CN115779134B

CN115779134B - Embolic microsphere and preparation method thereof

Info

Publication number: CN115779134B
Application number: CN202211460150.1A
Authority: CN
Inventors: 姚丽娟; 孙宏涛; 孙蓬; 车海波
Original assignee: Cardiolink Shenzhen Medical Technology Development Co ltd
Current assignee: Cardiolink Shenzhen Medical Technology Development Co ltd
Priority date: 2022-11-17
Filing date: 2022-11-17
Publication date: 2023-07-04
Anticipated expiration: 2042-11-17
Also published as: CN115779134A

Abstract

The application relates to the field of medical materials, and relates to an embolic microsphere and a preparation method thereof. The embolic microsphere comprises a carboxyl microsphere with a zwitterionic group and dopamine grafted on the surface of the carboxyl microsphere. The embolic microsphere provided by the application introduces amino, benzene ring and hydroxyl through dopamine. The introduction of amino can realize the loading of negative charge medicine. The introduction of benzene ring makes the space structure of microsphere be enlarged, makes the skeleton of microsphere more stable, and raises mechanical property, and is favorable for raising medicine carrying speed. The structure of catechol on dopamine improves the hydrophilicity of the microsphere on one hand, so that the microsphere has better elasticity, and on the other hand, when the microsphere is embolized to a target blood vessel, certain adhesion effect is formed between the microsphere and between the microsphere and the blood vessel, so that better embolization effect is achieved.

Description

Embolic microsphere and preparation method thereof

Technical Field

The application relates to the field of medical materials, in particular to an embolic microsphere and a preparation method thereof.

Background

In the practical application scene of the embolic microsphere loaded with the medicine, the single medicine has limited curative effect, and better curative effect can be realized only by the synergistic effect of the medicines with different charges.

However, many embolic microspheres currently on the market, such as Callispheres, DC Bead, etc., that have drug loading capabilities, are negatively charged and can only bind positively charged drugs. Some other embolic microspheres are structurally combined with two drugs with different charges simultaneously although positive charges and negative charges are introduced at the same time, but have the problems of low loading speed, small drug loading amount and the like, and cannot meet clinical use requirements. The main reason is that too much charge is introduced into the skeleton, the hydrophilicity is extremely high, the skeleton stability is poor, partial charge is neutralized along with the loading of the medicine, the original skeleton of the microsphere can be obviously changed, such as the rapid shrinkage of the particle size, and the subsequent medicine loading and embolism effects are affected.

Disclosure of Invention

The embodiment of the application aims at providing an embolism microsphere and a preparation method thereof.

In a first aspect, the present application provides an embolic microsphere comprising a carboxyl microsphere having a zwitterionic group and dopamine grafted to the surface of the carboxyl microsphere.

According to the embolic microsphere provided by the application, the carboxyl microsphere with the negative charge zwitterionic group is cooperated with the positively charged dopamine grafted on the surface of the carboxyl microsphere, so that the benzene ring and the hydroxyl are introduced through the dopamine while the partial carboxylic acid group of the carboxyl microsphere is reserved. The retention of carboxylic acid groups ensures that the whole microsphere still has negative charges and is not easy to aggregate, and simultaneously, the embolic microsphere can simultaneously load medicines with different charges by introducing positive charges through dopamine. The introduction of benzene ring makes the space structure of microsphere be enlarged, makes the skeleton of microsphere more stable, and raises mechanical property, and is favorable for raising medicine carrying speed. The structure of catechol on dopamine improves the hydrophilicity of the microsphere on one hand, so that the microsphere has better elasticity, and on the other hand, when the microsphere is embolized to a target blood vessel, certain adhesion effect is formed between the microsphere and between the microsphere and the blood vessel, so that better embolization effect is achieved.

In other embodiments of the present application, the Zeta potential of the embolic microspheres described above is from-0.5 mV to-10.3 mV. Preferably, the Zeta potential of the embolic microspheres is-6.5 mV to-3.2 mV.

In other embodiments of the present application, the embolic microspheres described above have an elasticity of 38.4% -65.4%; the strength of the embolic microsphere is 28/g-72.5/g.

In other embodiments of the present application, the embolic microspheres described above have a moisture content of 93% to 97.2%.

In other embodiments of the present application, the carboxyl microsphere backbone may be selected from at least one of polyacrylic acid, polyvinyl alcohol, acrylate, polyethylene glycol, sodium acrylate, and acrylamide. In other embodiments of the present application, the carboxyl microsphere comprises a backbone and zwitterionic groups;

the framework comprises at least one of sodium acrylate, polyvinyl alcohol, acrylic ester or acrylamide;

the zwitterionic groups are introduced by zwitterionic monomers that contain olefinic bonds.

In other embodiments of the present application, the zwitterionic monomer described above includes: the zwitterionic monomers include: at least one of sulfobetaine methacrylate, 2-methacryloyloxyethyl phosphorylcholine, methacryloyloxyethyl trimethylammonium chloride, acryloyloxyethyl trimethylammonium chloride, 2-acrylamido-2-methylpropanesulfonic acid, methacryloylethyl sulfobetaine, or 3- [ [2- (methacryloyloxy) ethyl ] dimethylammonium ] propionate.

In a second aspect, the present application provides a method for preparing embolic microspheres, comprising:

grafting positively charged dopamine on the surface of the carboxyl microsphere with the zwitterionic group;

preferably, the carboxyl microsphere is a polyacrylate carboxyl microsphere.

In other embodiments of the present application, the dopamine content is 10% to 100% of the molar amount of carboxyl groups in the polyacrylate carboxyl microsphere; alternatively, the dopamine content is 30% -80% of the carboxyl molar amount in the polyacrylate carboxyl microsphere.

In other embodiments of the present application, grafting positively charged dopamine onto the surface of negatively charged polyacrylate carboxyl microsphere comprises:

the polyacrylate carboxyl microsphere, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N-hydroxysuccinimide, water and dopamine are reacted.

In other embodiments of the present application, the preparation of polyacrylate carboxyl microsphere comprises:

mixing sodium acrylate, polyvinyl alcohol macromonomer, amphoteric ion monomer, cross-linking agent and initiator to obtain water phase;

mixing the water phase and the oil phase, and carrying out polymerization reaction at 60-70 ℃.

Drawings

In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings that are needed in the embodiments will be briefly described below, it being understood that the following drawings only illustrate some embodiments of the present application and therefore should not be considered limiting the scope, and that other related drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.

FIG. 1 is a schematic diagram of the reaction of the polyacrylate carboxyl microsphere surface grafted with positively charged dopamine.

Detailed Description

For the purposes of making the objects, technical solutions and advantages of the embodiments of the present application more clear, the technical solutions in the embodiments of the present application will be clearly and completely described below, and it is obvious that the described embodiments are some embodiments of the present application, but not all embodiments.

Thus, the following detailed description of the embodiments of the present application is not intended to limit the scope of the application, as claimed, but is merely representative of selected embodiments of the application. All other embodiments, which can be made by one of ordinary skill in the art based on the embodiments herein without making any inventive effort, are intended to be within the scope of the present application.

The embodiment of the application provides an embolic microsphere, which comprises carboxyl microsphere with a zwitterionic group and dopamine grafted on the surface of the carboxyl microsphere. Further, in some embodiments of the present application, the Zeta potential of the embolic microspheres is from-0.5 mV to-10.3 mV.

Further preferably, the Zeta potential of the embolic microsphere is-6.5 mV to-3.2 mV.

Illustratively, in some embodiments of the present application, the Zeta potential of the embolic microspheres described above is-0.8 mV, -1mV, -1.5mV, -2mV, -2.5mV, -3mV, -3.5mV, -4mV, -4.5mV, -5mV, -6mV, -7mV, -8mV, or-9 mV.

Further, in some embodiments of the present application, the embolic microspheres have an elasticity of 38.4% to 65.4%.

Further alternatively, in some embodiments of the present application, the embolic microsphere has an elasticity of 39% -64%.

Illustratively, in some embodiments of the present application, the embolic microspheres have an elasticity of 40%, 45%, 48%, 50%, 52%, 55%, 58%, 60%, 62%, or 63%.

Further, in some embodiments of the present application, the embolic microspheres have a strength of 28/g to 72.5/g.

Further alternatively, in some embodiments of the present application, the embolic microspheres have a strength of 30/g to 71/g.

Illustratively, in some embodiments of the present application, the embolic microspheres have a strength of 32g, 35g, 38g, 40g, 42g, 45g, 48g, 50g, 52g, 55g, 58g, 60g, 62g, 65g, 68g, or 70g.

Further, in some embodiments of the present application, the embolic microspheres have a moisture content of 93% to 97.2%.

Further alternatively, in some embodiments of the present application, the embolic microspheres have a moisture content of 93.5% -97%.

Illustratively, the embolic microspheres have a water content of 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, or 97%.

Further, in some embodiments of the present application, the carboxyl microsphere backbone may be selected from at least one of polyacrylic acid, polyvinyl alcohol, acrylate, polyethylene glycol, sodium acrylate, and acrylamide.

Further, in some embodiments of the present application, the carboxyl microsphere comprises a backbone and zwitterionic groups;

Further, in some embodiments of the present application, the zwitterionic monomer comprises: at least one of sulfobetaine methacrylate, 2-methacryloyloxyethyl phosphorylcholine, methacryloyloxyethyl trimethylammonium chloride, acryloyloxyethyl trimethylammonium chloride, 2-acrylamido-2-methylpropanesulfonic acid, methacryloylethyl sulfobetaine, or 3- [ [2- (methacryloyloxy) ethyl ] dimethylammonium ] propionate.

Illustratively, in some embodiments of the present application, the carboxyl microsphere is a polyacrylate carboxyl microsphere.

As stated earlier, further, in some embodiments of the present application, the dopamine content is 10% to 100% of the molar amount of carboxyl groups in the polyacrylate carboxyl microsphere.

Further alternatively, in some embodiments of the present application, the dopamine content is 15% to 95% of the molar amount of carboxyl groups in the polyacrylate carboxyl microsphere.

Illustratively, the dopamine content is 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or 90% of the molar amount of carboxyl groups in the polyacrylate carboxyl microsphere.

Some embodiments of the present application provide a method for preparing embolic microspheres, comprising:

and grafting positively charged dopamine on the surface of the carboxyl microsphere with the zwitterionic group.

Further, in some embodiments of the present application, the carboxyl microsphere having a zwitterionic group described above is preferably a polyacrylate carboxyl microsphere.

Further, in some embodiments of the present application, a method of preparing embolic microspheres comprises the steps of:

and S1, preparing the polyacrylate carboxyl microsphere.

Further, in some embodiments of the present application, the preparation of polyacrylate carboxyl microsphere comprises:

Further, in some embodiments of the present application, the cross-linking agent described above is selected from the group consisting of N, N-methylenebisacrylamide.

Further, in some embodiments of the present application, the initiator described above is selected from ammonium persulfate.

In other alternative embodiments of the present application, the cross-linking agents and initiators described above may also be selected from other cross-linking agents and initiators known in the art.

Further, in some embodiments of the present application, the zwitterionic monomer described above includes: at least one of sulfobetaine methacrylate, 2-methacryloyloxyethyl phosphorylcholine, methacryloyloxyethyl trimethylammonium chloride, acryloyloxyethyl trimethylammonium chloride, 2-acrylamido-2-methylpropanesulfonic acid, methacryloylethyl sulfobetaine, or 3- [ [2- (methacryloyloxy) ethyl ] dimethylammonium ] propionate.

Illustratively, in some embodiments of the present application, the zwitterionic monomer described above is selected from sulfobetaine methacrylate (SBMA).

Illustratively, in some embodiments of the present application, preparing the aqueous phase described above comprises:

adding 30g of sodium acrylate, 15g of acrylamide, 10g of sulfobetaine methacrylate (SBMA), 2g of N, N-methylene bisacrylamide (cross-linking agent) and 2g of ammonium persulfate (initiator) into a beaker, and fully and uniformly mixing to obtain a water phase.

Further, in some embodiments of the present application, the aqueous phase is mixed with an oil phase selected from the oil phase consisting of span 80 and paraffinic oil when polymerization occurs at 60-70 ℃.

The span 80 and the paraffin oil can be prepared according to any proportion.

Further, in some embodiments of the present application, the aqueous phase is mixed with the oil phase, and the polymerization reaction is carried out at 60-70 ℃ with stirring and dispersing, and further optionally, with stirring and dispersing at 300-500 rpm.

Further, in some embodiments herein, the aqueous phase is mixed with the oil phase and the polymerization reaction occurs at 60-70 ℃ for a period of time ranging from 6-10 hours.

Further, in some embodiments of the present application, the aqueous phase is mixed with the oil phase, and after polymerization at 60-70 ℃, the resulting product is filtered to filter out the microspheres, and the microspheres are washed. Further alternatively, the washing is sequentially performed with methanol and deionized water.

Further alternatively, the aqueous phase is mixed with the oil phase as described above and the polymerization reaction occurs at 61-69 ℃. Illustratively, the aqueous phase is mixed with the oil phase and polymerization occurs at 61, 62, 63, 64, 65, 66, 67, 68, or 69 ℃.

Further alternatively, the reaction time is selected from 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours.

Illustratively, mixing the aqueous phase with the oil phase, and polymerizing at 60-70 ℃ comprises:

adding the water phase into an oil phase consisting of span 80 and paraffin oil, stirring and dispersing at 400rpm, heating to 65 ℃, and initiating polymerization reaction for 8 hours. And after the reaction is finished, filtering out microspheres, and washing the microspheres with methanol and deionized water in sequence to obtain the polyacrylate carboxyl microspheres.

And S2, grafting positively charged dopamine on the surface of the polyacrylate carboxyl microsphere.

The structural formula of dopamine is as follows:

further, in some embodiments of the present application, grafting positively charged dopamine onto the surface of negatively charged polyacrylate carboxyl microsphere comprises:

And (3) reacting the polyacrylate carboxyl microsphere prepared in the step (S1), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N-hydroxysuccinimide, water and dopamine.

The specific reaction process is shown in figure 1 of the specification.

Further alternatively, the dopamine content is 10% -100% of the molar amount of carboxyl groups in the polyacrylate carboxyl microsphere. Further alternatively, the dopamine content is 15% -90% of the molar amount of carboxyl groups in the polyacrylate carboxyl microsphere.

Further alternatively, the dopamine content is 30% -80% of the molar amount of carboxyl groups in the polyacrylate carboxyl microsphere.

Illustratively, the dopamine content is 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80% or 85% of the molar amount of carboxyl groups in the polyacrylate carboxyl microsphere.

Further, in some embodiments of the present application, the polyacrylate carboxyl microsphere prepared in step S1, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N-hydroxysuccinimide, water, and dopamine are reacted for 5-8 hours. Illustratively, the reaction time is 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, or 8 hours.

Further, in some embodiments of the present application, the polyacrylate carboxyl microsphere prepared in step S1, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N-hydroxysuccinimide, water, and dopamine are reacted and then washed. Optionally, the washing is performed with deionized water.

Further, in some embodiments of the present application, the polyacrylate carboxyl microsphere prepared in step S1, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N-hydroxysuccinimide, water, and dopamine are reacted, and then the prepared product is further sieved. In the case of sieving, the particles are sieved according to a desired particle size range, and then the microspheres having the desired particle size range are obtained.

Further, in other embodiments of the present application, the microsphere scaffold may be exchanged for polyvinyl alcohol, acrylate, polyethylene glycol, sodium acrylate, acrylamide, and the like.

Illustratively, in some embodiments of the present application, 30mL of the polyacrylate carboxyl microsphere described above is placed in a 250mL flask, 1g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC hydrochloride), 1g N-hydroxysuccinimide (NHS), 60mL of water are added, followed by adding a certain amount of dopamine, stirring and dispersing, reacting at room temperature for 6 hours, after the reaction is completed, the modified microsphere is washed with deionized water, and the microsphere is sieved as needed to obtain microspheres of the desired particle size range.

The features and capabilities of the present application are described in further detail below in connection with the examples:

example 1

Providing an embolic microsphere, which is prepared according to the following steps:

(1) Synthesizing a microsphere main body structure by a suspension polymerization method:

adding 6g of sodium acrylate, 40g of polyvinyl alcohol macromer solution modified with double bonds (mass fraction 10%), 10g of sulfobetaine methacrylate (SBMA), 0.5g of N, N-methylene bisacrylamide (cross-linking agent), 0.1g of glutaraldehyde (cross-linking agent) and 0.2g of ammonium persulfate (initiator) into a beaker, and fully and uniformly mixing to obtain a water phase. Adding the water phase into an oil phase consisting of span 80 and cellulose acetate butyrate, stirring and dispersing at 400rpm, heating to 65 ℃, and initiating polymerization reaction for 8 hours. And after the reaction is finished, filtering out microspheres, and washing the microspheres with methanol and deionized water in sequence to obtain the polyacrylate carboxyl microspheres.

(2) Modification of dopamine:

placing 30mL of the microsphere prepared in the step (1) into a 250mL flask, adding 1g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC hydrochloride), 1g N-hydroxysuccinimide (NHS) and 60mL of water, then adding a certain amount of dopamine according to the proportion of the dopamine content to the carboxyl molar amount in the polyacrylate carboxyl microsphere, wherein the specific addition is shown in the table 1, stirring and dispersing, reacting for 6h at room temperature, washing the modified microsphere with deionized water after the reaction is finished, and sieving the microsphere according to the requirement to obtain the microsphere with the required particle size range.

Example 2-example 5

The procedure was the same as in example 1, except that dopamine was added in an amount as shown in Table 1.

Comparative example 1

Experimental example 1

The performance of embolic microspheres of examples 1-5 and comparative example 1 were tested.

1. Determination of Strength and elasticity

The obtained wet microspheres are tiled into a layer, the area of the wet microspheres needs to be larger than that of a texture analyzer probe, the strength and the elasticity of the microspheres are measured by the texture analyzer, and corresponding numerical values are recorded.

2. Determination of the Water content

Accurately weighing wet microspheres with certain mass, placing the wet microspheres in a weighing dish which is dried to constant weight and accurately weighed, drying the microspheres to constant weight at 105 ℃, and recording the mass before and after drying, thereby calculating the water content of the microspheres.

3. Measurement of potential

And measuring the potential of the microspheres by adopting a Markov nanometer particle size potentiometer, wherein the microspheres are required to be dispersed and not settled in the test process.

The results of the above performance tests are shown in Table 1.

TABLE 1

As can be seen from the results in Table 1, comparative example 1 has a large amount of carboxylic acid groups, exhibits a large negative charge, and is highly hydrophilic, and thus has the highest water content. Whereas examples 1-5 showed progressively lower water content with increasing dopamine grafting ratio, with less negative charge. The strength of the microsphere is too low, and the microsphere is easy to crush; too high a strength may be difficult to pass through a catheter with a relatively small lumen. The good elasticity is beneficial for the microspheres to smoothly pass through the catheter and quickly recover the spherical shape after passing through, so that the microspheres can be better attached to the blood vessel. As can be seen from the values of strength and elasticity in table 1, as the proportion of dopamine grafted increases, the microsphere strength increases more and more, because of the introduction of a relatively hydrophobic benzene ring; the elasticity shows a tendency of increasing and then decreasing, which shows that the optimal mechanical property can be obtained only when the proportion of each group is controlled within a certain range, and the elastic material has high strength and high elasticity. Wherein, example 4, while introducing part of rigid benzene ring, also retains part of hydrophilic negative charge carboxyl, thus endowing microsphere with optimal mechanical property. In addition, the whole microsphere maintains a charged state, is not easy to aggregate, and is easier to store and use stably.

Experimental example 2

Drug loading experiments were performed on embolic microspheres of examples 1-5 and comparative example 1.

(1) Positive charge drug: doxorubicin hydrochloride

2mL of wet microspheres are taken and placed in a syringe, 5mL of doxorubicin hydrochloride solution with the concentration of 20mg/mL is added, the solution is fully mixed, and the doxorubicin content (ultraviolet spectrophotometry) in the residual solution is tested for 5min and 30min respectively, so that the drug loading rate is calculated. After 1h the final drug loading was determined and calculated.

(2) Negative charge drug: methotrexate

The methotrexate drug solution is prepared according to the mol ratio of the methotrexate to the sodium hydroxide of 1:2, and the methotrexate disodium solution with the concentration of 10mg/ml is prepared. 2mL of wet microspheres are taken and placed in a syringe, 5mL of the methotrexate solution is added and fully mixed, and the methotrexate content (ultraviolet spectrophotometry) in the residual solution is tested for 5min and 30min respectively, so that the drug loading rate is calculated.

The experimental results are shown in Table 2.

TABLE 2

The drug loading rate of the microsphere to the doxorubicin depends on the quantity of negative charges contained on the microsphere, and the drug loading rate is mainly related to the pore channel structure and the hydrophobicity of the microsphere. As can be seen from the results in Table 2, comparative example 1, which contains a large amount of carboxylate ions, can be combined with a large amount of positively charged drug, i.e., doxorubicin, and theoretically has the highest drug loading, but in practice, after the combination with the drug, the charge is reduced, the microspheres undergo rapid shrinkage, which results in a lower drug loading rate, the drug loading rate of only 75.9% for 30min at the end, and the drug loading rate of only 39.0mg/mL at the end. In the embodiment of the application, through the introduction of grafted dopamine and benzene rings, the skeleton of the microsphere becomes more rigid, and after the microsphere is combined with the drug, the deformation is smaller, which is favorable for maintaining a larger transmission channel, so that the microsphere has a faster drug carrying rate, in particular to the embodiment 3-4, and the maximum drug carrying is realized in almost 5 min. However, too many benzene rings are introduced, which also results in strong hydrophobicity of the microspheres and is unfavorable for the transmission of hydrophilic drugs, so that the drug loading rate is further reduced as in example 5.

The drug loading rate of the microsphere to the methotrexate depends on the number of positive charges on the microsphere, the drug loading rate is also related to the pore channel structure and the hydrophobicity of the microsphere, and as the introduction of dopamine is increased, the positive charges of the microsphere are increased, and the skeleton is stabilized, so that the overall trend of faster and faster drug loading rate and increased drug loading rate is presented.

(3) Simultaneously loading positively and negatively charged drugs

Taking 2mL of wet microspheres in a syringe, adding 2mL of doxorubicin hydrochloride solution with the concentration of 20mg/mL, fully mixing, and recording the time T required for the solution to become colorless ₁ . Then the supernatant is pushed off, 2mL of methotrexate disodium solution with the concentration of 10mg/mL is added, and the mixture is fully mixed, and the time T required by the completion of loading is recorded ₂ 。

The results are shown in Table 3.

TABLE 3 Table 3

From the data in table 3, it can be seen that the loading of both drugs can be achieved for different groups, wherein the number of benzene rings introduced and the number of retained carboxyl groups in examples 3 and 4 are in a relatively balanced range, thus having a faster loading rate for both drugs, especially example 4.

The foregoing description is only of the preferred embodiments of the present application and is not intended to limit the same, but rather, various modifications and variations may be made by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application should be included in the protection scope of the present application.

Claims

1. An embolic microsphere characterized in that the embolic microsphere comprises a carboxyl microsphere having a zwitterionic group and dopamine grafted to the surface of the carboxyl microsphere;

the carboxyl microsphere is a polyacrylate carboxyl microsphere.

2. The embolic microsphere according to claim 1, wherein,

the Zeta potential of the embolic microsphere is-0.5 mV to-10.3 mV.

3. The embolic microsphere according to claim 1, wherein,

the Zeta potential of the embolic microspheres is-6.5 mV to-3.2 mV.

4. The embolic microsphere according to claim 1, wherein,

the elasticity of the embolic microsphere is 38.4% -65.4%; the strength of the embolic microsphere is 28g-72.5g.

5. The embolic microsphere according to claim 1, wherein,

the skeleton of the carboxyl microsphere is at least one selected from polyacrylic acid and sodium acrylate.

6. The embolic microsphere according to claim 5, wherein,

7. The embolic microsphere according to claim 6, wherein,

the zwitterionic monomer includes: at least one of sulfobetaine methacrylate, 2-methacryloyloxyethyl phosphorylcholine, methacryloyloxyethyl trimethylammonium chloride, acryloyloxyethyl trimethylammonium chloride, methacryloyloxyethyl sulfobetaine, or 3- [ [2- (methacryloyloxy) ethyl ] dimethylammonium ] propionate.

8. A method of preparing embolic microspheres according to any one of claims 1-7, comprising:

9. The method for preparing embolic microspheres according to claim 8, wherein,

the content of the dopamine is 10-100% of the molar quantity of carboxyl in the carboxyl microsphere with the zwitterionic group.

10. The method for preparing embolic microspheres according to claim 8, wherein,

the content of the dopamine is 30-80% of the molar quantity of carboxyl in the carboxyl microsphere with the zwitterionic group.

11. A method of preparing embolic microspheres according to claim 9 or 10, comprising:

grafting positively charged dopamine on the surface of the negatively charged carboxyl microsphere with the zwitterionic group, wherein the positively charged dopamine comprises the following components:

reacting the carboxyl microsphere with the zwitterionic group, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N-hydroxysuccinimide, water and dopamine.

12. A method of preparing embolic microspheres according to claim 9 or 10, comprising:

preparing the carboxyl microsphere with the zwitterionic group, which comprises the following steps:

mixing sodium acrylate, a polyvinyl alcohol macromonomer modified with double bonds, a zwitterionic monomer, a cross-linking agent and an initiator to obtain a water phase;