CN100413540C - Gene carrying rack and its producing method and use - Google Patents
Gene carrying rack and its producing method and use Download PDFInfo
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- CN100413540C CN100413540C CNB021367795A CN02136779A CN100413540C CN 100413540 C CN100413540 C CN 100413540C CN B021367795 A CNB021367795 A CN B021367795A CN 02136779 A CN02136779 A CN 02136779A CN 100413540 C CN100413540 C CN 100413540C
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Abstract
The present invention discloses a gene carrying rack, a preparation method and an application method thereof. Genes for inhibiting smooth muscle cell hyperplasia and smooth muscle cell migration and genes for inhibiting thrombopoiesis are adsorbed on the surface of the gene carrying rack with a coating layer, so the genes have high efficiency expression on a local part of blood vessels with the genes, the function of safe effective inhibition of restenosis after rack arrangement is achieved, and the goal of target conveyance or local gene positioning is realized. An adsorption layer of a blood vessel rack of the present invention is a protein coating layer which can carry therapeutic genes, and a large amount of sites which can form hydrogen bonds and other valence bonds with the genes are arranged on protein molecules. Raw materials of the protein coating layer of the present invention come from organism tissues, and have good biocompatibility and no side effect. Simultaneously, the carrier therapy genes are tightly adsorbed on the protein adsorption layer arranged on the surface of the blood vessel rack, so the genes can be easily fixed to therapy regions with the blood vessel rack to reach the goal of target conveyance or local gene positioning.
Description
Technical field
The present invention relates to medical instruments field, be specifically related to a kind of gene carrying rack with prevention of restenosis effect.
Background technology
Become the effective ways of coronary heart disease and peripheral vascular disease reconstructing blood vessel treatment based on interventional therapy in the blood vessel of balloon expandable, worldwide extensive use, but since in the postoperative 6 months the restenosis incidence rate up to 30-50% its application is restricted.Studies show that the main mechanism that restenosis takes place behind the balloon expandable is because vessel wall elasticity retraction, blood vessel negativity are reinvented (remodeling), the thrombosis parallel operationization is recognized and the too much hypertrophy of smooth muscle cell and extracellular matrix are built up and made luminal stenosis.The invention of endovascular stent and extensive use, reinvent by preventing vessel wall elasticity retraction and blood vessel negativity effectively, obviously reduced the restenosis incidence rate, but because stainless steel stent itself stimulates smooth muscle cell proliferation, therefore the restenosis incidence rate still reaches 20-30% in 6 months.The invention and the clinical trial of medication coat or FirebirdTM (drug-eluting stent) in recent years shown tempting prospect.Support significantly reduces restenosis rate by carrying the medicine that suppresses smooth muscle cell proliferation and migration, is reducing to 0-9% through strict 6 months restenosis incidence rates of pathological changes postoperative of selecting.But the problem of restenosis can not all solve by one or several medicine.
Along with development of molecular biology, the pathogeny of numerous disease is illustrated on gene level, and this makes becomes possibility from gene level diagnosis and radical curing of disease.Utilize the Therapeutic Method of gene transfer and positioning to further investigate at aspects such as curing heart disease, tumor, diabetes.For example antithrombotic is formed gene and import in the cardiovascular, make it in blood vessel, to express, thereby reach inhibition thrombosis, prevent the purpose of blood vessel blockage.Yet how gene targeting in organism is carried or local positioning, this critical technical problem is not resolved as yet.People such as U.S. Micheal Simons once used a kind of polyethers carrier, gene were added in the gel of this carrier, then it were sent in the carotid artery of animal (Nature, 359 (3), 67-70,1992.9).The shortcoming of this method is: this gel runs into and can be dissolved in very soon in the blood after blood flow impacts, and can't be positioned a certain position of blood vessel at all, therefore can't reach the purpose of targeted gene.
Summary of the invention
The technical issues that need to address of the present invention provide a kind of carrying and have the gene stent that can prevent and suppress the restenosis effect.
Another technical problem to be solved by this invention is to disclose above-mentioned preparation method of carrying gene stent.
Another technical problem to be solved by this invention is to disclose the application of above-mentioned intravascular stent in cardiovascular and peripheral blood vessel obstruction pathological changes interventional therapy.
Technical conceive of the present invention is such: inventor's imagination will suppress the gene of smooth muscle cell proliferation and migration and suppress the rack surface that thrombotic gene is adsorbed in coating, can make gene insert the blood vessel part and efficiently express, suppress the effect that support is inserted the back restenosis safely and effectively thereby reach at support.Gene is sticked on the intravascular stent securely, can be positioned any position of blood vessel, thereby realize the purpose of targeted or local positioning gene with intravascular stent.
The intravascular stent that reaches of the present invention comprises balloon expandable stent and self expandable support, and its version has been carried out open description in Chinese patent 01246774.x and other relevant documents, and the present invention repeats no more.They are mainly used in the obstruction pathological changes of coronary artery, cerebral arteries, pulmonary artery, renal artery, abdomen master, thoracic aorta and other blood vessels.
Gene carrying rack of the present invention comprises support and covers the adsorption layer and the carrier therapeutic genes layer that is coated on the adsorption layer surface of rack surface.
In optimized technical scheme of the present invention, between adsorption layer and support, can add a bottom, in order to improve the adhesion of adsorption layer and support.
Said bottom is a kind of pharmaceutically acceptable polymer, comprises the homopolymer of lactide, Acetic acid, hydroxy-, bimol. cyclic ester, 6-caprolactone and or three's copolymer, cellulose family, polyvidon, polyvinyl alcohol, arabic gum, tragakanta, sodium alginate, gelatin, polymethyl methacrylate, poly-methyl-prop diluted acid butyl ester, ethylene-vinyl alcohol copolymer, ethylene-vinyl acetate copolymer and above-mentioned mixture of polymers between the two.
Adsorption layer is a kind of containing through the molecular weight of crosslinking Treatment greater than 10,000 proteinic compositions, comprises the protein of 97-100wt%, the additive of 0-3wt%.
The protein of being addressed can be gelatin, collagen or albumin, preferably gelatin.
Certain performance according to different purposes, purpose or improvement coating can add one or more additives in protein coat, additive comprises that plasticizer, surfactant, cross-linking agent are or/and various certain drug with certain disease of assistance treatment etc.
The plasticizer of being addressed comprises glycerol, fatty acid, ethers, mineral oil or/and silicone oil etc., to increase the flexibility of coating;
The surfactant of being addressed comprises dodecyl sodium sulfate, alkyl quaternary amine salt or Tweens, in order to improve the spreading property of protein solution;
The cross-linking agent of being addressed comprises a kind of and composition thereof in aldehydes, two ketones, isocyanates or the epoxy compounds, and its effect is biological activity and the fixing protein carrier that destroys protein carrier.
The certain drug of being addressed comprises anticoagulant (as heparin sodium), antiplatelet deposition agent (as Tirofiban), and anti-smooth muscle cell proliferation agent (as Rapamycin) is in order to reduce the incidence rate of patient's complication or heart condition incident.
Carrier therapeutic genes in the carrier therapeutic genes layer of being addressed is selected from by cell, virus, plasmid, macromolecular material and other carrier mediated genes such as Keratin 8 genes, VEGF gene, EGF gene, PTEN, pro-urokinase (Pro-UK) gene, nitricoxide synthase (NOS) gene etc. and antisense oligonucleotide, as antisense C-myc etc.Carrier therapeutic genes, by suppressing the hyper-proliferative of vascular smooth muscle cell (VSMC), perhaps promote the growth of vascular endothelial cell, perhaps stop the migration of vascular smooth muscle cell, perhaps suppress vascular smooth muscle cell epimatrix hyperplasia, reach the purpose that prevents vascular restenosis, and portability prevents thrombotic gene or dual-gene to reach the various biological effect.
Preferred mediated cell comprises endotheliocyte, vascular smooth muscle cell; Preferred virus comprises adenovirus and gland helper viral vector; Preferred plasmid comprises pc DNA 3.1, pB322 redundant organism or pUC redundant organism.
The macromolecular material of being addressed is pharmaceutically acceptable macromolecular material.
The preparation method of the gene of above-mentioned vehicle treatment is a kind of method well known in the art, be summarized as follows: 1. the structure of people's inducible nitric oxide synthase gene plasmid, 2.-70 ℃ of preservations of plasmid transfection escherichia coli (strain number DH5 α), that 3. uses QIAGEN company removes endotoxin plasmid purification test kit and method purification plasmid.
Coating layer thickness of the present invention is the 0.1-100 micron.
The preparation method of carrying gene stent that the present invention has the prevention of restenosis coating comprises the following steps:
1. bottom applies: the method for coating can be dip-coating or spraying, carries out drying then.
2. the preparation of adsorption layer solution: protein is dissolved in water and/or organic solvent, adds additive as required, stir, being mixed with protein concentration is 0.1%-40wt%, 0.5%-15wt% more precisely, and the concentration of additive is 0-3wt%.
3. the coating of adsorption layer and crosslinked: can adopt high-energy radiation cross-linking method or chemical crosslink technique.
(1) high-energy radiation cross-linking method: shine the protein coat that is coated on the support with gamma-radiation, make its generation crosslinked.
(2) chemical crosslinking can adopt homogeneous phase crosslinked or heterogeneous crosslinked.Homogeneous phase is crosslinked to be that first chemical cross-linking agent with expense adds in the protein solution for preparing, and carries out coating behind the mix homogeneously, carries out drying then;
Perhaps after protein solution is applied to the intravascular stent surface, the cross-linking agent of expense is added on the coating, carry out drying then;
(3) heterogeneous crosslinked be after protein solution is applied to the intravascular stent surface, use the cross-linking agent vapor crosslinking, carry out drying then.
The chemical cross-linking agent of being addressed can be selected aldehydes for use, as formaldehyde, acetaldehyde, glutaraldehyde etc.; Two ketones are as diacetyl, acetyl butyryl etc.; Isocyanates is as toluene di-isocyanate(TDI), hexamethylene diisocyanate etc. or epoxy compounds, as in the epoxychloropropane one or more.
The consumption of chemical cross-linking agent is to add 0.01-10 gram (cross-linking agent is pressed the 100wt% densitometer) in per 100 gram protein.
The intravascular stent that scribbles protein coat can be put into baking oven when dry, or in natural environment, carry out drying.
4. carrier therapeutic genes layer: with the gene stock solution of vehicle treatment or be dissolved in the solvent, the support that will apply adsorption layer then is immersed in this solvent, makes the gene of vehicle treatment be adsorbed on the adsorption layer surface, and dry back obtains support of the present invention.
Said solvent comprises a kind of in water, dimethyl sulfoxide (DMSO), dimethyl formamide (DMF) or the dimethyl acetylamide (DMAC), water preferably, concentration with 0.5%-5% for suitable.
The thickness of carrier therapeutic genes layer is controlled by concentration and the coating number of times of adjusting solution.
The gene stent face coat that carries disclosed by the invention does not have biofilm, hangs silk, is evenly distributed, and does not have cracking, peeling phenomenon.
The present invention compares with existing other technology, and the advantage that has is: the adsorption layer of intravascular stent of the present invention is a kind of protein coat that can carry the therapeutic genes of interest.Why protein coat can adsorb gene consumingly, at first is because protein is the expression of gene thing, and the site that can form hydrogen bond and other valence link in a large number with gene is arranged on the protein molecule.Secondly, protein coat is a kind of hydrogel, and it is self-evident to the strong adsorption of water-soluble substanceses such as gene.The raw material of protein coating of the present invention has good biocompatibility from body tissue, after after a while nature by body absorption, metabolism, do not have toxic and side effects.Because carrier therapeutic genes is adsorbed on the intravascular stent surface protein adsorption layer consumingly,, reach the purpose of targeted or local positioning gene simultaneously so gene is easy to be fixed in therapentic part with intravascular stent.
Description of drawings
Fig. 1 is the balloon expandable stent structural representation.
Fig. 2 is the self expandable support.
The specific embodiment
Embodiment 1
The aqueous gelatin solution of preparation 100ml 10wt% concentration, add the formalin and 1.0 that 0.5ml concentration is 37wt% and restrain glycerol, mix homogeneously, the rustless steel intravascular stent dip-coating after 1 minute at above-mentioned solution, drying is 20 hours under 20 ℃, remove residual formaldehyde with acetone extraction, thereby on the intravascular stent surface, form the adsorption layer of one deck flexibility.
The rustless steel endovascular stent that scribbles this coating was soaked in the LacZ gene stock solution of adenovirus vector or plasmid (pcDNA.3.1) mediation 1 minute, and took out the back and it is implanted in miniature pig coronary artery with foley's tube.After seven days this coronary segment is carried out the xGal staining analysis.The result is that test section coronary endometrium and middle film visible part nucleus are dyed navy blue, and this shows that the LacZ gene is in the efficient transfection of this section coronary artery.Simultaneously, the protein coat rustless steel intravascular stent that does not carry Lac Z gene is carried out same controlled trial, the result is that the nucleus indigo plant that the experimental section femoral artery does not take place is dyed.This proves absolutely that protein coat can carrying gene, and successfully gene is delivered to target site.In addition, the NOS gene of Pro-UK gene that the absorption of this support is adenovirus vector-mediated or plasmid (pc DNA 3.1) mediation is implanted the miniature pig coronary artery, spend 30 days after with bare bracket relatively, can obviously suppress smooth muscle cell proliferation in the support, prevention of restenosis.
Embodiment 2
Preparation 100ml concentration is the poly-methyl-prop diluted acid butyl ester tetrahydrofuran solution of 2wt%, adopts the method priming operation of spraying, rate-of flow 0.5ml/min, spray time 100 seconds.Form a bottom at rack surface behind the surface drying, 40 ℃ of dryings 12 hours.
Preparation 100ml concentration is the aqueous gelatin solution of 2wt%, adds 1.0 gram glycerol, mix homogeneously.Following dry 10 hours after the dip-coating of rustless steel intravascular stent at 20 ℃, and then support is immersed concentration is 37% formalin 1 minute, take out the back in-4 ℃ of lyophilizations 24 hours, remove residual formaldehyde, thereby on the intravascular stent surface, form the adsorption layer of the firm flexibility of one deck with acetone extraction.
The rustless steel endovascular stent that scribbles this coating is soaked in the people of pcDNA3.1 plasmid vector mediation
1In the NOS synthase gene stock solution 10 minutes, natural drying 10 minutes-12 hours.
Embodiment 3
Preparation 100ml concentration is the ethylene-vinyl alcohol copolymer DMF solution of 2wt%, adopts the method priming operation of spraying, rate-of flow 0.2ml/min, spray time 100 seconds.Form a bottom at rack surface behind the surface drying, 80 ℃ of drying under reduced pressure 12 hours.
The aqueous gelatin solution of preparation 100ml 5wt% concentration adds 1.0 gram glycerol, mix homogeneously.Following dry 10 hours after the dip-coating of rustless steel intravascular stent at 20 ℃, and then support immersed the glutaraldehyde solution 60 minutes that concentration is 10wt%, take out the back in 20 ℃ of following drying under reduced pressure 20 hours, remove residual glutaraldehyde with acetone extraction, thereby on the intravascular stent surface, form the adsorption layer of the firm flexibility of one deck.
The rustless steel endovascular stent that scribbles this coating was soaked in the people iNOS synthase gene stock solution of pcDNA3.1 plasmid vector mediation natural drying 12 hours 90 minutes.
Embodiment 4
Preparation 100ml 2wt% (W
Diluted acid butyl ester in the poly-methyl/ W
Ethylene-vinyl alcohol copolymer=1/4) DMSO solution adopts the method priming operation that sprays, rate-of flow 0.3ml/min, spray time 100 seconds.Form a bottom at rack surface behind the surface drying, 80 ℃ of dryings 12 hours are cleaned with acetone, and dry back is standby.
The aqueous gelatin solution of preparation 100ml 1wt% concentration adds 1.0 gram glycerol, mix homogeneously.20 ℃ of following drying under reduced pressure 10 hours, and then support is suspended from the formalin top after the dip-coating of rustless steel intravascular stent, keeps 25 ℃ of solution temperatures, blast N with capillary tube
2, support was carried out vapor crosslinking 2 hours, take out back following dry 20 hours in 20 ℃.Thereby on the intravascular stent surface, form the adsorption layer of the firm flexibility of one deck.
The rustless steel endovascular stent that scribbles this coating was soaked in the people iNOS synthase gene stock solution of pcDNA3.1 plasmid vector mediation natural drying 12 hours 60 minutes.
Claims (17)
1. gene carrying rack, it is characterized in that adsorption layer that comprises support and cover rack surface and the carrier therapeutic genes layer that is coated on the adsorption layer surface, adsorption layer comprises that the molecular weight of process crosslinking Treatment of 97-100wt% is greater than 10,000 protein, the additive of 0-3wt%; Between adsorption layer and support, be provided with bottom in order to the adhesion that improves adsorption layer and support, said bottom is a kind of pharmaceutically acceptable polymer, and polymer is selected from the homopolymer of lactide, Acetic acid, hydroxy-, bimol. cyclic ester, 6-caprolactone and or three's copolymer, cellulose family, polyvidon, polyvinyl alcohol, arabic gum, tragakanta, sodium alginate, gelatin, polymethyl methacrylate, polybutyl methacrylate, ethylene-vinyl alcohol copolymer or ethylene-vinyl acetate copolymer and composition thereof between the two.
2. support according to claim 1 is characterized in that, protein is gelatin, collagen or albumin.
3. support according to claim 2 is characterized in that, protein is gelatin.
4. support according to claim 1 is characterized in that, additive comprises that plasticizer, surfactant, cross-linking agent are or/and various active medicine with assistance treatment disease.
5. support according to claim 4 is characterized in that, the plasticizer of being addressed comprises that glycerol, fatty acid, ethers, mineral oil are or/and silicone oil.
6. support according to claim 4 is characterized in that the surfactant of being addressed comprises dodecyl sodium sulfate, alkyl quaternary amine salt or Tweens.
7. support according to claim 4 is characterized in that, the cross-linking agent of being addressed comprises a kind of or its mixture in aldehydes, two ketones, isocyanates or the epoxy compounds.
8. support according to claim 4 is characterized in that the active medicine of being addressed is the anticoagulant heparin sodium.
9. support according to claim 4 is characterized in that, the active medicine of being addressed is anti-smooth muscle cell proliferation agent Rapamycin.
10. according to each described support of claim 1-9, it is characterized in that the carrier therapeutic genes in the carrier therapeutic genes layer of being addressed is selected from by cell, virus, plasmid, macromolecular material and other carrier mediated genes.
11. support according to claim 10 is characterized in that, the gene of being addressed is Keratin 8 genes, VEGF gene, EGF gene, PTEN, pro-urokinase (Pro-UK) gene, nitricoxide synthase (NOS) gene or antisense oligonucleotide.
12. support according to claim 11 is characterized in that, antisense oligonucleotide is antisense C-myc.
13. support according to claim 10 is characterized in that, mediated cell comprises endotheliocyte or vascular smooth muscle cell.
14. support according to claim 10 is characterized in that, mediation virus comprises adenovirus and gland helper viral vector.
15. support according to claim 10 is characterized in that, the mediation plasmid comprises pcDNA 3.1, pB322 redundant organism or pUC redundant organism.
16. support according to claim 10 is characterized in that, macromolecular material is pharmaceutically acceptable macromolecular material.
17. support according to claim 1 is characterized in that, the carrier therapeutic genes layer thickness is the 0.1-100 micron.
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| CNB021367795A CN100413540C (en) | 2002-09-03 | 2002-09-03 | Gene carrying rack and its producing method and use |
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| CNB021367795A CN100413540C (en) | 2002-09-03 | 2002-09-03 | Gene carrying rack and its producing method and use |
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| CN100413540C true CN100413540C (en) | 2008-08-27 |
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US9320829B2 (en) | 2000-03-15 | 2016-04-26 | Orbusneich Medical, Inc. | Progenitor endothelial cell capturing with a drug eluting implantable medical device |
| CN101141933B (en) * | 2004-03-10 | 2015-07-29 | 祥丰医疗有限公司 | The medical treatment device of endothelium ligand binding coating |
| CN101209360B (en) * | 2006-12-29 | 2012-06-20 | 微创医疗器械(上海)有限公司 | Method for preparing biological bracket |
| CN101406713B (en) * | 2007-10-12 | 2012-09-19 | 微创医疗器械(上海)有限公司 | Artificial blood vessel bracket and preparation method thereof |
| CN102416203B (en) * | 2011-11-29 | 2013-10-23 | 北京中孵友信医药科技股份有限公司 | RNA interference blood vessel stent coating material with local antiplatelet effect and local anticoagulation blood vessel stent prepared therefrom |
| CN112891619B (en) * | 2021-01-28 | 2021-10-26 | 四川大学 | Gene elution coating material with function of selectively inhibiting smooth muscle cell phenotype transformation and preparation method thereof |
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