Shear-thinning long-acting drug release hydrogel and application thereof

Abstract

The application provides a long-acting drug release hydrogel with shear-thinning property, which is crosslinked by star-shaped multi-arm polyethylene glycol coupled with drugs and having aldehyde group terminated end, and part of the terminal hydroxyl groups of the star-shaped multi-arm polyethylene glycol are coupled with drugs through chemical bonds by chemical reaction, and part of the terminal hydroxyl groups are terminated by aldehyde group through chemical reaction to form ester bonds. The hydrogel has the characteristics that it can flow under the action of physical shear force, and after standing, it can self-repair to form a gel, and can be prepared in advance, without real-time preparation when used, thereby greatly improving the convenience of use of the long-acting drug release hydrogel.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials technology, specifically relating to a shear-thinned, injectable, long-acting drug-releasing hydrogel and its applications. Background Technology

[0002] Hydrogels are a class of water-rich porous network structures with good tissue compatibility, making them widely used in the biomedical field. Injectable hydrogels, in particular, are favored due to their minimally invasive nature and malleability. Injectable gels are formed under controlled chemical reactions or physical conditions. For example, two-component hydrogels can form a gel within a certain timeframe after injection by mixing two solutions; photocrosslinked hydrogels form a gel under light after injecting a polymer solution; and thermosensitive hydrogels form a gel at body temperature after injection. However, a drawback of this type of hydrogel is that gel formation requires a certain amount of time and specific external conditions, limiting their widespread application in vivo.

[0003] Shear-thinning gels are hydrogels that flow under physical shear forces and self-repair to form a new gel upon standing. Since they are formed in vitro and then injected into the body, there is no in-situ gelation process, and therefore no specific gelation rate limitations or external conditions, making them more valuable for applications. Common shear-thinning gels include: peptide self-assembly hydrogels, recombinant protein hydrogels, dynamically covalently interacting hydrogels, positively and negatively charged adsorption hydrogels, and supramolecular interaction hydrogels.

[0004] Shear-thinning hydrogels have applications in many fields, including drug release, tissue repair, cell culture, and medical aesthetics. However, like other types of hydrogels, shear-thinning hydrogels still have significant limitations for the sustained release of small molecules. This is mainly because the pore size of the hydrogel is much larger than that of small molecule drugs, resulting in an extremely rapid diffusion rate within the hydrogel, which makes it impossible to achieve long-term sustained drug release. Summary of the Invention

[0005] To overcome the shortcomings of existing technologies, the present invention aims to provide a shear-thinning long-acting drug-releasing hydrogel. This hydrogel is flowable under physical shear force and self-heals to form a gel after standing. It can be pre-prepared, eliminating the need for real-time preparation during use, thus greatly improving the convenience of using long-acting drug-releasing hydrogels.

[0006] The specific technical solution of this invention is as follows:

[0007] A shear-thinning long-acting drug-releasing hydrogel is formed by crosslinking a star-shaped multi-arm polyethylene glycol with aldehyde-terminated ends and a drug-coupled component with chitosan. The aldehyde group of the star-shaped multi-arm polyethylene glycol reacts with the primary amine in chitosan to form a Schiff base reaction to form a dynamic covalent bond. The resulting hydrogel can flow under physical shear force and can self-repair to form a gel after standing.

[0008] Some of the terminal hydroxyl groups of the star-shaped multi-arm polyethylene glycol are chemically coupled with the drug through chemical bonds, and some of the terminal hydroxyl groups are chemically converted into ester bonds and capped by aldehyde groups.

[0009] The aldehyde group is selected from one or more aromatic aldehydes and alkyl aldehydes, preferably benzaldehyde.

[0010] Preferred examples of star-shaped multi-arm polyethylene glycol conjugated with drugs and end-capped with aldehyde groups are as follows:

[0011]

[0012] The star-shaped multi-arm polyethylene glycol of the present invention can be partially derivatized with the functional groups of a drug or by using conventional techniques in the art to give the drug a group that can react with the partially terminal hydroxyl groups of the star-shaped multi-arm polyethylene glycol, such as carboxyl, amino, isocyanate, etc., and coupled through ester bond, amide bond, urethane bond, etc.

[0013] In one example of the present invention, the drug coupled to the hydrogel is camptothecin, and the star-shaped multi-arm polyethylene glycol structure with aldehyde-terminated coupling is as follows:

[0014] Where n represents a positive integer from 1 to 6.

[0015] Preferably, the aldehyde-terminated star-shaped multi-arm polyethylene glycol has 2-8 arms and a single-arm molecular weight of 1000-5000 Da.

[0016] Preferably, the chitosan is one or more of water-soluble chitosan, hydroxyethyl alcohol chitosan, and carboxymethyl chitosan with a molecular weight between 5000-1000000 Da.

[0017] Preferably, the molar ratio of the amino groups in the chitosan to the star-shaped multi-arm polyethylene glycol-terminated aldehyde groups is between 3:1 and 1:5.

[0018] The star-shaped multi-arm polyethylene glycol with aldehyde-terminated coupling agent described in this invention can first couple some of the hydroxyl groups of the star-shaped multi-arm polyethylene glycol with the drug, and then the remaining free hydroxyl groups can be capped with aldehyde groups through a reaction. Alternatively, some of the hydroxyl groups of the star-shaped multi-arm polyethylene glycol can first be capped with aldehyde groups through a reaction, and then the remaining free hydroxyl groups can be coupled with the drug through a reaction.

[0019] The shear-thinned long-acting drug-releasing hydrogel of the present invention is prepared by the following method: a star-shaped multi-arm polyethylene glycol with aldehyde-terminated conjugate is dissolved in a pH 4-8 buffer solution to prepare solution A; chitosan is dissolved in a pH 2-8 buffer solution to prepare chitosan solution B; the two are then mixed to obtain the final product.

[0020] The mass-volume percentage concentration of the star-shaped multi-arm polyethylene glycol with aldehyde-terminated conjugate in solution A is 2%-15%, preferably 5%-10%; the mass-volume percentage concentration of the chitosan solution in solution B is 0.5%-10%, preferably 1%-5%.

[0021] Another objective of this invention is to provide the application of the shear-thinned long-acting drug-releasing hydrogel described herein in the preparation of sustained-release drugs.

[0022] Advantages of this invention:

[0023] The hydrogel of this invention forms dynamic covalent bonds through a Schiff base reaction between the aldehyde groups in the star-shaped multi-arm polyethylene glycol with aldehyde-terminated ends and the primary amines in chitosan. It has the characteristics of being flowable under physical shear force and self-repairing to form a gel after standing, thus achieving the injectability of the gel.

[0024] The hydrogel described in this invention, compared to existing shear-thinning gels, features drug coupling with PEG within the gel. As the coupling bonds break, the drug is slowly released, exhibiting excellent sustained-release properties. It has broad applications in areas such as local drug release, tumor treatment, medical filling, vascular embolization, and antibacterial applications, demonstrating significant medical potential. Attached Figure Description

[0025] Figure 1 The present invention describes a process involving shear-thinning injection and self-healing of the hydrogel 7 after gel formation.

[0026] Figure 2 Drug release results of hydrogels 4, 7, 16 and 17 described in this invention. Detailed Implementation

[0027] The specific steps of the present invention are illustrated below through examples, but are not limited to these examples.

[0028] The terms used in this invention, unless otherwise stated, generally have the meanings commonly understood by those skilled in the art.

[0029] The present invention will now be described in further detail with reference to specific embodiments and data. It should be understood that these embodiments are merely illustrative of the invention and are not intended to limit the scope of the invention in any way.

[0030] In the following embodiments, various processes and methods not described in detail are conventional methods known in the art.

[0031] Example 1: Preparation of star-shaped multi-arm polyethylene glycol for drug coupling

[0032] This invention uses camptothecin as an example to prepare a star-shaped multi-arm polyethylene glycol PEG-CPT4CHO4 coupled with camptothecin. This example is not intended to limit the type of drug; any drug that can be modified and react with an aldehyde group within the scope of this invention is within the drug category defined by the art.

[0033] 1. Synthesis of CPT-OOC(CH2)2COOH:

[0034]

[0035] Camptothecin (CPT-OH, 174 mg) and succinic anhydride (150 mg) were weighed into a 50 mL flask. Then, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.23 mL) and dichloromethane (DCM) were added. The mixture was placed in an ice bath and the temperature was gradually raised to room temperature for 4 hours. The reaction was quenched by adding hydrochloric acid aqueous solution, followed by extraction with a large amount of dichloromethane. The mixture was then separated by column chromatography to obtain 114 mg of a light yellow powdery solid. 1 H NMR(400MHz,DMSO-d6,)δ12.17(s,1H),8.69(s,1H),8.18 (d,J=8.5Hz,1H),8.13(d,J=8.2Hz,1H),7.91–7.82(m,1H),7.72(t,J=7.5Hz,1H),7.13(s,1 H),5.48(s,2H),5.30(s,2H),2.84–2.67(m,2H),2.47(m,2H),2.15(q,J=7.4Hz,2H),0.91(t, J=7.4Hz,3H).HRMS(positive ESI)m / z found(calcd for C 24 H 20 N₂O₇ + H⁺ + ):449.1344(449.1343). HRMS(positive ESI)m / z found(calcd for C 24 H 20 N2O7-H + ):447.1198(447.1198).

[0036] 2. Synthesis of PEG-(CPT)2(OH)6

[0037] Reaction equation:

[0038]

[0039] CPT-OOC(CH2)3COOH (208.0 mg), 8-arm PEG (3.00 g), EDCI (3.834 g), and DMAP (2.933 g) were placed in a round-bottom flask, and 30 ml of dichloromethane solvent was added. The reaction mixture was stirred overnight at room temperature. The mixture was then extracted, washed three times with water, and precipitated in diethyl ether.

[0040] Among them, chemical shifts δ8.7, 8.15, 7.87, 7.72, 7.06 represent aryl hydrogens in CPT, δ5.50, 5.31 represent hydrogens of the methylene CH2 group in CPT, δ2.15, 0.92 represent hydrogens of the CH2CH3 group in CPT, δ2.60, 2.40, 1.79 represent hydrogens of the CH2CH2CH2 group in CPT-OOC(CH2)3COO, δ4.59 represents the peak of the hydroxyl group in PEG, and δ4.11 represents the hydrogen of COOCH2 generated by esterification with the carboxyl group in PEG.

[0041] 3. Synthesis of PEG-(CPT)4(OH)4

[0042] Reaction equation:

[0043]

[0044] CPT-OOC(CH2)3COOH (415.8 mg), 8-arm PEG (3.00 g), EDCI (7.668 g), and DMAP (5.8664 g, 48 mmol) were placed in a round-bottom flask, and 30 mL of dichloromethane solvent was added. The reaction mixture was stirred overnight at room temperature. The mixture was then extracted, washed three times with water, and precipitated in diethyl ether.

[0045] Among them, chemical shifts δ8.7, 8.15, 7.87, 7.72, 7.06 represent aryl hydrogens in CPT, δ5.50, 5.31 represent hydrogens of the methylene CH2 group in CPT, δ2.15, 0.92 represent hydrogens of the CH2CH3 group in CPT, δ2.60, 2.40, 1.79 represent hydrogens of the CH2CH2CH2 group in CPT-OOC(CH2)3COO, δ4.59 represents the peak of the hydroxyl group in PEG, and δ4.11 represents the hydrogen of COOCH2 generated by esterification with the carboxyl group in PEG.

[0046] 4. Synthesis of PEG-(CPT)2(CHO)6

[0047] 2.0 g PEG-(CPT)2(OH)6, 0.59 g p-formylbenzoic acid (p-CBA), 1.0 g 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC) and 0.95 g 4-dimethylaminopyridine were added to dichloromethane (DCM) and stirred for 12 h.

[0048] The reaction solution was diluted in about 250 mL of DCM, washed three times with water, concentrated by rotary evaporation, precipitated in diethyl ether, and finally, the obtained solid sample was dried under vacuum and weighed to obtain the product.

[0049] 5. Synthesis of PEG-(CPT)4(CHO)4

[0050] 2.035 g PEG-(CPT)4(OH)4, 0.370 g p-formylbenzoic acid (p-CBA), 0.666 g 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC) and 0.634 g 4-dimethylaminopyridine were added to dichloromethane (DCM) and stirred for 12 h.

[0051] The reaction solution was diluted in about 250 mL of DCM, washed three times with water, concentrated by rotary evaporation, precipitated in diethyl ether, and finally, the obtained solid sample was dried under vacuum and weighed to obtain the product.

[0052] Table 1 records PEGs coupled with benzaldehyde and camptothecin. 1 The key chemical shifts in 1H NMR were used to confirm the substitution rate from the chemical shift ratios. This process can precisely control the ratio of drugs and cross-linked functional groups.

[0053] Table 1. Number of coupling groups of benzaldehyde and camptothecin obtained from NMR spectrum analysis.

[0054] Polymer Name Actual number of CPT grafts Actual number of grafted aldehyde groups <![CDATA[PEG-(CPT)2(CHO)6]]> 1.8 5.3 <![CDATA[PEG-(CPT)4(CHO)4]]> 3.5 3.7

[0055] Example 2: Preparation of shear-thinned long-acting drug-releasing hydrogel

[0056] Hydrogel 1:

[0057] Prepare gel reagent A by dissolving 200 mg PEG-(CPT)4(CHO)4 in 0.8 ml of 0.01 M PBS solution. Prepare gel reagent B by dissolving 30 mg chitosan in 0.97 ml of 1% acetic acid aqueous solution and adjusting the pH to 6. Using a syringe, draw equal volumes of reagent A and reagent B, attach them to a double injection rack, and quickly mix the solutions before injecting them into centrifuge tubes to obtain the gel.

[0058] Hydrogel 2:

[0059] Prepare gel reagent A by dissolving 150 mg PEG-(CPT)4(CHO)4 in 0.85 ml of 0.01 M PBS solution, and prepare gel reagent B by dissolving 30 mg chitosan in 0.97 ml of 1% acetic acid aqueous solution and adjusting the pH to 6. Using a syringe, draw equal volumes of reagent A and reagent B, attach them to a double syringe holder, and quickly mix the solutions before injecting them into centrifuge tubes to obtain the gel.

[0060] Hydrogel 3:

[0061] Prepare gel reagent A by dissolving 100 mg PEG-(CPT)4(CHO)4 in 0.9 ml of 0.01 M PBS solution, and prepare gel reagent B by dissolving 30 mg chitosan in 0.97 ml of 1% acetic acid aqueous solution and adjusting the pH to 6. Use a syringe to draw equal volumes of reagent A and reagent B, attach them to a double injection rack, and quickly mix the solutions before injecting them into centrifuge tubes to obtain the gel.

[0062] Hydrogel 4:

[0063] Prepare gel reagent A by dissolving 55 mg PEG-(CPT)4(CHO)4 in 0.945 ml of 0.01 M PBS solution, and prepare gel reagent B by dissolving 30 mg chitosan in 0.97 ml of 1% acetic acid aqueous solution and adjusting the pH to 6. Use a syringe to draw equal volumes of reagent A and reagent B, attach them to a double injection rack, and quickly mix the solutions before injecting them into centrifuge tubes to obtain the gel.

[0064] Hydrogel 5:

[0065] Prepare gel reagent A by dissolving 55 mg of PEG-(CPT)4(CHO)4 in 0.945 ml of 0.01 M PBS solution, and prepare gel reagent B by dissolving 30 mg of chitosan in 0.97 ml of 1% acetic acid aqueous solution. Using a syringe, draw equal volumes of reagent A and reagent B, attach them to a double syringe holder, and quickly mix the solutions before injecting them into centrifuge tubes to obtain the gel.

[0066] Hydrogel 6:

[0067] Prepare gel reagent A by dissolving 55 mg of PEG-(CPT)4(CHO)4 in 0.945 ml of 0.01 M PBS solution, and prepare gel reagent B by dissolving 30 mg of chitosan in 0.97 ml of 1% acetic acid aqueous solution and adjusting the pH to 8. Use a syringe to draw equal volumes of reagent A and reagent B, attach them to a double injection rack, and quickly mix the solutions before injecting them into centrifuge tubes to obtain the gel.

[0068] Hydrogel 7:

[0069] Prepare gel reagent A by dissolving 55 mg of PEG-(CPT)4(CHO)4 in 0.945 ml of 0.01 M PBS solution, and prepare gel reagent B by dissolving 15 mg of chitosan in 0.97 ml of 1% acetic acid aqueous solution and adjusting the pH to 6. Use a syringe to draw equal volumes of reagent A and reagent B, attach them to a double injection rack, and quickly mix the solutions before injecting them into centrifuge tubes to obtain the gel.

[0070] Hydrogel 8:

[0071] Prepare gel reagent A by dissolving 55 mg PEG-(CPT)4(CHO)4 in 0.945 ml of 0.01 M PBS solution, and prepare gel reagent B by dissolving 30 mg chitosan in 0.97 ml of 1% acetic acid aqueous solution and adjusting the pH to 6. Use a syringe to draw equal volumes of reagent A and reagent B, attach them to a double injection rack, and quickly mix the solutions before injecting them into centrifuge tubes to obtain the gel.

[0072] Hydrogel 9:

[0073] Prepare gel reagent A by dissolving 55 mg PEG-(CPT)4(CHO)4 in 0.945 ml of 0.01 M PBS solution, and prepare gel reagent B by dissolving 30 mg chitosan in 0.97 ml of 1% acetic acid aqueous solution and adjusting the pH to 6. Use a syringe to draw equal volumes of reagent A and reagent B, attach them to a double injection rack, and quickly mix the solutions before injecting them into centrifuge tubes to obtain the gel.

[0074] Hydrogel 10:

[0075] Prepare gel reagent A by dissolving 27.5 mg PEG-(CPT)4(CHO)4 in 0.945 ml of 0.01 M PBS solution, and prepare gel reagent B by dissolving 30 mg chitosan in 0.97 ml of 1% acetic acid aqueous solution and adjusting the pH to 6. Using a syringe, draw equal volumes of reagent A and reagent B, attach them to a double injection stand, and quickly mix the solutions before injecting them into centrifuge tubes to obtain the gel.

[0076] Hydrogel 11:

[0077] Prepare gel reagent A by dissolving 20 mg PEG-(CPT)4(CHO)4 in 0.98 ml of 0.01 M PBS solution, and prepare gel reagent B by dissolving 30 mg chitosan in 0.97 ml of 1% acetic acid aqueous solution and adjusting the pH to 6. Use a syringe to draw equal volumes of reagent A and reagent B, attach them to a double injection rack, and quickly mix the solutions before injecting them into centrifuge tubes to obtain the gel.

[0078] Hydrogel 12:

[0079] Prepare gel reagent A by dissolving 10 mg PEG-(CPT)4(CHO)4 in 0.99 ml of 0.01 M PBS solution, and prepare gel reagent B by dissolving 30 mg chitosan in 0.97 ml of 1% acetic acid aqueous solution and adjusting the pH to 6. Use a syringe to draw equal volumes of reagent A and reagent B, attach them to a double syringe holder, and quickly mix the solutions before injecting them into centrifuge tubes.

[0080] Hydrogel 13:

[0081] Prepare gel reagent A by dissolving 55 mg of PEG-(CPT)2(CHO)6 in 0.945 ml of 0.01 M PBS solution, and prepare gel reagent B by dissolving 30 mg of chitosan in 0.97 ml of 1% acetic acid aqueous solution and adjusting the pH to 6. Using a syringe, draw equal volumes of reagent A and reagent B, attach them to a double syringe holder, and quickly mix the solutions before injecting them into centrifuge tubes to obtain the gel.

[0082] Hydrogel 14:

[0083] Prepare gel reagent A by dissolving 100 mg PEG-(CPT)4(CHO)4 in 0.945 ml of 0.01 M PBS solution. Prepare gel reagent B by dissolving 30 mg polyethyleneimine (molecular weight 10 kDa) in 0.97 ml of deionized water solution and adjusting the pH to 6. Use a syringe to draw equal volumes of reagent A and reagent B, attach them to a double syringe holder, and quickly mix the solutions before injecting them into centrifuge tubes to obtain the gel.

[0084] Hydrogel 15:

[0085] Prepare gel reagent A by dissolving 100 mg PEG-(CPT)4(CHO)4 in 0.945 ml of 0.01 M PBS solution. Prepare gel reagent B by dissolving 30 mg polylysine in 0.97 ml of deionized water solution and adjusting the pH to 6. Use a syringe to draw equal volumes of reagent A and reagent B, attach them to a double syringe holder, and quickly mix the solutions before injecting them into a centrifuge tube to obtain the gel. Hydrogel 16:

[0086] Prepare gel reagent A by dissolving 55 mg PEG-(CHO)8 in 0.945 ml of 0.01 M PBS solution; prepare gel reagent B by dissolving 30 mg chitosan in 0.97 ml of 1% acetic acid aqueous solution and adjusting the pH to 6; and prepare gel reagent B by dissolving 10 mg irinotecan hydrochloride, a camptothecin-based drug, in reagent A solution. Using a syringe, draw equal volumes of reagent A and reagent B, attach them to a double injection stand, and quickly mix the solutions before injecting them into centrifuge tubes to obtain the gel.

[0087] Hydrogel 17:

[0088] Prepare gel reagent A by dissolving 55 mg PEG-(CHO)8 in 0.945 ml of 0.01 M PBS solution; prepare gel reagent B by dissolving 15 mg chitosan in 0.97 ml of 1% acetic acid aqueous solution and adjusting the pH to 6; and prepare gel reagent B by dissolving 10 mg irinotecan hydrochloride, a camptothecin-based drug, in reagent A solution. Using a syringe, draw equal volumes of reagent A and reagent B, attach them to a double injection rack, and quickly mix the solutions into centrifuge tubes to obtain the gel.

[0089] Example 3: Gel Performance Test

[0090] 1. Gel formation time

[0091] First, incubate solutions A and B at 37°C in a water bath for 10 minutes. Then, pipette 200 μL of solution A into a clear vial. Next, add 200 μL of solution B while simultaneously timing the process. After adding solution B, quickly shake the vial left and right for two to three seconds, then invert the vial and observe. If the vial does not flow, it is in a gel state. Record the gelation time as shown in Table 2. The results indicate that the polyethylene glycol benzaldehyde-based camptothecin coupling compound can form gels with chitosan over a wide concentration and pH range. The chitosan can be hydroxyethyl chitosan, chitosan, or carboxymethyl chitosan. When the coupling compound concentration is too low (1%), gel formation is impossible.

[0092] 2. Hydrogel Injection-Shear Thinning Validation

[0093] The prepared gel was loaded into a syringe, and the plunger was pushed to inject the gel into a vial through a 20G needle. The injectability of the gel was then observed (e.g., ...). Figure 1 The shear-thinning properties of the gel were determined based on whether it could be injected with a syringe. If the gel was injectable, it was considered to be shear-thinning. The test results are shown in Table 2. The following conclusions were drawn from the analysis of the test results: (1) By comparing hydrogels 1, 2, 3, 4 and 10, it was found that the gel could not be injected when the concentration of the polyethylene glycol coupling solution was too high (20%); (2) By comparing 4, 5 and 6, it was found that the pH of the solution had a certain influence on the injectability of the gel. When the pH of solution B was high (pH=8), the gel was difficult to inject; (3) By comparing gels 7, 8 and 9, the type of chitosan had no significant influence on the injectability of the gel; (4) By comparing gels 4, 14 and 15, it was found that the type of polyamine compound had a significant influence on the injectability of the gel. The gel formed by polyethyleneimine and polylysine could not be injected.

[0094] Table 2 Hydrogelation Properties - Gel Formation Time and Gel pH

[0095]

[0096] 3. Hydrogel drug sustained release

[0097] Hydrogels 4, 7, 16, and 17 were weighed, added to 10 times PBS buffer, and placed in a 37°C water bath shaker. The extracts were periodically collected, and the absorbance was measured using UV light. The camptothecin content in the extracts was calculated using the camptothecin UV absorption standard curve. (See attached image.) Figure 2 As shown, chemically coupled drugs can release 50%-60% of their drug in simulated body fluids over 7 weeks, achieving a long-term sustained-release effect; while uncoupled drugs are mostly released within 72 hours.

Claims

1. A shear-thinned, long-acting drug-releasing hydrogel, characterized in that... The hydrogel is formed by crosslinking drug-conjugated star-shaped multi-arm polyethylene glycol (PEG) with aldehyde-terminated ends with chitosan. The aldehyde groups of the star-shaped PEG react with the primary amines in chitosan via a Schiff base reaction to form dynamic covalent bonds. The resulting hydrogel is flowable under physical shear force and can self-repair to form a gel after standing. The star-shaped PEG has 2-8 arms, and the molecular weight of each arm is 1000-5000 Da. The hydrogel is prepared by dissolving the drug-conjugated star-shaped PEG with aldehyde-terminated ends in a pH 4-8 buffer solution; and dissolving chitosan in a pH 2-6 buffer solution to prepare a chitosan solution. The two are mixed to obtain a shear-thinned long-acting drug-releasing hydrogel; the mass-volume percentage concentration of the drug-coupled star-shaped multi-arm polyethylene glycol solution with aldehyde-terminated ends is 2%-10%; the mass-volume percentage concentration of the chitosan solution is 0.5%-10%. The star-shaped multi-arm polyethylene glycol structure with aldehyde-terminated conjugates is as follows: Where n represents a positive integer from 1 to 6.

2. The hydrogel according to claim 1, characterized in that... The chitosan is one or more of water-soluble chitosan, hydroxyethyl chitosan, and carboxymethyl chitosan with a molecular weight between 5,000 and 1,000,000 Da.

3. The hydrogel according to claim 1, characterized in that... The molar ratio of the amino groups in the chitosan to the star-shaped multi-arm polyethylene glycol-terminated aldehyde groups is 3:1 to 1:

5.

4. The hydrogel according to claim 1, characterized in that... The star-shaped multi-arm polyethylene glycol solution with aldehyde-terminated conjugate has a mass-volume percentage concentration of 5%-10%; the chitosan solution has a mass-volume percentage concentration of 1%-5%.

5. The use of the hydrogel according to any one of claims 1-4 in the preparation of sustained-release drugs for treating tumors.

Images