CN101209360B - Method for preparing biological bracket - Google Patents
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- CN101209360B CN101209360B CN2006101482613A CN200610148261A CN101209360B CN 101209360 B CN101209360 B CN 101209360B CN 2006101482613 A CN2006101482613 A CN 2006101482613A CN 200610148261 A CN200610148261 A CN 200610148261A CN 101209360 B CN101209360 B CN 101209360B
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Abstract
The invention relates to a preparation method of a biological stent, which takes a coating stent as a carrier and adopts an electrophoresis method to load one or more than two therapeutic target genes or/and oligonucleotide on the coating stent. The invention has a simple preparation method, easy operation, fast production speed and low cost, and the invention can generate tremendous economic benefits. The prepared gene or/and oligonucleotide eluting stent has the following advantages that: the load of the target genes or oligonucleotide and the release dynamics are controllable, the invention can load a plurality of therapeutic genes or/and oligonucleotides, the proportion of which is controllable. The prepared stent can greatly improve the directional introduction efficiency of the target genes or/and oligonucleotide in a target vessel, so as to prevent and treat the restenosis in a PTCA posterior coronary stent more effectively.
Description
Technical field
The present invention relates to a kind of method for preparing of new bio support.Be to adopt one or more to have the gene or the oligonucleotide that suppress the neointimal hyperplasia effect to make it to be carried on the coating bracket with electrophoretic method; Through this support local slow release action in the vascular lesion position, in order to the restenosis in prevention and the treatment endovascular stent plasty support.
Background technology
Heart disease is one of three big killers that threaten human health, cause every year the hundreds of thousands of them dead, and atherosclerosis causes that angiostenosis or obturation are to cause the main cause of ischemic heart desease (coronary heart disease).Since the seventies in last century, percutaneous transluminal coronary angioplasty (PTCA) has been widely used in treatment coronary heart disease.Though PTCA treatment coronary heart disease clinical effectiveness is satisfactory, its postoperative complication has seriously limited the development of PTCA.It is reported that probability that the coronary artery expanded behind the PTCA in 3～6 months restenosis takes place is then up to 30-50%.The endovascular stent plasty can be controlled the restenosis that the blood vessel elasticity retraction is caused behind the PTCA effectively; Acute or subacute ischemia complication in the time of can significantly reducing interventional therapy; But inserting for a long time of support; Stimulated vascular smooth muscle cell migration and a large amount of propagation cause neointimal tissue proliferation, and cause in-stent restenosis (ISR).According to statistics, still have the restenosis rate of 20-30% after support is implanted.How solving in-stent restenosis becomes the focus and the difficult problem of coronary heart disease interventional therapy.
Think that at present restenosis mainly is a kind of wound healing reaction, its possible mechanism has: (1) endovascular thrombosis; (2) elastical retraction of blood vessel wall; (3) the treatment partial inflammatory reaction in back; (4) formation of neointima comprises the propagation and the migration of middle level smooth muscle cell, the hypertrophy of extracellular matrix.Although adopt Therapeutic Method such as cutting balloon expandable, directed rotary-cut, laser angioplasty, the interior radiation of blood vessel, restenosis rate is still more than 10%.
The hyperplasia of thrombosis and new intima tissue is two main causes that cause in-stent restenosis, therefore, suppresses the formation of thrombosis and two important channels that hamartoplasia becomes the control stent restenosis.Given this, people have obtained certain effect with having chemoprophylaxis restenosiss such as anticoagulation, antiinflammatory and inhibition hypertrophy.The particularly application of bracket for eluting medicament reduces the incidence rate of in-stent restenosis greatly.
But clinical data shows, although drug stent greatly reduces the generation of in-stent restenosis, tardy property thrombosis is arranged, and causes acute myocardial infarction.Pathological study shows that drug stent has also suppressed the reparation of blood vessel endothelium when suppressing vascular smooth muscle cell proliferation, make the basement membrane long term exposure under the effect of blood flow, thereby cause tardy property thrombosis.
In recent years, along with the development of cytobiology and gene recombination technology, the gene therapy of coronary heart disease research has obtained very big progress, becomes the focus of current cardiovascular field research.Gene therapy is meant the gene that coding is had certain bioactive substance (generally being protein or peptide), transfers to artificially in human organ or the histiocyte, makes it at this active substance of local expression, thereby reaches the therapy of corresponding treatment or prevention purpose.The basic link of gene therapy comprises: select genes of interest; The importing of construction of expression vector and genes of interest.
To the possibility mechanism of restenosis, many scholars attempt preventing restenosis with gene therapy.They adopt, and intravenous injection, local direct injection, gene are sunken cord, foley's tube imports, use transformant encapsulates method of gene introduction such as crown inner support, and research comprises that VEGF (VEGF) gene, fibroblast growth factor (FGF) gene, platelet derived growth factor (PDGF) gene, hepatocyte growth factor (HGF) gene, insulin like growth factor (IGF) gene, cell divising regulatory gene (c-myc), antioncogene (p53), nitrous oxide synthetase gene (eNOS) and gene therapy means such as antisense, decoyOND and RNA perturbation technique are used for the control of restenosis.But the clinical experiment result is unsatisfactory, traces it to its cause, and the said gene introduction method lacks the guidance quality of pathological tissues; Effective utilization of gene is few, and genomic medicine is lower in the partial concentration of pathological changes, and the time of keeping valid density is shorter; And side effect is big, is difficult to bring into play the therapeutic effect.Thus, people expect with the coating bracket being carrier, and therapeutic genes is carried on the support, and through the positioning action of support, the gene that achieves the goal is at the directional sustained-release at target vessel position, thereby reach the purpose of treatment restenosis.
Summary of the invention
The present invention provides a kind of method for preparing of biological support.
The biological support that the inventive method makes is meant that a kind of or two kinds of the above object genes of load are or/and the FirebirdTM of oligonucleotide.
The method for preparing of biological support of the present invention is to be carrier with the coating bracket, adopt electrophoresis method with curative a kind of or two kinds of the above object genes or/and oligonucleotide be carried on the coating bracket.The step of method for preparing is to adopt prior art to make coating bracket earlier: support is cleaned with acetone and pure water respectively, dry, spray one deck Biodegradable high-molecular equably at rack surface then; Coating bracket is put in the vacuum drying oven; 37 ℃ of dryings 24 hours, handle coating bracket 72h with cross-linking agent then, with the cross-linking agent of distilled water flush away remnants; Support with coating was put in the vacuum drying oven again, 37 ℃ of dryings 24 hours; Then coating bracket is fixed on the inertia positive pole in the electrophoretic apparatus, inserts in the solution contain a kind of or two kinds of the above object genes or oligonucleotide and buffer composition, at the voltage of＞0-5V; Under＞0-0.6mA the electric current, electrophoresis 1-100 minute, voltage the best was 5V; Electric current the best is 0.4mA, takes out, and dries; Repeat electrophoresis up to reaching the load capacity that needs, be generally 250-600 μ g.
Electrophoretic apparatus is seen Fig. 1, and electrophoretic apparatus is the direct current electrophoresis.
Said genes of interest is inflammation-inhibiting, promote vascular endothelial cell proliferation or suppress the gene of vascular smooth muscle propagation, the vascular endothelial growth factor gene (VEGF) of for example encoding, is encoded into fibroblast growth factor gene (FGF) etc.
Said purpose oligonucleotide is the oligonucleotide that suppresses vascular smooth muscle propagation, for example decoy E2F or decoy NF-kB etc.
Described genes of interest can also be platelet derived growth factor (PDGF) gene, hepatocyte growth factor (HGF) gene, insulin like growth factor (IGF) gene, cell divising regulatory gene (c-myc), antioncogene (p53) or nitrous oxide synthetase gene (eNOS).
Said buffer is PBS (PBS), TE buffer, TAE buffer, tbe buffer liquid, TEN buffer or normal saline.
Said support is an intravascular stent, comprises arteria coronaria intravascular stent, carotid artery vascular support, intracranial vessel support, large artery trunks intravascular stent or peripheral blood vessel support etc., and support can also be esophageal stents appear, biliary tract rack and urethra rack etc.
The material of said support is rustless steel, chrome-cobalt alloy, Nitinol or other biological medical polymer material.
The inventive method is at 5V voltage, electrophoresis 3min under the 0.3mA electric current, and the genes of interest load capacity on the coating bracket can reach 250ug (referring to embodiment 1); And adopt common dip coating, and coating bracket submergence at room temperature absorption 24h, the active adsorption amount on the support also has only 9ug; Coating bracket with the inventive method preparation reaches 50 hours effective release time, and the coating bracket of common dip coating preparation has only 6 hours its effective release time.The support load capacity and the release kinetics profile of two kinds of method preparations are seen Fig. 2 and Fig. 3.
Key of the present invention is to adopt a kind of electrochemical deposition means, with a kind of or have more than two kinds different effects mechanism genes of interest or/and the oligonucleotide strong bonded to the support that scribbles Biodegradable high-molecular.Gene FirebirdTM with the method preparation has following advantage: 1) load capacity of genes of interest or oligonucleotide is controlled; 2) release dynamics of genes of interest or oligonucleotide is controlled; 3) can the multiple curative genes of interest of load or/and oligonucleotide; 4) the multiple therapeutic genes of interest of load is or/and the ratio of oligonucleotide is controlled.
The gene of the inventive method preparation is or/and the oligonucleotide FirebirdTM has slow releasing function; Can improve the therapeutic genes of interest greatly or/and oligonucleotide imports efficient in the orientation of target vessel, thereby effectively prevent and treat behind the PTCA restenosis in the coronary stent more.And method for preparing of the present invention is simple, processing ease, and manufacturing speed is fast, can produce huge economic benefit.
Description of drawings
The electrophoretic apparatus sketch map of Fig. 1 for using in the inventive method.
Fig. 2 is the release kinetics profile figure of the gene FirebirdTM load capacity 250 μ g of the inventive method preparation.
Fig. 3 is for adopting the release kinetics profile figure with the gene FirebirdTM load capacity 9 μ g of common dip coating preparation.
The specific embodiment
The preparation of embodiment 1 coding VEGF gene FirebirdTM
0.48g gelatin joins in the 20ml pure water, dissolving and mixing is sprayed at the stainless steel stent surface then, at air drying 24h.Contain in 37% the analytical pure formaldehyde being placed on, reaction 72h, with the cross-linking agent of distilled water flush away remnants, the support with coating was put in the vacuum drying oven again, 37 ℃ of dryings 24 hours; Then support is fixed on the platinum electrode, inserts PBS (137mmol/L NaCL, 2.7mmol/L KCL, the 10mmol/L Na of coding VEGF (VEGF) gene that contains 7mg/L
2HPO4,2mmol/L KH
2PO4) in the solution, at the voltage of 5V, electrophoresis 3min under the 0.3mA electric current takes out, and dries, and repeats electrophoresis, up to the load capacity that reaches 250ug.To prop up and be placed in the vacuum drying oven, evacuation is dry 24 hours under the room temperature.
The preparation of embodiment 2 coding FGF gene FirebirdTMs
The chitosan solution of preparation 5% is sprayed at the stainless steel stent surface, then at air drying 24h.Then support is fixed on the tungsten electrode, inserts the TAE that is encoded into fibroblast growth factor (FGF) gene (40mmol/L Tris-acetic acid, the 1mmol/L EDTA that contain 6mg/L; PH8.0) in the solution, at the voltage of 3V, electrophoresis 5min under the 0.4mA electric current; Take out; Dry, repeat electrophoresis, up to the load capacity that reaches 500ug.To prop up and be placed in the vacuum drying oven, evacuation is dry 24 hours under the room temperature.
The preparation of embodiment 3 coding HGF gene FirebirdTMs
The chrome-cobalt alloy support is cleaned with acetone and pure water respectively, dry, immerse the mixed solution of 1% polyvinyl alcohol and 2% collagen, take out, dry in the air, 3 times repeatedly, reach 800ug up to coating weight.Contain in 25% the analytical pure glutaraldehyde solution being placed on, reaction 24h, with the cross-linking agent of distilled water flush away remnants, the support with coating was put in the vacuum drying oven again, 37 ℃ of dryings 24 hours; Then support is fixed on the platinum electrode, inserts TE (100mmol/LTris-HCl, the 10mmol/L EDTA of coding hepatocyte growth factor (HGF) gene that contains 8mg/L; PH8.0) in the solution, at the voltage of 10V, electrophoresis 1min under the 0.3mA electric current; Take out; Dry, repeat electrophoresis, up to the load capacity that reaches 300ug.To prop up and be placed in the vacuum drying oven, evacuation is dry 24 hours under the room temperature.
The preparation of embodiment 4decoy E2F oligonucleotide FirebirdTM
Nick-eltitanium alloy stent is used isopropyl alcohol and pure water ultrasonic cleaning respectively 3 times, dry, immerse in the 10% polylysine solution, take out, dry in the air, 3 times repeatedly, reach 800ug up to coating weight.Contain in 25% the analytical pure oxidation glyceraldehyde solution being placed on, reaction 48h, with the cross-linking agent of distilled water flush away remnants, the support with coating was put in the vacuum drying oven again, 37 ℃ of dryings 24 hours; Then support is fixed on the gold electrode, inserts in the normal saline of the decoy E2F oligonucleotide contain 9mg/L, electrophoresis 10min under the voltage of 1V, 0.5mA electric current takes out, and dries, and repeats electrophoresis, up to the load capacity that reaches 300ug.To prop up and be placed in the vacuum drying oven, evacuation is 24 hours under the room temperature, and is vacuum-packed again, cryopreservation.
The preparation of embodiment 5decoy NF-kB and decoy E2F oligonucleotide FirebirdTM
Prepare the aqueous solution of 5% gelatin, spraying large artery trunks intravascular stent, coating weight reaches 800ug, and is subsequent use behind the vacuum drying.Preparation contains the decoy NF-kB of 8mg/L and TEN buffer (10mmol/LTris-HCl, 0.1mmol/LEDTA, the 01mol/LNaCl of decoy E2F oligonucleotide respectively; PH80); Then two kinds of solution are mixed with different volume ratios, 4 ℃ of cryopreservation are as nucleic acid electrophoresis liquid.The gelatin coating intravascular stent is connected on the platinum electrode, in the constant voltage of 5V, electrophoresis 5min under the 0.2mA electric current; Repeat electrophoresis, reach 400ug, wash support with ultra-pure water up to the load capacity of oligonucleotide; Remove the nucleic acid of absorption, natural airing, room temperature vacuum drying 24h again; In the nucleic acid of gained support load, decoyNF-kB and decoy E2F ratio can come through the relative amount of decoy NF-kB in the electrophoresis liquid and decoy E2F accurately to regulate.
The preparation of embodiment 6 coding VEGT genes and HGF gene FirebirdTM
Prepare the chloroformic solution of 0.5% polylactic acid, spraying intracranial vessel support, coating weight reaches 1000ug.Configuration concentration is coding VEGF (VEGF) gene of 8ug/ml and TBE (22.5mmol/L Tris-boric acid, 0.1mmol/L EDTA, pH8.0) solution of hepatocyte growth factor (HGF) gene respectively.The intravascular stent that is coated with the polylactic acid coating is connected in platinum electrode, and elder generation is with the constant voltage of 2.5V, 0.5mA electric current; Electrophoresis 5min in the electrophoresis liquid that contains the VEGF gene repeats the VEGF gene of load 100ug 2 times; The gained gene stent again in the electrophoresis liquid that contains hepatocyte growth factor (HGF) gene with the constant voltage of 2.5V, 0.3mA electric current, electrophoresis 5min; Repeat the HGF gene of load 300ug 6 times; Wash postlyophilization with PBS, sterilization final vacuum low temperature (20 ℃) is preserved, and the weight ratio of VEGF gene and HGF gene is 1: 3 on the gained gene stent.
Embodiment 7 has the preparation of the gene FirebirdTM of multiple therapeutical effect
Dispose the aqueous solution of 0.5% Polyethylene Glycol,, reach 800ug up to coating weight, vacuum drying the dip-coating repeatedly of arteria coronaria intravascular stent.Prepare the TAE solution of coding VEGF (VEGF) gene, fibroblast growth factor (FGF) gene, platelet derived growth factor (PDGF) gene, hepatocyte growth factor (HGF) gene, insulin like growth factor (IGF) gene and nitric oxide synthetase (eNOS) gene respectively; Then with range gene solution according to etc. the mixed of molar concentration; With blended cdna solution as electrophoresis liquid; With the constant voltage of above-mentioned Polyethylene Glycol coating bracket at 0.05V, electrophoresis 100min repeats electrophoresis under the 0.02mA electric current; Make the gene weight of load reach 600 μ g, promptly get gene FirebirdTM with multiple therapeutical effect.
The preparation of embodiment 8decoy E2F oligonucleotide and VEGF gene FirebirdTM
0.48g gelatin joins in the 40ml pure water, dissolving and mixing is sprayed at the nick-eltitanium alloy stent surface then, at air drying 48h.Configuration contains the PBS solution of the coding VEGF gene of 7mg/L, and the pH value to 8.0 of regulator solution is as electrophoresis liquid; The dose of gelatin coated stent is connected on the gold electrode, receives the positive pole of dc constant voltage electrophresis apparatus, 10V voltage, the 0.6mA electric current, electrophoresis 1min repeats 3 times, the VEGF gene of load 200 μ g.Again in the TEN solution of the decoy E2F oligonucleotide that contains 7mg/L with 1V voltage, 0.2mg electric current, electrophoresis 10min, repeat the decoy E2F oligonucleotide of load 100 μ g 2 times.Gained oligonucleotide and the rapid release decoy E2F of gene FirebirdTM elder generation oligonucleotide, and then discharge the VEGF gene, have simultaneously and suppress vascular smooth muscle cell proliferation and the dual function that promotes endothelialization;
Embodiment 9 zooperies
Miniature pig with 35-45kg is an animal model, estimates the effect of decoy E2F oligonucleotide FirebirdTM.After pig was anaesthetized and place on the operating-table, cervical region, right pars inguinalis preserved skin, sterilization, drape exposed RFA and implant 7F guide sheath pipe through surgical method.Before system's heparinization, blood sample collection is with the analysed for plasma chemical composition, CBC (leukocyte that comprises platelet and different differentiation states), and the blood clotting data comprise ACT and plasma fibrinogen.Give heparin 200 units/kg and prove conclusively ACT＞300 second through the sheath pipe, and in the support implantation process, keep it.
After system's heparinization about 5 minutes, measure ACT for the second time to guarantee ACT＞300 second.If ACT＜300 second, add with heparin (surveying a time ACT in the conduit operating process and during the process end at least again) and implant the 7F guide catheter afterwards and adjust the position so that the support implant procedure.The controllable coronarography inspection of record behind intracoronary injection 200 μ g nitroglycerin; Behind the observation coronary artery anatomy configuration; Selecting ramus descendens anterior arteriae coronariae sinistrae and right coronary artery proximal segment through observation with reference to 2.8mm diameter guide catheter is the support implantation site with the sections of the about 2.8mm of its central part diameter, and every animal will be implanted two pieces of supports.
Be ready to illumination gel coating group, carry decoy E2F groups of holders certainly.The release catheter that carries support follows 0.014 inch guiding steel wire through guide catheter and delivers to the target site of intending that discharges support, and the full pressurized equipment of adjustment fills sacculus and discharges support with suitable filling pressure (9-10atm) and arrives blood vessel wall.The situation that the record support is implanted in the zoopery process record.Implant second piece of support at another selected position subsequently.After 28 days, put to death animal and take out the blood vessel sample that contains support, carry out om observation and electron microscopic observation.The result shows (seeing table 1).The E2F group, the matched group of comparing has significantly reduced inner membrance area and the narrow ratio of testing arteria coronaria.
Table 1 animal test results
| Neointima area (mm2) | Narrow ratio (%) | |
| Matched group | 4.04 | 82 |
| The E2F group | 1.25 | 38 |
Claims (12)
1. the method for preparing of a biological support is to be carrier with the coating bracket, with the therapeutic genes of interest or/and oligonucleotide be carried on the coating bracket; It is characterized in that it being to adopt the electrophoresis method will be a kind of or genes of interest is or/and oligonucleotide is carried on the coating bracket more than two kinds, its step is that coating bracket is fixed on the positive pole in the electrophoretic apparatus, inserts in the solution that contains genes of interest or oligonucleotide and buffer composition; At voltage＞0-10V; Under electric current＞0-0.6mA electrophoresis 1-100 minute, take out, dry; Repeat electric arteries and veins; Up to reaching the load capacity that needs, wherein said genes of interest is inflammation-inhibiting, promotes vascular endothelial cell proliferation or suppress the gene that vascular smooth muscle is bred, and said purpose oligonucleotide is the oligonucleotide that suppresses vascular smooth muscle propagation.
2. method for preparing as claimed in claim 1 is characterized in that said genes of interest is the coding vascular endothelial growth factor gene or is encoded into the fibroblast growth factor gene.
3. method for preparing as claimed in claim 1 is characterized in that said purpose oligonucleotide is decoy E2F or decoy NF-kB.
4. method for preparing as claimed in claim 1 is characterized in that said genes of interest is platelet derived growth factor gene, liver cell growth factor gene, insulin-like growth factor i gene, cell divising regulatory gene, antioncogene or nitrous oxide synthetase gene.
5. method for preparing as claimed in claim 1 is characterized in that said electrophoretic apparatus is the direct current electrophoresis.
6. method for preparing as claimed in claim 1 is characterized in that said voltage is 5V.
7. method for preparing as claimed in claim 1 is characterized in that said electric current is 0.4mA.
8. method for preparing as claimed in claim 1 is characterized in that said buffer is PBS, TE buffer, TAE buffer, tbe buffer liquid, TEN buffer or normal saline.
9. method for preparing as claimed in claim 1 is characterized in that said support is an intravascular stent, comprises arteria coronaria intravascular stent, carotid artery vascular support, intracranial vessel support, large artery trunks intravascular stent or peripheral blood vessel support.
10. method for preparing as claimed in claim 1 is characterized in that said support is esophageal stents appear, biliary tract rack or urethra rack.
11. method for preparing as claimed in claim 1, the material that it is characterized in that said support are rustless steel, chrome-cobalt alloy, Nitinol or other biological medical polymer material.
12. a load has several kinds of target gene or/and the FirebirdTM of oligonucleotide obtains through each said method for preparing among the claim 1-11.
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| CN2006101482613A CN101209360B (en) | 2006-12-29 | 2006-12-29 | Method for preparing biological bracket |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2010048757A1 (en) * | 2008-10-31 | 2010-05-06 | Dong Heyan | Method for preparation of rack with micro-blind holes on the surface carrying gene material |
| CN101474456B (en) * | 2009-02-09 | 2012-02-22 | 乐普（北京）医疗器械股份有限公司 | A method for preparing a gene-carrying medical device |
| CN101748062B (en) * | 2010-01-05 | 2013-01-23 | 宁波大学 | Bioreactor for culturing tissue engineered esophageal stent |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1408446A (en) * | 2002-09-03 | 2003-04-09 | 微创医疗器械(上海)有限公司 | Gene carrying rack and its producing method and use |
| US6652581B1 (en) * | 1998-07-07 | 2003-11-25 | Boston Scientific Scimed, Inc. | Medical device with porous surface for controlled drug release and method of making the same |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6652581B1 (en) * | 1998-07-07 | 2003-11-25 | Boston Scientific Scimed, Inc. | Medical device with porous surface for controlled drug release and method of making the same |
| CN1408446A (en) * | 2002-09-03 | 2003-04-09 | 微创医疗器械(上海)有限公司 | Gene carrying rack and its producing method and use |
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