A multifunctional drug structure coating with regulation of lesion microenvironment homeostasis and a preparation method thereof

Abstract

The present application belongs to the technical field of biomedical functional materials, and particularly relates to a multifunctional drug structure coating with regulation of lesion microenvironment homeostasis and a preparation method thereof. The nano drug carrier can load drugs with anti-smooth muscle cell growth or regulation of inflammation, the drugs can resist the growth of smooth muscle cells or regulate microenvironment inflammation, and provide a stable and safe microenvironment for the adhesion and growth of endothelial cells. Under the action of an oxidizing agent, polyphenol and polyamine compounds undergo oxidation, crosslinking and polymerization reactions, and a polyphenol nanoparticle (10 nanometer level) film layer is generated outside the nano drug carrier (100 nanometer level). The polyphenol nanoparticle film layer not only serves as a protective layer for the nano drug carrier and crosslinking substances therebetween, but also can fix the nano drug carrier on the surface of a base material, and together with the drug carrier, a drug structure coating with a topological structure is constructed. The hydrophilic groups contained in the coating make the surface super-hydrophilic and negatively charged.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of biomedical functional materials, and particularly relates to a multifunctional drug structure coating with regulation of lesion microenvironment homeostasis and a preparation method thereof. BACKGROUND

[0002] When the implantation / intervention medical devices such as arterial stents, venous stents and heart valves contact the blood in the body, proteins will quickly non-specifically adhere and denature on the material surface, and the adhered and denatured proteins will further promote the adhesion, activation and aggregation of platelets, and finally induce the occurrence of acute thrombosis and acute inflammation; and a large number of adhered proteins will cover the bioactive components on the surface of the device / material, so that the biological function thereof is affected, and therefore, it is crucial to resist the adhesion and denaturation of proteins from the source to improve the biological function of the material.

[0003] At present, the commonly accepted view is that hydrophilic materials have better biocompatibility than hydrophobic materials. The hydrophilic surfaces mainly include polyethylene glycol coating and amphiphilic ionic molecular brush surface, and the two types of coatings can effectively resist the adhesion of proteins and cells by forming a hydration layer on the surface through effective combination with water molecules.

[0004] However, the anti-fouling performance of such coatings is highly dependent on the length and density of the modified molecular chain, and there are problems such as immune inflammation in long-term use. In addition, with the extension of the service time of the implantation / intervention material in the body, the hydration layer will be destroyed and cannot effectively maintain its anti-fouling performance.

[0005] Therefore, based on this, the technical scheme of the present application is proposed. SUMMARY

[0006] The inventor proposes the following ideas in order to solve the problems existing in the prior art.

[0007] 1. In order to solve the problem that the anti-fouling performance of the coating is highly dependent on the length and density of the modified molecular chain, and there are problems such as immune inflammation in long-term use, it is necessary to construct a super-hydrophilic surface layer, and the super-wetting surface is determined by chemical groups and topological structure, so if a super-hydrophilic surface is constructed, it is necessary to start from both the topological structure and the hydrophilic groups.

[0008] 2、To solve the problem that the hydration layer of the implantation / intervention material will be destroyed and cannot effectively maintain its anti-fouling performance as the service time of the implantation / intervention material in the body is prolonged, other factors need to be constructed to cooperatively maintain the stability of the implantation microenvironment. More specifically, the implantation / intervention material surface needs to be endowed with the performance of regulating the microenvironment inflammation to avoid the blood vessel wall cells (ECs, smooth muscle cells and fibroblasts) and blood cells in the microenvironment being stimulated by inflammatory factors to be activated (not conducive to the growth of blood vessel ECs on the surface of the implantation / intervention material), in addition, the excessive proliferation of smooth muscle cells will lead to restenosis in the implantation / intervention material, therefore, inhibiting the excessive proliferation of smooth muscle cells is also important for promoting the rapid endothelialization of the surface of the vascular stent or heart valve. The technology can be used for surface modification treatment of materials and instruments such as arterial vascular stents, venous vascular stents, heart valves and the like.

[0009] Therefore, the present application provides a preparation method of a multifunctional drug structure coating with regulation of lesion microenvironment homeostasis, which comprises the following steps:

[0010] (1) dispersing the nanodrug carrier in a solvent to obtain a nanodrug carrier suspension;

[0011] (2) mixing the nanodrug carrier suspension with a polyphenol compound acid buffer, a polyamine compound acid buffer and an oxidizing agent acid buffer to obtain a mixed solution;

[0012] (3) adding the mixed solution to the surface of the base material for reaction, and after completion, washing and drying to obtain a modified base material;

[0013] (4) soaking the modified base material in a NO catalyst acid buffer for reaction, and after completion, washing and drying to obtain the multifunctional drug structure coating with regulation of lesion microenvironment homeostasis.

[0014] In order to facilitate the understanding of the present application, the reaction process of the present application is described:

[0015] The present application firstly disperses the nano drug carrier loaded with anti-smooth muscle cell growth or inflammation regulating drugs uniformly in a solvent, and then generates a polyphenol nanoparticle structure (10 nanometer level) film layer by oxidizing, cross-linking and polymerizing the polyphenol compound and the polyamine compound under the action of an oxidizing agent in an acidic environment. The nano film layer uniformly wraps the nano drug carrier (100 nanometer level) and firmly fixes it on the surface of the base material, forms a topological structure, and constructs a drug structure coating with drugs as the coating bulk material. The topological structure in the coating and a large number of hydrophilic groups jointly make the surface have superhydrophilicity and negative charge. Then, in an acidic solution, the NO catalyst is modified on the surface of the coating by reacting with the active functional groups in the coating, so that the coating has the biological function of catalyzing the NO donor to release NO. Finally, the coating plays different biological functions at different stages after the implantation of the instrument through the synergistic effect of one or more of the superhydrophobic anti-fouling platform, NO, polyphenol and drugs, provides a steady state environment for the adhesion and growth of vascular ECs on the surface of the stent, and promotes rapid endothelialization of the stent surface.

[0016] Preferably, in step (1), the drug is an anti-proliferative drug or an inflammation regulating drug; the anti-proliferative drug is one or a combination of two or more of prednisone, rapamycin and paclitaxel; the inflammation regulating drug is one or a combination of two or more of curcumin, triptolide, bryanol, radix astragali, baicalin, honokiol and magnolol; and the nano drug carrier is one of exosome, solid lipid nanoparticle, nanoliposome and polymer micelle.

[0017] Preferably, in step (1), the solvent is an aqueous solution, an ethanol solution or a mixed solution of water and ethanol; and in the mixed solution of water and ethanol, the volume ratio of ethanol to water is 0.1-5:0.1-5.

[0018] Preferably, in step (2), the polyphenol compound is one or a combination of two or more of tannic acid, gallic acid, salvianolic acid B, epigallocatechin gallate, epicatechin gallate, epicatechin, epigallocatechin, catechol, pyrogallol and flavonoids; the polyamine compound is one or a combination of two or more of ethylenediamine, pentanediamine, 2,2,4-trimethylhexamethylene diamine, 1,8-diamino octane, methylcyclohexane diamine, 1,3-diaminomethylcyclohexane, 2,4,6-triaminomethylcyclohexane, 1,4-bis-diaminohexane and 2-(3,4-dihydroxyphenyl)ethylamine; and the oxidizing agent is one or a combination of two or more of hydrogen peroxide, ammonium persulfate, concentrated nitric acid, sodium periodate, potassium permanganate and potassium dichromate.

[0019] Preferably, the pH of the acid buffer is 3-7; the acid buffer is one of acetic acid-acetate buffer, 2-(N-morpholino)ethanesulfonic acid buffer, glycine-hydrochloric acid buffer, phthalic acid-hydrochloric acid buffer, potassium hydrogen phthalate-sodium hydroxide buffer, disodium hydrogen phosphate-citric acid buffer, citric acid-sodium hydroxide-hydrochloric acid buffer, and citric acid-sodium citrate buffer.

[0020] Preferably, in step (2), the concentration of the nanodrug carrier in the mixed solution is 0.5-10 mg / mL, the concentration of the polyphenol compound is 0.5-20 mg / mL, the concentration of the polyamine compound is 0.1-10 mg / mL, and the concentration of the oxidizing agent is 0.1-10 mg / mL. More preferably, the concentration of the nanodrug carrier is 2 mg / mL, the concentration of the polyphenol compound is 1 mg / mL, the concentration of the polyamine compound is 0.5 mg / mL, and the concentration of the oxidizing agent is 0.5 mg / mL.

[0021] Preferably, in step (3), the base material is one of metal-based biomaterials, polymer-based biomaterials, and composite biomaterials.

[0022] Preferably, in steps (3) and (4), the reaction temperature is 10-40℃, and the reaction time is 0.1-10 h. More preferably, in step (3), the reaction temperature is 30℃, and the reaction time is 1 h; in step (4), the reaction temperature is 30℃, and the reaction time is 2 h.

[0023] Preferably, in step (4), the NO catalyst can catalyze the release of NO from a nitric oxide (NO) donor; the NO catalyst is one or a combination of two or more of copper ions, copper porphyrin, selenocystamine, selenocysteine, and water-soluble ebselen; and the concentration of the NO catalyst in the acid buffer is 0.1-10 mg / mL, more preferably, the concentration of the NO catalyst is 0.5 mg / mL.

[0024] Based on the same technical concept, another aspect of the present application provides a multifunctional drug structure coating with the function of regulating the homeostasis of lesion microenvironment, which is prepared by the above method.

[0025] The present application has the following advantages:

[0026] 1. The preparation method of the application is based on the oxidation, cross-linking, polymerization and deposition reactions of polyphenol and polyamine-based compounds under the action of an oxidizing agent. A simple "one-pot" method is used to form a uniform polyphenol nanoparticle film layer on the surface of a nano-drug carrier. The polyphenol nanoparticle film layer not only increases the stability of the nano-drug carrier, but also firmly fixes the nano-drug carrier on the surface of the base material, realizes the bulk material constructed with the drug as the coating, and has the performance of long-acting biological function as long as the coating exists. The polyphenol nanoparticle film layer has non-material dependence and can be modified on the surface of base materials with different shapes and properties, and has wide applicability.

[0027] 2. Different from the traditional topological structure preparation method, the size of the polyphenol nanoparticles in the multifunctional drug structure coating of the application is in the order of ten nanometers, and the size of the nano-drug carrier is in the order of hundreds of nanometers. The nanoparticles with different sizes together make the coating have a topological structure, and the constructed topological structure does not need to damage the base and has biological activity and biological function. At the same time, the coating contains a large number of hydrophilic groups such as phenolic hydroxyl, carboxyl and amine groups, which can work together with the topological structure to make the drug structure coating have excellent hydrophilicity, and the surface of the coating is negatively charged, so that the surface has excellent anti-protein adhesion performance, avoiding the occurrence of acute thrombosis and acute inflammation. At the same time, the polyphenol nanoparticle film layer has the corresponding biological functions of polyphenol, such as antioxidant, free radical scavenging, inflammation regulation and friendliness to vascular ECs.

[0028] 3. Different from the traditional drug-loaded coating, the coating constructed by the preparation method of the application is a bulk material constructed with the drug as the coating. As long as the coating exists, the drug exists and can exert the corresponding biological function, and the outer layer of the nano-drug carrier is wrapped by a polyphenol nanoparticle composite layer, so that the controlled and long-acting release of the drug can be realized.

[0029] 4. Different from the traditional single-factor regulation of the biological performance of the material, the coating constructed by the preparation method of the application maintains the stable state of the microenvironment of the lesion site through the synergistic and non-interfering optimal mode of multiple factors (such as the super-hydrophilic platform, NO, polyphenol and active drugs), and provides favorable conditions for the growth of vascular ECs.

[0030] 5. The preparation method of the application has simple operation, does not need large equipment, high reaction efficiency and mild conditions, has wide spectrum of practicality, can maintain the microenvironment homeostasis for a long time, and promotes the rapid endothelialization of the surface of the stent / heart valve. BRIEF DESCRIPTION OF DRAWINGS

[0031] In order to more clearly illustrate the technical solutions of the embodiments of the present application or the prior art, the following will briefly introduce the drawings needed to be used in the embodiments or prior art description. Obviously, the drawings in the following description only constitute some embodiments of the present application, and for those skilled in the art, other drawings can also be obtained without creative labor on the basis of these drawings.

[0032] Figure 1 The surface morphology scanning electron microscope (SEM) image of the multifunctional drug structure coating prepared in Example 1.

[0033] Figure 2 The surface morphology micro-area element type and content analysis EDS image of the multifunctional drug structure coating prepared in Example 1.

[0034] Figure 3 The surface water contact angle value (WCA) of the multifunctional drug structure coating prepared in Example 1.

[0035] Figure 4 The concentration of the multifunctional drug structure coating prepared in Example 1 catalyzing the release of NO. DETAILED DESCRIPTION

[0036] In order to make the objects, technical solutions and advantages of the present application clearer, the technical solutions of the present application will be described in detail below. Obviously, the described embodiments only constitute some of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of the present application.

[0037] Example 1

[0038] The present embodiment provides a preparation method of a multifunctional drug structure coating with regulation of lesion microenvironment homeostasis, which comprises the following steps:

[0039] (1) uniformly dispersing Tween-80 micelles (polymer micelles) loaded with magnolol in a mixed solvent of ethanol / water to obtain a nanomedicine carrier suspension; wherein the volume ratio of ethanol to water is 1:4;

[0040] (2) dissolving tannic acid, ethylenediamine, sodium periodate and CuCl2 with sodium acetate buffer solution with pH of 5 to obtain tannic acid buffer solution, ethylenediamine buffer solution, sodium periodate buffer solution and CuCl2 buffer solution;

[0041] (3) the nano-drug carrier suspension liquid is mixed with tannic acid buffer, ethylenediamine buffer and sodium periodate buffer to obtain a mixed liquid; wherein the concentrations of the nano-drug carrier, tannic acid, ethylenediamine and sodium periodate are 2 mg / mL, 1 mg / mL, 0.5 mg / mL and 0.5 mg / mL respectively;

[0042] (4) the mixed liquid is added to a clean polymer substrate surface, and reacted at 25°C for 3 hours, then washed with RO water and dried with nitrogen to obtain a modified substrate material;

[0043] (5) the modified substrate material is immersed in a CuCl2 buffer solution with a concentration of 0.5 mg / mL, and reacted at 25°C for 3 hours, then washed with RO water and dried with nitrogen to obtain a multifunctional drug structure coating with regulation of the microenvironment homeostasis of a lesion.

[0044] Example 2

[0045] The embodiment provides a preparation method of a multifunctional drug structure coating with regulation of the microenvironment homeostasis of a lesion, and the preparation method comprises the following steps:

[0046] (1) a rapamycin-loaded nano-liposome is uniformly dispersed in water to obtain a nano-drug carrier suspension liquid;

[0047] (2) epigallocatechin gallate, pentanediamine, potassium permanganate and copper porphyrin are respectively dissolved in a sodium acetate buffer solution with a pH of 4 to obtain an epigallocatechin gallate buffer solution, a pentanediamine buffer solution, a potassium permanganate buffer solution and a copper porphyrin buffer solution;

[0048] (3) the nano-drug carrier suspension liquid is mixed with the epigallocatechin gallate buffer solution, the pentanediamine buffer solution and the potassium permanganate buffer solution to obtain a mixed liquid; wherein the concentrations of the nano-drug carrier, epigallocatechin gallate, pentanediamine and potassium permanganate are 5 mg / mL, 2 mg / mL, 2 mg / mL and 2 mg / mL respectively;

[0049] (4) the mixed liquid is added to a clean metal substrate material surface, and reacted at 20°C for 6 hours, then washed with RO water and dried with nitrogen to obtain a modified substrate material;

[0050] (5) the modified substrate material is immersed in a copper porphyrin buffer solution with a concentration of 1 mg / mL, and reacted at 20°C for 6 hours, then washed with RO water and dried with nitrogen to obtain a multifunctional drug structure coating with regulation of the microenvironment homeostasis of a lesion.

[0051] Example 3

[0052] The embodiment provides a preparation method of a multifunctional drug structure coating for regulating lesion microenvironment homeostasis, and the preparation method comprises the following steps:

[0053] (1) uniformly dispersing paclitaxel-loaded lecithin in water to obtain a nanometer drug carrier suspension;

[0054] (2) dissolving gallic acid, 2,2,4-trimethylhexamethylene diamine, sodium periodate and selenocysteine in a pH 3.5 phthalate-hydrochloric acid buffer solution respectively to obtain a gallic acid buffer solution, a 2,2,4-trimethylhexamethylene diamine buffer solution, a sodium periodate buffer solution and a selenocysteine buffer solution;

[0055] (3) mixing the nanometer drug carrier suspension with the gallic acid buffer solution, the 2,2,4-trimethylhexamethylene diamine buffer solution and the sodium periodate buffer solution to obtain a mixed solution; wherein the concentrations of the nanometer drug carrier, the gallic acid, the 2,2,4-trimethylhexamethylene diamine and the sodium periodate are 6 mg / mL, 3 mg / mL, 3 mg / mL and 3 mg / mL respectively;

[0056] (4) adding the mixed solution to the surface of a clean metal base material, reacting at 15 DEG C for 10 h, then fully washing with RO water and drying with nitrogen to obtain a modified base material;

[0057] (5) immersing the modified base material in a selenocysteine buffer solution with a concentration of 1 mg / mL, reacting at 10 DEG C in a constant temperature environment for 10 h, then fully washing with RO water and drying with nitrogen to obtain the multifunctional drug structure coating for regulating lesion microenvironment homeostasis.

[0058] Embodiment 4

[0059] The embodiment provides a preparation method of a multifunctional drug structure coating for regulating lesion microenvironment homeostasis, and the preparation method comprises the following steps:

[0060] (1) uniformly dispersing paclitaxel-loaded lecithin in water to obtain a nanometer drug carrier suspension;

[0061] (2) dissolving gallic acid, 2,2,4-trimethylhexamethylene diamine, sodium periodate and selenocysteine in a pH 3.5 phthalate-hydrochloric acid buffer solution respectively to obtain a gallic acid buffer solution, a 2,2,4-trimethylhexamethylene diamine buffer solution, a sodium periodate buffer solution and a selenocysteine buffer solution;

[0062] (3) mixing the nanometer drug carrier suspension liquid with pyrogallol buffer, 1,8-diamino octane buffer and ammonium persulfate buffer to obtain a mixed liquid; wherein the concentrations of the nanometer drug carrier, pyrogallol, 1,8-diamino octane and ammonium persulfate are 2 mg / mL, 2 mg / mL, 1.5 mg / mL and 2 mg / mL respectively;

[0063] (4) adding the mixed liquid to the surface of a clean ceramic base material, reacting at 35°C for 1 h, then fully washing with RO water and drying with nitrogen to obtain a modified base material;

[0064] (5) immersing the modified base material in a water-soluble ebselen buffer solution with a concentration of 0.1 mg / mL, reacting at 35°C for 1 h, then fully washing with RO water and drying with nitrogen to obtain a multifunctional drug structure coating with regulation of the microenvironment homeostasis of a lesion.

[0065] Example 5

[0066] The present embodiment provides a preparation method of a multifunctional drug structure coating with regulation of the microenvironment homeostasis of a lesion, which comprises the following steps:

[0067] (1) uniformly dispersing the nanometer liposome loaded with magnolol in water to obtain a nanometer drug carrier suspension liquid;

[0068] (2) dissolving epicatechin gallate, 1,3-diaminomethylcyclohexane, potassium dichromate and selenocystamine in a glycine-hydrochloric acid buffer solution with a pH of 6 to obtain an epicatechin gallate buffer solution, a 1,3-diaminomethylcyclohexane buffer solution, a potassium dichromate buffer solution and a selenocystamine buffer solution;

[0069] (3) mixing the nanometer drug carrier suspension liquid with the epicatechin gallate buffer solution, the 1,3-diaminomethylcyclohexane buffer solution and the potassium dichromate buffer solution to obtain a mixed liquid; wherein the concentrations of the nanometer drug carrier, epicatechin gallate, 1,3-diaminomethylcyclohexane and potassium dichromate are 6 mg / mL, 2 mg / mL, 2 mg / mL and 2 mg / mL respectively;

[0070] (4) adding the mixed liquid to the surface of a clean high polymer base material, reacting at 35°C for 0.5 h, then fully washing with RO water and drying with nitrogen to obtain a modified base material;

[0071] (5) immersing the modified base material in a water-soluble ebselen buffer solution with a concentration of 1.5 mg / mL, reacting at 35°C for 0.5 h, then fully washing with RO water and drying with nitrogen to obtain a multifunctional drug structure coating with regulation of the microenvironment homeostasis of a lesion.

[0072] Test Example

[0073] The SEM of the drug nano-multilevel structure coating of the product obtained in Example 1 is shown in Figure 1 Fig. 1(a) and Fig. 1(b), from which it can be seen that a layer of nano-drug carrier-based multilevel structure coating is formed on the surface of the substrate material, and the nano-drug carrier in the coating is amplified Figure 1 (a) and Fig. 1(b), it can be found that the outer surface is uniformly covered with polyphenol nanoparticles with a particle size of 10-20 nm, and the reaction process does not change the morphology of the nano-drug carrier, which has a multilevel structure. Figure 1

[0074] From the water contact angle results of Figure 2 the coating micro-area element distribution Figure 2 (a) and element content Figure 2 (b) test results, it can be found that there is a copper element on the surface of the coating that can catalyze the release of nitric oxide from the nitric oxide donor, and the element content is 1.4Wt%.

[0075] From the water contact angle results of Figure 3 , it can be seen that the water contact angle of the drug multilevel structure coating is less than 5°, which has superhydrophilicity (where Blank is the blank control group, and Coating is the test group coated with the drug structure coating).

[0076] The exogenous NO donor SNAP solution was added to the surface of the material, and the ability of the coating to catalyze the release of NO was observed. From Figure 4 , it can be found that the drug structure coating can long-acting catalyze the release of NO in the physiological concentration range, which shows that the coating has the corresponding biological function of NO in vivo.

[0077] The above is only a specific embodiment of the present application, but the protection scope of the present application is not limited thereto, any person skilled in the art can easily think of changes or replacements within the technical range disclosed by the present application, which should be covered within the protection scope of the present application. Therefore, the protection scope of the present application should be subject to the protection scope of the claims.​

Claims

1. A method of producing a multifunctional drug structure coating with regulation of the homeostasis of the microenvironment of a lesion, characterized in that, The preparation method comprises the following steps: (1) dispersing the nano drug carrier in a solvent to obtain a nano drug carrier suspension; wherein: The drug is an anti-proliferative drug or an inflammation regulating drug; The nano drug carrier is one of exosomes, solid lipid nanoparticles, nano liposomes, and polymer micelles; (2) mixing the nano drug carrier suspension with a polyphenol compound acid buffer, a polyamine compound acid buffer, and an oxidizing agent acid buffer to obtain a mixed solution; wherein: The polyphenol compound is one or a combination of two or more of tannic acid, gallic acid, salvianolic acid B, epigallocatechin gallate, epicatechin gallate, epicatechin, epigallocatechin, catechol, pyrogallol, and flavonoids; the polyamine compound is one or a combination of two or more of ethylenediamine, pentanediamine, 2,2,4-trimethylhexamethylene diamine, 1,8-diamino octane, methylcyclohexane diamine, 1,3-diaminomethylcyclohexane, 2,4,6-triaminomethylcyclohexane, 1,4-bis-diaminohexylcyclohexane, and 2-(3,4-dihydroxyphenyl)ethylamine; and the oxidizing agent is one or a combination of two or more of hydrogen peroxide, ammonium persulfate, concentrated nitric acid, sodium periodate, potassium permanganate, and potassium dichromate; In the mixed solution, the concentration of the nano drug carrier is 0.5-10 mg / mL, the concentration of the polyphenol compound is 0.5-20 mg / mL, the concentration of the polyamine compound is 0.1-10 mg / mL, and the concentration of the oxidizing agent is 0.1-10 mg / mL; (3) adding the mixed solution to the surface of a base material for reaction, and then cleaning and drying to obtain a modified base material; wherein: The polyphenol compound, the polyamine compound, and the oxidizing agent are oxidized, cross-linked, and polymerized to form a ten-nanometer polyphenol nanoparticle film layer, the polyphenol nanoparticle film layer uniformly wraps and fixes the hundred-nanometer nano drug carrier on the surface of the base material, and has a multi-level topological structure; (4) immersing the modified base material in an NO catalyst acid buffer for reaction, and then cleaning and drying to obtain the multifunctional drug structure coating with regulation of the lesion microenvironment homeostasis; wherein: The NO catalyst is one or a combination of two or more of copper ions, copper porphyrin, selenocystamine, selenocysteine, and water-soluble ebselen; and the concentration of the NO catalyst in the NO catalyst acid buffer is 0.1-10 mg / mL.

2. The method of claim 1, wherein the multifunctional drug structure coating with the regulation of the lesion microenvironment homeostasis is prepared by, In step (1), the anti-proliferative drug is one or a combination of two or more of prednisone, rapamycin, and paclitaxel; and the inflammation regulating drug is one or a combination of two or more of honokiol, magnolol, curcumin, triptolide, emodin, astragalus, and baicalin.

3. The method of claim 1, wherein the multifunctional drug structure coating with the regulation of the lesion microenvironment homeostasis is prepared by, In step (1), the solvent is an aqueous solution, an ethanol solution, or a mixed solution of water and ethanol; and in the mixed solution of water and ethanol, the volume ratio of ethanol to water is 0.1-5:0.1-5.

4. The method of claim 1, wherein the multifunctional drug construct coating that modulates the homeostasis of the lesion microenvironment is prepared by, The pH of the acid buffer is 3-7; the acid buffer is one of acetic acid-acetate buffer, 2-(N-morpholino)ethanesulfonic acid buffer, glycine-hydrochloric acid buffer, phthalic acid-hydrochloric acid buffer, potassium hydrogen phthalate-sodium hydroxide buffer, disodium hydrogen phosphate-citric acid buffer, citric acid-sodium hydroxide-hydrochloric acid buffer, and citric acid-sodium citrate buffer.

5. The method of claim 1, wherein the multifunctional drug construct coating that modulates the homeostasis of the lesion microenvironment is prepared by, In step (3), the base material is one of a metal-based biomaterial, a polymer-based biomaterial, and a composite biomaterial.

6. The method of claim 1, wherein the multifunctional drug construct coating that modulates the homeostasis of the lesion microenvironment is prepared by, In steps (3) and (4), the reaction temperature is 10-40°C, and the reaction time is 0.1-10 h.

7. The multifunctional drug structure coating with the function of regulating the steady state of lesion microenvironment obtained by the preparation method in any one of claims 1-6.

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