CN111603616B - Nanofibrous vascular stent material with dual drug loading and staged sustained release function and preparation method thereof - Google Patents
Nanofibrous vascular stent material with dual drug loading and staged sustained release function and preparation method thereof Download PDFInfo
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Abstract
本发明公开了一种具有双药负载和分阶缓释功能的新型纳米纤维血管支架材料及其制备方法，该支架材料外层偶联的免疫球蛋白lgG抗体刺激细胞形成上皮组织，降低形成血栓的风险；由于支架外层聚乳酸的分解，缓慢释放其负载的青霉素，抑制不正常细胞的分裂和生长；由于支架内层壳聚糖结合的一氧化氮供体分解，缓慢释放一氧化氮自由基，以扩张血管和抑制肿瘤生长；该支架材料具备负载青霉素和一氧化氮双重药物，并逐层分阶段缓释药物的功能，有望在临床上作为新型多功能血管支架，植入病人的心脏冠状动脉血管，达到支撑病灶血管、降低血栓风险、抑制细胞病变、自由基扩张血管、抑制肿瘤生长等诸多术后治疗效果。
The invention discloses a novel nanofiber vascular stent material with dual-drug loading and staged sustained release functions and a preparation method thereof. The immunoglobulin IgG antibody coupled to the outer layer of the stent material stimulates cells to form epithelial tissue and reduces the formation of thrombus. due to the decomposition of polylactic acid in the outer layer of the scaffold, slowly releasing its loaded penicillin, inhibiting the division and growth of abnormal cells; due to the decomposition of the nitric oxide donor bound to chitosan in the inner layer of the scaffold, slowly releasing nitric oxide free It can expand blood vessels and inhibit tumor growth; the stent material has the function of loading dual drugs of penicillin and nitric oxide, and slowly releasing drugs layer by layer. Coronary blood vessels, to support the focal blood vessels, reduce the risk of thrombosis, inhibit cytopathic changes, free radicals to expand blood vessels, inhibit tumor growth and many other postoperative treatment effects.
Description
Technical Field
The invention belongs to the technical field of preparation of nano-drug carriers and intravascular stent materials, and particularly relates to a novel nano-fiber intravascular stent material with double-drug loading and step-by-step slow release functions and a preparation method thereof.
Background
After cardiac vasodilator surgery, 30% of patients face the problem of vessel narrowing within half a year. Since the blood vessel of the patient is not normally restored after the operation, many cells are generated to block the blood vessel, so that the patient needs to perform a bypass operation or angioplasty again. In order to avoid narrowing and blocking of blood vessels after operation, an inner support is required to be placed in a focus section so as to achieve the purposes of supporting the narrow occlusion section blood vessels, preventing the blood vessels from elastic retraction and reshaping and keeping the blood flow in a lumen smooth. In the early 80 s of the 20 th century, physicians assumed to stented stiff, stenotic coronary arteries of the heart. At present, vascular stents have undergone the development process of metal stents, drug-coated stents and bioabsorbable stents. In order to avoid the problems of scar tissue regeneration, inflammatory reaction, artery restenosis, blockage and the like caused by the metal stent, a layer of medicine film is plated on the surface of the metal stent, and the medicine is slowly released, so that the growth of scar tissue around the stent can be inhibited, and the coronary artery is kept unblocked. However, the metal stent has high hardness, high toughness and poor biocompatibility, and the body can use the metal stent as a foreign body to form a wound area at the contact part of the metal stent and the artery membrane, thereby causing local inflammatory reaction. Scientists reported a third generation of bioabsorbable vascular stents at the beginning of the 21 st century. The soluble stent is absorbed by the body after being implanted for 7-10 days, completely disappears after 3 months, nearly 80% of arteries are still unblocked after 6 months, and the soluble stent is expected to leave a plurality of catheter treatment opportunities for patients.
The ideal blood vessel stent has the characteristics of flexibility, good tracer property, thrombus resistance, good biocompatibility, reliable expansion performance, good supporting force, accordance with hydromechanics and the like. In current clinical applications, although each stent has its own characteristics, there is no stent that fully satisfies the above characteristics, and development of a stent with ideal characteristics has become one of the goals of continuous efforts of researchers. For example, the mat discloses a vascular stent material consisting of a zinc alloy matrix, an amino functional group-rich polymeric coating and a drug-loaded polylactic acid-glycolic acid copolymer coating (the mat is a zinc alloy vascular stent material with a drug slow-release function and an ultrahigh flexible coating, namely Chinese patent publication No. CN 110180038A); lijun et al discloses a nano-gel body coated intravascular stent (Lijun; Chen Qi Xian, a nano-drug sustained release device used as an outer package of the intravascular stent, Chinese patent publication No. CN 208243663U); the lingchumei discloses a vascular stent coating with a drug slow-release function (the lingchumei, a vascular stent coating with a drug slow-release function and a preparation method thereof, Chinese invention patent publication No. CN 106139259A); the patent publication No. CN1557507 of China invention discloses a drug sustained-release type vascular stent (depot forest, Puyupo, Linnanhua, Scheixiao swallow, Shengang, restenosis-preventing drug sustained-release type vascular stent and a preparation method thereof) which can prevent vascular restenosis after stent operation.
The invention designs a novel nano fiber vascular stent material on the basis of a drug coating stent, and the stent material is implanted into a cardiac coronary artery blood vessel and is used for supporting a stenotic occlusion segment blood vessel. The antibody coupled to the outer layer of the stent stimulates cells to form epithelial tissues so as to reduce the risk of thrombosis; polymer-loaded antibiotics are slowly released due to the decomposition of the polymer on the outer layer of the stent (first stage), and abnormal cell division and growth are inhibited; the nitric oxide donor, bound by the polymer of the inner layer of the stent, decomposes, slowly releasing nitric oxide radicals (second stage) to expand the blood vessels and inhibit tumor growth. Based on the design, the invention discloses a preparation method of a novel nanofiber vascular stent material, and the stent material has the functions of loading double drugs and gradually releasing the drugs layer by layer in a staged manner. The stent material is expected to be used as a multifunctional vascular stent clinically, implanted into a heart coronary artery blood vessel, and achieves the postoperative treatment effects of supporting a focus blood vessel, reducing the risk of thrombus, inhibiting cytopathic effect, expanding the blood vessel by free radicals, inhibiting tumor growth and the like, which integrate multiple functions. At present, no domestic and foreign documents and patent reports of a nanofiber vascular stent material with double-drug loading and step-by-step slow release functions exist.
Disclosure of Invention
The invention aims to overcome the problems in the prior art and design a novel nanofiber vascular stent material which integrates multiple functions of supporting focus blood vessels, reducing thrombus risk, inhibiting cytopathic effect, expanding blood vessels by free radicals, inhibiting tumor growth and the like.
In order to achieve the aim, the invention relates to a novel nanofiber vascular stent material with double-drug loading and step-by-step slow release functions and a preparation method thereof, and the preparation method specifically comprises the following steps:
(1) weighing 2g of chitosan CS with the relative molecular mass of 1 ten thousand, dripping 2mL of acetic acid for dissolution, then adding 50mL of ethanol for dispersion, and forming a homogeneous solution under magnetic stirring; adding 5mL of tetraethyl orthosilicate TEOS into the homogeneous solution, and magnetically stirring for 6h to prepare a slightly viscous transparent TEOS/CS electrospinning precursor solution;
(2) filling the electrospinning precursor solution into a 5mL plastic syringe for electrospinning; wherein the voltage is 5-20 kV, the spinning solidification distance is 10-30 cm, the needle size is 0.2-0.8 mm, and the jet velocity is 0.2-0.8 mms–1The translation speed is 50-500 mmmin–1(ii) a Preparing the SiO dioxide/chitosan nano composite fiber material SiO2Performing freeze drying treatment to obtain a super-elastic three-dimensional ceramic fiber scaffold;
(3) the chitosan-coated beaded silicon dioxide nano-fiber SiO2/CS Dispersion in ethanol and dropwise addition of nitric oxide donor Lawsonia melanophore RBS, Fe, under magnetic stirring4S3(NO)7 –Aqueous solution of sodium salt to form homogeneous SiO2CS-RBS self-assembly solution;
(4) preparing 10-30 wt% of polylactic acid (PLA) ethanol solution and the SiO2Mixing the/CS-RBS self-assembly solution, forming homogeneous solution under magnetic stirring, and electrospinning with the homogeneous solution as electrospinning precursor solution to obtain SiO2a/CS-RBS/PLA nanocomposite fibre material;
(5) coupling the above SiO by using a carboxy-amine coupling reaction2Polylactic acid PLA on/CS-RBS/PLA coupled to immunoglobulin lgG antibody, then 5-25 UmL–1Incubating penicillin PG aqueous solution for 6-24 h, carrying out drug loading of PG, and freeze-drying to obtain SiO2The novel nanofiber vascular stent material of/CS-RBS/lgG-PLA-PG is ready for use;
(6) mixing SiO2Placing the/CS-RBS/lgG-PLA-PG for 1-15 days, slightly washing with ethanol, freeze-drying, weighing the product with an electronic balance, comparing the mass of the product at different placing times, calculating the loss of the mass of the lgG-PLA-PG caused by the decomposition of the polylactic acid PLG in different degradation times, and measuring the ultraviolet-visible absorption of the PGThe spectrum is obtained, the characteristic absorption peak is 210-215 nm, and the drug release concentration of PG is calculated;
(7) the SiO obtained after degradation2Dispersing the/CS-RBS self-assembly in ethanol, standing for 1-15 days, measuring the concentration change of Nitric Oxide (NO) in the ethanol solution in different degradation times by adopting a Grignard reaction and a colorimetric method, and calculating the SiO2Concentration of nitric oxide released by RBS in CS-RBS.
The invention has the following effects: discloses a novel nano-fiber intravascular stent material with double-drug loading and step-by-step slow release functions and a preparation method thereof. Preparing intrinsically rigid and structurally flexible chitosan-coated beaded silicon dioxide nanofiber SiO by using tetraethoxysilane TEOS as a silicon source and biocompatible chitosan CS as a bonding site through an electrostatic spinning technology2/CS, by-NH of CS3 +Fe site and NO donor RBS4S3(NO)7 –Self-assembly to form SiO2(ii) a CS-RBS self-assembly; adding degradable high molecular material polylactic acid (PLA) and SiO2the/CS-RBS is blended to form an electrospinning precursor for electrospinning to prepare SiO2a/CS-RBS/PLA nanocomposite fibre material; wherein PLA is coupled with immunoglobulin lgG antibody, then antibiotics such as penicillin PG is loaded into PLA network framework to prepare SiO2A novel nanofiber vascular stent material assembled layer by layer through/CS-RBS/lgG-PLA-PG. The novel intravascular stent material has multiple functions of clear layers: 1) the lgG antibody stimulates cells to form epithelial tissue, reducing the risk of thrombosis; 2) PG released from the PLA carrier inhibits the division and growth of abnormal cells, and prevents hyperplastic cells from blocking blood vessels; 3) after PLA is degraded, the combined donor on CS releases NO free radical to expand blood vessel, inhibit tumor growth and achieve the purpose of cancer prevention and resistance.
Drawings
FIG. 1 SiO2The preparation process of the novel/CS-RBS/lgG-PLA-PG nanofiber intravascular stent material, and the principle schematic diagram of double-drug loading and step-by-step slow release.
Detailed Description
The present invention will be described in detail below with reference to the accompanying drawings by way of specific embodiments.
Example 1
SiO according to the present embodiment2The preparation process of the/CS-RBS/lgG-PLA-PG novel nano-fiber intravascular stent material, the principle schematic diagram of double-drug loading and step slow release are shown in figure 1, and the specific steps are as follows:
weighing 2g of CS with the relative molecular mass of 1 ten thousand, dripping 2mL of acetic acid for dissolution, then adding 50mL of ethanol for dispersion, and forming a homogeneous solution under magnetic stirring; 5ml of TEOS is added into the homogeneous solution, and the solution is magnetically stirred for 6 hours to prepare slightly viscous transparent TEOS/CS electrospinning precursor solution. Filling the electrospinning precursor solution into a 5mL plastic syringe for electrospinning; wherein the voltage is (-3 kV,5kV), the spinning solidification distance is 10cm, the needle size is 0.2mm, and the jet velocity is 0.2mms–1The translation speed is 100mm min–1(ii) a To obtain SiO2And then carrying out freeze drying treatment on the/CS nano composite fiber material to obtain the super-elastic three-dimensional ceramic fiber scaffold.
Mixing SiO2/CS Dispersion in ethanol and dropwise addition of NO donor RBS, Fe, under magnetic stirring4S3(NO)7 –Aqueous solution of sodium salt to form homogeneous SiO2CS-RBS self-assembly solution. Preparing PLA ethanol solution with the mass fraction of 10 wt% and SiO2Mixing with CS-RBS, magnetically stirring to form homogeneous solution, and electrospinning to obtain SiO2a/CS-RBS/PLA nanocomposite fibre material. By coupling reaction of carboxyl-amine, SiO2PLA on/CS-RBS/PLA coupled to immunoglobulin lgG antibody, then 5UmL–1Incubating penicillin PG aqueous solution for 6h, carrying out drug loading of PG, and freeze-drying to obtain SiO2Novel nanofiber vascular stent material of/CS-RBS/lgG-PLA-PG.
Mixing SiO2placing/CS-RBS/lgG-PLA-PG for 1, 3, 5, 7, 9, 11, 13 and 15 days respectively, slightly washing with ethanol, freeze-drying, weighing the product with an electronic balance, comparing the mass of the product at different placing times, calculating the loss amount of the quality of the lgG-PLA-PG caused by the decomposition of the PLG at different degradation times, and determining the ultraviolet-visible property of the PGThe drug release concentration of PG is calculated by the characteristic absorption peak of 212nm in the absorption spectrum. The SiO obtained after degradation2Dispersing the/CS-RBS self-assembly in ethanol, standing for 1, 3, 5, 7, 9, 11, 13 and 15 days, measuring the change of the concentration of NO in the ethanol solution in different degradation times by adopting a Grignard reaction and a colorimetric method, and calculating the SiO2Concentration of NO released by RBS in CS-RBS.
Example 2
SiO according to the present embodiment2The preparation process of the/CS-RBS/lgG-PLA-PG novel nano-fiber intravascular stent material, the principle schematic diagram of double-drug loading and step slow release are shown in figure 1, and the specific steps are as follows:
weighing 2g of CS with the relative molecular mass of 1 ten thousand, dripping 2mL of acetic acid for dissolution, then adding 50mL of ethanol for dispersion, and forming a homogeneous solution under magnetic stirring; 5ml of TEOS is added into the homogeneous solution, and the solution is magnetically stirred for 6 hours to prepare slightly viscous transparent TEOS/CS electrospinning precursor solution. Filling the electrospinning precursor solution into a 5mL plastic syringe for electrospinning; wherein the voltage is (-3 kV,10kV), the spinning solidification distance is 15cm, the needle size is 0.4mm, and the jet velocity is 0.4mms–1The translation speed is 200mm min–1(ii) a To obtain SiO2And then carrying out freeze drying treatment on the/CS nano composite fiber material to obtain the super-elastic three-dimensional ceramic fiber scaffold.
Mixing SiO2/CS Dispersion in ethanol and dropwise addition of NO donor RBS, Fe, under magnetic stirring4S3(NO)7 –Aqueous solution of sodium salt to form homogeneous SiO2CS-RBS self-assembly solution. Preparing 15 wt% PLA ethanol solution and SiO2Mixing with CS-RBS, magnetically stirring to form homogeneous solution, and electrospinning to obtain SiO2a/CS-RBS/PLA nanocomposite fibre material. By coupling reaction of carboxyl-amine, SiO2PLA on/CS-RBS/PLA coupled to immunoglobulin lgG antibody, then 10UmL–1Incubating penicillin PG aqueous solution for 12h, carrying out drug loading of PG, and freeze-drying to obtain SiO2Novel nanofiber vascular stent material of/CS-RBS/lgG-PLA-PG。
Mixing SiO2Placing the/CS-RBS/lgG-PLA-PG for 1, 3, 5, 7, 9, 11, 13 and 15 days respectively, slightly washing with ethanol, freeze-drying, weighing the product by an electronic balance, comparing the mass of the product at different placing times, calculating the loss amount of the mass of the lgG-PLA-PG caused by the decomposition of the PLG at different degradation times, measuring the ultraviolet-visible absorption spectrum of the PG, wherein the characteristic absorption peak is 213nm, and calculating the drug release concentration of the PG. The SiO obtained after degradation2Dispersing the/CS-RBS self-assembly in ethanol, standing for 1, 3, 5, 7, 9, 11, 13 and 15 days, measuring the change of the concentration of NO in the ethanol solution in different degradation times by adopting a Grignard reaction and a colorimetric method, and calculating the SiO2Concentration of NO released by RBS in CS-RBS.
Example 3
SiO according to the present embodiment2The preparation process of the/CS-RBS/lgG-PLA-PG novel nano-fiber intravascular stent material, the principle schematic diagram of double-drug loading and step slow release are shown in figure 1, and the specific steps are as follows:
weighing 2g of CS with the relative molecular mass of 1 ten thousand, dripping 2mL of acetic acid for dissolution, then adding 50mL of ethanol for dispersion, and forming a homogeneous solution under magnetic stirring; 5ml of TEOS is added into the homogeneous solution, and the solution is magnetically stirred for 6 hours to prepare slightly viscous transparent TEOS/CS electrospinning precursor solution. Filling the electrospinning precursor solution into a 5mL plastic syringe for electrospinning; wherein the voltage is (-3 kV,15kV), the spinning solidification distance is 20cm, the needle size is 0.6mm, and the jet velocity is 0.6mms–1The translation speed is 300mm min–1(ii) a To obtain SiO2And then carrying out freeze drying treatment on the/CS nano composite fiber material to obtain the super-elastic three-dimensional ceramic fiber scaffold.
Mixing SiO2/CS Dispersion in ethanol and dropwise addition of NO donor RBS, Fe, under magnetic stirring4S3(NO)7 –Aqueous solution of sodium salt to form homogeneous SiO2CS-RBS self-assembly solution. Preparing 20 wt% PLA ethanol solution and SiO2Mixing with CS-RBS, magnetically stirring to obtain homogeneous solution, and electrospinningTo obtain SiO2a/CS-RBS/PLA nanocomposite fibre material. By coupling reaction of carboxyl-amine, SiO2PLA on/CS-RBS/PLA coupled to immunoglobulin lgG antibody, then 15UmL–1Incubating penicillin PG aqueous solution for 18h, carrying out drug loading of PG, and freeze-drying to obtain SiO2Novel nanofiber vascular stent material of/CS-RBS/lgG-PLA-PG.
Mixing SiO2Placing the/CS-RBS/lgG-PLA-PG for 1, 3, 5, 7, 9, 11, 13 and 15 days respectively, slightly washing with ethanol, freeze-drying, weighing the product by an electronic balance, comparing the mass of the product at different placing times, calculating the loss amount of the mass of the lgG-PLA-PG caused by the decomposition of the PLG at different degradation times, measuring the ultraviolet-visible absorption spectrum of the PG, wherein the characteristic absorption peak is 214nm, and calculating the drug release concentration of the PG. The SiO obtained after degradation2Dispersing the/CS-RBS self-assembly in ethanol, standing for 1, 3, 5, 7, 9, 11, 13 and 15 days, measuring the change of the concentration of NO in the ethanol solution in different degradation times by adopting a Grignard reaction and a colorimetric method, and calculating the SiO2Concentration of NO released by RBS in CS-RBS.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (1)
1. The preparation method of the nanofiber vascular stent material with double-drug loading and step-by-step slow release functions is characterized by comprising the following steps:
(1) weighing 2g of chitosan CS with the relative molecular mass of 1 ten thousand, dripping 2mL of acetic acid for dissolution, then adding 50mL of ethanol for dispersion, and forming a homogeneous solution under magnetic stirring; adding 5mL of tetraethyl orthosilicate TEOS into the homogeneous solution, and magnetically stirring for 6h to prepare a slightly viscous transparent TEOS/CS electrospinning precursor solution;
(2) filling the electrospinning precursor solution into a 5mL plastic syringe for electrospinning; wherein the voltage is 5-20 kV, the spinning solidification distance is 10-30 cm, needle size of 0.2-0.8 mm, and jet speed of 0.2-0.8 mm s–1The translation speed is 50-500 mm min–1(ii) a Preparing the SiO dioxide/chitosan nano composite fiber material SiO2Performing freeze drying treatment to obtain a super-elastic three-dimensional ceramic fiber scaffold;
(3) the obtained chitosan-coated beaded silicon dioxide nano-fiber SiO is subjected to silica gel filtration2/CS Dispersion in ethanol and dropwise addition of nitric oxide donor Lawsonia melanophore RBS, Fe, under magnetic stirring4S3(NO)7 –Aqueous solution of sodium salt to form homogeneous SiO2CS-RBS self-assembly solution;
(4) preparing 10-30 wt% of polylactic acid (PLA) ethanol solution and the SiO2Mixing the/CS-RBS self-assembly solution, forming homogeneous solution under magnetic stirring, and electrospinning with the homogeneous solution as electrospinning precursor solution to obtain SiO2a/CS-RBS/PLA nanocomposite fibre material;
(5) coupling the above SiO by using a carboxy-amine coupling reaction2Polylactic acid PLA on/CS-RBS/PLA coupled to immunoglobulin lgG antibody, then 5-25U mL–1Incubating penicillin PG aqueous solution for 6-24 h, carrying out drug loading of PG, and freeze-drying to obtain SiO2the/CS-RBS/lgG-PLA-PG nano fiber vascular stent material is ready for use;
(6) mixing SiO2Placing the/CS-RBS/lgG-PLA-PG for 1-15 days, slightly washing with ethanol, freeze-drying, weighing the product by using an electronic balance, comparing the mass of the product at different placing times, calculating the loss amount of the lgG-PLA-PG mass caused by the decomposition of polylactic acid PLA within different degradation times, measuring the ultraviolet-visible absorption spectrum of PG, wherein the characteristic absorption peak is 210-215 nm, and calculating the drug release concentration of PG;
(7) the SiO obtained after degradation2Dispersing the/CS-RBS self-assembly in ethanol, standing for 1-15 days, measuring the concentration change of Nitric Oxide (NO) in the ethanol solution in different degradation times by adopting a Grignard reaction and a colorimetric method, and calculating the SiO2Concentration of nitric oxide released by RBS in CS-RBS.
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| PCT/CN2020/100530 WO2021243796A1 (en) | 2020-06-04 | 2020-07-07 | New nanofiber vascular stent material with dual-drug loading and staged slow-release functions and preparation method therefor |
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