CN108992431B - Doxorubicin embolism microsphere and preparation method thereof - Google Patents
Doxorubicin embolism microsphere and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a doxorubicin embolism microsphere and a preparation method thereof, belonging to the technical field of medicines. The doxorubicin embolism microsphere is added with the polyaspartic acid to prepare the doxorubicin embolism microsphere, has a good embolism effect, has a multilayer structure, is not required to be stored in liquid, is easy to store, is convenient to carry and is convenient to use.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a doxorubicin embolization microsphere and a preparation method thereof.
Background
Liver cancer is one of the common malignant tumors worldwide, and the fatality rate is the third place in the malignant tumor. In China, about 38.3 thousands of people die of liver cancer each year, accounting for 51 percent of death cases of liver cancer all over the world, and bringing heavy burden to the society and medical treatment of China. Most of the patients with liver cancer are diagnosed at the middle and late stages, and Portal Vein Tumor Thrombosis (PVTT) is the typical clinical manifestation of the patients at this stage. The portal vein cancer embolus is that cancer tissues appear in the portal vein of the liver, the incidence rate is as high as 44.0-62.2%, if the patient is not treated, the median survival time of the patient is only 2.7-4.0 months, and the portal vein cancer embolus is one of important independent risk factors influencing the prognosis of the liver cancer patient. PVTT is typed according to a program, and is type I and type II, and is an operation indication; type III is a relative indication of surgery; type IV is a contraindication to surgery. Most patients are first diagnosed as PVTT type iii or IV, and many have lost surgical opportunity.
Transcatheter chemoembolization (TACE) has long been the mainstay treatment for patients with liver cancer who cannot be surgically resected or do not wish to be operated. Conventional TACE is usually administered in combination with iodine oil plus doxorubicin, cisplatin or other chemotherapeutic agents. However, this method has 2 major drawbacks: firstly, the local deposition of the iodized oil emulsion sometimes can not achieve satisfactory effect, and the cytotoxic effect of the chemotherapy drugs on tumor tissues is reduced along with the prolonging of time; secondly, the traditional drug carrier is lipid, while the chemotherapy drug is water-soluble, the traditional emulsion can cause the chemotherapy drug to be rapidly released into the blood stream, thereby rapidly entering the systemic circulation system, increasing the systemic adverse reaction and reducing the local efficacy. However, in the treatment of liver cancer, sustained release of drugs and maintenance of drug concentration inside tumors play an important role.
Recently, a new drug, namely doxorubicin-eluting microspheres (DEB), is developed to treat liver cancer, so that the concentration of the drug entering the interior of a tumor is increased, the systemic absorption of the drug is reduced, and blood supply arteries of the tumor can be embolized at the same time. Experiments prove that the liver toxicity of the doxorubicin eluting particle embolism group is obviously reduced, and the incidence rate of doxorubicin-related side reactions is obviously lower than that of a control group using a traditional method. Therefore, the doxorubicin eluting particles are considered to be safe and effective in the treatment of middle and late stage liver cancer by catheter arterial chemotherapy embolization, and can provide significant benefits for patients with serious disease. The doxorubicin embolization microsphere is used by taking the embolization microsphere stored in normal saline out, loading doxorubicin medicines and carrying out catheter injection, wherein the microsphere is most easily polluted when the medicines are loaded, so that the condition of a patient is aggravated. Therefore, the problem to be solved by the existing doxorubicin embolism particles is that on one hand, the microspheres have better embolism effect and better treatment effect; on one hand, the pretreatment step before use is reduced, the use is more convenient, and the pollution caused by excessive operation steps is avoided; on the other hand, the doxorubicin embolization particles are convenient to store, and currently used doxorubicin particles need to be stored in physiological saline, so that the doxorubicin embolization particles are inconvenient to store and are not easy to carry.
Disclosure of Invention
In view of the above, the present invention provides a doxorubicin embolization microsphere and a method for preparing the same, the doxorubicin embolization microsphere is prepared by adding polyaspartic acid, and has a good embolization effect, and the doxorubicin embolization microsphere has a multi-layer structure, is not stored in liquid, is easy to store, is convenient to carry, and is convenient to use.
The invention solves the technical problems by the following technical means:
the doxorubicin embolism microsphere is a three-layer structure which takes a slow-release microsphere as an inner layer, a gel layer as an intermediate layer and a composite membrane as an outer layer, the doxorubicin is loaded on the slow-release microsphere, and a sodium chloride solution is filled between the gel layer and the composite membrane.
Further, the slow release microspheres are porous polyvinyl alcohol microspheres.
Further, the gel layer is polyaspartic acid composite hydrogel.
The gel layer is the polyaspartic acid composite hydrogel, the polyaspartic acid is polyamino acid with a carboxyl side chain, has chelating and dispersing effects, has good biocompatibility and nontoxicity, can be used as a good drug-loaded gel, has a high swelling rate under neutral and weak alkaline conditions of a human body, and has a good blocking effect.
Furthermore, the raw materials of the composite membrane comprise collagen and sodium alginate.
Further, the drug loading rate of the sustained-release microspheres is 20-25%.
The invention also discloses a preparation method of the doxorubicin embolism microsphere, which comprises the following steps:
step one, dissolving polysuccinimide in N, N-dimethylformamide, adding ethyl cellulose, stirring for 6 hours in 50 ℃ water bath heating, adding ethanolamine at 5 ℃, adjusting the pH to 6.9-7.1, heating in water bath to 20 ℃, stirring for 10 hours, adding a cross-linking agent, stirring for reaction for 3 hours, heating to 25-35 ℃, adding polyvinyl alcohol, stirring for 5-8 minutes, continuously heating to 50-60 ℃, stirring for 2-3 hours, dripping 20 wt% of sodium hydroxide solution, hydrolyzing for 2 hours at 35 ℃, washing with deionized water to be neutral, and obtaining polyaspartic acid composite hydrogel;
step two, adding the slow release microspheres into the polyaspartic acid composite hydrogel, stirring at the speed of 2000-3000rpm for 2-3h, and then carrying out vacuum freeze drying to obtain the slow release microspheres wrapped with the gel layer;
dissolving sodium alginate in deionized water at 30 ℃, uniformly stirring, adding a collagen solution, uniformly stirring, adjusting the pH value to 6.5-6.7, stirring at the stirring speed of 1000-2000rpm for 1-2h, then performing shear thinning, adding a sodium chloride solution, uniformly stirring to prepare a suspension, adding the slow-release microspheres coated with the gel layer, uniformly stirring, dripping into a calcium lactate solution, and filtering to obtain the doxorubicin embolism microspheres.
Further, in the second step, the temperature of vacuum freeze drying is-10 ℃, and the vacuum degree is 15 Pa.
Further, in the third step, the mass ratio of the sodium alginate to the collagen is 7: 3.
Further, in the third step, the concentration of the sodium chloride solution is 0.9 wt%.
The invention has the following beneficial effects:
the sustained-release microspheres of the doxorubicin embolism microsphere are loaded with a liver cancer treatment drug doxorubicin, and are delivered to blood vessels of focus parts through a catheter to embolize so as to prevent blood supply and oxygen supply to the focus parts, wherein the sustained-release microspheres can continuously release the doxorubicin to treat liver tumors so as to improve the local drug concentration of the focus parts, prolong the action time, reduce the peripheral blood drug concentration and reduce the systemic adverse reactions. Because the sustained-release microspheres are spherical particles, the embolization effect is not good, namely, the blood supply and the oxygen supply to the focus part cannot be well blocked, the sustained-release microspheres are externally wrapped with a layer of gel layer, and when entering the focus part, because the gel layer has swelling property, blood vessels at the focus part are embolized, the nutrition and the blood supply of focus tissues are cut off, and the focus tissues are atrophied and necrotized due to ischemia and hypoxia. Because the doxorubicin embolism microsphere needs to be stored in physiological saline, and the glass bottle is fragile and inconvenient to store, the physiological saline prepared by sodium chloride solution is filled between the gel layer and the composite membrane, and the doxorubicin loaded embolism microsphere is directly stored in the sodium chloride solution, so that the medicine is stored, the operation steps of loading the medicine are reduced, the possibility of pollution of the medicine is reduced, and the medicine effect is ensured. The outer composite membrane is formed by calcium alginate and collagen which are prepared by mixing sodium alginate and calcium lactate solutions, has good biocompatibility and toughness, is formed in the calcium lactate solution, can be quickly decomposed by a human body due to the thin thickness of the composite membrane, exposes the internal medicine gel and the medicine, and achieves the purpose of treatment.
Detailed Description
The present invention will be described in detail below with reference to specific examples:
example 1: preparing doxorubicin embolic microspheres:
step one, dissolving 10g of polysuccinimide in 100ml of N, N-dimethylformamide, adding 3g of ethyl cellulose, stirring for 6 hours in 50 ℃ water bath heating, cooling to 5 ℃, adding 10ml of ethanolamine, adjusting the pH to 6.9, heating to 20 ℃ in water bath, stirring for 10 hours, adding a cross-linking agent, stirring for reaction for 3 hours, heating to 25 ℃, adding 8g of polyvinyl alcohol, stirring for 5 minutes, then heating to 60 ℃, continuously stirring for 2 hours, then dripping 20 wt% of sodium hydroxide solution, hydrolyzing for 2 hours at 35 ℃, then washing with deionized water to be neutral, and obtaining the polyaspartic acid composite hydrogel;
step two, adding 2g of slow-release microspheres into the polyaspartic acid composite hydrogel, stirring at 2000rpm for 3h, and performing vacuum freeze drying at-10 ℃ and a vacuum degree of 15Pa for 20min to obtain the slow-release microspheres wrapped with a gel layer;
step three, dissolving 14g of sodium alginate in deionized water at 30 ℃, uniformly stirring, adding a saturated collagen solution containing 6g of collagen, uniformly stirring, adjusting the pH to 6.5, stirring at a stirring speed of 1000rpm for 2 hours, performing shear thinning for 20min, adding a 0.9 wt% sodium chloride solution, uniformly stirring to prepare a suspension, adding the slow-release microspheres coated with a gel layer, manually stirring, uniformly stirring to obtain a mixed solution, dripping the mixed solution into a normal-temperature calcium lactate solution by using a dropper, filtering to obtain doxorubicin embolism microspheres, naturally drying in an air-drying sealed bottle at normal temperature for storage in an aseptic environment.
The sustained-release microspheres are directly purchased in the market, the sustained-release microspheres are porous polyvinyl alcohol microspheres, the drug-loading rate of the sustained-release microspheres is 20-25%, and the particle size is 150-155 mu m.
Aseptic handling is required in the preparation or use of the doxorubicin embolizing microspheres of the invention. When in use, 20ml of 0.9 wt% sodium chloride solution is injected into a sealed medicine bottle, after the sodium chloride solution and the sodium chloride solution are mixed uniformly, the syringe is drawn out and shaken in a small range to prevent the doxorubicin embolism microsphere from precipitating, a femoral artery puncture cannula is used by a Seldinger method, and doxorubicin embolism particles are slowly injected into a hepatic common artery or other blood vessels of a liver cancer lesion part through a catheter.
Example 2: preparing doxorubicin embolic microspheres:
step one, dissolving 8g of polysuccinimide in 100ml of N, N-dimethylformamide, adding 3g of ethyl cellulose, stirring for 6 hours in 50 ℃ water bath heating, cooling to 5 ℃, adding 10ml of ethanolamine, adjusting the pH to 7, heating to 20 ℃ in water bath, stirring for 10 hours, adding a cross-linking agent, stirring for reacting for 3 hours, heating to 25 ℃, adding 10g of polyvinyl alcohol, stirring for 6 minutes, then heating to 55 ℃, continuing to stir for 2 hours, then dripping 20 wt% of sodium hydroxide solution, hydrolyzing for 2 hours at 35 ℃, then washing with deionized water to be neutral, and obtaining the polyaspartic acid composite hydrogel;
step two, adding 1.5g of slow-release microspheres into the polyaspartic acid composite hydrogel, stirring at 2500rpm for 2h, and performing vacuum freeze drying at-10 ℃ and a vacuum degree of 15Pa for 20min to obtain the slow-release microspheres wrapped with a gel layer;
dissolving 7g of sodium alginate in deionized water at 30 ℃, uniformly stirring, adding a saturated collagen solution containing 3g of collagen, uniformly stirring, adjusting the pH to 6.6, stirring at a stirring speed of 1500rpm for 1h, then performing shear thinning for 30min, adding a 0.9 wt% sodium chloride solution, uniformly stirring to prepare a suspension, adding the slow-release microspheres coated with the gel layer, manually stirring, uniformly stirring to obtain a mixed solution, dripping the mixed solution into a normal-temperature calcium lactate solution by using a dropper, filtering to obtain doxorubicin embolism microspheres, naturally drying in air at normal temperature, and sealing and storing.
The sustained-release microspheres are directly purchased in the market, the sustained-release microspheres are porous polyvinyl alcohol microspheres, the drug-loading rate of the sustained-release microspheres is 20-25%, and the particle size is 160-165 mu m.
Aseptic handling is required in the preparation or use of the doxorubicin embolizing microspheres of the invention. When in use, 30ml of 0.9 wt% sodium chloride solution is injected into a sealed medicine bottle, after the sodium chloride solution and the sodium chloride solution are mixed uniformly, the mixture is drawn out by a syringe, the syringe is shaken in a small range to prevent the doxorubicin embolism microsphere from precipitating, a femoral artery puncture cannula is used by a Seldinger method, and the doxorubicin embolism particles are slowly injected into a hepatic common artery or other blood vessels of a liver cancer lesion part through a catheter.
Example 3: preparing doxorubicin embolic microspheres:
step one, dissolving 15g of polysuccinimide in 150ml of N, N-dimethylformamide, adding 5g of ethyl cellulose, stirring for 6 hours in 50 ℃ water bath heating, cooling to 5 ℃, adding 10ml of ethanolamine, adjusting the pH to 7.1, heating to 20 ℃ in water bath, stirring for 10 hours, adding a cross-linking agent, stirring for reaction for 3 hours, heating to 35 ℃, adding 12g of polyvinyl alcohol, stirring for 8 minutes, continuing to heat to 50 ℃, continuing to stir for 3 hours, then dripping 20 wt% of sodium hydroxide solution, hydrolyzing for 2 hours at 35 ℃, then washing with deionized water to be neutral, and obtaining the polyaspartic acid composite hydrogel;
step two, adding 2g of slow-release microspheres into the polyaspartic acid composite hydrogel, stirring at 3000rpm for 3h, and performing vacuum freeze drying at-10 ℃ and a vacuum degree of 15Pa for 20min to obtain the slow-release microspheres wrapped with a gel layer;
step three, dissolving 14g of sodium alginate in deionized water at 30 ℃, uniformly stirring, adding a saturated collagen solution containing 6g of collagen, uniformly stirring, adjusting the pH to 6.7, stirring at a stirring speed of 2000rpm for 2 hours, performing shear thinning for 30 minutes, adding a 0.9 wt% sodium chloride solution, uniformly stirring to prepare a suspension, adding the slow-release microspheres coated with a gel layer, manually stirring, uniformly stirring to obtain a mixed solution, dripping the mixed solution into a normal-temperature calcium lactate solution by using a dropper, filtering to obtain doxorubicin embolism microspheres, naturally drying in an air-drying sealed bottle at normal temperature for storage in an aseptic environment.
The sustained-release microspheres are directly purchased in the market, the sustained-release microspheres are porous polyvinyl alcohol microspheres, the drug-loading rate of the sustained-release microspheres is 20-25%, and the particle size is 220-230 mu m.
Aseptic handling is required in the preparation or use of the doxorubicin embolizing microspheres of the invention. When in use, 25ml of 0.9 wt% sodium chloride solution is injected into a sealed medicine bottle, after the sodium chloride solution and the sodium chloride solution are mixed uniformly, the mixture is drawn out by a syringe, the syringe is shaken in a small range to prevent the doxorubicin embolism microsphere from precipitating, a femoral artery puncture cannula is used by a Seldinger method, and the doxorubicin embolism particles are slowly injected into a hepatic common artery or other blood vessels of a liver cancer lesion part through a catheter.
Example 4: preparing doxorubicin embolic microspheres:
step one, dissolving 10g of polysuccinimide in 100ml of N, N-dimethylformamide, adding 2g of ethyl cellulose, stirring for 6 hours in 50 ℃ water bath heating, cooling to 5 ℃, adding 10ml of ethanolamine, adjusting the pH to 7, heating to 20 ℃ in water bath, stirring for 10 hours, adding a cross-linking agent, stirring for reacting for 3 hours, heating to 35 ℃, adding 12g of polyvinyl alcohol, stirring for 8 minutes, continuing to heat to 50 ℃, continuing to stir for 3 hours, then dripping 20 wt% of sodium hydroxide solution, hydrolyzing for 2 hours at 35 ℃, then washing with deionized water to be neutral, and obtaining the polyaspartic acid composite hydrogel;
step two, adding 2g of slow-release microspheres into the polyaspartic acid composite hydrogel, stirring at 3000rpm for 3h, and performing vacuum freeze drying at-10 ℃ and a vacuum degree of 15Pa for 20min to obtain the slow-release microspheres wrapped with a gel layer;
dissolving 7g of sodium alginate in deionized water at 30 ℃, uniformly stirring, adding a saturated collagen solution containing 3g of collagen, uniformly stirring, adjusting the pH to 6.7, stirring at a stirring speed of 2000rpm for 2h, then performing shear thinning for 30min, adding a 0.9 wt% sodium chloride solution, uniformly stirring to prepare a suspension, adding the slow-release microspheres coated with the gel layer, manually stirring, uniformly stirring to obtain a mixed solution, dripping the mixed solution into a normal-temperature calcium lactate solution by using a dropper, filtering to obtain doxorubicin embolism microspheres, naturally drying in air at normal temperature, and sealing and storing.
The sustained-release microspheres are directly purchased in the market, the sustained-release microspheres are porous polyvinyl alcohol microspheres, the drug-loading rate of the sustained-release microspheres is 20-25%, and the particle size is 245-250 mu m.
Aseptic handling is required in the preparation or use of the doxorubicin embolizing microspheres of the invention. When in use, 25ml of 0.9 wt% sodium chloride solution is injected into a sealed medicine bottle, after the sodium chloride solution and the sodium chloride solution are mixed uniformly, the mixture is drawn out by a syringe, the syringe is shaken in a small range to prevent the doxorubicin embolism microsphere from precipitating, a femoral artery puncture cannula is used by a Seldinger method, and the doxorubicin embolism particles are slowly injected into a hepatic common artery or other blood vessels of a liver cancer lesion part through a catheter.
Although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the spirit and scope of the invention as defined in the appended claims. The techniques, shapes, and configurations not described in detail in the present invention are all known techniques.
Claims (9)
1. The doxorubicin embolism microsphere is of a three-layer structure which takes a slow-release microsphere as an inner layer, a gel layer as an intermediate layer and a composite membrane as an outer layer, the doxorubicin is loaded on the slow-release microsphere, and a sodium chloride solution is filled between the gel layer and the composite membrane.
2. The embolic microsphere of doxorubicin according to claim 1, wherein said sustained release microsphere is a porous polyvinyl alcohol microsphere.
3. The embolic microsphere of claim 2, wherein said gel layer is a polyaspartic acid composite hydrogel.
4. A doxorubicin embolization microsphere according to claim 3, wherein the raw materials of the composite membrane comprise collagen and sodium alginate.
5. A doxorubicin embolic microsphere as in claim 4, wherein the drug loading of said sustained release microsphere is 20-25%.
6. A method of preparing embolic microspheres of doxorubicin according to any one of claims 1-5, wherein the method of preparation is as follows:
step one, dissolving polysuccinimide in N, N-dimethylformamide, adding ethyl cellulose, stirring for 6 hours in 50 ℃ water bath heating, adding ethanolamine at 5 ℃, adjusting the pH to 6.9-7.1, heating in water bath to 20 ℃, stirring for 10 hours, adding a cross-linking agent, stirring for reaction for 3 hours, heating to 25-35 ℃, adding polyvinyl alcohol, stirring for 5-8 minutes, continuously heating to 50-60 ℃, stirring for 2-3 hours, dripping 20 wt% of sodium hydroxide solution, hydrolyzing for 2 hours at 35 ℃, washing with deionized water to be neutral, and obtaining polyaspartic acid composite hydrogel;
step two, adding the slow release microspheres into the polyaspartic acid composite hydrogel, stirring at the speed of 2000-3000rpm for 2-3h, and then carrying out vacuum freeze drying to obtain the slow release microspheres wrapped with the gel layer;
dissolving sodium alginate in deionized water at 30 ℃, uniformly stirring, adding a collagen solution, uniformly stirring, adjusting the pH value to 6.5-6.7, stirring at the stirring speed of 1000-2000rpm for 1-2h, then performing shear thinning, adding a sodium chloride solution, uniformly stirring to prepare a suspension, adding the slow-release microspheres coated with the gel layer, uniformly stirring, dripping into a calcium lactate solution, and filtering to obtain the doxorubicin embolism microspheres.
7. The method for preparing embolic microspheres of doxorubicin according to claim 6, wherein in said second step, the temperature of vacuum freeze-drying is-10 ℃ and the vacuum degree is 15 Pa.
8. The method for preparing a doxorubicin embolism microsphere according to claim 7, wherein in step three, the mass ratio of sodium alginate to collagen is 7: 3.
9. The method for preparing embolic microspheres of doxorubicin according to claim 8, wherein in step three, the concentration of the sodium chloride solution is 0.9 wt%.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1283463A (en) * | 2000-08-17 | 2001-02-14 | 张新国 | Process for preparing solid-state-microspherical vascular suppository of sodium alginate |
| CN1430505A (en) * | 2000-03-24 | 2003-07-16 | 生物领域医疗公司 | Microspheres for active embolization |
| CN102585258A (en) * | 2012-03-31 | 2012-07-18 | 北京大学 | Gelatin embolism microsphere and preparation method and application thereof |
| CN104307036A (en) * | 2009-10-06 | 2015-01-28 | 明尼苏达大学董事会 | Embolic material in form of microspheres and forming method thereof, and embolic suspension |
| CN107715169A (en) * | 2017-11-07 | 2018-02-23 | 南京林业大学 | The sodium alginate of the nanoparticle containing PLGA carries the preparation method and product of the compound embolism microball of medicine |
| CN108236736A (en) * | 2016-12-26 | 2018-07-03 | 苏州恒瑞迦俐生生物医药科技有限公司 | A kind of synthetic method of Polyvinyl Alcohol Embolization microballoon for carrying chemotherapeutic epirubicin |
-
2018
- 2018-09-30 CN CN201811155257.9A patent/CN108992431B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1430505A (en) * | 2000-03-24 | 2003-07-16 | 生物领域医疗公司 | Microspheres for active embolization |
| CN1283463A (en) * | 2000-08-17 | 2001-02-14 | 张新国 | Process for preparing solid-state-microspherical vascular suppository of sodium alginate |
| CN104307036A (en) * | 2009-10-06 | 2015-01-28 | 明尼苏达大学董事会 | Embolic material in form of microspheres and forming method thereof, and embolic suspension |
| CN102585258A (en) * | 2012-03-31 | 2012-07-18 | 北京大学 | Gelatin embolism microsphere and preparation method and application thereof |
| CN108236736A (en) * | 2016-12-26 | 2018-07-03 | 苏州恒瑞迦俐生生物医药科技有限公司 | A kind of synthetic method of Polyvinyl Alcohol Embolization microballoon for carrying chemotherapeutic epirubicin |
| CN107715169A (en) * | 2017-11-07 | 2018-02-23 | 南京林业大学 | The sodium alginate of the nanoparticle containing PLGA carries the preparation method and product of the compound embolism microball of medicine |
Non-Patent Citations (3)
| Title |
|---|
| "Doxorubicin loading and eluting characteristics of bioresorbable hydrogel microspheres: In vitro study";Lihui Weng等;《International Journal of Pharmaceutics》;20110301;第409卷;第185-193页 * |
| "带药微球缓释栓塞制剂的研究现状";石拯拯等;《中华临床医师杂志( 电子版)》;20120731;第6卷(第13期);第3675-3678页 * |
| "肝癌介入治疗用微粒型栓塞剂的研究进展";刘影等;《介入放射学杂志》;20121130;第21卷(第11期);第969-972页 * |
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