In-situ polymerization hydrogel with pH responsiveness as well as preparation method and application thereof

Abstract

The invention provides in-situ polymerization hydrogel with pH responsiveness and a preparation method and application thereof, and belongs to the technical field of hydrogel, the in-situ polymerization hydrogel is obtained by in-situ polymerization of a component A and a component B. The component A comprises a block copolymer, a polypropylene glycol acrylate monomer and a reducing agent, the block copolymer is prepared from the following raw materials: sulfadimidine containing hydroxyl, polypropylene glycol and isocyanate; the component B is prepared from a contrast agent and an oxidizing agent; the specific component A and the specific component B are selected for matching, so that the obtained in-situ polymerization hydrogel has the pH response characteristic, secondary pH response gelling can be carried out in weak acid blood vessels around tumors, deeper and more complete embolism of the blood vessels is further achieved, meanwhile, the in-situ polymerization hydrogel is not prone to hydrolysis, and the in-situ polymerization hydrogel can be used for in-situ embolism of the blood vessels. The blood vessel embolism time length under different embolism requirements can be better met, operation is convenient and time-saving, and important research significance is achieved.

Description

Technical Field

[0001] The invention belongs to the technical field of hydrogels, and in particular relates to an in-situ polymerization hydrogel with pH responsiveness, a preparation method and an application thereof. Background Art

[0002] Transcatheter arterial chemoembolization (TACE) is the main treatment for inoperable liver cancer. However, due to the heterogeneity of liver cancer, TACE also has great heterogeneity. Therefore, how to achieve the most minimally invasive, precise, safe and efficient interventional method to reduce patient complications and achieve better treatment effects is a hot topic in the current interventional treatment of liver cancer.

[0003] Currently, the most common intravascular embolic materials can be divided into two categories: solid embolic materials and liquid embolic materials. Solid embolic materials can be roughly divided into granular embolic materials and mechanical embolic materials. Among them, granular embolic materials can be divided into spherical particles and non-spherical particles. However, both spherical particles and non-spherical particles often face the problem of low embolization degree and poor embolization effect. The reason is that the size of solid embolic particles is often uneven, and they cannot completely and uniformly adhere to the vascular wall in the blood vessel to completely block the blood flow, which leads to limited inhibitory effect on tumor growth. Liquid embolic materials mainly include iodized oil, n-butyl-2-cyanoacrylate (NBCA), etc. Among them, iodized oil is commonly used for embolic release of drugs in current applications. Iodized oil emulsion can enter tumor tissue (ultra-peripheral embolization), but iodized oil emulsion cannot embolize blood vessels and tumor tissue for a long time. It needs to be combined with other embolic materials. Microspheres or particles of different particle sizes are selected according to the diameter of tumor blood vessels. Multiple embolizations are performed from small to large particle sizes. The operation process is complicated and time-consuming. In addition, the recanalization speed of iodized oil embolization in blood vessels is relatively fast, but it still cannot achieve the expected effect. The solvents and products selected in the application process of NBCA are often harmful to the human body, and the operator is required to have rich professional experience. Otherwise, if the operation is improper, the head of the delivery catheter is easy to stick to the inside of the tumor, leading to adverse consequences.

[0004] Therefore, in order to solve the above problems, it is urgent to develop a liquid embolic material that can enter the tumor tissue like iodized oil emulsion, and can also achieve long-term embolization of tumor blood vessels by other embolic materials, and is easy to operate and time-saving. Hydrogel is a form formed by the cross-linked network of hydrophilic polymers swelling with water. It is a combination of a small amount of hydrophilic macromolecules and a large amount of water. The moderate physical or chemical cross-linking between the hydrophilic macromolecules can maintain the solid structure of the hydrogel, so that the hydrogel can be used as a liquid embolic agent.

[0005] At present, reports on the use of hydrogels for transcatheter embolization mainly focus on the use of temperature-sensitive and chemically cross-linked types. For example, CN114870064A discloses a photocurable composite hydrogel containing a contrast agent and a method for preparing and using the same; it includes: a sodium alginate solution, a contrast agent, and a sodium alginate solution of a certain concentration obtained by modifying the sodium alginate with a suitable RX modifier, which can be used for the dual effects of ionic crosslinking and photo-induced free radical crosslinking, and can ensure that the contrast agent is uniformly mixed in the solid gel after crosslinking and curing, and avoid the uneven dispersion of contrast properties causing the strength of the sodium alginate material to decrease; the composite gel provided by the invention can be used for minimally invasive interventional embolization, etc., and can effectively achieve the filling of aneurysm or embolic lesion tissue and blood vessels, avoid the problems of tumor recanalization, rebleeding and rupture caused by incomplete filling, and have high safety; however, the chemical crosslinking system has certain limitations, including the complex and technology-dependent procedures caused by the two materials. If the crosslinking time cannot be accurately controlled, it will cause the component system to gel prematurely or hydrolyze too quickly, affecting the embolization effect on the blood vessels.

[0006] Embrace Hydrogel Embolic System (Embrace HES) is a commercially available in situ polymerized liquid hydrogel embolic agent used for peripheral arterial embolization of blood-rich tumors such as the liver, kidney and bone, and can also be used for bleeding treatment. Its main components are water and polyethylene glycol, and it is dilution-sensitive. Embrace HES will only coagulate when the concentration is high enough. Therefore, even if a small amount enters the circulatory system, it will not cause ectopic embolism. However, it still has many problems, such as limited restriction on tumor growth and short recanalization time of arterial embolization (human clinical trials found that it is about 1 month). The main reason for this unfavorable factor is that the method of in situ polymerization into hydrogel has some disadvantages. When the monomer concentration is low, the size of the hydrogel particles formed is too small to completely embolize the target blood vessel. When the monomer concentration is high, the cross-linking speed is often too fast, and the gel volume is too large to achieve deep embolism. Ultimately, the gelation in the blood vessel is too uncontrollable.

[0007] Therefore, there is an urgent need to develop an in situ polymerized hydrogel that is pH responsive to deep vascular embolism and long embolism time. Summary of the invention

[0008] In view of the deficiencies in the prior art, the purpose of the present invention is to provide an in situ polymerized hydrogel with pH responsiveness and a preparation method and application thereof. The in situ polymerized hydrogel is obtained by in situ polymerization and has pH responsiveness. It can undergo secondary pH responsive gelation in the weakly acidic blood vessels around the tumor, thereby achieving deeper and more complete embolization of the blood vessels. At the same time, the in situ polymerized hydrogel is not easily hydrolyzed, which is more conducive to adapting the embolization time of the blood vessels under different embolization requirements, and is convenient and time-saving to operate, which has important research significance.

[0009] To achieve this object, the present invention adopts the following technical solutions:

[0010] In a first aspect, the present invention provides an in-situ polymerized hydrogel with pH responsiveness, wherein the pH responsive in-situ polymerized hydrogel is obtained by in-situ polymerization of component A and component B;

[0011] The component A comprises a block copolymer, a polypropylene glycol acrylate monomer and a reducing agent, and the raw materials of the block copolymer comprise hydroxyl-containing sulfadimethazine, polypropylene glycol and isocyanate;

[0012] The B component includes a contrast agent and an oxidizing agent.

[0013] The pH-responsive in-situ polymerized hydrogel provided by the present invention is obtained by in-situ polymerization of component A and component B. Firstly, the component A is defined to include a block copolymer, a polypropylene glycol acrylate monomer and a reducing agent, and further defined to include raw materials of the block copolymer including hydroxyl-containing sulfadimethazine, polypropylene glycol and isocyanate; secondly, the component B is defined to include a contrast agent and an oxidant;

[0014] Specifically, when using the in-situ polymerized hydrogel provided by the present invention, component A and component B need to be mixed together, for example, they can be injected together into the blood vessels around the tumor, and the component A and component B injected into the blood vessels can undergo in-situ polymerization after meeting each other. The specific process is that the reducing agent of component A and the oxidizing agent of component B meet each other and undergo redox reaction to produce an initiator, which then triggers the in-situ polymerization reaction of the polypropylene glycol acrylate monomer in component A to form hydrogel particles with smaller size; in addition, since the raw materials of the block copolymer in component A include hydroxyl-containing sulfadimethoxine, polypropylene glycol and isocyanate, the block copolymer can have excellent pH response characteristics, and the environment changes from weak alkaline (pH When the pH value of the in-situ polymerization hydrogel system is changed to weak acid (pH ≥ 7) and then to weak acid (pH < 7), the block copolymer can quickly change from an ionized state to a deionized state to form a gel. Therefore, when the above-mentioned smaller hydrogel particles reach the blood vessels in the weakly acidic environment around the tumor, the block copolymer can change from an ionized state to a gel state, and form a larger hydrogel particle by secondary gelation to make up for the incomplete gelation of the first in-situ polymerization, thereby achieving a deeper and more complete embolization of the blood vessels, and thus effectively inhibiting the growth of targeted cancer cells and promoting their death. In addition, since the ether group content in the in-situ polymerization hydrogel system provided by the present invention is relatively small, it is more conducive to maintaining its long-term presence in the blood vessels without hydrolysis, and thus can adapt to the embolization time under different embolization requirements.

[0015] Preferably, the mass ratio of component A to component B is 1:(0.5-1.5), for example, 1:0.5, 1:0.7, 1:0.9, 1:1.1, 1:1.3 or 1:1.5, etc.

[0016] Preferably, the temperature of the in-situ polymerization is 20-40°C, for example, 20°C, 22°C, 24°C, 26°C, 28°C, 30°C, 32°C, 34°C, 36°C, 38°C or 40°C.

[0017] Preferably, the in-situ polymerization time is 1 to 10 s, for example, 1 s, 2 s, 3 s, 4 s, 5 s, 6 s, 7 s, 8 s, 9 s or 10 s.

[0018] Preferably, the mass ratio of the block copolymer, the polypropylene glycol acrylate monomer and the reducing agent is 1:(1.5-2):(0.05-0.3), for example, 1:1.5:0.05, 1:1.6:0.1, 1:1.7:0.15, 1:1.8:0.2, 1:1.8:0.25 or 1:2:0.3, etc.

[0019] As a preferred technical solution of the present invention, the mass ratio of the block copolymer, the polypropylene glycol acrylate monomer and the reducing agent in the component A is further limited to 1:(1-2):(0.05-0.3), so that the obtained in situ polymerized hydrogel can have the most excellent gelling effect and pH response characteristics; on the one hand, if the amount of the block copolymer is relatively too high and the amount of the polypropylene glycol acrylate monomer is relatively too low, it is easy to cause the obtained in situ polymerized hydrogel to be overly dependent on pH, and the gel texture is relatively loose, which is easy to produce excessive uncertainty, and it is likely to cause incomplete embolism and reduced gel strength; on the other hand, if the proportion of the block copolymer is relatively too low and the amount of the polypropylene glycol acrylate monomer is relatively high, it is easy to cause the obtained in situ polymerized hydrogel to have poor pH response characteristics and be insensitive to changes in pH value, thereby insufficient effect of secondary supplementary embolism, and unable to achieve the effect of supplementary deep embolism.

[0020] Preferably, the molar ratio of the hydroxyl-containing sulfadimethoxine, polypropylene glycol and isocyanate is 1:(10-20):(11-21), for example, 1:10:11, 1:11:12, 1:12:13, 1:13:14, 1:14:15, 1:15:16, 1:16:17, 1:17:18, 1:18:19, 1:19:20 or 1:20:21, etc.

[0021] As a preferred technical solution of the present invention, the present invention can change the sensitivity of the obtained in situ polymerized hydrogel to pH by adjusting the ratio of hydroxyl-containing sulfadimethoxine and polypropylene glycol in the raw materials for preparing the block copolymer, thereby effectively controlling the gelation speed, gelation position and gelation strength of the in situ polymerized hydrogel; on the one hand, if the proportion of hydroxyl-containing sulfadimethoxine is relatively too low, it is easy to cause the obtained in situ polymerized hydrogel to be less sensitive to pH changes and insufficient overall pH response ability; on the other hand, if the proportion of the polypropylene glycol is relatively too low, it is easy to cause the obtained in situ polymerized hydrogel to be too loose after pH response gelation, with poor rigidity and too high swelling rate.

[0022] Preferably, the hydroxyl-containing sulfadimethoxine is prepared by the following method, which comprises the following steps:

[0023] (A1) reacting sulfadimethoxine and methacryloyl chloride to obtain an intermediate product (A);

[0024] (A2) reacting the intermediate product (A) obtained in step (A1) with α-thioglycerol to obtain the hydroxyl-containing sulfadimethazine (B).

[0025] In the present invention, the reaction formulas of the above steps (A1) and (A2) are as follows:

[0026]

[0027] Preferably, the molar ratio of sulfamethazine to methacryloyl chloride in step (A1) is 1:(0.8-1.2), for example, 1:0.8, 1:0.9, 1:1, 1:1.1 or 1:1.2.

[0028] Preferably, the reaction temperature in step (A1) is 70-90°C, for example, 70°C, 72°C, 74°C, 76°C, 78°C, 80°C, 82°C, 84°C, 86°C, 88°C or 90°C, etc.

[0029] Preferably, the reaction time of step (A1) is 20 to 30 h, for example, 20 h, 22 h, 24 h, 26 h, 28 h or 30 h.

[0030] Preferably, the molar ratio of the intermediate product to α-thioglycerol in step (A2) is 1:(0.8-1.2), for example, 1:0.8, 1:0.9, 1:1, 1:1.1 or 1:1.2, etc.

[0031] Preferably, the reaction temperature in step (A2) is 45-55°C, for example, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C or 55°C, etc.

[0032] Preferably, the reaction time of step (A2) is 30 to 40 h, for example, 30 h, 32 h, 34 h, 36 h, 38 h or 40 h.

[0033] Preferably, the weight average molecular weight of the polypropylene glycol is 800-5000, for example, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500 or 5000.

[0034] Preferably, the isocyanate comprises hexamethylene diisocyanate.

[0035] Preferably, the raw materials for preparing the block copolymer further include a catalyst.

[0036] Preferably, the catalyst comprises dibutyltin dilaurate.

[0037] Preferably, the reducing agent comprises ferrous gluconate (FeG).

[0038] Preferably, the weight average molecular weight of the polypropylene glycol acrylate monomer is 800 to 5000, for example, 800, 1000, 2000, 3000, 4000 or 5000.

[0039] Preferably, the mass ratio of the contrast agent to the oxidant is 10:(0.01-0.05), for example, 10:0.01, 10:0.015, 10:0.02, 10:0.025, 10:0.03, 10:0.035, 10:0.04, 10:0.045 or 10:0.05, etc.

[0040] Preferably, the contrast agent comprises iopromide 300.

[0041] Preferably, the oxidizing agent comprises tert-butyl hydroperoxide (TBHP).

[0042] In a second aspect, the present invention provides a method for preparing an in situ polymerized hydrogel having pH responsiveness, the preparation method being used to prepare the in situ polymerized hydrogel as described in the first aspect, the preparation method comprising the preparation of component A and the preparation of component B:

[0043] The preparation of the A component comprises: reacting sulfadimethoxine containing a hydroxyl group, polypropylene glycol, isocyanate and optionally a catalyst to obtain a block copolymer; then mixing the obtained block copolymer, polypropylene glycol acrylate monomer and a reducing agent in water to obtain the A component;

[0044] The preparation of the B component includes: mixing a contrast agent and an oxidant in water to obtain the B component.

[0045] In a third aspect, the present invention provides an application method of an in situ polymerized hydrogel with pH responsiveness, the application method comprising: simultaneously injecting component A and component B of the in situ polymerized hydrogel with pH responsiveness as described in the first aspect into a blood vessel to complete the application.

[0046] Preferably, the injection method is injection with a coaxial double-lumen catheter syringe, specifically: placing component A and component B in two lumens of the coaxial double-lumen catheter syringe respectively for push injection.

[0047] In a fourth aspect, the present invention provides an application of an in situ polymerized hydrogel with pH responsiveness, wherein the application comprises using the in situ polymerized hydrogel with pH responsiveness as described in the first aspect as a vascular embolic material.

[0048] Compared with the prior art, the present invention has the following beneficial effects:

[0049] The in-situ polymerized hydrogel with pH responsiveness provided by the present invention is obtained by in-situ polymerization of components A and B, wherein the component A comprises a block copolymer, a polypropylene glycol acrylate monomer and a reducing agent, the raw materials of the block copolymer comprise hydroxyl-containing sulfadimethoxine, polypropylene glycol and isocyanate, and the component B comprises a contrast agent and an oxidant; by selecting the above-mentioned specific components A and B for matching, the hydrogel obtained by in-situ polymerization has pH responsiveness, and secondary pH responsive gelation can be performed in the weakly acidic blood vessels around the tumor to achieve deeper and more complete embolization of the blood vessels. At the same time, the in-situ polymerized hydrogel is not easy to hydrolyze, which is more conducive to adapting the embolization time of the blood vessels under different embolization requirements, and the operation is convenient and time-saving, which has important research significance. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 A physical picture of the in-situ polymerized hydrogel with pH responsiveness provided in Example 1 formed after in-situ polymerization;

[0051] Figure 2 This is a physical picture of the hydrogel formed after the pH-responsive in-situ polymerized hydrogel provided in Example 1 responds to pH. DETAILED DESCRIPTION

[0052] The technical solution of the present invention is further described below by specific implementation methods. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0053] Unless otherwise specified, the materials and equipment involved in the following examples and comparative examples are conventional materials and equipment in the art.

[0054] Example 1

[0055] A pH-responsive in-situ polymerized hydrogel, obtained by in-situ polymerization of component A and component B in a mass ratio of 1:1;

[0056] Wherein, the preparation method of component A comprises the following steps:

[0057] (1) 30 mmol of sulfadimethoxine was dissolved in 10 mL of ethyl acetate, 31 mmol of methacryloyl chloride was added dropwise at 0°C, and the mixture was stirred at 80°C for 24 h. After the reaction was completed, the mixture was filtered, washed, and dried in a vacuum to obtain a white solid, which was the intermediate product;

[0058] (2) 50 mmol of the intermediate product obtained in step (1) and 55 mmol of α-thioglycerol were dissolved in 210 mL of a mixed solvent of anhydrous N,N-dimethylformamide (DMF) and anhydrous ethanol (the volume ratio of the two was 1:1), and the mixture was placed in a single-necked round flask and reacted at 50° C. for 36 hours. After the reaction was completed, the anhydrous DMF and anhydrous ethanol were removed by vacuum evaporation, and the residual product was dissolved in chloroform and precipitated with cold ether. Finally, it was filtered and dried at 25° C. for 48 hours to obtain hydroxyl-containing sulfadimethoxine;

[0059] (3) Weigh 15 mol of polypropylene glycol (weight average molecular weight of 1500) and 0.013 g of dibutyltin dilaurate in a 250 mL three-necked flask, dry under reduced pressure at 100 ° C for 2 h, then add 1 mol of hydroxyl-containing sulfadimethoxine obtained in step (2), dry at 60 ° C for 30 min, then add 70 mL of anhydrous DMF as a solvent, then add 16 mol of HDI, react at 60 ° C for 3 h under continuous magnetic stirring, after the reaction is completed, remove the anhydrous DMF by evaporation under reduced pressure, dissolve the reaction product in tetrahydrofuran, precipitate in cold ether, and finally filter the precipitate and dry at 25 ° C for 48 h to obtain a block copolymer;

[0060] (4) 0.206 g of ferrous gluconate (FeG) powder was dissolved in 19.794 g of pure water to form a 1% FeG solution; 1 g (about 1 mL, containing about 0.01 g FeG) of the FeG solution was weighed and added to a 10 mL reaction bottle, and then 0.15 g of polypropylene glycol acrylate monomer (molecular weight 1500 Da / mol) was added and mixed, and then 0.1 g of the block copolymer obtained in step (3) was added and mixed, and after ultrasonic dispersion treatment for 10 min, the A component was obtained and set aside;

[0061] The preparation method of component B comprises: weighing 0.032 g of tert-butyl hydroperoxide dihydrate and adding it into 11.2 g of iopromide 300 contrast solution to obtain the component B, which is set aside.

[0062] Example 2

[0063] A pH-responsive in-situ polymerized hydrogel, which differs from Example 1 in that the amount of polypropylene glycol acrylate monomer added in step (4) is 0.2 g, and other substances, amounts and preparation methods are the same as those in Example 1.

[0064] Example 3

[0065] A pH-responsive in-situ polymerized hydrogel, which differs from Example 1 in that the amount of polypropylene glycol acrylate monomer added in step (4) is 0.1 g, and other substances, amounts and preparation methods are the same as those in Example 1.

[0066] Example 4

[0067] A pH-responsive in-situ polymerized hydrogel, which differs from Example 1 in that the amount of polypropylene glycol acrylate monomer added in step (4) is 0.4 g, and other substances, amounts and preparation methods are the same as those in Example 1.

[0068] Example 5

[0069] A pH-responsive in-situ polymerized hydrogel, which differs from Example 1 in that the amount of polypropylene glycol added in step (3) is 10 mmol, the amount of HDI used is 11 mol, and other substances, amounts used and preparation methods are the same as those in Example 1.

[0070] Example 6

[0071] A pH-responsive in-situ polymerized hydrogel, which differs from Example 1 in that the amount of polypropylene glycol added in step (3) is 20 mmol, the amount of HDI used is 21 mol, and other substances, amounts used and preparation methods are the same as those in Example 1.

[0072] Comparative Example 1

[0073] An in-situ polymerized hydrogel, which is obtained by in-situ polymerization of component A and component B in a mass ratio of 1:1;

[0074] The preparation method of component A includes: dissolving 0.206g of ferrous gluconate (FeG) powder with 19.794g of pure water into a 1% FeG solution; weighing 1g (about 1mL, containing about 0.01g FeG) of the FeG solution into a 10mL reaction bottle, and then adding 0.1g of polypropylene glycol acrylate monomer (molecular weight 1500Da / mol) to mix, to obtain the component A, for standby use;

[0075] The preparation of the B component includes: weighing 0.032 g of tert-butyl hydroperoxide dihydrate and adding it into 11.2 g of iopromide 300 contrast solution to obtain the B component for standby use.

[0076] Performance Test:

[0077] (1) Appearance: At 25° C., component A and component B of the pH-responsive in situ polymerized hydrogel provided in Example 1 were mixed by push injection at a mass ratio of 1:1 using a coaxial double-lumen microcatheter delivery device. The hydrogel formed after 5 seconds of in situ polymerization is shown in the figure below. Figure 1 As shown;

[0078] Then, one drop of citric acid solution with a pH of 6 was added to the hydrogel formed after in-situ polymerization and shaken well. The hydrogel formed after 1 hour was as shown in the figure below. Figure 2 As shown;

[0079] from Figure 1 and Figure 2 The comparison shows that the hydrogel formed after 5s in situ polymerization still contains a certain amount of liquid ( Figure 1 ), and the whole gel system becomes compact after adding pH=6 citric acid solution for 1 hour ( Figure 2 ), which is due to the secondary gelation effect of the in situ polymerized hydrogel provided in Example 1 under acidic pH, indicating that the in situ polymerized hydrogel provided in Example 1 has excellent pH response characteristics.

[0080] Similarly, the above method was used to observe the in-situ polymerized hydrogels provided in Examples 1 to 6 and Comparative Example 1, and the results are summarized in Table 1;

[0081] The criteria for judging the in-situ polymerization gelation and pH response gelation are as follows: if the in-situ polymerization can form a hydrogel within 5 seconds, and the hydrogel formed is relatively compact, the in-situ polymerization gelation is excellent; if the in-situ polymerization can form a hydrogel within 5 seconds, but the part of the hydrogel formed is relatively loose, the in-situ polymerization gelation is good; if the in-situ polymerization cannot form a hydrogel within 5 seconds, the in-situ polymerization gelation is poor;

[0082] If there is no liquid in the entire hydrogel system 1 hour after the addition of citric acid solution, and the gel becomes very tight, the pH response gelation is excellent; if there is no liquid in the entire hydrogel system 1 hour after the addition of citric acid solution, but the firmness of the gel part is low, the pH response gelation is good; if there is still liquid in the hydrogel system 1 hour after the addition of citric acid solution, the pH response gelation is poor.

[0083] (2) Tensile strength and elongation at break: At 25°C, the components A and B in the in-situ polymerized hydrogels provided in Examples 1 to 6 and Comparative Example 1 were mixed in a stretching mold at a mass ratio of 1:1. After in-situ polymerization for 1 minute, 1 drop of citric acid solution with a pH of 6 was added and shaken. After 1 hour, a hydrogel sample with a length × width × thickness = 3 × 1 × 0.5 cm was obtained. After wiping off the liquid on the surface of the hydrogel sample, a universal testing machine was used for testing at a tensile speed of 5 mm / min.

[0084] (3) Storage modulus: At 25° C., component A and component B of the in-situ polymerized hydrogels provided in Examples 1 to 6 and Comparative Example 1 were mixed in a polytetrafluoroethylene mold (diameter 2.5 cm, thickness 3 mm) at a mass ratio of 1:1. After in-situ polymerization for 1 min, 1 drop of citric acid solution with a pH of 6 was added thereto and shaken well. After 1 h, mineral oil was applied to both surfaces of the obtained hydrogel to prevent water evaporation during the test. The hydrogel was then placed on the test platform of a rheometer, a 20 mm plate was selected, and a cylindrical sample (diameter 25 mm, thickness 3 mm) was placed on the bottom plate. The storage modulus of the hydrogel was monitored at a fixed shear strain of 0.2% at 37° C. at a frequency of 0.1 to 10 Hz.

[0085] Table 1

[0086]

[0087] From the data in Table 1, we can see that:

[0088] The in situ polymerization gelation of the pH-responsive in situ polymerization hydrogels provided in Examples 1 to 6 is excellent or good as is the pH-responsive gelation, and has higher tensile strength, elongation at break and storage modulus; further, it can be explained that the pH-responsive in situ polymerization hydrogels provided in Examples 1 to 6 have a stronger ability to maintain elasticity and restore shape in response to blood flushing and vascular contraction after intravascular embolism gelation; in comparison, the in situ polymerization hydrogel provided in Comparative Example 1 does not have pH responsiveness because no block copolymer is added, resulting in lower tensile strength, elongation at break and storage modulus of the final hydrogel.

[0089] By comparing the data of Example 1 and Examples 2 to 4, it can be seen that the amount of polypropylene glycol acrylate monomer added will directly affect the in-situ polymerization gelation and the pH response gelation. If the added mass ratio is too low (Example 3), the in-situ polymerization gelation and the pH response gelation will both deteriorate, thereby reducing the tensile strength of the final hydrogel. If the added mass ratio is too high (Example 4), the pH response gelation will deteriorate, which will also reduce the tensile strength of the final hydrogel. This shows that the amount of polypropylene glycol acrylate monomer should not be too low or too high.

[0090] Finally, by comparing the data of Example 1 and Examples 5 to 6, it can be seen that the dosage of hydroxyl-containing sulfadimethoxine should not be too low or too high. Too low dosage will lead to poor pH response ability of the block copolymer and inability to achieve complete embolization, while too high dosage will lead to insufficient polypropylene glycol segments and insufficient compatibility with the polypropylene glycol in situ polymerized in Example 1 (step 4). Too low or too high dosage will lead to poor pH response gelation, thereby causing a decrease in the tensile strength of the final hydrogel.

[0091] The applicant declares that the present invention illustrates a pH-responsive in-situ polymerized hydrogel and its application and application method through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A pH-responsive in-situ polymerized hydrogel, characterized in that: The pH-responsive in-situ polymerized hydrogel is obtained by in-situ polymerization of component A and component B; The component A comprises a block copolymer, a polypropylene glycol acrylate monomer and a reducing agent, and the raw materials of the block copolymer comprise hydroxyl-containing sulfadimethazine, polypropylene glycol and isocyanate; The B component includes a contrast agent and an oxidizing agent.

2. The pH-responsive in-situ polymerized hydrogel according to claim 1, characterized in that: The mass ratio of the component A to the component B is 1:(0.5-1.5).

3. The pH-responsive in-situ polymerized hydrogel according to claim 1, characterized in that: The mass ratio of the block copolymer, the polypropylene glycol acrylate monomer and the reducing agent is 1:(1.5-2):(0.05-0.3).

4. The pH-responsive in-situ polymerized hydrogel according to claim 1, characterized in that The molar ratio of the hydroxyl-containing sulfadimethoxine, polypropylene glycol and isocyanate is 1:(10-20):(11-21).

5. The pH-responsive in-situ polymerized hydrogel according to claim 1, characterized in that: The weight average molecular weight of the polypropylene glycol is 800-5000.

6. The pH-responsive in-situ polymerized hydrogel according to claim 1, characterized in that: The reducing agent includes ferrous gluconate.

7. The pH-responsive in-situ polymerized hydrogel according to claim 1, characterized in that The mass ratio of the contrast agent to the oxidant is 10:(0.01-0.05).

8. A method for preparing a pH-responsive in-situ polymerized hydrogel, characterized in that: The preparation method is used to prepare the pH-responsive in-situ polymerization hydrogel according to any one of claims 1 to 7, comprising the preparation of component A and the preparation of component B: The preparation of the A component includes: reacting sulfadimethoxine containing a hydroxyl group, polypropylene glycol and isocyanate to obtain a block copolymer; and then mixing the obtained block copolymer, polypropylene glycol acrylate monomer and a reducing agent in water to obtain the A component; The preparation of the B component includes: mixing a contrast agent and an oxidant in water to obtain the B component.

9. A method for applying a pH-responsive in-situ polymerized hydrogel, characterized in that: The application method comprises: injecting component A and component B of the pH-responsive in-situ polymerized hydrogel as claimed in any one of claims 1 to 7 into a blood vessel to complete the application of the in-situ polymerized hydrogel.

10. An application of an in-situ polymerized hydrogel with pH responsiveness, characterized in that: The application includes using the pH-responsive in-situ polymerized hydrogel as claimed in any one of claims 1 to 7 as a vascular embolization material.

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