Anticoagulant polymer-ZIF nano drug delivery system composite material and application

Abstract

The invention discloses an anticoagulant polymer-ZIF nano drug delivery system composite material and application, and particularly relates to the technical field of coating materials, the composite material is prepared by fixing an anticoagulant polymer and a ZIF nano drug delivery system through coordination; the anticoagulant polymer is at least one of hydroheparin, thiolated polyethylene glycol, a methacrylic acid phosphorylcholine-based polymer, a methacrylic acid sulphobetaine-based polymer and a methacrylic acid carboxyl betaine-based polymer; and the ZIF nano drug loading system is a ZIF nano carrier modified by a drug. According to the composite material, an organic-inorganic hybrid ZIF loaded medicine which is low in cost and stable in performance is utilized to construct a nano medicine carrying system, so that after the surface of an implanted instrument is coated with the composite material, endothelial cell proliferation can be promoted, active oxygen can be removed, and then the endothelial function is accelerated to be repaired.

Description

TECHNICAL FIELD

[0001] The application relates to the technical field of coating materials, in particular to an anti-aggregation polymer-ZIF nano drug delivery system composite material and application. BACKGROUND

[0002] Cardiovascular and cerebrovascular diseases are the top killer of human health. Although the commonly used cardiovascular and cerebrovascular stents, blood flow guiding devices, artificial blood vessels, heart valves and occluders in clinical practice have greatly improved the survival rate and quality of life of patients, complications such as thrombosis and stenosis caused by the implantation of the devices seriously affect the clinical performance. Studies have found that a natural and healthy endothelial layer can ensure long-term patency of blood flow, so promoting endothelial tissue regeneration on the surface of the implanted device is a promising strategy.

[0003] Patent CN202311491483.5 discloses a cardiovascular stent material surface Cu-MOF / sulfonated hyaluronic acid hybrid coating and a preparation method thereof. The patent relies on the combined action of Cu-MOF and sulfonated hyaluronic acid to achieve rapid repair of the endothelial layer. However, Cu-MOF is difficult to dissolve in the aqueous solution of sulfonated hyaluronic acid, resulting in limited actual loading of Cu-MOF, the key active component for promoting the repair of damaged vascular tissue, and also easily causing complications such as thrombosis and stenosis.

[0004] Meanwhile, patent CN202510340162.8 discloses a preparation method of an anticoagulant and endothelium-promoting sustained-release coating. However, the patent needs to undergo two-step photocuring operations to introduce the assembly layer and the regulation layer in sequence to prepare the anticoagulant and endothelium-promoting sustained-release coating, and the process is complex. Moreover, the endothelium-promoting active substances (recombinant type III humanized collagen, vascular endothelial growth factor and hepatocyte growth factor) described in the patent generally have poor resistance to ultraviolet light, resulting in limited actual effect of promoting endothelial tissue growth.

[0005] Furthermore, patent CN202210732765.9 discloses a nickel-titanium alloy vascular stent surface coating for promoting endothelialization and a preparation method thereof. The patent promotes the ordered growth of endothelial cells through an active polypeptide layer to construct a surface for promoting the growth of endothelial cells. However, the polypeptides (RGD, REDV and YIGSR) described in the patent need to be stored at low temperature, and even if they are stored at low temperature for a long time, there is still a risk of degradation, which further leads to poor actual effect of the coating on promoting endothelial tissue growth.

[0006] However, the above patent documents construct different growth factors for promoting endothelialization, but the excess of active oxygen in the blood will destroy the stability of the endothelial cell membrane, leading to imbalance of permeability, apoptosis and dysfunction, and none of the above-mentioned solutions has studied this. Therefore, the patent documents corresponding to the application numbers 2024115732152 and 2024115526884, although they respectively remove active oxygen according to hydrogen sulfide and CO gas. However, the above-mentioned gases not only have limited active oxygen removal effect, but also have the disadvantages of high toxicity and difficult dose control, which are not suitable for use as active oxygen removal components in blood vessels, and the above two patents also do not have related data to show the effect of removing active oxygen.

[0007] Based on the existing materials and the defects pointed out in the above patent documents, it is necessary for the skilled person to develop a new type of coating material to meet the needs of promoting the regeneration of endothelial tissue on the surface of implanted devices. SUMMARY

[0008] The application provides an anti-aggregation polymer-ZIF nano-drug delivery system composite material and its application in preparing a cardiovascular implant interventional device surface composite coating. The composite material uses an organic-inorganic hybrid ZIF to load drugs to construct a nano-drug delivery system, so that after being coated on the surface of an implanted device, it not only promotes endothelial cell proliferation, but also removes active oxygen, thereby accelerating the repair of endothelial function.

[0009] The purpose of the application is achieved by the following technical solutions: An anti-aggregation polymer-ZIF nano-drug delivery system composite material is made of an anti-aggregation polymer and a ZIF nano-drug delivery system fixed by coordination. The anti-aggregation polymer is at least one of aldehyde heparin, thiolated polyethylene glycol, methacrylic acid phosphoryl choline-based polymer, methacrylic acid sulfobetaine-based polymer and methacrylic acid carboxybetaine-based polymer; and the ZIF nano-drug delivery system is a drug-modified ZIF nano-carrier.

[0010] The ZIF nano-drug delivery system is fixed by coordination between metal ions and lone pair electrons of heteroatoms (N, O, S) in the anti-aggregation polymer. The coordination is relatively weaker than the covalent bond, and it is easier to release during the implantation of the device. The ZIF drug delivery system is ATP-responsive, and a relatively high concentration of multidentate negative charge ATP in cells can compete with metal ions more easily than ligands, resulting in the disintegration of the ZIF drug delivery system and the release of drugs.

[0011] At the same time, compared with other carriers, ZIF itself also acts as a "functional factor" while enhancing the efficacy of the drug, rather than just acting as a carrier, i.e. delivering functional factors.

[0012] And in the present application, the above-mentioned ZIF-based drug delivery system can remove excess active oxygen in a controllable and safe and non-toxic manner, which is more conducive to endothelial function repair after in vivo action. After removal, the bioavailability of nitric oxide (NO) in endothelial cells is improved, promoting vasodilation and inhibiting platelet aggregation, thereby enhancing the anti-thrombosis ability.

[0013] As a preferred, the drug includes at least one of curcumin, vitamin C, quercetin, epigallocatechin gallate (EGCG), resveratrol, and anthocyanin.

[0014] As a preferred, the mass ratio of the drug to the ZIF nano-drug delivery system is 1%-50%.

[0015] As a preferred, the ZIF nano-carrier is ZIF-67 or ZIF-7 or ZIF-8 or ZIF-90.

[0016] The application also provides a use of the above-mentioned anti-coagulation polymer-ZIF nano-drug delivery system composite material in the preparation of a composite coating on the surface of an implant interventional instrument, especially a cardiovascular implant instrument. For this application, the steps include: S01, the substrate material is sequentially cleaned with a cleaning solvent and deionized water, and then dried to obtain a cleaned sample; the substrate material includes titanium-nickel alloy, cobalt-chromium alloy, magnesium alloy, zinc alloy, 316L, polytetrafluoroethylene, polyurethane, polycaprolactone, polylactic acid-polycaprolactone copolymer, porcine pericardial acellular matrix, and bovine pericardial acellular matrix.

[0017] S02, the cleaned sample is activated, and an activated sample is obtained after completion; S03, the activated sample is soaked in an anti-coagulation polymer, washed, and an anti-coagulation pretreated sample is obtained; S04, the anti-coagulation pretreated sample is soaked in a solution containing a ZIF nano-drug delivery system, dried, and sterilized to obtain the anti-coagulation polymer-ZIF nano-drug delivery system composite material.

[0018] The implant interventional instrument prepared by the above steps is mainly used for cardiovascular implant instruments. As a preferred, in step S01, the cleaning solvent is selected from one of ethanol, methanol, and isopropanol.

[0019] As a preferred, in step S01, the titanium-nickel alloy, cobalt-chromium alloy, magnesium alloy, zinc alloy, 316L, polytetrafluoroethylene, polyurethane, polycaprolactone, polylactic acid-polycaprolactone copolymer, porcine pericardial acellular matrix, and bovine pericardial acellular matrix are one of the above-mentioned materials.

[0020] Preferably, in step S02, the activation treatment is specifically: sequentially activating the cleaned sample by oxygen plasma and silane coupling agent, and obtaining the activated sample after completion.

[0021] More specifically, the silane coupling agent is one of γ-aminopropyl triethoxysilane (KH550), N-(β-aminoethyl)-γ-aminopropyl trimethoxysilane (KH792), γ-mercaptopropyl trimethoxysilane (KH590), γ-methacryloxypropyl trimethoxysilane (KH570), vinyl triethoxysilane (A151), and vinyl tri(β-methoxyethoxy)silane (A-172). When the silane coupling agent is selected from KH550 and KH792, the purpose is to introduce amino groups on the surface of the sample. When the silane coupling agent is selected from KH590, the purpose is to introduce mercapto groups on the surface of the sample. When the silane coupling agent is selected from KH570, A151, and A-172, the purpose is to introduce double bonds on the surface of the sample.

[0022] Preferably, in step S03, the anti-aggregation polymer is aldehyde heparin, which is prepared by the following steps: adding sodium periodate (0.2%-10%) to a heparin sodium solution (1%-10%), adjusting the pH to 5.5-9.5, reacting at room temperature for 0.5h-12h, dialyzing, and freeze-drying to obtain aldehyde heparin.

[0023] Preferably, in step S04, the preparation method of the ZIF drug-loaded nanosystem is as follows: The metal salt solution and the organic ligand solution are mixed and stirred at 500 rpm-2000 rpm for 5-30 minutes. Then, the mixed solution is centrifuged at 10000 rpm-15000 rpm for 5-30 minutes, the solvent is discarded, and solid particles are obtained. After washing the solid particles, drying is performed to obtain a ZIF carrier. The ZIF carrier is soaked in the drug solution of claim 2, centrifuged, and the solvent is discarded to obtain drug-loaded nanosolid particles. After washing the nanosolid particles, drying is performed to obtain a ZIF drug-loaded nanosystem.

[0024] Preferably, the metal salt solution is selected from one of 0.01%-5% zinc acetate dihydrate, 0.01%-5% zinc nitrate hexahydrate, and 0.01%-5% cobalt nitrate hexahydrate.

[0025] Preferably, the organic ligand solution is selected from one of 0.01%-5% imidazole-2-carboxaldehyde, 0.01%-5% 2-methylimidazole, and 0.01%-5% benzimidazole.

[0026] Compared with the prior art, the technical scheme of the present application has the following advantages or beneficial effects: 1. The present technology utilizes a low-cost and stable organic-inorganic hybrid ZIF to load anti-inflammatory and antioxidant drugs to construct a nano-drug delivery system. Not only does it retain the ability of ZIF to promote endothelial cell proliferation, but it also first discovers that, compared to the same dose of drugs, the ZIF-based drug delivery system has a more excellent effect on removing excess reactive oxygen species, which is more conducive to endothelial function repair. Compared to traditional technologies such as relying on polypeptides, genes, growth factors, and biologically active gas NO to promote endothelial cell proliferation and migration, the material has better stability and lower production cost.

[0027] 2. The present application prepares a ZIF-based nano-drug delivery system and an anti-coagulation polymer composite material, so that the stent after coating has the ability to promote endothelialization and anticoagulation in situ, which is conducive to achieving long-term patency of the blood flow at the implant site, thereby reducing complications such as thrombosis and stenosis caused by implantation of the device. BRIEF DESCRIPTION OF DRAWINGS

[0028] Figure 1 SEM morphology of the modified substrate in Example 10; Figure 2 Chemical composition of the coating prepared in Example 11 - P fine spectrum; Figure 3 Chemical composition of the coating prepared in Example 11 - Zn fine spectrum; Figure 4 Statistical graph of the number of platelet adhesion on the surface of the samples in Example 8, Example 9, and Example 12; Figure 5 Statistical graph of the DPPH scavenging ability of the ZE nano-drug delivery system prepared in Example 13 and free EGCG; Figure 6 Statistical graph of the O2 .- scavenging ability of the ZE nano-drug delivery system prepared in Example 13 and free EGCG; Figure 7 Statistical graph of the DPPH scavenging ability of the surface of the samples in Example 8, Example 9, and Example 14; Figure 8 Statistical graph of the O2 .- scavenging ability of the surface of the samples in Example 8, Example 9, and Example 14; Figure 9 Fluorescence graph of the endothelial cells cultured on the surface of the samples in Example 8, Example 9, and Example 15 for 24 h; Figure 10 Statistical graph of the proportion of EdU positive cells after 24 h of endothelial cell culture on the surface of the samples in Example 8, Example 9, and Example 15. DETAILED DESCRIPTION

[0029] In the following, the embodiments of the present application will be described in detail with reference to the accompanying drawings and embodiments, so that how the present application applies technical means to solve technical problems and achieves corresponding technical effects can be fully understood and implemented. The embodiments of the present application and various features in the embodiments can be combined with each other without conflict, and the formed technical solutions are all within the protection scope of the present application.

[0030] It should be clear that the embodiments described below are only part of the embodiments of the present application, not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application.

[0031] Embodiment 1: The present embodiment specifically illustrates an anti-coagulation polymer-ZIF nano-drug delivery system composite material and its application in preparing a cardiovascular interventional device surface composite coating. The cardiovascular interventional device surface composite coating specifically comprises the following steps: (1) Cleaning of base material The base material is sequentially cleaned and treated with an alcohol solvent and deionized water, and then dried for use. The base material can be selected from titanium-nickel alloy, cobalt-chromium alloy, magnesium alloy, zinc alloy, 316L, polytetrafluoroethylene, polyurethane, polycaprolactone, polylactic acid-polycaprolactone copolymer, porcine pericardial acellular matrix, and bovine pericardial acellular matrix. The alcohol solvent can be selected from one of methanol, ethanol, and isopropanol.

[0032] (2) Sample activation The sample treated in step (1) is sequentially activated by oxygen plasma and silane coupling agent to construct one or more of a surface containing multiple hydroxyl groups, amino groups, thiol groups, and double bonds.

[0033] (3) Anti-coagulation pretreatment The sample treated in step (2) is soaked in an anti-coagulation polymer solution for 2h-24h, the polymer concentration is 0.02mg / mL-200mg / mL, the temperature is controlled at 4℃-100℃, and the pH is adjusted to 7.5-14.

[0034] (4) The sample treated in step (3) is washed to remove excess anti-coagulation polymer.

[0035] (5) Nano-drug delivery system treatment The sample treated in step (4) is soaked in a solution containing a ZIF nano-drug delivery system for 30min-24h, and the temperature is controlled at 4℃-50℃. (6) The sample treated in step (5) is dried and sterilized. The drying temperature is controlled at 20-100 DEG C, and the time is 2-24 hours. The drying method includes inert gas blowing or heating drying. The sterilization method is not limited to ultraviolet sterilization, ethylene oxide sterilization, Co-60 radiation sterilization, and X-ray sterilization.

[0036] Embodiment 2: Based on embodiment 1, a preparation method of an anticoagulant polymer is provided, and the specific steps are as follows: The anticoagulant polymer is aldehyde heparin.

[0037] The preparation method of the aldehyde heparin includes: adding sodium periodate (0.2%-10%) to a heparin sodium solution (1%-10%), adjusting the pH to 5.5-9.5, reacting at room temperature for 0.5-12 hours, dialyzing, and freeze-drying to obtain the aldehyde heparin.

[0038] Embodiment 3: Based on embodiment 1, a preparation method of an anticoagulant polymer is provided, and the specific steps are as follows: The anticoagulant polymer is thiolated polyethylene glycol.

[0039] The preparation method of the thiolated polyethylene glycol includes: adding N-succinimidyl-3-(2-pyridyl dithio) propionate (0.05%-5%) to an amino polyethylene glycol (2%-20%) solution, adjusting the pH to 5.5-9.5, reacting at room temperature for 0.5-12 hours, adding dithiothreitol and continuing to react for 10 minutes-3 hours, dialyzing, and freeze-drying to obtain the thiolated polyethylene glycol.

[0040] Embodiment 4: Based on embodiment 1, a preparation method of an anticoagulant polymer is provided, and the specific steps are as follows: The anticoagulant polymer is methacrylic acid phosphoryl choline-based polymer.

[0041] The preparation method of the methacrylic acid phosphoryl choline-based polymer includes: dissolving methacrylic acid (5%-45%) and 2-methacryloyloxyethyl phosphoryl choline (55%-95%) in one of water, ethanol, methanol, and isopropanol, adding an initiator (0.1%-10%, one of azobisisobutyronitrile, azobisisoheptyl nitrile, dimethyl azobis isobutyrate, 2,2'-azobis(2-methylpropionamidine) dihydrochloride, potassium persulfate, and ammonium persulfate), and reacting at 40-80 DEG C for 2-24 hours, dialyzing, and freeze-drying to obtain the methacrylic acid phosphoryl choline-based polymer.

[0042] Embodiment 5: Based on embodiment 1, a preparation method of an anticoagulant polymer is provided, and the specific steps are as follows: The anticoagulant polymer is methacrylic acid sulfobetaine-based polymer.

[0043] The preparation method of the methacrylic acid sulfobetaine-based polymer comprises the following steps: dissolving methacrylic acid (5%-45%) and 2-methacrylic acid sulfobetaine (55%-95%) in one of water, ethanol, methanol, and isopropanol; adding an initiator (0.1%-10%, one of azobisisobutyronitrile, azobisisoheptyl nitrile, dimethyl azobisisobutyrate, 2,2'-azobis(2-methylpropionamidine) dihydrochloride, potassium persulfate, and ammonium persulfate); reacting at 40-80°C for 2-24 hours; performing dialysis; and freeze-drying to obtain the methacrylic acid sulfobetaine-based polymer.

[0044] Example 6: Based on example 1, this embodiment provides a preparation method of an anti-aggregation polymer, and the specific steps are as follows: The anti-aggregation polymer is a methacrylic acid carboxybetaine-based polymer.

[0045] The preparation method of the methacrylic acid carboxybetaine-based polymer comprises the following steps: dissolving methacrylic acid (5%-45%) and methacryloyl ethyl carboxybetaine (55%-95%) in one of water, ethanol, methanol, and isopropanol; adding an initiator (0.1%-10%, one of azobisisobutyronitrile, azobisisoheptyl nitrile, dimethyl azobisisobutyrate, 2,2'-azobis(2-methylpropionamidine) dihydrochloride, potassium persulfate, and ammonium persulfate); reacting at 40-80°C for 2-24 hours; performing dialysis; and freeze-drying to obtain the methacrylic acid carboxybetaine-based polymer.

[0046] Example 7: Based on example 1, this embodiment provides a preparation method of a ZIF nano-drug delivery system loaded with drugs, and the specific steps are as follows: The preparation method of the ZIF nano-drug delivery system comprises the following steps: mixing a metal salt solution (one of 0.01%-5% zinc acetate dihydrate, zinc nitrate hexahydrate, and cobalt nitrate hexahydrate) and an organic ligand solution (one of 0.01%-5% imidazole-2-carboxaldehyde, 2-methylimidazole, and benzimidazole) and stirring at 500-2000 rpm for 5-30 minutes. Subsequently, the mixed solution is centrifuged at 10,000-15,000 rpm for 5-30 minutes, washed with methanol three times after the solvent is discarded, and finally dried in a vacuum drying box for 24 hours to obtain the ZIF material.

[0047] Next, the above-mentioned 5-100 mg of ZIF material is soaked in an antioxidant and anti-inflammatory drug solution (i.e., the drug) (1%-5%) at room temperature for 30 minutes-24 hours, and then centrifuged at 10,000-15,000 rpm for 5-30 minutes. After the solvent is discarded, it is washed with methanol three times, and finally dried in a vacuum drying box for 24 hours to obtain the ZIF nano-drug delivery system.

[0048] The composition of the above-mentioned drug includes: curcumin, vitamin C, quercetin, epigallocatechin gallate (EGCG), resveratrol, anthocyanin.

[0049] Example 8: The 316L substrate was cleaned with isopropyl alcohol and deionized water in sequence, dried and ready for use.

[0050] Example 9: The 316L substrate was treated according to the following steps: (1) The 316L substrate was cleaned with isopropyl alcohol and deionized water in sequence, dried and ready for use; (2) The 316L substrate treated in step (1) was activated by oxygen plasma for 5 minutes, and then was placed in a solution containing 2% by mass of vinyltriethoxysilane for 24 hours to introduce vinyl groups; (3) The substrate treated in step (2) was placed in a solution of mercaptized polyethylene glycol and irradiated with ultraviolet light (intensity of 100 μW / cm 2 ) for 10 minutes, wherein the concentration of mercaptized polyethylene glycol was 0.02 mg / mL, the temperature was controlled at 25°C, and the pH was adjusted to 6.5; (4) The sample treated in step (3) was washed to remove excess polymer; (5) The sample treated in step (4) was placed in a ZIF-8 methanol solution with a concentration of 50 μg / mL for 10 min, and the temperature was controlled at 50°C.

[0051] (6) The preparation method of ZIF-8 is as follows: a solution of zinc nitrate hexahydrate with a mass percentage of 0.01% was mixed with a solution of 2-methylimidazole with a mass percentage of 5% and stirred at 500 rpm for 30 minutes. Then, the mixed solution was centrifuged at 10000 rpm for 30 minutes, washed with methanol for 3 times after discarding the solvent, and finally dried in a vacuum drying oven for 24 hours to obtain ZIF-8 material.

[0052] (7) The sample treated in step (5) was heated and dried, and sterilized. The drying temperature was controlled at 100°C, and the time was 24h, and sterilized by Co-60 radiation for standby.

[0053] Example 10: A modified 316L substrate was obtained based on the preparation method provided in Example 9, and the difference between the preparation methods of Example 9 and Example 10 is that ZIF-8 in step (5) is replaced by ZIF-8 nano drug delivery system.

[0054] The preparation method of the above-mentioned ZIF-8 nano drug delivery system is as follows (the drug selected is a curcumin solution): the prepared ZIF-8 material is placed in a 5% curcumin solution by mass fraction, soaked at room temperature for 30 min, then centrifuged at 15000 rpm for 5 min, washed with methanol for 3 times after the solvent is discarded, and finally dried in a vacuum drying box for 24 hours to obtain the ZIF-8 nano drug delivery system.

[0055] The surface morphology is observed by a scanning electron microscope, and it can be seen that the ZIF-8 nano drug delivery system is successfully attached to the surface of the 316L substrate, and the result is shown in FIG. 2. Figure 1

[0056] Example 11: A modified polycaprolactone substrate is obtained based on the preparation method provided in Example 9, and the difference between the preparation methods of Example 9 is that the 316L substrate in step (1) is replaced by a polycaprolactone substrate. The activation treatment process in step (2) is as follows: the treated polycaprolactone substrate in (1) is treated with oxygen plasma for 5 min, then placed in a 2% γ-aminopropyl triethoxysilane solution by mass fraction, and treated for 24 hours to introduce amino groups. The anticoagulation pretreatment process in step (3) is as follows: the substrate treated in step (2) is placed in a methacrylic acid phosphorylcholine-based polymer solution for 24 h, the polymer concentration is 100 mg / mL, the temperature is controlled at 60°C, the pH is adjusted to 7.5, and 2 mg / mL of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 2.5 mg / mL of N-hydroxysuccinimide are added to accelerate the reaction.

[0057] The preparation method of the above-mentioned methacrylic acid phosphorylcholine-based polymer is as follows: 45% methacrylic acid by mass fraction and 55% 2-methacryloyloxyethyl phosphorylcholine by mass fraction are dissolved in water, an initiator (10%, one of 2,2'-azobis(2-methylpropionamidine) dihydrochloride) is added, and the reaction is carried out at 70°C for 24 h. After dialysis, freeze-drying is performed to obtain the methacrylic acid phosphorylcholine-based polymer. In step (5), the ZIF-8 is replaced by a ZIF-90 nano drug delivery system.

[0058] ​The preparation method of the ZIF-90 nano-drug delivery system is as follows (vitamin C solution is selected as the drug): a 5% mass percentage zinc acetate dihydrate solution and a 5% mass percentage imidazole-2-carboxaldehyde solution are mixed and stirred at 2000 rpm for 5 minutes. Subsequently, the mixed solution is centrifuged at 12000 rpm for 15 minutes, and after the solvent is discarded, the ZIF-90 material is obtained by washing with methanol for 3 times and drying in a vacuum drying box for 24 hours. The prepared ZIF-90 material is placed in a 1% mass percentage vitamin C solution, soaked at room temperature for 24 hours, and then centrifuged at 12000 rpm for 15 minutes. After the solvent is discarded, the ZIF-90 nano-drug delivery system is obtained by washing with methanol for 3 times and drying in a vacuum drying box for 24 hours.

[0059] The chemical components of the modified polycaprolactone substrate are observed by X-ray photoelectron spectroscopy. It can be seen that the surface of the modified polycaprolactone substrate has characteristic phosphorus and zinc elements. In addition, the Zn 2p3 / 2 peak observed near 1021 ev confirms that the ZIF-90 nano-drug delivery system on the surface of the coating is attached to the surface of the coating by coordination. The results are shown in FIGS. 1-3. Figure 2 and Figure 3

[0060] Example 12: A modified 316L substrate is obtained based on the preparation method provided in Example 9, but the preparation method is different from that of Example 9 in that ZIF-8 is replaced by ZIF-67 nano-drug delivery system in step (5).

[0061] The preparation method of the ZIF-67 nano-drug delivery system is as follows (quercetin solution is selected as the drug): a 2% mass percentage cobalt nitrate hexahydrate solution and a 2.5% mass percentage 2-methylimidazole solution are mixed and stirred at 1500 rpm for 10 minutes. Subsequently, the mixed solution is centrifuged at 13000 rpm for 12 minutes, and after the solvent is discarded, the ZIF-67 material is obtained by washing with methanol for 3 times and drying in a vacuum drying box for 24 hours. The prepared ZIF-67 material is placed in a 2% mass percentage quercetin solution, soaked at room temperature for 12 hours, and then centrifuged at 13000 rpm for 12 minutes. After the solvent is discarded, the ZIF-67 nano-drug delivery system is obtained by washing with methanol for 3 times and drying in a vacuum drying box for 24 hours.

[0062] The number of activated platelets on the surface of different samples is observed by platelet activation experiment, as shown in Figure 4 ​As shown, the modified 316L substrate prepared by the application has excellent anticoagulation effect, and can reduce the adhesion of activated platelets by about 78% compared with the substrate of Example 8. In addition, the anticoagulation effect of the substrate prepared in Example 9 and the modified substrate prepared in this example is equivalent, which shows that the introduction of the ZIF nano-drug delivery system does not affect the efficacy of the anticoagulation layer.

[0063] Example 13: A modified 316L substrate is obtained based on the preparation method provided in Example 9, but the difference between the preparation method and Example 9 is that ZIF-8 is replaced by ZIF-67 nano-drug delivery system in step (5).

[0064] The preparation method of the ZIF-67 nano-drug delivery system is (drug selection table: epigallocatechin gallate solution): a 1% mass percentage cobalt nitrate hexahydrate solution is mixed with a 3% mass percentage 2-methylimidazole solution and stirred at 1500 rpm for 10 minutes. Then, the mixed solution is centrifuged at 13000 rpm for 12 minutes, and after the solvent is discarded, it is washed with methanol for 3 times, and finally dried in a vacuum drying box for 24 hours to obtain ZIF-67 material. The prepared ZIF-67 material is respectively placed in a 1%, 2%, 3% and 4% mass percentage epigallocatechin gallate solution, soaked at room temperature for 18 hours to obtain ZIF-67 nano-drug delivery systems with different drug loadings (hereinafter abbreviated as: ZE), and then the ZE with different drug loadings, marked as I, II, III and IV, are centrifuged at 14000 rpm for 9 minutes, and after the solvent is discarded, they are washed with methanol for 3 times, and finally dried in a vacuum drying box for 24 hours to obtain ZE with different drug loadings.

[0065] The DPPH and O2 .- scavenging experiments were used to evaluate the active oxygen scavenging capacity of ZE with different drug loadings, as shown in Figure 5 and Figure 6 As shown, the ZE with different drug loadings prepared by the application has stronger DPPH and O2 .- scavenging capacity than the free drug EGCG of the same dose.

[0066] Example 14: A modified 316L substrate is obtained based on the preparation method provided in Example 9, but the difference between the preparation method and Example 9 is that ZIF-8 is replaced by ZIF-90 nano-drug delivery system in step (5).

[0067] The preparation method of the ZIF-90 nano-drug delivery system (the drug selected is a resveratrol solution) is as follows: 3% zinc acetate dihydrate solution and 1.5% imidazole-2-formaldehyde solution are mixed and stirred at 1000 rpm for 10 minutes. Then, the mixed solution is centrifuged at 10000 rpm for 30 minutes, washed with methanol for 3 times after the solvent is discarded, and finally dried in a vacuum drying box for 24 hours to obtain the ZIF-90 material. The prepared ZIF-90 material is placed in a 2.5% resveratrol solution, soaked at room temperature for 15 hours, then centrifuged at 15000 rpm for 5 minutes, washed with methanol for 3 times after the solvent is discarded, and finally dried in a vacuum drying box for 24 hours to obtain the ZIF-90 nano-drug delivery system.

[0068] The DPPH and O2 .- scavenging experiments are used to evaluate the surface reactive oxygen scavenging capacity of different samples, such as Figure 7 and Figure 8 As shown in the above table, the modified substrate prepared by the present application can increase the DPPH scavenging rate by 2.62 times, and the O2 .- scavenging rate by about 0.96 times, compared with the substrate prepared in Example 8.

[0069] Example 15: A modified 316L substrate is prepared based on the preparation method provided in Example 9, but the difference between the preparation methods of Example 9 is that ZIF-8 in step (5) is replaced by ZIF-7 nano-drug delivery system.

[0070] The preparation method of the ZIF-7 nano-drug delivery system (the drug selected is an anthocyanin solution) is as follows: zinc nitrate hexahydrate solution (2%) and benzimidazole solution (5%) are mixed and stirred at 1200 rpm for 12 minutes. Then, the mixed solution is centrifuged at 10000 rpm for 20 minutes, washed with methanol for 3 times after the solvent is discarded, and finally dried in a vacuum drying box for 24 hours to obtain the ZIF-7 material. The prepared ZIF-7 material is placed in a 2.5% anthocyanin solution, soaked at room temperature for 12 hours, then centrifuged at 15000 rpm for 10 minutes, washed with methanol for 3 times after the solvent is discarded, and finally dried in a vacuum drying box for 24 hours to obtain the ZIF-7 nano-drug delivery system.

[0071] The cell proliferation experiment is used to observe the number of newly generated endothelial cells on different surfaces, such as Figure 9 and Figure 10 As shown in the above table, the modified substrate prepared by the present application has excellent promotion effect, and can increase the proliferation of endothelial cells by about 1.14 times, compared with the ordinary substrate prepared in Example 8.

Claims

1. A composite material of an anticoagulant polymer-ZIF nanoparticle drug delivery system, characterized in that, It is made by immobilizing anticoagulant polymers and ZIF nanoparticle drug delivery systems through coordination; The anticoagulant polymer is at least one of aldehyde heparin, mercapto-modified polyethylene glycol, phosphoryl methacrylate choline polymer, sulfobetaine methacrylate polymer, and carboxyl betaine methacrylate polymer. The ZIF nanocarrier system is a ZIF nanocarrier modified with a drug.

2. The anticoagulation polymer-ZIF nanoparticle drug delivery system composite material according to claim 1, characterized in that, The drugs are selected from curcumin, vitamin C, quercetin, epigallocatechin gallate, resveratrol and anthocyanins.

3. The anticoagulation polymer-ZIF nanoparticle drug delivery system composite material according to claim 2, characterized in that, The percentage of drug content in the ZIF nanoparticle drug delivery system ranges from 1% to 50%.

4. The anticoagulation polymer-ZIF nanoparticle drug delivery system composite material according to claim 1, characterized in that, The ZIF nanocarriers are ZIF-67, ZIF-7, ZIF-8, or ZIF-90.

5. A method for preparing a composite coating on the surface of an implantable interventional device, characterized in that, The preparation steps include the following: S01. The substrate material is cleaned sequentially with a cleaning solvent and then with deionized water, and then dried to obtain a clean sample. S02. The clean sample is activated to obtain an activated sample. S03. Immerse the activated sample in the anticoagulant polymer described in claim 1, and wash it to obtain the anticoagulant pretreated sample. S04. Immerse the anticoagulation pretreated sample in a solution containing the ZIF nano-drug delivery system described in claim 1, drain, and sterilize to obtain the anticoagulation polymer-ZIF nano-drug delivery system composite material.

6. The preparation method according to claim 5, characterized in that, In step S01, the cleaning solvent is selected from methanol, ethanol, and isopropanol.

7. The preparation method according to claim 5, characterized in that, In step S01, the substrate material is one of the following: titanium-nickel alloy, cobalt-chromium alloy, magnesium alloy, zinc alloy, 316L, polytetrafluoroethylene, polyurethane, polycaprolactone, polylactic acid-polycaprolactone copolymer, porcine pericardial decellularized matrix, and bovine pericardial decellularized matrix.

8. The preparation method according to claim 5, characterized in that, In step S02, the activation process specifically involves: activating the clean sample sequentially with oxygen plasma and a silane coupling agent, resulting in an activated sample.

9. The preparation method according to claim 8, characterized in that, The silane coupling agent is one of γ-aminopropyltriethoxysilane, N-(β-aminoethyl)-γ-aminopropyltrimethoxysilane, γ-mercaptopropyltrimethoxysilane, γ-methacryloyloxypropyltrimethoxysilane, vinyltriethoxysilane, and vinyltri(β-methoxyethoxy)silane.

10. The preparation method according to claim 5, characterized in that, In step S03, the method for preparing the anticoagulant polymer is as follows: The anticoagulant polymer is aldehyde heparin, which is prepared by the following steps: Sodium periodate was added to the heparin sodium solution to adjust the pH to 5.5-9.5, and the reaction was carried out at room temperature for 0.5-12 hours. After dialysis, the solution was freeze-dried to obtain heparin aldehyde.

11. The preparation method according to claim 5, characterized in that, In step S04, the ZIF nanoparticle drug delivery system is prepared as follows: After mixing the metal salt solution and the organic ligand solution, stir at 500 rpm-2000 rpm for 5-30 minutes; Subsequently, the mixed solution was centrifuged at 10,000 rpm to 15,000 rpm for 5 to 30 minutes, the solvent was discarded, and solid particles were obtained; After washing and drying, the solid particles are used to obtain the ZIF support. The ZIF carrier was immersed in the drug solution described in claim 2, centrifuged, and the solvent was discarded to obtain drug-loaded nanoparticles; after washing and drying, the ZIF nanoparticle drug delivery system was obtained.

12. The preparation method according to claim 11, characterized in that, The metal salt solution is selected from 0.01%-5% zinc acetate dihydrate, 0.01%-5% zinc nitrate hexahydrate, and 0.01%-5% cobalt nitrate hexahydrate.

13. The preparation method according to claim 11, characterized in that, The organic ligand solution is selected from 0.01%-5% imidazole-2-carboxaldehyde, 0.01%-5% 2-methylimidazolium and 0.01%-5% benzimidazole.

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