Color embolization microspheres and preparation method and application thereof

Abstract

The present application belongs to the field of biomedical materials, discloses a kind of color embolization microspheres and its preparation method and application, color embolization microspheres are synthesized by dispersed phase and continuous phase for inverse suspension polymerization one-step method, dispersed phase is prepared by iodine alkenyl reactive dye, polyvinyl alcohol modified macromolecule solution, initiator and water for injection as main raw material, continuous phase is prepared by oil phase, dispersing agent and catalyst as main raw material;Iodine alkenyl reactive dye in dispersed phase is first obtained by substitution reaction of reactive dye and iodine element, periodic acid in reaction medium, iodine active dye, iodine active dye is then obtained by ring-opening addition under the catalysis of alkaline solution with epoxy butene;The color embolization microspheres synthesized by inverse suspension polymerization one-step method of the present application have the function of developing under X-ray, have drug loading function, dyeing is firm and not easy to decolor, and dyeing process is simple.

Description

Technical Field

[0001] This invention relates to the field of biomedical materials, and in particular to a colored embolic microsphere, its preparation method, and its application. Background Technology

[0002] Primary liver cancer is one of the most common malignant tumors, and its incidence is on the rise worldwide, with a persistently high mortality rate, seriously endangering people's health. In my country, only about 25% of patients are suitable for surgical resection, with a 5-year survival rate ranging from 29% to 70%, but the recurrence rate after surgical resection is still as high as 75%. Catheter embolization is an important interventional therapy technique. It involves the controlled injection of artificial embolic materials into the target blood vessels supplying the diseased tissue or organ, causing occlusion and blocking the blood supply, thereby controlling bleeding, treating vascular lesions, eliminating diseased organs, and treating tumors.

[0003] Embolizing microspheres, as a novel embolic material, overcome the shortcomings of traditional embolic particles due to their irregular shape (leading to unpredictable embolization). Microspheres possess characteristics such as smooth surface, precise size, compressibility, and resistance to clumping, making them easily passable through microcatheters. This allows for better embolization of blood vessels at the tumor's terminal end, thus more thoroughly reducing tumor blood supply. Simultaneously, microsphere embolization can significantly reduce the dosage of iodized oil and chemotherapy drugs, reducing other complications. Currently, most commercially available embolic microspheres require preparation into suspensions with contrast agents such as iodized oil / iohexol / iopalatine before vascular embolization. However, microspheres of different sizes exhibit varying suspension states in contrast agents, requiring clinicians to adjust the suspension on-site to achieve optimal suspension. Furthermore, the contrast agent itself may irritate blood vessels, increasing the risk. Therefore, embolic microspheres with built-in imaging capabilities are more suitable for clinical applications.

[0004] Reactive dyes are characterized by bright colors, good uniformity, high color fastness, complete color spectrum and low cost. They are widely used in the dyeing and printing of fibers such as cotton, linen, viscose, silk, wool and their blended fabrics. However, due to the disadvantages such as complex dyeing process, harsh conditions, low dye utilization rate and the need for secondary treatment of dyes physically adsorbed on the surface, their application in the field of biomedical materials is limited.

[0005] In existing technologies, staining of embolization microspheres is mostly carried out after the microspheres are synthesized. Drug loading is achieved by introducing functional monomers with sulfonic acid / carboxylic acid groups into the reaction, and development is achieved by introducing compounds containing iodine into the reaction. These processes often require multiple steps and are quite cumbersome, and cannot simultaneously possess the functions of different colors, drug loading, and development. Summary of the Invention

[0006] Therefore, the purpose of this invention is to address the shortcomings of existing technologies by providing a colored embolization microsphere, its preparation method, and its application.

[0007] To achieve the above objectives, the present invention adopts the following technical solution:

[0008] This invention provides color embolism microspheres, characterized in that they are synthesized in one step by reverse-phase suspension polymerization of a dispersed phase and a continuous phase, possess X-ray imaging capability, and have drug loading capability, with a drug loading capacity of 34-99 mg for doxorubicin-type drugs; the mass ratio of the dispersed phase to the continuous phase is 3:1-6:1; the dispersed phase is prepared from iodoalkenyl reactive dyes, polyvinyl alcohol modified macromolecular solutions, initiators, and water for injection as main raw materials, and the continuous phase is prepared from oil phases, dispersants, and catalysts as main raw materials;

[0009] The dispersed phase contains the following components by mass percentage: 0.05-0.2 wt% iodoalkenyl reactive dye, 50-70 wt% polyvinyl alcohol modified macromolecular solution, 0.4-1 wt% initiator, and 28.8-49.55 wt% water for injection; wherein the mass concentration of the polyvinyl alcohol modified macromolecular solution is 5-15 wt%.

[0010] The continuous phase comprises the following components by mass percentage: oil phase 99-99.8 wt%, dispersant 0.1-0.5 wt%, catalyst 0.1-0.5 wt%;

[0011] The iodoalkenyl reactive dye in the dispersed phase is first obtained by a substitution reaction between the reactive dye and elemental iodine and periodic acid in a reaction medium. The iodoalkenyl reactive dye is then obtained by a ring-opening addition reaction with glycidene under alkaline solution catalysis.

[0012] As a further improvement of the present invention, the substitution reaction comprises the following components by mass percentage: 4-10 wt% reactive dye, 2-10 wt% elemental iodine, 2-10 wt% periodic acid, and 70-92 wt% reaction medium; the substitution reaction is carried out under light-protected conditions and at room temperature with stirring for 5-10 hours.

[0013] As a further improvement of the present invention, the reactive dye is any one of Reactive Blue 4, Reactive Brilliant Blue K-GR, Reactive Green 8, and Reactive Black 5; the reaction medium is any one of tetrahydrofuran, tetrahydropyran, and 1,4-dioxane.

[0014] As a further improvement of the present invention, the ring-opening addition reaction comprises the following components in mass percentage: 70-89 wt% iodoactive dye, 10-20 wt% epoxybutene, and 1-10 wt% alkaline solution; the conditions for the ring-opening addition reaction are 50-70°C and stirring for 5-10 hours.

[0015] As a further improvement of the present invention, the initiator is any one of potassium persulfate or ammonium persulfate; the oil phase is any one of liquid paraffin, petroleum ether, cyclohexane, and dichloromethane; the dispersant is any one of Span 20, Span 40, and Span 80; and the catalyst is any one of tetramethylethylenediamine, tetramethylpropylenediamine, and tetramethylbutyldiamine.

[0016] This invention also provides a method for preparing colored embolic microspheres, characterized by comprising the following steps:

[0017] S1 Preparation of iodoalkenyl reactive dyes: Weigh a quantitative amount of reactive dye powder, add elemental iodine, periodic acid, and reaction medium, and a substitution reaction occurs under light-protected conditions. Purify by column chromatography to obtain iodoalkenyl reactive dyes. Weigh a quantitative amount of iodoalkenyl reactive dye, add epoxybutene and alkaline solution, and a ring-opening addition reaction occurs. Purify by column chromatography to obtain iodoalkenyl reactive dyes.

[0018] S2 Preparation of Polyvinyl Alcohol Modified Macromolecular Solution: Polyvinyl alcohol solution and N-(2,2-dimethoxyethyl)-2-acrylamide are used as the main raw materials. After transesterification under the action of concentrated hydrochloric acid, the solution is obtained by neutralization, dialysis, drying and dissolution.

[0019] S3 Preparation of dispersed phase: Weigh the iodoalkenyl reactive dye mentioned in step S1, the polyvinyl alcohol modified macromolecular solution mentioned in step S2, the initiator, and water for injection, and stir evenly to obtain the dispersed phase;

[0020] S4 Preparation of Continuous Phase: Weigh a quantitative amount of oil phase and dispersant, stir evenly and set aside;

[0021] S5 Preparation of Color Embolism Microspheres: Under stirring, the dispersed phase is transferred to the continuous phase, a catalyst is added, and a reverse suspension polymerization reaction is carried out. The continuous phase on the surface of the microspheres is washed to obtain 70-900μm color embolism microspheres. After wet sieving, 300-500μm color embolism microspheres with drug loading and imaging functions are obtained.

[0022] S6 Drug Loading Detection: Transfer 2 mL of embolization microspheres into a syringe, add 4 mL of 25 mg / mL drug solution, let stand for 10 min to load the drug, and use a UV-Vis spectrophotometer to test the absorbance of the residual drug solution to calculate the actual drug loading of the microspheres;

[0023] S7 CT Imaging Detection: Place the microspheres under a CT imaging device and observe the imaging of the microspheres under X-rays;

[0024] S8 Dye Dissolution Detection: The entire bottle of embolized microspheres (2 mL microspheres + 6 mL preservation solution) was placed at 60°C and 60% humidity for 65 days for accelerated aging. The absorbance of the microsphere preservation solution was measured using a UV-Vis spectrophotometer, and the dye dissolution concentration was calculated.

[0025] As a further improvement of the present invention, the alkaline solution in step S1 includes a sodium hydroxide or potassium hydroxide solution with a concentration of 1M.

[0026] As a further improvement of the present invention, the eluent for column chromatography in step S1 includes any one of the following: a compound of ethyl acetate and petroleum ether, a compound of dichloromethane and ethyl acetate, or a compound of dichloromethane and petroleum ether, with a compounding ratio of 1:2 to 2:1.

[0027] As a further improvement of the present invention, the polyvinyl alcohol solution in step S2 is prepared by using polyvinyl alcohol powder and water for injection as the main raw materials, under the conditions of swelling at 40℃-60℃ for 3-5 hours and dissolving at 90℃-100℃ for 3-5 hours; the polyvinyl alcohol modified macromolecule solution in step S2 is prepared by using polyvinyl alcohol modified macromolecule and water for injection as the main raw materials, under the conditions of swelling at 40℃-60℃ for 3-5 hours and dissolving at 90℃-100℃ for 3-5 hours; the polyvinyl alcohol modified macromolecule is prepared by using polyvinyl alcohol solution, N-(2,2-dimethoxyethyl)-2-acrylamide and concentrated hydrochloric acid as the main raw materials, after dialysis of the mixed solution neutralized by alkaline solution to remove the chloride small molecules generated by the neutralization reaction, and then drying.

[0028] As a further improvement of the present invention, the mass concentration of the polyvinyl alcohol solution in step S2 is 5-15 wt%, the amount of N-(2,2-dimethoxyethyl)-2-acrylamide added is 0.1-0.5 wt% of the polyvinyl alcohol solution, the amount of concentrated hydrochloric acid added is 5-15 wt% of the polyvinyl alcohol solution, and neutralization is performed using 1M sodium hydroxide solution or potassium hydroxide solution.

[0029] As a further improvement of the present invention, the reverse suspension polymerization in step S5 is carried out at room temperature to 60°C under nitrogen protection for 1 to 3 hours, and the microspheres are washed sequentially with Tween 80 solution and 0.9% sodium chloride injection solution.

[0030] As a further improvement of the present invention, the particle size of the color embolization microspheres in step S5 is between 300-500 μm; the drug-loaded microspheres are obtained by ion exchange between the abundant sulfonic acid ion groups in the iodoalkenyl reactive dye and doxorubicin drugs; the drug loading of the drug-loaded microspheres is between 34-99 mg; the doxorubicin drugs are any one of doxorubicin, epirubicin, and pirarubicin.

[0031] This invention also provides an application of color embolization microspheres in the embolization treatment of arteriovenous malformations, highly vascular tumors, uterine fibroids, and other vascular embolization conditions.

[0032] The beneficial effects of this invention are:

[0033] 1. The color embolization microspheres provided by this invention, through the iodine element in the iodoalkenyl reactive dye, enable the color embolization microspheres themselves to have imaging function, which facilitates the doctor's intuitive observation before and during the operation.

[0034] 2. The colored embolization microspheres provided by this invention can exchange ions with doxorubicin drugs through the abundant sulfonic acid ion groups in the iodoalkenyl reactive dye, thereby enabling the embolization microspheres to have the function of loading drugs. The embolization microspheres can load doxorubicin drugs at a rate of 34-99 mg, which meets the needs of different patients for doxorubicin antitumor drugs.

[0035] 3. The colored embolization microspheres provided by the present invention introduce the color of the iodoalkenyl reactive dye into the microspheres through a polymerization reaction, so that the embolization microspheres have a rich variety of colors such as blue, bright blue, green and black.

[0036] 4. The method for preparing colored embolism microspheres provided by the present invention is to directly synthesize colored microspheres in one step. The microspheres are more uniformly colored, and the amount of modified reactive dye used is small and the utilization rate is high, thereby reducing the generation of colored wastewater and also reducing damage to the microsphere structure.

[0037] 5. The application method of the color embolization microspheres provided by the present invention reduces the use of contrast agents during surgery and weakens the stimulation of blood vessels by contrast agents by imaging under X-rays. It also facilitates the doctor's direct observation before surgery (microspheres need to be separated from the preservation solution before drug loading, and color imaging can help guide the doctor to the separation of microspheres) and during surgery (imaging). This provides convenience for the clinical treatment of vascular embolism, especially for arteriovenous malformations, highly vascular tumors, uterine fibroids, etc.

[0038] 6. The modified alkenyl reactive dyes provided by this invention are suitable for other biomedical materials that require dyeing or drug loading. They have strong staining properties, are not easy to fade, have a simple dyeing process, and can also load ionic drugs.

[0039] 7. The colored embolic microspheres provided by this invention have abundant and inexpensive raw materials, a simple reaction process, and are easy to operate, and have good application prospects in the medical field. Attached Figure Description

[0040] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0041] Appendix Figure 1 Photographs of the microspheres in Examples 1-18 and Comparative Examples 19-20.

[0042] Appendix Figure 2 The images show microspheres under X-rays for Examples 1-18 and Comparative Examples 19-20.

[0043] Appendix Figure 3 These are photographs of Examples 2, 14, 16, and 18 taken under a microscope.

[0044] Appendix Figure 4 This refers to the synthesis steps of iodoalkenyl reactive blue 4.

[0045] Appendix Figure 5 The 1H NMR spectrum is that of iodoalkenyl reactive blue 4.

[0046] Appendix Figure 6 The steps for synthesizing iodoalkenyl reactive brilliant blue K-GR are described.

[0047] Appendix Figure 7 The 1H NMR spectrum of iodoalkenyl reactive brilliant blue K-GR is shown.

[0048] Appendix Figure 8 This is the synthesis step for iodoalkenyl reactive green 8.

[0049] Appendix Figure 9 The 1H NMR spectrum of iodoalkenyl reactive green 8.

[0050] Appendix Figure 10 This refers to the synthesis steps of iodoalkenyl reactive black 5.

[0051] Appendix Figure 11 The 1H NMR spectrum of iodoalkenyl reactive black 5. Detailed Implementation

[0052] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention. Example 1

[0053] Preparation of Iodoalkenyl Reactive Blue 4 (S1): 4 g of Reactive Blue 4 was weighed and placed in a Srank flask. 92 g of tetrahydrofuran, 2 g of iodine, and 2 g of periodic acid were added. The mixture was stirred at room temperature for 10 hours under light-protected conditions. Purification was performed by column chromatography using a mixture of ethyl acetate and petroleum ether in a 1.5:1 ratio as the eluent, yielding 5.59 g of iodoalkenyl Reactive Blue 4 (93.2% yield). 5.5 g of iodoalkenyl Reactive Blue 4 was weighed and placed in a Srank flask. 0.6 g of epoxybutene and 0.1 g of 1M sodium hydroxide solution were added as a catalyst. The mixture was stirred at 50°C for 10 hours. Purification was performed by column chromatography using a mixture of ethyl acetate and petroleum ether in a 1.5:1 ratio as the eluent, yielding 5.64 g of iodoalkenyl Reactive Blue 4 (92.5% yield). The synthesis steps of iodoalkenyl Reactive Blue 4 are described below. Figure 4 The 1H NMR spectrum of iodoalkenyl Reactive Blue 4 is shown below. Figure 5 (The synthesis steps and 1H NMR spectra of the iodo-reactive blue 4 and iodo-alkenyl-reactive blue 4 prepared in Examples 2-12 can be referred to in this example, and will not be listed one by one.)

[0054] S2 Preparation of Polyvinyl Alcohol Modified Macromolecular Solution: Weigh 5g of polyvinyl alcohol powder, add 95g of water for injection, swell at 60℃ for 4 hours, dissolve at 95℃ for 4 hours, and slowly cool to obtain a 5wt% polyvinyl alcohol solution; add 0.1g of N-(2,2-dimethoxyethyl)-2-acrylamide and 5mL of concentrated hydrochloric acid to the polyvinyl alcohol solution and react for 7 hours, then neutralize with 1M potassium hydroxide solution; dialyze the mixed solution to remove the small molecules of potassium chloride generated in the neutralization reaction, and then dry to obtain polyvinyl alcohol modified macromolecules; weigh 5g of polyvinyl alcohol modified macromolecules, add 95g of water for injection, swell at 60℃ for 4 hours, dissolve at 95℃ for 4 hours, and slowly cool to obtain a 5wt% polyvinyl alcohol modified macromolecular solution.

[0055] S3 Preparation of Dispersed Phase: Weigh 25g of polyvinyl alcohol modified macromolecular solution, 0.2g of potassium persulfate, 0.025g of iodoalkenyl reactive blue 4, and 24.775g of water for injection, and stir evenly to obtain the dispersed phase.

[0056] Preparation of continuous phase S4: Weigh 149.7g of liquid paraffin and 0.15g of Span 80, stir evenly and set aside.

[0057] Preparation of blue embolic microspheres (S5): Under stirring, the dispersed phase was transferred to the continuous phase, 0.15 g of tetramethylethylenediamine was added, and the reaction was carried out at 60 °C under nitrogen protection for 1 hour. The microspheres were washed successively with Tween 80 solution and 0.9% sodium chloride injection to obtain blue embolic microspheres of 70-900 μm. After wet sieving, blue embolic microspheres of 300-500 μm (a) were obtained.

[0058] Drug loading detection of blue embolization microspheres a in S6: The doxorubicin drug loading of blue embolization microspheres a prepared in S5 was 35 mg.

[0059] CT imaging of S7 blue embolization microspheres a: Blue embolization microspheres a prepared in S5 are visualized under X-rays.

[0060] Dye leaching detection of S8 blue embolization microspheres a: After accelerated aging, no dye was detected in the preservation solution of the blue embolization microspheres a prepared in S5. Example 2

[0061] Preparation of Iodoalkenyl Reactive Blue 4 (S1): 10g of Reactive Blue 4 was weighed and placed in a Srank flask. 70g of anhydrous tetrahydropyran, 10g of iodine, and 10g of periodic acid were added. The mixture was stirred at room temperature for 5 hours under light-protected conditions. Purification was performed by column chromatography using a mixture of dichloromethane and ethyl acetate in a 1:1.2 ratio as the eluent, yielding 18.9g of iodoalkenyl Reactive Blue 4, with a yield of 94.5%. 14g of iodoalkenyl Reactive Blue 4 was weighed and placed in a Srank flask. 4g of epoxybutene and 2g of 1M potassium hydroxide solution were added as a catalyst. The mixture was stirred at 70°C for 5 hours. Purification was performed by column chromatography using a mixture of dichloromethane and ethyl acetate in a 1:1.2 ratio as the eluent, yielding 16.42g of iodoalkenyl Reactive Blue 4, with a yield of 91.2%.

[0062] S2 Preparation of polyvinyl alcohol modified macromolecular solution: Same as step S2 in Example 1.

[0063] S3 Preparation of Dispersed Phase: Weigh 35g of polyvinyl alcohol modified macromolecular solution, 0.5g of ammonium persulfate, 0.1g of iodoalkenyl reactive blue 4, and 14.4g of water for injection, and stir evenly to obtain the dispersed phase.

[0064] Preparation of continuous phase S4: Weigh 148.5g of liquid paraffin and 0.75g of Span 20, stir evenly and set aside.

[0065] Preparation of blue embolic microspheres (S5): Under stirring, the dispersed phase was transferred to the continuous phase, 0.75 g of tetramethylpropanediamine was added, and the reaction was carried out at 60 °C under nitrogen protection for 1.5 hours. The microspheres were washed successively with Tween 80 solution and 0.9% sodium chloride injection to obtain blue embolic microspheres of 70-900 μm. After wet sieving, blue embolic microspheres of 300-500 μm (b) were obtained.

[0066] Drug loading detection of blue embolization microspheres b in S6: The doxorubicin drug loading of blue embolization microspheres b prepared in S5 was 72 mg.

[0067] CT imaging of blue embolic microspheres b in S7: Blue embolic microspheres b prepared in S5 are visualized under X-rays.

[0068] Dye leaching detection of S8 blue embolization microspheres b: After accelerated aging, no dye was detected in the preservation solution of the blue embolization microspheres b prepared in S5. Example 3

[0069] Preparation of Iodoalkenyl Reactive Blue 4 (S1): 8 g of Reactive Blue 4 was weighed and placed in a Srank flask. 82 g of 1,4-dioxane, 5 g of iodine, and 5 g of periodic acid were added. The mixture was stirred at room temperature for 8 hours under light-protected conditions. Purification was performed by column chromatography using a mixture of dichloromethane and petroleum ether in a 2:1 ratio as the eluent, yielding 12.19 g of iodoalkenyl Reactive Blue 4, with a yield of 93.8%. 10 g of iodoalkenyl Reactive Blue 4 was weighed and placed in a Srank flask. 2.5 g of epoxybutene and 1 g of 1M sodium hydroxide solution were added as a catalyst. The mixture was stirred at 60°C for 8 hours. Purification was performed by column chromatography using a mixture of dichloromethane and petroleum ether in a 2:1 ratio as the eluent, yielding 11.68 g of iodoalkenyl Reactive Blue 4, with a yield of 93.4%.

[0070] S2 Preparation of Polyvinyl Alcohol Modified Macromolecular Solution: Weigh 10g of polyvinyl alcohol powder, add 90g of water for injection, swell at 60℃ for 4 hours, dissolve at 95℃ for 4 hours, and slowly cool to obtain a 10wt% polyvinyl alcohol solution; add 0.25g of N-(2,2-dimethoxyethyl)-2-acrylamide and 10mL of concentrated hydrochloric acid to the polyvinyl alcohol solution and react for 7 hours, then neutralize with 1M sodium hydroxide solution; dialyze the mixed solution to remove the small sodium chloride molecules generated in the neutralization reaction, and then dry to obtain polyvinyl alcohol modified macromolecules; weigh 5g of polyvinyl alcohol modified macromolecules, add 95g of water for injection, swell at 60℃ for 4 hours, dissolve at 95℃ for 4 hours, and slowly cool to obtain a 5wt% polyvinyl alcohol modified macromolecular solution.

[0071] S3 Preparation of Dispersed Phase: Weigh 25g of polyvinyl alcohol modified macromolecular solution, 0.2g of potassium persulfate, 0.025g of iodoalkenyl reactive blue 4, and 24.775g of water for injection, and stir evenly to obtain the dispersed phase.

[0072] Preparation of continuous phase S4: Weigh 299.4g of petroleum ether and 0.3g of Span 20, stir evenly and set aside.

[0073] Preparation of blue embolic microspheres (S5): Under stirring, the dispersed phase was transferred to the continuous phase, 0.3 g of tetramethylethylenediamine was added, and the reaction was carried out at 60 °C under nitrogen protection for 1 hour. The microspheres were washed successively with Tween 80 solution and 0.9% sodium chloride injection to obtain blue embolic microspheres of 70-900 μm. After wet sieving, blue embolic microspheres of 300-500 μm (c) were obtained.

[0074] Drug loading detection of blue embolic microspheres c in S6: The epirubicin loading of blue embolic microspheres c prepared in S5 was 40 mg.

[0075] CT imaging of S7 blue embolization microspheres c: The blue embolization microspheres c prepared in S5 are visualized under X-rays.

[0076] Dye leaching detection of S8 blue embolization microspheres c: After accelerated aging, no dye was detected in the preservation solution of the blue embolization microspheres c prepared in S5. Example 4

[0077] Preparation of Iodoalkenyl Reactive Blue 4 (S1): 9 g of Reactive Blue 4 was weighed and placed in a Srank flask. 83 g of anhydrous tetrahydropyran, 4 g of iodine, and 4 g of periodic acid were added. The mixture was stirred at room temperature for 8 hours under light-protected conditions. Purification was performed by column chromatography using a mixture of ethyl acetate and petroleum ether in a 1.5:1 ratio as the eluent, yielding 12.23 g of iodoalkenyl Reactive Blue 4, with a yield of 94.1%. 12 g of iodoalkenyl Reactive Blue 4 was weighed and placed in a Srank flask. 2.5 g of epoxybutene and 1.7 g of 1M potassium hydroxide solution were added as a catalyst. The mixture was stirred at 60°C for 8 hours. Purification was performed by column chromatography using a mixture of ethyl acetate and petroleum ether in a 1.5:1 ratio as the eluent, yielding 13.56 g of iodoalkenyl Reactive Blue 4, with a yield of 93.5%.

[0078] S2 Preparation of polyvinyl alcohol modified macromolecular solution: Same as step S2 in Example 3.

[0079] S3 Preparation of Dispersed Phase: Weigh 35g of polyvinyl alcohol modified macromolecular solution, 0.5g of ammonium persulfate, 0.1g of iodoalkenyl reactive blue 4, and 14.4g of water for injection, and stir evenly to obtain the dispersed phase.

[0080] Preparation of continuous phase S4: Weigh 297g petroleum ether and 1.5g Span 20, stir evenly and set aside.

[0081] Preparation of blue embolic microspheres (S5): Under stirring, the dispersed phase was transferred to the continuous phase, 1.5 g of tetramethylpropanediamine was added, and the reaction was carried out at 60 °C under nitrogen protection for 1.5 hours. The microspheres were washed successively with Tween 80 solution and 0.9% sodium chloride injection to obtain blue embolic microspheres of 70-900 μm. After wet sieving, blue embolic microspheres of 300-500 μm (d) were obtained.

[0082] Drug loading detection of blue embolic microspheres d in S6: The epirubicin loading of blue embolic microspheres d prepared in S5 was 79 mg.

[0083] CT imaging of S7 blue embolization microspheres d: The blue embolization microspheres d prepared in S5 are visualized under X-ray.

[0084] Dye leaching detection of S8 blue embolization microspheres d: After accelerated aging, no dye was detected in the preservation solution of the blue embolization microspheres d prepared in S5. Example 5

[0085] Preparation of Iodoalkenyl Reactive Blue 4 (S1): 5g of Reactive Blue 4 was weighed and placed in a Srank flask. 87g of anhydrous tetrahydropyran, 4g of iodine, and 4g of periodic acid were added. The mixture was stirred at room temperature for 10 hours under light-protected conditions. Purification was performed by column chromatography using a mixture of dichloromethane and ethyl acetate in a 1:1.2 ratio as the eluent, yielding 8.33g of iodoalkenyl Reactive Blue 4 with a yield of 92.5%. 7.5g of iodoalkenyl Reactive Blue 4 was weighed and placed in a Srank flask. 2.1g of epoxybutene and 1g of 1M sodium hydroxide solution were added as a catalyst. The mixture was stirred at 70°C for 5 hours. Purification was performed by column chromatography using a mixture of dichloromethane and ethyl acetate in a 1:1.2 ratio as the eluent, yielding 8.86g of iodoalkenyl Reactive Blue 4 with a yield of 92.3%.

[0086] S2 Preparation of Polyvinyl Alcohol Modified Macromolecular Solution: Weigh 10g of polyvinyl alcohol powder, add 90g of water for injection, swell at 60℃ for 4 hours, dissolve at 95℃ for 4 hours, and slowly cool to obtain a 10wt% polyvinyl alcohol solution; add 0.25g of N-(2,2-dimethoxyethyl)-2-acrylamide and 10mL of concentrated hydrochloric acid to the polyvinyl alcohol solution and react for 7 hours, then neutralize with 1M sodium hydroxide solution; after dialysis to remove the small sodium chloride molecules generated in the neutralization reaction, dry to obtain polyvinyl alcohol modified macromolecules; weigh 6g of polyvinyl alcohol modified macromolecules, add 94g of water for injection, swell at 60℃ for 4 hours, dissolve at 95℃ for 4 hours, and slowly cool to obtain a 6wt% polyvinyl alcohol modified macromolecular solution.

[0087] S3 Preparation of Dispersed Phase: Weigh 30g of polyvinyl alcohol modified macromolecular solution, 0.4g of potassium persulfate, 0.04g of iodoalkenyl reactive blue 4, and 19.56g of water for injection, and stir evenly to obtain the dispersed phase.

[0088] Preparation of continuous phase S4: Weigh 248.75g cyclohexane and 0.625g Span 40, stir evenly and set aside.

[0089] Preparation of blue embolic microspheres (S5): Under stirring, the dispersed phase was transferred to the continuous phase, and 0.625 g of tetramethylpropanediamine was added. The reaction was carried out at room temperature under nitrogen protection for 3 hours. The microspheres were washed successively with Tween 80 solution and 0.9% sodium chloride injection to obtain blue embolic microspheres of 70-900 μm. After wet sieving, blue embolic microspheres of 300-500 μm (e) were obtained.

[0090] Drug loading detection of S6 blue embolization microspheres e: The epirubicin drug loading of the blue embolization microspheres e prepared in S5 was 76 mg.

[0091] CT imaging of S7 blue embolization microspheres e: The blue embolization microspheres e prepared in S5 are visualized under X-rays.

[0092] Dye leaching detection of S8 blue embolization microspheres e: After accelerated aging, no dye was detected in the preservation solution of the blue embolization microspheres e prepared in S5. Example 6

[0093] S1 Preparation of Iodobenzyl Reactive Blue 4: Same as step S1 in Example 5.

[0094] S2 Preparation of Polyvinyl Alcohol Modified Macromolecular Solution: Weigh 10g of polyvinyl alcohol powder, add 90g of water for injection, swell at 60℃ for 4 hours, dissolve at 95℃ for 4 hours, and slowly cool to obtain a 10wt% polyvinyl alcohol solution; add 0.25g of N-(2,2-dimethoxyethyl)-2-acrylamide and 10mL of concentrated hydrochloric acid to the polyvinyl alcohol solution and react for 7 hours, then neutralize with 1M sodium hydroxide solution; dialyze the mixed solution to remove the small sodium chloride molecules generated in the neutralization reaction, and then dry to obtain polyvinyl alcohol modified macromolecules; weigh 8g of polyvinyl alcohol modified macromolecules, add 92g of water for injection, swell at 60℃ for 4 hours, dissolve at 95℃ for 4 hours, and slowly cool to obtain an 8wt% polyvinyl alcohol modified macromolecular solution.

[0095] S3 Preparation of Dispersed Phase: Weigh 30g of polyvinyl alcohol modified macromolecular solution, 0.4g of potassium persulfate, 0.06g of iodoalkenyl reactive blue 4, and 19.54g of water for injection, and stir evenly to obtain the dispersed phase.

[0096] Preparation of continuous phase S4: Weigh 248.75g cyclohexane and 0.625g Span 40, stir evenly and set aside.

[0097] Preparation of blue embolic microspheres (S5): Under stirring, the dispersed phase was transferred to the continuous phase, and 0.625 g of tetramethylpropanediamine was added. The reaction was carried out at room temperature under nitrogen protection for 3 hours. The microspheres were washed successively with Tween 80 solution and 0.9% sodium chloride injection to obtain blue embolic microspheres of 70-900 μm. After wet sieving, blue embolic microspheres of 300-500 μm were obtained.

[0098] Drug loading detection of S6 blue embolization microspheres f: The epirubicin drug loading of the blue embolization microspheres f prepared in S5 was 82 mg.

[0099] CT imaging of S7 blue embolization microspheres f: The blue embolization microspheres f prepared in S5 are visualized under X-rays.

[0100] Dye leaching detection of S8 blue embolization microspheres f: After accelerated aging, no dye was detected in the preservation solution of the blue embolization microspheres f prepared in S5. Example 7

[0101] S1 Preparation of Iodobenzyl Reactive Blue 4: Same as step S1 in Example 5.

[0102] S2 Preparation of Polyvinyl Alcohol Modified Macromolecular Solution: Weigh 10g of polyvinyl alcohol powder, add 90g of water for injection, swell at 60℃ for 4 hours, dissolve at 95℃ for 4 hours, and slowly cool to obtain a 10wt% polyvinyl alcohol solution; add 0.25g of N-(2,2-dimethoxyethyl)-2-acrylamide and 10mL of concentrated hydrochloric acid to the polyvinyl alcohol solution and react for 7 hours, then neutralize with 1M sodium hydroxide solution; after dialysis to remove the small sodium chloride molecules generated in the neutralization reaction, dry to obtain polyvinyl alcohol modified macromolecules; weigh 9g of polyvinyl alcohol modified macromolecules, add 91g of water for injection, swell at 60℃ for 4 hours, dissolve at 95℃ for 4 hours, and slowly cool to obtain a 9wt% polyvinyl alcohol modified macromolecular solution.

[0103] S3 Preparation of Dispersed Phase: Weigh 30g of polyvinyl alcohol modified macromolecular solution, 0.4g of potassium persulfate, 0.08g of iodoalkenyl reactive blue 4, and 19.52g of water for injection, and stir evenly to obtain the dispersed phase.

[0104] Preparation of continuous phase S4: Weigh 248.75g cyclohexane and 0.625g Span 40, stir evenly and set aside.

[0105] Preparation of blue embolic microspheres (S5): Under stirring, the dispersed phase was transferred to the continuous phase, and 0.625 g of tetramethylpropanediamine was added. The reaction was carried out at room temperature under nitrogen protection for 3 hours. The microspheres were washed successively with Tween 80 solution and 0.9% sodium chloride injection to obtain blue embolic microspheres of 70-900 μm. After wet sieving, 300-500 μm blue embolic microspheres were obtained.

[0106] Drug loading detection of blue embolic microspheres g in S6: The epirubicin drug loading of blue embolic microspheres g prepared in S5 was 87 mg.

[0107] CT imaging of blue embolic microspheres g prepared in S5: Blue embolic microspheres g were visualized under X-rays.

[0108] Dye leaching detection of S8 blue embolization microspheres g: After accelerated aging, no dye was detected in the preservation solution of the blue embolization microspheres g prepared in S5. Example 8

[0109] Preparation of Iodoalkenyl Reactive Blue 4 (S1): 5g of Reactive Blue 4 was weighed and placed in a Srank flask. 89g of 1,4-dioxane, 3g of iodine, and 3g of periodic acid were added. The mixture was stirred at room temperature for 8 hours under light-protected conditions. Purification was performed by column chromatography using a 2:1 mixture of dichloromethane and petroleum ether as the eluent, yielding 7.47g of iodoalkenyl Reactive Blue 4, with a yield of 93.4%. 6.5g of iodoalkenyl Reactive Blue 4 was weighed and placed in a Srank flask. 1.2g of epoxybutene and 0.8g of 1M sodium hydroxide solution were added as a catalyst. The mixture was stirred at 70°C for 5 hours. Purification was performed by column chromatography using a 2:1 mixture of dichloromethane and petroleum ether as the eluent, yielding 7.21g of iodoalkenyl Reactive Blue 4, with a yield of 93.7%.

[0110] S2 Preparation of Polyvinyl Alcohol Modified Macromolecular Solution: Weigh 13g of polyvinyl alcohol powder, add 87g of water for injection, swell at 60℃ for 4 hours, dissolve at 95℃ for 4 hours, and slowly cool to obtain a 13wt% polyvinyl alcohol solution; add 0.35g of N-(2,2-dimethoxyethyl)-2-acrylamide and 12mL of concentrated hydrochloric acid to the polyvinyl alcohol solution and react for 7 hours, then neutralize with 1M sodium hydroxide solution; dialyze the mixed solution to remove the small sodium chloride molecules generated in the neutralization reaction, and then dry to obtain polyvinyl alcohol modified macromolecules; weigh 8g of polyvinyl alcohol modified macromolecules, add 92g of water for injection, swell at 60℃ for 4 hours, dissolve at 95℃ for 4 hours, and slowly cool to obtain an 8wt% polyvinyl alcohol modified macromolecular solution.

[0111] S3 Preparation of Dispersed Phase: Weigh 32g of polyvinyl alcohol modified macromolecular solution, 0.6g of ammonium persulfate, 0.06g of iodoalkenyl reactive blue 4, and 17.34g of water for injection, and stir evenly to obtain the dispersed phase.

[0112] Preparation of continuous phase S4: Weigh 198.4g of dichloromethane and 0.8g of Span 80, stir evenly and set aside.

[0113] Preparation of blue embolic microspheres (S5): Under stirring, the dispersed phase was transferred to the continuous phase, 0.8 g of tetramethylethylenediamine was added, and the reaction was carried out at 50 °C under nitrogen protection for 2 hours. The microspheres were washed successively with Tween 80 solution and 0.9% sodium chloride injection to obtain blue embolic microspheres of 70-900 μm. After wet sieving, blue embolic microspheres of 300-500 μm (h) were obtained.

[0114] Drug loading detection of blue embolic microspheres h in S6: The epirubicin loading of blue embolic microspheres h prepared in S5 was 89 mg.

[0115] CT imaging of blue embolic microspheres h prepared in S5: Blue embolic microspheres h were visualized under X-rays.

[0116] Dye leaching detection of S8 blue embolization microspheres h: After accelerated aging, no dye was detected in the preservation solution of the blue embolization microspheres h prepared in S5. Example 9

[0117] S1 Preparation of Iodobenzyl Reactive Blue 4: Same as step S1 in Example 8.

[0118] S2 Preparation of Polyvinyl Alcohol Modified Macromolecular Solution: Weigh 13g of polyvinyl alcohol powder, add 87g of water for injection, swell at 60℃ for 4 hours, dissolve at 95℃ for 4 hours, and slowly cool to obtain a 13wt% polyvinyl alcohol solution; add 0.35g of N-(2,2-dimethoxyethyl)-2-acrylamide and 12mL of concentrated hydrochloric acid to the polyvinyl alcohol solution and react for 7 hours, then neutralize with 1M sodium hydroxide solution; after dialysis to remove the small sodium chloride molecules generated in the neutralization reaction, dry to obtain polyvinyl alcohol modified macromolecules; weigh 10g of polyvinyl alcohol modified macromolecules, add 90g of water for injection, swell at 60℃ for 4 hours, dissolve at 95℃ for 4 hours, and slowly cool to obtain a 10wt% polyvinyl alcohol modified macromolecular solution.

[0119] S3 Preparation of Dispersed Phase: Weigh 32g of polyvinyl alcohol modified macromolecular solution, 0.6g of ammonium persulfate, 0.08g of iodoalkenyl reactive blue 4, and 17.32g of water for injection, and stir evenly to obtain the dispersed phase.

[0120] Preparation of continuous phase S4: Weigh 198.4g of dichloromethane and 0.8g of Span 80, stir evenly and set aside.

[0121] Preparation of blue embolic microspheres (S5): Under stirring, the dispersed phase was transferred to the continuous phase, 0.8 g of tetramethylethylenediamine was added, and the reaction was carried out at 50 °C under nitrogen protection for 2 hours. The microspheres were washed successively with Tween 80 solution and 0.9% sodium chloride injection to obtain blue embolic microspheres of 70-900 μm. After wet sieving, blue embolic microspheres of 300-500 μm were obtained.

[0122] Drug loading detection of S6 blue embolization microspheres i: The epirubicin drug loading of the blue embolization microspheres i prepared in S5 was 93 mg.

[0123] CT imaging of S7 blue embolization microspheres i: The blue embolization microspheres i prepared in S5 are visualized under X-ray.

[0124] Dye leaching detection of S8 blue embolization microspheres i: After accelerated aging, no dye was detected in the preservation solution of the blue embolization microspheres i prepared in S5. Example 10

[0125] S1 Preparation of Iodobenzyl Reactive Blue 4: Same as step S1 in Example 8.

[0126] Preparation of polyvinyl alcohol modified macromolecular solution S2: Weigh 13g of polyvinyl alcohol powder, add 87g of water for injection, swell at 60℃ for 4 hours, dissolve at 95℃ for 4 hours, and slowly cool to obtain a 13wt% polyvinyl alcohol solution; add 0.35g of N-(2,2-dimethoxyethyl)-2-acrylamide and 12mL of concentrated hydrochloric acid to the polyvinyl alcohol solution and react for 7 hours, then neutralize with 1M sodium hydroxide solution; after dialysis to remove the small sodium chloride molecules generated in the neutralization reaction, dry to obtain polyvinyl alcohol modified macromolecules; weigh 12g of polyvinyl alcohol modified macromolecules, add 88g of water for injection, swell at 60℃ for 4 hours, dissolve at 95℃ for 4 hours, and slowly cool to obtain a 12wt% polyvinyl alcohol modified macromolecular solution.

[0127] S3 Preparation of Dispersed Phase: Weigh 32g of polyvinyl alcohol modified macromolecular solution, 0.6g of ammonium persulfate, 0.1g of iodoalkenyl reactive blue 4, and 17.30g of water for injection, and stir evenly to obtain the dispersed phase;

[0128] Preparation of continuous phase S4: Weigh 198.4g of dichloromethane and 0.8g of Span 80, stir evenly and set aside.

[0129] Preparation of blue embolic microspheres (S5): Under stirring, the dispersed phase was transferred to the continuous phase, 0.8 g of tetramethylethylenediamine was added, and the reaction was carried out at 50 °C under nitrogen protection for 2 hours. The microspheres were washed successively with Tween 80 solution and 0.9% sodium chloride injection to obtain blue embolic microspheres of 70-900 μm. After wet sieving, blue embolic microspheres of 300-500 μm were obtained.

[0130] Drug loading detection of blue embolic microspheres j in S6: The epirubicin loading of blue embolic microspheres j prepared in S5 was 99 mg.

[0131] CT imaging of blue embolic microspheres j prepared in S5: Blue embolic microspheres j were visualized under X-rays.

[0132] Dye leaching detection of S8 blue embolization microspheres j: After accelerated aging, no dye was detected in the preservation solution of the blue embolization microspheres j prepared in S5. Example 11

[0133] S1 Preparation of Iodobenzyl Reactive Blue 4: Same as step S1 in Example 1.

[0134] Preparation of polyvinyl alcohol modified macromolecular solution S2: Weigh 15g of polyvinyl alcohol powder, add 85g of water for injection, swell at 60℃ for 4 hours, dissolve at 95℃ for 4 hours, and slowly cool to obtain a 15wt% polyvinyl alcohol solution; add 0.5g of N-(2,2-dimethoxyethyl)-2-acrylamide and 15mL of concentrated hydrochloric acid to the polyvinyl alcohol solution and react for 7 hours, then neutralize with 1M potassium hydroxide solution; after dialysis to remove the small molecules of potassium chloride generated in the neutralization reaction, dry to obtain polyvinyl alcohol modified macromolecules; weigh 15g of polyvinyl alcohol modified macromolecules, add 85g of water for injection, swell at 60℃ for 4 hours, dissolve at 95℃ for 4 hours, and slowly cool to obtain a 15wt% polyvinyl alcohol modified macromolecular solution.

[0135] S3 Preparation of Dispersed Phase: Weigh 25g of polyvinyl alcohol modified macromolecular solution, 0.2g of ammonium persulfate, 0.025g of iodoalkenyl reactive blue 4, and 24.775g of water for injection, and stir evenly to obtain the dispersed phase.

[0136] S4 Preparation of Continuous Phase: Weigh 149.7g of liquid paraffin and 0.15g of Span 20, stir evenly and set aside.

[0137] Preparation of blue embolic microspheres (S5): Under stirring, the dispersed phase was transferred to the continuous phase, 0.15 g of tetramethylethylenediamine was added, and the reaction was carried out at 60 °C under nitrogen protection for 1 hour. The microspheres were washed successively with Tween 80 solution and 0.9% sodium chloride injection to obtain blue embolic microspheres of 70-900 μm. After wet sieving, blue embolic microspheres of 300-500 μm (k) were obtained.

[0138] Drug loading detection of blue embolization microspheres k in S6: The pirarubicin drug loading of blue embolization microspheres k prepared in S5 was 40 mg.

[0139] CT imaging of S7 blue embolization microspheres k: Blue embolization microspheres k prepared in S5 are visualized under X-rays.

[0140] Dye leaching detection of S8 blue embolization microspheres k: After accelerated aging, no dye was detected in the preservation solution of the blue embolization microspheres k prepared in S5. Example 12

[0141] S1 Preparation of Iodobenzyl Reactive Blue 4: Same as step S1 in Example 1.

[0142] S2 Preparation of polyvinyl alcohol modified macromolecular solution: Same as step S2 in Example 11.

[0143] S3 Preparation of Dispersed Phase: Weigh 35g of polyvinyl alcohol modified macromolecular solution, 0.5g of ammonium persulfate, 0.1g of iodoalkenyl reactive blue 4, and 14.4g of water for injection, and stir evenly to obtain the dispersed phase.

[0144] Preparation of continuous phase S4: Weigh 148.5g of liquid paraffin and 0.75g of Span 20, stir evenly and set aside.

[0145] Preparation of blue embolic microspheres (S5): Under stirring, the dispersed phase was transferred to the continuous phase, 0.75 g of tetramethylethylenediamine was added, and the reaction was carried out at 60 °C under nitrogen protection for 1.5 hours. The microspheres were washed successively with Tween 80 solution and 0.9% sodium chloride injection to obtain blue embolic microspheres of 70-900 μm. After wet sieving, blue embolic microspheres of 300-500 μm were obtained.

[0146] Drug loading detection of blue embolization microspheres l in S6: The pirarubicin drug loading of blue embolization microspheres l prepared in S5 was 76 mg.

[0147] CT imaging of blue embolic microspheres l prepared in S5: Blue embolic microspheres l prepared in S5 are visualized under X-ray.

[0148] Dye leaching detection of S8 blue embolization microspheres l: After accelerated aging, no dye was detected in the preservation solution of the blue embolization microspheres l prepared in S5. Example 13

[0149] Preparation of Iodoalkenyl Reactive Brilliant Blue K-GR (S1): 4 g of Brilliant Blue K-GR was weighed and placed in a Srank flask. 92 g of tetrahydrofuran, 2 g of iodine, and 2 g of periodic acid were added. The mixture was stirred at room temperature for 10 hours under light-protected conditions. Purification was performed by column chromatography using a mixture of ethyl acetate and petroleum ether in a 1.5:1 ratio as the eluent, yielding 5.58 g of iodoalkenyl Reactive Brilliant Blue K-GR (93.0% yield). 5.5 g of iodoalkenyl Reactive Brilliant Blue K-GR was weighed and placed in a Srank flask. 0.6 g of glycidene and 0.1 g of 1M sodium hydroxide solution were added as catalysts. The mixture was stirred at 50°C for 10 hours. Purification was performed by column chromatography using a mixture of ethyl acetate and petroleum ether in a 1.5:1 ratio as the eluent, yielding 5.63 g of iodoalkenyl Reactive Brilliant Blue K-GR (92.3% yield). The synthesis steps of iodoalkenyl Reactive Brilliant Blue K-GR are described below. Figure 6 The 1H NMR spectrum of iodoalkenyl reactive brilliant blue K-GR is shown in [reference needed]. Figure 7 .

[0150] Preparation of polyvinyl alcohol modified macromolecular solution S2: Weigh 5g of polyvinyl alcohol powder, add 95g of water for injection, swell at 60℃ for 4 hours, dissolve at 95℃ for 4 hours, and slowly cool to obtain a 5wt% polyvinyl alcohol solution; add 0.1g of N-(2,2-dimethoxyethyl)-2-acrylamide and 5mL of concentrated hydrochloric acid to the polyvinyl alcohol solution and react for 7 hours, then neutralize with 1M sodium hydroxide solution; after dialysis to remove the small sodium chloride molecules generated in the neutralization reaction, dry to obtain polyvinyl alcohol modified macromolecules; weigh 5g of polyvinyl alcohol modified macromolecules, add 95g of water for injection, swell at 60℃ for 4 hours, dissolve at 95℃ for 4 hours, and slowly cool to obtain a 5wt% polyvinyl alcohol modified macromolecular solution.

[0151] S3 Preparation of Dispersed Phase: Weigh 25g of polyvinyl alcohol modified macromolecular solution, 0.2g of potassium persulfate, 0.025g of iodoalkenyl reactive brilliant blue K-GR, and 24.775g of water for injection, and stir evenly to obtain the dispersed phase.

[0152] Preparation of continuous phase S4: Weigh 149.7g of liquid paraffin and 0.15g of Span 80, stir evenly and set aside.

[0153] Preparation of bright blue embolic microspheres by S5: Under stirring, the dispersed phase was transferred to the continuous phase, 0.15 g of tetramethylethylenediamine was added, and the reaction was carried out at 60 °C under nitrogen protection for 1 hour. The microspheres were washed successively with Tween 80 solution and 0.9% sodium chloride injection to obtain bright blue embolic microspheres of 70-900 μm. After wet sieving, bright blue embolic microspheres of 300-500 μm were obtained.

[0154] Drug loading detection of S6 bright blue embolic microspheres m: The epirubicin loading of the bright blue embolic microspheres m prepared in S5 was 36 mg.

[0155] CT imaging of S7 bright blue embolic microspheres m: The bright blue embolic microspheres m prepared in S5 were visualized under X-rays.

[0156] Dye leaching detection of S8 bright blue embolic microspheres m: After accelerated aging, no dye was detected in the preservation solution of the bright blue embolic microspheres m prepared in S5. Example 14

[0157] S1 Preparation of iodoalkenyl reactive brilliant blue K-GR: Same as step S1 in Example 13.

[0158] S2 Preparation of polyvinyl alcohol modified macromolecular solution: Same as step S2 in Example 13.

[0159] S3 Preparation of Dispersed Phase: Weigh 35g of polyvinyl alcohol modified macromolecular solution, 0.5g of potassium persulfate, 0.1g of iodoalkenyl reactive brilliant blue K-GR, and 14.4g of water for injection, and stir evenly to obtain the dispersed phase.

[0160] Preparation of continuous phase S4: Weigh 149.7g of liquid paraffin and 0.15g of Span 80, stir evenly and set aside.

[0161] Preparation of bright blue embolic microspheres by S5: Under stirring, the dispersed phase was transferred to the continuous phase, 0.15 g of tetramethylethylenediamine was added, and the reaction was carried out at 60 °C under nitrogen protection for 1 hour. The microspheres were washed successively with Tween 80 solution and 0.9% sodium chloride injection to obtain bright blue embolic microspheres of 70-900 μm. After wet sieving, bright blue embolic microspheres of 300-500 μm were obtained.

[0162] Drug loading detection of S6 bright blue embolic microspheres n: The epirubicin loading of the bright blue embolic microspheres n prepared in S5 was 75 mg.

[0163] CT imaging of S7 bright blue embolic microspheres n: The bright blue embolic microspheres n prepared in S5 are visualized under X-ray.

[0164] Dye leaching detection of S8 bright blue embolic microspheres n: After accelerated aging, no dye was detected in the preservation solution of the bright blue embolic microspheres n prepared in S5. Example 15

[0165] Preparation of Iodoalkenyl Reactive Green 8 (S1): 4 g of Reactive Green 8 was weighed and placed in a Srank flask. 92 g of tetrahydrofuran, 2 g of iodine, and 2 g of periodic acid were added. The mixture was stirred at room temperature for 10 hours under light-protected conditions. Purification was performed by column chromatography using a mixture of ethyl acetate and petroleum ether in a 1.5:1 ratio as the eluent, yielding 5.56 g of iodoalkenyl Reactive Green 8 (92.7% yield). 5.5 g of iodoalkenyl Reactive Green 8 was weighed and placed in a Srank flask. 0.6 g of epoxybutene and 0.1 g of 1M potassium hydroxide solution were added as a catalyst. The mixture was stirred at 50°C for 10 hours. Purification was performed by column chromatography using a mixture of ethyl acetate and petroleum ether in a 1.5:1 ratio as the eluent, yielding 5.59 g of iodoalkenyl Reactive Green 8. The synthesis steps of iodoalkenyl Reactive Green 8 are described below. Figure 8 The 1H NMR spectrum of iodoalkenyl reactive green 8 is shown below. Figure 9 .

[0166] Preparation of polyvinyl alcohol modified macromolecular solution S2: Weigh 5g of polyvinyl alcohol powder, add 95g of water for injection, swell at 60℃ for 4 hours, dissolve at 95℃ for 4 hours, and slowly cool to obtain a 5wt% polyvinyl alcohol solution; add 0.1g of N-(2,2-dimethoxyethyl)-2-acrylamide and 5mL of concentrated hydrochloric acid to the polyvinyl alcohol solution and react for 7 hours, then neutralize with 1M sodium hydroxide solution; after dialysis to remove the small sodium chloride molecules generated in the neutralization reaction, dry to obtain polyvinyl alcohol modified macromolecules; weigh 5g of polyvinyl alcohol modified macromolecules, add 95g of water for injection, swell at 60℃ for 4 hours, dissolve at 95℃ for 4 hours, and slowly cool to obtain a 5wt% polyvinyl alcohol modified macromolecular solution.

[0167] S3 Preparation of Dispersed Phase: Weigh 25g of polyvinyl alcohol modified macromolecular solvent, 0.2g of potassium persulfate, 0.025g of iodoalkenyl active green 8, and 24.775g of water for injection, and stir evenly to obtain the dispersed phase.

[0168] Preparation of continuous phase S4: Weigh 149.7g of liquid paraffin and 0.15g of Span 80, stir evenly and set aside.

[0169] Preparation of green embolization microspheres (S5): Under stirring, the dispersed phase was transferred to the continuous phase, 0.15 g of tetramethylethylenediamine was added, and the reaction was carried out at 60 °C under nitrogen protection for 1 hour. The microspheres were washed successively with Tween 80 solution and 0.9% sodium chloride injection to obtain green embolization microspheres of 70-900 μm. After wet sieving, green embolization microspheres of 300-500 μm were obtained.

[0170] Drug loading detection of S6 green embolization microspheres: The epirubicin loading of the green embolization microspheres prepared in S5 was 34 mg.

[0171] CT imaging of S7 green embolization microspheres: The green embolization microspheres prepared in S5 were visualized under X-rays.

[0172] Dye leaching detection of S8 green embolization microspheres: After accelerated aging, no dye was detected in the preservation solution of the green embolization microspheres prepared in S5. Example 16

[0173] S1 Preparation of iodoalkenyl active green 8: Same as step S1 in Example 15.

[0174] S2 Preparation of polyvinyl alcohol modified macromolecular solution: Same as step S2 in Example 15.

[0175] S3 Preparation of Dispersed Phase: Weigh 35g of polyvinyl alcohol modified macromolecular solution, 0.5g of potassium persulfate, 0.1g of iodoalkenyl reactive green 8, and 14.4g of water for injection, and stir evenly to obtain the dispersed phase.

[0176] Preparation of continuous phase S4: Weigh 149.7g of liquid paraffin and 0.15g of Span 80, stir evenly and set aside.

[0177] Preparation of green embolization microspheres (S5): Under stirring, the dispersed phase was transferred to the continuous phase, 0.15 g of tetramethylethylenediamine was added, and the reaction was carried out at 60 °C under nitrogen protection for 1 hour. The microspheres were washed successively with Tween 80 solution and 0.9% sodium chloride injection to obtain green embolization microspheres of 70-900 μm. After wet sieving, green embolization microspheres of 300-500 μm (p) were obtained.

[0178] Drug loading detection of S6 green embolization microspheres p: The epirubicin loading of the green embolization microspheres p prepared in S5 was 73 mg.

[0179] CT imaging of S7 green embolization microspheres p: The green embolization microspheres p prepared in S5 are visualized under X-rays.

[0180] Dye leaching detection of S8 green embolization microspheres p: After accelerated aging, no dye was detected in the preservation solution of the green embolization microspheres p prepared in S5. Example 17

[0181] Preparation of Iodoalkenyl Reactive Black 5 (S1): 4g of Reactive Black 5 was weighed and placed in a Srank flask. 92g of tetrahydrofuran, 2g of iodine, and 2g of periodic acid were added. The mixture was stirred at room temperature for 10 hours under light-protected conditions. Purification was performed by column chromatography using a mixture of ethyl acetate and petroleum ether in a 1.5:1 ratio as the eluent, yielding 5.57g of iodoalkenyl Reactive Black 5 with a yield of 92.9%. 5.5g of iodoalkenyl Reactive Black 5 was weighed and placed in a Srank flask. 0.6g of epoxybutene and 0.1g of 1M potassium hydroxide solution were added as a catalyst. The mixture was stirred at 50°C for 10 hours. Purification was performed by column chromatography using a mixture of ethyl acetate and petroleum ether in a 1.5:1 ratio as the eluent, yielding 5.61g of iodoalkenyl Reactive Black 5 with a yield of 91.9%. The synthesis steps of iodoalkenyl Reactive Black 5 are described below. Figure 10 The 1H NMR spectrum of iodoalkenyl active black 5 is shown below. Figure 11 .

[0182] Preparation of polyvinyl alcohol modified macromolecular solution S2: Weigh 5g of polyvinyl alcohol powder, add 95g of water for injection, swell at 60℃ for 4 hours, dissolve at 95℃ for 4 hours, and slowly cool to obtain a 5wt% polyvinyl alcohol solution; add 0.1g of N-(2,2-dimethoxyethyl)-2-acrylamide and 5mL of concentrated hydrochloric acid to the polyvinyl alcohol solution and react for 7 hours, then neutralize with 1M sodium hydroxide solution; after dialysis to remove the small sodium chloride molecules generated in the neutralization reaction, dry to obtain polyvinyl alcohol modified macromolecules; weigh 5g of polyvinyl alcohol modified macromolecules, add 95g of water for injection, swell at 60℃ for 4 hours, dissolve at 95℃ for 4 hours, and slowly cool to obtain a 5wt% polyvinyl alcohol modified macromolecular solution.

[0183] S3 Preparation of Dispersed Phase: Weigh 25g of polyvinyl alcohol modified macromolecular solution, 0.2g of potassium persulfate, 0.025g of iodoalkenyl reactive black 5, and 24.775g of water for injection, and stir evenly to obtain the dispersed phase.

[0184] Preparation of continuous phase S4: Weigh 149.7g of liquid paraffin and 0.15g of Span 80, stir evenly and set aside.

[0185] Preparation of black embolic microspheres by S5: Under stirring, the dispersed phase was transferred to the continuous phase, 0.15 g of tetramethylethylenediamine was added, and the reaction was carried out at 60 °C under nitrogen protection for 1 hour. The microspheres were washed successively with Tween 80 solution and 0.9% sodium chloride injection to obtain black embolic microspheres of 70-900 μm. After wet sieving, black embolic microspheres of 300-500 μm were obtained.

[0186] Drug loading detection of S6 black embolization microspheres q: The epirubicin drug loading of the black embolization microspheres q prepared in S5 was 37 mg.

[0187] CT imaging of black embolic microspheres q prepared in S5: Black embolic microspheres q were visualized under X-rays.

[0188] Dye leaching detection of S8 black embolization microspheres q: After accelerated aging, no dye was detected in the preservation solution of the black embolization microspheres q prepared in S5. Example 18

[0189] Preparation of S1 iodoalkenyl reactive black 5: Same as step S1 in Example 17.

[0190] Preparation of S2 polyvinyl alcohol modified macromolecular solution: Same as step S2 in Example 17.

[0191] S3 Preparation of Dispersed Phase: Weigh 35g of polyvinyl alcohol modified macromolecular solution, 0.5g of potassium persulfate, 0.1g of iodoalkenyl reactive black 5, and 14.4g of water for injection, and stir evenly to obtain the dispersed phase.

[0192] Preparation of continuous phase S4: Weigh 149.7g of liquid paraffin and 0.15g of Span 80, stir evenly and set aside.

[0193] Preparation of black embolic microspheres by S5: Under stirring, the dispersed phase was transferred to the continuous phase, 0.15 g of tetramethylethylenediamine was added, and the reaction was carried out at 60 °C under nitrogen protection for 1 hour. The microspheres were washed successively with Tween 80 solution and 0.9% sodium chloride injection to obtain black embolic microspheres of 70-900 μm. After wet sieving, black embolic microspheres of 300-500 μm were obtained.

[0194] Drug loading detection of S6 black embolization microspheres r: The epirubicin drug loading of the black embolization microspheres r prepared in S5 was 77 mg.

[0195] CT imaging of black embolic microspheres r prepared in S5: black embolic microspheres r were visualized under X-rays.

[0196] Dye leaching detection of S8 black embolization microspheres r: After accelerated aging, no dye was detected in the preservation solution of the black embolization microspheres r prepared in S5. Comparative Example 1

[0197] Preparation of polyvinyl alcohol modified macromolecular solution S1: Weigh 5g of polyvinyl alcohol powder, add 95g of water for injection, swell at 60℃ for 4 hours, dissolve at 95℃ for 4 hours, and slowly cool to obtain a 5wt% polyvinyl alcohol solution; add 0.1g of N-(2,2-dimethoxyethyl)-2-acrylamide and 5mL of concentrated hydrochloric acid to the polyvinyl alcohol solution and react for 7 hours, then neutralize with 1M sodium hydroxide solution; after dialysis to remove the small sodium chloride molecules generated in the neutralization reaction, dry to obtain polyvinyl alcohol modified macromolecules; weigh 5g of polyvinyl alcohol modified macromolecules, add 95g of water for injection, swell at 60℃ for 4 hours, dissolve at 95℃ for 4 hours, and slowly cool to obtain a 5wt% polyvinyl alcohol modified macromolecular solution.

[0198] S2 Preparation of Dispersed Phase: Weigh 25g of polyvinyl alcohol modified macromolecular solution, 0.2g of potassium persulfate, and 24.8g of water for injection, and stir evenly to obtain the dispersed phase.

[0199] S3 Preparation of Continuous Phase: Weigh 149.7g of liquid paraffin and 0.15g of Span 80, stir evenly and set aside.

[0200] S4 Preparation of colorless embolic microspheres: Under stirring, the dispersed phase was transferred to the continuous phase, 0.15 g of tetramethylethylenediamine was added, and the reaction was carried out at 60 °C under nitrogen protection for 1 hour. The microspheres were washed successively with Tween 80 solution and 0.9% sodium chloride injection to obtain colorless embolic microspheres of 70-900 μm. After wet sieving, colorless embolic microspheres of 300-500 μm were obtained.

[0201] Drug loading detection of colorless embolic microspheres y in S5: The epirubicin loading of colorless embolic microspheres y prepared in S4 was 3 mg.

[0202] CT imaging of colorless embolic microspheres y prepared in S4: The colorless embolic microspheres y prepared in S4 are not visible under X-rays.

[0203] Dye leaching detection of S7 colorless embolization microspheres y: After accelerated aging, no dye was detected in the preservation solution of the colorless embolization microspheres y prepared in S4. Comparative Example 2

[0204] Preparation of polyvinyl alcohol modified macromolecular solution S1: Weigh 15g of polyvinyl alcohol powder, add 85g of water for injection, swell at 60℃ for 4 hours, dissolve at 95℃ for 4 hours, and slowly cool to obtain a 15wt% polyvinyl alcohol solution; add 0.5g of N-(2,2-dimethoxyethyl)-2-acrylamide and 15mL of concentrated hydrochloric acid to the polyvinyl alcohol solution and react for 7 hours, then neutralize with 1M sodium hydroxide solution; dialyze the mixed solution to remove the small sodium chloride molecules generated in the neutralization reaction, and then dry to obtain polyvinyl alcohol modified macromolecules; weigh 15g of polyvinyl alcohol modified macromolecules, add 85g of water for injection, swell at 60℃ for 4 hours, dissolve at 95℃ for 4 hours, and slowly cool to obtain a 15wt% polyvinyl alcohol modified macromolecular solution.

[0205] S2 Preparation of Dispersed Phase: Weigh 35g of polyvinyl alcohol modified macromolecular solution, 0.5g of ammonium persulfate, and 14.5g of water for injection, and stir evenly to obtain the dispersed phase.

[0206] Preparation of continuous phase S3: Weigh 148.5g of liquid paraffin and 0.75g of Span 20, stir evenly and set aside.

[0207] Preparation of colorless embolic microspheres (S4): Under stirring, the dispersed phase was transferred to the continuous phase, 0.75 g of tetramethylethylenediamine was added, and the reaction was carried out at 60 °C under nitrogen protection for 1.5 hours. The microspheres were washed successively with Tween 80 solution and 0.9% sodium chloride injection to obtain colorless embolic microspheres of 70-900 μm. After wet sieving, colorless embolic microspheres of 300-500 μm (z) were obtained.

[0208] Drug loading detection of colorless embolization microspheres z in S5: The epirubicin loading of colorless embolization microspheres z prepared in S4 was 5 mg.

[0209] CT imaging of colorless embolization microspheres z prepared in S4: The colorless embolization microspheres z prepared in S4 are not visible under X-rays.

[0210] Dye leaching detection of S7 colorless embolization microspheres z: After accelerated aging, no dye was detected in the preservation solution of the colorless embolization microspheres z prepared in S4.

[0211] Table 1

[0212]

[0213] Table 1 shows the test results for iodinated reactive dye yield, iodoalkenyl reactive dye yield, microsphere color, drug loading of 300-500 μm microspheres, CT imaging, and dye dissolution in Examples 1-18 and Comparative Examples 19-20; as can be seen from Table 1:

[0214] The embolic microspheres prepared in Comparative Examples 1-2 were colorless and transparent, making them difficult for doctors to observe and impossible to visualize under X-rays, resulting in a low drug loading.

[0215] Examples 1-18 describe the preparation of colored embolic microspheres, synthesized via a one-step reverse-phase suspension polymerization of a dispersed phase and a continuous phase. This method results in more uniform microsphere coloring, a simpler and easier reaction process. The yields of iodoform reactive dyes and iodoform-alkenyl reactive dyes are between 92% and 95%, respectively. The color of the iodoform-alkenyl reactive dyes is introduced into the microspheres through the polymerization reaction, giving the embolic microspheres a rich array of colors including blue, bright blue, green, and black, which aids in observation by doctors. The color of the iodoform-alkenyl reactive dyes is further enhanced by the polymerization process. Iodine gives the color embolization microspheres imaging capabilities, reducing the use of contrast agents during surgery and minimizing vascular irritation. The abundant sulfonic acid ion groups in the iodoalkenyl reactive dyes facilitate ion exchange with doxorubicin-type drugs, enabling the microspheres to load drugs. The drug loading capacity of the microspheres for doxorubicin-type drugs is 34-99 mg, meeting the needs of different patients for doxorubicin-type antitumor drugs. The staining is firm and does not easily fade. The color embolization microspheres provided by this invention use abundant and inexpensive raw materials, showing promising application prospects in the medical field.

[0216] Finally, it should be noted that in this document, relational terms such as "first" and "second" are used only to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Without further limitations, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element.

[0217] The various embodiments in this specification are described in a progressive manner, with each embodiment focusing on the differences from other embodiments. The same or similar parts between the various embodiments can be referred to each other.

[0218] The above description of the disclosed embodiments enables those skilled in the art to make or use the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the invention. Therefore, the invention is not to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

[0219] The above are preferred embodiments of the present application. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the embodiments of the present application, and these improvements and modifications are also considered to be within the scope of protection of the present application.

Claims

1. Color embolizing microspheres, characterized in that, Synthesized by inverse suspension polymerization one-step method with dispersed phase and continuous phase, having X-ray developing function and drug loading function, doxorubicin drug loading capacity is 34-99mg; the mass ratio of the dispersed phase and the continuous phase is 3:1-6:1; the dispersed phase is prepared from iodine alkylene active dye, polyvinyl alcohol modified macromolecule solution, initiator and water for injection as main raw materials, the continuous phase is prepared from oil phase, dispersant and catalyst as main raw materials; The dispersed phase contains the following components by mass percentage: iodine alkylene active dye 0.05-0.2wt%, polyvinyl alcohol modified macromolecule solution 50-70wt%, initiator 0.4-1wt%, water for injection 28.8-49.55wt%; wherein the mass concentration of the polyvinyl alcohol modified macromolecule solution is 5-15wt%; The continuous phase contains the following components by mass percentage: oil phase 99-99.8wt%, dispersant 0.1-0.5wt%, catalyst 0.1-0.5wt%; The iodine alkylene active dye in the dispersed phase is first obtained by substitution reaction of active dye with iodine, periodic acid in a reaction medium to obtain iodine active dye, and then the iodine active dye is subjected to ring-opening addition reaction with epoxy butene in alkaline solution to obtain iodine alkylene active dye, which contains iodine element, sulfonic ion group and unsaturated bond obtained by ring-opening addition reaction; The polyvinyl alcohol modified macromolecule solution is prepared from polyvinyl alcohol solution and N-(2,2-dimethoxyethyl)-2-propenamide as main raw materials, ester exchange reaction under the action of concentrated hydrochloric acid, and then neutralization, dialysis, drying and dissolution.

2. The colored embolizing microspheres according to claim 1, characterized in that, The substitution reaction contains the following components by mass percentage: active dye 4-10wt%, iodine 2-10wt%, periodic acid 2-10wt%, reaction medium 70-92wt%; the substitution reaction conditions are light shielding, room temperature stirring reaction for 5-10 hours.

3. The colored embolizing microspheres according to claim 1, characterized in that, The active dye is any one of reactive blue 4, reactive brilliant blue K-GR, reactive green 8, reactive black 5; the reaction medium is any one of tetrahydrofuran, tetrahydropyran, 1,4-dioxane.

4. The colored embolizing microspheres according to claim 1, characterized in that, The ring-opening addition reaction contains the following components by mass percentage: iodine active dye 70-89wt%, epoxy butene 10-20wt%, alkaline solution 1-10wt%; the ring-opening addition reaction conditions are 50-70℃, stirring reaction for 5-10 hours.

5. The colored embolizing microspheres according to claim 1, characterized in that, The initiator is any one of potassium persulfate or ammonium persulfate; the oil phase is any one of liquid paraffin, petroleum ether, cyclohexane, dichloromethane, the dispersant is any one of Span 20, Span 40, Span 80, and the catalyst is any one of tetramethyl ethylenediamine, tetramethyl propylenediamine, tetramethyl butylenediamine.

6. A process for the preparation of the color embolization microspheres of any one of claims 1-5, characterized by, The method comprises the following steps: S1 preparation of iodine alkylene active dye: weigh the active dye powder, add iodine, periodic acid, reaction medium, and carry out substitution reaction in the light shielding condition, purify by column chromatography to obtain iodine active dye; The iodine active dye is weighed, and ring-opening addition reaction is carried out by adding epoxy butene and a basic solution, and the iodine active dye is purified by column chromatography to obtain the iodine active dye; S2: Preparation of polyvinyl alcohol modified macromolecule solution: using polyvinyl alcohol solution and N-(2,2-dimethoxyethyl)-2-propenamide as main raw materials, ester exchange reaction is carried out under the action of concentrated hydrochloric acid, and then neutralization, dialysis, drying and dissolution are carried out to obtain; S3: Preparation of dispersed phase: the iodine active dye prepared in step S1, the polyvinyl alcohol modified macromolecule solution prepared in step S2, an initiator and water for injection are weighed and uniformly stirred to obtain the dispersed phase; S4: Preparation of continuous phase: the oil phase and the dispersing agent are weighed and uniformly stirred to obtain the continuous phase; S5: Preparation of color embolism microspheres: under the stirring action, the dispersed phase is transferred to the continuous phase, a catalyst is added, and reverse suspension polymerization is carried out, and the continuous phase on the surface of the microspheres is cleaned to obtain color embolism microspheres with a particle size of 70-900 μm, and then wet screening is carried out to obtain color embolism microspheres with a particle size of 300-500 μm, which have the functions of drug loading and imaging.

7. The method of claim 6, wherein the color embolization microspheres are prepared by the steps of: The basic solution in step S1 includes a sodium hydroxide solution or a potassium hydroxide solution with a concentration of 1 M.

8. The method of claim 6, wherein the color embolization microspheres are prepared by the steps of: The eluent of the column chromatography in step S1 includes any one of a compound of ethyl acetate and petroleum ether, a compound of dichloromethane and ethyl acetate, and a compound of dichloromethane and petroleum ether, and the compound ratio is 1:2-2:

1.

9. The method of claim 6, wherein the color embolization microspheres are prepared by the steps of: The polyvinyl alcohol solution in step S2 is prepared by using polyvinyl alcohol powder and water for injection as main raw materials, swelling at 40-60°C for 3-5 hours, and dissolving at 90-100°C for 3-5 hours; the polyvinyl alcohol modified macromolecule solution in step S2 is prepared by using polyvinyl alcohol modified macromolecule and water for injection as main raw materials, swelling at 40-60°C for 3-5 hours, and dissolving at 90-100°C for 3-5 hours; the polyvinyl alcohol modified macromolecule is prepared by using polyvinyl alcohol solution, N-(2,2-dimethoxyethyl)-2-propenamide and concentrated hydrochloric acid as main raw materials, dialyzing the mixed solution after neutralization to remove the small molecule chloride generated in the neutralization reaction, and drying.

10. The method of claim 6, wherein the color embolization microspheres are prepared by the steps of: The mass concentration of the polyvinyl alcohol solution in step S2 is 5-15 wt%, the addition amount of N-(2,2-dimethoxyethyl)-2-propenamide accounts for 0.1-0.5 wt% of the polyvinyl alcohol solution, the addition amount of concentrated hydrochloric acid accounts for 5-15 wt% of the polyvinyl alcohol solution, and 1 M sodium hydroxide solution or potassium hydroxide solution is used for neutralization. ​ 11. The method of any one of claims 7-10, wherein the color embolization microspheres are prepared by the process of: The reverse suspension polymerization in step S5 is carried out at room temperature-60°C under the protection of nitrogen for 1-3 hours, and the microspheres are sequentially cleaned with Tween 80 solution and 0.9% sodium chloride injection.

12. The method of claim 11, wherein the color embolization microspheres are prepared by the steps of: The color embolism microspheres in step S5 have a particle size of 300-500 μm; the iodine active dye can be ion exchanged with doxorubicin drugs to obtain drug-loaded microspheres; the drug loading amount of the drug-loaded microspheres is 34-99 mg; and the doxorubicin drugs are any one of doxorubicin, epirubicin and pirarubicin.

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