CN114887117A - Drug-loaded nanoparticle and intravascular stent for reducing postoperative restenosis rate - Google Patents
Drug-loaded nanoparticle and intravascular stent for reducing postoperative restenosis rate Download PDFInfo
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Abstract
The invention aims to provide a drug-loaded nanoparticle MPDA-JTE013 and a vascular stent containing the drug-loaded nanoparticle and capable of reducing restenosis rate in a blood vessel after operation, wherein the drug-loaded nanoparticle MPDA-JTE013 is a porous material, JTE-013 drugs are loaded in holes of the porous material, a drug slow-release coating is coated on the surface of the vascular stent capable of reducing restenosis rate in the stent, the coating contains the drug-loaded nanoparticle MPDA-JTE013, and a stent matrix is a nickel-titanium-copper alloy. The invention constructs Mesoporous Poly Dopamine (MPDA) -JTE013 particle nano-particles, places a vascular stent containing the particle nano-particles into a stenotic/occlusive artery, continuously releases JTE-013 medicines to a stent placement part through slow degradation of poly dopamine, increases the concentration of local tissue JTE-013, and further achieves the purpose of inhibiting restenosis after stent placement operation.
Description
Technical Field
The invention belongs to the field of medical appliances, and particularly provides a drug-loaded nanoparticle MPDA-JTE013 and a nickel-titanium-copper/JTE 013 drug/polydopamine coated intravascular stent for reducing the restenosis rate in a blood vessel after operation.
Background
Cardio-cerebral and peripheral vascular diseases are global diseases with morbidity and mortality rates and early mortality rates, and the number of patients who die globally from the disease has increased by 12.5% over the last 10 years, accounting for about one-third of the total number of deaths. In China, the death and the premature death are the main reasons, and the death rate of the patients is about 40 percent. Therefore, the cardiovascular and cerebrovascular diseases and peripheral vascular diseases become one of the global major public health problems which seriously jeopardize the life health and the quality of life of human beings and need to be solved urgently. Atherosclerosis is the main culprit in the occurrence and development of cardiovascular and cerebrovascular diseases, especially vascular stenosis/occlusive diseases. The interventional therapy mainly based on the stent implantation has become the first choice method for the clinical treatment of the diseases due to the advantages of small trauma, high success rate of the operation, less complications, quick recovery after the operation and the like. However, the incidence of restenosis in the post-operative stent is always high, thereby seriously affecting the medium and long term efficacy of stent therapy. Therefore, how to reduce the restenosis rate of the vascular stent is a major clinical problem troubling the medical field, and has become one of the research hotspots and difficulties in the fields of interventional medicine, materials science and biomedical engineering.
Lower limb arteriosclerotic occlusion refers to progressive narrowing or occlusion of the lumen of a lower limb artery due to diseases such as atherosclerosis. With the change of people's life style and the coming of aging society, the disease seriously jeopardizes people's physical health and gradually becomes one of the major public health problems that people must face at present and even in the future. Interventional therapy based on stenting has become the first choice for treating atherosclerosis-induced stenosis/occlusive disease of the lower extremities, especially long-term occlusive lesions.
However, the occurrence of restenosis in the stent seriously affects the medium-term and long-term efficacy of interventional therapy and limits the wide application of the minimally invasive treatment method. Various intravascular stents applied and developed at present have the problem that the restenosis in the middle and long periods after the stent is implanted cannot be solved. Therefore, how to reduce the restenosis rate of the vascular stent becomes a research difficulty and a hotspot in the medical field and even the material field.
Disclosure of Invention
The invention aims to provide a drug-loaded nanoparticle MPDA-JTE013 and a vascular stent containing the drug-loaded nanoparticle and capable of reducing postoperative restenosis rate.
The technical scheme of the invention is as follows:
a drug-loaded nanoparticle MPDA-JTE013 is characterized in that the drug-loaded nanoparticle is a porous material, JTE-013 drugs are loaded in holes of the drug-loaded nanoparticle, and the specific preparation method is as follows:
1) and synthesizing mesoporous polydopamine
Dissolving poloxamer and 1,3, 5-trimethylbenzene in an ethanol water solution, stirring and dissolving, firstly adding a trihydroxymethylaminomethane solution, then adding dopamine hydrochloride, reacting the obtained mixture for 24-72h at room temperature, and preliminarily collecting a product; extracting to remove the template, and centrifuging at a high speed to collect the synthesized mesoporous polydopamine;
2) JTE-013 medicine loading
Dispersing mesoporous polydopamine and JTE-013 medicines in a mass ratio of 1:1-1:5 in a methanol solution, stirring for 24-72h to carry medicines, enriching the JTE-013 medicines in the mesoporous polydopamine, and centrifugally collecting medicine carrying nanoparticles MPDA-JTE 013.
As a preferred technical scheme:
in the step 1), the concentration of the ethanol aqueous solution is 30-60%, and the mass ratio of poloxamer to 1,3, 5-trimethylbenzene is 1:1-1: 2.
In the step 2), the mesoporous polydopamine and JTE-013 drugs are dispersed in a methanol solution according to the mass ratio of 1:1-1: 5.
The optimal preparation method of the drug-loaded nanoparticle MPDA-JTE013 comprises the following steps:
1) and synthesizing mesoporous polydopamine
Preparation of 65 mL H 2 Mixing of O and 60 mL ethanolDissolving 0.36 g of poloxamer and 0.36 g of 1,3, 5-trimethylbenzene in the solution, stirring and dissolving, firstly adding 90 mg of 90% trihydroxymethylaminomethane solution, then adding 60 mg of dopamine hydrochloride, reacting the obtained mixture at room temperature for 24 hours, and primarily collecting the product; extracting to remove the template, and centrifuging at a high speed to collect the synthesized mesoporous polydopamine;
2) JTE-013 medicine loading
Dispersing mesoporous polydopamine and JTE-013 medicines in a mass ratio of 1:1 in a methanol solution, stirring for 24 hours to carry medicines, enriching the JTE-013 medicines in the mesoporous polydopamine, and centrifugally collecting medicine-carrying nanoparticles MPDA-JTE 013.
The invention also provides a vascular stent for reducing the restenosis rate in the stent, which is characterized in that: the surface of the stent is coated with a drug sustained-release coating, the coating contains drug-loaded nanoparticles MPDA-JTE013, and the stent matrix is nickel-titanium-copper alloy.
The invention relates to a preparation method of a vascular stent for reducing the restenosis rate in the stent, which is characterized by comprising the following steps: soaking the nickel-titanium-copper alloy stent matrix in a Tris buffer solution-dopamine hydrochloride solution at room temperature overnight to form a polydopamine coating; then taking out the nickel-titanium-copper alloy bracket, washing with distilled water and drying; dispersing drug-loaded nanoparticles MPDA-JTE013 in PBS (phosphate buffer solution) with the pH of 7.4 to form MPDA-JTE013 particle solution; and putting the nickel-titanium-copper alloy stent coated with the polydopamine into MPDA-JTE013 particle solution for reaction for 24-72h to prepare the polydopamine-MPDA-JTE 013-nickel-titanium-copper coated stent.
As a preferred technical scheme:
the pH value of the Tris buffer solution-dopamine hydrochloride solution is 8.5, the concentration of Tris is 10 mM, and the concentration of dopamine hydrochloride is 2 mg/ml.
In the polydopamine-MPDA-JTE 013-nickel-titanium-copper coating, the concentration of dopamine is 2-50 mg/ml, and the concentration of JTE-013 drugs is 1-50 mu M.
JTE-013 drug (hereinafter referred to as JTE 013): are antagonists of sphingosine-1-phosphate receptor 2 (S1 PR 2). High expression of S1PR2 increases endothelial cell permeability, resulting in decreased endothelial barrier function. The invention protects the barrier function of endothelial cells by selectively inhibiting S1PR2, thereby achieving the purpose of reducing the restenosis rate after stent implantation.
The invention puts JTE-013 medicine into medicine-carrying nano-particles, fixes the JTE-013 medicine on the surface of a vascular stent to form a medicine slow-release coating, puts the vascular stent with the medicine slow-release coating into a stenotic/occluded artery, continuously releases JTE-013 medicine to the stent placement part through the slow degradation of polydopamine, increases the concentration of JTE-013 local tissues, and further achieves the purpose of inhibiting restenosis after stent placement.
The invention has the beneficial effects that:
1. the invention constructs Mesoporous Polydopamine (MPDA) -JTE013 particle nanoparticles, is used for reducing the restenosis rate of a vascular stent, and provides a new idea for surface functionalization of a titanium implant.
2. The invention utilizes the polydopamine coating to adhere the JTE-013 drugs to the surface of the nickel-titanium-copper substrate and achieves the effect of slow release.
3. The vascular stent is placed into a stenotic/occlusive artery, JTE-013 drugs are continuously released to the stent placement part through slow degradation of polydopamine, the concentration of JTE-013 in local tissues is increased, and the purpose of inhibiting restenosis after stent placement is achieved.
Drawings
FIG. 1 is a schematic cross-sectional view of a vascular stent of the present invention.
FIG. 2 scanning electron micrographs of NiTi-Cu-polydopamine coating.
FIG. 3 is a scanning electron micrograph of NiTi-Cu.
FIG. 4 endothelial cell scratching experiment (CON: control group; JTE013 group: drug concentration 1. mu.M).
FIG. 5 CCK8 smooth muscle cell proliferation experiment (CON: control; JTE 013: drug concentration 1. mu.M).
Reference numerals: 1. the stent comprises a stent matrix, 2, a polydopamine coating, 3, copper ions and 4, drug-loaded nanoparticles.
Detailed Description
Example 1
Preparing medicine-carrying nanoparticles MPDA-JTE 013:
1) and synthesizing mesoporous polydopamine
Preparation of 65 mL H 2 O and 60 mL of ethanol, 0.36 g of poloxamer (F127) and 0.36 g of 1,3, 5-Trimethylbenzene (TMB) are dissolved in the above solution, and after stirring and dissolution, 90 mg of TRIS solution (H) is added 2 O10 mL), then adding 60 mg of dopamine hydrochloride, reacting the obtained mixture at room temperature for 24 hours, and primarily collecting the product; extracting to remove the template, and centrifuging at high speed to collect the synthesized Mesoporous Polydopamine (MPDA);
2) JTE-013 medicine loading
MPDA and JTE-013 drugs are dispersed in methanol solution according to the mass ratio of 1:1, the mixture is stirred for 24 hours for carrying drugs, the JTE-013 drugs are gradually enriched in mesoporous polydopamine through pi-pi aggregation and hydrophilic/hydrophobic effects, and drug-carrying nanoparticles MPDA-JTE013 are centrifugally collected.
Example 2
Preparing the vascular stent:
soaking a nickel-titanium-copper alloy stent matrix in a Tris buffer solution-dopamine hydrochloride solution (pH 8.5, the concentration of Tris is 10 mM, and the concentration of dopamine hydrochloride is 2 mg/ml) at room temperature overnight to form a polydopamine coating; then taking out the nickel-titanium-copper alloy bracket, washing the nickel-titanium-copper alloy bracket with distilled water for three times, and drying the nickel-titanium-copper alloy bracket; dispersing drug-loaded nanoparticles MPDA-JTE013 in PBS (phosphate buffer solution) with the pH of 7.4 to form MPDA-JTE013 particle solution; and putting the nickel-titanium-copper alloy stent coated with the polydopamine into an MPDA-JTE013 particle solution for reaction for 24 hours to prepare the polydopamine-MPDA-JTE 013-nickel-titanium-copper coating stent, wherein the concentration of the JTE-013 drugs in the polydopamine-MPDA-JTE 013-nickel-titanium-copper coating is 1 mu M.
The surface topography of the different scaffold samples was characterized using a field emission scanning electron microscope (FE-SEM), as shown in fig. 2, 3.
Example 3
1) And synthesizing mesoporous polydopamine
Preparation of 65 mL H 2 O and 60 mL of ethanol, 0.36 g of poloxamer (F127) and 0.72 g of 1,3, 5-trimethylbenzene(TMB) was dissolved in the above solution, and after stirring and dissolving, 90 mg of TRIS solution (H) was added 2 O10 mL), then adding 60 mg of dopamine hydrochloride, reacting the obtained mixture at room temperature for 24 hours, and primarily collecting the product; extracting to remove the template, and centrifuging at high speed to collect the synthesized Mesoporous Polydopamine (MPDA);
2) JTE-013 medicine loading
MPDA and JTE-013 drugs are dispersed in methanol solution according to the mass ratio of 1:1, the mixture is stirred for 24 hours for carrying drugs, the JTE-013 drugs are gradually enriched in mesoporous polydopamine through pi-pi aggregation and hydrophilic/hydrophobic effects, and drug-carrying nanoparticles MPDA-JTE013 are centrifugally collected.
3) Preparation of vascular stent
Preparing the vascular stent:
soaking a nickel-titanium-copper alloy stent matrix in a Tris buffer solution-dopamine hydrochloride solution (pH 8.5, the concentration of Tris is 10 mM, and the concentration of dopamine hydrochloride is 2 mg/ml) at room temperature overnight to form a polydopamine coating; then taking out the nickel-titanium-copper alloy bracket, washing the nickel-titanium-copper alloy bracket with distilled water for three times, and drying the nickel-titanium-copper alloy bracket; dispersing drug-loaded nanoparticles MPDA-JTE013 in PBS (phosphate buffer solution) with the pH of 7.4 to form MPDA-JTE013 particle solution; and putting the nickel-titanium-copper alloy stent coated with the polydopamine into an MPDA-JTE013 particle solution for reaction for 48 hours to prepare the polydopamine-MPDA-JTE 013-nickel-titanium-copper coating stent, wherein the concentration of the JTE-013 drugs in the polydopamine-MPDA-JTE 013-nickel-titanium-copper coating is 1 mu M.
As shown in fig. 4, the results of the endothelial cell scratch test were obtained by dividing the area of cell migration by the area of the original scratch area to obtain the relative migration area. The larger the relative migration area data, the stronger the endothelial cell lateral migration ability. The experimental results show that the data of JTE013 group and the control group are statistically different (P < 0.0001) after 6h and 24h of drug administration, so JTE013 can promote the lateral migration of endothelial cells.
FIG. 5 shows the result of CCK8 experiment on smooth muscle cell proliferation, the proliferation of smooth muscle cells in JTE013(1 μ M) containing medium can be studied by CCK8 experiment, and the result of CCK8 experiment shows that JTE013 can inhibit the proliferation of smooth muscle cells (P <0.01) compared with the control group, and the absorbance values of blank wells are subtracted.
The invention is not the best known technology.
The above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (8)
1. A drug-loaded nanoparticle MPDA-JTE013 is characterized in that the drug-loaded nanoparticle is a porous material, JTE-013 drugs are loaded in holes of the drug-loaded nanoparticle, and the specific preparation method is as follows:
1) and synthesizing mesoporous polydopamine
Dissolving poloxamer and 1,3, 5-trimethylbenzene in an ethanol water solution, stirring and dissolving, firstly adding a trihydroxymethylaminomethane solution, then adding dopamine hydrochloride, reacting the obtained mixture for 24-72h at room temperature, and preliminarily collecting a product; extracting to remove the template, and collecting the synthesized mesoporous polydopamine by high-speed centrifugation;
2) JTE-013 medicine loading
Dispersing mesoporous polydopamine and JTE-013 medicines in a mass ratio of 1:1-1:5 in a methanol solution, stirring for 24-72h to carry medicines, enriching the JTE-013 medicines in the mesoporous polydopamine, and centrifugally collecting medicine carrying nanoparticles MPDA-JTE 013.
2. The drug-loaded nanoparticle MPDA-JTE013 according to claim 1, wherein: in the step 1), the concentration of the ethanol aqueous solution is 30-60%, and the mass ratio of poloxamer to 1,3, 5-trimethylbenzene is 1:1-1: 2.
3. The drug-loaded nanoparticle MPDA-JTE013 according to claim 1, wherein: in the step 2), the mesoporous polydopamine and JTE-013 drugs are dispersed in a methanol solution according to the mass ratio of 1:1-1: 5.
4. The drug-carrying nanoparticle MPDA-JTE013 according to claim 1, wherein the preparation method of the drug-carrying nanoparticle MPDA-JTE013 comprises the following steps:
1) and synthesizing mesoporous polydopamine
Preparation of 65 mL H 2 Dissolving 0.36 g of poloxamer and 0.36 g of 1,3, 5-trimethylbenzene in a mixture of O and 60 mL of ethanol, stirring to dissolve, adding 90 mg of 90% trihydroxymethyl aminomethane solution, adding 60 mg of dopamine hydrochloride, reacting the obtained mixture at room temperature for 24 hours, and primarily collecting a product; extracting to remove the template, and centrifuging at a high speed to collect the synthesized mesoporous polydopamine;
2) JTE-013 medicine loading
Dispersing mesoporous polydopamine and JTE-013 medicines in a mass ratio of 1:1 in a methanol solution, stirring for 24 hours to carry medicines, enriching the JTE-013 medicines in the mesoporous polydopamine, and centrifugally collecting medicine-carrying nanoparticles MPDA-JTE 013.
5. A vascular stent for reducing the rate of in-stent restenosis, characterized by: the surface of the stent is coated with a drug sustained-release coating, the coating contains drug-loaded nanoparticles MPDA-JTE013, and the stent matrix is nickel-titanium-copper alloy.
6. A method for preparing a vascular stent for reducing the restenosis rate in a stent according to claim 5, wherein: soaking the nickel-titanium-copper alloy stent matrix in a Tris buffer solution-dopamine hydrochloride solution at room temperature overnight to form a polydopamine coating; then taking out the nickel-titanium-copper alloy bracket, washing with distilled water and drying; dispersing drug-loaded nanoparticles MPDA-JTE013 in PBS (phosphate buffer solution) with pH 7.4 to form MPDA-JTE013 particle solution; and putting the nickel-titanium-copper alloy stent coated with the polydopamine into MPDA-JTE013 particle solution for reaction for 24-72h to prepare the polydopamine-MPDA-JTE 013-nickel-titanium-copper coated stent.
7. A vascular stent for reducing the rate of in-stent restenosis according to claim 5, wherein: the pH value of the Tris buffer solution-dopamine hydrochloride solution is 8.5, the concentration of Tris is 10 mM, and the concentration of dopamine hydrochloride is 2 mg/ml.
8. A vascular stent for reducing the rate of in-stent restenosis according to claim 5, wherein: in the polydopamine-MPDA-JTE 013-nickel-titanium-copper coating, the concentration of dopamine is 2-50 mg/ml, and the concentration of JTE-013 drugs is 1-50 mu M.
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