dextran with an oxidizing agent, sodium periodate, the oxidation degree of the dextran is 10% to 60%, and the molecular weight of the dextran is 10 to 200 kDa.

[0009] Preferably, the solvent is one of ultrapure water, PBS buffer, and physiological saline.

[0010] Preferably, the concentration of the self-crosslinking gel is 5.0 wt% to 60.0 wt%, and the mass ratio of the aminophenylboronic acid-modified oxidized dextran to the tertiary amine compound-modified oxidized dextran is 1:1 to 8:1.

[0011] The present application also provides a method for preparing the above self-crosslinking hydrogel, comprising the following steps:

[0012] Step 1, dissolving the dextran with a NaH2PO4 solution, adding a NaIO4 solution dropwise under light-shielding conditions to obtain a mixed solution, stirring the reaction, adding ethylene glycol to terminate the reaction, and continuing to stir. The obtained mixed solution is dialyzed at room temperature for 3 days, and freeze-dried to obtain oxidized dextran solid;

[0013] Step 2: dissolving the oxidized dextran solid obtained in step 1 in a solvent medium to obtain an oxidized dextran solution, adding 3-aminophenylboronic acid, and continuing to stir the reaction. After the reaction is completed, dialyzing at room temperature for 3 days, and freeze-drying to obtain a 3-aminophenylboronic acid-modified oxidized dextran solid; the solvent medium is one of ultrapure water, PBS buffer, and physiological saline;

[0014] Step 3, dissolving the oxidized dextran solid obtained in step 1 in a coal-soluble medium, adding 1-(2-aminoethyl)piperidine or piperazine-1-amine, wherein the molar ratio of the aldehyde group / tertiary amine compound is about 1:1.25, mixing, stirring at room temperature, dialyzing the obtained mixed solution for 2 days, replacing deionized water every 6 hours, and freeze-drying after the dialysis is completed to obtain oxidized dextran modified with 1-(2-aminoethyl)piperidine or oxidized dextran modified with piperazine-1-amine;

[0015] Step 4: dissolve the 3-aminophenylboronic acid grafted oxidized dextran solid obtained in step 2 and the 1-(2-aminoethyl)piperidine-modified oxidized dextran or piperazine-1-amine-modified oxidized dextran obtained in step 3 in PBS buffer (pH = 6.5) to prepare a 25wt% mixed solution, place it in a 37°C water bath, and after dissolution, self-crosslink into a gel after 6-8 hours to obtain a self-crosslinking hydrogel with tertiary amine groups.

[0016] Preferably, in step one, dextran is dissolved with a NaH2PO4 solution, and a NaIO4 solution is added dropwise under light-proof conditions, so that the molar ratio of sugar units to sodium periodate in the obtained mixed solution is 3:1 to 5:1; in step two, 3-aminophenylboronic acid is added at a molar ratio of aldehyde group to amino group of 1:1 to 1:2.

[0017] The self-crosslinked hydrogel loaded with hypoglycemic drugs of the present application is used for blood sugar regulation.

[0018] Therefore, the present application provides a self-crosslinking hydrogel having a tertiary amine group and its preparation and application, which has the following beneficial effects:

[0019] The dual-responsive self-crosslinking hydrogel with tertiary amine groups provided by the present invention has a simple structure and is easy to prepare. Its crosslinking molecules are simply modified natural polymer materials, dextran, and have good biocompatibility; and the crosslinking points (phenylboronic acid) of the gel network are the response units of glucose. Moreover, the hydrogel of the present invention can effectively avoid the uncontrollable drug release caused by non-responsive factors, and improve the response release efficiency of the drug; by loading the hypoglycemic drug insulin and applying it to the treatment research process of diabetes, not only can the occurrence of hypoglycemia be avoided, but also the possibility of realizing the intelligent controlled release of insulin through blood sugar response is provided. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 Schematic diagram of the mechanism of hydrogel;

[0021] Figure 2 This is the NMR characterization image of the oxidized dextran prepared in Example 1 of the present invention;

[0022] Figure 3 This is the NMR characterization image of 3-aminophenylboronic acid grafted oxidized dextran obtained in Example 2 of the present invention;

[0023] Figure 4 This is a gelation photograph of the self-crosslinked hydrogel of Example 4 of the present invention;

[0024] Figure 5 is the Zate potential diagram of the hydrogel material;

[0025] Figure 6 This is a gelation diagram of the self-crosslinking hydrogel with tertiary amine groups in Example 7 of the present invention;

[0026] Figure 7 This is a scanning electron microscope image of a freeze-dried sample of a hydrogel prepared in Example 7 of the present invention;

[0027] Figure 8 This is a responsive degradation curve diagram of the hydrogel prepared in Example 7 of the present invention under different glucose concentration conditions;

[0028] Fig. 9 This is a graph showing the responsive drug release of the hydrogel prepared in Example 7 of the present invention under different glucose concentration conditions;

[0029] Fig.10 To test the biocompatibility of the hydrogel material of the present invention;

[0030] Fig.11 This is a self-healing photo of the hydrogel of the present invention. DETAILED DESCRIPTION

[0031] The technical solution of the present invention is further described below by means of the accompanying drawings and embodiments. It should be understood that these embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention. Any other changes, modifications, substitutions, combinations, simplifications made without violating the spirit and principle of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention. In addition, it should be understood that after reading the content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application and belong to the scope of protection of the present invention.

[0032] Reference to "embodiment" herein means that the specific features, structures or characteristics described in conjunction with the embodiment may be included in at least one embodiment of the present application. The term "embodiment" appearing in various places in the specification does not necessarily refer to the same embodiment, nor does it particularly limit its independence or association with other embodiments. In principle, in the present application, as long as there is no technical contradiction or conflict, the various technical features mentioned in the embodiments can be combined in any way to form a corresponding implementable technical solution.

[0033] Unless otherwise defined, the technical terms used in this document have the same meanings as those generally understood by those skilled in the art to which this application belongs; the use of relevant terms in this document is only for describing specific embodiments and is not intended to limit this application.

[0034] Unless otherwise specified in the present invention, the reagents, instruments, and equipment used are those commonly used by technicians in this field.

[0035] Figure 1 This is a diagram of the preparation mechanism of the hydrogel of the present invention.

[0036] Example 1

[0037] Preparation of oxidized dextran: Dissolve 2.5 g of dextran (molecular weight 100 kDa) in 25 mL of NaH2PO4 solution (20 mM) at room temperature and stir until completely dissolved to obtain a dextran solution. Add sodium periodate solution dropwise under light-proof conditions, the molar ratio of sugar units to sodium periodate in the mixed solution is 4:1, and stir for 1.5 hours. Then add ethylene glycol to terminate the reaction and continue stirring for 15 minutes. The resulting mixed solution is dialyzed for 3 days, with deionized water replaced every 6 hours. After dialysis is completed, freeze-dry to obtain an oxidized dextran solid with a degree of formylation of approximately 25% (i.e., 25 out of every 100 sugar units are oxidized). Figure 2 This is the NMR characterization of oxidized dextran, verifying its successful preparation.

[0038] Example 2

[0039] Preparation of 3-aminophenylboronic acid grafted oxidized dextran: Dissolve 200 mg of the oxidized dextran solid obtained in Example 1 in 5 mL of ultrapure water, add 3-aminophenylboronic acid solid powder (the molar ratio of aldehyde group / phenylboronic acid is about 1:1.25), mix well, and stir at room temperature for 12 hours. The resulting mixed solution was dialyzed for 2 days, and the deionized water was replaced every 6 hours. After the dialysis was completed, freeze-dried to obtain 3-aminophenylboronic acid grafted oxidized dextran solid. Nuclear magnetic resonance analysis was performed, and the results were as follows Figure 3 As shown ( Figure 3 3-aminophenylboronic acid grafted aldehyde-modified dextran prepared in the embodiment of the present invention). The results show that the 3-aminophenylboronic acid grafted oxidized dextran prepared in the embodiment of the present invention was successfully synthesized.

[0040] Example 3

[0041] Three portions of 2.5 g of dextran (molecular weight 100 kDa) were dissolved in 25 mL of NaH2PO4 solution (20 mM) at room temperature and stirred until completely dissolved to obtain a dextran solution. Then, sodium periodate solution was added dropwise under light-proof conditions. The molar ratio of sugar units to sodium periodate in the mixed solution was 10:1, 10:3, 5:2, 1:1, 5:3, respectively, and stirred for 1.5 hours. After treatment, oxidized dextran with oxidation degrees of 10%, 30%, 40%, 50%, and 60% were obtained. Then, aminophenylboronic acid was modified as in Example 2 to obtain oxidized dextran grafted with different phenylboronic acids.

[0042] Example 4

[0043] Preparation of self-crosslinked hydrogel: Weigh 200 mg of the obtained oxidized dextran grafted with different phenylboronic acid, dissolve it in a solvent medium, and place it in a 37°C water bath or shaker. Observe the gelation for a certain period of time. Under the same mass concentration, the higher the grafting rate of phenylboronic acid, the faster the gelation speed. Under the condition of low material concentration, the one with high grafting rate of phenylboronic acid can still gel, while the one with low grafting rate cannot gel. ( Figure 4 )

[0044] Example 5

[0045] 1-(2-aminoethyl)piperidine modified oxidized dextran: 200 mg of oxidized dextran solid with 40% oxidation degree obtained in Example 3 was dissolved in 5 mL of ultrapure water, 1-(2-aminoethyl)piperidine (the aldehyde group / piperidine molar ratio was about 1:1.25) was added, mixed evenly, and stirred at room temperature for 12 hours. The obtained mixed solution was dialyzed for 3 days, and the deionized water was replaced every 6 hours. After the dialysis was completed, it was freeze-dried to obtain oxidized dextran modified with a tertiary amine small molecule.

[0046] Example 6

[0047] Piperazine-1-amine modified oxidized dextran: 200 mg of oxidized dextran solid with 30% oxidation degree obtained in Example 3 was dissolved in 5 mL of ultrapure water, piperazine-1-amine (the aldehyde group / piperazine molar ratio was about 1:1.5) was added, mixed evenly, and stirred at room temperature for 12 hours. The obtained mixed solution was dialyzed for 1.5 days, and deionized water was replaced every 6 hours. After the dialysis was completed, it was freeze-dried to obtain oxidized dextran modified with tertiary amine small molecules.

[0048] Example 7

[0049] Preparation of self-crosslinked hydrogel with tertiary amine groups: 100 mg of the obtained 3-aminophenylboronic acid grafted oxidized dextran solid and 25 mg of 1-(2-aminoethyl)piperidine modified oxidized glucose were dissolved in 500 μL PBS buffer (pH = 7.0) to prepare a 25 wt % mixed solution, which was placed in a 37°C water bath and self-crosslinked into a gel after 6-8 h after complete dissolution. Figure 6 ).

[0050] The hydrogel prepared in Example 7 of the present invention was quickly frozen by liquid nitrogen quick freezing method, and freeze-dried to obtain a freeze-dried gel sample; the sample was tested by scanning electron microscope to obtain a microscopic morphology photo of the gel. Figure 7 It can be seen that the complex hydrogel material has an interconnected macroporous structure, which is conducive to the transmission and release of drugs in the gel material.

[0051] Example 8

[0052] Preparation of self-crosslinked hydrogel with tertiary amine groups (piperazine-1-amine): 80 mg of the obtained 3-aminophenylboronic acid grafted oxidized dextran solid and 20 mg of piperazine-1-amine modified oxidized dextran were dissolved in 500 μL PBS buffer (pH=6.8) to prepare a 20wt% mixed solution, which was placed in a 25°C water bath and self-crosslinked into gel after 8-12 hours after complete dissolution. The hydrogel was quickly frozen by liquid nitrogen quick freezing method, and freeze-dried to obtain a freeze-dried gel sample.

[0053] Example 9

[0054] Determination of the Zate potential of self-crosslinked hydrogel materials with tertiary amine groups: The Zate potential of the gel material was measured using a dynamic laser scattering instrument. Figure 5 As shown in the figure, the 3-aminophenylboronic acid grafted oxidized dextran material alone has a weak negative charge under physiological conditions, but after adding 1-(2-aminoethyl)piperidine-modified oxidized dextran, the potential changes and becomes strongly positively charged, proving that it can produce electrostatic adsorption on negatively charged drugs.

[0055] Example 10

[0056] Sugar-responsive degradation behavior of hydrogel: First, measure the mass of a 2 mL glass vial, recorded as M0, and then prepare a 400 μL volume of hydrogel in a vial. After the hydrogel is completely stabilized, weigh the sample mass and the vial weight, recorded as M1. Add 200 μL of the above-mentioned degradation solution with different glucose concentrations to the top of the hydrogel, and transfer all the vials to a shaker at 37°C and shake at 75 rpm. Aspirate the degradation solution on the top of the gel at a pre-set time point, and weigh the remaining mass of the hydrogel and the bottle weight with a precision balance before adding new degradation solution and continuing the culture operation, recorded as M. x Then the mass retention rate of the hydrogel was calculated according to the following formula, that is, the percentage of the hydrogel mass retained over time.

[0057] Mass retention rate of hydrogel: (M x -M0) / (M1-M0)×100%

[0058] Hydrogel degradation experiments Figure 8 As shown, the results indicate that the hydrogel has a good glucose-responsive degradation behavior, degrading slowly at normal sugar concentrations and rapidly at high sugar concentrations.

[0059] Embodiment 11

[0060] Glucose-responsive release of insulin: FITC-modified insulin was loaded into the hydrogel, added to a pre-configured glucose solution (0, 100, 500 mg / dL, pH = 7.4, 1 mL), and incubated at 37°C. 100 μL of the solution was drawn at a pre-set time point, and the FITC fluorescence value was detected on a microplate reader to obtain the concentration of free FITC-modified insulin released from the hydrogel.

[0061] The results show that Fig. 9 ), the release curve of the gel stimulated by high blood glucose solution gradually increased over time, proving that it was rapidly releasing the insulin inside. In contrast, no rapid release of insulin from the gel was found in the two control groups (no glucose and 100 mg / dL glucose).

[0062] Example 12

[0063] Biocompatibility test of hydrogel: The biocompatibility of the gel was evaluated by MTT method, as follows: NIH-3T3 cells with a density of 8000 cells per well were inoculated into 96-well plates, each of which was added with 200 μL DMEM culture medium containing 10% bovine growth serum (BGS) and 1% penicillin-streptomycin double antibody solution (PS). The 96-well plates were then incubated at 37°C in 5% CO2 for 12 hours to reach a saturation of about 80%, and then the gel material dilution solution (polymer concentration: 0.5-20 mg / mL) and the blank control PBS solution were added. After 24 hours of continuous culture, the cells were washed three times with PBS solution, and 10 μL MTT was added to 180 μL DMEM for cytotoxicity test. MTT required an additional 3 hours of treatment time, and then the absorbance (OD) of each well plate was measured at 490 nm using a multifunctional microplate reader (Tacan spark).

[0064] like Fig.10 As shown, at higher concentrations of the gel material, the cells still have a good survival rate (survival rate>90%), which shows that the hydrogel does have very good biocompatibility, which will be beneficial to the subsequent use of the gel in in vivo application research.

[0065] Embodiment 13

[0066] Self-healing properties of hydrogels: First, hydrogels of different colors were prepared. The two-color hydrogels were placed in a humid environment at 37°C for 1 hour, and the self-adhesion of the hydrogels was observed and photographed.

[0067] Self-crosslinked hydrogels have self-healing properties, which can enable the hydrogels to maintain their structural integrity, restore their original functions through self-repair and extend their service life. Fig.11As shown, two hydrogels of different colors are combined together through a self-healing phase, demonstrating the self-healing properties of the hydrogel.

[0068] Embodiment 14

[0069] Step 1, preparation of oxidized dextran: dissolve 3g of dextran (molecular weight 200kDa) in 30mL of NaH2PO4 solution (20mM) at room temperature, stir until completely dissolved to obtain a dextran solution. Add sodium periodate solution dropwise under light-proof conditions, the molar ratio of sugar units to sodium periodate in the mixed solution is 4:1, and stir for 1.5 hours. Then add ethylene glycol to terminate the reaction, and continue stirring for 20 minutes. The obtained mixed solution is dialyzed for 4 days, and deionized water is replaced every 8 hours. After dialysis is completed, freeze-dry to obtain oxidized dextran solid.

[0070] Step 2: Dissolve 100 mg of the oxidized dextran solid obtained in step 1 in 50 mL of ultrapure water, add 3-aminophenylboronic acid solid powder (the molar ratio of aldehyde group to phenylboronic acid is about 1:1.5), mix well, and stir at room temperature for 12 hours. The resulting mixed solution is dialyzed for 1 day, and the deionized water is replaced every 4 hours. After the dialysis is completed, freeze-drying is performed to obtain 3-aminophenylboronic acid grafted oxidized dextran solid.

[0071] Step 3: Dissolve 200 mg of the oxidized dextran solid obtained in step 1 in 5 mL of ultrapure water, add 1-(2-aminoethyl)piperidine (the aldehyde group / piperidine molar ratio is about 1:1.25), mix well, and stir at room temperature for 12 hours. The resulting mixed solution is dialyzed for 2 days, and the deionized water is replaced every 6 hours. After the dialysis is completed, freeze-drying is performed to obtain 1-(2-aminoethyl)piperidine-modified oxidized dextran solid.

[0072] Step 4: Dissolve the 3-aminophenylboronic acid grafted oxidized dextran solid and the 1-(2-aminoethyl)piperidine modified oxidized dextran solid obtained in step 2 in 500 μL PBS buffer (pH=7.5) at a mass ratio of 8:1 to prepare a 20 wt % mixed solution, place it in a 37°C water bath, and after it is completely dissolved and evenly dissolved, let it stand at room temperature for 8-12 hours before self-crosslinking into a gel.

[0073] Embodiment 15

[0074] Step 1, preparation of oxidized dextran: dissolve 3g of dextran (molecular weight 50kDa) in 30mL of NaH2PO4 solution (10mM) at room temperature, and stir until completely dissolved to obtain a dextran solution. Add sodium periodate solution dropwise under light-proof conditions, the molar ratio of sugar units to sodium periodate in the mixed solution is 3:1, and stir for 1 hour. Then add ethylene glycol to terminate the reaction, and continue stirring for 30 minutes. The obtained mixed solution is dialyzed for 4 days, and the deionized water is replaced every 12 hours. After the dialysis is completed, freeze-drying is performed to obtain oxidized dextran solid.

[0075] Step 2: Dissolve 500 mg of the oxidized dextran solid obtained in step 1 in 20 mL of ultrapure water, add 3-aminophenylboronic acid solid powder (the molar ratio of aldehyde group to phenylboronic acid is about 1:1.2), mix well, and stir at room temperature for 24 hours. The resulting mixed solution is dialyzed for 3 days, and the deionized water is replaced every 8 hours. After the dialysis is completed, freeze-drying is performed to obtain 3-aminophenylboronic acid grafted oxidized dextran solid.

[0076] Step 3: Dissolve 200 mg of the oxidized dextran solid obtained in step 1 in 10 mL of ultrapure water, add 1-(2-aminoethyl)piperidine (the aldehyde / piperidine molar ratio is about 1:2), mix well, and stir at room temperature for 48 hours. The resulting mixed solution is dialyzed for 2 days, and deionized water is replaced every 8 hours. After the dialysis is completed, freeze-drying is performed to obtain 1-(2-aminoethyl)piperidine-modified oxidized dextran solid.

[0077] Step 4: Dissolve the 3-aminophenylboronic acid grafted oxidized dextran solid and the 1-(2-aminoethyl)piperidine modified oxidized dextran solid obtained in step 2 in 600 μL PBS buffer (pH = 6.5) at a mass ratio of 1:1 to prepare a 30 wt % mixed solution, place it in a 37°C water bath, and after it is completely dissolved and uniformly dissolved, self-crosslink into a gel after 10 hours.

[0078] Therefore, the present application provides a self-crosslinking hydrogel with tertiary amine groups and its preparation and application. The aminophenylboronic acid-modified oxidized dextran can self-crosslink into a gel and has double crosslinking points of Schiff base bonds and phenylboronic acid ester bonds, corresponding to acid-responsive and glucose-responsive groups, respectively. In addition to participating in the network construction of the self-crosslinking hydrogel, the positive charge generated by the oxidized dextran under physiological conditions can further bind negatively charged drugs. The hydrogel with tertiary amine groups can reduce drug leakage caused by non-responsive factors and improve the controlled release behavior of drugs.

[0079] In the description of this specification, the description with reference to the terms "an experimental example", "example", "specific example", etc. means that the specific features, structures, materials or characteristics described in conjunction with the experimental example or example are included in at least one experimental example or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same experimental example or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more experimental examples or examples in a suitable manner.

[0080] Finally, it should be noted that the above experimental examples are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred experimental examples, those skilled in the art should understand that they can still modify or replace the technical solution of the present invention with equivalents, and these modifications or equivalent replacements cannot cause the modified technical solution to deviate from the spirit and scope of the technical solution of the present invention.

Claims

1. A self-crosslinking hydrogel having tertiary amine groups, characterized in that: The method comprises aminophenylboronic acid-modified oxidized dextran, tertiary amine compound-modified oxidized dextran and a solvent medium; the aminophenylboronic acid-modified oxidized dextran and the tertiary amine compound-modified oxidized dextran are dissolved in the solvent medium, mixed and allowed to stand, and self-crosslinked to form a gel, thereby obtaining a self-crosslinked hydrogel with tertiary amine groups.

2. A self-crosslinking hydrogel having tertiary amine groups according to claim 1, characterized in that: The tertiary amine compound is a positively charged molecule that is protonated in a physiological environment of pH 6.5-7.

5. The oxidized dextran modified with the tertiary amine compound includes one or more of oxidized dextran modified with 1-(2-aminoethyl)piperidine, oxidized dextran modified with piperazine-1-amine, and oxidized dextran modified with N-(2-azidoethyl)-pyrrolidine.

3. The self-crosslinking hydrogel having tertiary amine groups according to claim 1, characterized in that: Oxidized dextran is prepared by the reaction of dextran and oxidant sodium periodate. The oxidation degree of dextran is 10% to 60%, and the molecular weight of dextran is 20 to 200 kDa.

4. The self-crosslinking hydrogel having tertiary amine groups according to claim 1, characterized in that: The solvent medium is one of ultrapure water, PBS buffer and physiological saline.

5. The self-crosslinking hydrogel having tertiary amine groups according to claim 1, characterized in that: The concentration of self-crosslinking gel is 10.0wt%-50.0wt%, and the mass ratio of the oxidized dextran modified by aminophenylboronic acid to the oxidized dextran modified by the tertiary amine compound is 1:1-8:

1.

6. A method for preparing a self-crosslinking hydrogel having tertiary amine groups according to any one of claims 1 to 5, characterized in that: The following steps are involved: Step 1, dissolving the dextran with a NaH2PO4 solution, adding a NaIO4 solution dropwise under light-shielding conditions to obtain a mixed solution, stirring the reaction, adding ethylene glycol to terminate the reaction, and continuing to stir. The obtained mixed solution is dialyzed at room temperature for 3 days, and freeze-dried to obtain oxidized dextran solid; Step 2: dissolving the oxidized dextran solid obtained in step 1 in a solvent medium to obtain an oxidized dextran solution, adding 3-aminophenylboronic acid, and continuing to stir the reaction. After the reaction is completed, dialyzing at room temperature for 1 to 3 days, and freeze-drying to obtain a 3-aminophenylboronic acid-modified oxidized dextran solid; the solvent medium is one of ultrapure water, PBS buffer, and physiological saline; Step 3, dissolving the oxidized dextran solid obtained in step 1 in a coal-soluble medium, adding 1-(2-aminoethyl)piperidine or piperazine-1-amine, wherein the molar ratio of the aldehyde group / tertiary amine compound is about 1:1.2 to 1:1.5, mixing, stirring at room temperature, dialyzing the obtained mixed solution for 2 days, replacing deionized water every 6 hours, and freeze-drying after the dialysis is completed to obtain 1-(2-aminoethyl)piperidine-modified oxidized dextran or piperazine-1-amine-modified oxidized dextran, respectively; Step 4: dissolve the 3-aminophenylboronic acid grafted oxidized dextran solid obtained in step 2 and the 1-(2-aminoethyl)piperidine-modified oxidized dextran or piperazine-1-amine-modified oxidized dextran obtained in step 3 in LPBS buffer to prepare a 25wt% mixed solution, place it in a 37°C water bath, and after dissolution, self-crosslink into a gel after 6-8 hours to obtain a self-crosslinking hydrogel with tertiary amine groups.

7. The method for preparing a self-crosslinking hydrogel having tertiary amine groups according to claim 6, characterized in that: In step 1, dextran is dissolved with NaH2PO4 solution, and NaIO4 solution is added dropwise under light-proof conditions, and the molar ratio of sugar unit to sodium periodate in the obtained mixed solution is 3:1 to 5:1; in step 2, 3-aminophenylboronic acid is added at a molar ratio of aldehyde group to amino group of 1:1.2 to 1:

2.

8. A self-crosslinked hydrogel with tertiary amine groups loaded with hypoglycemic drugs as described in any one of claims 1 to 5 is used for blood sugar regulation.

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