CN114887117B - Drug-loaded nanoparticle and vascular stent for reducing restenosis rate in blood vessel after operation - Google Patents
Drug-loaded nanoparticle and vascular stent for reducing restenosis rate in blood vessel after operation Download PDFInfo
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Abstract
The invention aims to provide drug-loaded nano-particles MPDA-JTE013 and a vascular stent containing the drug-loaded nano-particles, wherein the drug-loaded nano-particles MPDA-JTE013 are porous materials, JTE-013 drugs are loaded in holes of the drug-loaded nano-particles MPDA-JTE013, a drug slow release coating is coated on the surface of the vascular stent capable of reducing the restenosis rate in the stent, the drug-loaded nano-particles MPDA-JTE013 are contained in the coating, and a stent matrix is nickel titanium copper alloy. The invention constructs Mesoporous Polydopamine (MPDA) -JTE013 particle nanometer, places a vascular stent containing the particle nanometer into a stenosed/occluded artery, continuously releases JTE-013 medicine to a stent placement position through slow degradation of polydopamine, and increases the concentration of local tissue JTE-013, thereby achieving the purpose of inhibiting restenosis after stent placement.
Description
Technical Field
The invention belongs to the field of medical equipment, and particularly provides a drug-loaded nanoparticle MPDA-JTE013 and a nickel titanium copper/JTE 013 drug/polydopamine coated vascular stent for reducing restenosis rate in a blood vessel after operation.
Background
Cardiovascular and cerebrovascular diseases are global diseases with incidence and mortality and early mortality in the forefront, and the number of patients dying from the disease worldwide increases by 12.5% in the past 10 years, accounting for about one third of the total number of deaths. In China, the main causes of death and premature death are about 40% of the patients dying from the diseases. Therefore, cardiovascular and cerebrovascular diseases and peripheral vascular diseases have become one of the global serious public health problems which seriously endanger human life health and quality of life and need to be solved. Atherosclerosis is the leading cause of heart, brain and peripheral vascular disease, especially vascular stenosis/occlusive disease. The interventional treatment mainly based on stent implantation has become the first choice for clinical treatment of the diseases due to the advantages of small trauma, high success rate of operation, less complications, quick postoperative recovery and the like. However, the incidence of restenosis in postoperative stents has remained high, severely affecting the mid-to-long-term efficacy of stent treatment. Therefore, how to reduce the restenosis rate of vascular stents has been a major clinical problem plaguing the medical community and has become one of the research hotspots and difficulties in the fields of interventional medicine and materials as well as biomedical engineering.
The lower limb arteriosclerosis obliterans refer to progressive stenosis or occlusion of the lumen of the lower limb artery due to diseases such as atherosclerosis. With the advent of life style changes and social aging, the disease has seriously endangered the physical health of people and has become one of the major public health problems that people must face at present or even in the future. Stenting-based interventions have become the method of choice for the treatment of arterial stenosis/occlusive disease of the lower extremities, especially long-range occlusive lesions, caused by atherosclerosis.
However, occurrence of restenosis in the stent seriously affects the mid-to-long term efficacy of the interventional procedure and limits the wide application of such minimally invasive procedures. Various intravascular stents applied and developed at present can not solve the problem of middle and long-term restenosis after stent implantation. Therefore, how to reduce the restenosis rate of vascular stents has become a difficult and hot point of research in the medical and even material industries.
Disclosure of Invention
The invention aims to provide a drug-loaded nanoparticle MPDA-JTE013 and a vascular stent containing the drug-loaded nanoparticle, which can reduce the restenosis rate in a blood vessel after operation.
The technical scheme of the invention is as follows:
the medicine carrying nanoparticle MPDA-JTE013 is characterized in that the medicine carrying nanoparticle is a porous material, and JTE-013 medicine is loaded in the pores of the medicine carrying nanoparticle, and the specific preparation method is as follows:
1) Synthesis of mesoporous polydopamine
Dissolving poloxamer and 1,3, 5-trimethylbenzene in ethanol water solution, stirring and dissolving, adding a tris (hydroxymethyl) aminomethane solution, adding dopamine hydrochloride, reacting the obtained mixture at room temperature for 24-72h, and primarily collecting a product; extracting to remove a template, and centrifuging at a high speed to collect synthesized mesoporous polydopamine;
2) JTE-013 loaded medicament
Dispersing mesoporous polydopamine and JTE-013 drugs in a methanol solution according to a mass ratio of 1:1-1:5, stirring for 24-72h for drug loading, enriching the JTE-013 drugs in the mesoporous polydopamine, and centrifugally collecting drug loading nano particles MPDA-JTE013.
As a preferable 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), mesoporous polydopamine and JTE-013 drugs are dispersed in a methanol solution according to a mass ratio of 1:1-1:5.
The optimal preparation method of the drug-loaded nanoparticle MPDA-JTE013 comprises the following steps:
1) Synthesis of mesoporous polydopamine
Preparation of 65 mL H 2 O and 60 mL ethanol, 0.36: 0.36 g poloxamerAnd 0.36 g of 1,3, 5-trimethylbenzene are dissolved in the solution, after stirring and dissolving, 90 mg percent of tris (hydroxymethyl) aminomethane solution with the concentration of 90 percent is added, then 60 mg dopamine hydrochloride is added, the obtained mixture reacts at room temperature for 24h, and the product is collected initially; extracting to remove a template, and centrifuging at a high speed to collect synthesized mesoporous polydopamine;
2) JTE-013 loaded medicament
Dispersing mesoporous polydopamine and JTE-013 drugs in a methanol solution according to a mass ratio of 1:1, stirring for 24 hours to carry out drug loading, enriching the JTE-013 drugs in the mesoporous polydopamine, and centrifugally collecting drug loading nano particles MPDA-JTE013.
The invention also provides a vascular stent for reducing restenosis rate in the stent, which is characterized in that: the surface of the stent is coated with a drug release coating, the coating contains drug-loaded nano particles MPDA-JTE013, and the stent matrix is nickel-titanium-copper alloy.
The preparation method of the vascular stent for reducing the restenosis rate in the stent is characterized by comprising the following steps of: soaking a nickel-titanium-copper alloy stent matrix in Tris buffer-dopamine hydrochloride solution, and standing overnight at room temperature to form a polydopamine coating; then taking out the nickel-titanium-copper alloy bracket, washing with distilled water and drying; dispersing the drug-loaded nano-particles MPDA-JTE013 in PBS with the pH of 7.4 to form MPDA-JTE013 particle solution; and (3) placing the polydopamine coated nickel-titanium-copper alloy stent into MPDA-JTE013 particle solution to react for 24-72h, so as to obtain the polydopamine-MPDA-JTE 013-nickel-titanium-copper coated stent.
As a preferable technical scheme:
the pH of the Tris buffer solution-dopamine hydrochloride solution is 8.5, the Tris concentration is 10 mM, and the dopamine hydrochloride concentration 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 medicine is 1-50 mu M.
JTE-013 drug (hereinafter referred to as JTE 013): is an antagonist of sphingosine-1-phosphate receptor 2 (S1 PR 2). High expression of S1PR2 increases endothelial cell permeability, resulting in reduced endothelial barrier function. The invention can protect the barrier function of endothelial cells by selectively inhibiting S1PR2, thereby achieving the purpose of reducing restenosis rate after stent implantation.
The JTE-013 drug is placed in the drug-loaded nano-particles and fixed on the surface of the vascular stent to form a drug slow-release coating, the vascular stent with the drug slow-release coating is placed in a stenosed/occluded artery, JTE-013 is continuously released to the stent placement position through slow degradation of polydopamine, and the concentration of local tissue JTE-013 is increased, so that the aim of inhibiting restenosis after stent placement is fulfilled.
The beneficial effects of the invention are as follows:
1. the invention constructs Mesoporous Polydopamine (MPDA) -JTE013 particle nanometer, which is used for reducing restenosis rate of vascular stents and provides a new idea for surface functionalization of titanium implant.
2. The JTE-013 drug is adhered to the surface of the nickel-titanium-copper substrate by utilizing the polydopamine coating, and the slow release effect is achieved.
3. The vascular stent is placed in a stenosed/occluded artery, JTE-013 medicine is continuously released to the stent placement position through slow degradation of polydopamine, and the concentration of local tissue JTE-013 is increased, so that the purpose of inhibiting restenosis after stent placement is achieved.
Drawings
Figure 1 is a schematic cross-sectional view of a stent according to the present invention.
FIG. 2 is a scanning electron microscope image of a nickel titanium copper-polydopamine coating.
FIG. 3 is a diagram of a nickel titanium copper scanning electron microscope.
FIG. 4 endothelial cell scoring experiment (CON: control; JTE 013: drug concentration 1. Mu.M).
FIG. 5 CCK8 smooth muscle cell proliferation assay (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, and drug-loaded nano particles.
Detailed Description
Example 1
Preparation of drug-loaded nano-particles MPDA-JTE 013:
1) Synthesis of mesoporous polydopamine
Preparation of 65 mL H 2 O and 60 mL ethanol, dissolving 0.36 g poloxamer (F127) and 0.36 g 1,3, 5-Trimethylbenzene (TMB) in the above solution, stirring to dissolve, adding 90 mg TRIS solution (H 2 O10 mL), then 60 mg dopamine hydrochloride is added, the obtained mixture reacts at room temperature for 24h, and the product is collected initially; extracting to remove a template, and centrifuging at a high speed to collect synthesized Mesoporous Polydopamine (MPDA);
2) JTE-013 loaded medicament
And dispersing MPDA and JTE-013 drugs in a methanol solution according to a mass ratio of 1:1, stirring for 24 hours to carry out drug loading, gradually enriching the JTE-013 drugs in mesoporous polydopamine through pi-pi aggregation and hydrophilic/hydrophobic action, and centrifugally collecting drug loading nano particles MPDA-JTE013.
Example 2
Preparation of vascular stents:
soaking a nickel-titanium-copper alloy stent matrix in a Tris (Tris buffer) -dopamine hydrochloride solution (pH 8.5, tris concentration 10 mM and dopamine hydrochloride concentration 2 mg/ml) at room temperature overnight to form a polydopamine coating; then taking out the nickel-titanium-copper alloy bracket, washing with distilled water for three times, and drying; dispersing the drug-loaded nano-particles MPDA-JTE013 in PBS with the pH of 7.4 to form MPDA-JTE013 particle solution; and (3) placing the polydopamine coated nickel-titanium-copper alloy stent into MPDA-JTE013 particle solution for reaction for 24h to obtain the polydopamine-MPDA-JTE 013-nickel-titanium-copper coated stent, wherein the concentration of the JTE-013 drug in the polydopamine-MPDA-JTE 013-nickel-titanium-copper coating is 1 mu M.
The surface morphology 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) Synthesis of mesoporous polydopamine
Preparation of 65 mL H 2 O and 60 mL ethanol, 0.36 g poloxamer (F127) and 0.72 g 1,3, 5-Trimethylbenzene (TMB) were dissolved in the above solutionAfter stirring and dissolution, 90 mg TRIS solution (H 2 O10 mL), then 60 mg dopamine hydrochloride is added, the obtained mixture reacts at room temperature for 24h, and the product is collected initially; extracting to remove a template, and centrifuging at a high speed to collect synthesized Mesoporous Polydopamine (MPDA);
2) JTE-013 loaded medicament
And dispersing MPDA and JTE-013 drugs in a methanol solution according to a mass ratio of 1:1, stirring for 24 hours to carry out drug loading, gradually enriching the JTE-013 drugs in mesoporous polydopamine through pi-pi aggregation and hydrophilic/hydrophobic action, and centrifugally collecting drug loading nano particles MPDA-JTE013.
3) Preparation of vascular stents
Preparation of vascular stents:
soaking a nickel-titanium-copper alloy stent matrix in a Tris (Tris buffer) -dopamine hydrochloride solution (pH 8.5, tris concentration 10 mM and dopamine hydrochloride concentration 2 mg/ml) at room temperature overnight to form a polydopamine coating; then taking out the nickel-titanium-copper alloy bracket, washing with distilled water for three times, and drying; dispersing the drug-loaded nano-particles MPDA-JTE013 in PBS with the pH of 7.4 to form MPDA-JTE013 particle solution; and (3) placing the polydopamine coated nickel-titanium-copper alloy stent into MPDA-JTE013 particle solution for reaction 48 h to prepare the polydopamine-MPDA-JTE 013-nickel-titanium-copper coated stent, wherein the concentration of the JTE-013 drug in the polydopamine-MPDA-JTE 013-nickel-titanium-copper coating is 1 mu M.
As shown in fig. 4, the result of the endothelial cell scratch test is that the area of cell migration was divided by the area of the original area of the scratch to obtain the relative migration area. The larger the relative migration area data, the more the endothelial cells have a lateral migration ability. Experimental results showed that there was a statistical difference (P < 0.0001) between the data of the JTE013 group and the control group 6h and 24h after dosing, so JTE013 was able to promote lateral migration of endothelial cells.
Fig. 5 shows the results of CCK8 smooth muscle cell proliferation experiments, in which the proliferation of smooth muscle cells in a culture medium containing JTE013 (1 μm) was studied by CCK8 experiments, and the results of CCK8 experiments showed that JTE013 inhibited proliferation of smooth muscle cells (P < 0.01) compared with the control group, and the absorbance values of blank wells were subtracted.
The invention is not a matter of the known technology.
The above embodiments are provided to illustrate the technical concept and features of the present invention and are intended to enable those skilled in the art to understand the content of the present invention and implement the same, and are not intended to limit the scope of the present invention. All equivalent changes or modifications made in accordance with the spirit of the present invention should be construed to be included in the scope of the present invention.
Claims (4)
1. A vascular stent for reducing the rate of restenosis in the stent, comprising: the surface of the stent is coated with a drug-release coating, the coating contains drug-loaded nano particles MPDA-JTE013, and the stent matrix is nickel-titanium-copper alloy; the drug-loaded nano-particles are porous materials, JTE-013 drugs are loaded in the pores of the drug-loaded nano-particles, and the specific preparation method is as follows:
1) Synthesis of mesoporous polydopamine
Dissolving poloxamer and 1,3, 5-trimethylbenzene in ethanol water solution, stirring and dissolving, adding a tris (hydroxymethyl) aminomethane solution, adding dopamine hydrochloride, reacting the obtained mixture at room temperature for 24-72h, and primarily collecting a product; extracting to remove a template, and centrifuging at a high speed to collect synthesized mesoporous polydopamine; 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;
2) JTE-013 loaded medicament
Dispersing mesoporous polydopamine and JTE-013 drugs in a methanol solution according to a mass ratio of 1:1-1:5, stirring for 24-72 hours to carry out drug loading, enriching the JTE-013 drugs in the mesoporous polydopamine, and centrifugally collecting drug loading nano particles MPDA-JTE013;
the preparation method of the vascular stent comprises the following steps:
soaking a nickel-titanium-copper alloy stent matrix in Tris buffer-dopamine hydrochloride solution, and standing overnight at room temperature to form a polydopamine coating; then taking out the nickel-titanium-copper alloy bracket, washing with distilled water and drying; dispersing the drug-loaded nano-particles MPDA-JTE013 in PBS with the pH of 7.4 to form MPDA-JTE013 particle solution; and (3) placing the polydopamine coated nickel-titanium-copper alloy stent into MPDA-JTE013 particle solution to react for 24-72h, so as to obtain the polydopamine-MPDA-JTE 013-nickel-titanium-copper coated stent.
2. The vascular stent for reducing the restenosis rate in a stent according to claim 1, wherein the drug-loaded nanoparticle MPDA-JTE013 is prepared by the following steps:
1) Synthesis of mesoporous polydopamine
Preparation of 65 mL H 2 O and 60 mL ethanol, dissolving 0.36 g poloxamer and 0.36 g 1,3, 5-trimethylbenzene in the above solution, stirring and dissolving, adding 90 mg% of a tris (hydroxymethyl) aminomethane solution, adding 60 mg dopamine hydrochloride, reacting the obtained mixture at room temperature to 24h, and primarily collecting the product; extracting to remove a template, and centrifuging at a high speed to collect synthesized mesoporous polydopamine;
2) JTE-013 loaded medicament
Dispersing mesoporous polydopamine and JTE-013 drugs in a methanol solution according to a mass ratio of 1:1, stirring for 24 hours to carry out drug loading, enriching the JTE-013 drugs in the mesoporous polydopamine, and centrifugally collecting drug loading nano particles MPDA-JTE013.
3. A vascular stent for reducing the rate of restenosis within a stent as defined in claim 1, wherein: the pH value of the Tris buffer solution-dopamine hydrochloride solution is 8.5, the Tris concentration is 10 mM, and the dopamine hydrochloride concentration is 2 mg/mL.
4. A vascular stent for reducing the rate of restenosis within a stent as defined in claim 1, 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 medicine is 1-50 mu M.
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