A pH-responsive interpenetrating network hydrogel

Abstract

The present invention relates to a pH-responsive interpenetrating network hydrogel. The interpenetrating network hydrogel comprises, by weight, an aldehyde-containing aliphatic polyester; a polyamine compound (0.05 to 0.1 times the weight of the aldehyde-containing aliphatic polyester); hydroxyethyl acrylate (0.4 to 0.6 times the weight of the aldehyde-containing aliphatic polyester); an acrylate crosslinker (0.05 to 0.1 times the weight of the aldehyde-containing aliphatic polyester); and a photoinitiator (0.005 to 0.01 times the weight of the aldehyde-containing aliphatic polyester). The aldehyde-containing aliphatic polyester is obtained by ring-opening polymerization of diglycolic anhydride and epoxy acrolein diethyl acetal. The interpenetrating network hydrogel has excellent swelling properties, mechanical properties, and pH sensitivity, and can be used for pH-sensitive drug release.

Description

Technical Field

[0001] The invention relates to a polymer gel, in particular to an interpenetrating network hydrogel. The interpenetrating network hydrogel is suitable for preparing an anticancer drug preparation capable of releasing drugs in response to pH. Background Art

[0002] Interpenetrating network hydrogels are formed by the entanglement and interpenetration of two or more polymers, and contain at least one cross-linked network structure formed by chemical bonds. pH-responsive hydrogels refer to hydrogels that can swell or eliminate swelling behavior in response to changes in the pH of the surrounding environment. They have the advantages of good water absorption and storage stability, and are widely used in biomedical fields such as controlled drug release. Fan Zhiping et al. prepared polyglutamic acid / hyaluronic acid-based interpenetrating network hydrogels and achieved pH-controlled drug release of tetracycline hydrochloride (Fan Zhiping, Cheng Ping, Ding Zhuang, Zhao Yanna, Li Jun, Liu Min, Sangeeta Prakash, Zhang Demeng, Wang Wenli, Wang Zhengping, Han Jun, Preparation and Characterization of pH-Sensitive Polyglutamic Acid / Hyaluronic Acid-Based Interpenetrating Network Medical Hydrogels, Polymer Bulletin, 2020, 02, 23). Shao Xue et al. used polyvinyl alcohol (PVA) and chitosan (CS) as raw materials and adopted a process combining physical crosslinking with chemical crosslinking to prepare PVA / CS interpenetrating network hydrogels. They studied the effect of pH on their swelling rate and achieved pH-controlled drug release of chloramphenicol (Shao Xue, Liang Tianyu, Ding Keyi, Liu Jun. Study on the swelling and drug loading and release properties of pH-sensitive polyvinyl alcohol / chitosan interpenetrating network hydrogels. Journal of Southwest University for Nationalities (Natural Science Edition). 2015, 41(05), 582). However, the above-mentioned interpenetrating network hydrogels have poor mechanical properties.

[0003] Aliphatic polyesters are a class of important biomedical materials whose main chains are composed of aliphatic structural units connected by easily hydrolyzed ester bonds. The main chains are flexible and have good biocompatibility and biodegradability. They are widely used in the field of biomedicine, such as sustained drug release, surgical sutures, bone fixation materials, tissue engineering materials, etc. Introducing pH-responsive groups or structural units into aliphatic polyesters gives them pH-responsive properties. By changing the pH, changes such as swelling / collapse, hydrophilic / hydrophobic transition, and bond breakage of the aliphatic polyester are caused, thereby achieving the purpose of drug release. Patent application No. CN104262600A introduces Schiff bases and sulfhydryl groups into the side chains of amphiphilic copolymers to achieve pH- and glutathione (GSH)-responsive drug release. Patent application CN106265509A introduces pH-sensitive amino esters and GSH-sensitive disulfide bonds into the backbone to synthesize polyethylene glycol-polyaminoester-ss-polylactic-co-glycolic acid copolymers. The amphiphilic polymer self-assembles into nanomicelles with excellent pH and GSH responsiveness. However, the pH-responsive fatty polyester exhibits poor mechanical properties and water absorption. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a pH-responsive interpenetrating network hydrogel, which has good mechanical properties and pH sensitivity.

[0005] The technical solution of the present invention to solve the above problems is:

[0006] A pH-responsive interpenetrating network hydrogel, comprising, by weight, an aldehyde-containing aliphatic polyester, a polyamine compound in an amount of 0.05 to 0.1 times the weight of the aldehyde-containing aliphatic polyester, 0.4 to 0.6 times the weight of the aldehyde-containing aliphatic polyester in an amount of hydroxyethyl acrylate, 0.05 to 0.1 times the weight of the aldehyde-containing aliphatic polyester in an amount of a crosslinking agent, 0.005 to 0.01 times the weight of the aldehyde-containing aliphatic polyester in an amount of a photoinitiator; wherein:

[0007] The aldehyde-containing aliphatic polyester is prepared by the following method: diglycolic anhydride, epoxy acrolein diethanol acetal, and zinc acetate are dissolved in DMF at a molar ratio of diglycolic anhydride: epoxy acrolein diethanol acetal: zinc acetate = 1:1:0.001-0.005, the temperature is raised to 60-65°C under nitrogen protection, and a ring-opening polymerization reaction is carried out for 8-12 hours. The temperature is then lowered to room temperature, and the mixture is added to water with a pH of 2-4 for precipitation. The precipitate is collected to obtain the aliphatic polyester. The aliphatic polyester has a network structure and a weight-average molecular weight of 1000-2000.

[0008] The crosslinking agent acrylate is one or more of triethylene glycol dimethacrylate, 1,6-hexanediol diacrylate, neopentyl glycol diacrylate and 1,4-decanediol diacrylate;

[0009] The photoinitiator is 1-hydroxycyclohexyl phenyl ketone and / or (2,4,6-trimethylbenzoyl) diphenyl phosphine oxide;

[0010] The polyamine compound is one or more of 1,4-piperazinediethylamine, N-(2-aminoethyl)-1,4-piperazinediyldiethylamine, 3-oxopentanediamine, diethylenetriamine, triethylenetetramine, and tris(2-aminoethyl)amine.

[0011] The interpenetrating network hydrogel of the present invention is prepared by the following method: adding the aldehyde-containing aliphatic polyester, polyamine compound, hydroxyethyl acrylate, cross-linked acrylate and photoinitiator to DMF obtained separately and mixing them evenly, and then irradiating the mixture with a wavelength of 395nm and a light intensity of 300mW / cm 2 The solution was cured under an LED light; then, the solution was repeatedly soaked and washed with distilled water, purified, and dried to a constant weight to obtain the pH-sensitive interpenetrating network hydrogel.

[0012] The pH-responsive interpenetrating network hydrogel of the present invention is suitable for preparing an anticancer drug preparation, which is composed of 99.5-99.9% pH-responsive interpenetrating network hydrogel and 0.1-0.5% anticancer drug by weight; wherein the anticancer drug is doxorubicin, curcumin, aclarubicin or pyrarubicin.

[0013] The anticancer drug preparation is prepared by the following method: first dissolving the anticancer drug in ethanol to a concentration of 0.1 to 0.5 mg / mL, finally adding the pH-responsive interpenetrating network hydrogel and soaking for 36 to 72 hours, washing with distilled water, and freeze-drying to obtain the anticancer drug preparation.

[0014] The pH-responsive interpenetrating network hydrogel described in the present invention comprises an aldehyde-containing aliphatic polyester with aldehyde groups attached to its side chains. This polyester reacts with polyamine compounds to form a Schiff base, creating a pH-responsive dynamic crosslinked network. Simultaneously, hydroxyethyl acrylate and a crosslinking agent, acrylate, undergo a photocuring reaction under the action of a photoinitiator to form an interpenetrating network structure. This interpenetrating network hydrogel exhibits excellent mechanical properties.

[0015] Because the pH-responsive interpenetrating network hydrogel contains a Schiff base network. When in an acidic medium, the Schiff base dissociates and the interpenetrating network is destroyed, causing the hydrogel network to collapse, showing pH sensitivity. It can be seen that the pH-responsive interpenetrating network hydrogel described in the present application is suitable for the preparation of sustained-release anti-tumor drug preparations. The sustained-release anti-tumor drug preparation releases the drug in an acidic environment. Therefore, when the pH-responsive interpenetrating network hydrogel described in the present application is loaded with anti-tumor drugs to prepare a sustained-release anti-tumor drug preparation, the anti-tumor drug in the preparation will not be released in neutral normal tissues; but it will be rapidly released in acidic tumor tissues, killing tumors, reducing the toxic side effects of anti-tumor drugs, and achieving targeted treatment of tumors. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 Drug release curves of doxorubicin-loaded pH-responsive interpenetrating network hydrogels under different pH conditions. Specific embodiments

[0017] The preparation method of the present invention and its effects are further described in detail below with reference to specific examples.

[0018] Example 1

[0019] 1. Synthesis of aldehyde-containing aliphatic polyesters

[0020] Take 10 mmol of diglycolic anhydride, 10 mmol of epoxy acrolein diethyl acetal and 0.04 mmol of zinc acetate, add them to 10 mL of DMF, heat to 64 ° C under nitrogen protection, and carry out ring-opening polymerization for 10 hours. Cool to room temperature, add into water with a pH of 3, stir, filter the precipitate, and dry to obtain aldehyde-containing aliphatic polyester.

[0021] The weight-average molecular weight and mass-average molecular weight of the obtained aldehyde-containing aliphatic polyester were measured using a Jasco Gulliver system (PU-980, CO-965, RI-930, and UV-1570) gel permeation chromatography instrument. Equipped with polystyrene gel columns (Shode x columns K804, K805, and J806), DMF was used as the eluent, and polystyrene was used as a calibration standard. Measurements were performed at 30°C. The results showed that the weight-average molecular weight of the aldehyde-containing aliphatic polyester was 1503.

[0022] 2. Interpenetrating hydrogel

[0023] Synthesis of interpenetrating network hydrogels

[0024] Take 10g of the synthesized aldehyde aliphatic polyester, 0.06g of diethylenetriamine, 5.5g of hydroxyethyl acrylate, 0.065g of triethylene glycol dimethacrylate and 0.07g of 1-hydroxycyclohexyl phenyl ketone and add them into 10mL of DMF, mix them evenly, put them into the mold, and irradiate them under a wavelength of 395nm and an intensity of 300mW / cm 2 After light curing under an LED light, the solution was repeatedly immersed in distilled water for washing and purification, and dried to a constant weight to obtain the pH-responsive interpenetrating network hydrogel.

[0025] In the above reaction, the aldehyde groups on the side chains of the aldehyde-containing aliphatic polyester react with the polyamine compound to form a Schiff base cross-linked network; at the same time, hydroxyethyl acrylate and the cross-linking agent triethylene glycol dimethacrylate are photocured and cross-linked under the action of a photoinitiator to form an interpenetrating network structure with the Schiff base cross-linked network.

[0026] 2.2. Swelling rate of pH-responsive interpenetrating network hydrogels

[0027] At room temperature, the interpenetrating network hydrogel was taken and accurately weighed to obtain W o Soak it in water at room temperature until it reaches swelling equilibrium, wipe off excess water on the surface of the scaffold with filter paper, and measure the mass of the hydrogel again to obtain W e The absorption rate of the interpenetrating network hydrogel was calculated as follows: Swelling rate (%) = (We - W0) / W0. The swelling rate was found to be 225%.

[0028] 2.3. Tensile strength of pH-responsive interpenetrating network hydrogels

[0029] The prepared pH-responsive interpenetrating network hydrogel was tested for its elongation on a Zwick / Roell 2202 universal material testing machine (Zwick, Germany).

[0030] According to the above method, the stretchability of the prepared pH-responsive interpenetrating network hydrogel was 183%.

[0031] pH sensitivity of interpenetrating network hydrogels

[0032] At room temperature, the pH-sensitive interpenetrating network hydrogel was taken and immersed in buffer solutions with pH values of 2, 3, 4, 5, 6, 7, and 8, respectively. After swelling equilibrium, the hydrogel was weighed, and the swelling rates at different pH values were calculated.

[0033] At room temperature, the pH-sensitive interpenetrating network hydrogel was immersed in buffer solutions with pH values of 2, 3, 4, 5, 6, 7, and 8. After swelling equilibrium, its elongation was measured. The results are shown in Table 1.

[0034] Table 1 Swelling rate and stretching rate of pH-sensitive interpenetrating network hydrogels at different pH values

[0035] pH 2 3 4 5 6 7 8 Swelling rate (%) 81 135 162 210 221 234 216 Elongation (%) 58 69 153 162 174 183 178

[0036] The pH-sensitive interpenetrating network hydrogel described herein contains a Schiff base formed by aldehyde and amine groups. Under acidic conditions, the Schiff base dissociates, causing the network structure formed by the aldehyde-containing saturated polyester and polyamine compounds to collapse, resulting in a decrease in mechanical properties and significant pH sensitivity. As shown in the table above, the pH-responsive interpenetrating network hydrogel exhibits minimal changes in swelling and elongation under neutral conditions, while significantly decreasing under acidic conditions.

[0037] 3. Drug-loaded pH-responsive interpenetrating network hydrogels

[0038] 3.1. Preparation of drug-loaded interpenetrating network hydrogels

[0039] 2 g of the pH-responsive interpenetrating network hydrogel was soaked in a 0.4 mg / mL doxorubicin ethanol solution for 36 h, washed with distilled water, and freeze-dried to a constant weight to obtain a drug-loaded pH-responsive interpenetrating network hydrogel.

[0040] 3.2. Drug loading capacity of drug-loaded interpenetrating network hydrogels

[0041] The drug-loaded pH-responsive interpenetrating network hydrogel was accurately weighed to obtain W1. The hydrogel was then immersed in DMF for 7 days. The DMF solution was collected and its UV absorbance was measured. The weight of doxorubicin in the DMF was calculated using a standard curve method as W2. The drug loading capacity of the drug-loaded interpenetrating network hydrogel was calculated using the following formula: Drug loading (μg / g) = W2 / W1. The resulting drug loading capacity was 4225 μg / g.

[0042] 3.2. Drug Release Behavior of Drug-Loaded Interpenetrating Network Hydrogels

[0043] At room temperature, drug release experiments were conducted in buffer solutions with pH values of 4.01 and 6.8. The drug-loaded interpenetrating network hydrogel was placed in a bottle containing 30 mL of buffer solution (pH 4.01 and 6.8, respectively), oscillated at a constant temperature, and 3 mL of buffer solution was removed at regular intervals to determine the drug release rate. An equal volume of fresh blank buffer was then added. The absorbance at 480 nm was measured by UV-visible spectrophotometry to determine the concentration of doxorubicin in the medium, and the cumulative drug release curve was calculated and plotted. The results are shown in Figure 2. Figure 1 shown.

[0044] The results are as follows Figure 1As described. After 2 hours, the cumulative release rate of doxorubicin at pH 4.01 was greater than that at pH 6.8. This is because under neutral conditions, the hydrogel network is in a swollen state, and the release of doxorubicin mainly depends on the concentration difference between the inside and the outside, and is released from the inside to the outside through the porous network inside the hydrogel. Under acidic conditions, the Schiff base in the pH-responsive interpenetrating network hydrogel dissociates, and the network structure formed by the aldehyde-containing saturated polyester and the polyamino compound collapses, promoting the release of doxorubicin. Therefore, the interpenetrating network hydrogel shows pH-sensitive drug release performance.

[0045] Example 2

[0046] 1. Synthesis of aldehyde-containing aliphatic polyesters

[0047] Take 10 mmol of diglycolic anhydride, 10 mmol of epoxy acrolein diethyl acetal and 0.05 mmol of zinc acetate, add them to 15 mL of DMF, heat to 65 ° C under nitrogen protection and carry out ring-opening polymerization for 12 hours, cool to room temperature, add into water with a pH of 4, stir, filter the precipitate, and dry to obtain aldehyde-containing aliphatic polyester.

[0048] The obtained aldehyde-containing aliphatic polyester was tested using the same method as in Example 1, and the weight average molecular weight of the aldehyde-containing aliphatic polyester was found to be 2008.

[0049] 2. Interpenetrating network hydrogel

[0050] Synthesis of interpenetrating network hydrogels

[0051] Take 10 g of the above-synthesized aldehyde-containing aliphatic polyester, 0.2 g of 1,4-piperazinediethylamine, 0.3 g of N-(2-aminoethyl)-1,4-piperazinediyldiethylamine, 0.1 g of 3-oxopentanediamine, 0.4 g of tris(2-aminoethyl)amine, 6 g of hydroxyethyl acrylate, 0.3 g of 1,6-hexanediol diacrylate, 0.2 g of neopentyl glycol diacrylate, 0.5 g of 1,4-decanediol diacrylate, 0.05 g of 1-hydroxycyclohexylphenyl ketone and 0.05 g of (2,4,6-trimethylbenzoyl)diphenylphosphine oxide, add them to 15 mL of DMF, mix well, put into a mold, and irradiate at a wavelength of 395 nm and a light intensity of 300 mW / cm 2 After light curing under an LED light, the solution was repeatedly immersed in distilled water for washing and purification, and dried to a constant weight to obtain the pH-responsive interpenetrating network hydrogel.

[0052] In the above reaction, the aldehyde groups on the side chains of the aldehyde-containing aliphatic polyester react with the polyamine compounds to form a Schiff base cross-linked network; at the same time, hydroxyethyl acrylate and the cross-linking agents neopentyl glycol diacrylate and 1,4-decanediol diacrylate are photocured and cross-linked under the action of a photoinitiator to form an interpenetrating network structure with the Schiff base cross-linked network.

[0053] 2.2. Swelling rate of pH-responsive interpenetrating network hydrogels

[0054] The swelling ratio of the interpenetrating network hydrogel prepared by the method described in Example 1 was 281%.

[0055] 2.3. Tensile strength of pH-responsive interpenetrating network hydrogels

[0056] The elongation of the interpenetrating network hydrogel prepared according to the method described in Example 1 was 157%.

[0057] pH-responsive properties of interpenetrating network hydrogels

[0058] At room temperature, the pH-responsive interpenetrating network hydrogel was taken and immersed in buffer solutions with pH values of 2, 3, 4, 5, 6, 7, and 8, respectively. After swelling equilibrium, the hydrogel was weighed, and the swelling rates at different pH values were calculated.

[0059] At room temperature, the pH-responsive interpenetrating network hydrogel was immersed in buffer solutions with pH values of 2, 3, 4, 5, 6, 7, and 8. After swelling equilibrium, its elongation was measured. The results are shown in Table 2.

[0060] Table 2 Swelling rate and stretching rate of pH-responsive interpenetrating network hydrogels at different pH values

[0061] pH 2 3 4 5 6 7 8 Swelling rate (%) 62 132 197 230 261 277 249 Elongation (%) 52 78 106 143 155 162 151

[0062] The pH-responsive interpenetrating network hydrogel described herein contains a Schiff base formed by aldehyde and amine groups. Under acidic conditions, the Schiff base dissociates, causing the network structure formed by the aldehyde-containing saturated polyester and polyamine compounds to collapse, resulting in a decrease in mechanical properties and significant pH sensitivity. As shown in the table above, the pH-responsive interpenetrating network hydrogel exhibits minimal changes in swelling and elongation under neutral conditions, while significantly decreasing under acidic conditions.

[0063] 3. Drug-loaded pH-responsive interpenetrating network hydrogels

[0064] 3.1. Preparation of drug-loaded interpenetrating network hydrogels

[0065] 2 g of the pH-responsive interpenetrating network hydrogel was soaked in a 0.5 mg / mL curcumin ethanol solution for 72 h, washed with distilled water, and freeze-dried to a constant weight to obtain a drug-loaded pH-responsive interpenetrating network hydrogel.

[0066] 3.2. Drug loading capacity of drug-loaded interpenetrating network hydrogels

[0067] The drug loading capacity of the drug-loaded interpenetrating network hydrogel was detected by the method described in Example 1 and was 5221 ug / g.

[0068] 3.3. Drug Release Behavior of Drug-Loaded Interpenetrating Network Hydrogels

[0069] The drug release behavior of the drug-loaded interpenetrating network hydrogel was tested using the method described in Example 1. The results showed that at a pH of 4.01, the cumulative release rate of doxorubicin after 2 hours was 72.1%. However, under neutral conditions, the cumulative release rate of curcumin after 2 hours was only 38.2%. This indicates that the release rate under acidic conditions is higher than that under neutral conditions. Therefore, the interpenetrating network hydrogel exhibits pH-sensitive drug release properties.

[0070] Example 3

[0071] 1. Synthesis of aldehyde-containing aliphatic polyesters

[0072] Take 10 mmol of diglycolic anhydride, 10 mmol of epoxy acrolein diethyl acetal and 0.01 mmol of zinc acetate, add them to 10 mL of DMF, heat to 60 ° C under nitrogen protection and carry out ring-opening polymerization for 8 hours, cool to room temperature, add into water with a pH of 2, stir, filter the precipitate, and dry to obtain aldehyde-containing aliphatic polyester.

[0073] The obtained aldehyde-containing aliphatic polyester was tested in the same manner as in Example 1. The test results showed that the weight average molecular weight of the aldehyde-containing aliphatic polyester was 997, and PDI was 2.03.

[0074] 2. Interpenetrating hydrogel

[0075] Synthesis of interpenetrating network hydrogels

[0076] Take 10 g of the synthesized aldehyde-containing aliphatic polyester, 0.3 g of 3-oxypentanediamine, 0.2 g of tris(2-aminoethyl)amine, 4 g of hydroxyethyl acrylate, 0.1 g of 1,6-hexanediol diacrylate, 0.4 g of triethylene glycol dimethacrylate and 0.01 g of (2,4,6-trimethylbenzoyl)diphenylphosphine oxide, add them into 5 mL of DMF, mix them evenly, put them into a mold, and irradiate them under a wavelength of 395 nm and a light intensity of 300 mW / cm 2 After light curing under an LED light, the solution was repeatedly immersed in distilled water for washing and purification, and dried to a constant weight to obtain the pH-responsive interpenetrating network hydrogel.

[0077] In the above reaction, the aldehyde groups on the side chains of the aldehyde-containing aliphatic polyester react with the polyamine compounds to form a Schiff base cross-linked network; at the same time, hydroxyethyl acrylate and the cross-linking agents triethylene glycol dimethacrylate and 1,6-hexanediol diacrylate are photocured and cross-linked under the action of a photoinitiator to form an interpenetrating network structure with the Schiff base cross-linked network.

[0078] 2.2. Swelling rate of pH-responsive interpenetrating network hydrogels

[0079] The swelling ratio of the interpenetrating network hydrogel prepared according to the method described in Example 1 was 121%.

[0080] 2.3. Tensile strength of pH-responsive interpenetrating network hydrogels

[0081] The elongation of the interpenetrating network hydrogel prepared according to the method described in Example 1 was 109%.

[0082] pH sensitivity of interpenetrating network hydrogels

[0083] At room temperature, the pH-responsive interpenetrating network hydrogel was taken and immersed in buffer solutions with pH values of 2, 3, 4, 5, 6, 7, and 8, respectively. After swelling equilibrium, the hydrogel was weighed, and the swelling rates at different pH values were calculated.

[0084] At room temperature, the pH-responsive interpenetrating network hydrogel was immersed in buffer solutions with pH values of 2, 3, 4, 5, 6, 7, and 8. After swelling equilibrium, its elongation was measured. The results are shown in Table 3.

[0085] Table 3 Swelling rate and stretching rate of pH-responsive interpenetrating network hydrogels at different pH values

[0086] pH 2 3 4 5 6 7 8 Swelling rate (%) 28 49 63 90 110 118 107 Elongation (%) 21 26 47 78 103 112 99

[0087] The pH-responsive interpenetrating network hydrogel described herein contains a Schiff base formed by aldehyde and amine groups. Under acidic conditions, the Schiff base dissociates, causing the network structure formed by the aldehyde-containing saturated polyester and polyamine compounds to collapse, resulting in a decrease in mechanical properties and significant pH sensitivity. As shown in the table above, the pH-responsive interpenetrating network hydrogel exhibits minimal changes in swelling and elongation under neutral conditions, while significantly decreasing under acidic conditions.

[0088] 3. Drug-loaded pH-responsive interpenetrating network hydrogels

[0089] 3.1. Preparation of drug-loaded interpenetrating network hydrogels

[0090] 2 g of the pH-responsive interpenetrating network hydrogel was soaked in a 0.1 mg / mL aclarubicin ethanol solution for 36 h, washed with distilled water, and freeze-dried to a constant weight to obtain a drug-loaded pH-responsive interpenetrating network hydrogel.

[0091] 3.2. Drug loading capacity of drug-loaded interpenetrating network hydrogels

[0092] The drug loading capacity of the drug-loaded interpenetrating network hydrogel was detected by the method described in Example 1 and was 1017 ug / g.

[0093] 3.3. Drug Release Behavior of Drug-Loaded Interpenetrating Network Hydrogels

[0094] The drug release behavior of the drug-loaded interpenetrating network hydrogel was tested using the method described in Example 1. The results showed that at a pH of 4.01, the cumulative release rate of doxorubicin after 2 hours was 87.9%. Under neutral conditions, however, the cumulative release rate of aclarubicin after 2 hours was only 46.9%. This indicates that the release rate under acidic conditions is higher than that under neutral conditions. Therefore, the interpenetrating network hydrogel exhibits pH-sensitive drug release properties.

[0095] Example 4

[0096] 1. Synthesis of aldehyde-containing aliphatic polyesters

[0097] Take 10 mmol of diglycolic anhydride, 10 mmol of epoxy acrolein diethyl acetal and 0.024 mmol of zinc acetate, add them to 13 mL of DMF, heat to 63 ° C under nitrogen protection and carry out ring-opening polymerization for 9 hours, cool to room temperature, add into water with a pH of 3, stir, filter the precipitate, and dry to obtain aldehyde-containing aliphatic polyester.

[0098] The obtained aldehyde-containing aliphatic polyester was tested using the same method as in Example 1. The test results showed that the weight average molecular weight of the aldehyde-containing aliphatic polyester was 1442, and PDI was 1.61.

[0099] 2. Interpenetrating network hydrogel

[0100] Synthesis of interpenetrating network hydrogels

[0101] Take 10 g of the synthesized aldehyde-containing saturated aliphatic polyester, 0.75 g of tris(2-aminoethyl)amine, 5 g of hydroxyethyl acrylate, 0.85 g of 1,6-hexanediol diacrylate and 0.06 g of (2,4,6-trimethylbenzoyl)diphenylphosphine oxide, add them into 12 mL of DMF, mix them evenly, put them into a mold, and irradiate them under a wavelength of 395 nm and a light intensity of 300 mW / cm 2 After light curing under an LED light, the pH-responsive interpenetrating network hydrogel is obtained by repeatedly soaking, washing, and purification in distilled water and drying to a constant weight.

[0102] In the above reaction, the aldehyde groups on the side chains of the aldehyde-containing aliphatic polyester react with the polyamine compounds to form a Schiff base cross-linked network; at the same time, hydroxyethyl acrylate and the cross-linking agent 1,6-hexanediol diacrylate are photocured and cross-linked under the action of a photoinitiator to form an interpenetrating network structure with the Schiff base cross-linked network.

[0103] 2.2. Swelling rate of pH-responsive interpenetrating network hydrogels

[0104] The swelling ratio of the interpenetrating network hydrogel prepared by the method described in Example 1 was 246%.

[0105] 2.3. Tensile strength of pH-responsive interpenetrating network hydrogels

[0106] The elongation of the interpenetrating network hydrogel prepared according to the method described in Example 1 was 169%.

[0107] pH sensitivity of interpenetrating network hydrogels

[0108] At room temperature, the pH-responsive interpenetrating network hydrogel was taken and immersed in buffer solutions with pH values of 2, 3, 4, 5, 6, 7, and 8, respectively. After swelling equilibrium, the hydrogel was weighed, and the swelling rates at different pH values were calculated.

[0109] At room temperature, the pH-responsive interpenetrating network hydrogel was immersed in buffer solutions with pH values of 2, 3, 4, 5, 6, 7, and 8. After swelling equilibrium, its elongation was measured. The results are shown in Table 4.

[0110] Table 4 Swelling rate and stretching rate of pH-responsive interpenetrating network hydrogels at different pH values

[0111] pH 2 3 4 5 6 7 8 Swelling rate (%) 78 120 153 222 249 263 255 Elongation (%) 56 67 74 127 144 158 150

[0112] The pH-responsive interpenetrating network hydrogel described herein contains a Schiff base formed by aldehyde and amine groups. Under acidic conditions, the Schiff base dissociates, causing the network structure formed by the aldehyde-containing saturated polyester and polyamine compounds to collapse, resulting in a decrease in mechanical properties and significant pH sensitivity. As shown in the table above, the pH-responsive interpenetrating network hydrogel exhibits minimal changes in swelling and elongation under neutral conditions, while significantly decreasing under acidic conditions.

[0113] 3. Drug-loaded pH-responsive interpenetrating network hydrogels

[0114] 3.1. Preparation of drug-loaded interpenetrating network hydrogels

[0115] 2 g of the pH-responsive interpenetrating network hydrogel was soaked in a 0.15 mg / mL pyrarubicin ethanol solution for 48 h, washed with distilled water, and freeze-dried to a constant weight to obtain a drug-loaded pH-responsive interpenetrating network hydrogel.

[0116] 3.2. Drug loading capacity of drug-loaded interpenetrating network hydrogels

[0117] The drug loading capacity of the drug-loaded interpenetrating network hydrogel was measured using the method described in Example 1, and the drug loading capacity was found to be 1667 μg / g.

[0118] 3.3. Drug Release Behavior of Drug-Loaded Interpenetrating Network Hydrogels

[0119] The drug release behavior of the drug-loaded interpenetrating network hydrogel was tested using the method described in Example 1. The results showed that at a pH of 4.01, the cumulative release rate of doxorubicin after 6 hours was 83.1%. Under neutral conditions, however, the cumulative release rate of pyrarubicin after 2 hours was only 41.1%. This indicates that the release rate under acidic conditions is higher than that under neutral conditions. Therefore, the interpenetrating network hydrogel exhibits pH-sensitive drug release properties.

[0120] Example 5

[0121] 1. Synthesis of aldehyde-based aliphatic polyesters

[0122] Take 10 mmol of diglycolic anhydride, 10 mmol of epoxy acrolein diethyl acetal and 0.035 mmol of zinc acetate, add them to 12 mL of DMF, heat to 64 ° C under nitrogen protection and carry out ring-opening polymerization for 11 hours, cool to room temperature, add into water with a pH of 3, stir, filter the precipitate, and dry to obtain aldehyde aliphatic polyester.

[0123] The obtained aldehyde-containing aliphatic polyester was tested using the same method as in Example 1. The test results showed that the weight average molecular weight of the aldehyde-containing aliphatic polyester was 1661, and PDI was 1.83.

[0124] 2. Interpenetrating network hydrogel

[0125] Synthesis of interpenetrating network hydrogels

[0126] Take 10 g of the synthesized aldehyde-containing saturated aliphatic polyester, 0.8 g of tris(2-aminoethyl)amine, 5.5 g of hydroxyethyl acrylate, 0.7 g of 1,6-hexanediol diacrylate and 0.055 g of (2,4,6-trimethylbenzoyl)diphenylphosphine oxide, add them into 15 mL of DMF, mix them evenly, put them into a mold, and irradiate them under a wavelength of 395 nm and a light intensity of 300 mW / cm 2 After light curing under an LED light, the solution was repeatedly immersed in distilled water for washing and purification, and dried to a constant weight to obtain the pH-responsive interpenetrating network hydrogel.

[0127] In the above reaction, the aldehyde groups on the side chains of the aldehyde-containing aliphatic polyester react with the polyamine compounds to form a Schiff base cross-linked network; at the same time, hydroxyethyl acrylate and the cross-linking agent 1,6-hexanediol diacrylate are photocured and cross-linked under the action of a photoinitiator to form an interpenetrating network structure with the Schiff base cross-linked network.

[0128] 2.2. Swelling rate of pH-responsive interpenetrating network hydrogels

[0129] The swelling rate of the interpenetrating network hydrogel prepared by the method described in Example 1 was 213%.

[0130] 2.3. Tensile strength of pH-responsive interpenetrating network hydrogels

[0131] The elongation of the interpenetrating network hydrogel prepared according to the method described in Example 1 was 145%.

[0132] pH sensitivity of interpenetrating network hydrogels

[0133] At room temperature, the pH-responsive interpenetrating network hydrogel was taken and immersed in buffer solutions with pH values of 2, 3, 4, 5, 6, 7, and 8, respectively. After swelling equilibrium, the hydrogel was weighed, and the swelling rates at different pH values were calculated.

[0134] At room temperature, the pH-responsive interpenetrating network hydrogel was immersed in buffer solutions with pH values of 2, 3, 4, 5, 6, 7, and 8. After swelling equilibrium, its elongation was measured. The results are shown in Table 5.

[0135] Table 5 Swelling rate and stretching rate of pH-responsive interpenetrating network hydrogels at different pH values

[0136] pH 2 3 4 5 6 7 8 Swelling rate (%) 67 76 166 203 211 220 217 Elongation (%) 46 77 95 129 138 151 147

[0137] The pH-responsive interpenetrating network hydrogel described herein contains a Schiff base formed by aldehyde and amine groups. Under acidic conditions, the Schiff base dissociates, causing the network structure formed by the aldehyde-containing saturated polyester and polyamine compounds to collapse, resulting in a decrease in mechanical properties and significant pH sensitivity. As shown in the table above, the pH-responsive interpenetrating network hydrogel exhibits minimal changes in swelling and elongation under neutral conditions, while significantly decreasing under acidic conditions.

[0138] 3. Drug-loaded pH-responsive interpenetrating network hydrogels

[0139] 3.1. Preparation of drug-loaded interpenetrating network hydrogels

[0140] 2 g of the pH-responsive interpenetrating network hydrogel was soaked in a 0.35 mg / mL doxorubicin ethanol solution for 48 h, washed with distilled water, and freeze-dried to a constant weight to obtain a drug-loaded pH-responsive interpenetrating network hydrogel.

[0141] 3.2. Drug loading capacity of drug-loaded interpenetrating network hydrogels

[0142] The drug loading capacity of the drug-loaded interpenetrating network hydrogel was detected by the method described in Example 1 and was 3482 ug / g.

[0143] 3.3. Drug Release Behavior of Drug-Loaded Interpenetrating Network Hydrogels

[0144] The drug release behavior of the drug-loaded interpenetrating network hydrogel was tested using the method described in Example 1. The results showed that at a pH of 4.01, the cumulative release rate of doxorubicin after 6 hours was 80.8%. Under neutral conditions, however, the cumulative release rate of doxorubicin after 2 hours was only 38.9%. This indicates that the release rate under acidic conditions is higher than that under neutral conditions. Therefore, the interpenetrating network hydrogel exhibits pH-sensitive drug release properties.

[0145] Example 6 (Control Experiment)

[0146] Control experiment 1

[0147] 1. Reference substance 1 was prepared as follows:

[0148] Take 10 g of the aldehyde-containing aliphatic polyester described in Example 1 and 0.06 g of diethylenetriamine, add them to 5 mL of DMF, mix them evenly, react at room temperature for 12 hours, then repeatedly soak and wash with distilled water, purify, and dry to constant weight to obtain a cross-linked aldehyde-containing aliphatic polyester.

[0149] 2. Reference substance 2 was prepared as follows:

[0150] Take 5.5g of hydroxyethyl acrylate, 0.065g of triethylene glycol dimethacrylate and 0.07g of 1-hydroxycyclohexyl phenyl ketone and add them into 5mL of DMF. 2 The product was cured under an LED light, then repeatedly soaked and washed with distilled water, purified, and then dried to a constant weight to obtain cross-linked polyhydroxyethyl acrylate.

[0151] 3. The sample is the interpenetrating network hydrogel prepared in Example 1.

[0152] 4. Detection Methods

[0153] The swelling ratio and elongation of the samples and reference products 1 and 2 were measured using the method described in Example 1. The results are shown in Table 6.

[0154] Table 6 Comparison of swelling ratio and elongation

[0155] Swelling rate (%) Elongation (%) sample 225 183 Reference substance 1 53 62 Reference substance 2 74 56

[0156] As can be seen from Table 13, the swelling ratio and elongation of the sample are significantly better than those of the reference products 1 and 2.

[0157] Control experiment 2

[0158] The sample in this comparative experiment is the dry interpenetrating network hydrogel prepared by the method described in Example 1, and the reference substance 3 is the polyglutamic acid / hyaluronic acid-based interpenetrating network medical hydrogel prepared according to the method described in comparative document 1 (Fan Zhiping, Cheng Ping, Ding Zhuang, Zhao Yanna, Li Jun, Liu Min, Sangeeta Prakash, Zhang Demeng, Wang Wenli, Wang Zhengping, Han Jun, Preparation and Characterization of pH-sensitive polyglutamic acid / hyaluronic acid-based interpenetrating network medical hydrogel, Polymer Bulletin, 2020, 02, 23). The reference substance 4 is the PVA / CS interpenetrating network hydrogel prepared according to the method described in comparative document 2 (Shao Xue, Liang Tianyu, Ding Keyi, Liu Jun, Study on the Swelling and Drug Loading and Release Performance of pH-sensitive Polyvinyl Alcohol / Chitosan Interpenetrating Network Hydrogel, Journal of Southwest University for Nationalities (Natural Science Edition). 2015, 41(05), 582).

[0159] 3. Elongation comparison

[0160] The elongation of the samples and reference products 3 and 4 was measured using the method described in Example 1. The results are shown in Table 7.

[0161] Table 7 Comparison of swelling ratio and elongation

[0162] Elongation (%) sample 183 Reference substance 3 102 Reference substance 4 97

[0163] As can be seen from Table 7, the elongation of the sample is significantly better than that of the reference products 3 and 4.

Claims

1. A pH-responsive interpenetrating network hydrogel, comprising, by weight, an aldehyde-containing aliphatic polyester, a polyamine compound in an amount of 0.05 to 0.1 times the weight of the aldehyde-containing aliphatic polyester, 0.4 to 0.6 times the weight of the aldehyde-containing aliphatic polyester in an amount of hydroxyethyl acrylate, 0.05 to 0.1 times the weight of the aldehyde-containing aliphatic polyester in an amount of a crosslinker acrylate, and 0.005 to 0.01 times the weight of the aldehyde-containing aliphatic polyester in an amount of a photoinitiator; wherein: The aldehyde-containing aliphatic polyester is prepared by the following method: diglycolic anhydride, epoxy acrolein diethanol acetal, and zinc acetate are dissolved in DMF at a molar ratio of diglycolic anhydride: epoxy acrolein diethanol acetal: zinc acetate = 1:1:0.001-0.005, the mixture is heated to 60-65°C under nitrogen protection for ring-opening polymerization for 8-12 hours, the mixture is cooled to room temperature, the mixture is added to water with a pH of 2-4, and the precipitate is collected to obtain the aldehyde-containing aliphatic polyester; the aldehyde-containing aliphatic polyester has a network structure and a weight-average molecular weight of 1000-2000; The crosslinking agent acrylate is one or more of triethylene glycol dimethacrylate, 1,6-hexanediol diacrylate, neopentyl glycol diacrylate and 1,4-decanediol diacrylate; The photoinitiator is 1-hydroxycyclohexyl phenyl ketone and / or (2,4,6-trimethylbenzoyl) diphenyl phosphine oxide; The polyamine compound is one or more of 1,4-piperazinediethylamine, N-(2-aminoethyl)-1,4-piperazinediyldiethylamine, 3-oxopentanediamine, diethylenetriamine, triethylenetetramine, and tris(2-aminoethyl)amine.

2. The pH-responsive interpenetrating network hydrogel according to claim 1, wherein the hydrogel is prepared by: adding the aldehyde-containing aliphatic polyester, polyamine compound, hydroxyethyl acrylate, crosslinking agent acrylate and photoinitiator to DMF obtained separately, mixing them uniformly; and irradiating the solution at a wavelength of 395 nm and a light intensity of 300 mW / cm 2 The solution was cured under an LED light; then it was repeatedly soaked and washed with distilled water, purified, and dried to a constant weight to obtain the pH-responsive interpenetrating network hydrogel.

3. An anti-tumor preparation, which is composed of the pH-responsive interpenetrating network hydrogel according to claim 1 and an anti-tumor drug in an amount of 0.1 to 0.5% by weight of the pH-responsive interpenetrating network hydrogel; wherein the anti-tumor drug is doxorubicin, curcumin, aclarubicin or pyrarubicin.

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