CN113288908A - Application of Corilagin in preparation of drug for stent coating - Google Patents
Application of Corilagin in preparation of drug for stent coating Download PDFInfo
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- CN113288908A CN113288908A CN202110588763.2A CN202110588763A CN113288908A CN 113288908 A CN113288908 A CN 113288908A CN 202110588763 A CN202110588763 A CN 202110588763A CN 113288908 A CN113288908 A CN 113288908A
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- corilagin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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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
- A61L31/08—Materials for coatings
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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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
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/23—Carbohydrates
- A61L2300/232—Monosaccharides, disaccharides, polysaccharides, lipopolysaccharides
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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
- A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
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Abstract
The invention relates to application of Corilagin in a stent coating drug, and belongs to the technical field of biological medicines. According to the invention, by establishing an in vitro vascular Epidermal Growth Factor (EGF) -induced smooth muscle cell (VSMCs) proliferation model, the result proves that Corilagin can inhibit the proliferation and migration of VSMCs and induce the apoptosis of smooth muscle cells. In order to further verify the value of Corilagin in preventing restenosis (ISR) in a stent after percutaneous transluminal coronary intervention (PCI), a preclinical pig coronary artery stent model is established, and research results prove that the Corilagin coating stent can effectively inhibit the intimal hyperplasia of the pig coronary artery and shows good histocompatibility and safety; the invention provides theoretical basis and experimental support for clinical application of the drug stent coating with Corilagin as a natural source in prevention and treatment of ISR after PCI operation.
Description
Technical Field
The invention belongs to the technical field of biomedicine, and particularly relates to application of Corilagin in preparation of a drug for a stent coating.
Background
Cardiovascular and cerebrovascular diseases (CVD) are a serious disease that seriously endangers human health and life, and about 1670 thousands of people die of CVD each year worldwide, accounting for the first mortality rate worldwide, while Atherosclerosis (AS) is the important pathological basis for the development of CVD. Coronary atherosclerotic heart disease, abbreviated as coronary heart disease, is a common disease and frequently encountered disease in vascular diseases and seriously harms human health. Percutaneous transluminal coronary artery intervention (PCI) has become one of the main methods for treating coronary heart disease at present, but restenosis (ISR) in a stent after operation limits the application thereof to a certain extent, and the stent can prevent elastic recoil and late remodeling of blood vessels, but the incidence rate of ISR is still about 15% -30%. ISR occurs mostly due to local microthrombosis and concurrent inflammatory reactions from stent implantation. Subcutaneous tissue of damaged endothelium is exposed after the stent is implanted, platelets are activated, local adhesion and aggregation of the platelets are caused, various vascular smooth muscle growth factors and coagulation factors are released, and the Vascular Smooth Muscle Cells (VSMC) are acted and enter a proliferation state from a resting state, so that migration, proliferation and matrix reconstruction of the VSMC are caused, and a proliferative intima tissue is formed together.
Clinically, after PCI surgery, clopidogrel, aspirin and other medicaments are generally orally taken to prevent and treat ISR, and although certain curative effect is achieved, prognosis of the occurrence of acute coronary events caused by ISR is still not optimistic. Attempts to inhibit neointimal formation by drugs have been a major focus of domestic and foreign research for a long time, in recent years, countries such as europe and the united states have successively screened drugs with immunological activities from drugs with immunological activities for preventing ISR in stents, such as rapamycin (rapamycin), paclitaxel, everolimus and the like, and some drugs have already obtained good curative effects clinically, so that the search for anti-ISR drugs from traditional Chinese medicines with relatively small toxic and side effects has become a new domestic and foreign research focus. Therefore, from both basic research and clinical application perspectives, it is necessary and urgent to find anti-RS drugs with positive efficacy and less adverse reactions.
Disclosure of Invention
The technical scheme adopted by the invention for solving the technical problems is as follows:
the invention relates to application of Corilagin in preparation of a drug for stent coating.
Preferably, the Coriaglin is a Coriaglin monomer and/or a Coriaglin salt.
Preferably, the Corilagin exerts an anti-ISR effect by inhibiting proliferation, migration of VSMCs while inducing apoptosis of smooth muscle cells.
Preferably, the Corilagin coated stent is 0.6-2.8. mu.g/mm2The compound preparation can effectively inhibit the porcine coronary intimal hyperplasia and has good histocompatibility and safety.
Preferably, the Corilagin has application against ISR.
Compared with the prior art, the invention has the beneficial effects that:
1) according to the invention, an EGF (epidermal growth factor) -induced VSMCs proliferation model is established, results prove that Corilagin can inhibit proliferation and migration of VSMCs and induce apoptosis of smooth muscle cells, in order to further verify the value of preventing the anti-ISR (inter-simple reaction) of Corilagin after PCI (peripheral component interconnect) operation, a preclinical pig coronary artery stent model is established, Corilagin with different doses is coated on the surface of a stent, a rapamycin-coated stent is used as a positive control group, a metal bare stent is used as a negative control group, and coronary angiography is used for evaluating the safety and effectiveness of the Corilagin-coated stent in preventing restenosis after PCI operation.
2) The invention provides theoretical basis and experimental support for clinical application of the drug stent coating with Corilagin as a natural source in prevention and treatment of ISR after PCI operation.
The present invention will be explained in detail below with reference to the drawings and specific embodiments.
Drawings
FIG. 1 is a schematic diagram of the chemical structure of Corilagin provided by the present invention.
FIG. 2 shows that Coriaglin provided by the present invention inhibits migration of VSMCs at various time points.
FIG. 3 is a statistical analysis of the migration of Coriaglin-inhibited VSMCs provided by the present invention.
Detailed Description
The invention is further described below by way of examples, it being understood that these examples are for illustrative purposes only and in no way limit the scope of the invention.
Coriaglin (beta-1-o-galloy l-3,6- (R) -hexahydroxyphenylyl-d-glucose, 1-acyl-3, 6-hexahydroxybiphenyl diformylglucose, figure 1) is a water-soluble polyphenol monomer compound extracted from common medical plant phyllanthus urinaria in Yunnan province. Our earlier studies showed that Corilagin can protect vascular endothelial cells, significantly reduce LOX-1 protein and mRNA expression; corilagin can reduce the expression of NF-kB protein and mRNA in vascular smooth muscle cells; corilagin can also reduce the expression of protein and mRNA of an inflammatory disease marker CRP in macrophages, and the Corilagin is suggested to have further research value in the aspect of preventing and treating ISR.
Corilagin, purchased from China institute for testing pharmaceutical and biological products, has molecular weight of 634.46 and purity of 99.5%, is a tan powder, has no odor, and is dried and stored away from light. (1) Human umbilical artery VSMC was obtained from Shanghai Hufeng Biotechnology Limited, and in order to prevent the influence of the change of cell properties due to excessive passage times on experimental results, earlier cells were used: 3-8 passages of VSMC, and 4-10 passages of cells with good growth are selected for the experiment.
VSMCs culture and passage
VSMCs cells were cultured in DMEM complete medium containing 10% fetal bovine serum at 37 ℃ with 5% CO295% saturated humidity CO2Culturing in an incubator. After 80% -90% of cells are fused, the culture medium is discarded, the cells are washed for 3 times by PBS (phosphate buffer solution), 0.25% pancreatin is added for digestion, the culture flask is shaken and slightly tapped to separate the cells from the flask wall, and the cells are observed under a microscope. When the cells shrink and become round, the cells are separated from the bottle wall, the complete culture medium is added to stop digestion, the centrifugation is carried out for 5min at 1000r/min, the supernatant is discarded, the new complete culture medium is added to blow the cells apart, and the cells are divided into bottles for passage. After subculture, the medium was changed once for 3 days.
(2) Grouping experiments:
cells were randomly divided into 8 groups
1) Control group (control): normal Vascular Smooth Muscle Cells (VSMCs)
2) Model group (model): EGF10ng/mL + VSMC
3) Corilagin group: corilagin 25ug/mL + EGF15ng/mL + VSMCs
4) Corilagin group: corilagin 50ug/mL + EGF15ng/mL + VSMCs
5) Corilagin group: corilagin 100ug/mL + EGF15ng/mL + VSMCs
6) Simvastatin group: 10ug/mL + EGF15ng/mL + VSMCs
The above groups of cells were placed in a DMEM high-glucose medium containing 10% fetal bovine serum (Gibco). Culturing at 37 deg.C in 5% CO2 saturated humidity incubator.
Corilagin inhibits proliferation of VSMCs
The Optical Density (OD) values of each group were measured by MTT colorimetry, and the OD values reflected the growth and proliferation of the cells. The OD value of the EGF model group is obviously increased compared with that of the control group, (P <0.01), which indicates that EGF can promote the proliferation of VSMCs and the modeling is successful, and is shown in Table 1.
TABLE 1 MTT method for the determination of the Effect of Corilagin on the proliferation of VSMCs
Comparison of blank control group with model group, P <0.01
After incubation of complete culture medium containing Coriaglin with VSMCs at different concentrations (25,50,100ug/ml) for 48 hours, MTT colorimetric analysis results showed that cell viability decreased gradually with increasing drug concentration, and the difference from the model group was statistically significant (P <0.01), confirming that Coriaglin has significant effect of inhibiting VSMCs proliferation, see Table 2.
To determine the effect of Corilagin on VSMCs at different time points, MTT colorimetric assays were performed at 24, 48, and 72 hours after dosing (25,50,100ug/ml) and the results confirmed that each concentration group had significant inhibitory effect (P < 0.01). The effect of Corilagin on the survival rate of VSMCs gradually decreased with the increase of the incubation time, and the survival rate of VSMCs reached 26%, 8.9% and 5.9% respectively at each concentration group to 72 hours, thus confirming that the inhibitory effect of Corilagin on VSMCs is concentration-dependent and time-dependent. (Table 3)
TABLE 2 Effect of different concentrations of Corilagin on cell viability 48h after VSMCs
Note: each experimental group showed P <0.01 as compared to the model group
TABLE 3 Effect of Corilagin on VSMCs at various concentrations and times on cell viability
Note: each experimental group represented P <0.01 compared to the model group.
Corilagin inhibits migration of VSMCs
The results of the monolayer culture cell scraping analysis show that different concentrations of Corilagin have significant statistical significance on the inhibition of the migration distance of the VSMCs compared with the control group (P <0.01), the inhibition effect of the Corilagin is dependent on the concentration of the Corilagin, the inhibition rate of the Corilagin on the migration of the VSMCs at the concentration of 50ug/ml is 49.8%, and the inhibition rate of the Corilagin on the migration of the VSMCs at the concentration of 100ug/ml is 79.3%, as shown in figure 2.
Corilagin induced apoptosis of VSMCs
Flow cytometry was used to detect changes in apoptosis occurring 48h after Corlagin treatment of VSMCs cells at various concentrations. The proportion of cells undergoing late apoptosis after VSMC treatment for 48h at 50ug/ml and 100ug/ml Corilagin was 9.59 soil 2.13% and 20.35 soil 3.52%, respectively; the proportion of normal living cells is 82.20 soil 1.43% and 62.85 soil 1.35%, respectively, compared with a blank control group, P is less than 0.01, and the result has obvious statistical difference; the proportion of cells that underwent early apoptosis after 48h treatment of VSMC with 100ug/ml Corilagin was 2.92% in 8.36 soils with P <0.05, with statistical differences, see Table 4.
TABLE 4 detection of changes in 48h apoptosis by Corilagin-treated VSMC cells by flow cytometry
Compared to the blank Control (Control),#p is less than 0.05, and statistical difference exists; p <0.01, with significant statistical differences;△△p is less than 0.01, and the statistical difference is obvious.
Example 3: establishment of pre-clinical pig coronary artery stent model and coronary angiography examination
1. Grouping and treating miniature pigs
(1) 20 piglets were randomly and equally divided into a negative control group (BMS) and a Corilagin low dose stent group (0.14. mu.g/mm)2) Corilagin Medium dose Stent group (0.70. mu.g/mm)2) Corilagin high dose stent group (2.8. mu.g/mm)2) Positive control (SES), and records the number marked on the piglets.
(2) Coronary angiography and stenting
After the experimental animal is completely anesthetized, the left and right coronary arteries are imaged through the right femoral artery or the left femoral artery, one stent of the same type is respectively placed in a left anti-anterior coronary artery (LAD), a Right Coronary Artery (RCA) or a left circulatory flex (LCX), the ratio of the diameters of the stent vessels is 1.1-1.2: 1, the condition of the wall adhesion of the stent is observed by applying the OCT technology, the coronary angiography is performed again on all observed objects for 28 days, the internal diameter of the reference vessel is quantitatively measured by the coronary angiography, the minimum internal diameter in the stent is used for calculating the stenosis degree.
3. Results
3.1 coronary angiography and quantitative analysis
Coronary angiography evaluation is carried out after 28 days of stent placement, obvious stenosis in the stent is not seen in the middle-dose Corilagin group and the positive control group by visual inspection, and restenosis in the stent with different degrees is seen in the negative control group, the low-dose Corilagin group and the high-dose Corilagin group. The stenosis degree of each group was quantitatively measured and calculated: 0.25 +/-0.05 of a negative control group, 0.25 +/-0.03 of a low-dose Corilagin group, 0.10 +/-0.03 of a medium-dose Corilagin group, 0.20 +/-0.02 of a high-dose Corilagin group and 0.10 +/-0.05 of a positive control group. Degree of stenosis (reference vessel id-stent minimum id)/reference vessel id (see table 5)
TABLE 528 day group angiography quantitative results
Note: p <0.05, P <0.01, compared to negative control group
The results indicate that the difference of the stenosis degree of the Corilagin medium-dose group, the Corilagin high-dose group and the Corilagin positive control group is statistically significant (P is less than 0.05). The medium and high dose groups of the Corilagin coated stent can inhibit the small-sized pig coronary intimal hyperplasia in a dose-dependent manner, the low dose group has no obvious effect, meanwhile, the negative control group, the Corilagin low and medium dose groups have different degrees of vascular stenosis, and the high dose and positive control groups have no obvious vascular stenosis.
Conventional techniques in the above embodiments are known to those skilled in the art, and therefore, will not be described in detail herein. The above embodiments are merely illustrative, and not restrictive, and those skilled in the art can make various changes and modifications without departing from the spirit and scope of the invention. Therefore, all equivalent technical solutions also belong to the scope of the present invention, and the protection scope of the present invention should be defined by the claims.
Claims (5)
- The application of Corilagin in preparing medicine for coating rack.
- 2. Use according to claim 1, characterized in that: the Corilagin is a Corilagin monomer and/or a Corilagin salt.
- 3. Use according to claim 2, characterized in that: the Corilagin exerts an anti-ISR effect by inhibiting the proliferation and migration of VSMCs while inducing apoptosis of smooth muscle cells.
- 4. Use according to claim 1, characterized in that: the Corilagin coating support is 0.6-2.8 mu g/mm2The compound preparation can effectively inhibit the porcine coronary intimal hyperplasia and has good histocompatibility and safety.
- 5. The use according to claim 1, characterized in that said Corilagin has an anti-ISR application.
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Citations (1)
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| US20070282422A1 (en) * | 2006-05-10 | 2007-12-06 | Cook Incorporated | Medical devices and methods for local delivery of elastin-stabilizing compounds |
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| US20070282422A1 (en) * | 2006-05-10 | 2007-12-06 | Cook Incorporated | Medical devices and methods for local delivery of elastin-stabilizing compounds |
Non-Patent Citations (5)
| Title |
|---|
| LI YUN 等: "Corilagin alleviates hypertrophic scars via inhibiting the transforming growth factor (TGF)-β/Smad signal pathway", 《LIFE SCI》, vol. 277, pages 1 - 9 * |
| 刘韬等: "Corilagin 对 HUVEC 增殖及细胞周期的影响", 《昆明医科大学学报》, vol. 35, no. 12, pages 7 - 11 * |
| 刘韬等: "Corilagin 对家兔动脉粥样硬化斑块及 ox-LDL 损伤的血管内皮细胞 TLR4 表达的影响", 《昆明医科大学学报》, vol. 41, no. 10, pages 15 - 20 * |
| 李天助等: "冠状支架植入对血管平滑肌细胞力生长因子影响的研究", 《锦州医科大学学报》, vol. 41, no. 4, pages 48 - 53 * |
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