Composite gel with ROS (reactive oxygen species) and pH (potential of hydrogen) dual responsiveness as well as preparation method and application of composite gel

Abstract

The invention discloses composite gel with ROS and pH dual responsiveness and a preparation method and application thereof.The preparation method comprises the steps that gold nanoparticles are prepared, gold nanostars GNS grow, a surfactant and biguanide drugs are added to obtain drug-loaded gold nanostars GM, a metal organic framework is introduced to obtain drug-loaded nanoparticles GMZ of a core-shell structure, and the composite gel is prepared. And reacting with a TSPBA solution, an astaxanthin solution and a polyvinyl alcohol PVA solution for crosslinking to obtain the ROS and pH dual responsive composite gel. According to the invention, the gold nanostars are used as a photosensitizer to construct the multifunctional composite gel, and the metal organic framework structure degrades under a slightly acidic condition of a psoriasis epithelium microenvironment to release released zinc ions, so that the gel is endowed with various treatment effects, excellent photo-thermal treatment performance and controlled release performance of the zinc ions and drugs. The gel has ROS responsiveness, can remove excessive ROS in a psoriasis microenvironment, and realizes the treatment of oxidation resistance, inflammation resistance and keratinocyte proliferation inhibition of psoriasis by combining with a nano drug delivery system.

Description

Technical Field

[0001] The present invention belongs to the gel delivery system, and relates to a composite gel with dual responsiveness to ROS and pH, its preparation method and use, and specifically relates to a synthesis method of a multifunctional composite gel with dual responsiveness to ROS and pH having ROS scavenging and anti-inflammatory and antioxidant effects, and its application in the treatment of psoriasis. Background Art

[0002] Autoimmune diseases are diseases in which the body's immune system functions abnormally, leading to the body attacking its own tissues. The occurrence of autoimmune diseases can lead to chronic inflammatory diseases. Psoriasis is a type of chronic inflammatory skin disease, which mainly shows silver scales, erythema, increased thickness and plaque formation morphologically, and epidermal hyperplasia, dermal angiogenesis and dermal lymphocyte infiltration pathologically. Although the cause of psoriasis is not yet clear, genetics, environment, immune system disorders, etc. are all related to the occurrence of psoriasis. Among them, oxidative stress caused by the imbalance of the body's oxidation and antioxidant systems is also one of the main mechanisms of psoriasis onset, and reactive oxygen species (ROS) are the main cause of oxidative stress.

[0003] ROS mainly includes molecular oxygen (O2), superoxide anion (·O 2- )), hydrogen peroxide (H2O2), hydroxyl radical (·OH), peroxynitrite (ONOO - )), and hypochlorous acid (HOCl), etc. When ROS is overproduced or scavenged insufficiently, it can lead to oxidative stress, causing changes in metabolism, signal transduction disorders (such as the NF-κB signaling pathway), and biomolecular damage to lipids, proteins and DNA, which can lead to lesions in cell and tissue functions. To cope with oxidative stress, organisms are equipped with effective defense mechanisms, mainly the oxidation and antioxidant systems. The imbalance of this system may lead to skin diseases such as psoriasis. At the same time, through exploration, it has been found that there is abnormal release and accumulation of ROS in the skin lesions of psoriasis patients; during psoriasis, abnormal activation of tumor necrosis factor (TNFα) induces keratinocytes and fibroblasts to release ROS. Neutrophils infiltrate the epidermis and form Munro microabscesses, which produce a large amount of ROS. The abnormal release and accumulation of ROS in these cells cause the body to be in a redox imbalance state, ultimately leading to oxidative stress. In short, oxidative stress caused by excessive ROS leads to redox imbalance in the body, which in turn leads to the occurrence of psoriasis. Therefore, antioxidant is considered an effective way to treat psoriasis.

[0004] Currently, the treatment of psoriasis mainly includes drug therapy, physical therapy, and psychological therapy, etc. Among them, drug therapy can use a variety of drugs including traditional Chinese medicine and natural active ingredients, small molecule drugs, and biological inhibitors, such as corticosteroids, vitamin D3 derivatives, calcineurin inhibitors, retinoids, dithranol, methotrexate, etc. However, drug therapy often has problems such as limited efficacy, obvious local adverse reactions, and low patient compliance. Physical therapy can include long-wave ultraviolet light (UVA), photochemotherapy (PUVA), and photothermal therapy (PTT), etc. In the actual application process, physical therapy is often accompanied by some side effects. Such as sunburn, photoaging, etc. that occur in long-wave ultraviolet light therapy. There are also problems in other physical therapy methods such as a large number of treatment times and long duration, which increase the burden on patients. In addition, due to the long course and easy recurrence of psoriasis, it often brings psychological pressure to patients, and psychological factors may also affect the development of the disease. Therefore, psychological therapy also has important significance in the treatment of psoriasis. Common ones include cognitive behavioral therapy, supportive psychotherapy, and biofeedback therapy. Although psychological therapy is generally safe and effective, it still cannot replace drug therapy and is greatly affected by patient differences, and the treatment effect is closely related to patient cooperation.

[0005] Therefore, a new way is needed to improve the treatment effect of psoriasis. Summary of the Invention

[0006] The purpose of the present invention is to provide a ROS and pH dual-responsive composite gel with ROS scavenging and anti-inflammatory and antioxidant effects, a preparation method and uses, aiming at the deficiencies of the prior art. By loading astaxanthin in the gel, the deficiencies of astaxanthin (ATX) such as poor solubility and easy oxidation are overcome. The synthesized gel largely avoids the adverse reactions of drug therapy, reduces the burden brought by physical therapy to patients, and is more effective than psychological therapy. By scavenging reactive oxygen species, inhibiting the transcriptional activity of NF-κB, and regulating the expression of TNFα, IL-23, IL-6, IL-8, and IL-1β, the treatment of psoriasis is realized.

[0007] In the first aspect, the present invention provides a preparation method of a composite gel with ROS and pH dual responsiveness, including the following steps:

[0008] Step (1), under stirring conditions, add a reducing agent to the boiling chloroauric acid solution, and react the solution for 10 - 20 min under boiling conditions, stop heating, and filter with a nitrocellulose membrane after the solution cools to room temperature to obtain gold nanoparticles;

[0009] Preferably, the diameter of the gold nanoparticles is 10 - 20 nm.

[0010] Step (2), under stirring conditions, successively add the gold nanoparticles obtained in step (1) and the seed growth solution to the chloroauric acid solution to prepare gold nanorods (GNS);

[0011] Preferably, the diameter of the GNS is 80 - 115 nm;

[0012] Preferably, the seed growth solution is hydrochloric acid, silver nitrate and ascorbic acid.

[0013] Step (3), under stirring conditions, add a surfactant and a biguanide drug to the gold nanorods in step (2) to obtain drug-loaded gold nanorods GM;

[0014] Preferably, the surfactant is cetyltrimethylammonium chloride;

[0015] Preferably, the biguanide drug is metformin hydrochloride;

[0016] Preferably, the diameter of the GM is 100 - 150 nm.

[0017] Step (4), under stirring conditions, mix the 2-methylimidazole solution and the zinc nitrate hexahydrate solution to prepare an aqueous ZIF-8 precursor solution, and then add the drug-loaded gold nanorods obtained in step (3) to obtain drug-loaded nanoparticles GMZ with a core-shell structure;

[0018] Preferably, the volume ratio of 2-methylimidazole, zinc nitrate hexahydrate and the drug-loaded gold nanorods is 1:1:(1 - 1.5), more preferably 1:1:1;

[0019] Preferably, the diameter of the GMZ is 180 - 250 nm.

[0020] Step (5), under stirring conditions, add tetramethylpropylenediamine and tetrabromomethylphenylboronic acid to an organic solvent, heat overnight for reaction, add tetrahydrofuran after cooling, and a white precipitate is produced. After drying the precipitate and dissolving it, an active oxygen-responsive crosslinking agent TSPBA solution is obtained; wherein the mass ratio of tetramethylpropylenediamine to tetrabromomethylphenylboronic acid is 1:(1 - 5), and the volume ratio of the organic solvent to tetrahydrofuran is 1:(1 - 10).

[0021] Preferably, the organic solvent is dimethylformamide.

[0022] Preferably, the heating condition is 60 - 65 °C, more preferably 60 °C.

[0023] Step (6), under stirring conditions, mix the TSPBA solution (5% aqueous solution), the suspension of GMZ, and the astaxanthin solution uniformly and crosslink with the polyvinyl alcohol PVA solution to obtain the composite gel with dual ROS and pH responsiveness.

[0024] Preferably, the mass percentage concentration of the TSPBA solution is 5-7%, the final concentration of the GMZ suspension is 50-60 ppm, the final concentration of the astaxanthin solution is 20-30 μg / mL, and the volume ratio of the PVA solution to the TSPBA solution is 1:(0.25-1).

[0025] The second object of the present invention is to provide a composite gel with dual responsiveness to ROS and pH, which is prepared by the above method.

[0026] The third object of the present invention is to provide the application of the above composite gel with dual responsiveness to ROS and pH in the preparation of a psoriasis treatment preparation.

[0027] The composite gel with dual responsiveness to ROS and pH obtained in the present invention collapses at high ROS content in the psoriasis lesion site, releasing ATX and drug-loaded nanoparticles. ATX acts as an antioxidant to scavenge ROS and reduce the production of inflammatory factors. The drug-loaded gold nanospheres act as photosensitizers in the photothermal treatment of psoriasis to produce a photothermal effect to inhibit the growth of keratinocytes and can also release metformin to play an anti-inflammatory role; moreover, the ZIF-8 shell has pH-responsive properties and releases zinc ions in an acidic microenvironment, enhancing the activity of SOD and contributing to the scavenging of ROS in the skin microenvironment.

[0028] The composite gel can scavenge excessive ROS in the psoriasis lesion site due to its own ROS responsiveness and the loading of astaxanthin and drug-loaded nanoparticles. By scavenging excessive ROS, the transcriptional activity of NF-κB is inhibited, thereby inhibiting the production of inflammatory factors.

[0029] The composite gel can release zinc ions and metformin in an acidic microenvironment. Zinc ions can enhance the activity of SOD, enhance the body's antioxidant system, relieve oxidative stress, and treat psoriasis. Metformin can regulate the transcriptional activity of NF-κB in HaCaT cells, thereby reducing the production of inflammatory factors.

[0030] The composite gel carries the photosensitizer gold nanospheres and can be combined with photothermal treatment. Under 1w / cm 2 Irradiation with a 1064 nm laser for five minutes can raise the temperature to about 45°C, inhibiting the proliferation of HaCaT cells.

[0031] The composite gel described in the present invention can be delivered by transdermal administration.

[0032] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0033] The present invention provides a new administration method, and at the same time combines gold nanospheres, biguanide drugs, reactive oxygen-responsive crosslinking agents and astaxanthin, reducing the side effects of drugs and providing a new idea for the treatment of psoriasis; specifically:

[0034] 1. The present invention realizes multi-mechanism collaborative treatment. By integrating four major mechanisms of photothermal therapy, antioxidant, anti-inflammatory, and ion regulation, it achieves collaborative intervention in multiple pathological links (inflammation, oxidative stress, and excessive keratinocyte proliferation) of psoriasis, significantly improving the comprehensive curative effect. Among them, gold nanospheres (GNS) are used as photothermal agents, which locally heat up under near-infrared light excitation. They can not only directly kill excessively proliferating keratinocytes but also enhance the vascular permeability at the lesion site, promoting subsequent drug penetration. In addition, astaxanthin directly scavenges ROS and inhibits inflammatory factors such as TNFα, IL-23, IL-6, IL-8, and IL-1β, and Zn 2+ enhances the endogenous antioxidant defense by activating copper-zinc superoxide dismutase (CuZn SOD), and metformin targets and inhibits the NF-κB-mediated inflammatory pathway, breaking through the limitations of single therapies.

[0035] 2. The present invention utilizes the characteristics of high reactive oxygen species content and slightly acidic microenvironment in the psoriasis microenvironment to achieve targeted release of drugs and Zn 2+ through the ROS-responsive degradation of the hydrogel and the pH-responsive degradation of ZIF-8: Trigger degradation in the high-ROS and slightly acidic microenvironment of psoriasis lesions, reduce the exposure of normal tissues, enhance the treatment accuracy, and reduce systemic toxicity.

[0036] In summary, the present invention first combines gold nanospheres, ZIF-8, biguanide drugs, astaxanthin with ROS-responsive hydrogels to achieve multi-functional integration of the photothermal performance, ion release, drug loading, and environmental response of the material, filling the research gap in this composite gel system and providing a new strategy for psoriasis treatment. Brief Description of the Drawings

[0037] Figure 1 is the ultraviolet-visible near-infrared spectrum of gold nanospheres (GNS) and drug-loaded gold nanospheres (GM).

[0038] Figure 2 is the transmission electron microscope photograph of gold nanoparticles.

[0039] Figure 3 is the transmission electron microscope photograph of drug-loaded gold nanospheres (GM).

[0040] Figure 4 is the morphology and size of the drug-loaded core-shell structure GMZ.

[0041] Figure 5 is of the ROS and pH dual-responsive composite gel with ROS scavenging and anti-inflammatory and antioxidant effects.

[0042] Figure 6Experimental results of the free radical scavenging ability of a ROS and pH dual-responsive composite gel with ROS scavenging and anti-inflammatory antioxidant effects.

[0043] Figure 7 ROS responsiveness results of a ROS and pH dual-responsive composite gel with ROS scavenging and anti-inflammatory antioxidant effects.

[0044] Figure 8 Experimental results of the in vitro cytotoxicity of a ROS and pH dual-responsive composite gel with ROS scavenging and anti-inflammatory antioxidant effects. Detailed implementation manners

[0045] In order to make the objectives, technical solutions and advantages of the present invention clearer and more understandable, the present invention will be further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the structural diagrams and specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0046] As described above, the present invention provides a preparation method of a composite gel with dual responsiveness to ROS and pH, comprising the following steps:

[0047] Step (1), under stirring conditions, add sodium citrate tribasic as a reducing agent to the boiling chloroauric acid solution, and react the solution for 10 - 20 min under boiling conditions, then stop heating. After the solution is cooled to room temperature, filter it with a nitrocellulose membrane to obtain gold nanoparticles with a diameter of 10 - 20 nm.

[0048] Step (2), under stirring conditions, add the gold nanoparticles obtained in step (1) and a seed growth solution to the chloroauric acid solution in sequence to prepare gold nanorods (GNS) with a diameter of 80 - 115 nm; the seed growth solution is a mixed solution of hydrochloric acid, silver nitrate and ascorbic acid.

[0049] Step (3), under stirring conditions, add a surfactant cetyltrimethylammonium chloride and metformin hydrochloride to the gold nanorods in step (2) to obtain drug-loaded gold nanorods GM with a diameter of 100 - 150 nm.

[0050] Step (4), under stirring conditions, mix a 2-methylimidazole solution, a zinc nitrate hexahydrate solution and the drug-loaded gold nanorods in a volume ratio of 1:1:1 to obtain drug-loaded nanoparticles GMZ with a core-shell structure and a diameter of 180 - 250 nm.

[0051] Step (5): Under stirring conditions, add tetramethylpropylenediamine and tetrabromomethylphenylboronic acid with a mass ratio of 1:(1 - 5) into the organic solvent dimethylformamide, heat to 60 - 65 °C and react overnight. After cooling, add tetrahydrofuran to produce a white precipitate, where the volume ratio of the organic solvent to tetrahydrofuran is 1:(1 - 10). Dry the precipitate and dissolve it to obtain an active oxygen-responsive crosslinker TSPBA solution;

[0052] Step (6): Under stirring conditions, mix a 5 - 7% TSPBA solution by mass concentration, a GMZ suspension with a final concentration of 50 - 60 ppm, and an astaxanthin solution with a final concentration of 20 - 30 μg / mL evenly, and crosslink with a polyvinyl alcohol PVA solution, where the volume ratio of the PVA solution to the TSPBA solution is 1:(0.25 - 1) to obtain the composite gel with dual responsiveness to ROS and pH.

[0053] The following further describes the present invention.

[0054] Example 1:

[0055] Prepare drug-loaded gold nanorods by a two-step synthesis method. Add 100 mL of 1 mM chloroauric acid solution (HAuCl4) to a 250 mL two-necked round-bottom flask, heat to boiling, then add 15 mL of 1% sodium citrate (C6H5Na3O7) solution by mass fraction, and continue boiling for 15 min to obtain a gold seed suspension. Cool to room temperature and filter with a 0.22 μm nitrocellulose membrane to obtain gold seeds with a particle size of 10 - 20 nm, and store them at 4 °C for later use.

[0056] Under uniform stirring conditions, sequentially add 20 μL of 1 M HCl solution and 100 μL of gold seed solution to 7 mL of 0.25 mM HAuCl4, and simultaneously quickly add 100 μL of silver nitrate (AgNO3) solution and 50 μL of ascorbic acid (L-Ascorbic acid, AA) solution. After 1 min, the mixed solution changes from light red to blue-black, and gold nanorods are synthesized. After 5 min, add 0.46 mM cetyltrimethylammonium chloride and metformin hydrochloride with a concentration of 150 mg / mL, and stir evenly for 1 h to obtain drug-loaded gold nanorods with a particle size of 100 - 150 nm. After centrifugation and filtration, wash with deionized water and store for later use.

[0057] Add 1 mL of the above gold nanorod suspension to an aqueous ZIF-8 precursor solution (1 mL of 1.32 M 2-methylimidazole solution and 1 mL of 24 mM zinc nitrate solution), react for 1 - 3 h, and wash 2 - 3 times with deionized water. Remove the pure ZIF-8 precursor that has not formed a core-shell structure to obtain drug-loaded core-shell structured nanoparticles with a particle size of 180 - 250 nm, and store them at 4 °C for later use.

[0058] Under the condition of uniform stirring, tetramethylpropylenediamine (0.1 g, 0.75 mmol) and tetrabromomethylphenylboronic acid (0.5 g, 2.3 mmol) were dissolved in dimethylformamide (10 mL), and stirred overnight at 60 °C; cooled to room temperature, 100 mL of tetrahydrofuran was added and mixed to obtain a precipitate. The precipitate was washed three times with tetrahydrofuran (3×20 mL), and the precipitate was volatilized and dried, and then dissolved in water to obtain a TSPBA solution;

[0059] Polyvinyl alcohol (PVA, 5 g) was added to deionized water and stirred overnight at 90 °C, and stored for later use after cooling to room temperature; TSPBA (2 mL of 5% aqueous solution), the drug-loaded core-shell structure nanoparticle suspension, astaxanthin ethanol solution (20 μg / mL) and polyvinyl alcohol (2 mL) were mixed to form a gel crosslinking.

[0060] The above-prepared dual-responsive multifunctional composite gel has anti-inflammatory and ROS scavenging functions, and the efficacy of combined photothermal therapy for psoriasis.

[0061] Test Example 1

[0062] The synthesized core-shell nanoparticles were characterized by ultraviolet-visible spectrophotometer (UV-Vis), transmission electron microscope (TEM), scanning electron microscope and in vitro cytotoxicity experiment:

[0063] (1) Ultraviolet-visible spectrophotometer (UV-Vis)

[0064] Ultraviolet-visible near-infrared spectrum, indicating the characteristic spectra of gold nanorods and drug-loaded gold nanorods synthesized by this method. After the material was synthesized, it was diluted 20 times with water, and the absorption peaks at wavelengths of 200 - 1300 nm were measured. The results were referred to Figure 1 , after the gold nanorods were loaded with drugs, a characteristic absorption peak of metformin appeared at 233 nm, proving that the drug was successfully loaded.

[0065] (2) Transmission electron microscope (TEM)

[0066] Transmission electron microscope photos showed the morphology and size of gold nanoparticles, drug-loaded GNS and Au@ZIF-8. After the material was synthesized, it was diluted and dropped on a copper grid and dried. The prepared copper grid sample was observed under a transmission electron microscope for the morphology of the nanomaterial. From Figure 2 it can be seen that the gold nanoparticles are spherical, with a uniform particle size distribution, and the particle size is about 10 - 20 nm. As Figure 3 shown, star-shaped gold nanoparticles can be observed. Figure 4 The shell thickness of the drug-loaded core-shell material GMZ and ZIF-8 can be seen to be about 60 - 150 nm.

[0067] (3) Scanning electron microscope

[0068] After the gel was synthesized, it was dried for 24 h by means of a freeze dryer or the like, then brittle fractured in liquid nitrogen, and the cross section was observed under a scanning electron microscope. As Figure 5 shown, the scanning electron microscope photograph indicates that the ROS-responsive TSPBA-PVA gel has a good crosslinked structure, and the crosslinked pore structure is 1-2 μm.

[0069] (4) Radical scavenging experiment

[0070] The ability of scavenging ROS radicals was evaluated by the Fenton-like reaction, and the absorbance of the solution was measured after incubating with the gel for different times. As Figure 6 shown, the ROS-responsive hydrogel has a good ability to scavenge radicals.

[0071] (5) ROS responsiveness

[0072] PBS solutions with pH of 7.4 and H2O2 concentrations of 0, 0.2, 0.5, and 1 mM were respectively taken for the evaluation of the ROS responsiveness of the gel. The gel was placed in different groups of PBS solutions and incubated for different durations, and the volume change of the gel was observed. As Figure 7 shown, the gel has good ROS responsiveness.

[0073] (6) In vitro cytotoxicity test

[0074] The in vitro cytotoxicity experiment was to evaluate the safety performance of the drug-loaded nanoparticles. HaCaT cells were cultured in DMEM culture medium in an incubator at 37 °C and 5% CO2. Then, the original culture medium was replaced with the culture medium containing the nanomaterial and cultured for 24 h, and then 5 mg / mL of MTT solution was added. After incubating for 4 h, 33 μL of DMSO was added. As Figure 8 visible, when the concentration of the core-shell nanomaterial reached 20 μg / mL, the cell survival rate was still greater than 80%.

[0075] The above description of the present invention is illustrative rather than restrictive. Those skilled in the art understand that many modifications, variations or equivalents can be made within the spirit and scope defined by the claims, but they will all fall within the protection scope of the present invention.

Claims

1. A preparation method of a composite gel with dual responsiveness to ROS and pH, characterized in that, The preparation method includes the following steps: Step (1): Under stirring conditions, a reducing agent is added to the boiling chloroauric acid solution. After the reaction is complete, heating is stopped. After the solution cools to room temperature, gold nanoparticles are obtained by filtration. Step (2): Under stirring conditions, gold nanoparticles and a seed growth solution are successively added to the chloroauric acid solution to prepare gold nanorods GNS. Step (3): Under stirring conditions, a surfactant and a biguanide drug are added to the gold nanorods GNS to obtain drug-loaded gold nanorods GM. Step (4): Under stirring conditions, a 2-methylimidazole solution and a zinc nitrate hexahydrate solution are mixed to prepare an aqueous solution of the ZIF-8 precursor, and then the drug-loaded gold nanorods GM are added to obtain drug-loaded nanoparticles GMZ with a core-shell structure. Step (5): Under stirring conditions, tetramethylpropylenediamine and tetrabromomethylphenylboronic acid are added to an organic solvent, and the reaction is carried out overnight under heating. After cooling, tetrahydrofuran is added to produce a precipitate. The precipitate is dried and dissolved in water to obtain an active oxygen-responsive crosslinking agent TSPBA solution. Step (6): Under stirring conditions, the TSPBA solution, the suspension of GMZ, and the astaxanthin solution are mixed evenly and crosslinked with a polyvinyl alcohol PVA solution to obtain the composite gel with dual responsiveness to ROS and pH.

2. The preparation method according to claim 1, characterized in that, In step (1), the reaction time is 10 - 20 min.

3. The preparation method according to claim 1, characterized in that, In step (2), the seed growth solution is prepared from hydrochloric acid, silver nitrate, and ascorbic acid.

4. The preparation method according to claim 1, characterized in that, In step (3), the surfactant is cetyltrimethylammonium chloride, and the biguanide drug is metformin hydrochloride.

5. The preparation method according to claim 1, characterized in that, In step (4), the volume ratio of 2-methylimidazole, zinc nitrate hexahydrate, and the drug-loaded gold nanorods GM is 1:1:(1 - 1.5).

6. The preparation method according to claim 1, wherein, In step (5), the organic solvent is dimethylformamide.

7. The preparation method according to claim 1, characterized in that, In step (5), the dosage ratio of tetramethylpropylenediamine and tetrabromomethylphenylboronic acid is 1:(1 - 5), and the volume ratio of the organic solvent to tetrahydrofuran is 1:(1 - 10).

8. The preparation method according to claim 1, wherein In step (6), the mass percentage concentration of the TSPBA solution is 5 - 7%, the final concentration of the suspension of GMZ is 50 - 60 ppm, the final concentration of the astaxanthin solution is 20 - 30 μg / mL, and the dosage ratio of the polyvinyl alcohol PVA solution to the TSPBA solution is 1:(0.25 - 1).

9. A composite gel with dual responsiveness to ROS and pH, characterized in that, Prepared by the method described in any one of claims 1 - 8.

10. Use of the composite gel with dual responsiveness to ROS and pH as described in claim 9 in the preparation of a therapeutic preparation for psoriasis.

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