CN105727379A - Haem oxygenase drug eluting stent - Google Patents
Haem oxygenase drug eluting stent Download PDFInfo
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- CN105727379A CN105727379A CN201610104876.XA CN201610104876A CN105727379A CN 105727379 A CN105727379 A CN 105727379A CN 201610104876 A CN201610104876 A CN 201610104876A CN 105727379 A CN105727379 A CN 105727379A
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- stent
- heme oxygenase
- oxygenase
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- haem oxygenase
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/16—Biologically active materials, e.g. therapeutic substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/08—Materials for coatings
- A61L31/10—Macromolecular materials
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
- A61L33/0005—Use of materials characterised by their function or physical properties
- A61L33/0047—Enzymes, e.g. urokinase, streptokinase
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- A—HUMAN NECESSITIES
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
- A61L33/06—Use of macromolecular materials
- A61L33/12—Polypeptides, proteins or derivatives thereof, e.g. degradation products thereof
- A61L33/128—Other specific proteins or polypeptides not covered by A61L33/122 - A61L33/126
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L89/00—Compositions of proteins; Compositions of derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/42—Anti-thrombotic agents, anticoagulants, anti-platelet agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Surgery (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
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- Vascular Medicine (AREA)
- Materials Engineering (AREA)
- Medicinal Chemistry (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Materials For Medical Uses (AREA)
Abstract
The invention relates to a haem oxygenase drug eluting stent. The haem oxygenase drug eluting stent comprises a stent body, and haem oxygenase is adsorbed to the surface of the stent body. According to the haem oxygenase drug eluting stent, HO is adsorbed to the surface of an intravascular stent, After the stent is placed in an embolism blood vessel, enzymolysis and lesion are conducted on abundant heme at the blood vessel, CO is generated, CO can be freely diffused to adjacent vascular endothelial cells and smooth muscles to generate a biological effect, proliferation of smooth muscle cells can be inhibited, restoration of the endothelial cells can be promoted, meanwhile, the effects of inhibiting the inflammatory reaction, inhibiting the foreign matter rejection reaction and resisting to platelet aggregation are achieved, the efficacy of preventing post-stenting restenosis and stent throbosis formation is achieved, and the haem oxygenase is an ideal stent coating drug integrating multiple functions.
Description
[technical field]
The present invention relates to the support of blood vessel, be specifically related to a kind of Heme oxygenase bracket for eluting medicament.
[background technology]
Coronary atherosclerotic heart disease is called for short coronary heart disease (CHD), refers to the heart disease caused owing to coronary atherosclerosis makes luminal stenosis or obstruction cause myocardial ischemia, anoxia.Coronary heart disease is the current developed country topmost cause of death of population.Expect the year two thousand twenty CHD and will become the topmost cause of death in the world.Since half a century, the medical and surgical treatment of coronary heart disease all obtains the appearance of remarkable break-throughs, particularly interventional technique, and the treatment for coronary heart disease brings Gospel.
Coronary Artery Disease Intervention Treatment has 32 years history, and first case percutaneous transluminal coronary angioplasty (being called for short PTCA) was completed by German doctor Gruentzig in 1977 in the world, from then on opened new era of coronary heart disease percutaneous interventional.Within 1987, coronary artery stent implantation (BMS) is first applied to clinic by Sigwart, is second milestone of coronary heart disease treatment.The extensive use of stenting makes the complication rate of interventional therapy be decreased obviously, success rate significantly improves, significantly improve Percutaneous coronary interventions (PCI) at once and long-term results.But, although BMS can effectively reduce PTCA postoperative restenosis incidence rate, but in-stent restenosis (ISR) can be there is in the case still having 20%～30%, in diabetes, Small vessel, Long lesion, Chronic total occlusion and bifurcated lesions patient, ISR incidence rate is even as high as 30%～70%.Research shows, affect that the principal element of ISR includes local intra-arterial damage and allosome inflammatory reaction, platelet aggregation and thrombosis, extracellular matrix metabolism is disorderly, vascular smooth muscle cell (VSMC) is divided a word with a hyphen at the end of a line and breeds, blood vessel endothelium delayed union etc., various factors comprehensive function causes blood vessel neointima (NI) hypertrophy, and final tube chamber diminishes.In recent years, for capturing this difficult problem of ISR, relevant prevention and controls continues to bring out, and wherein bracket for eluting medicament (DES) is one of the most promising method of generally acknowledging at present.DES carries medicine by being coated in the polymer of metal support surface, after vessel inner lesion position inserted by support, medicine autohemagglutination compound coating is controlledly discharged to vascular wall tissue by type of elution, play and suppress neointimal hyperplasia, anti-immunization inflammatory reaction and suppress the biological effects such as platelet aggregation, and then play the prevention ISR effect occurred.The DES of listing only has observation on sirolimus-eluting stent (CYPHER) and Paclitaxel-Eluting (TAXUS) at present.Clinical practice through nearly 10 years proves, the effectiveness of DES is unquestionable, RAVEL, SIRIUS, the test such as TAXUSI-IV, DELIVER-II all shows that DES has shown good effectiveness in reducing restenosis rate and dependent event thereof so that the incidence rate of ISR is further reduced to less than 10%.DES opens a Tiao Xin road for solving restenosis problem, and Coronary Artery Disease Intervention Treatment is pushed to new stage, is the 3rd milestone in Coronary Artery Disease Intervention Treatment history by its significant effect.
DES has significantly reduced the advantage of BMS restenosis incidence rate by it, has worldwide obtained fast development, even presented the situation outshined othersOne branch of the tree is particularly thriving since coming out.But along with the arrival in DES epoch, the drawback of DES appears gradually, and the arguement of its safety effectiveness also grows in intensity, especially stent thrombosis in late period problem seems to become the weakness of DES.The relative human body of coating on support itself and surface thereof is a kind of foreign body, can cause inflammatory reaction and the allergy of implant site.Its entrained medicine (rapamycin and derivant paclitaxel etc. thereof) can delay the normal repair process of blood vessel endothelium while playing resisting vascular smooth muscle proliferative effect, suppress the endothelialization again of vascular injury site, it is possible to cause catastrophic clinical consequences thrombus in stents in late period (LST) or pole thrombus in stents in late period (VLST).Number of mechanisms take part in DES thrombosis, penetrates in downright bad speckle core and to support polymer coating allergy etc. as postponed adherent bad, the support of endothelialization, endothelium phenotypic alternation, support, and most important of which factor is that vessel endothelialisation postpones.More clinical trial (ESC/WCC2006) result shows that what the Thrombosis in sten of DES compared BMS with mortality rate has notable rising, and this long-term existence being possibly due to the DES reparation and polymer support being delayed rack surface endothelium causes allergy and what inflammatory reaction caused.Additionally, in the clinical trial of nearly all DES, if using death+acute myocardial infarction as endpoints, rather than current used MACE, then there are no significant for DES and BMS comparing difference, say, that currently used DES does not reduce dead and acute myocardial infarction incidence rate.This result also points out the supporting structure of DES to be likely to require further improvement.It is also assumed that DES now is still not up to the requirement of desirable intravascular stent.
For this, vast clinic and researcher pay significant effort, it is intended to a kind of perfect bracket for eluting medicament of exploitation, smooth muscle cell proliferation can be suppressed, reduce the generation of in-stent restenosis, endotheliocyte reparation can be promoted again, it is prevented that the formation of thrombus in stents.But, result allows of no optimist, anti-proliferative drugs newly developed mostly is the derivant of rapamycin, including Ze Tamosi (Zotarolimus) everolimus (Everolimus), Ta Mosi (Biolimus), tacrolimus (Tacrolimus) etc., but mechanism of action is all similar to rapamycin, from clinical effectiveness, act on and not over rapamycin, and still suffer from the risk of Thrombosis in sten.Research additionally includes vascular endothelial cell growth factor (VEGF), nitricoxide synthase (iNOS, eNOS), estrogen, 17 β estradiol etc., but zoopery is all not very good.The research of other newtype drugs is also in the experimental stage.
At present, the research and development of drug stent are in an important turning point, and its efficacy assessments is not only in that suppression restenosis, are more in that to reduce the bad cardiovascular endpoints event of patient.Endothelium reparation becomes the novel targets of support research, improve from rack platform and the aspect such as coating medicine and release thereof, it is made to have the effect of resisting vascular smooth muscle propagation while promoting blood vessel endothelium quickly to repair, maintain stablizing of blood vessel endothelium systemic-function, reduce the incidence rate of restenosis, reduce or avoid the generation of thrombus in stents event, i.e. exploitation " endothelium friendly " drug stent, this R&D direction that will be a new generation DES.
Bracket for eluting medicament endothelialization postpones the main cause being to form advanced thrombus, the factor wherein playing main effect is the medicine entrained by bracket for eluting medicament, rapamycin, paclitaxel and their derivant are while suppressing vascular smooth muscle cell proliferation to reduce in-stent restenosis, also inhibits the propagation of vascular endothelial cell, therefore the endothelialization of rack surface it is delayed, thus adding the incidence rate of stent thrombosis.Promote the reparation of blood vessel endothelium, it is possible to reduce thrombosis and suppression smooth muscle cell proliferation, thus reducing the generation of ISR.Therefore exploitation can promote rack surface endothelialization medicine, suppress smooth muscle cell proliferation and Human Umbilical Vein Endothelial Cells does not affect, even can promote that rack surface endothelialization can suppress again the medicine of smooth muscle cell proliferation significant for solving bracket for eluting medicament advanced thrombus.
[summary of the invention]
It is an object of the invention to solve existing drug stent and inhibit the propagation of vascular endothelial cell, the problem postponing the endothelialization of rack surface.
The present invention provides a kind of bracket for eluting medicament that is used for by Heme oxygenase to solve the technical scheme of the problems referred to above for this.
This Heme oxygenase bracket for eluting medicament, including support, is adsorbed with Heme oxygenase at described rack surface.Heme oxygenase (HO) respectively organizes wide expression at Whole Body, particularly in blood vessel endothelium system, after research display myocardial infarction, the HO up-regulated of blocking vascular endothelial cell, HO can pass through the process enzymolysis haemachrome of Fig. 1 and generate carbon monoxide (CO), CO is the another important gasotransmitter found after nitric oxide (NO), and it all has very powerful and physiologic function widely in each system of whole body.At cardiovascular system, big quantity research shows that CO can suppress the propagation of vascular smooth muscle, reduces the generation of in-stent restenosis, can promote again endotheliocyte reparation, it is prevented that Thrombosis in sten simultaneously.Additionally, CO also has antiinflammatory, suppresses the effect of allosome rejection and antiplatelet aggregation, it is possible to well solve the thrombotic problem of chronic inflammatory disease, anaphylaxis and rack surface that support causes.
In Heme oxygenase coating, the coating concentration of Heme oxygenase is 1umol/mm2。
Shown in the aminoacid sequence SEQIDNO:1 of described Heme oxygenase.
Being prepared by of described Heme oxygenase utilizes gene clone technology, enter in carrier for expression of eukaryon Pichia sp. by people's Heme oxygenase gene transfection, carry out the synthesis of albumen in Pichia sp., destination protein is purified afterwards again, concentrates and obtain.
The application in preparing bracket for eluting medicament of a kind of Heme oxygenase.
The present invention by being adsorbed on intravascular stent surface by HO, after vascular embolization inserted by support, the haemachrome abundant by enzymolysis lesion vessels place generates CO, CO can produce biological effect to the vascular endothelial cell closed on and smooth muscle by free diffusing, smooth muscle cell proliferation can be suppressed, endotheliocyte reparation can be promoted again, also there is suppression inflammatory reaction simultaneously, suppress foreign material repulsion reaction and antiplatelet aggregative activity, play effect of prevention support postoperative restenosis and Thrombosis in sten, be the ideal stent coating medicine integrating multiple function.
[accompanying drawing explanation]
Fig. 1 haemachrome-Heme oxygenase-CO metabolic pathway schematic diagram.
Fig. 2 is Heme oxygenase support schematic diagram.
1. left coronary artery 2. Atherosclerotic plaque 3. support 4. right coronary artery 5. intravascular space in figure.
[detailed description of the invention]
Hereinafter, with accompanying drawing, the present invention is described further, it will be appreciated that embodiment is only used for illustrating rather than limiting the scope of the invention in conjunction with the embodiments.
In the present embodiment, FirebirdTM is the bracket for eluting medicament being adsorbed with Heme oxygenase on bare bracket.In Heme oxygenase coating, the coating concentration of Heme oxygenase is 1umol/mm2。
" coating concentration " meaning alleged in the present invention is: the heme oxygenase enzyme amount contained on rack surface every square millimeter area.
The Heme oxygenase that the present embodiment adopts can be prepared by following synthetic method:
People's Heme oxygenase gene transfection is entered in carrier for expression of eukaryon Pichia sp., in Pichia sp., carries out the synthesis of albumen, again destination protein purified afterwards, concentrate.The HO being synthetically derived may refer to SEQIDNO:1.Those skilled in the art can adopt suitable artificial synthesis according to what this sequence carried out Heme oxygenase, or carries out external synthesis by gene clone technology.The synthetic method of Heme oxygenase in the present embodiment can adopt following method:
(1) HO-1 structure of expression vector in Pichia sp.
With restricted enzyme, HO-1 gene carried out double digestion, then endonuclease bamhi is attached with the plasmid ligase through same enzyme double digestion, product will be connected and convert competent escherichia coli cell, hoof selects positive recombinant, upgrading grain, enzyme action is identified, is being checked order by the positive colony after qualification.
(2) electricity of yeast convert, the screening of positive transformant and expression
Prepare Pichia sp. GSM115 bacterial strain competent cell, then the carrier built before is proceeded in Pichia sp. GSM115 bacterial strain competent cell by electricity, be coated with MD flat board and carry out positive colony screening.Then using resistant panel screening multicopy transformant, the monoclonal that picking has been identified from G418 flat board is cultivated, to OD600=2-6.Taking 1ml bacterium solution conservation in EP pipe, 1ml bacterium solution is centrifuged, 1500g, centrifugal 5min, thalline changes 3ml derivant abduction delivering, and every 24h adds 0.5% methanol, collect bacterium solution, 12000g high speed centrifugation 5min after expressing three days, collect upper cleer and peaceful precipitation respectively and carry out SDS-PAGE, Western-Blot analysis.
The metal rack that the present embodiment adopts can directly be obtained by market purchasing, and it is generally obtained by metal incision by cochrome, and inside has engraved structure, and it has light weight, the advantage of good toughness.
After lesion vessels position inserted by this support, CO in the slowly lasting generation of near support, and can discharge and diffuse to contiguous vascular wall tissue, and its concrete mechanism is as it is shown in figure 1, Heme oxygenase is at NADPH and O2Deposit in case, enzymolysis haemachrome, produce the products such as carbon monoxide:
Haemachrome+NADPH+H++2O2→ biliverdin+Fe2++CO+NADP++H2O
And CO can produce to suppress smooth muscle proliferation, promotes endothelium reparation, suppress the effect such as inflammatory reaction, antiplatelet aggregation.
Claims (5)
1. a Heme oxygenase bracket for eluting medicament, including support, it is characterised in that be adsorbed with Heme oxygenase coating at described rack surface.
2. Heme oxygenase bracket for eluting medicament as claimed in claim 1, in described Heme oxygenase coating, the coating concentration of Heme oxygenase is 1umol/mm2。
3. Heme oxygenase bracket for eluting medicament as claimed in claim 1, it is characterised in that shown in the aminoacid sequence SEQIDNO:1 of described Heme oxygenase.
4. Heme oxygenase bracket for eluting medicament as claimed in claim 1, it is characterized in that described Heme oxygenase be prepared by utilize gene clone technology, people's Heme oxygenase gene transfection is entered in carrier for expression of eukaryon Pichia sp., in Pichia sp., carry out the synthesis of albumen, again destination protein purified afterwards, concentrate and obtain.
5. the Heme oxygenase application in preparing bracket for eluting medicament.
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