A method for preparing a cellulose-based aerogel drug carrier having a stimuli responsiveness

Abstract

The present application belongs to the technical field of drug sustained release and cellulose aerogel material, and discloses a preparation method of a cellulose-based aerogel drug carrier with stimulus responsiveness. The bleached mechanical pulp is used as raw material, and carboxymethylated nanocellulose is obtained by organic and inorganic mixed acid treatment. Then, the nanocellulose is dispersed in a solvent, and a temperature-sensitive monomer, an initiator and a promoter are added. Ultrasonic reaction is carried out at room temperature to obtain a cellulose hydrogel. The obtained hydrogel is soaked and washed for multiple times, solvent replacement is carried out in an anhydrous ethanol solution containing 5-fluorouracil, and supercritical drying is carried out to obtain a drug-loaded cellulose-based aerogel with temperature and pH response performance. The cellulose-based aerogel prepared by the present application has temperature and pH response performance, has a high adsorption capacity for 5-fluorouracil, and has a certain drug release behavior, so that the problems of low drug loading capacity and short drug release time are solved. The present application can be applied to anti-tumor research and has good clinical research application value.

Description

Technical Field

[0001] This invention belongs to the field of drug carrier technology, specifically, it relates to a method for preparing a cellulose-based aerogel drug carrier with stimulus responsiveness, and more particularly to a method for preparing a temperature and pH responsive cellulose aerogel, an aerogel material that efficiently adsorbs drugs and controls the slow release of drugs. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] In recent years, the incidence of cancer has been increasing year by year. Over the past few decades, 5-fluorouracil has been widely used as an effective chemotherapy drug for treating cancers such as breast cancer, stomach cancer, colorectal cancer, and colon cancer. Due to the short half-life of 5-fluorouracil, repeated dosing is necessary, and intravenous infusion therapy is both inconvenient and expensive. Therefore, developing a controllable, oral administration method would be highly beneficial for cancer treatment. Commonly used drug delivery materials mainly include ion exchange resins, membranes, microspheres, and gels, but these methods suffer from problems such as inconvenient portability, low drug loading, and short drug release time.

[0004] To address the above issues, application number 201811567956.4 uses 5-fluorouracil as a model drug and calcium polyglutamate, a reaction product of nano-CaO and biodegradable polyglutamic acid with nutritional benefits, as a solid template to prepare self-assembled nanocarriers. The nanocarriers prepared by this method have a particle size of 50–100 nm, which is smaller than existing technologies, but exhibits better permeability and a drug loading of 9.1–11.0%, significantly improving the drug loading capacity compared to traditional drug carriers. However, this method requires high-temperature processing, and the drug loading capacity still needs further improvement to meet clinical application requirements.

[0005] Patent CN106829913B uses waste fruit shells as raw materials and prepares bio-based microporous carbon microspheres through hydrothermal reaction and carbonization. Due to their high specific surface area, the adsorption capacity of 5-fluorouracil is significantly increased to 480.9 mg / g. However, the sustained-release rate of the drug after loading 5-fluorouracil using this method is only 67.4%, indicating a low drug release rate. Furthermore, this method requires multiple calcinations, making the preparation process cumbersome and unsuitable for large-scale production.

[0006] The inventor's previous paper, "Construction and Drug Release Performance Study of Stimulus-Responsive Cellulose-Based Aerogels," prepared HPMC-NIPAM thermosensitive cellulose aerogels, as well as temperature- and pH-responsive CMC / PNIPAM and CMC / Ca aerogels. 2+ / PNIPAM cellulose-based aerogel, CNT and GO hybrid CMC / Ca 2+ / PNIPAM cellulose aerogel, among which the GO hybrid CMC / Ca aerogel has the best performance. 2 + / PNIPAM cellulose aerogel has a drug loading capacity of 240.59 mg / g and a sustained-release performance extended to 480 min, but the drug loading and sustained-release performance still need to be further improved to better meet the application requirements. Summary of the Invention

[0007] To address the aforementioned problems, this invention provides a method for preparing a cellulose-based aerogel drug carrier with stimulus responsiveness. The method for preparing temperature- and pH-responsive nanocellulose aerogels using bleached chemimechanical pulp as raw material fully utilizes the excellent biodegradability and biocompatibility of nanocellulose, introduces stimulus-responsive functional groups, and endows the cellulose-based aerogel with good drug loading and controlled drug release properties, resulting in a cellulose-based aerogel drug carrier with temperature and pH responsiveness.

[0008] To achieve the above objectives, the present invention adopts the following technical solution:

[0009] In a first aspect, the present invention provides a method for preparing a cellulose-based aerogel drug carrier with stimulus responsiveness, comprising:

[0010] Cellulose raw material is dispersed in a mixed aqueous solution containing organic and inorganic acids and treated at 50-80°C for 2-3 hours. The resulting suspension is washed until the pH is neutral and then dispersed using high-pressure nano-homogeneous dispersion for 10-20 minutes to obtain carboxylated nanocellulose.

[0011] The carboxylated nanocellulose was mixed evenly with a temperature-sensitive monomer, an initiator, a promoter, and a crosslinking agent, and then ultrasonically mixed to obtain a cellulose-based hydrogel.

[0012] The cellulose-based hydrogel was subjected to solvent displacement in an ethanol solution containing the drug, followed by supercritical drying to obtain a drug-loaded cellulose-based aerogel.

[0013] Studies have found that the low cost, stability, renewability, biodegradability, and low toxicity of cellulose materials make them excellent materials for drug sustained-release systems. Due to the large surface area and open porous structure of aerogels, their biocompatibility has been increasingly studied in recent years. The interconnected three-dimensional network and porosity of aerogels can serve as drug carriers to construct drug sustained-release systems. Through systematic research and long-term experimental exploration, this invention has discovered that using biodegradable cellulose aerogels to load 5-fluorouracil can both improve its drug loading rate and achieve its controlled sustained release.

[0014] In a second aspect, the present invention provides a cellulose-based aerogel drug carrier with stimuli responsiveness prepared by the above-described method.

[0015] A third aspect of the present invention provides the use of the above-described stimuli-responsive cellulose-based aerogel drug carrier in the preparation of sustained-release drugs.

[0016] Beneficial effects of the present invention

[0017] (1) Existing technologies mainly involve improving the bioavailability of 5-fluorouracil, but do not address the efficient loading and slow release behavior of 5-fluorouracil. This invention, based on the homogenization reaction of cellulose, yields carboxymethylated nanocellulose, with a carboxyl content exceeding 5 mmol / g determined by charge density analysis. The carboxyl groups attached to the nanocellulose impart a pH-responsive network structure. N-isopropylacrylamide is used to construct a temperature-responsive network structure through free radical polymerization and chemical crosslinking. A high-performance interpenetrating network hydrogel is prepared through physicochemical crosslinking, and after supercritical drying, a cellulose-based aerogel with temperature and pH responsive properties is obtained. The preparation process of this aerogel material is green and environmentally friendly, simple to operate, and uses mild reaction conditions. The materials used are non-toxic, readily biodegradable, and pose no harm to the human body.

[0018] (2) In this invention, the hydrogel is immersed in a 5-fluorouracil ethanol solution. Through solvent displacement, 5-fluorouracil diffuses in the pores of the hydrogel and is adsorbed onto the active sites such as amino and carboxyl groups of the hydrogel by various chemical or physical actions. This causes 5-fluorouracil to be deposited in the network of the hydrogel. The gel shrinkage adjusts the network pores, increases the non-covalent bond forces of the drug in the aerogel network, increases the loading efficiency, and prolongs the drug release time.

[0019] (3) The aerogel material loaded with 5-fluorouracil obtained in this invention exhibits different sustained-release behaviors at different temperatures and pH values, demonstrating certain temperature and pH response performance. By adjusting the proportion and amount of mixed acid in the aerogel network, the content of nanocellulose and temperature-sensitive monomers, as well as the ultrasonic time during gel preparation, the concentration of ethanol during solvent replacement, and the supercritical drying process conditions, the cellulose-based aerogel is endowed with efficient loading and adjustable sustained-release rate of 5-fluorouracil.

[0020] (4) Compared with "HPMC-NIPAM thermosensitive cellulose aerogel, temperature and pH dual-responsive CMC / PNIPAM and CMC / Ca 2 + / PNIPAM cellulose-based aerogel, CNT and GO hybrid CMC / Ca 2+Compared to "PNIPAM cellulose aerogel", the cellulose-based aerogel constructed by the present invention using carboxylated nanocellulose and temperature-sensitive monomers has a more efficient loading capacity and adjustable sustained release rate for 5-fluorouracil.

[0021] (5) The preparation method of the present invention is simple, practical and easy to promote. Detailed Implementation

[0022] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0023] A method for preparing a stimuli-responsive cellulose-based aerogel drug carrier, comprising:

[0024] (1) Preparation of nanocellulose

[0025] Using bleached chemimechanical pulp as raw material, cellulose raw material is dispersed in a mixed aqueous solution containing organic and inorganic acids. After reacting at a certain temperature for a period of time, the resulting suspension is washed with deionized water until the pH is neutral. The washed suspension is then treated with a nano-homogenizer for a certain period of time to obtain carboxylated nanocellulose.

[0026] (2) Preparation of drug-loaded cellulose-based aerogels

[0027] Add a thermosensitive monomer, sodium persulfate as an initiator, tetramethylethylenediamine as an accelerator, and N,N'-methylenebisacrylamide as a crosslinking agent to step (1). Stir and mix evenly at room temperature, pour into a mold, and sonicate to obtain a cellulose-based hydrogel. After soaking and washing the obtained hydrogel, dissolve a certain amount of 5-fluorouracil in an ethanol solution for solvent replacement, and obtain a drug-loaded cellulose-based aerogel by supercritical drying.

[0028] In some embodiments, in the mixed aqueous solution of the organic and inorganic acids, the inorganic acid is one or more of hydrochloric acid, sulfuric acid, and nitric acid; the organic acid is one or more of citric acid, salicylic acid, lactic acid, acetic acid, and malic acid.

[0029] In some embodiments, the molar ratio of the organic acid to the inorganic acid is 1:1 to 1:3.

[0030] In some embodiments, the molar ratio of pulp fiber monomer glucose to mixed acid is 1:1 to 1:2.5.

[0031] In some embodiments, the temperature-sensitive monomer is selected from N-isopropylacrylamide, 2-(N,N-dimethylamino) methacrylate, and N-vinylpyrrolidone.

[0032] In some embodiments, the mass ratio of the thermosensitive monomer to carboxylated nanocellulose is 1:1-3:1;

[0033] In some embodiments, the initiator is sodium persulfate, and its mass is 1%-4% of the thermosensitive monomer;

[0034] In some embodiments, the accelerator is tetramethylethylenediamine, and its mass is 0.05%-3% of the thermosensitive monomer;

[0035] In some embodiments, the crosslinking agent is N,N'-methylenebisacrylamide, and its mass is 5%-10% of the thermosensitive monomer.

[0036] In some embodiments, the ultrasonic time is 5 min-30 min and the ultrasonic power is 100-120 W.

[0037] In some embodiments, the volume fraction of ethanol in the ethanol solution containing the drug is 50%-80%, and the mass fraction of the drug is 10-30%.

[0038] In some embodiments, the drug is 5-fluorouracil.

[0039] In some embodiments, during supercritical drying, the temperature inside the reactor is controlled at 30-50°C and the pressure is controlled at 9-16 MPa. The reactor is kept in a supercritical state for 1-5 hours. After drying is complete, the pressure is released at a rate of 0.5-2 MPa / h, and the product is obtained after natural cooling to room temperature.

[0040] The present invention will be further described in detail below with reference to specific embodiments. It should be noted that the specific embodiments are explanations of the present invention and not limitations thereof.

[0041] In the following examples, the bleached mechanical pulp (cellulose raw material) is alkaline hydrogen peroxide mechanical pulp from Shandong Sun Paper Co., Ltd.

[0042] Example 1

[0043] (1) Preparation of nanocellulose

[0044] Using alkaline hydrogen peroxide mechanical pulp from Shandong Sun Paper Industry Co., Ltd. as raw material, cellulose raw material was dispersed in a mixed aqueous solution containing hydrochloric acid and salicylic acid. The molar ratio of salicylic acid to hydrochloric acid was 1:2, and the molar ratio of pulp fiber monomer glucose to mixed acids was 1:2. After reacting at 50°C for 2 hours, the resulting suspension was washed with deionized water until the pH was neutral. The washed suspension was then treated with a nano-homogenizer for 10 minutes to obtain carboxylated nanocellulose.

[0045] (2) Preparation of drug-loaded cellulose-based aerogel: In step (1), the mass of the thermosensitive monomer N-isopropylacrylamide was twice the mass of the nanocellulose, the mass of the initiator sodium persulfate was 2% of the mass of the thermosensitive monomer N-isopropylacrylamide, the mass of the accelerator tetramethylethylenediamine was 1% of the mass of the thermosensitive monomer N-isopropylacrylamide, and the mass of the crosslinking agent N,N'-methylenebisacrylamide was 8% of the mass of the thermosensitive monomer N-isopropylacrylamide. The mixture was stirred and mixed evenly at room temperature and poured into a mold. The mixture was ultrasonicated for 10 min to obtain a cellulose-based hydrogel. The obtained hydrogel was soaked in water to remove residual chemicals. A certain proportion of ethanol drug solution was used for solvent replacement. The volume fraction of ethanol was 50%, and the mass fraction of 5-fluorouracil was 20%. The mixture was dried by supercritical drying. During supercritical drying, the temperature inside the reactor was controlled at 30℃ and the pressure was controlled at 9MPa. The mixture was kept in the supercritical state for 1 h to ensure complete drying. Then the pressure was released at a rate of 0.5MPa / h. After natural cooling to room temperature, the reactor was opened to obtain the drug-loaded cellulose-based aerogel.

[0046] The properties of drug-loaded cellulose-based aerogels were tested, and the results are as follows:

[0047] The cellulose-based aerogel was loaded with 612.5 mg / g of 5-fluorouracil. The drug-loaded cellulose aerogel exhibited a significantly faster drug release rate at 37°C than at 25°C, and a significantly faster release rate at pH 3 than at pH 7.4, demonstrating good temperature and pH response properties. At 37°C and pH 3, the drug-loaded cellulose aerogel achieved a 92.5% drug release rate after 24 hours; at 25°C and pH 7.4, the 24-hour release rate was 31.3%.

[0048] Example 2

[0049] (1) Preparation of nanocellulose: Using bleached chemimechanical pulp as raw material, the cellulose raw material was dispersed in a mixed aqueous solution containing hydrochloric acid and salicylic acid. The molar ratio of salicylic acid to hydrochloric acid was 1:1, and the molar ratio of pulp fiber monomer glucose to mixed acid was 1:1. After reacting at 50℃ for 2 hours, the resulting suspension was washed with deionized water until the pH was neutral. The washed suspension was then treated with a nano-homogenizer for 10 minutes to obtain carboxylated nanocellulose.

[0050] (2) Preparation of drug-loaded cellulose-based aerogel: In step (1), the mass of the thermosensitive monomer N-isopropylacrylamide was 3 times the mass of the nanocellulose, the mass of the initiator sodium persulfate was 3% of the mass of the thermosensitive monomer N-isopropylacrylamide, the mass of the accelerator tetramethylethylenediamine was 3% of the mass of the thermosensitive monomer N-isopropylacrylamide, and the mass of the crosslinking agent N,N'-methylenebisacrylamide was 10% of the mass of the thermosensitive monomer N-isopropylacrylamide. The mixture was stirred and mixed evenly at room temperature and poured into a mold. The mixture was ultrasonicated for 30 min to obtain cellulose-based hydrogel. The obtained hydrogel was soaked in water to remove residual chemicals. A certain proportion of ethanol drug solution was used for solvent replacement. The volume fraction of ethanol was 50%, and the mass fraction of 5-fluorouracil was 20%. During supercritical drying, the temperature in the reactor was controlled at 30℃ and the pressure was controlled at 9MPa. The reactor was kept in the supercritical state for 1 h to ensure complete drying. Then the pressure was released at a rate of 0.5MPa / h. After natural cooling to room temperature, the reactor was opened to obtain the drug-loaded cellulose-based aerogel.

[0051] The properties of drug-loaded cellulose-based aerogels were tested, and the results are as follows:

[0052] The cellulose-based aerogel was loaded with 548.3 mg / g of 5-fluorouracil. The drug-loaded cellulose aerogel exhibited a significantly faster drug release rate at 37°C than at 25°C, and a significantly faster release rate at pH 3 than at pH 7.4, demonstrating good temperature and pH response properties. At 37°C and pH 3, the drug-loaded cellulose aerogel achieved a drug release rate of 85.6% after 24 hours; at 25°C and pH 7.4, the release rate was 43.5% after 24 hours.

[0053] Example 3

[0054] (1) Preparation of nanocellulose: Using bleached chemimechanical pulp as raw material, the cellulose raw material was dispersed in a mixed aqueous solution containing hydrochloric acid and salicylic acid. The molar ratio of salicylic acid to hydrochloric acid was 1:1, and the molar ratio of pulp fiber monomer glucose to mixed acid was 1:1. After reacting at 50℃ for 2 hours, the resulting suspension was washed with deionized water until the pH was neutral. The washed suspension was then treated with a nano-homogenizer for 10 minutes to obtain carboxylated nanocellulose.

[0055] (2) Preparation of cellulose-based aerogel: In step (1), the mass of the thermosensitive monomer N-isopropylacrylamide was 1 times the mass of the nanocellulose, the mass of the initiator sodium persulfate was 2% of the mass of the thermosensitive monomer N-isopropylacrylamide, the mass of the accelerator tetramethylethylenediamine was 2% of the mass of the thermosensitive monomer N-isopropylacrylamide, and the mass of the crosslinking agent N,N'-methylenebisacrylamide was 5% of the mass of the thermosensitive monomer N-isopropylacrylamide. The mixture was stirred and mixed evenly at room temperature and poured into a mold. The mixture was ultrasonicated for 5 min to obtain cellulose-based hydrogel. The obtained hydrogel was soaked in water to remove residual chemicals. A certain proportion of ethanol drug solution was used for solvent replacement. The volume fraction of ethanol was 50%, and the mass fraction of 5-fluorouracil was 20%. The mixture was dried by supercritical drying. During supercritical drying, the temperature inside the reactor was controlled at 30℃ and the pressure was controlled at 9MPa. The mixture was kept in the supercritical state for 1 h to ensure complete drying. Then the pressure was released at a rate of 0.5MPa / h. After natural cooling to room temperature, the reactor was opened to obtain drug-loaded cellulose-based aerogel.

[0056] The properties of drug-loaded cellulose-based aerogels were tested, and the results are as follows:

[0057] The cellulose-based aerogel was loaded with 452.6 mg / g of 5-fluorouracil. The drug-loaded cellulose aerogel exhibited a significantly faster drug release rate at 37°C than at 25°C, and a significantly faster release rate at pH 3 than at pH 7.4, demonstrating good temperature and pH response properties. At 37°C and pH 3, the drug-loaded cellulose aerogel achieved a drug release rate of 91.8% after 24 hours; at 25°C and pH 7.4, the release rate was 46.5% after 24 hours.

[0058] Comparative Example 1

[0059] (1) Preparation of nanocellulose: Nanocellulose modification: Using bleached chemimechanical pulp as raw material, the cellulose raw material was dispersed in an aqueous solution containing hydrochloric acid. The molar ratio of salicylic acid to hydrochloric acid was 0:2, and the molar ratio of pulp fiber monomer glucose to mixed acid was 1:1. After reacting at 50℃ for 2 hours, the resulting suspension was washed with deionized water until the pH was neutral. The washed suspension was then treated with a nano-homogenizer for 10 minutes to obtain nanocellulose.

[0060] (2) Preparation of drug-loaded cellulose-based aerogel: The mass of the thermosensitive monomer N-isopropylacrylamide was twice the mass of the nanocellulose, and the mass of the initiator sodium persulfate was 2% of the mass of the thermosensitive monomer N-isopropylacrylamide; the mass of the accelerator tetramethylethylenediamine was 2% of the mass of the thermosensitive monomer N-isopropylacrylamide; and the mass of the crosslinking agent N,N'-methylenebisacrylamide was 5% of the mass of the thermosensitive monomer N-isopropylacrylamide. The mixture was stirred and mixed evenly at room temperature and poured into a mold. The mixture was ultrasonicated for 5 min to obtain a cellulose-based hydrogel. The obtained hydrogel was soaked in water to remove residual chemicals. A certain proportion of ethanol drug solution was used for solvent replacement. The volume fraction of ethanol was 50%, and the mass fraction of 5-fluorouracil was 20%. The mixture was dried by supercritical drying. During supercritical drying, the temperature inside the reactor was controlled at 30℃ and the pressure was controlled at 9 MPa. The mixture was kept in the supercritical state for 1 h to ensure complete drying. Then the pressure was released at a rate of 0.5 MPa / h, and the mixture was naturally cooled to room temperature before the reactor was opened to obtain the drug-loaded cellulose-based aerogel.

[0061] The properties of drug-loaded cellulose-based aerogels were tested, and the results are as follows:

[0062] The cellulose-based aerogel was loaded with 247.6 mg / g of 5-fluorouracil. The drug-loaded cellulose aerogel exhibited a significantly faster drug release rate at 37°C than at 25°C, and at pH 3, the release rate was equivalent to pH 7.4, demonstrating good temperature response but no pH response. At 37°C and pH 3, the drug-loaded cellulose aerogel achieved a 90.5% drug release rate after 24 hours; at 25°C and pH 7.4, the release rate was 67.4%.

[0063] Comparative Example 2

[0064] (1) Preparation of nanocellulose: Using bleached chemimechanical pulp as raw material, the cellulose raw material was dispersed in a mixed aqueous solution containing hydrochloric acid and salicylic acid. The molar ratio of salicylic acid to hydrochloric acid was 1:2, and the molar ratio of pulp fiber monomer glucose to mixed acid was 1:2. After reacting at 60°C for 2 hours, the resulting suspension was washed with deionized water until the pH was neutral. The washed suspension was then treated with a nano-homogenizer for 10 minutes to obtain carboxylated nanocellulose.

[0065] (2) Preparation of drug-loaded cellulose-based aerogel: Carboxylated nanocellulose was stirred and mixed evenly at room temperature and poured into a mold. The mixture was ultrasonicated for 10 min to obtain cellulose-based hydrogel. The obtained hydrogel was soaked in water to remove residual chemicals. A certain proportion of ethanol drug solution was used for solvent replacement. The volume fraction of ethanol was 50%, and the mass fraction of 5-fluorouracil was 20%. The mixture was dried by supercritical drying. During supercritical drying, the temperature inside the reactor was controlled at 30℃ and the pressure was controlled at 9MPa. The reactor was kept in the supercritical state for 1 h to ensure complete drying. Then, the pressure was released at a rate of 0.5MPa / h, and the reactor was naturally cooled to room temperature before the drug-loaded cellulose-based aerogel was obtained.

[0066] The properties of drug-loaded cellulose-based aerogels were tested, and the results are as follows:

[0067] The cellulose-based aerogel loaded with 286.5 mg / g of 5-fluorouracil exhibited a drug-loaded cellulose aerogel. The drug release rate at 37°C was equal to that at 25°C, and significantly faster at pH 3 than at pH 7.4, demonstrating good pH-responsiveness but no temperature-responsiveness. At 37°C and pH 3, the drug release rate after 24 hours reached 94.6%; at 25°C and pH 7.4, the release rate was 65.3%.

[0068] Table 1

[0069]

[0070] The above comparison shows that the drug-loaded cellulose aerogel prepared using the above method exhibits temperature and pH responsiveness, significantly increases drug loading, prolongs drug release time, and enhances drug release rate. This is attributed to the introduction of carboxyl and amino groups into the nanocellulose molecular chain, which enhances its non-covalent interactions with the drug, such as hydrogen bonding, electrostatic attraction, and van der Waals forces.

[0071] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing a cellulose-based aerogel drug carrier with stimulus responsiveness, characterized in that, include: Cellulose raw material is dispersed in a mixed aqueous solution containing organic and inorganic acids and treated at 50-80°C for 2-3 hours. The resulting suspension is washed until the pH is neutral and then dispersed using high-pressure nano-homogeneous dispersion for 10-20 minutes to obtain carboxylated nanocellulose. The carboxylated nanocellulose was mixed evenly with a temperature-sensitive monomer, an initiator, a promoter, and a crosslinking agent, and then ultrasonically mixed to obtain a cellulose-based hydrogel. The cellulose-based hydrogel was subjected to solvent displacement in an ethanol solution containing the drug, followed by supercritical drying to obtain a drug-loaded cellulose-based aerogel. In the mixed aqueous solution of the organic and inorganic acids, the inorganic acid is hydrochloric acid; the organic acid is salicylic acid. The molar ratio of the organic acid to the inorganic acid is 1:1 to 1:3; The drug is 5-fluorouracil; The temperature-sensitive monomer is N-isopropylacrylamide; The initiator is sodium persulfate; The accelerator is tetramethylethylenediamine; The crosslinking agent is N,N'-methylenebisacrylamide.

2. The method for preparing a stimuli-responsive cellulose-based aerogel drug carrier as described in claim 1, characterized in that, The molar ratio of pulp fiber monomer glucose and mixed acid in the cellulose raw material is 1:1 to 1:2.

5.

3. The method for preparing a stimuli-responsive cellulose-based aerogel drug carrier as described in claim 1, characterized in that, The mass ratio of the thermosensitive monomer to carboxylated nanocellulose is 1:1-3:1; Alternatively, the initiator is sodium persulfate, with a mass of 1%-4% of the temperature-sensitive monomer; Alternatively, the accelerator is tetramethylethylenediamine, with a mass of 0.05%-3% of the temperature-sensitive monomer; Alternatively, the crosslinking agent is N,N'-methylenebisacrylamide, with a mass of 5%-10% of the temperature-sensitive monomer.

4. The method for preparing a stimuli-responsive cellulose-based aerogel drug carrier as described in claim 1, characterized in that, Ultrasound duration: 5 min-30 min; ultrasound power: 100-120 W.

5. The method for preparing a stimuli-responsive cellulose-based aerogel drug carrier as described in claim 1, characterized in that, In an ethanol solution containing a drug, the volume fraction of ethanol is 50%-80%, and the mass fraction of the drug is 10-30%.

6. The method for preparing a stimuli-responsive cellulose-based aerogel drug carrier as described in claim 1, characterized in that, During supercritical drying, the temperature inside the reactor is controlled at 30-50℃ and the pressure is controlled at 9-16 MPa. The reactor is kept in a supercritical state for 1-5 hours. After drying is complete, the pressure is released at a rate of 0.5-2 MPa / h and the product is obtained after natural cooling to room temperature.

7. A stimuli-responsive cellulose-based aerogel drug carrier prepared by the method of any one of claims 1-6.

8. The use of the stimuli-responsive cellulose-based aerogel drug carrier of claim 7 in the preparation of sustained-release drugs.

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