Acrylate copolymer liquid embolic agents chemically bonded to iodine and methods of making same

Abstract

The present application belongs to the technical field of embolic materials, and particularly relates to a chemical bonding iodine acrylate copolymer liquid embolic agent and a preparation method thereof. The chemical bonding iodine acrylate copolymer liquid embolic agent comprises iodine-containing acrylate copolymer; the iodine-containing acrylate copolymer is copolymerized from iodine-containing acrylate monomers and non-developing comonomers; and the iodine-containing acrylate monomers are prepared from hydroxyl-containing acrylate monomers and iodine-substituted aromatic carboxylic acid through chemical bonding. Through systematic innovation at the level of molecular structure, the present application realizes the technical targets of wide-range accurate adjustment of iodine content, uniform development without artifacts, on-demand design of embolic performance, and safe and convenient clinical operation, and precisely adapts to the clinical requirements of cerebral vascular interventional embolization treatment.

Description

Technical Field

[0001] This invention belongs to the field of embolization materials technology, specifically relating to a liquid embolizing agent of acrylate copolymer with chemically bonded iodine and its preparation method. Background Technology

[0002] Transcatheter endovascular embolization (TEV) is a core minimally invasive diagnostic and treatment technique in the field of neurointervention. Due to its advantages such as minimal trauma, protection of neurological function, and rapid postoperative recovery, it has become the preferred treatment for high-risk cerebrovascular diseases such as arteriovenous malformations and intracranial aneurysms. The embolization material, as the core and key medium of this technique, directly determines the success rate of the procedure, the integrity of lesion embolization, and the long-term clinical prognosis of the patient.

[0003] Currently, the most widely used liquid embolization agents in clinical practice are based on ethylene-vinyl alcohol copolymer (EVOH), with the Onyx® series being a typical example. These materials typically involve physically suspending inorganic metal contrast agents such as tantalum powder in a dimethyl sulfoxide solution of EVOH. Compared to traditional N-butyl-2-cyanoacrylate (NBCA) embolization agents, while improving issues like catheter adhesion, heat generation, and incomplete embolization, and enabling non-adhesive vascular embolization, this type of physically blended embolization system has many inherent technical drawbacks, making it difficult to meet the needs of high-end clinical precision treatment. For example, in terms of imaging performance, the metal contrast agent, physically dispersed as solid particles in the polymer solution, is prone to sedimentation and aggregation, leading to uneven and discontinuous imaging during and after the procedure. Simultaneously, the metal particles produce radial artifacts on CT images, severely interfering with the surgeon's accurate judgment of the embolization boundary and the morphology of the diseased vessel, hindering precise intraoperative operation and long-term postoperative imaging review and evaluation. In terms of biosafety, physically blended metal contrast agents have no chemical bonding with the polymer matrix, posing a risk of particle precipitation and migration during long-term in vivo placement. This can easily lead to adverse reactions such as local chronic inflammation and foreign body granulomas, further increasing the safety risks in clinical applications. At the clinical operation level, existing physically blended systems suffer from poor stability, requiring on-site mixing and preparation before clinical use. This process is cumbersome and highly dependent on the experience of medical personnel. Furthermore, solid particle aggregation can easily cause microcatheter blockage, leading to surgical interruption and embolization failure. Batch-to-batch product stability is also difficult to guarantee, resulting in poor repeatability. In addition, traditional physically blended embolization systems have fixed formulations, no chemical interaction between components, and limited functionality, only capable of basic vascular embolization and contrast enhancement. They cannot be functionally derived or performance-controlled, failing to meet the multifunctional, precise, and personalized development needs of modern interventional therapy, and exhibiting significant technical limitations.

[0004] To address the issue of phase separation in contrast agents, existing technologies attempt to covalently graft iodine atoms onto a polymer backbone (e.g., US11,986,571B2 grafts a specific tetraiodine compound onto EVOH). However, such approaches are limited by the number of reaction sites in the EVOH backbone, resulting in an extremely narrow window for adjusting iodine content, and the synthetic routes are lengthy. Furthermore, while patents such as MicroVention (e.g., US11,051,826B2) involve iodine-containing polymers, their independent claims explicitly limit the kinematic viscosity of the composition at 25°C to below 15-16 cSt. This severely restricts the clinical selection of high-viscosity, highly cohesive emboli, and the contrast agent unit and embolic backbone are mutually constrained, making it difficult to independently control contrast agent performance and embolic physical properties, thus hindering performance decoupling.

[0005] In summary, existing liquid embolization materials either employ physical blending of metal particles, resulting in a series of problems such as uneven imaging, image artifacts, biosafety hazards, and poor operational stability; or they use an intrinsic imaging scheme of iodine atom grafting EVOH, which suffers from drawbacks such as a narrow range of iodine content adjustment, complex synthesis process, limited viscosity window, and inability to independently control imaging performance and thrombogenic physical properties. There is still a lack of a contrasting liquid embolization material with a wide range of precisely controllable iodine content, a simple synthesis route, uniform imaging without artifacts, customizable imaging and thrombogenic properties, and safe and convenient clinical operation. Summary of the Invention

[0006] The purpose of this invention is to overcome the technical shortcomings of existing precipitation-type liquid embolic agents (such as the ethylene-vinyl alcohol copolymer (EVOH) / dimethyl sulfoxide (DMSO) / tantalum powder system), including uneven imaging due to contrast agent sedimentation, CT artifacts caused by inorganic metal particles, narrow iodine content adjustment window, difficulty in independently controlling the interaction between imaging performance and thrombogenic physical properties, complex synthesis routes, and poor functional scalability. This invention provides a chemically bonded iodine-based acrylate copolymer liquid embolic agent and its preparation method. Through systematic innovation at the molecular structure level, this invention achieves the technical goals of wide-range and precise adjustment of iodine content, uniform imaging without artifacts, on-demand design of thrombogenic properties, and safe and convenient clinical operation, precisely meeting the clinical needs of cerebrovascular interventional embolization therapy.

[0007] The technical solution of this invention is: A liquid embolizing agent of iodine-bonded acrylate copolymer includes an iodine-containing acrylate copolymer; the iodine-containing acrylate copolymer is copolymerized from an iodine-containing acrylate monomer and a non-radioactive comonomer; the iodine-containing acrylate monomer is prepared by chemical bonding of a hydroxyl-containing acrylate monomer and an iodoaromatic carboxylic acid.

[0008] The chemically bonded iodine-based acrylate copolymer liquid embolizing agent provided by this invention is a homogeneous solution system. Its core material is an acrylate copolymer with iodinated radioactive groups introduced through chemical bonding, formulated with a biocompatible organic solvent. Unlike existing technologies that use iodinated compounds as independent additives in physical blending or only perform post-grafting modification on the finished polymer, this invention starts from the monomer design source. First, radiopaque iodinated aromatic groups are introduced into polymerizable monomers (hydroxyl-containing acrylate monomers) through stable covalent bonds. Then, the synthesized iodine-containing acrylate monomer is copolymerized with a non-radioactive comonomer, so that iodine atoms are uniformly distributed as comonomer units on the side groups of the polymer backbone, forming an intrinsically radioactive copolymer (iodine-containing acrylate copolymer).

[0009] Preferably, the hydroxyl-containing acrylate monomer is selected from one or more of hydroxyethyl acrylate (HEA), 3-hydroxypropyl acrylate (3-HPA), hydroxypropyl acrylate, 4-hydroxybutyl acrylate (4-HBA), hydroxybutyl acrylate, hydroxyethyl methacrylate (HEMA), diethylene glycol monoacrylate, and dimethyl glutarate (DEGA).

[0010] More preferably, the hydroxyl-containing acrylate monomer is selected from hydroxyethyl acrylate (HEA) or 4-hydroxybutyl acrylate (4-HBA). Through extensive inventive experiments, this invention has found that hydroxyethyl acrylate or 4-hydroxybutyl acrylate exhibits suitable hydroxyl reactivity and high esterification yield, and that the iodinated acrylate monomer obtained by reacting hydroxyethyl acrylate or 4-hydroxybutyl acrylate as a hydroxyl-containing acrylate monomer with iodoaromatic carboxylic acids possesses excellent polymerization stability.

[0011] Preferably, the iodoaromatic carboxylic acid is selected from one or more of 2,3,5-triiodobenzoic acid, 2,4,6-triiodobenzoic acid, 3,5-diiodo-4-hydroxybenzoic acid, and 3,5-diiodosalicylic acid.

[0012] More preferably, the iodoaromatic carboxylic acid is selected from 2,3,5-triiodobenzoic acid, which contains three iodine atoms per molecule, has the highest iodine content efficiency, and has moderate carboxyl reactivity and mild esterification conditions.

[0013] Preferably, the chemical bonding method is an ester bond, carbonate bond, ether bond, or carbamate bond.

[0014] More preferably, the chemical bonding mode is an ester bond. This invention has found that when the chemical bonding mode is an ester bond, the synthesis conditions for preparing iodinated acrylate monomers from hydroxyl-containing acrylate monomers and iodoaromatic carboxylic acids are mild, the bonding stability is high, and the resulting iodinated acrylate monomers have good biocompatibility.

[0015] Preferably, the molar content (iodine-containing unit content) of structural units derived from iodine-containing acrylate monomers in the iodine-containing acrylate copolymer is 20% to 80%.

[0016] More preferably, the molar content of structural units derived from iodinated acrylate monomers in the iodinated acrylate copolymer is 30% to 60%. Extensive inventive experiments have revealed that when the molar content of structural units derived from iodinated acrylate monomers in the iodinated acrylate copolymer is less than 20%, the iodine content of the copolymer is insufficient (<38 wt%), and the CT imaging intensity is less than 800 HU, making it difficult to meet the requirements for effective clinical visualization. When the molar content of structural units derived from iodinated acrylate monomers in the iodinated acrylate copolymer is greater than 80%, although the iodine content of the copolymer can be increased to over 61 wt%, the introduction of a large number of iodinated side groups leads to excessively rigid molecular chains and increased brittleness, making the embolus easily breakable, and the solution viscosity is too high (>100 cSt), making it difficult to inject smoothly through a microcatheter. The preferred range of 30% to 60% achieves the optimal balance between imaging intensity, mechanical compliance, and injection operability.

[0017] Preferably, the weight-average molecular weight of the iodine-containing acrylate copolymer is 10,000 to 500,000 g / mol.

[0018] More preferably, the weight-average molecular weight of the iodinated acrylate copolymer is 20,000 to 100,000 g / mol. This invention has found that when the weight-average molecular weight of the iodinated acrylate copolymer is below 10,000 g / mol, the copolymer precipitation rate is too slow and the embolic body strength is insufficient, making it difficult to form a dense embolus; while when the weight-average molecular weight of the iodinated acrylate copolymer is above 500,000 g / mol, the solution viscosity is too high, and the resistance to microcatheter injection increases significantly. The preferred range of 20,000 to 100,000 g / mol in this invention achieves the best match between precipitation rate, embolic body mechanical strength, and injection smoothness.

[0019] Preferably, the non-reproducible comonomer is selected from one or more of acrylates, methacrylates, styrene, ethylene, vinyl alcohol, butadiene, vinyl acetate, and N-vinylpyrrolidone; More preferably, the non-radioactive comonomer is selected from methyl methacrylate (MMA) and / or butyl acrylate (BA). This invention has found that methyl methacrylate imparts a high glass transition temperature and rigidity to the copolymer, making it suitable for embolization scenarios requiring strong support; butyl acrylate imparts good flexibility and elasticity to the copolymer, making it suitable for embolization filling of tortuous blood vessels. By adjusting the blending ratio of methyl methacrylate and butyl acrylate, the mechanical properties of the embolic body can be continuously controlled while maintaining a constant iodine content, achieving independent design of radioactive properties and thrombogenic mechanical properties.

[0020] Preferably, the mass fraction (iodine content) of iodine in the iodine-containing acrylate copolymer is 38% to 61%.

[0021] More preferably, the mass fraction of iodine in the iodine-containing acrylate copolymer is 45% to 55%. When the iodine content is within this range, the CT value can reach 1600 to 2500 HU, which ensures clear visualization under intraoperative X-ray fluoroscopy while avoiding the risk of radiation-induced sclerosis artifacts that may be caused by excessively high iodine concentrations.

[0022] Preferably, the chemical bonding is an ester bond, and the method for preparing the iodine-containing acrylate monomer is as follows: Iodoaromatic carboxylic acids are dissolved in a solvent, an activator is added, and hydroxyl-containing acrylate monomers and polymerization inhibitors are added dropwise at 0–5 °C. The reaction is carried out for 10–15 hours. After the reaction is completed, the mixture is filtered to obtain a filtrate. The filtrate is washed with water, dried, and purified by column chromatography to obtain the final product.

[0023] Preferably, the preparation method of the iodine-containing acrylate copolymer is as follows: dissolve the iodine-containing acrylate monomer and the non-developable comonomer in a solvent, add an initiator, react at 50-100℃ for 8-15 hours under nitrogen protection, add excess methanol dropwise to the reaction solution to precipitate, wash, and vacuum dry to obtain the copolymer.

[0024] The present invention also provides a method for preparing the chemically bonded iodine acrylate copolymer liquid embolizing agent, comprising the following steps: taking an iodine-containing acrylate copolymer, dissolving it in a biocompatible organic solvent to prepare a homogeneous solution, and filtering it to obtain the liquid embolizing agent.

[0025] Compared with the prior art, the present invention has the following advantages: (1) The chemically bonded iodine acrylate copolymer liquid embolizing agent provided by the present invention has a short synthesis route, simple operation steps, mild reaction conditions, significantly reduced production energy consumption and process cost, and is conducive to realizing industrial scale-up production.

[0026] (2) The chemically bonded iodine acrylate copolymer liquid embolizing agent provided by the present invention is a homogeneous solution system with excellent storage stability and no risk of sedimentation.

[0027] (3) The chemically bonded iodine acrylate copolymer liquid embolizer provided by the present invention has excellent biosafety. Its solidified embolization is structurally stable during long-term in vivo placement, with no risk of particle shedding or migration, and will not induce adverse tissue reactions such as local chronic inflammation or foreign body granuloma.

[0028] (4) The present invention achieves the technical goals of wide-range and precise adjustment of iodine content, uniform imaging without artifacts, thrombus formation performance designed as needed, and safe and convenient clinical operation, which precisely meets the clinical needs of interventional embolization therapy for cerebrovascular diseases. Attached Figure Description

[0029] Figure 1 This is a synthetic route diagram of the iodine-containing acrylate monomer 2-(acryloyloxy)ethyl 2,3,5-triiodobenzoate in Example 1 of the present invention; Figure 2 The diagram shows the copolymerization reaction of the iodine-containing acrylate monomer prepared in Example 1 with methyl methacrylate. Figure 3 Here are the appearance images of the liquid embolic agent F1-12 prepared in Example 5 of this invention; Figure 4 This is a diagram illustrating the solvent diffusion-copolymer precipitation and plugging mechanism of the present invention. Figure 5 This is a graph showing the in vitro imaging test results of the liquid embolic agent F1-8 prepared in Example 5 of the present invention; Figure 6 The graph shows the effect of iodine content on the regulation of iodine content and development intensity by the content of iodine-containing units. Detailed Implementation

[0030] The present invention will be further described below through specific embodiments, but this is not a limitation of the present invention. Those skilled in the art can make various modifications or improvements based on the basic idea of ​​the present invention, but as long as they do not depart from the basic idea of ​​the present invention, they are all within the scope of the present invention.

[0031] Example 1: Synthesis of iodine-containing acrylate monomer 2-(acryloyloxy)ethyl 2,3,5-triiodobenzoate Example 1 of this invention: The synthetic route of the iodinated acrylate monomer 2-(acryloyloxy)ethyl 2,3,5-triiodobenzoate is shown below. Figure 1 As shown. Figure 1 The process of synthesizing 2-(acryloyloxy)ethyl 2,3,5-triiodobenzoate, an iodine-containing acrylate monomer that can be polymerized by free radicals, is demonstrated by esterification of hydroxyethyl acrylate with 2,3,5-triiodobenzoic acid to remove one molecule of water.

[0032] 0.10 mol of 2,3,5-triiodobenzoic acid was dissolved in 200 mL of anhydrous dichloromethane. N,N'-dicyclohexylcarbodiimide (DCC) (0.11 mol) and 0.01 mol of 4-dimethylaminopyridine (DMAP) were added for activation. Hydroxyethyl acrylate (HEA, 0.10 mol) and hydroquinone (0.05% of the mass of hydroxyethyl acrylate) were added dropwise at 5 °C, and the reaction was carried out at room temperature for 12 h. Dicyclohexylurea was removed by filtration. The filtrate was washed with water, dried, and purified by column chromatography to obtain a white solid iodine-containing acrylate monomer, 2-(acryloyloxy)ethyl 2,3,5-triiodobenzoate (M1). The theoretical iodine content is approximately 63–64%.

[0033] Example 2: Synthesis of iodine-containing acrylate monomers 4-(acryloyloxy)butyltriiodobenzoate and 3-(acryloyloxy)propyltriiodobenzoate The iodinated acrylate monomers 4-(acryloyloxy)butyltriiodobenzoate (M2) and 3-(acryloyloxy)propyltriiodobenzoate (M3) were prepared by replacing hydroxyethyl acrylate (HEA) in Example 1 with 4-hydroxybutyl acrylate (4-HBA) and 3-hydroxypropyl acrylate (3-HPA), respectively, according to the method of Example 1.

[0034] The structural formula of 4-(acryloyloxy)butyltriiodobenzoate is shown below:

[0035] The structural formula of 3-(acryloyloxy)propyltriiodobenzoate is shown below:

[0036] Example 3: Preparation of iodine-containing acrylate copolymer (iodine unit content approximately 40 mol%) The copolymerization reaction diagram of the iodine-containing acrylate monomer prepared in Example 1 with methyl methacrylate is shown in Figure 1. Figure 2 As shown, Figure 2 middle" "" indicates the polymer chain end (free radical polymerization continuation site). The iodinated acrylate monomer M1 (0.40 mol) prepared in Example 1 and methyl methacrylate (MMA, 0.60 mol) were dissolved in 500 mL of anhydrous N,N-dimethylformamide (DMF). Azobisisobutyronitrile (AIBN, 0.5% of the total molar amount of the iodinated acrylate monomer) was added, and the reaction was carried out under nitrogen protection at 70 °C for 12 h. Excess methanol was added dropwise to precipitate the precipitate, followed by washing and vacuum drying to obtain the iodinated acrylate copolymer P1. GPC analysis showed that the weight-average molecular weight (Mw) of the iodinated acrylate copolymer P1 was approximately 120,000; the molar content of structural units derived from the iodinated acrylate monomer in the iodinated acrylate copolymer P1 was 40%, and the mass fraction of iodine in the iodinated acrylate copolymer P1 was approximately 50%.

[0037] Example 4: A series of copolymers with different iodine unit contents Following the method in Example 3, the molar ratio of M1 to methyl methacrylate (MMA) was adjusted to 20:80, 30:70, 50:50, 60:40, and 80:20 to prepare copolymers P2, P3, P4, P5, and P6 with iodine unit contents of 20 mol%, 30 mol%, 50 mol%, 60 mol%, and 80 mol%, respectively.

[0038] Example 5: Preparation of Liquid Embolizing Agent The iodine-containing acrylate copolymer P1 prepared in Example 3 was dissolved in dimethyl sulfoxide (DMSO) to prepare homogeneous solutions with concentrations of 6%, 8%, and 12% (w / v), respectively, to obtain liquid embolic agents F1-6, F1-8, and F1-12.

[0039] Taking a 6% concentration as an example, 6 g of the iodine-containing acrylate copolymer P1 prepared in Example 3 was dissolved in 80 mL of dimethyl sulfoxide (DMSO). After dissolution, a small amount of DMSO was added to bring the volume to 100 mL. The solution was filtered through a 0.22 μm filter membrane to prepare a homogeneous solution with a concentration of 6% (w / v), yielding liquid embolizing agent F1-6. The appearance of liquid embolizing agent F1-12 prepared in Example 5 of this invention is shown in the image below. Figure 3 As shown. By Figure 3 It can be seen that the liquid embolizing agent F1-12 prepared in Example 5 of the present invention is an orange-red liquid and is a homogeneous solution system.

[0040] Experimental Example 1: Evaluation of In Vitro Thrombosis Formation and Imaging Performance The solvent diffusion-polymer precipitation plugging mechanism of this invention is shown in the diagram below. Figure 4 As shown, the iodine-containing copolymer / DMSO homogeneous solution of the present invention, after coming into contact with blood in the blood vessel, diffuses into the blood through DMSO, inducing the polymer to precipitate from the solution and form a solid embolism, thereby achieving vascular embolism.

[0041] The liquid embolic agent F1-8 prepared in Example 5 was injected into physiological saline at 37°C via a microcatheter. Dimethyl sulfoxide (DMSO) diffused rapidly, and the copolymer precipitated within seconds to form a non-adhesive solid embolus with intact morphology. The in vitro imaging test results of the liquid embolic agent F1-8 prepared in Example 5 of this invention are shown in Figure 5. Figure 5 As can be seen, the X-ray imaging is clear, uniform, and free of metal artifacts.

[0042] Experimental Example 2: Relationship between Iodine-containing unit content and performance The copolymer series prepared in Examples 3 and 4 were formulated into 8% (w / v) dimethyl sulfoxide (DMSO) embolic agents, and the relationship between iodine-containing unit content and performance was determined. The test results are shown in Table 1.

[0043] Table 1 Relationship between Iodine-containing unit content and performance

[0044] The following conclusions can be drawn from Table 1: ① Iodine content and development intensity increase monotonically with the content of iodine-containing units. The iodine content is about 38-61 wt% in the range of 20-80 mol%, preferably 30-60 mol%; ② The viscosity of each formulation at 25℃ is designed to be ≥16 cSt to distinguish it from low viscosity systems; ③ Precipitation and plugging are rapid (about 4-8 s).

[0045] The effect of iodine-containing unit content on the regulation of iodine content and development intensity is shown in the figure below. Figure 6 As shown. By Figure 6 It can be seen that as the molar fraction of iodine units in the copolymer increases, the iodine content of the copolymer and the CT imaging value of the precipitated emboli both increase synchronously, with 30-60 mol% being the optimal performance range.

Claims

1. A liquid embolic agent of acrylate copolymer with chemically bonded iodine, characterized in that, It includes iodine-containing acrylate copolymers; the iodine-containing acrylate copolymers are copolymerized from iodine-containing acrylate monomers and non-reproducible comonomers; the iodine-containing acrylate monomers are prepared by chemical bonding of hydroxyl-containing acrylate monomers and iodoaromatic carboxylic acids.

2. The chemically bonded iodine-based acrylate copolymer liquid embolizing agent according to claim 1, characterized in that, The hydroxyl-containing acrylate monomers are selected from one or more of hydroxyethyl acrylate, 3-hydroxypropyl acrylate, hydroxypropyl acrylate, 4-hydroxybutyl acrylate, hydroxybutyl acrylate, hydroxyethyl methacrylate, diethylene glycol monoacrylate, and dimethyl glutarate; the iodoaromatic carboxylic acid is selected from one or more of 2,3,5-triiodobenzoic acid, 2,4,6-triiodobenzoic acid, 3,5-diiodo-4-hydroxybenzoic acid, and 3,5-diiodosalicylic acid.

3. The chemically bonded iodine-based acrylate copolymer liquid embolizing agent according to claim 1, characterized in that, The chemical bonding method is ester bond, carbonate bond, ether bond or carbamate bond.

4. The chemically bonded iodine-based acrylate copolymer liquid embolizing agent according to claim 1, characterized in that, The molar content of structural units derived from iodine-containing acrylate monomers in the iodine-containing acrylate copolymer is 20% to 80%.

5. The chemically bonded iodine-based acrylate copolymer liquid embolizing agent according to claim 1, characterized in that, The weight-average molecular weight of the iodine-containing acrylate copolymer is 10,000 to 500,000 g / mol.

6. The chemically bonded iodine-based acrylate copolymer liquid embolizing agent according to claim 1, characterized in that, The non-reproducible comonomer is selected from one or more of acrylates, methacrylates, styrene, ethylene, vinyl alcohol, butadiene, vinyl acetate, and N-vinylpyrrolidone.

7. The chemically bonded iodine-based acrylate copolymer liquid embolizing agent according to claim 1, characterized in that, The iodine-containing acrylate copolymer has an iodine content of 38% to 61% by mass.

8. The chemically bonded iodine-based acrylate copolymer liquid embolizing agent according to claim 3, characterized in that, The chemical bonding is an ester bond, and the preparation method of the iodine-containing acrylate monomer is as follows: Iodoaromatic carboxylic acids are dissolved in a solvent, an activator is added, and hydroxyl-containing acrylate monomers and polymerization inhibitors are added dropwise at 0–5 °C. The reaction is carried out for 10–15 hours. After the reaction is completed, the mixture is filtered to obtain a filtrate. The filtrate is washed with water, dried, and purified by column chromatography to obtain the final product.

9. The chemically bonded iodine-based acrylate copolymer liquid embolizing agent according to claim 1, characterized in that, The preparation method of the iodine-containing acrylate copolymer is as follows: dissolve the iodine-containing acrylate monomer and the non-developable comonomer in a solvent, add an initiator, react at 50-100℃ for 8-15 hours under nitrogen protection, add excess methanol dropwise to the reaction solution to precipitate, wash, and vacuum dry to obtain the copolymer.

10. The method for preparing the chemically bonded iodine-acrylate copolymer liquid embolizing agent according to any one of claims 1-9, characterized in that, The process includes the following steps: taking an iodine-containing acrylate copolymer, dissolving it in a biocompatible organic solvent to prepare a homogeneous solution, and filtering it to obtain the final product.

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