CN111450326A - Drug coating for selenazolidone-loaded blood vessel stent and preparation method thereof - Google Patents
Drug coating for selenazolidone-loaded blood vessel stent and preparation method thereof Download PDFInfo
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Abstract
The invention provides a selenazolidone-loaded vascular stent drug coating, which is a selenazolidone-loaded redox-responsive vascular stent drug coating and comprises a drug and a drug carrier, wherein the drug is a selenazolidone compound, and the drug carrier is a degradable high molecular polymer with the mass ratio of 1-30%. The invention provides a preparation method of two selenazolone compounds and a preparation method of a drug coating. The application direction of the drug coating is intravascular stent, which can eliminate generated free radicals, reduce the damage of endothelial cells caused by oxidative stress and realize rapid endothelialization through the controlled release of the loaded drug, thereby having the function of resisting the formation of atherosclerosis and reducing the occurrence of stent neoatherosclerosis.
Description
Technical Field
The invention belongs to the field of medical appliances, and particularly relates to a selenium-loaded oxazolone redox-responsive intravascular stent drug coating, and a preparation method and application thereof.
Background
The formation of atherosclerotic plaques remains a major cause of high morbidity and mortality of cardiovascular disease in developed and developing countries. The world health organization estimates that about 1670 million people die each year from atherosclerotic cardiovascular disease. Atherosclerotic plaque rupture is a common cause of cardiovascular disease, and the pathogenesis and progression are mostly related to oxidative stress resulting from disruption of normal homeostatic mechanisms. The progression of atherosclerosis in cardiovascular disease is caused by oxidative stress leading to the oxidation of low density lipoproteins in endothelial cells, leading to the event of endothelial injury forming fibrous plaques.
Oxidative stress is defined as an unbalanced redox state in which pro-oxidants are higher than antioxidant capacity, resulting in increased production of reactive oxygen species. Reactive oxygen species in physiological states, which are involved in various modifications of cell growth, stress adaptation, and injury response. While reactive oxygen species in pathological states are associated with apoptosis, cell functional impairment and tissue damage. The major vasoactive oxygen species are superoxide anions which inactivate nitric oxide, and the high levels of reactive oxygen species and nitric oxide bioavailability reduce their critical role in vascular remodeling, which can oxidize proteins, lipids and nucleic acids, leading to cellular damage, all contributing to narrowing of the arterial lumen.
Selenazolone compounds are a class of organic selenium compounds that can mimic the activity of glutathione peroxidase. The selenium-nitrogen bond has unique selenium-nitrogen bond, and once the selenium-nitrogen bond meets active free radicals, the selenium-nitrogen bond can be broken and reacts with the free radicals to consume the free radicals, so that the selenium-nitrogen bond has good oxidation resistance. Wherein the most basic one of the selenazolone compounds is ebselen. Research shows that ebselen can reduce oxidative stress associated with ischemia/reperfusion and prevent apoptosis caused by ischemic heart reperfusion by protecting glutathione. Ebselen also reduces apoptotic cell death during open heart surgery by preventing free radical formation. In spontaneously hypertensive rats prone to stroke, ebselen protects the endothelium and vascular structure during chronic hypertension. Therefore, the selenazolone compound can be used as a potential medicament for treating atherosclerosis.
Disclosure of Invention
Aiming at promoting the formation of atherosclerosis by oxidative stress, the invention aims to provide a selenium-loaded oxazolone redox-responsive intravascular stent drug coating and a preparation method thereof.
The technical scheme of the invention is as follows:
a drug coating of a selenazolone-loaded vascular stent is a redox-responsive vascular stent drug coating of selenazolone, and comprises a drug and a drug carrier, wherein the drug is a selenazolone compound, the drug carrier is a degradable high-molecular polymer, and the drug is a selenazolone compound and comprises one or more of N-phenyl-benzisoselenazolone (also called ebselen), N- (4-carboxyphenyl) -benzisoselenazolone, N- (4-hydroxymethylphenyl) -benzisoselenazolone, N-phenyl-6-fluoro-benzisoselenazolone or N- (4-hydroxymethylphenyl) -6-fluoro-benzisoselenazolone;
wherein the chemical structural formula of the N-phenyl-6-fluoro-benzisoselenazolone is as follows:
the chemical structural formula of the N- (4-hydroxymethyl phenyl) -6-fluoro-benzisoselenazolone is as follows:
the drug carrier is degradable high molecular polymer, and comprises one or more of polytrimethylene carbonate (PTMC), polylactic acid (P L A), polylactic acid-glycolic acid copolymer (P L GA) and polycaprolactone (PC L).
Wherein: the chemical structural formulas of N-phenyl-benzisoselenazolone (also known as ebselen), N- (4-carboxyphenyl) -benzisoselenazolone and N- (4-hydroxymethylphenyl) -benzisoselenazolone are as follows: a is N-phenyl-benzisoselenazolone, B is N- (4-carboxyphenyl) -benzisoselenazolone, C is N- (4-hydroxymethylphenyl) -benzisoselenazolone:
preferably, the mass ratio of the drug to the drug carrier is 1% to 30%.
The mass ratio of the medicine to the medicine carrier is 1-30: 100, namely the medicine loading is 1-30%.
The selenazolone compound can be used as a potential medicament for treating atherosclerosis. However, selenazolone compounds such as ebselen have poor water solubility and have certain limitations in practical use, and therefore, improvement of the structure thereof is required. The fluorine element has better hydrophilicity, and the introduction of the fluorine element can improve the water solubility of the selenazolidone compound to a certain extent.
The invention also provides a synthetic method of the N-phenyl-6-fluoro-benzisoselenazolone and the N- (4-hydroxymethyl phenyl) -6-fluoro-benzisoselenazolone.
The method for synthesizing the N-phenyl-6-fluoro-benzisoselenazolone or the N- (4-hydroxymethyl phenyl) -6-fluoro-benzisoselenazolone comprises the following steps:
s1: measuring volume ratio of 1: 1, weighing 0.5-50 g of 4-fluoro-2-aminobenzoic acid and adding into the mixed solvent of concentrated hydrochloric acid and water; dropwise adding an aqueous solution of sodium nitrite into the solution in ice bath, and continuously stirring for 1 hour to obtain a diazonium salt solution;
s2: weighing 0.5-50 g of potassium borohydride and adding the potassium borohydride into water; under argon atmosphere and ice bath, adding 1g to 100g of selenium powder into the solution in batches, continuously stirring for half an hour, and then adding an aqueous solution of sodium hydroxide to obtain a potassium diselenide solution;
s3: dropwise adding the solution of S1 into the solution of S2 in an argon atmosphere and ice bath, continuously stirring for 3 hours at the temperature of 60-70 ℃, filtering the solution, taking filtrate, dropwise adding dilute hydrochloric acid, separating out a precipitate, filtering, taking a filter cake, purifying by using a column, and drying in vacuum to obtain 2, 2-diselenide bis (4-fluorobenzoic acid);
s4: weighing 0.5-50 g of 2, 2-diselenide bis (4-fluorobenzoic acid) and adding the 2, 2-diselenide bis (4-fluorobenzoic acid) into dichloromethane, continuously stirring for 3 hours at 70-80 ℃, and removing the solvent by rotary evaporation to obtain 4-fluoro-2-chloroselenobenzoyl chloride;
s5: 1. adding 0.5-50 g of aniline and triethylamine into dichloromethane, dropwise adding a dichloromethane solution containing 4-fluoro-2-chloroselenobenzoyl chloride into the solution under ice bath, continuously stirring for 6 hours at room temperature, extracting, washing with water, removing the solvent by rotary evaporation, purifying with a column, and drying in vacuum to obtain N-phenyl-6-fluoro-benzisoselenazolone; 2. adding 0.5-50 g of p-hydroxymethylbenzoic acid and triethylamine into dichloromethane, dropwise adding a dichloromethane solution containing 4-fluoro-2-chloroselenobenzoyl chloride into the solution under ice bath, continuously stirring for 6 hours at room temperature, extracting, washing with water, removing the solvent by rotary evaporation, purifying with a column, and drying in vacuum to obtain the N- (4-hydroxymethylphenyl) -6-fluoro-benzoisoselenazolone.
The invention also provides a preparation method of the intravascular stent drug coating.
The preparation method of the intravascular stent drug coating comprises the following steps:
s1: stirring the medicine and the medicine carrier in a solvent according to a certain proportion to fully dissolve the medicine and the medicine carrier to obtain a dispersion solution of the medicine and the medicine carrier;
s2, immersing the obtained dispersion solution on the surface of a 316L stainless steel sheet, and naturally drying;
s3, putting the 316L stainless steel sheet with the drug coating into a vacuum drying oven for vacuum drying for 24h to obtain the selenium-loaded oxazolone redox-responsive intravascular stent drug coating.
The preparation method of the intravascular stent drug coating comprises the steps of using one or two of tetrahydrofuran and dichloromethane as a solvent, naturally drying the solvent at room temperature through natural volatilization, and drying the solvent at room temperature in vacuum.
The selenazolidone-loaded intravascular stent drug coating is a selenazolidone-loaded redox-responsive intravascular stent drug coating, and is used for controlling the release of the loaded drug, eliminating generated free radicals, reducing the damage of endothelial cells caused by oxidative stress and realizing rapid endothelialization of the intravascular stent, thereby having the function of resisting the formation of atherosclerosis and reducing the occurrence of stent neoatherosclerosis.
Drawings
FIG. 1 is a surface topography of a prepared PE5 drug coating observed by a scanning electron microscope;
FIG. 2 is a surface topography of a prepared PE10 drug coating observed by a scanning electron microscope;
FIG. 3 shows the result of CCK-8 co-culture of the selenium-loaded coating with endothelial cells in the presence of hydrogen peroxide.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in further detail below with reference to the accompanying drawings and specific embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
Weighing a mixed solvent of 10ml of concentrated hydrochloric acid and 10ml of water, and weighing 3.10g of 4-fluoro-2-aminobenzoic acid and adding the solvent; dropwise adding an aqueous solution containing 1.45g of sodium nitrite into the solution under ice bath, and continuously stirring for 1 hour to obtain a diazonium salt solution; 0.79g of potassium borohydride is weighed and added into 40ml of water; under argon atmosphere and ice bath, adding 1.74 of selenium powder into the solution in batches, continuously stirring for half an hour, and then adding an aqueous solution containing 5.2g of sodium hydroxide to obtain a potassium diselenide solution; dropwise adding the solution of S1 into the solution of S2 in an argon atmosphere and ice bath, continuously stirring for 3 hours at the temperature of 60-70 ℃, filtering the solution, taking filtrate, dropwise adding dilute hydrochloric acid, separating out a precipitate, filtering, taking a filter cake, purifying by using a column, and drying in vacuum to obtain 2, 2-diselenide bis (4-fluorobenzoic acid);
weighing 1.00g of 2, 2-diselenide bis (4-fluorobenzoic acid) and adding the weighed 2, 2-diselenide bis (4-fluorobenzoic acid) into 5ml of thionyl chloride, continuously stirring for 3 hours at the temperature of 70-80 ℃, and removing the solvent by rotary evaporation to obtain 4-fluoro-2-chloroselenobenzoyl chloride;
adding 0.5ml of aniline and 0.8ml of triethylamine into 20ml of dichloromethane, dropwise adding a dichloromethane solution containing 1.48g of 4-fluoro-2-chloroselenobenzoyl chloride into the solution under ice bath, continuously stirring for 6 hours at room temperature, extracting, washing with water, removing the solvent by rotary evaporation, purifying with a column, and drying in vacuum to obtain the N-phenyl-6-fluoro-benzisoselenazolone.
Example 2
Weighing a mixed solvent of 10ml of concentrated hydrochloric acid and 10ml of water, and weighing 3.10g of 4-fluoro-2-aminobenzoic acid and adding the solvent; dropwise adding an aqueous solution containing 1.45g of sodium nitrite into the solution under ice bath, and continuously stirring for 1 hour to obtain a diazonium salt solution; 0.79g of potassium borohydride is weighed and added into 40ml of water; under argon atmosphere and ice bath, adding 1.74 of selenium powder into the solution in batches, continuously stirring for half an hour, and then adding an aqueous solution containing 5.2g of sodium hydroxide to obtain a potassium diselenide solution; dropwise adding the solution of S1 into the solution of S2 in an argon atmosphere and ice bath, continuously stirring for 3 hours at the temperature of 60-70 ℃, filtering the solution, taking filtrate, dropwise adding dilute hydrochloric acid, separating out a precipitate, filtering, taking a filter cake, purifying by using a column, and drying in vacuum to obtain 2, 2-diselenide bis (4-fluorobenzoic acid);
weighing 1.00g of 2, 2-diselenide bis (4-fluorobenzoic acid) and adding the weighed 2, 2-diselenide bis (4-fluorobenzoic acid) into 5ml of thionyl chloride, continuously stirring for 3 hours at the temperature of 70-80 ℃, and removing the solvent by rotary evaporation to obtain 4-fluoro-2-chloroselenobenzoyl chloride;
0.56g of p-hydroxymethylbenzoic acid and 0.8ml of triethylamine are taken and added into 20ml of dichloromethane, under ice bath, dichloromethane solution containing 1.24g of 4-fluoro-2-chloro-selenobenzoyl chloride is dripped into the solution, the mixture is continuously stirred for 6 hours at room temperature, extracted, washed by water, and subjected to rotary evaporation to remove the solvent, column purification and vacuum drying, thus obtaining the N- (4-hydroxymethyl-phenyl) -6-fluoro-benzoisoselenazolone.
Example 3
The selected drug is ebselen, the selected drug carrier is polytrimethylene carbonate, 5mg of ebselen and 100mg of polytrimethylene carbonate are respectively weighed and dissolved in 10ml of dichloromethane, ultrasonic degassing is slowly transferred to a polytetrafluoroethylene sample cell, a clean 316L stainless steel sheet is placed in the solution, after the solvent is naturally volatilized, vacuum drying is carried out for 24h, and the drug coating with the drug-loading mass proportion of 5 percent is obtained, and the scanning electron microscope picture of the coating is marked as PE5 and is shown in figure 1.
Example 4
Respectively weighing 10mg of ebselen and 100mg of polytrimethylene carbonate, dissolving the ebselen and the polytrimethylene carbonate into 10ml of dichloromethane, slowly transferring the solutions into a polytetrafluoroethylene sample cell by ultrasonic degassing, placing a clean 316L stainless steel sheet into the solutions, and after the solvent is naturally volatilized, carrying out vacuum drying for 24 hours to obtain a drug coating with the drug-loading mass proportion of 10%, wherein the picture of a scanning electron microscope of the coating is marked as PE10 and is shown in an attached figure 1.
Example 5
The preparation method comprises the steps of selecting N- (4-carboxyphenyl) -benzisoselenazolone as a selected medicine, selecting polytrimethylene carbonate as a selected medicine carrier, weighing 30mg of N- (4-carboxyphenyl) -benzisoselenazolone and 100mg of polytrimethylene carbonate respectively, dissolving in 20ml of tetrahydrofuran, carrying out ultrasonic degassing, slowly transferring into a polytetrafluoroethylene sample cell, placing a clean 316L stainless steel sheet into the solution, and carrying out vacuum drying for 24 hours after the solvent is naturally volatilized to obtain the medicine coating with the medicine loading mass proportion of 30%.
Example 6
Respectively weighing 1mg of N- (4-hydroxymethyl phenyl) -benzisoselenazolone and 100mg of polytrimethylene carbonate, dissolving in 15ml of tetrahydrofuran, ultrasonically degassing, slowly transferring into a polytetrafluoroethylene sample cell, placing a clean 316L stainless steel sheet into the solution, and drying in vacuum for 24 hours after the solvent is naturally volatilized to obtain the drug coating with the drug loading mass ratio of 1%.
Example 7
Respectively weighing 20mg of N-phenyl-6-fluoro-benzisoselenazolone and 100mg of polytrimethylene carbonate, dissolving in 10ml of dichloromethane, slowly transferring into a polytetrafluoroethylene sample cell by ultrasonic degassing, placing a clean 316L stainless steel sheet into the solution, naturally volatilizing the solvent, and drying in vacuum for 24 hours to obtain the drug coating with the drug loading mass ratio of 20%.
Example 8
Respectively weighing 8mg of N- (4-hydroxymethyl phenyl) -6-fluoro-benzisoselenazolone and 100mg of polytrimethylene carbonate, dissolving in 15ml of tetrahydrofuran, ultrasonically degassing, slowly transferring into a polytetrafluoroethylene sample cell, placing a clean 316L stainless steel sheet into the solution, and drying in vacuum for 24h after the solvent is naturally volatilized to obtain the drug coating with the drug loading mass ratio of 8%.
Example 9
Respectively weighing 10mg of ebselen and 100mg of polylactic acid, dissolving in 10ml of chloroform, ultrasonically degassing, slowly transferring into a polytetrafluoroethylene sample cell, placing a clean 316L stainless steel sheet into the solution, naturally volatilizing the solvent, and vacuum drying for 24h to obtain a drug coating with the drug loading mass ratio of 10%.
Example 10
Respectively weighing 10mg of ebselen and 100mg of polylactic acid-glycolic acid copolymer, dissolving in 10ml of dichloromethane, ultrasonically degassing, slowly transferring into a polytetrafluoroethylene sample cell, placing a clean 316L stainless steel sheet into the solution, and vacuum drying for 24 hours after the solvent is naturally volatilized to obtain the drug coating with the drug loading mass ratio of 10%.
Example 11
Respectively weighing 10mg of ebselen and 100mg of polycaprolactone, dissolving the ebselen and the polycaprolactone in 10ml of dichloromethane, slowly transferring the ebselen and the polycaprolactone into a polytetrafluoroethylene sample cell by ultrasonic degassing, placing a clean 316L stainless steel sheet into the solution, and performing vacuum drying for 24 hours after the solvent is naturally volatilized to obtain the drug coating with the drug loading mass ratio of 10%.
Test methods and results:
1. the surface topography of the drug coating was observed using a scanning electron microscope and the results from fig. 1 and 2 show that the PE5 and PE10 drug coatings had smooth, non-shedding, and non-cracking surfaces.
2. By co-culturing the drug coating and endothelial cells in different environments and performing CCK-8 measurements, it is shown from the results of fig. 3 that the activity of endothelial cells cultured on Stainless Steel (SS) and PTMC coatings is greatly inhibited in the presence of hydrogen peroxide relative to the normal environment, but the activity of endothelial cells cultured on PE5 and PE10 coatings is not significantly affected.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (5)
1. The drug coating of the selenazolidone-loaded blood vessel stent is a redox-responsive blood vessel stent drug coating of the selenazolidone-loaded blood vessel stent, and comprises a drug and a drug carrier, wherein the drug is a selenazolidone compound, and the drug carrier is a degradable high molecular polymer, and is characterized in that:
the medicine is a selenazolone compound, and comprises one or more of N-phenyl-benzisoselenazolone (also known as ebselen), N- (4-carboxyphenyl) -benzisoselenazolone, N- (4-hydroxymethyl phenyl) -benzisoselenazolone, N-phenyl-6-fluoro-benzisoselenazolone or N- (4-hydroxymethyl phenyl) -6-fluoro-benzisoselenazolone;
wherein the chemical structural formula of the N-phenyl-6-fluoro-benzisoselenazolone is as follows:
the chemical structural formula of the N- (4-hydroxymethyl phenyl) -6-fluoro-benzisoselenazolone is as follows:
the drug carrier is degradable high molecular polymer, and comprises one or more of polytrimethylene carbonate (PTMC), polylactic acid (P L A), polylactic acid-glycolic acid copolymer (P L GA) and polycaprolactone (PC L).
2. The drug coating of the vascular stent according to claim 1, wherein the mass ratio of the drug to the drug carrier is 1-30%.
3. The drug coating for vascular stents according to claim 1, characterized in that the method for synthesizing N-phenyl-6-fluoro-benzisoselenazolone or N- (4-hydroxymethylphenyl) -6-fluoro-benzisoselenazolone comprises the following steps:
s1: measuring volume ratio of 1: 1, weighing 0.5-50 g of 4-fluoro-2-aminobenzoic acid and adding into the mixed solvent of concentrated hydrochloric acid and water; dropwise adding an aqueous solution of sodium nitrite into the solution in ice bath, and continuously stirring for 1 hour to obtain a diazonium salt solution;
s2: weighing 0.5-50 g of potassium borohydride and adding the potassium borohydride into water; under argon atmosphere and ice bath, adding 1g to 100g of selenium powder into the solution in batches, continuously stirring for half an hour, and then adding an aqueous solution of sodium hydroxide to obtain a potassium diselenide solution;
s3: dropwise adding the solution of S1 into the solution of S2 in an argon atmosphere and ice bath, continuously stirring for 3 hours at the temperature of 60-70 ℃, filtering the solution, taking filtrate, dropwise adding dilute hydrochloric acid, separating out a precipitate, filtering, taking a filter cake, purifying by using a column, and drying in vacuum to obtain 2, 2-diselenide bis (4-fluorobenzoic acid);
s4: weighing 0.5-50 g of 2, 2-diselenide bis (4-fluorobenzoic acid) and adding the 2, 2-diselenide bis (4-fluorobenzoic acid) into dichloromethane, continuously stirring for 3 hours at 70-80 ℃, and removing the solvent by rotary evaporation to obtain 4-fluoro-2-chloroselenobenzoyl chloride;
s5: 1. adding 0.5-50 g of aniline and triethylamine into dichloromethane, dropwise adding a dichloromethane solution containing 4-fluoro-2-chloroselenobenzoyl chloride into the solution under ice bath, continuously stirring for 6 hours at room temperature, extracting, washing with water, removing the solvent by rotary evaporation, purifying with a column, and drying in vacuum to obtain N-phenyl-6-fluoro-benzisoselenazolone; 2. adding 0.5-50 g of p-hydroxymethylbenzoic acid and triethylamine into dichloromethane, dropwise adding a dichloromethane solution containing 4-fluoro-2-chloroselenobenzoyl chloride into the solution under ice bath, continuously stirring for 6 hours at room temperature, extracting, washing with water, removing the solvent by rotary evaporation, purifying with a column, and drying in vacuum to obtain the N- (4-hydroxymethylphenyl) -6-fluoro-benzoisoselenazolone.
4. A method for preparing a drug coating of a vascular stent according to claim 1, which comprises the following steps:
s1: stirring the medicine and the medicine carrier in a solvent according to a certain proportion to fully dissolve the medicine and the medicine carrier to obtain a dispersion solution of the medicine and the medicine carrier;
s2, immersing the obtained dispersion solution on the surface of a 316L stainless steel sheet, and naturally drying;
s3, putting the 316L stainless steel sheet with the drug coating into a vacuum drying oven for vacuum drying for 24h to obtain the selenium-loaded oxazolone redox-responsive intravascular stent drug coating.
5. The preparation method of the drug coating of the vascular stent according to claim 4, wherein the solvent is one or a mixture of tetrahydrofuran and dichloromethane, the natural drying is natural volatilization of the solvent at room temperature, and the vacuum drying is at room temperature.
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