CN1692960A - Stent carried with gene with function of preventing from restenosis in coronary artery stent - Google Patents
Stent carried with gene with function of preventing from restenosis in coronary artery stent Download PDFInfo
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- CN1692960A CN1692960A CN 200510023715 CN200510023715A CN1692960A CN 1692960 A CN1692960 A CN 1692960A CN 200510023715 CN200510023715 CN 200510023715 CN 200510023715 A CN200510023715 A CN 200510023715A CN 1692960 A CN1692960 A CN 1692960A
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Abstract
A gene-carrying scaffold based on the theory that the ICE gene transfection can suppress the generation of new endomembrane for preventing and treating the restricture inside the arteria coronaria scaffold is a gelatin coated stainless steel scaffold carrying the plasmid pc DNA4 mediated interleukin-1 beta conveyzyme (ICE) genes.
Description
Technical field
The invention belongs to medicine and medical instruments field, relate to restenosis support in the control coronary stent.Be specifically related to a kind of stent carried with gene of preventing and treating restenosis in the coronary stent.
Background technology
Stent has replaced most balloon dilatation, becomes the main method of coronary heart disease interventional therapy (PCI).But in-stent restenosis has seriously hindered further developing of this technology.Research prediction, gene therapy are expected to become the effective way that solves post stent implantation restenosis.It is reported that present most gene therapy is a therapeutic strategy to suppress smooth muscle cell (SMC) propagation and migration.But, studies show that apoptotic relative deficiency is the major reason that restenosis forms.Interleukin-1 (ICE) gene is the common pathway that the apoptosis signal transmits, have and discover that this gene has the vascular SMC apoptotic effect of inducing In vitro culture, but whether can suppress neointimal hyperplasia by cell death inducing, prevent PCI after restenosis do not appear in the newspapers.
Summary of the invention
The purpose of this invention is to provide restenosis support in a kind of control coronary stent, be specifically related to a kind of stent carried with gene of preventing and treating restenosis in the coronary stent.
The present invention can suppress neointima by cell death inducing mechanism according to experiment ICE gene transfection in the body and form the theoretical basis of control restenosis; Preparation is carrier with the plasmid, is the ICE gene stent of delivery system with the The dose of gelatin coated stent.
The present invention adopts gelatin coating metal stainless steel stent, carry interleukin-1 (ICE) gene of plasmid pcDNA4 mediation, confirm through curative effect and mechanism of action experimentation, this support can make gene localized transfection blood vessel wall energy cell death inducing, suppress neointimal hyperplasia, can be used for preventing and treating restenosis in the coronary stent, have safety and feasibility.
Support of the present invention prepares by following method and step:
1. obtain genes of interest ICE
Described gene ICE can adopt restriction enzyme enzyme process, chemical synthesis, pcr amplification or RT-PCR method, genomic library or cDNA library screening method to obtain.
2. be carrier with eukaryotic expression vector plasmid or virus, make up people ICE clone.
Described plasmid can be pcDNA4, pSI or pCMV-HA; Virus can be retrovirus, adenovirus or adeno-associated virus.
3.pcDNA4-ICE after recombinant plasmid transformed, amplification, the evaluation, be dissolved in 0.1M Tris (PH 8.0) or the pure water, concentration is 4～15mg/ml.
4. the pcDNA4-ICE gene stent is carried in preparation.
5. effectiveness, the safety of zoopery checking ICE The dose of gelatin coated stent transfection dog arteria coronaria, the histopathology of transfection dog arteria coronaria changes (biocompatibility), the morphological change of transfection dog arteria coronaria, the apoptotic variation of transfection dog arteria coronaria, exponential influence of transfection dog arteria coronaria on cell proliferation and support transfection dog arteria coronaria are to the influence of α-smooth muscle actin (α-SM actin).
The present invention starts with from cell death inducing mechanism, select the ICE gene, with pcDNA4 is carrier, made up people pcDNA4-ICE eukaryotic expression recombiant plasmid, preparation gelatin coating metal stainless steel stent carries the interleukin-1 gene localized transfection dog coronary artery safety, effective, feasible of plasmid pcDNA4 mediation.Described gelatin coating metal stainless steel stent has good biocompatibility, the ICE gene that described support carries plasmid pcDNA4 mediation has significantly suppressed restenosis in the dog coronary stent, can induce the coronary tissue new intima and the middle film SMC apoptosis of restenosis.
Description of drawings
Fig. 1 is pcDNA4-ICE eukaryotic expression construction of recombinant plasmid figure.
Fig. 2 model group: support is implanted back 4w damage arteria coronaria histopathology variation (HE * 14) inner membrance and is obviously thickened.
Fig. 3 coating group: support is implanted back 4w damage arteria coronaria histopathology variation (HE * 14) inner membrance and is obviously thickened.
Fig. 4 empty plasmid group: support is implanted back 4w damage arteria coronaria histopathology variation (HE * 14) inner membrance and is obviously thickened.
Fig. 5 gene transfection group: support is implanted back 4w damage arteria coronaria histopathology variation (HE * 14) inner film thickness and is reduced than other groups.
The specific embodiment
Embodiment 1
Obtain genes of interest ICE
Adopt restriction enzyme enzyme process, chemical synthesis, pcr amplification or RT-PCR method, genomic library or cDNA library screening method to obtain genes of interest ICE.The present invention uses pcr amplification and obtains ICE from human nasopharyngeal carcinoma cDNA library.
Make up people ICE clone
With pcDNA4/myc-His is carrier, reorganization pcDNA4-ICE eukaryon expression plasmid; Use EcoR I, XhoI double digestion genes of interest segment and pcDNA4 carrier, two cohesive end link reorganization.
After pcDNA4-ICE recombinant plasmid transformed, amplification, the evaluation, be dissolved in 0.1M Tris (PH 8.0) or the pure water, concentration is 4～15mg/ml.
Described pcDNA4-ICE recombiant plasmid has the sequence of sequence 1.
The pcDNA4-ICE gene stent is carried in preparation
Gelatin is water-soluble, be made into 5% solution, add the glutaraldehyde of gelatine content 2%, after stirring, be sprayed on the support 50～60 ℃ of oven for drying, the support that coats is pressed and is held on the foley's tube, and a part is packaged in the plastic packaging bag, and is stand-by behind the oxirane disinfection, another part immerses 10min in the pcDNA4-ICE solution for preparing, take out, after aseptic the drying up, repeated impregnations again, encapsulation, standby.
Zoopery
Adopt standard ball ductus bursae technology, stent diameter, arteria coronaria diameter are with 1.2～1.3: 1 ratio implant frame is made the crown moving in-stent restenosis model of dog, to be adsorbed with people ICE gene (10mg/ml) the support implantation dog anterior descending coronary of plasmid pcDNA4 mediation or a correspondent section of circling round as the gene transfection group, every animal is implanted two supports, implant gelatin coating in the same way and add plasmid support, simple The dose of gelatin coated stent or bare bracket respectively as empty plasmid group, coating group, model group (respectively organizing 10 dogs, 20 supports).Put to death the part dog respectively at postoperative 1w and 4w.During 1w, RT-PCR technology for detection gene transfection pack support vessel segment and vitals people ICEmRNA express, and the SABC method detects people ICE protein expression.During 4w, computer picture quantitative analysis support vessel segment new intima area, cavity area and average inner film thickness.Different time points, each pack support vessel segment of optical microscope and scanning electron microscopic observation and vitals histopathology change, the SABC method measures support vessel segment inner membrance and middle film proliferating cell nuclear antigen (PCNA), α-SM actin express and the image semi-quantitative analysis analysis of TUNEL method combining image, low cytometric analysis, transmission electron microscope observing and detection apoptosis.
The result shows:
This ICE The dose of gelatin coated stent transfection dog arteria coronaria effectively, safety
Implant back 1w at the dog support, have only gene transfection pack support vessel segment to show human specific ICEmRNA and ICE protein expression, the whole body vitals are not expressed with all the other 3 groups.
2.ICE the histopathology of The dose of gelatin coated stent transfection dog arteria coronaria changes (biocompatibility)
The visible support injury region of optics microscopically new intima layer inflammatory cell infiltration during 1w, scanning electron microscope show that respectively group damage arteria coronaria is organized the similar endothelial cell surface leukocyte adhesion of equal visible level, platelet and fibrin deposition, and endothelial regeneration is imperfect.During 4w, scanning electron microscope shows gene transfection group, coating group and empty plasmid group endotheliocyte maturation, and endothelium is complete, no leukocyte adhesion and fibrin deposition; The model group endotheliocyte is immature, and endothelium is complete, fibrin deposition, no leukocyte adhesion.Each time point does not all have aneurysm for 4 groups and forms, and no thrombosis forms, film, adventitia necrosis in the nothing.
3.ICE the morphological change of The dose of gelatin coated stent transfection dog arteria coronaria
The morphology quantitative analysis results shows: gene transfection group cavity area is 5.10 ± 0.68mm
2, obviously increase (model group, 2.92 ± 0.49mm than other 3 groups
2The coating group, 3.22 ± 0.80mm
2The empty plasmid group, 2.83 ± 0.31mm
2N=8; P＜0.05).The new intima area significantly reduces (model group, 2.23 ± 0.22mm than model group, coating group, empty plasmid group
2The coating group, 2.16 ± 0.33mm
2The empty plasmid group, 1.92 ± 0.18mm
2The gene transfection group, 1.49 ± 0.14mm
2N=8; P＜0.05).Average inner film thickness also significantly reduces (model group, 0.32 ± 0.06mm than other 3 groups; The coating group, 0.25 ± 0.06mm; The empty plasmid group, 0.30 ± 0.08mm; The gene transfection group, 0.13 ± 0.04mm; N=8; P＜0.05).
4.ICE the apoptotic variation of The dose of gelatin coated stent transfection dog arteria coronaria
Transmission electron microscope: the transmission electron microscope morphologic detection finds that gene transfection group apoptotic cell quantity is obviously more than all the other each groups when 1w, 4w.
The flow cytometer quantitative analysis:
The flow cytometer quantitative analysis finds that gene transfection group percentage of cell apoptosis is apparently higher than other each group.Respectively organize percentage of cell apoptosis during 1w: model group, 25.05 ± 3.96%; The coating group, 28.03 ± 5.76%; Empty plasmid group 27.65 ± 4.32%; The gene transfection group, 34.74 ± 2.89%; N=8; P＜0.05.Respectively organize percentage of cell apoptosis during 4w: model group, 23.94 ± 0.14%; The coating group, 26.91 ± 9.43%; Empty plasmid group 25.43 ± 3.26%; The gene transfection group, 30.77 ± 7.34%; N=8; P＜0.05.
Apoptotic index:
Gene transfection group apoptotic index is apparently higher than model group, coating group, empty plasmid group.1w, inner membrance: model group, 30.33 ± 5.69%; The coating group, 35.67 ± 6.59%; Empty plasmid group 29.00 ± 3.61%; The gene transfection group, 50.00 ± 4.58%; N=8; P＜0.05.4w, inner membrance: model group, 21.00 ± 6.00%; The coating group, 18.33 ± 2.08%; Empty plasmid group 20.67 ± 4.04%; The gene transfection group, 35.67 ± 6.03%.n＝8；P＜0.05。1w, middle film: model group 13.33 ± 3.79, %; Coating group 7.67 ± 2.08, %; The empty plasmid group, 12.00 ± 3.61%; The gene transfection group, 25.01 ± 4.99%; N=8; P＜0.05.4w, middle film: model group, 9.00 ± 5.29%; The coating group, 9.33 ± 3.51%; Empty plasmid group 7.33 ± 3.52%; The gene transfection group, 20.67 ± 4.51%.n＝8；P＜0.05。
5.ICE the exponential influence of The dose of gelatin coated stent transfection dog arteria coronaria on cell proliferation
1w, the proliferation index of gene transfection group arterial intima, middle film and matched group relatively do not have statistical significance (P＞0.05) during 4w.
6.ICE The dose of gelatin coated stent transfection dog arteria coronaria is to the influence of α-SM actin
The SABC method detects α-SM actin, and the positive area percentage rate of gene transfection group is significantly less than other 3 groups when 1w and 4w.1w: model group, 61.24 ± 6.46%; The coating group, 58.16 ± 2.40%; The empty plasmid group, 56.00 ± 5.57%; The gene transfection group, 41.13 ± 3.99%; N=8; P＜0.05.4w: model group, 40.33 ± 3.51%; The coating group, 42.67 ± 7.23%; The empty plasmid group, 41.67 ± 3.06%; The gene transfection group, 28.67 ± 4.73%; N=8; P＜0.05.
SEQUENCE?LISTING
＜110〉No.1 People's Hospital Shanghai City
＜120〉a kind of stent carried with gene of preventing and treating restenosis in the coronary stent
＜130〉pcDNA4-ICE recombiant plasmid
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<141>2005-01-31
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Met?Ala?Asp?Lys?Val?Leu?Lys?Glu?Lys?Arg?Lys?Leu?Phe?Ile?Arg?Ser
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aca?gtt?atg?gat?aag?acc?cga?gct?ttg?att?gac?tcc?gtt?att?ccg?aaa 192
Thr?Val?Met?Asp?Lys?Thr?Arg?Ala?Leu?Ile?Asp?Ser?Val?Ile?Pro?Lys
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ggg?gca?cag?gca?tgc?caa?att?tgc?atc?aca?tac?att?tgt?gaa?gaa?gac 240
Gly?Ala?Gln?Ala?Cys?Gln?Ile?Cys?Ile?Thr?Tyr?Ile?Cys?Glu?Glu?Asp
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agt?tac?ctg?gca?ggg?acg?ctg?gga?ctc?tca?gca?gat?caa?aca?tct?gga 288
Ser?Tyr?Leu?Ala?Gly?Thr?Leu?Gly?Leu?Ser?Ala?Asp?Gln?Thr?Ser?Gly
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aat?tac?ctt?aat?atg?caa?gac?tct?caa?gga?gta?ctt?tct?tcc?ttt?cca 336
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tca?gaa?ggg?aat?gtc?aag?ctt?tgc?tcc?cta?gaa?gaa?gct?caa?agg?ata 432
Ser?Glu?Gly?Asn?Val?Lys?Leu?Cys?Ser?Leu?Glu?Glu?Ala?Gln?Arg?Ile
130 135 140
tgg?aaa?caa?aag?tcg?gca?gag?att?tat?cca?ata?atg?gac?aag?tca?agc 480
Trp?Lys?Gln?Lys?Ser?Ala?Glu?Ile?Tyr?Pro?Ile?Met?Asp?Lys?Ser?Ser
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Arg?Thr?Arg?Leu?Ala?Leu?Ile?Ile?Cys?Asn?Glu?Glu?Phe?Asp?Ser?Ile
165 170 175
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Pro?Arg?Arg?Thr?Gly?Ala?Glu?Val?Asp?Ile?Thr?Gly?Met?Thr?Met?Leu
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cta?caa?aat?ctg?ggg?tac?agc?gta?gat?gtg?aaa?aaa?aat?ctc?act?gct 624
Leu?Gln?Asn?Leu?Gly?Tyr?Ser?Val?Asp?Val?Lys?Lys?Asn?Leu?Thr?Ala
195 200 205
tcg?gac?atg?act?aca?gag?ctg?gag?gca?ttt?gca?cac?cgc?cca?gag?cac 672
Ser?Asp?Met?Thr?Thr?Glu?Leu?Glu?Ala?Phe?Ala?His?Arg?Pro?Glu?His
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gaa?ggc?att?tgt?ggg?aag?aaa?cac?tct?gag?caa?gtc?cca?gat?ata?cta 768
Glu?Gly?Ile?Cys?Gly?Lys?Lys?His?Ser?Glu?Gln?Val?Pro?Asp?Ile?Leu
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Gln?Leu?Asn?Ala?Ile?Phe?Asn?Met?Leu?Asn?Thr?Lys?Asn?Cys?Pro?Ser
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ttg?aag?gac?aaa?ccg?aag?gtg?atc?atc?atc?cag?gcc?tgc?cgt?ggt?gac 864
Leu?Lys?Asp?Lys?Pro?Lys?Val?Ile?Ile?Ile?Gln?Ala?Cys?Arg?Gly?Asp
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agc?cct?ggt?gtg?gtg?tgg?ttt?aaa?gat?tca?gta?gga?gtt?tct?gga?aac 912
Ser?Pro?Gly?Val?Val?Trp?Phe?Lys?Asp?Ser?Val?Gly?Val?Ser?Gly?Asn
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Leu?Ser?Leu?Pro?Thr?Thr?Glu?Glu?Phe?Glu?Asp?Asp?Ala?Ile?Lys?Lys
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gcc?cac?ata?gag?aag?gat?ttt?atc?gct?ttc?tgc?tct?tcc?aca?cca?gat 1008
Ala?His?Ile?Glu?Lys?Asp?Phe?Ile?Ala?Phe?Cys?Ser?Ser?Thr?Pro?Asp
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Asn?Val?Ser?Trp?Arg?His?Pro?Thr?Met?Gly?Ser?Val?Phe?Ile?Gly?Arg
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Leu?Ile?Glu?His?Met?Gln?Glu?Tyr?Ala?Cys?Ser?Cys?Asp?Val?Glu?Glu
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att?ttc?cgc?aag?gtt?cga?ttt?tcatttgagc?agccagatgg?tagagcgcag 1155
Ile?Phe?Arg?Lys?Val?Arg?Phe
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atgcccacca?ctgaaagagt?gactttgaca?agatgtttct?acctcttccc?aggacattaa 1215
Claims (6)
1, a kind of stent carried with gene of preventing and treating restenosis in the coronary stent is characterized in that adopting gelatin coating metal stainless steel stent, carries the interleukin-1 gene of plasmid pcDNA4 mediation.
2, by the stent carried with gene of restenosis in the described control coronary stent of claim 1, it is characterized in that described interleukin-1 gene has the sequence of sequence 1.
3, press the preparation method of the stent carried with gene of restenosis in the described control coronary stent of claim 1, it is characterized in that by following method and step preparation:
1) obtains genes of interest ICE
Described gene ICE adopts restriction enzyme enzyme process, chemical synthesis, pcr amplification or RT-PCR method, genomic library or cDNA library screening method to obtain;
2) be carrier with eukaryotic expression vector plasmid or virus, make up people ICE clone;
3) after pcDNA4-ICE recombinant plasmid transformed, amplification, the evaluation, be dissolved in 0.1M Tris (PH8.0) or the pure water, concentration is 4～15mg/ml;
4) the pcDNA4-ICE gene stent is carried in preparation;
5) zoopery checking.
4, press the preparation method of the stent carried with gene of restenosis in the described control coronary stent of claim 3, wherein said plasmid is pcDNA4, pSI or pCMV-HA.
5, by the method for claim 3, wherein said vector virus is retrovirus, adenovirus or adeno-associated virus.
6, by the method for claim 3, the concentration of wherein said pcDNA4-ICE solution is 4～15mg/ml.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200510023715 CN1692960A (en) | 2005-01-31 | 2005-01-31 | Stent carried with gene with function of preventing from restenosis in coronary artery stent |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510023715 CN1692960A (en) | 2005-01-31 | 2005-01-31 | Stent carried with gene with function of preventing from restenosis in coronary artery stent |
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| CN1692960A true CN1692960A (en) | 2005-11-09 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011082694A1 (en) * | 2010-01-11 | 2011-07-14 | 上海优益基国际贸易有限公司 | Targeted delivery slow-release stent of gene pharmaceutical for revascularization |
-
2005
- 2005-01-31 CN CN 200510023715 patent/CN1692960A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011082694A1 (en) * | 2010-01-11 | 2011-07-14 | 上海优益基国际贸易有限公司 | Targeted delivery slow-release stent of gene pharmaceutical for revascularization |
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