Injectable hydrogel with myocardial tissue repair function as well as preparation method and application of injectable hydrogel

Abstract

The invention discloses injectable hydrogel with a myocardial tissue repairing function as well as a preparation method and application of the injectable hydrogel, and relates to the technical field of medical materials. The preparation method of the injectable hydrogel comprises the following steps: carrying out a reaction on deferoxamine and DSPE-PEG-NHS, so as to obtain DSPE-PEG-DFO; the preparation method comprises the following steps: wrapping carvedilol with DSPE-PEG-DFO under the hydrophilic and hydrophobic action, so as to obtain a drug-loaded nano-micelle; the preparation method comprises the following steps: reacting a polymer containing amino or hydroxyl with methacrylic anhydride to obtain a methylacryloyl modified polymer; reacting the carboxyl-containing polymer with cysteamine hydrochloride to obtain a sulfydryl modified polymer; mixing the drug-loaded nano-micelle, the methylacryloyl modified polymer and the sulfydryl modified polymer, and reacting under ultraviolet radiation to obtain the injectable hydrogel. The hydrogel disclosed by the invention is good in biocompatibility, can release deferoxamine and carvedilol in a ladder manner, is matched with a myocardial repair process, and realizes a function of repairing damaged myocardial tissues.

Description

Technical Field

[0001] The present invention relates to the technical field of medical materials, and particularly relates to an injectable hydrogel with myocardial tissue repair function, a preparation method thereof and an application thereof. Background Art

[0002] Myocardial infarction (MI) is a cardiovascular disease in which the blood supply to the coronary artery is sharply reduced or interrupted, resulting in myocardial injury and thus myocardial necrosis. Myocardial infarction is a major cause of death worldwide. At present, the treatment of myocardial infarction emphasizes the early restoration of ischemic myocardial reperfusion, but the occurrence of complications is difficult to predict. Therefore, it is necessary to seek more innovative and effective ways to protect myocardial function. Myocardial ischemia is the direct cause of myocardial infarction and can lead to irreversible myocardial necrosis. In addition, persistent ischemia can cause oxidative stress and inflammatory responses. Persistent inflammation and excessive production of reactive oxygen species (ROS) can lead to DNA damage, myocardial death and ventricular remodeling, thus accelerating the outcome of cardiac rupture. Therefore, reconstructing the vascular network of myocardial tissue while effectively inhibiting inflammatory responses and oxidative stress is an important strategy for the treatment of myocardial infarction.

[0003] Deferoxamine (DFO) is an iron chelator and hypoxia mimetic agent approved by the FDA, which can promote the signal transduction of hypoxia-inducible factor 1α (HIF-1α) and up-regulate the expression of downstream key angiogenesis-related factors such as vascular endothelial growth factor (VEGF), thereby triggering a multi-faceted angiogenic response, improving ischemia and promoting tissue repair. Carvedilol is one of the most effective β-blockers in clinical practice and has been proven to have effective antioxidant stress and anti-inflammatory effects. However, as a lipophilic compound, carvedilol is not easily absorbed by the gastrointestinal tract and has a low oral bioavailability. In-situ administration can improve the bioavailability of carvedilol.

[0004] After myocardial infarction, it undergoes three stages: acute inflammation, proliferative repair and maturation remodeling. In order to better match the myocardial repair process, deferoxamine is attached to DSPE-PEG-NHS through an amidation reaction and then encapsulates carvedilol to achieve sequential release. At the same time, it is loaded by an injectable hydrogel and has the potential to promote the repair of damaged myocardial tissue. Summary of the Invention

[0005] In order to solve the above technical problems, the purpose of the present invention is to provide an injectable hydrogel with myocardial tissue repair function, a preparation method thereof and an application thereof, which has good biocompatibility, can sequentially release deferoxamine and carvedilol, match the myocardial repair process, first rapidly release carvedilol to reduce the level of reactive oxygen species in myocardial tissue during the acute inflammation period and inhibit inflammatory responses, and slowly release deferoxamine to promote angiogenesis in the damaged heart area, and finally achieve the function of repairing damaged myocardial tissue.

[0006] The technical solution of the present invention to solve the above technical problems is as follows: A preparation method of an injectable hydrogel with myocardial tissue repair function is provided, including the following steps: (1) React deferoxamine with amphiphilic polymer DSPE-PEG-NHS to obtain DSPE-PEG-DFO; (2) Use the hydrophilic-hydrophobic interaction of DSPE-PEG-DFO obtained in step (1) to encapsulate carvedilol to obtain drug-loaded nanomicelles; (3) React a polymer containing amino or hydroxyl group with methacrylic anhydride to obtain a methacryloyl-modified polymer; (4) React a polymer containing carboxyl group with cysteamine hydrochloride to obtain a thiol-modified polymer; (5) Mix the drug-loaded nanomicelles obtained in step (2), the methacryloyl-modified polymer obtained in step (3), and the thiol-modified polymer obtained in step (4), and react under ultraviolet irradiation to obtain an injectable hydrogel with myocardial tissue repair function.

[0007] Further, the specific process of step (1) is: Dissolve deferoxamine and amphiphilic polymer DSPE-PEG-NHS in a benign solvent, stir in the dark, dialyze with deionized water, and freeze-dry to obtain DSPE-PEG-DFO.

[0008] Further, in step (1), the molar ratio of deferoxamine to amphiphilic polymer DSPE-PEG-NHS is 1:1.

[0009] Further, in step (1), the benign solvent is dimethyl sulfoxide, N,N-dimethylformamide, methanol or acetone.

[0010] Further, the specific process of step (2) is: Dissolve DSPE-PEG-DFO obtained in step (1) in a benign solvent, then add carvedilol and mix evenly, and then drop it into deionized water with three times the volume of the benign solvent, stir in the dark, and dialyze with deionized water to obtain drug-loaded nanomicelles.

[0011] Further, in step (2), the molar ratio of carvedilol to DSPE-PEG-DFO is 1:1.

[0012] Further, in step (2), the benign solvent is dimethyl sulfoxide, N,N-dimethylformamide, methanol or acetone.

[0013] Further, the specific process of step (3) is: Dissolve a polymer containing amino or hydroxyl group in phosphate buffer solution, then drop methacrylic anhydride under stirring conditions, and stir at 50-60 °C for 2-3 h, dialyze with deionized water, and freeze-dry to obtain a methacryloyl-modified polymer.

[0014] Further, in step (3), the mass ratio of the polymer containing amino or hydroxyl group to methacrylic anhydride is 1:0.1 - 1:1.

[0015] Further, in step (3), the polymer containing amino or hydroxyl group is gelatin, chitosan, hyaluronic acid, dextran, sodium alginate, carboxymethyl cellulose or their derivatives.

[0016] Further, the mass ratio of the polymer containing amino or hydroxyl group to methacrylic anhydride is 1:0.1 - 1:1.

[0017] Further, the specific process of step (4) is as follows: Dissolve the polymer containing carboxyl group in deionized water, then add 1-ethyl-(3-dimethylaminopropyl)carbodiimide and N-hydroxysuccinimide and stir for 2 - 4 h, then add cysteamine hydrochloride, maintain the pH value at 4.75 - 5.0, stir for 24 h, add dithiothreitol to break the disulfide bond, dialyze, and freeze-dry to obtain the thiol-modified polymer.

[0018] Further, in step (4), the molar ratio of 1-ethyl-(3-dimethylaminopropyl)carbodiimide, N-hydroxysuccinimide to the polymer containing carboxyl group is 1:1:1 - 2:2:1.

[0019] Further, in step (4), the molar ratio of the polymer containing carboxyl group to cysteamine hydrochloride is 1:1 - 1:2.

[0020] Further, in step (4), the polymer containing carboxyl group is sodium alginate, hyaluronic acid, carboxymethyl chitosan, carboxymethyl cellulose, gelatin or their modified products.

[0021] Further, the specific process of step (5) is as follows: Dissolve the drug-loaded nanomicelles obtained in step (2), the methacryloyl-modified polymer obtained in step (3) and the thiol-modified polymer obtained in step (4) in phosphate buffer, add a photoinitiator, and cure under the condition of 365 nm ultraviolet light with 30 mW / cm 2 for 240 s to obtain an injectable hydrogel with myocardial tissue repair function.

[0022] Further, in step (5), the mass concentrations of the drug-loaded nanomicelles, the methacryloyl-modified polymer and the thiol-modified polymer are 50 μg / mL, 1 - 5 wt% and 0.5 - 5 wt% respectively.

[0023] Further, in step (5), the photoinitiator is lithium phenyl(2,4,6-trimethylbenzoyl)phosphate LAP.

[0024] Further, in step (5), the volume ratio of the methacryloyl-modified polymer to the thiol-modified polymer obtained in step (4) is 1:1 - 1:3.

[0025] In a sterile environment, the injectable hydrogel with myocardial tissue repair function of the present invention uniformly mixes drug-loaded nanomicelles, a methacryloyl-modified polymer solution, and a mercapto-modified polymer solution, adds a photoinitiator (0.25 wt.% LAP), and cures it under 365 nm ultraviolet light (30 mW / cm 2 ) for 240 s to rapidly undergo a "thiol-ene" click chemical reaction to form a hydrogel; then it is filled into a syringe or a delivery system and directly injected into the ventricular wall for treatment.

[0026] The present invention also provides an injectable hydrogel with myocardial tissue repair function, which is prepared by using the preparation method of the above injectable hydrogel with myocardial tissue repair function.

[0027] The present invention also provides the application of the above injectable hydrogel with myocardial tissue repair function in the preparation of drugs for treating myocardial infarction.

[0028] The present invention has the following beneficial effects: 1. The injectable hydrogel with myocardial tissue repair function of the present invention loads deferoxamine and carvedilol, which can inhibit inflammation, reduce the level of reactive oxygen species, and effectively promote the angiogenesis of the damaged heart part.

[0029] 2. The preparation process of the hydrogel of the present invention is simple, and the hydrogel has excellent rheological properties and injectability.

[0030] 3. The hydrogel of the present invention not only plays a role in mechanical support, but also has obvious cell growth promotion function and antioxidant activity, and can effectively promote the angiogenesis of the damaged heart part and the repair of myocardial tissue. Description of the Drawings

[0031] Figure 1 It is a transmission electron micrograph of the drug-loaded nanomicelles loaded with DFO and carvedilol in Example 1; Figure 2 It is a scanning electron micrograph of hydrogel group 2 in Example 1; Figure 3 It is an injectable result diagram of hydrogel group 2 in Example 1; Figure 4 It is a frequency scanning test result diagram of the hydrogel; Figure 5 It is an amplitude scanning test result diagram of the hydrogel; Figure 6 It is the result of live-dead staining of HUVECs cells; Figure 7 It is the cytotoxicity result of the hydrogel on HUVECs cells; Figure 8Results of cardiac ultrasound experiments for the hydrogel at 14 d and 28 d Figure 9 Results of H&E staining and Masson staining of the short-axis section of the heart for the hydrogel at 28 d Detailed implementation manners

[0032] The principles and features of the present invention are described below. The examples given are only used to explain the present invention and are not intended to limit the scope of the present invention. For those not specified in the examples, the operations are carried out under conventional conditions or conditions recommended by the manufacturer. Reagents or instruments not indicated with the manufacturer are all conventional products that can be obtained through commercial purchase

[0033] Example 1 An injectable hydrogel with myocardial tissue repair function, and its preparation method includes the following steps (1) Dissolve deferoxamine and amphiphilic polymer DSPE-PEG-NHS at a molar ratio of 1:1 in N,N-dimethylformamide, stir in the dark for 12 h, dialyze with deionized water for 24 h, and freeze-dry to obtain DSPE-PEG-DFO (2) Dissolve the DSPE-PEG-DFO obtained in step (1) in N,N-dimethylformamide, then add carvedilol and mix well, and then drop it into deionized water with a volume three times that of N,N-dimethylformamide, stir in the dark for 30 min, and dialyze with deionized water for 24 h to obtain drug-loaded nanomicelles; the molar ratio of carvedilol to DSPE-PEG-DFO is 1:1 (3) Dissolve 10 g of gelatin in phosphate buffer at 50 °C, then dropwise add 8 mL of methacrylic anhydride under stirring conditions, and magnetically stir at 50 °C for 2 h, dialyze with deionized water for 7 d, and freeze-dry to obtain methacryloyl-modified polymer GelMA (4) Dissolve 4 g of hyaluronic acid in deionized water, then add 0.03 mol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide and 0.03 mol of N-hydroxysuccinimide and stir for 3 h, then add 0.05 mol of cysteamine hydrochloride, keep the pH value at 4.75 - 5.0, stir for 24 h, add dithiothreitol to break the disulfide bond, and dialyze in dilute hydrochloric acid solution (pH = 3.5) for 72 h, and freeze-dry to obtain thiol-modified polymer HA-SH (5) Dissolve 100 μg of the drug-loaded nanomicelles obtained in step (2), 1 mL of the methacryloyl-modified polymer obtained in step (3) (2 wt%), and 1 mL of the thiol-modified polymer obtained in step (4) in phosphate buffer, add a photoinitiator (0.25 wt% LAP), and irradiate at 30 mW / cm 2Cured under 365 nm ultraviolet light for 240 s to obtain an injectable hydrogel with myocardial tissue repair function.

[0034] Example 2 An injectable hydrogel with myocardial tissue repair function, and its preparation method includes the following steps: (1) Deferoxamine and amphiphilic polymer DSPE-PEG-NHS were dissolved in N,N-dimethylformamide at a molar ratio of 1:1, stirred in the dark for 12 h, dialyzed with deionized water for 24 h, and freeze-dried to obtain DSPE-PEG-DFO; (2) The DSPE-PEG-DFO obtained in step (1) was dissolved in N,N-dimethylformamide, then carvedilol was added and mixed evenly, and then dropped into deionized water with three times the volume of N,N-dimethylformamide, stirred in the dark for 30 min, and dialyzed with deionized water for 24 h to obtain drug-loaded nanomicelles; the molar ratio of carvedilol to DSPE-PEG-DFO was 1:1; (3) Chitosan (1.5 wt%) was dissolved in a 2 vt% acetic acid solution, then methacrylic anhydride (molar ratio 1:1) was added dropwise under stirring conditions, and magnetically stirred at 60 °C for 3 h, neutralized with a 10 wt% sodium bicarbonate solution, dialyzed with deionized water for 4 d, and freeze-dried to obtain methacryloyl-modified polymer CSMA; (4) 4 g of hyaluronic acid was dissolved in deionized water, then 0.03 mol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide and 0.03 mol of N-hydroxysuccinimide were added and stirred for 3 h, then 0.05 mol of cysteamine hydrochloride was added, the pH value was kept at 4.75 - 5.0, stirred for 24 h, dithiothreitol was added to break the disulfide bond, dialyzed in a dilute hydrochloric acid solution (pH = 3.5) for 72 h, and freeze-dried to obtain thiol-modified polymer HA-SH; (5) 100 μg of the drug-loaded nanomicelles obtained in step (2), 1 mL of the methacryloyl-modified polymer (2 wt%) obtained in step (3), and 1 mL of the thiol-modified polymer obtained in step (4) were dissolved in phosphate buffer, and a photoinitiator (0.25 wt% LAP) was added, and cured under 365 nm ultraviolet light at 30 mW / cm 2 Cured under 365 nm ultraviolet light for 240 s to obtain an injectable hydrogel with myocardial tissue repair function.

[0035] Example 3 An injectable hydrogel with myocardial tissue repair function, and its preparation method includes the following steps: (1)Dissolve deferoxamine and amphiphilic polymer DSPE-PEG-NHS in N,N-dimethylformamide at a molar ratio of 1:1, stir in the dark for 12 h, dialyze against deionized water for 24 h, and freeze-dry to obtain DSPE-PEG-DFO; (2)Dissolve the DSPE-PEG-DFO obtained in step (1) in N,N-dimethylformamide, then add carvedilol and mix well, and then drop it into deionized water with three times the volume of N,N-dimethylformamide, stir in the dark for 30 min, and dialyze against deionized water for 24 h to obtain drug-loaded nanomicelles; the molar ratio of carvedilol to DSPE-PEG-DFO is 1:1; (3)Dissolve 10 g of sodium hyaluronate in deionized water, then dropwise add 8 mL of methacrylic anhydride under stirring conditions, adjust the pH to 8-9 (NaOH), stir overnight, precipitate with cold ethanol and collect the crude product, then dissolve it in deionized water, dialyze against deionized water for 7 d, and freeze-dry to obtain methacryloyl-modified polymer HAMA; (4)Dissolve 4 g of hyaluronic acid in deionized water, then add 0.03 mol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide and 0.03 mol of N-hydroxysuccinimide and stir for 3 h, then add 0.05 mol of cysteamine hydrochloride, maintain the pH value at 4.75-5.0, stir for 24 h, add dithiothreitol to break the disulfide bond, dialyze in dilute hydrochloric acid solution (pH = 3.5) for 72 h, and freeze-dry to obtain thiol-modified polymer HA-SH; (5)Dissolve 100 μg of the drug-loaded nanomicelles obtained in step (2), 1 mL of the methacryloyl-modified polymer obtained in step (3) (2 wt%), and 1 mL of the thiol-modified polymer obtained in step (4) in phosphate buffer, add a photoinitiator (0.25 wt% LAP), and cure under 365 nm ultraviolet light at 30 mW / cm 2 for 240 s to obtain an injectable hydrogel with myocardial tissue repair function.

[0036] Example 4 An injectable hydrogel with myocardial tissue repair function, and its preparation method includes the following steps: (1)Dissolve deferoxamine and amphiphilic polymer DSPE-PEG-NHS in N,N-dimethylformamide at a molar ratio of 1:1, stir in the dark for 12 h, dialyze against deionized water for 24 h, and freeze-dry to obtain DSPE-PEG-DFO; (2) Dissolve the DSPE-PEG-DFO obtained in step (1) in N,N-dimethylformamide, then add carvedilol and mix well, and then dropwise add it to deionized water with a volume three times that of N,N-dimethylformamide. Stir in the dark for 30 min and dialyze against deionized water for 24 h to obtain drug-loaded nanomicelles; the molar ratio of carvedilol to DSPE-PEG-DFO is 1:1; (3) Dissolve 10 g of gelatin in phosphate buffer at 50 °C, then dropwise add 8 mL of methacrylic anhydride under stirring conditions, and stir magnetically at 50 °C for 2 h. Dialyze against deionized water for 7 d and freeze-dry to obtain methacryloyl-modified polymer GelMA; (4) Dissolve 4 g of carboxymethyl chitosan in deionized water, then add 0.03 mol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide and 0.03 mol of N-hydroxysuccinimide and stir for 3 h. Then add 0.05 mol of cysteamine hydrochloride, maintain the pH value at 4.75 - 5.0, stir for 24 h, add an excessive amount of PBS or deionized water to terminate the reaction, adjust the pH to 7.0 with dilute hydrochloric acid solution, dialyze against deionized water for 72 h, and freeze-dry to obtain thiol-modified polymer CMCS-SH; (5) Dissolve 100 μg of the drug-loaded nanomicelles obtained in step (2), 1 mL of the methacryloyl-modified polymer (2 wt%) obtained in step (3), and 1 mL of the thiol-modified polymer obtained in step (4) in phosphate buffer, add a photoinitiator (0.25 wt% LAP), and under the condition of 365 nm ultraviolet light with 30 mW / cm 2 cure for 240 s to obtain an injectable hydrogel with myocardial tissue repair function Example 5 An injectable hydrogel with myocardial tissue repair function, and its preparation method includes the following steps: (1) Dissolve deferoxamine and amphiphilic polymer DSPE-PEG-NHS in N,N-dimethylformamide at a molar ratio of 1:1, stir in the dark for 12 h, dialyze against deionized water for 24 h, and freeze-dry to obtain DSPE-PEG-DFO; (2) Dissolve the DSPE-PEG-DFO obtained in step (1) in N,N-dimethylformamide, then add carvedilol and mix well, and then dropwise add it to deionized water with a volume three times that of N,N-dimethylformamide. Stir in the dark for 30 min and dialyze against deionized water for 24 h to obtain drug-loaded nanomicelles; the molar ratio of carvedilol to DSPE-PEG-DFO is 1:1; (3) Dissolve 10 g of dextran in 100 mL of phosphate buffered saline, then dropwise add 8 mL of methacrylic anhydride under stirring conditions, and magnetically stir for 2 h at 50 °C. Dialyze with deionized water for 7 d, and freeze-dry to obtain methacryloyl-modified polymer DEXMA; (4) Dissolve 4 g of carboxymethyl cellulose in deionized water, then add 0.03 mol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide and 0.03 mol of N-hydroxysuccinimide and stir for 3 h. Then add 0.05 mol of cysteamine hydrochloride, maintain the pH value at 4.75 - 5.0, stir for 24 h, add an excessive amount of PBS or deionized water to terminate the reaction, adjust the pH = 7.0 with dilute hydrochloric acid solution, dialyze with deionized water for 72 h, and freeze-dry to obtain thiol-modified polymer CMC-SH; (5) Dissolve 100 μg of the drug-loaded nanomicelles obtained in step (2), 1 mL of the methacryloyl-modified polymer obtained in step (3) (2 wt%), and 1 mL of the thiol-modified polymer obtained in step (4) in phosphate buffer. Add a photoinitiator (0.25 wt% LAP), and cure under 365 nm ultraviolet light at 30 mW / cm 2 for 240 s to obtain an injectable hydrogel with myocardial tissue repair function Test Examples Detect with the substances in Example 1, and the specific process is as follows: Among them, the specific meanings of hydrogel group 1 - hydrogel group 2 are as follows: Myocardial infarction group: the model-making group, without hydrogel treatment; Hydrogel group 1: blank hydrogel; Hydrogel group 2: hydrogel + nanomicelles loaded with deferoxamine and carvedilol (the injectable hydrogel with myocardial tissue repair function obtained in Example 1).

[0037] 1. Detection of gel-forming performance The transmission electron micrograph of the drug-loaded nanomicelles simultaneously loaded with DFO and carvedilol in Example 1, the scanning electron micrograph of hydrogel group 2, and the injectable result diagram of hydrogel group 2 are respectively as Figures 1 - 3 shown.

[0038] Moreover, the rheological properties of the hydrogel were tested with an MCR302 rheometer. Under the condition of 37 °C, a double-concentric cylinder geometry with a gap of 4 mm was used for steady-state shear flow. The frequency scan was carried out with a strain of 0.5% and an oscillation frequency of 0.1 - 100 rad / s, and the oscillation frequency of the strain scan was 1 Hz, and the strain was 0.01 - 1000%. The results are as Figures 4 - 5 shown.

[0039] ByFigures 1 - 3 It can be seen that the hydrogel can be injected through a 27G needle, demonstrating the injectability of the hydrogel.

[0040] From Figures 4 - 5 it can be seen that the storage modulus (G') of the hydrogel is greater than the loss modulus (G"), proving the successful preparation of the hydrogel.

[0041] 2. In vitro biocompatibility detection Human umbilical vein endothelial cells (HUVECs) were used to evaluate the biocompatibility of the hydrogel; the hydrogel after ultraviolet sterilization was extracted in cell culture medium (0.1 g / mL) for 48 h to prepare a material extract; HUVECs cells were inoculated in a 96-well plate at an inoculation density of 8000 cells per well; after 24 h, the cell culture medium was removed, and the hydrogel extract was used to replace different hydrogel samples and added to the plate. The proliferation rate and morphology of HUVECs cells cultured for 24 h and 72 h were detected by CCK-8 and FDA / PI staining respectively; after staining HUVECs cells with FDA (30 μg / mL) and PI (10 μg / mL) and standing for 5 min, the cells were observed with a fluorescence microscope, as Figure 6 shown; after incubation for 24 h and 72 h, fresh culture medium (90 μL) and diluted CCK-8 solution (10 μL) were added to each well. After 2 h, the cell proliferation rate was calculated by measuring the absorbance at 450 nm with an enzyme-linked immunosorbent assay reader; the results of the survival rate of HUVECs cells by the hydrogel are as Figure 7 shown.

[0042] From Figures 6 - 7 it can be seen that the hydrogel group showed no toxicity to cells at 24 h and 72 h. In addition, after the hydrogel was loaded with nanomicelles containing DFO and carvedilol, the cell survival rate was higher than that of the blank hydrogel group, indicating that hydrogel group 2 (i.e., the injectable hydrogel with myocardial tissue repair function of the present invention) effectively promoted the proliferation of HUVECs cells, and the hydrogel had good biocompatibility.

[0043] 3. In vivo heart repair effect detection A disease model of acute myocardial infarction in rats was constructed by the method of permanently ligating the left anterior descending branch of the heart; echocardiography was performed on the myocardial infarction rats with successful modeling on the 14th day and the 28th day, and the results are shown in Figure 8; the hematoxylin and eosin (H&E) staining results and Masson staining results on the 28th day are as Figure 9 shown.

[0044] From Figure 8 it can be seen that the systolic and diastolic movements of the ventricular wall in hydrogel group 2 were significantly better.

[0045] From Figure 9It can be seen that the hydrogel treatment group 2 effectively reduced the scar area at the myocardial infarction site, proving that the injectable hydrogel with myocardial tissue repair function of the present invention has good cardiac repair function.

[0046] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. Preparation method of injectable hydrogel with myocardial tissue repair function, characterized in that, It includes the following steps: (1) React deferoxamine with the amphiphilic polymer DSPE-PEG-NHS to obtain DSPE-PEG-DFO; (2) Use the hydrophilic-hydrophobic interaction of the DSPE-PEG-DFO obtained in step (1) to encapsulate carvedilol to obtain drug-loaded nanomicelles; (3) React the polymer containing amino or hydroxyl group with methacrylic anhydride to obtain a methacryloyl-modified polymer; (4) React the polymer containing carboxyl group with cysteamine hydrochloride to obtain a thiol-modified polymer; (5) Mix the drug-loaded nanomicelles obtained in step (2), the methacryloyl-modified polymer obtained in step (3) and the thiol-modified polymer obtained in step (4), and react under ultraviolet irradiation to obtain an injectable hydrogel with myocardial tissue repair function.

2. The preparation method of the injectable hydrogel with myocardial tissue repair function according to claim 1, characterized in that, The specific process of step (1) is as follows: Dissolve deferoxamine and the amphiphilic polymer DSPE-PEG-NHS in a benign solvent, stir in the dark, dialyze with deionized water, and freeze-dry to obtain DSPE-PEG-DFO.

3. The preparation method of the injectable hydrogel with myocardial tissue repair function according to claim 1, wherein, The specific process of step (2) is as follows: Dissolve the DSPE-PEG-DFO obtained in step (1) in a benign solvent, then add carvedilol and mix well, and then drop it into deionized water with a volume three times that of the benign solvent, stir in the dark, and dialyze with deionized water to obtain drug-loaded nanomicelles.

4. The preparation method of the injectable hydrogel with myocardial tissue repair function according to claim 1, characterized in that, The specific process of step (3) is as follows: Dissolve the polymer containing amino or hydroxyl group in phosphate buffer solution, then drop methacrylic anhydride under stirring conditions, and stir at 50-60 °C for 2-3 h, dialyze with deionized water, and freeze-dry to obtain a methacryloyl-modified polymer.

5. The preparation method of the injectable hydrogel with myocardial tissue repair function according to claim 1, characterized in that, In step (3), the mass ratio of the polymer containing amino or hydroxyl group to methacrylic anhydride is 1:0.1-1:

1.

6. The preparation method of the injectable hydrogel with myocardial tissue repair function according to claim 1, wherein The specific process of step (4) is as follows: Dissolve the polymer containing carboxyl group in deionized water, then add 1-ethyl-(3-dimethylaminopropyl)carbodiimide and N-hydroxysuccinimide and stir for 2-4 h, then add cysteamine hydrochloride, keep the pH value at 4.75-5.0, stir for 24 h, dialyze, and freeze-dry to obtain a thiol-modified polymer.

7. The preparation method of the injectable hydrogel with myocardial tissue repair function according to claim 1, characterized in that, The specific process of step (5) is as follows: Dissolve the drug-loaded nanomicelles obtained in step (2), the methacryloyl-modified polymer obtained in step (3), and the thiol-modified polymer obtained in step (4) in phosphate buffer, add a photoinitiator, and cure under 365 nm ultraviolet light with an intensity of 30 mW / cm 2 for 240 s to obtain an injectable hydrogel with myocardial tissue repair function.

8. The preparation method of the injectable hydrogel with myocardial tissue repair function according to claim 1, characterized in that, In step (5), the mass concentrations of the drug-loaded nanomicelles, the methacryloyl-modified polymer and the thiol-modified polymer are 50 μg / mL, 1-5 wt% and 0.5-5 wt% respectively.

9. An injectable hydrogel with myocardial tissue repair function, characterized in that, It is prepared by using the preparation method of the injectable hydrogel with myocardial tissue repair function described in any one of claims 1-8.

10. Use of the injectable hydrogel with myocardial tissue repair function described in claim 9 in the preparation of drugs for treating myocardial infarction.

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