Developing embolism microspheres with high elasticity and high drug loading rate and preparation method thereof

Abstract

The application relates to a high-elasticity and high-drug-loading-rate developing embolism microsphere and a preparation method thereof. A compound containing a chlorine or bromine group is reacted with a microsphere taking a polyhydroxy polymer as a main chain to obtain a microsphere intermediate with an ATRP reaction site; and the microsphere intermediate is subjected to an ATRP polymerization reaction with a developing molecule containing an unsaturated bond to prepare the developing embolism microsphere with high compression resilience and high drug loading rate. The developing embolism microsphere prepared by the method realizes the carrying of the developing function on the basis of not affecting the original performance of the microsphere, and effectively improves the drug loading efficiency of the developing microsphere.

Description

Technical Field

[0001] This invention belongs to the field of medical materials technology, specifically relating to a radioactive embolization microsphere with high elasticity and high drug loading rate and its preparation method. Background Technology

[0002] Transarterial chemoembolization (TACE) is currently the preferred treatment for unresectable liver cancer. This treatment allows highly vascularized liver tumors to rapidly shrink and die due to lack of blood supply, while simultaneously delivering chemotherapy drugs locally for precise treatment, avoiding the unnecessary harm caused by systemic medication. TACE treatment requires continuous evaluation of subsequent treatment plans based on the patient's surgical progress; typically, one cycle of treatment is insufficient to achieve optimal results. Therefore, patients need to return to the hospital for follow-up after a period of treatment. Follow-up usually includes CT or MRI of the liver, primarily assessing tumor development and the embolization of blood vessels by the microspheres. Currently, most polyvinyl alcohol (PVA) embolization microspheres used clinically lack X-ray imaging properties, making them difficult to observe under imaging equipment. This makes clinical assessment of the microspheres' embolization of blood vessels very challenging. To address this issue, some medical device companies have combined the main components of contrast agents with polyvinyl alcohol (PVA) embolizing microspheres, giving the microspheres X-ray imaging properties. This allows the microspheres within the patient's body to be clearly observed under contrast-enhancing equipment, significantly reducing the difficulty in assessing tumor progression and microsphere embolism. This lays the groundwork for providing patients with more precise treatment plans in the future.

[0003] Currently, most radiopaque embolization microspheres are made by post-modifying polyvinyl alcohol embolization microspheres with iodine-containing compounds (usually triiodobenzaldehyde) to give them radiopaque properties. This approach affects several key properties of the microspheres, such as: 1. Triiodobenzaldehyde is a hydrophobic compound that needs to be grafted onto the embolization microspheres via a reaction with hydroxyl groups. Its continuous consumption of the polymer backbone leads to a decrease in the hydrophilicity of the microspheres, resulting in poorer compression resilience; 2. The modification of the embolization microspheres with triiodobenzaldehyde creates steric hindrances within the polymer network structure, especially on the microsphere surface. This reduces the adsorption efficiency of chemotherapy drugs, thus prolonging the preparation time before clinical surgery. Summary of the Invention

[0004] To address the technical problems existing in the prior art, this invention proposes an embolic microsphere with high elasticity and high drug loading rate and its preparation method, aiming to achieve the imaging of microspheres while maintaining their high resilience and high drug loading rate.

[0005] In a first aspect, the present invention provides a radioactive embolization microsphere having high elasticity and high drug loading rate, having any one of the following structural formulas I-V:

[0006] , , , , , where n represents the degree of aggregation.

[0007] This invention further protects a method for preparing radioactive embolic microspheres with high elasticity and high drug loading rate as described above, comprising the following steps:

[0008] Compounds containing chlorine or bromine groups are reacted with microspheres with a polyhydroxy polymer backbone to obtain microsphere intermediates with ATRP reaction sites.

[0009] By subjecting the microsphere intermediate to ATRP polymerization with imaging molecules containing unsaturated bonds, imaging embolization microspheres with high compressibility and high drug loading rate were prepared.

[0010] As a further improvement of the present invention, the compounds containing chlorine or bromine groups include p-chloromethylbenzaldehyde, p-bromomethylbenzaldehyde, 3-chloropropanal dimethyl acetal, 4-chlorobutanal diethyl acetal, 3-chloropropanal diethyl acetal, 3-bromopropanal dimethyl acetal, chloroacetaldehyde diethanol, 2-chloroacetaldehyde dimethyl acetal, bromoacetyl dimethyl acetal, 2-chloromethyl-1,3-dioxolane, 3-bromopropanal dimethyl acetal, and bromoacetyl dimethyl acetal.

[0011] As a further improvement of the present invention, the method for preparing the imaging embolism microspheres satisfies at least one of the following conditions (1) to (2):

[0012] (1) The mass molar ratio of microspheres with polyhydroxy polymer as the main chain to compounds containing chlorine or bromine groups is 1 g: (0.01~1) mol;

[0013] (2) The mass molar ratio of microspheres with polyhydroxy polymer as the main chain to developing molecules containing unsaturated bonds is 1 g: (0.01~1) mol.

[0014] As a further improvement of the present invention, the microspheres with polyhydroxy polymers as the main chain are polyvinyl alcohol microspheres.

[0015] As a further improvement of the present invention, the method for preparing the developing molecule containing unsaturated bonds is selected from any one of the following a to c:

[0016] a. Formed by grafting carbon-carbon double bonds onto iodine-containing compounds using organic modifiers containing double bonds;

[0017] b. The iodine-containing compound is halogenated with a chlorinating agent to generate an iodine-containing chloride, which is then reacted with a modifier containing double bonds and sulfonic acid groups under the action of an alkaline catalyst to obtain a developing molecule containing unsaturated bonds and sulfonic acid groups.

[0018] c. An iodine-containing compound undergoes a nucleophilic substitution reaction with an organic sulfonyl chloride to generate an iodine-containing sulfonate derivative, which then undergoes a further nucleophilic substitution reaction with an amino-containing nucleophilic reagent to generate an amino-containing iodide. This is further reacted with a modifier containing double bonds and hydroxyl groups to obtain a developing molecule containing unsaturated bonds and hydroxyl groups.

[0019] As a further improvement of the present invention, the iodine-containing compound is selected from any one of triiodobenzyl alcohol, triiodophenol, and triiodobenzaldehyde.

[0020] As a further improvement of the present invention, the preparation process of the developing molecule containing unsaturated bonds satisfies at least one of the following conditions (1) to (6):

[0021] (1) The double-bonded organic modifier is selected from either 4-vinylbenzyl chloride or 4-vinylbenzyl bromide;

[0022] (2) The chlorination reagent is selected from either hydrochloric acid or hydrobromic acid;

[0023] (3) The modifier with double bonds and sulfonic acid groups is sodium 3-allyloxy-2-hydroxy-1-propanesulfonate;

[0024] (4) The organic sulfonyl chloride is selected from any one of p-toluenesulfonyl chloride, benzenesulfonyl chloride, 4-propylbenzenesulfonyl chloride, 4-ethylbenzenesulfonyl chloride, 3,5-dimethylbenzenesulfonyl chloride, 2,5-dimethylbenzenesulfonyl chloride, 3,4-dimethylbenzenesulfonyl chloride, 4-cyclohexylbenzenesulfonyl chloride, 2,4-dimethylbenzenesulfonyl chloride, 4-tert-butylbenzenesulfonyl chloride, and 2,3,5,6-tetramethylbenzenesulfonyl chloride;

[0025] (5) The modifier with double bonds and hydroxyl groups is selected from any one of glycidyl methacrylate, oxetane methacrylate, tetrahydrofurfuryl methacrylate, and allyl glycidyl ether;

[0026] (6) The amino-containing nucleophile is selected from any one of 1,3-propanediamine, 1,2-propanediamine, 2,2-dimethyl-1,3-propanediamine, and 2-methyl-1,3-propanediamine.

[0027] As a further improvement of the present invention, the molar ratio of the iodine-containing compound to the organic modifier containing double bonds, the modifier with double bonds and sulfonic acid groups, and the modifier with double bonds and hydroxyl groups is 1:(1~2).

[0028] This invention further protects the application of a contrast-enhancing embolization microsphere in the preparation of a combined radiotherapy, chemotherapy, and embolization therapy drug for tumors and a contrast-enhancing diagnostic reagent, wherein the contrast-enhancing embolization microsphere is the contrast-enhancing embolization microsphere as described above; or, the contrast-enhancing embolization microsphere is the contrast-enhancing embolization microsphere prepared by the preparation method described above.

[0029] This invention provides a radioactive embolization microsphere with high elasticity and high drug loading rate, and a method for preparing the same, which has the following beneficial effects:

[0030] The radiopaque microspheres prepared by the method of this invention have radiopaque molecules attached to their surface in the form of polymer chain segments, thus forming core-shell structured microspheres. When radiopaque molecules are introduced into the embolization microspheres, the original hydrophilic functional groups in the microspheres are not consumed, nor is the chemical structure of the polymer cross-linking network of the microspheres altered, thereby maintaining the original physical properties of the embolization microspheres. This achieves radiopaque functionality without affecting the original performance of the microspheres. It effectively improves the compressibility, suspension, and catheter permeability of the radiopaque microspheres.

[0031] To change the current situation where imaging molecules are enriched inside imaging microspheres, causing significant steric hindrance, imaging molecules are dispersed as polymer chain segments on the surface of the polymer cross-linked network structure framework of the embolizing microspheres. This increases the space of the polymer cross-linked network structure of the microspheres themselves, effectively improving the drug loading efficiency of the imaging microspheres.

[0032] It should be understood that the above general description and the following detailed description are exemplary and explanatory only, and are not intended to limit this disclosure. Detailed Implementation

[0033] The following will describe the concept and technical effects of the present invention clearly and completely with reference to embodiments, so as to fully understand the purpose, features and effects of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are all within the scope of protection of the present invention.

[0034] Experimental methods not specified in the examples are generally performed under conventional conditions in the art or under conditions recommended by the manufacturer; the raw materials and reagents used, unless otherwise specified, are all commercially available from the conventional market.

[0035] Example 1: Preparation of developing molecule A1

[0036] Add 4.00 g of sodium hydroxide to 80.00 mL of dimethyl sulfoxide and stir vigorously at room temperature for 6 hours to dissolve the sodium hydroxide. Add 100 mmol of 48.58 g of 2,4,6-triiodobenzyl alcohol and continue stirring at room temperature for 4 hours. Add 100 mmol of 15.26 g of 4-vinylbenzyl chloride and stir at room temperature for 2 hours. The reaction is then complete. Evaporate the solution using a rotary evaporator at 60 °C. o After rotary evaporation at C, distilled water was added to allow the product to settle. The product was collected by vacuum filtration. The collected product was redissolved in dimethyl sulfoxide, distilled water was added, and the product was collected by vacuum filtration. The product was then redissolved in dimethyl sulfoxide again, distilled water was added, and the product was collected by vacuum filtration. The product was placed in a vacuum drying oven at 40°C. o Vacuum dry for 12 hours under C conditions.

[0037] Example 2: Preparation of developing molecule A2

[0038] Add 4.00 g of sodium hydroxide to 100.00 mL of dimethyl sulfoxide and stir vigorously at room temperature for 6 hours to dissolve the sodium hydroxide. Add 100 mmol of 47.18 g of 2,4,6-triiodophenol and continue stirring at room temperature for 3 hours. Add 200 mmol of 39.41 g of 4-vinylbenzyl bromide and stir at room temperature for 3 hours. The reaction is then complete. Evaporate the solution using a rotary evaporator at 60 °C. o After rotary evaporation at C, distilled water was added to allow the product to settle. The product was collected by vacuum filtration. The collected product was redissolved in dimethyl sulfoxide, distilled water was added, and the product was collected by vacuum filtration. The product was then redissolved in dimethyl sulfoxide again, distilled water was added, and the product was collected by vacuum filtration. The product was placed in a vacuum drying oven at 40°C. o Vacuum dry for 12 hours under C conditions.

[0039] Example 3: Preparation of the developing molecule A3

[0040] Mix 48.58 g (100 mmol) of triiodobenzyl alcohol, 8.30 mL of hydrochloric acid, and 84 mL of N,N-dimethylformamide, and slowly add 6.00 mL of concentrated sulfuric acid at 80 °C. o The solution was heated under reflux at C for 5 hours. The resulting solution was then added to water for precipitation to obtain the small molecule product, triiodobenzyl chloride. 21.82 g (100 mmol) of sodium 3-allyloxy-2-hydroxy-1-propanesulfonate was slowly added to 4.00 mL of sodium hydroxide solution. After stirring at room temperature for 4 hours, triiodobenzyl chloride was added, and the reaction was continued for another 6 hours. The resulting solution was then evaporated using a rotary evaporator at 60 °C. oRotary evaporation was performed at C conditions, and distilled water was added to allow the product to settle. The product was collected by vacuum filtration. The collected product was redissolved in N,N-dimethylformamide, distilled water was added, and the product was collected by vacuum filtration. The product was then redissolved in N,N-dimethylformamide again, distilled water was added, and the product was collected by vacuum filtration. The product was placed in a vacuum drying oven at 40°C. o Vacuum dry for 12 hours under C conditions.

[0041] Example 4: Preparation of developing molecule A4

[0042] Mix 47.18 g of triiodophenol (100 mmol), 11.50 mL of hydrobromic acid (48%), and 84 mL of N,N-dimethylformamide, and slowly add 6.00 mL of concentrated sulfuric acid at 80 °C. o The solution was heated under reflux at C for 5 hours. The resulting solution was then added to water for precipitation to obtain the small molecule product, triiodobenzyl chloride. 43.64 g of sodium 3-allyloxy-2-hydroxy-1-propanesulfonate was slowly added to 4.00 mL of sodium hydroxide solution. After stirring at room temperature for 4 hours, triiodobenzyl chloride was added, and the reaction continued for another 6 hours. The resulting solution was then evaporated using a rotary evaporator at 60 °C. o Rotary evaporation was performed at C conditions, and distilled water was added to allow the product to settle. The product was collected by vacuum filtration. The collected product was redissolved in N,N-dimethylformamide, distilled water was added, and the product was collected by vacuum filtration. The product was then redissolved in N,N-dimethylformamide again, distilled water was added, and the product was collected by vacuum filtration. The product was placed in a vacuum drying oven at 40°C. o Vacuum dry for 12 hours under C conditions.

[0043] Example 5: Preparation of the developing molecule A5

[0044] Step 1: Dissolve 6.41 g (13.2 mmol) of triiodobenzyl alcohol in 125 mL of purified water, and slowly add 5 mL (41 mmol) of NaOH solution while stirring vigorously until completely dissolved. Dissolve 2.50 g (13.2 mmol) of p-toluenesulfonyl chloride in 7.5 mL of acetonitrile solution and slowly add it dropwise to the reaction system. After the addition is complete, 5... o The reaction proceeds at C for 3 hours. After the reaction is complete, the solution is filtered under reduced pressure to remove the solid, and the filtrate is collected. The filtrate is then distilled under reduced pressure and acetone is added for sedimentation. After sedimentation, the solid is collected by filtration under reduced pressure. The solid is then placed at 40°C. o Dry overnight in a vacuum drying oven at C.

[0045] Step 2: Take 7.68g (12mmol) of the product from Step 1 and 1.0mL (12mmol) of 1,3-propanediamine, mix them, and then heat at 80°C.o The reaction mixture was stirred for 6 hours at C. The reaction solution was then distilled under reduced pressure, followed by the addition of acetone for sedimentation. After sedimentation, the solid was collected by vacuum filtration. The solid was then placed at 40°C. o Dry overnight in a vacuum drying oven at C.

[0046] Step 3: Dissolve 6.00 g (11 mmol) of the product from Step 2 and 1.5 mL of glycidyl methacrylate (13.2 mmol) in 10 mL of N,N-dimethylformamide. After purging with N2 for 30 min, heat the system to 60°C. o The reaction proceeded at C for 6 hours. After the reaction was complete, excess acetone was added dropwise to the reaction solution to allow sedimentation. After sedimentation, the solid was collected by vacuum filtration. The solid was then placed at 40°C. o Dry overnight in a vacuum drying oven at C.

[0047] Example 6: Preparation of the developing molecule A6

[0048] Step 1: Dissolve 6.41 g (13.2 mmol) of triiodobenzyl alcohol in 125 mL of purified water, and slowly add 5 mL (41 mmol) of NaOH solution while stirring vigorously until completely dissolved. Dissolve 2.50 g (13.2 mmol) of p-toluenesulfonyl chloride in 7.5 mL of acetonitrile solution and slowly add it dropwise to the reaction system. After the addition is complete, 5... o The reaction proceeds at C for 3 hours. After the reaction is complete, the solution is filtered under reduced pressure to remove the solid, and the filtrate is collected. The filtrate is then distilled under reduced pressure and acetone is added for sedimentation. After sedimentation, the solid is collected by filtration under reduced pressure. The solid is then placed at 40°C. o Dry overnight in a vacuum drying oven at C.

[0049] Step 2: Take 7.68g (12mmol) of the product from Step 1 and 1.0mL (12mmol) of 1,3-propanediamine, mix them, and then heat at 80°C. o The reaction mixture was stirred for 6 hours at C. The reaction solution was then distilled under reduced pressure, followed by the addition of acetone for sedimentation. After sedimentation, the solid was collected by vacuum filtration. The solid was then placed at 40°C. o Dry overnight in a vacuum drying oven at C.

[0050] Step 3: Dissolve 6.00 g of the product from Step 2 and 4.06 g (22 mmol) of oxetane methacrylate in 10 mL of N,N-dimethylformamide, purge with N2 for 30 min, and then heat the system to 60°C. o The reaction proceeded at C for 6 hours. After the reaction was complete, excess acetone was added dropwise to the reaction solution to allow sedimentation. After sedimentation, the solid was collected by vacuum filtration. The solid was then placed at 40°C. o Dry overnight in a vacuum drying oven at C.

[0051] Example 7: Preparation of the developing molecule A7

[0052] Step 1: Dissolve 6.41 g (13.2 mmol) of triiodobenzyl alcohol in 125 mL of purified water, and slowly add 5 mL (41 mmol) of NaOH solution while stirring vigorously until completely dissolved. Dissolve 2.89 g (13.2 mmol) of 4-propylbenzenesulfonyl chloride in 7.5 mL of acetonitrile solution and slowly add it dropwise to the reaction system. After the addition is complete, 5... o The reaction proceeds at C for 3 hours. After the reaction is complete, the solution is filtered under reduced pressure to remove the solid, and the filtrate is collected. The filtrate is then distilled under reduced pressure and acetone is added for sedimentation. After sedimentation, the solid is collected by filtration under reduced pressure. The solid is then placed at 40°C. o Dry overnight in a vacuum drying oven at C.

[0053] Step 2: Take 8.02 g (12 mmol) of the product from Step 1 and 1.0 mL (12 mmol) of 1,3-propanediamine, mix them, and then heat at 80 °C. o The reaction mixture was stirred for 6 hours at C. The reaction solution was then distilled under reduced pressure, followed by the addition of acetone for sedimentation. After sedimentation, the solid was collected by vacuum filtration. The solid was then placed at 40°C. o Dry overnight in a vacuum drying oven at C.

[0054] Step 3: Dissolve 6.00 g of the product from Step 2 and 2.81 g (11 × 1.5 mmol) of tetrahydrofurfuryl methacrylate in 10 mL of N,N-dimethylformamide, purge with N2 for 30 min, and then heat the system to 60°C. o The reaction proceeded at C for 6 hours. After the reaction was complete, excess acetone was added dropwise to the reaction solution to allow sedimentation. After sedimentation, the solid was collected by vacuum filtration. The solid was then placed at 40°C. o Dry overnight in a vacuum drying oven at C.

[0055] Example 8: Preparation of the developing molecule A8

[0056] Step 1: Dissolve 6.41 g (13.2 mmol) of triiodobenzyl alcohol in 125 mL of purified water, and slowly add 5 mL (41 mmol) of NaOH solution while stirring vigorously until completely dissolved. Dissolve 2.70 g (13.2 mmol) of 3,5-dimethylbenzenesulfonyl chloride in 7.5 mL of acetonitrile solution and slowly add it dropwise to the reaction system. After the addition is complete, 5... o The reaction proceeds at C for 3 hours. After the reaction is complete, the solution is filtered under reduced pressure to remove the solid, and the filtrate is collected. The filtrate is then distilled under reduced pressure and acetone is added for sedimentation. After sedimentation, the solid is collected by filtration under reduced pressure. The solid is then placed at 40°C. o Dry overnight in a vacuum drying oven at C.

[0057] Step 2: Take 7.85g (12mmol) of the product from Step 1 and 1.3mL of 2-methyl-1,3-propanediamine, mix them, and then dilute at 80°C. oThe reaction mixture was stirred for 6 hours at C. The reaction solution was then distilled under reduced pressure, followed by the addition of acetone for sedimentation. After sedimentation, the solid was collected by vacuum filtration. The solid was then placed at 40°C. o Dry overnight in a vacuum drying oven at C.

[0058] Step 3: Dissolve 6.12 g (11 mmol) of the product from Step 2 and 1.3 mL of allyl glycidyl ether (11 mmol) in 10 mL of N,N-dimethylformamide. Purge with N2 for 30 min, then heat the system to 60°C. o The reaction proceeded at C for 6 hours. After the reaction was complete, excess acetone was added dropwise to the reaction solution to allow sedimentation. After sedimentation, the solid was collected by vacuum filtration. The solid was then placed at 40°C. o Dry overnight in a vacuum drying oven at C.

[0059] Example 9-Example 15: Preparation of developing molecules A9-A15

[0060] The difference between the preparation method of Example 9-Example 15 and Example 5 is that the same molar amounts of 4-ethylbenzenesulfonyl chloride, 2,5-dimethylbenzenesulfonyl chloride, 3,4-dimethylbenzenesulfonyl chloride, 4-cyclohexylbenzenesulfonyl chloride, 2,4-dimethylbenzenesulfonyl chloride, 4-tert-butylbenzenesulfonyl chloride, and 2,3,5,6-tetramethylbenzenesulfonyl chloride are used instead of toluenesulfonyl chloride.

[0061] Example 16: Preparation of Implantable Embolizing Microspheres B1

[0062] Step 1: Add 50 mL of polyvinyl alcohol microspheres to acetone for sedimentation. After sedimentation, collect the solid by vacuum filtration. Place the solid at 40°C. o The microspheres were dried overnight in a vacuum oven at C. 0.1 g of dried microspheres were added to 10 mL of dimethyl sulfoxide to swell, and then 0.01 mol of p-chloromethylbenzaldehyde was added. Under acidic conditions, the system was heated to 63 °C and reacted for 12 h. The system was then cooled to room temperature. The sample was washed three times with dimethyl sulfoxide and deionized water, respectively, and then dried under vacuum to obtain the microsphere intermediate.

[0063] Step 2: Mix the reactants and solvent according to the mass-volume ratio M 微球中间体 M cuBr2 M PMDETA M 显影分子A1 V 二甲基亚砜 The solution was added to a Schlenk flask at a ratio of 40 mg: 0.34 mg: 5.44 mg: 0.05 mol: 1 mL. Nitrogen gas was bubbled into the system for 30 min, and then CuBr (M...) was added. cuBr2 M cuBr=0.34:4.28). After continuing to purge with nitrogen for 30 min, the system was heated to 65℃ and reacted for 8 h. After the reaction was complete, the system was cooled to room temperature, and the sample was washed three times each with dimethyl sulfoxide and deionized water, and then dried under vacuum.

[0064] Example 17: Preparation of Implantable Embolism Microspheres B2

[0065] Step 1: Add 50 mL of polyvinyl alcohol microspheres to acetone for sedimentation. After sedimentation, collect the solid by vacuum filtration. Place the solid at 40°C. o The microspheres were dried overnight in a vacuum oven at C. 0.1 g of dried microspheres were added to 10 mL of dimethyl sulfoxide to swell, and then 0.001 mol of p-bromomethylbenzaldehyde was added. Under acidic conditions, the system was heated to 63 °C and reacted for 12 h. The system was then cooled to room temperature. The sample was washed three times with dimethyl sulfoxide and deionized water, respectively, and then dried under vacuum to obtain the microsphere intermediate.

[0066] Step 2: Mix the reactants and solvent according to the mass-volume ratio M 微球中间体 M cuBr2 M PMDETA M 显影分子A2 V 二甲基亚砜 The solution was added to a Schlenk flask at a ratio of 40 mg: 0.34 mg: 5.44 mg: 0.02 mol: 1 mL. Nitrogen gas was bubbled into the system for 30 min, and then CuBr (M...) was added. cuBr2 M cuBr =0.34:4.28). After continuing to purge with nitrogen for 30 min, the system was heated to 65℃ and reacted for 4 h. After the reaction was complete, the system was cooled to room temperature, and the sample was washed three times each with dimethyl sulfoxide and deionized water, and then dried under vacuum.

[0067] Example 18: Preparation of Implantable Embolizing Microspheres B3

[0068] Step 1: Add 50 mL of polyvinyl alcohol microspheres to acetone for sedimentation. After sedimentation, collect the solid by vacuum filtration. Place the solid at 40°C. o The microspheres were dried overnight in a vacuum oven at C. 0.1 g of dried microspheres were added to 10 mL of dimethyl sulfoxide to swell them, and then 0.9 mol of 3-chloropropanal dimethyl acetal was added. Under acidic conditions, the system was heated to 63 °C and reacted for 12 h. The system was then cooled to room temperature. The sample was washed three times with dimethyl sulfoxide and deionized water, respectively, and then dried under vacuum to obtain the microsphere intermediate.

[0069] Step 2: Mix the reactants and solvent according to the mass-volume ratio M 微球中间体 M cuBr2 M PMDETA M 显影分子A3 V 二甲基亚砜The solution was added to a Schlenk flask at a ratio of 40 mg: 0.34 mg: 5.44 mg: 0.1 mol: 1 mL. Nitrogen gas was bubbled into the system for 30 min, and then CuBr (M...) was added. cuBr2 M cuBr =0.34:4.28). After continuing to purge with nitrogen for 15 min, the system was heated to 65℃ and reacted for 4 h. After the reaction was complete, the system was cooled to room temperature, and the sample was washed three times each with dimethyl sulfoxide and deionized water, and then dried under vacuum.

[0070] Example 19: Preparation of Implantable Embolism Microspheres B4

[0071] Step 1: Add 50 mL of polyvinyl alcohol microspheres to acetone for sedimentation. After sedimentation, collect the solid by vacuum filtration. Place the solid at 40°C. o The microspheres were dried overnight in a vacuum oven at C. 0.1 g of dried microspheres were added to 10 mL of dimethyl sulfoxide to swell, and then 0.05 mol of 4-chlorobutyraldehyde diethyl acetal was added. Under acidic conditions, the system was heated to 63 °C and reacted for 12 h. The system was then cooled to room temperature. The sample was washed three times with dimethyl sulfoxide and deionized water, respectively, and then dried under vacuum to obtain the microsphere intermediate.

[0072] Step 2: Mix the reactants and solvent according to the mass-volume ratio M 微球中间体 M cuBr2 M PMDETA M 显影分子A4 V 二甲基亚砜 The solution was added to a Schlenk flask in a ratio of 40 mg: 0.34 mg: 5.44 mg: 0.6 mol: 1 mL. Nitrogen gas was bubbled into the system for 30 min, and then CuBr (M...) was added. cuBr2 M cuBr =0.34:4.28). After continuing to purge with nitrogen for 30 min, the system was heated to 65℃ and reacted for 4 h. After the reaction was complete, the system was cooled to room temperature, and the sample was washed three times each with dimethyl sulfoxide and deionized water, and then dried under vacuum.

[0073] Example 20: Preparation of Implantable Embolism Microspheres B5

[0074] Step 1: Add 50 mL of polyvinyl alcohol microspheres to acetone for sedimentation. After sedimentation, collect the solid by vacuum filtration. Place the solid at 40°C. o The microspheres were dried overnight in a vacuum oven at C. 0.1 g of dried microspheres were added to 10 mL of dimethyl sulfoxide to swell, and then 0.05 mol of 3-chloropropanal diethyl acetal was added. Under acidic conditions, the system was heated to 63 °C and reacted for 12 h. The system was then cooled to room temperature. The sample was washed three times with dimethyl sulfoxide and deionized water, respectively, and then dried under vacuum to obtain the microsphere intermediate.

[0075] Step 2: Mix the reactants and solvent according to the mass-volume ratio M 微球中间体 M cuBr2 M PMDETA M 显影分子A5 V 二甲基亚砜 The solution was added to a Schlenk flask at a ratio of 40 mg: 0.34 mg: 5.44 mg: 0.1 mol: 1 mL. Nitrogen gas was bubbled into the system for 30 min, and then CuBr (M...) was added. cuBr2 M cuBr =0.34:4.28). After continuing to purge with nitrogen for 30 min, the system was heated to 65℃ and reacted for 4 h. After the reaction was complete, the system was cooled to room temperature, and the sample was washed three times each with dimethyl sulfoxide and deionized water, and then dried under vacuum.

[0076] Example 21: Preparation of Implantable Embolizing Microspheres B6

[0077] Step 1: Add 50 mL of polyvinyl alcohol microspheres to acetone for sedimentation. After sedimentation, collect the solid by vacuum filtration. Place the solid at 40°C. o The microspheres were dried overnight in a vacuum oven at C. 0.1 g of dried microspheres were added to 10 mL of dimethyl sulfoxide to swell, and then 0.001 mol of 3-bromopropanal dimethyl acetal was added. Under acidic conditions, the system was heated to 63 °C and reacted for 12 h. The system was then cooled to room temperature. The sample was washed three times with dimethyl sulfoxide and deionized water, respectively, and then dried under vacuum to obtain the microsphere intermediate.

[0078] Step 2: Mix the reactants and solvent according to the mass-volume ratio M 微球中间体 M cuBr2 M PMDETA M 显影分子A6 V 二甲基亚砜 The solution was added to a Schlenk flask at a ratio of 40 mg: 0.34 mg: 5.44 mg: 0.1 mol: 1 mL. Nitrogen gas was bubbled into the system for 30 min, and then CuBr (M...) was added. cuBr2 M cuBr =0.34:4.28). After continuing to purge with nitrogen for 15 min, the system was heated to 65℃ and reacted for 4 h. After the reaction was complete, the system was cooled to room temperature, and the sample was washed three times each with dimethyl sulfoxide and deionized water, and then dried under vacuum.

[0079] Example 22: Preparation of Implantable Embolizing Microspheres B7

[0080] Step 1: Add 50 mL of polyvinyl alcohol microspheres to acetone for sedimentation. After sedimentation, collect the solid by vacuum filtration. Place the solid at 40°C. oThe microspheres were dried overnight in a vacuum oven at C. 0.1 g of dried microspheres were added to 10 mL of dimethyl sulfoxide to swell, and then 0.01 mol of chloroacetaldehyde diethanol condensate was added. Under acidic conditions, the system was heated to 63 °C and reacted for 12 h. The system was then cooled to room temperature. The sample was washed three times with dimethyl sulfoxide and deionized water, respectively, and then dried under vacuum to obtain the microsphere intermediate.

[0081] Step 2: Mix the reactants and solvent according to the mass-volume ratio M 微球中间体 M cuBr2 M PMDETA M 显影分子A7 V 二甲基亚砜 The solution was added to a Schlenk flask at a ratio of 40 mg: 0.34 mg: 5.44 mg: 0.05 mol: 1 mL. Nitrogen gas was bubbled into the system for 30 min, and then CuBr (M...) was added. cuBr2 M cuBr =0.34:4.28). After continuing to purge with nitrogen for 15 min, the system was heated to 65℃ and reacted for 4 h. After the reaction was complete, the system was cooled to room temperature, and the sample was washed three times each with dimethyl sulfoxide and deionized water, and then dried under vacuum.

[0082] Example 23: Preparation of Immunoembolic Microspheres B8

[0083] Step 1: Add 50 mL of polyvinyl alcohol microspheres to acetone for sedimentation. After sedimentation, collect the solid by vacuum filtration. Place the solid at 40°C. o The microspheres were dried overnight in a vacuum oven at C. 0.1 g of dried microspheres were added to 10 mL of dimethyl sulfoxide to swell, and then 0.01 mol of chloroacetaldehyde diethanol condensate was added. Under acidic conditions, the system was heated to 63 °C and reacted for 12 h. The system was then cooled to room temperature. The sample was washed three times with dimethyl sulfoxide and deionized water, respectively, and then dried under vacuum to obtain the microsphere intermediate.

[0084] Step 2: Mix the reactants and solvent according to the mass-volume ratio M 微球中间体 M cuBr2 M PMDETA M 显影分子A8 V 二甲基亚砜 The solution was added to a Schlenk flask at a ratio of 40 mg: 0.34 mg: 5.44 mg: 0.05 mol: 1 mL. Nitrogen gas was bubbled into the system for 30 min, and then CuBr (M...) was added. cuBr2 M cuBr =0.34:4.28). After continuing to purge with nitrogen for 15 min, the system was heated to 65℃ and reacted for 4 h. After the reaction was complete, the system was cooled to room temperature, and the sample was washed three times each with dimethyl sulfoxide and deionized water, and then dried under vacuum.

[0085] Example 24: Preparation of Implantable Embolizing Microspheres B9

[0086] Step 1: Add 50 mL of polyvinyl alcohol microspheres to acetone for sedimentation. After sedimentation, collect the solid by vacuum filtration. Place the solid at 40°C. o The microspheres were dried overnight in a vacuum oven at C. 0.1 g of dried microspheres were added to 10 mL of dimethyl sulfoxide to swell, and then 0.01 mol of bromoacetyl dimethyl acetal was added. Under acidic conditions, the system was heated to 63 °C and reacted for 12 h. The system was then cooled to room temperature. The sample was washed three times with dimethyl sulfoxide and deionized water, respectively, and then dried under vacuum to obtain the microsphere intermediate.

[0087] Step 2: Mix the reactants and solvent according to the mass-volume ratio M 微球中间体 M cuBr2 M PMDETA M 显影分子A9 V 二甲基亚砜 The solution was added to a Schlenk flask at a ratio of 40 mg: 0.34 mg: 5.44 mg: 0.05 mol: 1 mL. Nitrogen gas was bubbled into the system for 30 min, and then CuBr (M...) was added. cuBr2 M cuBr =0.34:4.28). After continuing to purge with nitrogen for 30 min, the system was heated to 65℃ and reacted for 8 h. After the reaction was complete, the system was cooled to room temperature, and the sample was washed three times each with dimethyl sulfoxide and deionized water, and then dried under vacuum.

[0088] Example 25: Preparation of Implantable Embolizing Microspheres B10

[0089] Step 1: Add 50 mL of polyvinyl alcohol microspheres to acetone for sedimentation. After sedimentation, collect the solid by vacuum filtration. Place the solid at 40°C. o The microspheres were dried overnight in a vacuum oven at C. 0.1 g of dried microspheres were added to 10 mL of dimethyl sulfoxide to swell, and then 0.01 mol of 2-chloromethyl-1,3-dioxolane was added. Under acidic conditions, the system was heated to 63 °C and reacted for 12 h. The system was then cooled to room temperature. The sample was washed three times with dimethyl sulfoxide and deionized water, respectively, and then dried under vacuum to obtain the microsphere intermediate.

[0090] Step 2: Mix the reactants and solvent according to the mass-volume ratio M 微球中间体 M cuBr2 M PMDETA M 显影分子A10 V 二甲基亚砜 The solution was added to a Schlenk flask in a ratio of 40 mg: 0.34 mg: 5.44 mg: 0.5 mol: 1 mL. Nitrogen gas was bubbled into the system for 30 min, and then CuBr (M...) was added. cuBr2 M cuBr=0.34:4.28). After continuing to purge with nitrogen for 30 min, the system was heated to 65℃ and reacted for 8 h. After the reaction was complete, the system was cooled to room temperature, and the sample was washed three times each with dimethyl sulfoxide and deionized water, and then dried under vacuum.

[0091] Example 26: Preparation of Implantable Embolizing Microspheres B11

[0092] Step 1: Add 50 mL of polyvinyl alcohol microspheres to acetone for sedimentation. After sedimentation, collect the solid by vacuum filtration. Place the solid at 40°C. o The microspheres were dried overnight in a vacuum oven at C. 0.1 g of dried microspheres were added to 10 mL of dimethyl sulfoxide to swell them, and then 0.01 mol of 3-bromopropanal dimethyl acetal was added. Under acidic conditions, the system was heated to 63 °C and reacted for 12 h. The system was then cooled to room temperature. The sample was washed three times with dimethyl sulfoxide and deionized water, respectively, and then dried under vacuum to obtain the microsphere intermediate.

[0093] Step 2: Mix the reactants and solvent according to the mass-volume ratio M 微球中间体 M cuBr2 M PMDETA M 显影分子A11 V 二甲基亚砜 The solution was added to a Schlenk flask in a ratio of 40 mg: 0.34 mg: 5.44 mg: 0.5 mol: 1 mL. Nitrogen gas was bubbled into the system for 30 min, and then CuBr (M...) was added. cuBr2 M cuBr =0.34:4.28). After continuing to purge with nitrogen for 30 min, the system was heated to 65℃ and reacted for 8 h. After the reaction was complete, the system was cooled to room temperature, and the sample was washed three times each with dimethyl sulfoxide and deionized water, and then dried under vacuum.

[0094] Example 27: Preparation of Implantable Embolizing Microspheres B12

[0095] Step 1: Add 50 mL of polyvinyl alcohol microspheres to acetone for sedimentation. After sedimentation, collect the solid by vacuum filtration. Place the solid at 40°C. o The microspheres were dried overnight in a vacuum oven at C. 0.1 g of dried microspheres were added to 10 mL of dimethyl sulfoxide to swell, and then 0.01 mol of bromoacetyl dimethyl acetal was added. Under acidic conditions, the system was heated to 63 °C and reacted for 12 h. The system was then cooled to room temperature. The sample was washed three times with dimethyl sulfoxide and deionized water, respectively, and then dried under vacuum to obtain the microsphere intermediate.

[0096] Step 2: Mix the reactants and solvent according to the mass-volume ratio M 微球中间体 M cuBr2 M PMDETA M 显影分子A12 V 二甲基亚砜The solution was added to a Schlenk flask in a ratio of 40 mg: 0.34 mg: 5.44 mg: 0.5 mol: 1 mL. Nitrogen gas was bubbled into the system for 30 min, and then CuBr (M...) was added. cuBr2 M cuBr =0.34:4.28). After continuing to purge with nitrogen for 30 min, the system was heated to 65℃ and reacted for 8 h. After the reaction was complete, the system was cooled to room temperature, and the sample was washed three times each with dimethyl sulfoxide and deionized water, and then dried under vacuum.

[0097] Example 28-Example 30: Preparation of Implantable Embolism Microspheres B13-B15

[0098] The only difference between the preparation method of Example 28-Example 30 and Example 16 is that A1 in Example 16 is replaced by the same molar amount of A13~A15 in sequence to prepare B13~B15;

[0099] Comparative Example 1: This comparative example provides a radiopaque embolic microsphere, the preparation method of which includes the following steps:

[0100] Dehydrate 200 mL of polyvinyl alcohol microspheres in excess acetone until the polyvinyl alcohol-impregnated microspheres form white, dehydrated, dry spheres. 60 o After vacuum drying at 6°C for 6 hours, weigh 1.0 g of the dried bulbs and pour them into a four-necked flask. Add 200 mL of dimethyl sulfoxide and heat at 63°C. o Stir at C for 1 hour. Then, lower the temperature to room temperature, weigh 15.0 g of triiodobenzaldehyde and add it to the flask, stirring for 30 minutes. Raise the temperature of the system to 63°C. o C. Continue to slowly add 40 mL of methanesulfonic acid to the flask and stir the reaction for 24 h. Finally, wash the microspheres 6 times each with dimethyl sulfoxide and purified water to obtain microspheres with different particle size distributions for imaging embolism.

[0101] Comparative Example 2: This comparative example provides another type of imaging embolism microsphere, the preparation method of which includes the following steps:

[0102] Add 100g of purified water and 12g of polyvinyl alcohol with a weight-average molecular weight of 67,000 to a reaction flask, and heat to 95°C. o C completely dissolves the polyvinyl alcohol. Add 1.5 g of N-(2,2-dimethoxyethyl)-2-acrylamide and 20 mL of concentrated hydrochloric acid, and stir at 30 °C. oThe reaction was carried out at C for 4 hours. After the reaction was completed, the pH of the reaction system was adjusted to 7 with 2M sodium hydroxide solution. Finally, the solution was concentrated to a viscosity of 1800 cps to obtain 40 g of polyvinyl alcohol drug-loaded embolic microsphere intermediate. 9 g of the polyvinyl alcohol drug-loaded embolic microsphere intermediate, 4 g of 5-acrylamido-2,4,6-triiodobenzene-1,3-dicarboxylic acid, 1.3 g of sodium bicarbonate, 0.6 g of sodium 2-acrylamido-2-methylpropanesulfonate, and 0.3 g of potassium persulfate were added to a reaction flask, followed by 5 mL of water to dissolve completely. Then, 60 mL of butyl acetate and 0.5 g of cellulose acetate butyrate were added. After purging with nitrogen, 0.5 mL of tetramethylethylenediamine was added, and the mixture was heated at 55 °C. o The reaction was carried out at C for 5 hours. Finally, the microspheres were washed successively with ethyl acetate and acetone to obtain X-ray-detectable drug-loaded embolic microspheres. Elemental analysis showed that iodine accounted for approximately 38% of the mass of the microspheres.

[0103] Comparative Example 3: This comparative example provides a commercially available non-radioactive embolism microsphere product, DC Bead (Biocompatibles, UK).

[0104] Comparative Example 4: This comparative example provides a commercially available radiopaque embolization microsphere product, DC Bead LUMI (Biocompatibles, UK).

[0105] Comparative Example 5: This comparative example provides a commercially available imaging embolization microsphere product, Vispearl (Shanghai Huihe Medical Technology Co., Ltd.).

[0106] Test Example 1: Comparison of development performance of B1~B15 with Comparative Examples 1~5;

[0107] Embolization microspheres of B1~B15 and Comparative Examples 1~5 were subjected to the following tests:

[0108] Weigh 1.0 g of agarose powder at room temperature, measure 99.0 mL of purified water using a graduated cylinder, and add it to a 250 mL Erlenmeyer flask. Mix the mixture and heat it to boiling using a glass rod with constant stirring on a hot plate. Pipette 5 mL of the heated agarose solution into a 10 mL centrifuge tube. After cooling to room temperature, use an 18G needle to puncture a hollow cylinder approximately 0.5 cm in diameter and 2 cm in length at its center. Then, use a 5 mL syringe to draw 2 mL of microspheres and insert them into the 10 mL centrifuge tube. Slowly push the microspheres into the hollow cylinder until it is full. Add a drop of heated agarose solution on top and allow it to cool to obtain a linear model. Place the centrifuge tube under DSA and CT imaging equipment. The data are shown in Table 1.

[0109] Table 1. CT values ​​of B1~B15 and Comparative Examples 1~5

[0110] sample CT value B1 4104 HU B2 3323 HU B3 4314HU B4 3681 HU B5 4293 HU B6 4351 HU B7 4010 HU B8 4007 HU B9 4080 HU B10 4101 HU B11 3998 HU B12 4162 HU B13 4043 HU B14 4082 HU B15 4014 HU Comparative Example 1 3799 HU Comparative Example 2 3928 HU Comparative Example 3 / Comparative Example 4 3787 HU Comparative Example 5 3881 HU

[0111] As can be seen from Table 1, the developing embolism microspheres B1-B15 prepared in Examples 1-15 of this application all have good developing properties. The developing properties of the developing embolism microspheres prepared in Comparative Examples 1 and 2, as well as the commercially available developing embolism microspheres in Comparative Examples 4 and 5, are slightly worse than those of the developing embolism microspheres B1-B15 prepared in the examples of this application. The commercially available DC Bead microspheres in Comparative Example 3 do not have developing properties.

[0112] Test Example 2: Comparison of physical properties of B1~B15 with Comparative Examples 1~5

[0113] 1. Comparison of compression resilience

[0114] Embolization microspheres of B1~B15 and Comparative Examples 1~5 were subjected to the following tests:

[0115] The microspheres were transferred to a petri dish equipped with a micrometer. Ten microspheres were randomly selected under a microscope, and the microspheres were compressed using the end of tweezers. After the microsphere particles were compressed and deformed to 30% of their original size, the load was removed, and the rebound of the microsphere particles was observed. The compression rebound data are shown in Table 2.

[0116] Suspension comparison

[0117] Embolization microspheres of B1~B15 and Comparative Examples 1~5 were subjected to the following tests:

[0118] Draw all the microspheres and preservation solution from the vial using a 20mL syringe. Remove the preservation solution and add an appropriate amount of contrast agent to mix (at a microsphere to contrast agent volume ratio of 1:5, for example: 1mL microspheres to 5mL contrast agent, 2mL microspheres to 10mL contrast agent) to obtain a suspension. Use a three-way valve to inject the suspension from the 20mL syringe into a 1mL syringe. Repeat this injection and injection process 10 times to ensure thorough mixing. Then, remove the 1mL syringe from the three-way valve, keep it vertical, and start timing. The time taken to reach suspension is T1, and the time taken to end suspension is T2. The criterion for ending suspension is that 2 / 3 of the syringe volume contains microspheres. The time to maintain suspension is (T2-T1). The suspension time data are shown in Table 2.

[0119] Catheter passability

[0120] Embolization microspheres of B1~B15 and Comparative Examples 1~5 were subjected to the following tests:

[0121] Draw 10 mL of 0.9% sodium chloride injection solution into a syringe, connect the corresponding tubing to the syringe, and slowly inject the 0.9% sodium chloride injection solution into the tubing for rinsing. After rinsing, remove the syringe. Draw all the polyvinyl alcohol embolized microspheres and preservation solution from the vial into a 20 mL syringe, then expel the air and supernatant from the syringe, leaving only the microspheres. Draw an appropriate amount of contrast agent into another syringe (at a microsphere to contrast agent volume ratio of 1:5). Connect the syringes containing the microspheres and contrast agent separately using a three-way valve, and repeatedly inject the microspheres and contrast agent from the two syringes to mix them until a homogeneous suspension is obtained. Inject all of the suspension into the 20 mL syringe and remove the syringe containing the contrast agent. Connect a 1 mL syringe and a corresponding tubing to the three-way valve, adjust the three-way valve knob to connect the 20 mL and 1 mL syringes separately, and inject the microsphere and contrast agent suspension into the 1 mL syringe. Visually inspect the microspheres in the 1 mL syringe to ensure they are in suspension. Readjust the three-way valve knob, connect the 1mL syringe and the catheter separately, and push the 1mL syringe to push the microspheres out of the catheter at a rate of 1mL / min. During the injection, maintain the microspheres in suspension until all the microsphere solution has been injected. Observe the state of the microspheres passing through the catheter. The catheter permeability data are shown in Table 2.

[0122] Table 2 Compression resilience, suspension time, and catheter permeability of B1-B15 and Comparative Examples 1-5

[0123] sample Compression resilience Suspension time Catheter passability B1 80% 25min pass B2 80% 26min pass B3 80% 24min pass B4 80% 25min pass B5 80% 23min pass B6 80% 24min pass B7 80% 26min pass B8 80% 27min pass B9 80% 25min pass B10 80% 24min pass B11 80% 27min pass B12 80% 28min pass B13 80% 26min pass B14 80% 26min pass B15 80% 27min pass Comparative Example 1 30% 12 min pass Comparative Example 2 30% 14 min pass Comparative Example 3 80% 28min pass Comparative Example 4 30% 13min pass Comparative Example 5 30% 16 min pass

[0124] As shown in Table 2, the radiopaque embolization microspheres B1-B15 prepared in Examples 1-15 exhibit high elasticity and suspension time, comparable to those of the commercially available non-radioplastic embolization microspheres in Comparative Example 3. While possessing good suspension properties, they can be delivered into catheters without breakage, meeting the needs of complex interventional situations such as catheter bending. However, the radiopaque embolization microspheres prepared in Comparative Examples 1 and 2, as well as the commercially available radiopaque embolization microspheres in Comparative Examples 4 and 5, have excessively low elasticity and short suspension times, which are unfavorable for practical applications. Therefore, the radiopaque embolization microspheres B1-B15 prepared in Examples 1-15 achieve radiopaque functionality without affecting the original performance of the microspheres.

[0125] Test Example 3: Comparison of drug loading rates of B1~B15 with Comparative Examples 1~5;

[0126] Take three groups of embolic microspheres (B1~B15 and Comparative Examples 1~5), and randomly select one group for the following test:

[0127] Using a 1.0 mL syringe with a needle, take a sample, invert the syringe, and allow it to settle. After the microspheres settle, drain the supernatant and the microspheres until 0.10 mL of microspheres remain in the syringe. Prepare a 20 mg / mL doxorubicin solution in advance. Use a 20 μL pipette to transfer 6 μL of the doxorubicin solution to a cuvette, add 3000 μL of purified water, and mix well. Place the cuvette in the sample cell of a UV spectrophotometer, measure the absorbance of the doxorubicin solution, and record the value. Take another 1.0 mL syringe, draw 0.20 mL of the doxorubicin solution, and add it to the syringe containing the microspheres. Invert the syringe to mix well. Sample and test at the following time points and record the data (1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min).

[0128] Two other groups of embolic microspheres, B1-B15 and Comparative Examples 1-5, were taken and subjected to the same drug loading test as described above, using the same amount of idarubicin solution and epirubicin solution instead of doxorubicin solution, respectively. The drug loading rate data are shown in Table 3 after processing.

[0129] Table 3 shows the drug loading rates of the three drugs in Examples B1-B15 and Comparative Examples 1-5.

[0130] sample Doxorubicin loading rate (>99%) Idabicin delivery rate (>99%) Epirubicin drug delivery rate (>99%) B1 2min 2min 2min B2 3min 3min 3min B3 1min 1min 1min B4 2min 2min 2min B5 2min 2min 2min B6 2min 2min 2min B7 1min 1min 1min B8 2min 2min 2min B9 2min 2min 2min B10 2min 1min 1min B11 1min 2min 2min B12 1min 1min 1min B13 2min 1min 2min B14 1min 2min 2min B15 1min 1min 1min Comparative Example 1 5min 6min 5min Comparative Example 2 6min 5min 5min Comparative Example 3 4min 5min 4min Comparative Example 4 5min 5min 7min Comparative Example 5 5min 6min 5min

[0131] As shown in Table 3, the radioactive embolization microspheres B1-B15 prepared in Examples 1-15 exhibit high loading efficiency, surpassing not only the radioactive embolization microspheres prepared in Comparative Examples 1 and 2, and the commercially available radioactive embolization microspheres in Comparative Examples 4 and 5, but also the loading efficiency of the commercially available non-radioactive embolization microspheres in Comparative Example 3. This is because the radioactive molecules in the radioactive embolization microspheres prepared in Comparative Examples 1 and 2, and the commercially available products in Comparative Examples 4 and 5, are enriched within the microspheres, resulting in significant steric hindrance and thus low loading efficiency. The radioactive embolization microspheres B1-B15 prepared in Examples 1-15 disperse radioactive molecules as polymer chain segments on the surface of the polymer cross-linked network structure framework of the embolization microspheres, increasing the space of the polymer cross-linked network structure of the microspheres themselves and effectively improving the drug loading efficiency of the radioactive microspheres. Test Example 3 demonstrates that the radioactive embolization microspheres B1-B15 prepared in Examples 1-15 achieve both increased drug loading rate and radioactive function.

[0132] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0133] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A radioactive embolic microsphere with high elasticity and high drug loading rate, characterized in that, It has any one of the following structural formulas: I-V , , , , Where n represents the degree of aggregation; The method for preparing the imaging embolization microspheres includes the following steps: Compounds containing chlorine or bromine groups are reacted with microspheres with a polyhydroxy polymer backbone to obtain microsphere intermediates with ATRP reaction sites. The microsphere intermediate was subjected to ATRP polymerization with a imaging molecule containing unsaturated bonds to prepare imaging embolization microspheres with high compressibility and high drug loading rate. Among them, the microspheres with polyhydroxy polymers as the main chain are polyvinyl alcohol microspheres.

2. A method for preparing imaging embolic microspheres with high elasticity and high drug loading rate as described in claim 1, characterized in that, Includes the following steps: Compounds containing chlorine or bromine groups are reacted with microspheres with a polyhydroxy polymer backbone to obtain microsphere intermediates with ATRP reaction sites. By subjecting the microsphere intermediate to ATRP polymerization with imaging molecules containing unsaturated bonds, imaging embolization microspheres with high compressibility and high drug loading rate were prepared.

3. The preparation method according to claim 2, characterized in that, The compounds containing chlorine or bromine groups include p-chloromethylbenzaldehyde, p-bromomethylbenzaldehyde, 3-chloropropanal dimethyl acetal, 4-chlorobutanal diethyl acetal, 3-chloropropanal diethyl acetal, 3-bromopropanal dimethyl acetal, chloroacetaldehyde diethanol, 2-chloroacetaldehyde dimethyl acetal, bromoacetyl dimethyl acetal, 2-chloromethyl-1,3-dioxolane, 3-bromopropanal dimethyl acetal, and bromoacetyl dimethyl acetal.

4. The preparation method according to claim 2, characterized in that, The method for preparing the imaging embolization microspheres satisfies at least one of the following conditions (1) to (2): (1) The mass molar ratio of microspheres with polyhydroxy polymer as the main chain to compounds containing chlorine or bromine groups is 1 g: (0.01~1) mol; (2) The mass molar ratio of microspheres with polyhydroxy polymer as the main chain to developing molecules containing unsaturated bonds is 1 g: (0.01~1) mol.

5. The preparation method according to claim 2, characterized in that, The method for preparing the developing molecule containing unsaturated bonds is selected from any one of the following a~c: a. Formed by grafting carbon-carbon double bonds onto iodine-containing compounds using organic modifiers containing double bonds; b. The iodine-containing compound is halogenated with a chlorinating agent to generate an iodine-containing chloride, which is then reacted with a modifier containing double bonds and sulfonic acid groups under the action of an alkaline catalyst to obtain a developing molecule containing unsaturated bonds and sulfonic acid groups. c. An iodine-containing compound undergoes a nucleophilic substitution reaction with an organic sulfonyl chloride to generate an iodine-containing sulfonate derivative, which then undergoes a further nucleophilic substitution reaction with an amino-containing nucleophilic reagent to generate an amino-containing iodide. This is further reacted with a modifier containing double bonds and hydroxyl groups to obtain a developing molecule containing unsaturated bonds and hydroxyl groups.

6. The preparation method according to claim 5, characterized in that, The iodine-containing compound is selected from any one of triiodobenzyl alcohol, triiodophenol, and triiodobenzaldehyde.

7. The preparation method according to claim 5, characterized in that, The preparation process of the developing molecule containing unsaturated bonds satisfies at least one of the following conditions (1) to (6): (1) The double-bonded organic modifier is selected from either 4-vinylbenzyl chloride or 4-vinylbenzyl bromide; (2) The chlorination reagent is selected from either hydrochloric acid or hydrobromic acid; (3) The modifier with double bonds and sulfonic acid groups is sodium 3-allyloxy-2-hydroxy-1-propanesulfonate; (4) The organic sulfonyl chloride is selected from any one of p-toluenesulfonyl chloride, benzenesulfonyl chloride, 4-propylbenzenesulfonyl chloride, 4-ethylbenzenesulfonyl chloride, 3,5-dimethylbenzenesulfonyl chloride, 2,5-dimethylbenzenesulfonyl chloride, 3,4-dimethylbenzenesulfonyl chloride, 4-cyclohexylbenzenesulfonyl chloride, 2,4-dimethylbenzenesulfonyl chloride, 4-tert-butylbenzenesulfonyl chloride, and 2,3,5,6-tetramethylbenzenesulfonyl chloride; (5) The modifier with double bonds and hydroxyl groups is selected from any one of glycidyl methacrylate, oxetane methacrylate, tetrahydrofurfuryl methacrylate, and allyl glycidyl ether; (6) The amino-containing nucleophile is selected from any one of 1,3-propanediamine, 1,2-propanediamine, 2,2-dimethyl-1,3-propanediamine, and 2-methyl-1,3-propanediamine.

8. The preparation method according to claim 5, characterized in that, The molar ratio of the iodine-containing compound to the organic modifier containing double bonds, the modifier with double bonds and sulfonic acid groups, and the modifier with double bonds and hydroxyl groups is 1:(1~2).

9. The application of a contrast-enhancing embolization microsphere in the preparation of combined radiotherapy, chemotherapy, and embolization therapy drugs and contrast-enhancing diagnostic reagents for tumors, characterized in that, The radiopaque embolic microspheres are those described in claim 1; or... The radiopaque embolism microspheres are radiopaque embolism microspheres prepared by the preparation method according to any one of claims 2 to 8.

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