CN113797383A

CN113797383A - High-elasticity high-drug-loading-rate embolism microsphere and preparation method thereof

Info

Publication number: CN113797383A
Application number: CN202111141353.XA
Authority: CN
Inventors: 曹秀开
Original assignee: Digray Medical Technology Suzhou Co ltd
Current assignee: Digray Medical Technology Suzhou Co ltd
Priority date: 2021-09-28
Filing date: 2021-09-28
Publication date: 2021-12-17

Abstract

The invention discloses a high-elasticity high-drug-loading embolization microsphere and a preparation method thereof, and relates to the field of medical high polymer materials.

Description

High-elasticity high-drug-loading-rate embolism microsphere and preparation method thereof

Technical Field

The invention relates to the field of medical high polymer materials, in particular to a high-elasticity and high-drug-loading-rate embolization microsphere and a preparation method thereof.

Background

Liver cancer is one of the most common 10 tumors in the world, and China is a country with the highest incidence of primary liver cancer and accounts for more than 50% of patients in the world. The treatment method for the primary liver cancer comprises treatment schemes such as surgical resection, liver transplantation, microwave ablation, transcatheter hepatic artery chemoembolization (TACE), radiotherapy and the like. Clinical practice and research show that the traditional Chinese medicine composition is the first choice and the most effective treatment scheme for middle and late stage liver cancer patients who cannot be resected by surgery as a transhepatic artery embolism treatment technology, can bring longer life cycle, and has remarkable clinical effect.

At present, the TACE action mechanism is mainly to carry out super-selective embolization on blood supply arteries of tumors through an embolization agent, so that the blood supply arteries of the tumors are occluded, and cytotoxic chemotherapeutic drugs are injected into the depths of secondary blood vessels, so that the first pass effect of drug treatment is achieved, and ischemic necrosis of tumor lesions is induced. Thus, the ideal TACE treatment would be to maximize and sustain the concentration of chemotherapeutic agents within the tumor lesion, to achieve low peripheral blood levels, and to precisely embolize the blood-supplying arteries of the tumor lesion. The drug-loaded microsphere embolization technology is used as a novel interventional treatment scheme of TACE, the particle size distribution of the microspheres is uniform, so that the corresponding blood vessels can be selected in a targeted mode, and meanwhile, the microspheres have the functions of loading drugs and slowly releasing chemotherapeutic drugs to achieve a good interventional operation effect, so that the preparation of the polymer embolization microspheres which can be used for loading drugs, can be used for slowly releasing the chemotherapeutic drugs and have good biocompatibility is a research hotspot at present.

The microsphere embolization agents which are currently on the market at home and abroad comprise polyvinyl alcohol embolization microspheres, chitosan microspheres, sodium alginate microspheres, albumin microspheres and the like. However, each microsphere product has different biochemical characteristics such as elasticity, compressibility, compliance and the like, and the biochemical characteristics have great influence on the efficacy of the microsphere product and also determine the clinical application range of the microsphere product. Specific defects and deficiencies are as follows: (1) for example, sodium alginate microspheres are poor in elasticity and incapable of being compressed and repaired due to the fact that the sodium alginate microspheres are polymerized in an ionic crosslinking mode, and the microspheres are easily crushed after being conveyed through a catheter, so that embolism is subjected to drift risk, and vascular embolism is not tight; (2) for example, chitosan microspheres have certain degradation capability, but the mechanical properties are poor, so that the chitosan microspheres cannot bear the impact of blood flow and limit the clinical application of the chitosan microspheres; (3) however, the existing polyvinyl alcohol embolism microsphere in the market has no biodegradability, and as the polyvinyl alcohol embolism microsphere capable of carrying the medicine, the polyvinyl alcohol needs to be modified and derivatized, more toxicological substances are introduced, so that the process is complex, and secondly, the medicine carrying amount of the polyvinyl alcohol embolism microsphere is still lower, and the polyvinyl alcohol embolism microsphere releases the chemotherapeutic medicine in the blood vessel more quickly, so that the medicine is short in detention time in the target tumor tissue, and the treatment effect is influenced. Meanwhile, the current microsphere particle size range (100-. These factors greatly reduce the clinical efficacy of drug-loaded microsphere embolization agents.

Therefore, in order to overcome the above technical deficiencies, the technicians in the field are dedicated to develop a novel embolization microsphere with excellent variable elasticity, high drug loading, long drug sustained-release time and uniform particle size distribution and a preparation method thereof, so that the microsphere is perfectly matched with the blood vessel, embolization is more thorough, and chemotherapeutic drugs are slowly released, so that the drug concentration in the tumor area is maintained at a higher level for a long time, the drug concentration in the systemic circulation is reduced, and the treatment effect is improved.

Disclosure of Invention

In view of the above-mentioned defects of the prior art, the technical problem to be solved by the present invention is how to develop an embolization microsphere with excellent variable elasticity, high drug loading, long drug release time and uniform particle size distribution.

In order to achieve the purpose, the invention provides a high-elasticity high-drug-loading-rate embolization microsphere which is prepared by randomly copolymerizing polyvinyl alcohol macromolecules serving as a matrix, a ring-forming grafting agent, a double-bond-containing micromolecule bridging agent and an ionic crosslinking agent, wherein the embolization microsphere is of a network structure taking micromolecule crosslinking body stretching vibration and polyvinyl alcohol macromolecules as a framework, and has the advantages of high elasticity, high drug loading rate, long drug sustained and controlled release time and uniform particle size distribution.

A preparation method of high-elasticity high-drug-loading-capacity embolism microsphere comprises the following steps:

step 1, synthesizing a modified polyvinyl alcohol derivative, and carrying out chemical reaction on hydroxyl on a polyvinyl alcohol macromolecular chain through a ring-forming grafting agent to form a macromolecular hydrogel structure containing a stable six-membered ring and a functional side group containing double bonds, so as to obtain the modified polyvinyl alcohol derivative;

step 2, synthesizing the embolism microsphere, wherein a reaction system is divided into a dispersion phase and a continuous phase, and the dispersion phase consists of a modified polyvinyl alcohol derivative, a double-bond-containing micromolecule bridging agent, an ionic crosslinking agent and a first initiator; and the continuous phase consists of an oil-soluble solvent, a surfactant and a second initiator, the dispersed phase is dispersed in the continuous phase through a dispersing device, and the embolism microsphere is prepared through fluid shear force.

Further, step 1 further comprises:

step 1.1, adding 80-120g of polyvinyl alcohol macromolecules into a flask, adding 500-1000ml of water, heating to 92-98 ℃ and dissolving to completely dissolve the polyvinyl alcohol macromolecules;

step 1.2, after cooling to room temperature, adding 0.5-5g of ring-forming grafting agent into the reaction system, stirring at the speed of 100-.

Further, step 2 further comprises:

step 2.1, mixing an ionic cross-linking agent, a first initiator, a double-bond-containing micromolecule bridging agent and a modified polyvinyl alcohol derivative according to the weight ratio of 5-80: 0.5-5: 0.1-2: feeding materials in a proportion of 80-100, and uniformly stirring to form a dispersed phase homogeneous liquid;

step 2.2, mixing a surfactant, a second initiator and an oil-soluble solvent according to the ratio of 5-50: 800-1000: feeding materials in a ratio of 0.5-2, and uniformly stirring to form a continuous phase homogeneous liquid;

step 2.3, mixing the dispersed phase homogeneous phase liquid and the continuous phase homogeneous phase liquid according to the ratio of 1: 3-30 proportion to the reaction system, stirring speed is 100-;

and 2.4, after the dispersed phase is uniformly dispersed, heating to perform free radical polymerization reaction under the protection of inert gas, then preserving the temperature for 1-5 hours at the temperature of 40-70 ℃, washing, filtering, drying, swelling and sterilizing after the reaction is finished, and preparing the embolism microsphere with high elasticity and high drug loading.

Furthermore, the polymerization degree of the polyvinyl alcohol macromolecule is in the range of 1000-2000, the molecular weight is 5-15 ten thousand, and the polyvinyl alcohol macromolecule has good biocompatibility.

Further, the ring-forming grafting agent comprises an alkene boric acid structure derivative or an alkene aldehyde structure derivative, the alkene boric acid structure derivative is one of pent-4-ene-1-yl boric acid, vinyl benzene boric acid and 4-allyl carbamoyl benzene boric acid, and the alkene aldehyde structure derivative is one of acrolein and propylene aldehyde acetal.

Further, the double bond-containing micromolecule bridging agent is a derivative containing a single or more than two double bond structures, and is preferably one of acrylamide and N, N-methylene bisacrylamide.

Further, the ionic crosslinking agent is a sulfonate derivative containing negative charges, and preferably contains an ionic acrylamide monomer.

Furthermore, the ionic acrylamide monomer is one of 2-acrylamide-2-methyl sodium propane sulfonate or 2-acrylamide-2-methyl propane sulfonic acid.

Further, the particle size of the plug microsphere is 75-125 μm, 150-250 μm, 350-450 μm, 550-650 μm, 750-850 μm or 900-1200 μm.

The invention has the following technical effects:

(1) according to the invention, the double-bond-containing micromolecule bridging agent is introduced, so that a chain structure of micromolecule crosslinking is combined with a polyvinyl alcohol macromolecule net structure, and the chain structure has certain telescopic vibration, so that the elastic performance of the whole polyvinyl alcohol embolism microsphere is greatly improved.

(2) According to the invention, the modified polyvinyl alcohol macromolecule side chain group has a stable six-membered ring structure, and the double bond polymerization is carried out on the functional side group containing the double bond, the double bond-containing micromolecule bridging agent and the cross-linking agent, so that the conversion rate, the content and the space density of the ionic acrylamide monomer are greatly improved, and the drug loading capacity is greatly improved. Meanwhile, as the space density is improved, the electric field distribution of the anion groups is uniform, so that the medicine can be slowly released, and meanwhile, the gradient release is achieved.

(3) The invention simultaneously introduces functional side group polyvinyl alcohol macromolecules containing double bonds, micromolecule bridging agents containing double bonds and ionic cross-linking agent monomers containing double bonds, and the three generate random copolymerization reaction, and compared with the block copolymerization of the conventional polyvinyl alcohol microspheres, the random copolymerization reaction has the advantages that the mechanical property, the heat resistance and the transparency are obviously improved.

(4) The embolism microsphere prepared by the invention has uniform particle size, the surface tension of a disperse phase is changed by controlling the proportion of a small molecular bridging agent, the particle size is uniformly distributed in a mobile phase by the surface tension of the small molecular bridging agent under the action of the same fluid shearing force, and the particle size distribution of the microsphere prepared microscopically is uniform.

(5) According to the invention, a specific dispersing device is introduced in the preparation process of the embolism microsphere, the dispersed phase is orderly added into the continuous phase through a device for locally limiting the size of liquid drops, and the particle size distribution of the prepared microsphere is uniform macroscopically;

(6) the embolism microsphere is matched with blood vessels to realize super-selective embolism treatment, meanwhile, the microsphere structure is rich in anion groups, and can attract chemotherapy medicaments with positive charges (such as adriamycin, irinotecan and the like) to form ionic bonds to load higher chemotherapy medicaments, when the drug-loaded microsphere enters a human body, other ions in body fluid compete with drug molecules, so that the chemotherapy medicaments can be slowly released for a long time, the drug concentration in a tumor area is maintained at a higher level, and the interventional therapy effect is improved.

The conception, the specific structure and the technical effects of the present invention will be further described with reference to the accompanying drawings to fully understand the objects, the features and the effects of the present invention.

Drawings

FIG. 1 is a 20X photomicrograph of 75-125um embolic microspheres according to a preferred embodiment of the present invention;

FIG. 2 is a 4X photomicrograph of 900-1200um embolic microspheres according to a preferred embodiment of the present invention;

FIG. 3 is a compression set stress diagram of 900-1200um embolic microspheres according to a preferred embodiment of the present invention;

fig. 4 shows the test results of drug loading performance of the embolization microspheres according to a preferred embodiment of the invention, where a is the drug loading result and b is the photomicrograph after loading the drug-loaded microspheres;

FIG. 5 shows the result of testing the drug release performance of the embolizing microspheres according to a preferred embodiment of the present invention.

Detailed Description

The technical contents of the preferred embodiments of the present invention will be more clearly and easily understood by referring to the drawings attached to the specification. The present invention may be embodied in many different forms of embodiments and the scope of the invention is not limited to the embodiments set forth herein.

Example 1

Synthesis of polyvinyl alcohol derivatives

Adding 600ml of purified water into a reaction flask, adding 100g of polyvinyl alcohol macromolecules, controlling the stirring speed to be 100r/min, uniformly stirring, heating to 92-98 ℃ for dissolution, keeping the temperature for 2h, and cooling to room temperature to form the polyvinyl alcohol hydrogel. The polymerization degree of the polyvinyl alcohol macromolecule is in the range of 1000-2000, the molecular weight is 5-15 ten thousand, and the polyvinyl alcohol macromolecule has good biocompatibility.

Adding 1g of vinylphenylboronic acid into 600ml of dissolved polyvinyl alcohol hydrogel, stirring for 30min to mix uniformly, adjusting the pH value of the reaction system to 3-4 by using 1M hydrochloric acid, and stirring for 24h at room temperature. Dialyzing in water solution by using a dialysis bag with molecular weight cut-off of 5000, removing unreacted small molecular weight compounds and impurities, removing water under reduced pressure, after a reaction system is viscous, proving that hydrogel produced by coordination bonds is formed, stopping reaction, and collecting a product to obtain a modified polyvinyl alcohol derivative;

synthesis of embolic microspheres

Weighing 10g of 2-acrylamide-2-methylpropanesulfonic acid sodium salt, 0.8g of potassium persulfate and 1.2g of acrylamide in a beaker, adding magnetons, placing on a magnetic stirrer, stirring at the rotating speed of 300r/min for 10min, pouring the solution in the beaker into the beaker containing 100g of the prepared polyvinyl alcohol derivative, continuously stirring for 30min, and uniformly mixing to form dispersed phase homogeneous liquid.

Under the protection of inert gas, adding 1500ml of liquid paraffin into a flask, adding 15g of Tween 80 solution, starting stirring at the rotating speed of 300r, and uniformly stirring for 10min to form continuous phase homogeneous liquid.

And then dispersing the dispersion phase homogeneous liquid into liquid drops through a 60um dispensing needle head connected with an injector and a 50-1000um screen, slowly injecting the liquid drops into a reaction system for about 1h, sucking 1.5ml of tetramethylethylenediamine by using a liquid transfer gun, adding the liquid drops into the system, starting to raise the temperature to 60 ℃, starting to time, keeping the temperature for 2.5h, after the reaction is finished, washing, filtering and drying by using acetone to prepare a 75-125um microsphere crude product, swelling and sterilizing to prepare the 75-125um embolic microsphere with high elasticity, high drug loading capacity and uniform particle size, and observing the microsphere by using a 20X microscope as shown in figure 1.

Example 2

Synthesis of polyvinyl alcohol derivatives

Adding 600ml of purified water into a reaction flask, adding 100g of polyvinyl alcohol macromolecules, controlling the stirring speed to be 100r/min, uniformly stirring, heating to 92-98 ℃ for dissolution, keeping the temperature for 2h, and cooling to room temperature to form the polyvinyl alcohol hydrogel.

Adding 4g of acrolein into 500ml of dissolved polyvinyl alcohol hydrogel, stirring for 60min at the speed of 150r/min, slowly dropwise adding 60ml of concentrated hydrochloric acid into a reaction system, continuing to stir for 8h after dropwise adding is finished, slowly dropwise adding 2mol/L sodium hydroxide into the system after reaction is finished, adjusting the reaction system to be neutral 7.0 by adopting online pH monitoring, continuing to stir for 30min, finally collecting a product, and performing dialysis and desalination treatment to obtain a modified polyvinyl alcohol derivative;

synthesis of embolic microspheres

Under the protection of inert gas, adding 1500ml of liquid paraffin into a flask, adding 15g of Tween 80 solution, starting stirring at the rotating speed of 300r, and uniformly stirring for 10min to form continuous phase homogeneous liquid. And slowly injecting the dispersion phase homogeneous liquid into a reaction system for about 1 hour through a 60um dispensing needle connected with an injector, sucking 1.5ml of tetramethylethylenediamine by using a liquid transfer gun, adding the tetramethylethylenediamine into the system, starting to raise the temperature to 60 ℃, starting to time, keeping the temperature for 2.5 hours, washing, filtering and drying the mixture by using acetone after the reaction is finished, preparing a 75-125um microsphere crude product, and swelling and sterilizing the product to prepare the 75-125um embolic microsphere with high elasticity, high drug loading capacity and uniform particle size.

Example 3

Synthesis of polyvinyl alcohol derivatives

synthesis of embolic microspheres

Weighing 15g of 2-acrylamide-2-methylpropanesulfonic acid sodium salt, 0.6g of potassium persulfate and 0.5g of N, N-methylene bisacrylamide in a beaker, adding magnetons, placing on a magnetic stirrer, stirring for 10min at the rotating speed of 300r/min, pouring the solution in the beaker into the beaker containing 100g of the prepared polyvinyl alcohol derivative, continuously stirring for 30min, and uniformly mixing to form dispersed phase homogeneous liquid.

Adding 1500ml of butyl acetate into a flask, adding 20g of cellulose substance solution, starting stirring at the rotation speed of 150r for 10min, and uniformly stirring to form continuous phase homogeneous liquid. Under the protection of inert gas, slowly injecting the dispersed phase homogeneous liquid into a reaction system for about 20min through an 800-micron dispensing needle connected with an injector, sucking 1.0ml of tetramethylethylenediamine by using a liquid-transferring gun, adding the tetramethylethylenediamine into the system, starting to raise the temperature to 62 ℃, starting to time, keeping the temperature for 3.5h, after the reaction is finished, washing, filtering and drying by acetone to prepare a 900-plus-1200-micron microsphere crude product, swelling and sterilizing to prepare the 900-plus-1200-micron embolic microsphere with high elasticity, high drug loading capacity and uniform particle size, and observing the microsphere by a microscope 4X as shown in figure 2.

Example 4

Synthesis of polyvinyl alcohol derivatives

synthesis of embolic microspheres

Adding 1500ml of butyl acetate into a flask, adding 20g of cellulose substance solution, starting stirring at the rotation speed of 150r for 10min, and uniformly stirring to form continuous phase homogeneous liquid. Under the protection of inert gas, slowly injecting the dispersed phase homogeneous liquid into a reaction system for about 20min through an 800-micron dispensing needle connected with an injector, sucking 1.0ml of tetramethylethylenediamine by using a liquid-transferring gun, adding the tetramethylethylenediamine into the system, starting to raise the temperature to 62 ℃, starting to time, keeping the temperature for 3.5h, after the reaction is finished, washing, filtering and drying by acetone to prepare a 900-plus-1200-micron microsphere crude product, and swelling and sterilizing to prepare the 900-plus-1200-micron embolic microsphere with high elasticity, high drug loading rate and uniform particle size.

Performance testing of the embolic microspheres prepared in examples 1-4

1. Microsphere elastic property test

A physical property tester is selected to test the strength and elasticity of the 900-1200um microsphere. In the measuring process, a force sensing element and a proper probe are arranged, the compression speed is selected to be 0.2mm/s, the compression deformation is selected to be 80%, the holding time is 10s, and the return speed is 0.2 mm/s. And the repeatability and the usability of the data are ensured. As shown in the result of FIG. 3, the compression deformation of the microspheres is 80% and the microspheres are not broken, and the stress steps of the microspheres stably show that the retention force is good, thereby proving the excellent elastic property of the microspheres.

2. Microsphere drug loading performance test

Weighing 0.25g of 100-150um wet embolization microspheres, putting into a 20mL penicillin bottle, adding 4mL of 2.5mg/mL doxorubicin solution, and shaking up. Samples were taken at intervals of 40uL at 5, 10, 20, 30, 60, and 120min, diluted in 5mL of physiological saline, and the absorbance was measured at 485 nm. And substituting the measured absorbance into a standard curve equation to calculate the drug loading rate of the microspheres. The result is shown in FIG. 4a, the maximum drug loading of the microsphere reaches 38 mg/g; and the drug-loaded microspheres still maintain a better spherical shape, as shown in fig. 4 b. With the preparation under better conditions, the drug loading of the microspheres can be further improved.

3. Drug-loaded microsphere drug release performance test

20mg/g microspheres loaded with adriamycin (drug-loaded adriamycin/g microspheres) are placed in a 250mL triangular flask, 100mL PBS phosphate buffer solution with pH7.4 is added, and the mixture is stirred and released in a water bath at 37 ℃. And (3) diluting 1mL of release solution at the time of 30, 60, 90, 120, 180 and 240min respectively, adding 3mL of physiological saline, measuring the absorbance at 485nm, substituting the measured absorbance into an adriamycin standard curve equation, and calculating the drug release amount. The result is shown in fig. 5, the drug-loaded microspheres slowly release the drug, and the release linearity is good, so the prepared microspheres can achieve the slow and controlled release, can slowly release the chemotherapeutic drug at the focus for a long time in clinical application, has low burst release concentration of the drug, greatly reduces the inflammatory reaction to surrounding tissues, and has important significance.

The foregoing detailed description of the preferred embodiments of the invention has been presented. It should be understood that numerous modifications and variations could be devised by those skilled in the art in light of the present teachings without departing from the inventive concepts. Therefore, the technical solutions available to those skilled in the art through logic analysis, reasoning and limited experiments based on the prior art according to the concept of the present invention should be within the scope of protection defined by the claims.

Claims

1. The embolism microsphere with high elasticity and high drug loading capacity is characterized by being prepared by carrying out random copolymerization on polyvinyl alcohol macromolecules serving as a matrix, a ring-forming grafting agent, a double-bond-containing micromolecule bridging agent and an ionic crosslinking agent, wherein the structure of the embolism microsphere is a network structure taking micromolecule crosslinking body stretching vibration and polyvinyl alcohol macromolecules as a framework, and the embolism microsphere has the advantages of high variable elasticity, high drug loading capacity, long drug sustained and controlled release time and uniform particle size distribution.

2. A method of preparing highly elastic, high drug loading embolic microspheres according to claim 1, comprising the steps of:

step 1, synthesizing a modified polyvinyl alcohol derivative, and carrying out chemical reaction on hydroxyl on a macromolecular chain of the polyvinyl alcohol by using the ring-forming grafting agent to form a macromolecular hydrogel structure containing a stable six-membered ring and a functional side group containing double bonds, so as to obtain the modified polyvinyl alcohol derivative;

step 2, synthesizing the embolism microsphere, wherein a reaction system is divided into a dispersion phase and a continuous phase, and the dispersion phase consists of the modified polyvinyl alcohol derivative, the double-bond-containing micromolecule bridging agent, the ionic crosslinking agent and a first initiator; and the continuous phase consists of an oil-soluble solvent, a surfactant and a second initiator, the dispersed phase is dispersed in the continuous phase through a dispersing device, and the embolism microsphere is prepared through fluid shear force.

3. The method for preparing a highly elastic, high drug loading embolic microsphere of claim 2, wherein the step 1 further comprises:

step 1.1, adding 80-120g of the polyvinyl alcohol macromolecules into a flask, adding 500-1000ml of water, heating to 92-98 ℃ for dissolution, and completely dissolving the polyvinyl alcohol macromolecules;

step 1.2, after cooling to room temperature, adding 0.5-5g of the ring-forming grafting agent into the reaction system, stirring at the speed of 100-.

4. The method for preparing a highly elastic, high drug-loading embolic microsphere of claim 2 or 3, wherein the step 2 further comprises:

step 2.1, mixing the ionic cross-linking agent, the first initiator, the double-bond-containing small molecule bridging agent and the modified polyvinyl alcohol derivative according to the weight ratio of 5-80: 0.5-5: 0.1-2: feeding materials in a proportion of 80-100, and uniformly stirring to form the dispersed phase homogeneous liquid;

step 2.2, mixing the surfactant, the second initiator and the oil-soluble solvent according to a ratio of 5-50: 800-1000: feeding materials in a proportion of 0.5-2, and uniformly stirring to form the continuous phase homogeneous liquid;

step 2.3, mixing the dispersed phase homogeneous phase liquid and the continuous phase homogeneous phase liquid according to the ratio of 1: 3-30 proportion, stirring at a speed of 100-;

5. The method for preparing embolization microspheres with high elasticity and high drug loading rate according to claim 3, wherein the degree of polymerization of the polyvinyl alcohol macromolecules is in the range of 1000-2000, the number average molecular weight is 5-15 ten thousand daltons, and the embolization microspheres have good biocompatibility.

6. The method of claim 3, wherein the cyclic grafting agent comprises an alkene boronic acid derivative or an alkene aldehyde derivative, the alkene boronic acid derivative is one of pent-4-en-1-yl boronic acid, vinyl phenyl boronic acid and 4-allyl carbamoyl phenyl boronic acid, and the alkene aldehyde derivative is one of acrolein and acrolein acetal.

7. The preparation method of the embolization microsphere with high elasticity and high drug loading capacity according to claim 4, wherein the double bond-containing micromolecule bridging agent is a derivative containing a single or more than two double bond structures, preferably one of acrylamide and N, N-methylene bisacrylamide.

8. The method for preparing high elasticity and high drug loading capacity embolization microspheres according to claim 4, wherein the ionic cross-linking agent is a sulfonate derivative containing negative charges, preferably an ionic acrylamide monomer.

9. The method for preparing high elasticity embolization microspheres with high drug loading according to claim 8, wherein the monomer containing ionic acrylamide is one of 2-acrylamide-2-methylpropanesulfonic acid sodium salt and 2-acrylamido-2-methylpropanesulfonic acid.

10. The method for preparing a high elasticity and high drug loading rate embolic microsphere as claimed in claim 4, wherein the particle size of the embolic microsphere is 75-125 μm, 150-250 μm, 350-450 μm, 550-650 μm, 750-850 μm or 900-1200 μm.