WO2024041484A1 - 一种血管栓塞剂及其制备方法与应用 - Google Patents

一种血管栓塞剂及其制备方法与应用 Download PDF

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WO2024041484A1
WO2024041484A1 PCT/CN2023/114026 CN2023114026W WO2024041484A1 WO 2024041484 A1 WO2024041484 A1 WO 2024041484A1 CN 2023114026 W CN2023114026 W CN 2023114026W WO 2024041484 A1 WO2024041484 A1 WO 2024041484A1
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Prior art keywords
embolic agent
mixed solution
vascular
preparation
vascular embolic
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English (en)
French (fr)
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单鸿
彭欣
刘孟辉
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Fifth Affiliated Hospital Sun Yat-Sen University
Fifth Affiliated Hospital of Sun Yat Sen University
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Fifth Affiliated Hospital Sun Yat-Sen University
Fifth Affiliated Hospital of Sun Yat Sen University
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Priority to JP2024546357A priority Critical patent/JP2024536933A/ja
Priority to US18/702,805 priority patent/US20250228996A1/en
Priority to CA3237741A priority patent/CA3237741A1/en
Priority to EP23856574.1A priority patent/EP4410321A4/en
Priority to AU2023329278A priority patent/AU2023329278A1/en
Priority to KR1020247015168A priority patent/KR20240073977A/ko
Publication of WO2024041484A1 publication Critical patent/WO2024041484A1/zh
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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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0031—Hydrogels or hydrocolloids
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/0005—Ingredients of undetermined constitution or reaction products thereof
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/043—Mixtures of macromolecular materials
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0015—Medicaments; Biocides
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/02—Surgical adhesives or cements; Adhesives for colostomy devices containing inorganic materials
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A61L26/0066—Medicaments; Biocides
    • 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
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
    • 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
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A61L2300/406—Antibiotics
    • 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
    • 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
    • A61L2300/418—Agents promoting blood coagulation, blood-clotting agents, embolising agents
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/04—Materials for stopping bleeding
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/36—Materials or treatment for tissue regeneration for embolization or occlusion, e.g. vaso-occlusive compositions or devices
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present application relates to the technical field of vascular embolic agents, and in particular to a vascular embolic agent and its preparation method and application.
  • Vascular embolization therapy has become an effective means of clinical treatment of vascular lesions and tumor lesions due to its advantages of small trauma, high reproducibility, and quick results, especially for hemorrhagic lesions, vascular malformations, aneurysms, and Barcelona staging (Barcelona staging).
  • Clinic Liver Cancer intermediate primary liver cancer.
  • embolic materials currently used clinically can be divided into solid embolic materials and liquid embolic materials.
  • Solid embolic materials mainly include spring coils, gelatin sponge particles and polyvinyl alcohol microspheres.
  • Liquid embolization materials mainly include N-butyl-cyanoacrylate (nBCA), Onyx (main components ethylene-vinyl alcohol copolymer and dimethyl sulfoxide), and iodized oil.
  • Spring coils can easily cause blood vessel rupture during the filling process, and they can also be unable to be delivered to the target site due to excessive twisting of blood vessels.
  • Gelfoam particles are easily degraded, leading to vascular recanalization. Both polyvinyl alcohol microspheres and gelatin sponge particles are prone to agglomeration, making it difficult to reach microvessels.
  • nBCA encounters blood, it rapidly polymerizes to form an embolism.
  • the reaction products have poor dispersion and tend to adhere to the catheter, posing greater risks to patients. Onyx cannot be degraded and can easily lead to local chronic inflammation and/or body rejection.
  • Lipiodol has strong fluidity, which can easily lead to poor blood vessel recanalization and embolization effects, and it cannot effectively load and sustain the release of drugs.
  • most embolization agents and contrast agents cannot be tightly cross-linked, and the embolization agents and contrast agents are prone to separation during or after surgery, and the position of the embolization agents cannot be effectively monitored, resulting in incomplete embolization or ectopic embolization.
  • the object of the present invention is to overcome the shortcomings of the above-mentioned prior art and provide a vascular embolic agent and its preparation method and application.
  • the vascular embolic agent has stable mechanical properties in blood vessels, excellent biocompatibility, and good It is diffusible and can be easily delivered to microvessels and complex-shaped target blood vessels. It is non-sticky to the tube. Can effectively load drugs.
  • the vascular embolization agent is tightly cross-linked with the contrast agent and will not produce imaging artifacts.
  • a method for preparing a vascular embolic agent which is characterized by comprising the following steps:
  • 1,2-Dithiolane compounds and polyphenols can be grafted to the benzene ring of polyphenols through Michael addition reaction to form a C-S bond, 1,
  • the carboxyl groups on 2-dithiolane compounds can form hydrogen bonds with the phenolic hydroxyl group, carboxyl group or amino group of polyphenolic compounds; in addition, alkaloids can neutralize excess hydrogen ions in the system and reduce the cell toxicity of the product. toxicity, avoid product irritation to the blood vessel wall, and can enhance the cross-linking density of the gel through hydrogen bonding with 1,2-dithiolane compounds and polyphenol compounds to improve the embolization effect. Injecting the vascular embolic agent into physiological fluids (such as blood, etc.) and aqueous solutions can quickly form gels.
  • the organic solvent A and the organic solvent B are at least one of dimethyl sulfoxide (DMSO) and ethanol respectively, and the organic solvent A and the organic solvent B are the same or different. Further preferably, the organic solvent A and organic solvent B are dimethyl sulfoxide, which is less irritating to blood vessels than other organic solvents.
  • DMSO dimethyl sulfoxide
  • the organic solvent A and organic solvent B are dimethyl sulfoxide, which is less irritating to blood vessels than other organic solvents.
  • the mass ratio of 1,2-dithiolane compounds, polyphenol compounds and alkaloids is (0.05 ⁇ 1): (0.0001 ⁇ 1): (0.01 ⁇ 1) ;
  • the mass ratio of the organic solvent A to the mixed solution A is (2-4): 10;
  • the mass ratio of the organic solvent B to the vascular embolic agent is (1-5.8): 10.
  • the mass ratio of 1,2-dithiolane compounds, polyphenol compounds, and alkaloids is 0.6:0.05:0.3.
  • the prepared vascular embolic agent can solidify quickly, is not easy to stick to the tube, has excellent operability, has good mechanical properties, and can form a good blocking effect on blood vessels.
  • reaction product prepared under the above conditions has the characteristics of stable mechanical properties, lower viscosity and suitable gelling time, and the reaction efficient.
  • the 1,2-dithiolane compound is at least one of lipoic acid, asparagus acid, dithiopyrrolone antibiotics, and kottamide E;
  • the polyphenolic compound is tannic acid, gallic acid , caffeic acid, catechol, dopamine, polydopamine, resveratrol, quercetin, curcumin, chlorogenic acid, isoflavones, anthocyanins, cocoa polyphenols, limonin, catechin, rutin
  • At least one of the alkaloids is at least one of tromethamine, ephedrine, motherwort, and cinchona.
  • the 1,2-dithiolane compound is lipoic acid
  • the polyphenol compound is tannic acid
  • the alkaloid is tromethamine.
  • the above ingredients have good biocompatibility, high reaction efficiency, and high economic benefits.
  • a developer is added in an amount of 10 wt% to 80 wt% of the mass of the vascular embolic agent; the developer is a liquid metal with a melting point below 35°C. Or tantalum powder microparticles.
  • the above-mentioned contrast agent an X-ray opaque vascular embolization agent can be obtained, which is helpful for detecting the position of the vascular embolization agent during and after surgery.
  • the adding amount of the developer is 30 wt% of the vascular embolic agent, and the developer is a gallium-indium alloy.
  • the developer can firmly and stably combine with the reaction products of 1,2-dithiolane compounds and polyphenol compounds through electrostatic interaction or chelation, and will not interact with the embolic agent during use or long-term placement. Detachment occurs. This enables precise positioning of vascular embolic agents during and after surgery.
  • the present invention also discloses a vascular embolic agent prepared by the above method, the application of the vascular embolic agent in preparing a drug carrier, and the invention also discloses the use of the vascular embolic agent in various organs of the human body.
  • the vascular embolic agent prepared by the present invention using 1,2-dithiolane compounds, polyphenols compounds, and alkaloids as main raw materials has moderate solidification after being injected into physiological fluids (such as blood, etc.) or aqueous solutions.
  • physiological fluids such as blood, etc.
  • aqueous solutions The time and viscosity are good, and the operability is good.
  • the gel is not easy to stick to the tube, and it is easy to extubate after embolization surgery.
  • the vascular embolic agent of the present invention has good mechanical strength and embolization pressure after curing. The plugging effect is excellent.
  • the raw materials selected for preparation in the present invention have good biocompatibility, and the vascular embolic agent prepared has excellent dispersibility and can diffuse into microvessels and complex-shaped target blood vessels.
  • liquid metal or tantalum powder microparticles that can be combined with the reaction products of 1,2-dithiolan compounds and phenolic compounds through electrostatic interaction or chelation are used as developers. It is not only beneficial to monitor the location of the embolic agent during surgery, but also reduces imaging artifacts, which is beneficial to monitoring the efficacy after interventional surgery.
  • the vascular embolization agent of the present invention can be used to treat hemorrhagic lesions, aneurysms, and arteriovenous malformations in various organs of the human body, for embolization of blood supply arteries of benign and malignant tumors, and to effectively load and sustain the release of chemotherapy drugs (such as A At least one of mycin, cisplatin, carboplatin, loplatin, raltitrexed, gemcitabine, 5-fluorouracil, irinotecan, bleomycin, and vinpocetine), targeted drugs (such as sorafen at least one of sorafenib, lenvatinib, regorafenib, cabozantinib, apatinib, anlotinib) and immunosuppressants (such as atezolizumab, at least one of keytruda, nivolumab, camrelizumab, sintilimab), etc.
  • chemotherapy drugs such as
  • Figure 1 is a schematic diagram of the preparation of vascular embolic agents using 1,2-dithiolane compounds and polyphenol compounds as main raw materials;
  • Figure 2 is a schematic diagram of preparing a vascular embolic agent using lipoic acid and tannic acid as main raw materials;
  • Figure 3 shows the Raman spectra of lipoic acid and poly(lipoic acid-tannic acid);
  • Figure 4 shows the embolic agent injection pressure test diagram.
  • A is the test schematic diagram
  • B is the test result diagram of different embolic agents in the 1.7F microcatheter
  • C is the diagram of different catheter specifications
  • D is the PLA-TA-Tro-Ga embolization Picture of the injection pressure test results of the agent in different catheters;
  • Figure 5 is a diagram of the in vitro embolization pressure test, in which A is a schematic diagram of the test, and B is a diagram of the test results of different embolization agents;
  • Figure 6 shows the results of the biocompatibility test.
  • A is the hemolysis photos of different experimental groups
  • B is the hemolysis rate test results
  • C is the live/dead cell staining of L929 cells after incubation with different embolic agents
  • D is Cell viability test chart
  • Figure 7 shows the in vitro drug release curve, A to C are loaded with doxorubicin, sorafenib, and ati Release profile of lizumab;
  • Figure 8 shows X-ray imaging images inside and outside the body, where A is the X-ray imaging image of a syringe containing angioembolic agent, B is an X-ray imaging image of rabbit ear arteries and branch vessels containing angioembolic agent, and C is an X-ray imaging image containing blood vessels.
  • A is the X-ray imaging image of a syringe containing angioembolic agent
  • B is an X-ray imaging image of rabbit ear arteries and branch vessels containing angioembolic agent
  • C is an X-ray imaging image containing blood vessels.
  • Figure 9 is a comparison of rabbit renal artery and renal parenchyma before and after embolization.
  • A is the optical image before and after rabbit renal artery embolization
  • B is the color Doppler ultrasound imaging image before and after rabbit renal artery embolization
  • C is the two-dimensional gray image before and after renal parenchyma embolization.
  • Step ultrasound imaging D is the color Doppler ultrasound imaging before and after renal parenchyma embolization;
  • Figure 10 is a comparison picture before and after embolization of rabbit femoral artery.
  • A is the optical image of rabbit femoral artery before embolization
  • B is the color Doppler ultrasound imaging image of rabbit femoral artery before embolization
  • C is the optical image of rabbit femoral artery after embolization
  • D is Color Doppler ultrasound imaging of rabbit femoral artery after embolization;
  • Figure 11 is a schematic diagram of the preparation of Example 3.
  • Figure 12 is a schematic diagram of the preparation of Example 4.
  • Figure 13 is a schematic diagram of the preparation of Example 5.
  • Figure 14 is a schematic diagram of the preparation of Example 6;
  • Figure 15 is a schematic diagram of the preparation of Example 7.
  • Figure 16 is a schematic diagram of the preparation of Example 8.
  • Figure 17 is a schematic diagram of the preparation of Example 9;
  • Figure 18 is a schematic diagram of the preparation of Example 10.
  • Figure 19 is a schematic diagram of the preparation of Example 11.
  • Figure 20 is a schematic diagram of the preparation of Example 12.
  • Figure 21 is a schematic diagram of the preparation of Example 13;
  • Figure 22 is a schematic diagram of the preparation of Example 14.
  • Figure 23 is a schematic diagram of the preparation of Example 15;
  • Figure 24 is a schematic diagram of the preparation of Example 16.
  • Figure 25 is a schematic diagram of the preparation of Example 17.
  • An embodiment of the preparation method of the vascular embolic agent of the present invention is as follows.
  • the mass ratio of each component is shown in Table 1:
  • the PLA-TA-Tro (DMSO) was mixed with simulated physiological fluid to form a PLA-TA-Tro hydrogel, which was recorded as PLA-TA-Tro (Gel).
  • Figure 1 is a schematic diagram of the preparation of vascular embolization agents using 1,2-dithiolane compounds and polyphenols as the main raw materials
  • Figure 2 is a schematic diagram of the preparation of vascular embolization agents using lipoic acid and tannins as the main raw materials. It can be seen from the figure that lipoic acid and tannic acid generate compounds containing C-S covalent bonds and hydrogen bonds through Michael addition reaction, which together with alkaloids and DMSO form the vascular embolic agent of the present invention.
  • the vascular embolic agent is injected When injected into physiological fluids (such as blood, etc.) or water, PLA-TA-Tro (DMSO) can form a dense three-dimensional cross-linked network driven by hydrophobic interactions to form PLA-TA-Tro (Gel).
  • physiological fluids such as blood, etc.
  • DMSO physiological fluids
  • PLA-TA-Tro DMSO
  • Gel PLA-TA-Tro
  • sample 22 has the best comprehensive performance
  • PLA-TA-Tro (DMSO) has a moderate curing time
  • PLA-TA-Tro (Gel) has a suitable viscosity
  • the operability of the vascular embolic agent good usability, not easy to stick to the tube, and easy to extubate after embolization.
  • Figure 3 shows lipoic acid monomer and sample 22 vascular embolic agent (lipoic acid and poly(lipoic acid-tannic acid))
  • the Raman spectrum shows that 510cm -1 corresponds to the SS bond and 676cm -1 corresponds to the CS bond. This result shows that the grafting of 1,2-dithiolane compounds and polyphenols compounds is successful.
  • the preparation method of the vascular embolization agent in this embodiment is: combining the vascular embolization agent PLA-TA-Tro (DMSO) described in sample 22 in Example 1 and Gallium indium tin alloy is mixed in different proportions to obtain the vascular embolic agent PLA-TA-Tro-Ga (DMSO).
  • the proportions of the two components are shown in Table 2.
  • PLA-TA-Tro-Ga hydrogel recorded as PLA-TA-Tro -Ga(Gel).
  • the PLA-TA-Tro-Ga (DMSO) used in the following performance test experiments is the vascular embolization agent PLA-TA-Tro-Ga (DMSO) described in Sample 32.
  • Hemolysis experiment Collect rabbit whole blood red blood cells by centrifugation (200 ⁇ g, 10 min) and dilute to 5% (v/v) with physiological saline. Add 50 ⁇ L of PLA-TA-Tro-Ga(DMSO), PLA-TA-Tro(DMSO), DMSO, normal saline (negative control) and deionized water (positive control) to 1 mL of the above blood cell solution, and incubate at 37 Incubate at °C for 24h. After centrifuging the red blood cell suspension (500 ⁇ g, 15 min), transfer the supernatant to a 96-well plate, and use a microplate reader to test the absorbance of the solution at 540 nm.
  • PLA-TA-Tro-Ga(DMSO) PLA-TA-Tro(DMSO)
  • DMSO normal saline
  • deionized water positive control
  • the hemolysis rate of PLA-TA-Tro-Ga (DMSO) is less than 5%, which meets the requirements for the use of biological materials.
  • Cytotoxicity experiment Add L929 cells to a 12-well plate (25,000 cells/well) and incubate in a 37°C incubator for 12 hours. Then, 50 mg of PLA-TA-Tro-Ga(Gel), PLA-TA-Tro(Gel), and Ga were added to the wells containing cells, and the group without any materials was used as a positive control. After 24 h of incubation, cell viability was assessed using live/dead cell staining. To ensure the reliability of the data, each set of experiments was repeated three times. The results are shown in Figure 6. The cell survival rate in all groups was greater than 98%, and the cells showed a normal spreading spindle shape. This result shows that the gel is non-cytotoxic and has good cell biocompatibility.
  • doxorubicin measure the UV-visible spectrum of the doxorubicin solution, and take the wavelength value corresponding to the maximum absorbance (480nm) as its characteristic wavelength. Prepare doxorubicin solutions of different concentrations, test their absorbance at a wavelength of 480nm, and draw an absorbance-concentration standard curve. Dissolve 10 mg of doxorubicin in 2 mL of PLA-TA-Tro-Ga (DMSO), incubate at 37°C for 24 h, and then inject the above solution into 20 mL of phosphate buffered saline (PBS).
  • DMSO PLA-TA-Tro-Ga
  • PBS phosphate buffered saline
  • Sorafenib release curve measure the UV-visible spectrum of sorafenib solution, and take the wavelength value corresponding to the maximum absorbance (265nm) as its characteristic wavelength. Prepare sorafenib solutions of different concentrations, test their absorbance at a wavelength of 265 nm, and draw an absorbance-concentration standard curve. Then, 200 mg of sorafenib was dissolved in 2 mL of PLA-TA-Tro-Ga (DMSO), and after incubation at 37°C for 24 hours, the above solution was injected into 20 mL of phosphate buffered saline (PBS) for a specific time.
  • PBS phosphate buffered saline
  • PLA-TA-Tro-Ga(Gel) can slowly release doxorubicin, reaching nearly 100% release on the 21st day, while lipiodol reached nearly 100% on the 3rd day. of release.
  • the above results show that the vascular embolic agent of the present invention also has a good sustained-release effect on targeted drugs such as sorafenib.
  • Atezolizumab release curve Use Enzyme Linked Immunosorbent Assay, ELISA, R&D, DY1086) kit to determine the concentration of monoclonal antibody. Use a microplate reader to detect the absorbance of the standard in the kit at 450 nm, and draw an absorbance-concentration standard curve. Add 0.1 ⁇ g of programmed cell death protein 1 (PD-1) to the 96-well plate in sequence. Dissolve 60 mg of atezolizumab in 2 mL of PLA-TA-Tro-Ga (DMSO), incubate at 37°C for 24 hours, and then inject the above mixed solution loaded with atezolizumab into 20 mL of phosphate buffer. in saline solution (PBS).
  • PBS saline solution
  • PLA-TA-Tro-Ga(Gel) can slowly release atezolizumab, reaching nearly 100% release on the 25th day, while lipiodol reached the 100% release on the 3rd day. Nearly 100% release.
  • the above results show that the vascular embolic agent of the present invention can load atezolizumab and other immunosuppressants, and has good drug sustained release properties.
  • PLA-TA-Tro-Ga(DMSO) In vitro X-ray imaging experiment: Use a 1mL syringe to draw 1mL of PLA-TA-Tro-Ga(DMSO) X-ray imaging was performed. As shown in Figure 8A, PLA-TA-Tro-Ga (DMSO) showed a uniform high-density image under X-ray without artifacts.
  • Rabbit renal artery embolization experiment After the experimental rabbit was under general anesthesia, fixed, and sterilized and draped, the skin, muscles, and fascia were incised along the midline of the abdomen, and the renal artery was bluntly separated layer by layer, and the color Doppler ultrasound instrument was used to Perform imaging observations. Subsequently, 1.5 mL of PLA-TA-Tro-Ga (DMSO) was injected into the renal artery. After 1 minute, the needle was pulled out. There was no gel adhesion on the needle and no bleeding at the puncture point. It shows that the liquid embolic agent does not stick to the tube. Subsequently, color Doppler ultrasound was used to image the embolization site.
  • PLA-TA-Tro-Ga PLA-TA-Tro-Ga
  • Rabbit femoral artery embolization After the experimental rabbit was under general anesthesia, immobilized, and the left groin area was sterilized and draped, the skin and muscles were incised, the femoral artery was bluntly separated layer by layer, and imaged and observed with a color Doppler ultrasound instrument. Subsequently, 1 mL of PLA-TA-Tro-Ga (DMSO) was injected into the femoral artery. After 1 minute, the needle was pulled out. No gel adhesion was seen on the needle, and no bleeding was seen at the puncture point, indicating that the liquid embolic agent did not stick to the tube. Subsequently, color Doppler ultrasound was used to image the embolization site. As shown in Figure 10, after embolization, the femoral artery blood flow signal disappeared. This result shows that PLA-TA-Tro-Ga (DMSO) gel can successfully embolize the femoral artery of experimental rabbits.
  • An embodiment of the vascular embolic agent of the present invention is as follows:
  • An embodiment of the vascular embolic agent of the present invention is as follows:
  • vascular embolic agent had a curing time of 9 minutes, a viscosity of 92 mPa.s, and a storage modulus of 480 kPa.
  • the schematic diagram of the preparation of the vascular embolic agent described in this embodiment is shown in Figure 12.
  • An embodiment of the vascular embolic agent of the present invention is as follows:
  • vascular embolic agent had a curing time of 11 minutes, a viscosity of 80 mPa.s, and a storage modulus of 465 kPa.
  • Figure 13 The schematic diagram of the preparation of the vascular embolic agent described in this embodiment is shown in Figure 13.
  • An embodiment of the vascular embolic agent of the present invention is as follows:
  • vascular embolic agent had a curing time of 9 minutes, a viscosity of 82 mPa.s, and a storage modulus of 493 kPa.
  • Figure 14 The schematic diagram of the preparation of the vascular embolic agent described in this embodiment is shown in Figure 14.
  • An embodiment of the vascular embolic agent of the present invention is as follows:
  • vascular embolic agent had a curing time of 12 minutes, a viscosity of 77 mPa.s, and a storage modulus of 520 kPa.
  • Figure 15 The schematic diagram of the preparation of the vascular embolic agent described in this embodiment is shown in Figure 15.
  • An embodiment of the vascular embolic agent of the present invention is as follows:
  • vascular embolic agent had a curing time of 10 minutes, a viscosity of 86 mPa.s, and a storage modulus of 489 kPa.
  • the schematic diagram of the preparation of the vascular embolic agent described in this embodiment is shown in Figure 16.
  • An embodiment of the vascular embolic agent of the present invention is as follows:
  • vascular embolic agent had a curing time of 11 minutes, a viscosity of 76 mPa.s, and a storage modulus of 490 kPa.
  • the schematic diagram of the preparation of the vascular embolic agent described in this embodiment is shown in Figure 17.
  • An embodiment of the vascular embolic agent of the present invention is as follows:
  • An embodiment of the vascular embolic agent of the present invention is as follows:
  • vascular embolic agent had a curing time of 8 minutes, a viscosity of 80 mPa.s, and a storage modulus of 466 kPa.
  • Figure 19 The schematic diagram of the preparation of the vascular embolic agent described in this embodiment is shown in Figure 19.
  • An embodiment of the vascular embolic agent of the present invention is as follows:
  • An embodiment of the vascular embolic agent of the present invention is as follows:
  • vascular embolic agent had a curing time of 10 minutes, a viscosity of 86 mPa.s, and a storage modulus of 489 kPa.
  • the schematic diagram of the preparation of the vascular embolic agent described in this embodiment is shown in Figure 21.
  • An embodiment of the vascular embolic agent of the present invention is as follows:
  • vascular embolic agent had a curing time of 12 minutes, a viscosity of 65 mPa.s, and a storage modulus of 412 kPa.
  • the schematic diagram of the preparation of the vascular embolic agent described in this embodiment is shown in Figure 22.
  • An embodiment of the vascular embolic agent of the present invention is as follows:
  • An embodiment of the vascular embolic agent of the present invention is as follows:
  • vascular embolic agent had a curing time of 12 minutes, a viscosity of 65 mPa.s, and a storage modulus of 412 kPa.
  • Figure 24 The schematic diagram of the preparation of the vascular embolic agent described in this embodiment is shown in Figure 24.
  • An embodiment of the vascular embolic agent of the present invention is as follows:

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Abstract

一种血管栓塞剂及其制备方法与应用，所述血管栓塞剂的制备方法包括如下步骤：(1)将1,2-二硫戊环类化合物、多酚类化合物、生物碱溶解于有机溶剂A中，得到混合溶液A；(2)将所述混合溶液A密封后置于70℃以上的环境中反应5～12h，得到混合溶液B；(3)将所述混合溶液B冷却至室温，向其中加入有机溶剂B进行稀释，得到所述血管栓塞剂通过采用上述方法制备出的血管栓塞剂具有出色的生物相容性、稳定的机械性能、优异的血管内弥散性、易输送至微血管以及形状复杂的靶血管，不粘管，可显影且无影像学伪影。

Description

一种血管栓塞剂及其制备方法与应用
本申请要求于2022年8月24日提交中国专利局、申请号为202211019192.1、发明名称为“一种血管栓塞剂及其制备方法与应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本申请涉及血管栓塞剂技术领域，尤其涉及一种血管栓塞剂及其制备方法与应用。
背景技术
血管栓塞治疗由于其创伤小、重复性高、见效快等优点，已成为临床上治疗血管性病变和肿瘤性病变的有效手段，尤其是针对出血性病变、血管畸形、动脉瘤和巴塞罗那分期(Barcelona Clinic Liver Cancer)中期的原发性肝癌。根据物理性状，可将当前临床使用的栓塞材料分为固体栓塞材料和液体栓塞材料。固体栓塞材料主要包括弹簧圈、明胶海绵颗粒和聚乙烯醇微球等。液体栓塞材料主要包括氰基丙烯酸丁酯(N-butyl-cyanoacrylate，nBCA)、Onyx(主要成分乙烯-乙烯醇共聚物和二甲基亚砜)和碘化油等。
弹簧圈在填塞过程中既易引起血管破裂，又会因血管过度扭曲而无法输送至目标部位。明胶海绵颗粒易降解，导致血管再通。聚乙烯醇微球和明胶海绵颗粒均易发生团聚，从而很难达到微血管。nBCA遇到血液迅速发生聚合反应，形成栓塞。然而，反应产物弥散性差，易与导管粘附在一起，给患者带来较大的危险。Onyx无法降解，易导致局部慢性炎症和(或)机体排斥反应。碘化油流动性较强，易导致血管再通、栓塞效果不佳，而且无法有效地装载和缓释药物。此外，大部分栓塞剂与显影剂无法紧密交联，术中或术后容易出现栓塞剂和显影剂分离，无法有效监测栓塞剂的位置，导致栓塞不完全或异位栓塞。
发明内容
本发明的目的在于克服上述现有技术的不足之处而提供一种血管栓塞剂及其制备方法与应用，所述血管栓塞剂在血管内具有稳定的机械性能，出色的生物相容性，良好的弥散性，易输送至微血管以及形状复杂的靶血管，不粘管， 可有效地装载药物。所述血管栓塞剂与显影剂紧密交联，不会产生影像学伪影。
为实现上述目的，本发明所采取的技术方案为：
一种血管栓塞剂的制备方法，其特征在于，包括如下步骤：
(1)将1,2-二硫戊环类化合物、多酚类化合物、生物碱溶解于有机溶剂A中，得到混合溶液A；
(2)将所述混合溶液A密封后置于70℃以上的环境中反应5～12h，得到混合溶液B；
(3)将所述混合溶液B冷却至室温，向其中加入有机溶剂B进行稀释，得到所述血管栓塞剂。
1,2-二硫戊环类化合物与多酚类化合物可通过迈克尔加成反应将1,2-二硫戊环类化合物接枝到多酚类化合物的苯环上，形成C-S键，1,2-二硫戊环类化合物上的羧基等基团能与多酚类化合物的酚羟基、羧基或者氨基形成氢键；另外，生物碱既可以中和体系中多余的氢离子，降低产物的细胞毒性、避免产物刺激血管壁，又能通过氢键的作用与1,2-二硫戊环类化合物和多酚类化合物增强凝胶的交联密度，提高栓塞效果。将所述血管栓塞剂注射到生理液(如血液等)以及水溶液中，可以快速形成凝胶。
优选地，所述有机溶剂A、有机溶剂B分别为二甲基亚砜(DMSO)、乙醇中的至少一种，所述有机溶剂A和有机溶剂B相同或不同。进一步优选地，所述有机溶剂A和有机溶剂B为二甲基亚砜，与其他有机溶剂相比，二甲基亚砜对血管的刺激更小。
优选地，所述步骤(1)中，1,2-二硫戊环类化合物、多酚类化合物、生物碱的质量比为(0.05～1)：(0.0001～1)：(0.01～1)；所述有机溶剂A与混合溶液A的质量比为(2～4)：10；所述步骤(3)中，有机溶剂B与血管栓塞剂的质量比为(1～5.8)：10。通过对各成分的配比作上述优选，可以保证反应能够充分进行，并且制备的血管栓塞剂具有良好的栓塞效果。
优选地，所述步骤(1)中，1,2-二硫戊环类化合物、多酚类化合物、生物碱的质量比为0.6：0.05：0.3。在满足上述配比的情况下，制备的血管栓塞剂可快速固化，不易粘管，具有优良的操作性，并且具有较好的机械性能，可以对血管形成良好的堵塞作用。
优选地，所述步骤(2)中，混合溶液A在90℃下反应10h，在上述条件下制备的反应产物具有稳定的机械性能、较低的粘度和合适的成胶时间等特点，并且反应效率高。
优选地，所述1,2-二硫戊环类化合物为硫辛酸、芦笋酸、二硫吡咯酮类抗生素、kottamide E中的至少一种；所述多酚类化合物为单宁酸、没食子酸、咖啡酸、儿茶酚、多巴胺、聚多巴胺、白藜芦醇、槲皮素、姜黄素、绿原酸、异黄酮、花青素、可可多酚、柠檬黄素、儿茶素、芸香苷中的至少一种；所述生物碱为氨丁三醇、麻黄碱、益母草碱、金鸡纳碱中的至少一种。
进一步优选地，所述1,2-二硫戊环类化合物为硫辛酸，所述多酚类化合物为单宁酸，所述生物碱为氨丁三醇。上述成分具有良好的生物相容性，并且反应效率高，具有较高的经济效益。
优选地，所述步骤(3)中，稀释后，加入显影剂，所述显影剂的加入量为血管栓塞剂质量的10wt％～80wt％；所述显影剂为熔点在35℃以下的液态金属或钽粉微颗粒。加入上述显影剂可以得到不透X射线的血管栓塞剂，有利于手术中和术后检测血管栓塞剂的位置。
进一步优选地，所述显影剂的加入量为血管栓塞剂的30wt％，所述显影剂为镓铟合金。所述显影剂能通过静电作用或螯合作用与1,2-二硫戊环类化合物和多酚类化合物的反应产物牢固且稳定的结合，在使用或者长时间放置过程中不会和栓塞剂发生脱离。因此能在手术过程中和手术后对血管栓塞剂实现精准定位。
此外，本发明还公开了一种由上述方法制备而成的血管栓塞剂，所述血管栓塞剂在制备药物载体中的应用，并且本发明还公开了所述血管栓塞剂在人体各脏器动静脉出血性病变、动脉瘤、动静脉畸形以及装载化疗药物/靶向药物/免疫抑制剂后用于肿瘤的化疗栓塞治疗中的应用。
相比于现有技术，本发明的有益效果为：
(1)本发明以1,2-二硫戊环类化合物、多酚类化合物、生物碱为主要原料制备的血管栓塞剂在注射入生理液(如血液等)或水溶液中后具有适中的固化时间以及粘度，操作性较好，凝胶不易粘管，易于栓塞手术后拔管。
(2)本发明所述血管栓塞剂固化后具有较好的机械强度和栓塞压力，栓 塞效果优异。
(3)本发明选用的制备原料具有良好的生物相容性，制备的血管栓塞剂具有优异的弥散性，可弥散至微血管和形状复杂的靶血管。
(4)本发明将能通过静电作用或螯合作用与1,2-二硫戊环类化合物和酚类化合物的反应产物结合的液态金属或钽粉微颗粒作为显影剂。不仅有利于术中监测栓塞剂的位置，而且减轻了影像学伪影，有利于介入术后的疗效监测。
(5)本发明所述血管栓塞剂可适用于治疗人体各脏器出血性病变、动脉瘤、动静脉畸形，用于良恶性肿瘤的供血动脉栓塞，以及有效装载及缓释化疗药物(如阿霉素、顺铂、卡铂、洛铂、雷替曲塞、吉西他滨、5-氟尿嘧啶、伊立替康、博来霉素、长春西汀中的至少一种)、靶向药物(如索拉菲尼(sorafenib)、仑伐替尼(lenvatinib)、瑞戈非尼(regorafenib)、卡博替尼(cabozantinib)、阿帕替尼、安罗替尼中的至少一种)以及免疫抑制剂(如阿替利珠单抗(atezolizumab)，可瑞达(keytruda)、纳武利尤单抗(nivolumab)、卡瑞利珠单抗、信迪利单抗中的至少一种)等后用于多种恶性肿瘤的化疗栓塞治疗。
附图说明
图1为以1,2-二硫戊环类化合物和多酚类化合物为主要原料制备血管栓塞剂的示意图；
图2为以硫辛酸和单宁酸为主要原料制备血管栓塞剂的示意图；
图3为硫辛酸和聚(硫辛酸-单宁酸)的拉曼光谱图；
图4为栓塞剂注射压力测试图，其中，A为测试示意图，B为不同栓塞剂在1.7F微导管中的测试结果图，C为不同导管规格图，D为PLA-TA-Tro-Ga栓塞剂在不同导管中的注射压力测试结果图；
图5为体外栓塞压力测试图，其中，A为测试示意图，B为不同栓塞剂的测试结果图；
图6为生物相容性测试结果图，其中，A为不同实验组溶血照片，B为溶血率测试结果图，C为L929细胞与不同栓塞剂共同孵育后的活/死细胞染色图，D为细胞存活率测试图；
图7为体外药物释放曲线图，A～C分别为装载阿霉素、索拉菲尼、阿替 利珠单抗的释放曲线图；
图8为体内外X光成像图，其中，A为装有血管栓塞剂的注射器的X光成像图，B为含有血管栓塞剂的兔耳动脉及分支血管的X光成像图，C为含有血管栓塞剂的肾动脉及分支血管的X光成像图；
图9为兔肾动脉和肾实质栓塞前后对比图，其中，A为兔肾动脉栓塞前后光学图，B为兔肾动脉栓塞前后彩色多普勒超声成像图，C为肾实质栓塞前后二维灰阶超声成像图，D为肾实质栓塞前后彩色多普勒超声成像图；
图10为兔股动脉栓塞前后对比图，其中，A为兔股动脉栓塞前光学图，B为兔股动脉栓塞前彩色多普勒超声成像图，C为兔股动脉栓塞后光学图，D为兔股动脉栓塞后彩色多普勒超声成像图；
图11为实施例3的制备示意图；
图12为实施例4的制备示意图；
图13为实施例5的制备示意图；
图14为实施例6的制备示意图；
图15为实施例7的制备示意图；
图16为实施例8的制备示意图；
图17为实施例9的制备示意图；
图18为实施例10的制备示意图；
图19为实施例11的制备示意图；
图20为实施例12的制备示意图；
图21为实施例13的制备示意图；
图22为实施例14的制备示意图；
图23为实施例15的制备示意图；
图24为实施例16的制备示意图；
图25为实施例17的制备示意图。
具体实施方式
为更好地说明本发明的目的、技术方案和优点，下面将结合附图和具体实 施例对本发明作进一步说明。
实施例1
本发明所述血管栓塞剂的制备方法的一种实施例，本实施例所述血管栓塞剂的制备方法如下，各成分的质量比如表1所示：
(1)将不同质量配比的硫辛酸、单宁酸、氨丁三醇粉末溶解于DMSO中，得到混合溶液A；
(2)将所述混合溶液A密封后置于90℃下反应10h，得到混合溶液B；
(3)将混合溶液B冷却至室温，加入DMSO稀释，得到所述血管栓塞剂，记为PLA-TA-Tro(DMSO)。
将所述PLA-TA-Tro(DMSO)与模拟生理液混合，形成PLA-TA-Tro水凝胶，记为PLA-TA-Tro(Gel)。
图1为以1,2-二硫戊环类化合物和多酚类化合物为主要原料制备血管栓塞剂的示意图；图2为以硫辛酸和单宁酸为主要原料制备血管栓塞剂的示意图，从图中可以看到，硫辛酸和单宁酸通过迈克尔加成反应生成含C-S共价键以及氢键的化合物，与生物碱、DMSO组成本发明所述血管栓塞剂，将所述血管栓塞剂注射入生理液(如血液等)或水中，PLA-TA-Tro(DMSO)能在疏水作用等作用的驱动下形成致密的三维交联网络，形成PLA-TA-Tro(Gel)。
对不同原料配比下制备的PLA-TA-Tro(DMSO)的固化时间，PLA-TA-Tro(Gel)的pH值、粘度、储能模量进行测试，测试结果如表1所示。
表1

备注：样品5、10、15、20中由于氨丁三醇浓度过高，其与聚硫辛酸上的羧基形成较强的静电作用，阻止了聚合物之间氢键的形成，导致无法成胶，用“—”表示。样品25中DMSO浓度过高，聚合物的浓度及相互作用力显著下降，导致其无法通过氢键交联成胶，用“—”表示。
由表1可知，样品22具有最优的综合性能，PLA-TA-Tro(DMSO)具有适中的固化时间，PLA-TA-Tro(Gel)具有合适的粘度，所述血管栓塞剂的可操作性、使用性较好，不易粘管，栓塞后易拔管。
图3为硫辛酸单体和样品22血管栓塞剂(硫辛酸和聚(硫辛酸-单宁酸)) 的拉曼光谱图，其中，510cm-1对应S-S键，676cm-1处对应C-S键。该结果表明1,2-二硫戊环类化合物与多酚类化合物接枝成功。
实施例2
本发明所述血管栓塞剂的制备方法的一种实施例，本实施例所述血管栓塞剂的制备方法为：将实施例1中样品22所述血管栓塞剂PLA-TA-Tro(DMSO)与镓铟锡合金按不同配比混合，得到血管栓塞剂PLA-TA-Tro-Ga(DMSO)，两种成分的配比如表2所示。将所述PLA-TA-Tro-Ga(DMSO)注射至模拟生理液(即1L的去离子水中加入8.035g氯化钠、0.355g碳酸氢钠、0.225g氯化钾、0.231g磷酸氢二钾、0.311g六水合氯化镁、39mL 1M盐酸、0.292g氯化钙、0.072g硫酸钠和6.118g氨丁三醇)中，形成PLA-TA-Tro-Ga水凝胶，记为PLA-TA-Tro-Ga(Gel)。
对不同原料配比下制备的PLA-TA-Tro-Ga(DMSO)的固化时间，PLA-TA-Tro-Ga(Gel)的粘度、储能模量以及CT值进行测试，测试结果如表2所示。
表2

备注：样品35中液态金属浓度过高，聚合物的浓度及相互作用力显著下降，导致其无法通过氢键交联成胶，用“—”表示。
由表2可知，当显影剂的加入量为所述血管栓塞剂PLA-TA-Tro-Ga(DMSO)质量的30wt％时，具有最优的综合性能。PLA-TA-Tro-Ga(DMSO)的固化时间为9min，形成的PLA-TA-Tro-Ga(Gel)的粘度适中，并且还具有极高的储能模量，栓塞效果优异，而且CT值可达1000Hu，治疗过程中易于追踪。
以下性能测试实验中使用的PLA-TA-Tro-Ga(DMSO)均为样品32所述血管栓塞剂PLA-TA-Tro-Ga(DMSO)。
栓塞剂的注射压力测试：将1mL螺口注射器按图4A放置在自制的测试仪器上，注射器上端跟上压板接触，下端被夹具垂直固定并连接不同规格的导管。1)分别将1mL PLA-TA-Tro-Ga(DMSO)、Onyx、碘化油、生理盐水添加到注射器内，下端连接1.7F微导管；然后，使用上压板匀速地(流量：2mL/min)按压注射器，同时记录上压板压力的变化。结果如图4B所示，碘化油、PLA-TA-Tro-Ga(DMSO)、Onyx、生理盐水的注射压力依次降低，说明PLA-TA-Tro-Ga(DMSO)的注射还是较为容易的。2)将1mL PLA-TA-Tro-Ga(DMSO)添加到注射器内，下端连接不同规格的导管(图4C)；然后，使用上压板匀速地(流量：2mL/min)按压注射器，同时记录上压板压力的变化，结果如图4D所示，注射压力随着微导管直径的增加而降低。综上，PLA-TA-Tro-Ga(DMSO)容易通过导管被注射，具有优良的使用性能。
体外栓塞实验：将注射泵、注射器、压力计、猪的主动脉(内径：6mm)、聚二甲基硅氧烷(Polydimethylsiloxane，PDMS)管道(内径：6mm)按照图5A连接，并在整个管道内充满37℃的抗凝血液，再将猪的主动脉和PDMS管道浸泡在37℃的抗凝血液中。随后，分别将PLA-TA-Tro-Ga(DMSO)(1mL)、Onyx(1mL)、弹簧圈(1枚，6mm*6mm)通过5F微导管(内径：1.7mm)注入猪主动脉内。取出导管后(血管栓塞剂已形成凝胶)，以80mL/min 的流量推送抗凝血液直至血管栓塞剂凝胶PLA-TA-Tro-Ga(Gel)从血管中排出，同时利用压力表记录体系压力的变化，最大值记为栓塞剂的栓塞压力。由图5B可知，相对于弹簧圈和Onyx，PLA-TA-Tro-Ga(Gel)具有更大的栓塞压力，能有利于栓塞具有较大血压的动脉血管。
溶血实验：通过离心(200×g，10min)收集兔全血红细胞，用生理盐水稀释至5％(v/v)。分别将50μL PLA-TA-Tro-Ga(DMSO)、PLA-TA-Tro(DMSO)、DMSO、生理盐水(阴性对照)和去离子水(阳性对照)加到1mL上述血细胞溶液中，并在37℃孵育24h。将红细胞悬液离心(500×g，15min)后，将上层清液转移到96孔板，使用酶标仪测试溶液在540nm处的吸光度。溶血率计算如下：溶血率(％)＝(As-An)/(Ad-An)×100％(As、An和Ad分别为样品、生理盐水和去离子水组的吸光度)。为保证数据的可靠性，每组实验重复3次。结果如图6所示，PLA-TA-Tro-Ga(DMSO)溶血率小于5％，满足生物材料的使用要求。
细胞毒性实验：将L929细胞加入12孔板(25000个/孔)，并在37℃培育箱孵育12h。然后，分别将50mg PLA-TA-Tro-Ga(Gel)、PLA-TA-Tro(Gel)、Ga加入含有细胞的孔中，将不添加任何材料的组作为阳性对照。孵育24h后，用活/死细胞染色法评估细胞活力。为保证数据的可靠性，每组实验重复3次。结果如图6所示，所有组别的细胞存活率均大于98％，且细胞呈现正常铺展的梭形。该结果说明，凝胶无细胞毒性，具有良好的细胞生物相容性。
阿霉素缓释能力：测定阿霉素溶液的紫外-可见光谱，将最大吸光度所对应的波长值(480nm)作为其特征波长。配置不同浓度的阿霉素溶液，并测试它们在480nm波长下的吸光度，绘制吸光度-浓度标准曲线。将10mg阿霉素溶解于2mL PLA-TA-Tro-Ga(DMSO)中，于37℃条件下孵育24h后，将上述溶液注射于20mL的磷酸缓冲盐溶液(PBS)中。在设置的时间点取200μL上清液，测试其在480nm波长下的吸光度，根据吸光度-浓度标准曲线计算出溶液里阿霉素的浓度。将载有阿霉素的碘化油作为对照实验。结果如图7A所示，PLA-TA-Tro-Ga(Gel)可以缓慢地释放阿霉素，在第35天才达到近100％的释放，而碘化油在第3天就达到了近100％的释放。该结果表明，本发明所述 血管栓塞剂可以负载阿霉素等化疗药物，并具有良好的缓释效果。
索拉菲尼释放曲线：测定索拉菲尼溶液的紫外-可见光谱，将最大吸光度所对应的波长值(265nm)作为其特征波长。配置不同浓度的索拉菲尼溶液，并测试它们在265nm波长下的吸光度，绘制吸光度-浓度标准曲线。然后，将200mg索拉菲尼溶解于2mL PLA-TA-Tro-Ga(DMSO)中，于37℃条件下孵育24h后，将上述溶液注射于20mL的磷酸缓冲盐溶液(PBS)中，特定时间点取200μL上清液，测试其265nm吸光度，根据吸光度-浓度标准曲线计算出溶液里索拉菲尼的浓度。将载有索拉菲尼的碘化油作为对照实验。结果如图7B所示，PLA-TA-Tro-Ga(Gel)能缓慢地释放阿霉素，在第21天才达到近100％的释放，而碘化油在第3天就达到了近100％的释放。上述结果表明，本发明所述血管栓塞剂对索拉菲尼等靶向药物也具有良好的缓释效果。
阿替利珠单抗释放曲线：采用酶联免疫吸附实验(Enzyme Linked Immunosorbent Assay,ELISA,R&D,DY1086)试剂盒测定单抗的浓度。利用酶标仪检测试剂盒内标准品在450nm处的吸光度，绘制吸光度-浓度标准曲线。分别将0.1μg程序性细胞死亡蛋白1(Programmed cell death protein 1,PD-1)依次加入96孔板中。取60mg阿替利珠单抗溶解于2mL PLA-TA-Tro-Ga(DMSO)中，于37℃条件下孵育24h后，将上述装载阿替利珠单抗的混合溶液注射于20mL的磷酸缓冲盐溶液(PBS)中。在设置的时间点取200μL上清液并用PBS稀释1000倍，再将500μL上述稀释溶液加入装有PD-1蛋白的96孔板中。随后，加入Peroxidase Affinipure Goat Anti-human IgG二抗，利用3,3',5,5'-四甲基联苯胺(3,3',5,5'-Tetramethylbenzidine,TMB)染色。最后利用酶标仪于450nm处读取吸光度，再根据吸光度-浓度标准曲线计算出溶液里阿替利珠单抗的浓度。将载有阿替利珠单抗的碘化油作为对照实验。结果如图7C所示，PLA-TA-Tro-Ga(Gel)能缓慢地释放阿替利珠单抗，在第25天才达到近100％的释放，而碘化油在第3天就达到了近100％的释放。上述结果表明，本发明所述血管栓塞剂可以负载阿替利珠单抗等免疫抑制剂，并且具有良好的药物缓释性能。
体外X光成像实验：使用1mL注射器抽取1mL PLA-TA-Tro-Ga(DMSO) 进行X光成像，如图8A所示，PLA-TA-Tro-Ga(DMSO)X线下呈均匀一致高密度像、无伪影。
体内X光成像实验：利用注射器分别向兔耳动脉和肾动脉分别注入1mL和1.5mL PLA-TA-Tro-Ga(DMSO)，在X线下可以清楚地看到充满动脉和分支血管的PLA-TA-Tro-Ga(DMSO)，且无伪影(图8B、8C)。
兔肾动脉栓塞实验：将实验兔全麻、固定、消毒铺巾后，沿着正中腹部切开皮肤、肌肉、筋膜，逐层钝性分离出肾动脉，并用彩色多普勒超声仪对其进行成像观察。随后，向肾动脉注入1.5mL PLA-TA-Tro-Ga(DMSO)。1分钟后，将针头拔出，针头未见凝胶粘连，穿刺点未见出血。说明该液体栓塞剂不粘管。随后，用彩色多普勒超声仪对栓塞部位进行成像观察。如图9所示，栓塞后，肾动脉血流信号消失，肾实质内多发散在高回声。该结果说明PLA-TA-Tro-Ga(DMSO)凝胶后能成功栓塞实验兔的肾动脉。
兔股动脉栓塞：实验兔全麻、固定、左侧腹股沟区消毒铺巾后，切开皮肤及肌肉，逐层钝性分离出股动脉，并用彩色多普勒超声仪对其进行成像观察。随后，向股动脉内注入1mL PLA-TA-Tro-Ga(DMSO)。1分钟后，将针头拔出，针头未见凝胶粘连，穿刺点未见出血，说明该液体栓塞剂不粘管。随后，用彩色多普勒超声仪对栓塞部位进行成像观察。如图10所示，栓塞后，股动脉血流信号消失。该结果说明PLA-TA-Tro-Ga(DMSO)凝胶后能成功栓塞实验兔的股动脉。
实施例3
本发明所述血管栓塞剂的一种实施例，本实施例所述血管栓塞剂的制备方法如下：
(1)将1.2g硫辛酸、0.8g没食子酸和0.6g氨丁三醇粉末溶解于0.6g的DMSO中，得到混合溶液A；
(2)将所述混合溶液A密封后置于90℃条件下反应10h，得到混合溶液B；
(3)将所述混合溶液B取出，冷却至室温，加入2.5g DMSO稀释，最后，加入1.5g显影剂镓铟锡合金，得到所述血管栓塞剂。所得到的血管栓塞 剂固化时间为10min，粘度为89mPa.s，储能模量为470kPa。本实施例所述血管栓塞剂的制备示意图如图11所示。
实施例4
本发明所述血管栓塞剂的一种实施例，本实施例所述血管栓塞剂的制备方法如下：
(1)1.2g硫辛酸、0.5g咖啡酸和0.6g氨丁三醇粉末溶解于0.6g的DMSO后，得到混合溶液A；
(2)将所述混合溶液A密封后置于90℃下反应10h，得到混合溶液B；
(3)将所述混合溶液B取出，冷却至室温，加入2.5g DMSO进行稀释，最后，加入1.0g显影剂镓铟锡合金，得到所述血管栓塞剂。所得到的血管栓塞剂固化时间为9min，粘度为92mPa.s，储能模量为480kPa。本实施例所述血管栓塞剂的制备示意图如图12所示。
实施例5
本发明所述血管栓塞剂的一种实施例，本实施例所述血管栓塞剂的制备方法如下：
(1)1.2g硫辛酸、0.8g儿茶酚和0.6g氨丁三醇粉末溶解于0.6g的DMSO后，得到混合溶液A；
(2)将所述混合溶液A密封后置于90℃下反应10h，得到混合溶液B；
(3)将所述混合溶液B取出，冷却至室温，加入1.5g DMSO进行稀释，最后，加入1.2g显影剂镓铟锡合金，得到所述血管栓塞剂。所得到的血管栓塞剂固化时间为11min，粘度为80mPa.s，储能模量为465kPa。本实施例所述血管栓塞剂的制备示意图如图13所示。
实施例6
本发明所述血管栓塞剂的一种实施例，本实施例所述血管栓塞剂的制备方法如下：
(1)1.2g硫辛酸、1.0g多巴胺和0.6g氨丁三醇粉末溶解于0.6g的DMSO 后，得到混合溶液A；
(2)将所述混合溶液A密封后置于90℃下反应10h，得到混合溶液B；
(3)将所述混合溶液B取出，冷却至室温，加入2.5g DMSO进行稀释，最后，加入1.6g显影剂镓铟锡合金，得到所述血管栓塞剂。所得到的血管栓塞剂固化时间为9min，粘度为82mPa.s，储能模量为493kPa。本实施例所述血管栓塞剂的制备示意图如图14所示。
实施例7
本发明所述血管栓塞剂的一种实施例，本实施例所述血管栓塞剂的制备方法如下：
(1)将1.2g硫辛酸、0.2g聚多巴胺和0.6g氨丁三醇粉末溶解于0.4g的DMSO后，得到混合溶液A；
(2)将所述混合溶液A密封后置于90℃下反应10h，得到混合溶液B；
(3)将所述混合溶液B取出，冷却至室温，加入1.5g DMSO进行稀释，最后，加入1.2g显影剂镓铟锡合金，得到所述血管栓塞剂。所得到的血管栓塞剂固化时间为12min，粘度为77mPa.s，储能模量为520kPa。本实施例所述血管栓塞剂的制备示意图如图15所示。
实施例8
本发明所述血管栓塞剂的一种实施例，本实施例所述血管栓塞剂的制备方法如下：
(1)将1.2g硫辛酸、0.2g白藜芦醇和0.6g氨丁三醇粉末溶解于0.4g的DMSO后，得到混合溶液A；
(2)将所述混合溶液A密封后置于90℃下反应10h，得到混合溶液B；
(3)将所述混合溶液B取出，冷却至室温，加入1.5g DMSO进行稀释，最后，加入1.0g显影剂镓铟锡合金，得到所述血管栓塞剂。所得到的血管栓塞剂固化时间为10min，粘度为86mPa.s，储能模量为489kPa。本实施例所述血管栓塞剂的制备示意图如图16所示。
实施例9
本发明所述血管栓塞剂的一种实施例，本实施例所述血管栓塞剂的制备方法如下：
(1)将1.2g硫辛酸、0.6g槲皮素和0.6g氨丁三醇粉末溶解于0.5g的DMSO后，得到混合溶液A；
(2)将所述混合溶液A密封后置于90℃下反应10h，得到混合溶液B；
(3)将所述混合溶液B取出，冷却至室温，加入2.0g DMSO进行稀释，最后，加入1.2g显影剂镓铟锡合金，得到所述血管栓塞剂。所得到的血管栓塞剂固化时间为11min，粘度为76mPa.s，储能模量为490kPa。本实施例所述血管栓塞剂的制备示意图如图17所示。
实施例10
本发明所述血管栓塞剂的一种实施例，本实施例所述血管栓塞剂的制备方法如下：
(1)将1.4g芦笋酸、0.1g单宁酸和0.5g氨丁三醇粉末溶解于0.4g的DMSO后，得到混合溶液A；
(2)将所述混合溶液A密封后置于90℃下反应10h，得到混合溶液B；
(3)将所述混合溶液B取出，冷却至室温，加入2.0g DMSO进行稀释，最后，加入1.0g显影剂镓铟锡合金，得到所述血管栓塞剂。所得到的血管栓塞剂固化时间为9min，粘度为80mPa.s，储能模量为477kPa。本实施例所述血管栓塞剂的制备示意图如图18所示。
实施例11
本发明所述血管栓塞剂的一种实施例，本实施例所述血管栓塞剂的制备方法如下：
(1)将1.2g芦笋酸、1.0g没食子酸和0.5g氨丁三醇粉末溶解于0.6g的DMSO后，得到混合溶液A；
(2)将所述混合溶液A密封后置于90℃下反应10h，得到混合溶液B；
(3)将所述混合溶液B取出，冷却至室温，加入2.0g DMSO进行稀释， 最后，加入1.6g显影剂镓铟锡合金，得到所述血管栓塞剂。所得到的血管栓塞剂固化时间为8min，粘度为80mPa.s，储能模量为466kPa。本实施例所述血管栓塞剂的制备示意图如图19所示。
实施例12
本发明所述血管栓塞剂的一种实施例，本实施例所述血管栓塞剂的制备方法如下：
(1)将1.2g芦笋酸、1.0g咖啡酸和0.5g氨丁三醇粉末溶解于0.5g的DMSO后，得到混合溶液A；
(2)将所述混合溶液A密封后置于90℃下反应10h，得到混合溶液B；
(3)将所述混合溶液B取出，冷却至室温，加入2.5g DMSO进行稀释，最后，加入1.8g显影剂镓铟锡合金，得到所述血管栓塞剂。所得到的血管栓塞剂固化时间为9min，粘度为77mPa.s，储能模量为482kPa。本实施例所述血管栓塞剂的制备示意图如图20所示。
实施例13
本发明所述血管栓塞剂的一种实施例，本实施例所述血管栓塞剂的制备方法如下：
(1)将1.4g芦笋酸、1.0g儿茶酚和0.5g氨丁三醇粉末溶解于0.6g的DMSO后，得到混合溶液A；
(2)将所述混合溶液A密封后置于90℃下反应10h，得到混合溶液B；
(3)将所述混合溶液B取出，冷却至室温，加入3.0g DMSO进行稀释，最后，加入1.8g显影剂镓铟锡合金，得到所述血管栓塞剂。所得到的血管栓塞剂固化时间为10min，粘度为86mPa.s，储能模量为489kPa。本实施例所述血管栓塞剂的制备示意图如图21所示。
实施例14
本发明所述血管栓塞剂的一种实施例，本实施例所述血管栓塞剂的制备方法如下：
(1)将1.4g芦笋酸、0.6g多巴胺和0.5g氨丁三醇粉末溶解于0.5g的DMSO后，得到混合溶液A；
(2)将所述混合溶液A密封后置于90℃下反应10h，得到混合溶液B；
(3)将所述混合溶液B取出，冷却至室温，加入2.5g DMSO进行稀释，最后，加入1.2g显影剂镓铟锡合金，得到所述血管栓塞剂。所得到的血管栓塞剂固化时间为12min，粘度为65mPa.s，储能模量为412kPa。本实施例所述血管栓塞剂的制备示意图如图22所示。
实施例15
本发明所述血管栓塞剂的一种实施例，本实施例所述血管栓塞剂的制备方法如下：
(1)将1.4g芦笋酸、0.1g聚多巴胺和0.5g氨丁三醇粉末溶解于0.5g的DMSO后，得到混合溶液A；
(2)将所述混合溶液A密封后置于90℃下反应10h，得到混合溶液B；
(3)将所述混合溶液B取出，冷却至室温，加入2.0g DMSO进行稀释，最后，加入1.0g显影剂镓铟锡合金，得到所述血管栓塞剂。所得到的血管栓塞剂固化时间为9min，粘度为78mPa.s，储能模量为482kPa。本实施例所述血管栓塞剂的制备示意图如图23所示。
实施例16
本发明所述血管栓塞剂的一种实施例，本实施例所述血管栓塞剂的制备方法如下：
(1)将1.4g芦笋酸、0.5g白藜芦醇和0.5g氨丁三醇粉末溶解于0.5g的DMSO后，得到混合溶液A；
(2)将所述混合溶液A密封后置于90℃下反应10h，得到混合溶液B；
(3)将所述混合溶液B取出，冷却至室温，加入2.5g DMSO进行稀释，最后，加入1.2g显影剂镓铟锡合金，得到所述血管栓塞剂。所得到的血管栓塞剂固化时间为12min，粘度为65mPa.s，储能模量为412kPa。本实施例所述血管栓塞剂的制备示意图如图24所示。
实施例17
本发明所述血管栓塞剂的一种实施例，本实施例所述血管栓塞剂的制备方法如下：
(1)将1.4g芦笋酸、0.3g槲皮素和0.5g氨丁三醇粉末溶解于0.4g的DMSO后，得到混合溶液A；
(2)将所述混合溶液A密封后置于90℃下反应10h，得到混合溶液B；
(3)将所述混合溶液B取出，冷却至室温，加入2.0g DMSO进行稀释，最后，加入1.0g显影剂镓铟锡合金，得到所述血管栓塞剂。所得到的血管栓塞剂固化时间为10min，粘度为88mPa.s，储能模量为378kPa。本实施例所述血管栓塞剂的制备示意图如图25所示。最后所应当说明的是，以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制，尽管参照较佳实施例对本发明作了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，但并不脱离本发明技术方案的实质和范围。

Claims (10)

  1. 一种血管栓塞剂的制备方法，其特征在于，包括如下步骤：
    (1)将1,2-二硫戊环类化合物、多酚类化合物、生物碱溶解于有机溶剂A中，得到混合溶液A；
    (2)将所述混合溶液A密封后置于70℃以上的环境中反应5～12h，得到混合溶液B；
    (3)将所述混合溶液B冷却至室温，向其中加入有机溶剂B进行稀释，得到所述血管栓塞剂。
  2. 如权利要求1所述的制备方法，其特征在于，所述有机溶剂A、有机溶剂B分别为二甲基亚砜、乙醇中的至少一种，所述有机溶剂A和有机溶剂B相同或不同。
  3. 如权利要求1所述的制备方法，其特征在于，所述步骤(1)中，1,2-二硫戊环类化合物、多酚类化合物、生物碱的质量比为(0.05～1)：(0.0001～1)：(0.01～1)；所述有机溶剂A与混合溶液A的质量比为(2～4)：10；所述步骤(3)中，有机溶剂B与血管栓塞剂的质量比为(1～5.8)：10。
  4. 如权利要求3所述的制备方法，其特征在于，所述步骤(1)中，1,2-二硫戊环类化合物、多酚类化合物、生物碱的质量比为0.6：0.05：0.3。
  5. 如权利要求1所述的制备方法，其特征在于，所述1,2-二硫戊环类化合物为硫辛酸、芦笋酸、二硫吡咯酮类抗生素、kottamide E中的至少一种；所述多酚类化合物为单宁酸、没食子酸、咖啡酸、儿茶酚、多巴胺、聚多巴胺、白藜芦醇、槲皮素、姜黄素、绿原酸、异黄酮、花青素、可可多酚、柠檬黄素、儿茶素、芸香苷中的至少一种；所述生物碱为氨丁三醇、麻黄碱、益母草碱、金鸡纳碱中的至少一种。
  6. 如权利要求5所述的制备方法，其特征在于，所述1,2-二硫戊环类化合物为硫辛酸，所述多酚类化合物为单宁酸，所述生物碱为氨丁三醇，所述有机溶剂A和有机溶剂B为二甲基亚砜。
  7. 如权利要求1所述的制备方法，其特征在于，所述步骤(3)中，稀释结束后，加入显影剂，所述显影剂的加入量为血管栓塞剂质量的10wt％～80wt％；所述显影剂为熔点在35℃以下的液态金属或钽粉微颗粒。
  8. 如权利要求7所述的制备方法，其特征在于，所述显影剂的加入量为血管栓塞剂的30wt％，所述显影剂为镓铟合金。
  9. 一种血管栓塞剂，其特征在于，所述血管栓塞剂由如权利要求1～8任一项所述方法制备而成。
  10. 一种如权利要求9所述血管栓塞剂在制备药物载体中的应用。
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