Developing embolism microsphere, preparation method thereof and drug-loading developing embolism microsphere

Abstract

The invention provides a developing embolism microsphere, a preparation method thereof and a drug-loaded developing embolism microsphere, and relates to the technical field of embolism microspheres. The developing embolism microsphere comprises a polymer network structure formed by cross-linking polymerization of an iodine-substituted tyrosine derivative and a cross-linking agent with an epoxypropane end group; the iodine-substituted tyrosine derivative comprises at least two active groups capable of reacting with an end group of epoxypropane. The preparation method of the developing embolism microspheres comprises the following steps: adding an alkaline catalyst into water to prepare an alkaline aqueous solution, sequentially adding an iodine-substituted tyrosine derivative and a crosslinking agent with an epoxypropane end group, and pre-crosslinking for a period of time to obtain an aqueous phase solution; mixing an oil-phase solvent and a dispersing agent to obtain an oil-phase solution; and adding the oil-phase solution into the water-phase solution to obtain a water-in-oil reversed-phase suspension system, and heating for reaction to obtain the developing embolism microspheres. The developing embolism microsphere provided by the invention is more uniform in developing, can load more types of medicines, and has a better slow release effect.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of embolic microspheres, in particular to a developing embolic microsphere and a preparation method thereof and a drug-loaded developing embolic microsphere. BACKGROUND

[0002] Embolic microspheres (EMs) are a kind of "microspherical" vascular embolic materials with uniform particle size and precise control of embolic level, which have gradually replaced traditional irregular particles (such as gelatin sponge particles, polyvinyl alcohol particles, etc.) and become the core consumables for interventional treatment of transarterial chemoembolization (TACE), benign and malignant tumors, vascular malformations and internal organs bleeding. DEB-TACE (Drug-Eluting Bead-Transarterial Chemoembolization) is an interventional therapy for liver cancer developed on the basis of traditional TACE, and the core improvement is to replace the traditional iodized oil-chemotherapy emulsion with "chemotherapeutic drug-loaded and slow-release" embolic microspheres to achieve the dual effects of "embolization + continuous local chemotherapy".

[0003] With the development of DEB-TACE, people's demand for its visualization, precision and traceable treatment is increasing. Most of the embolic microspheres used in DEB-TACE on the market are not developed under X-ray, and the embolic position, displacement or recurrence after operation cannot be judged in real time, which seriously affects the efficacy evaluation and secondary intervention. To solve this bottleneck, researchers have tried to introduce iodine oil, tantalum powder, metal oxide and other developing components into the embolic microsphere system, so that it has the triple functions of "embolization", "development" and "drug loading and release" to realize real-time navigation during operation and long-term follow-up after operation. However, the developing embolic agent containing metal salt has potential toxicity, iodine oil is easy to leak and unstable, and many other problems, prompting people to develop a new developing microsphere platform that can be fused, low toxicity, good biocompatibility and good drug loading and release performance.

[0004] Therefore, it is particularly important to develop a developing embolic microsphere with good developing effect, drug loading and good sustained release effect for the development of DEB-TACE. SUMMARY

[0005] The purpose of the present application is to provide a developing embolic microsphere and a preparation method thereof and a drug-loaded developing embolic microsphere to solve the above problems.

[0006] To achieve the above purpose, the following technical solutions are adopted in the present application: In a first aspect of the present application, a developing embolization microsphere is provided, comprising a polymer network structure formed by cross-linking polymerization of an iodine-substituted tyrosine derivative and a cross-linking agent with a terminal epoxypropane group, wherein the iodine-substituted tyrosine derivative comprises at least two active groups that can react with the terminal epoxypropane group.

[0007] The developing embolization microsphere provided in the present application comprises a polymer network structure formed by cross-linking polymerization of an iodine-substituted tyrosine derivative and a cross-linking agent with a terminal epoxypropane group. The iodine-substituted tyrosine derivative has a high iodine content, which can endow the microsphere with X-ray developing ability. The iodine-substituted tyrosine derivative participates in the polymerization reaction to become the main chain of the network structure through two active groups and the cross-linking agent, which is more conducive to the uniform distribution of iodine groups, thereby endowing the microsphere with more uniform developing effect. The iodine-substituted tyrosine derivative in the microsphere has abundant carboxylate groups, which can achieve efficient loading and release of various cationic drugs, thereby realizing drug sustained-release treatment effect.

[0008] In a second aspect of the present application, a preparation method of the developing embolization microsphere is provided, comprising: After the alkaline catalyst is added to water to configure an alkaline aqueous solution, the iodine-substituted tyrosine derivative and the cross-linking agent with a terminal epoxypropane group are sequentially added, and a water phase solution is obtained after pre-cross-linking for a period of time; The oil phase solvent and the dispersing agent are mixed to obtain an oil phase solution; The oil phase solution is added to the water phase solution to obtain a water-in-oil reverse suspension system, and the developing embolization microsphere is obtained by heating reaction.

[0009] The preparation method of the developing embolization microsphere provided in the present application introduces iodine elements into the high molecular chain through the epoxy group of the cross-linking agent with a terminal epoxypropane group and the epoxy ring-opening reaction of the iodine-substituted tyrosine derivative, and successfully synthesizes the developing microsphere. Without introducing pore-forming agents and other aids, the amount of the iodine-substituted tyrosine derivative and the chain length of the cross-linking agent can be adjusted to control the phase separation degree caused by the coupling of the iodine-substituted tyrosine derivative, so that the microsphere has a unique porous structure, which is conducive to the loading and release of drugs.

[0010] In a third aspect of the present application, a drug-loaded developing embolization microsphere is provided. The developing embolization microsphere described above loads cationized drugs through anion groups, and the anion groups include carboxyl groups on the developing embolization microsphere.

[0011] The drug-loaded developing embolization microsphere provided in the present application efficiently loads cationized drugs through the carboxyl groups on the developing embolization microsphere, and cooperates with the unique porous structure of the microsphere to achieve efficient loading and release of various cationic drugs, has good developing effect, can load drugs and has good sustained-release effect, thereby realizing precise embolization, local drug delivery, and DEB-TACE treatment with visualization and traceability. Attached Figure Description

[0012] To more clearly illustrate the technical solutions of the embodiments of this application, the accompanying drawings used in the embodiments will be briefly described below. It should be understood that the following drawings only show some embodiments of this application and should not be regarded as a limitation on the scope of this application.

[0013] Figure 1 This is an optical micrograph of the microspheres that were developed into embolic microspheres obtained in Example 3. Detailed Implementation

[0014] To better illustrate the technical solution provided in this application, the technical solution will be described in its entirety before the embodiments, as follows: This application provides a radioactive embolization microsphere comprising a polymer network structure formed by crosslinking polymerization of an iodine-substituted tyrosine derivative and a crosslinking agent having propylene oxide end groups, wherein the iodine-substituted tyrosine derivative comprises at least two active groups capable of reacting with the propylene oxide end groups.

[0015] The radiopaque embolization microspheres provided in this application comprise a polymer network structure formed by cross-linking polymerization of an iodine-substituted tyrosine derivative and a cross-linking agent with propylene oxide end groups. The iodine-substituted tyrosine derivative has a high iodine content, which endows the microspheres with X-ray radiopaqueness. The iodine-substituted tyrosine derivative participates in the polymerization reaction through two active groups and the cross-linking agent to become the main chain of the network structure, which is more conducive to the uniform distribution of iodine groups, thereby giving the microspheres a more uniform radiopaque effect. Since the iodine-substituted tyrosine derivative in the microspheres has abundant carboxyl groups, it can achieve efficient loading and release of various cationic drugs, thereby achieving a sustained-release therapeutic effect.

[0016] In an alternative embodiment, the two active groups include an amino group and a phenolic hydroxyl group, wherein the amino group includes at least one of a primary amine and a secondary amine.

[0017] In this application, the iodine-substituted tyrosine derivative includes amine and phenolic hydroxyl groups that can react with propylene oxide end groups, generating a polymer network structure through a ring-opening reaction, which makes the polymer network structure more stable.

[0018] In an optional embodiment, the iodine-substituted tyrosine derivative includes at least one of a monoiodotyrosine derivative, a diiodotyrosine derivative, and a polyiodotyrosine derivative, wherein the monoiodotyrosine derivative comprises a tyrosine derivative with one iodine-substituted group, the diiodotyrosine derivative comprises a tyrosine derivative with two iodine-substituted groups, and the polyiodotyrosine derivative comprises a tyrosine derivative with three, four, or more iodine-substituted groups. Exemplarily, iodine-substituted tyrosine derivatives include at least one of 3-iodo-L-tyrosine, 3,5-diiodo-L-tyrosine, triiodothyronine, and thyroxine.

[0019] In the present application, the iodine content in the final imaging embolization microspheres can be controlled by controlling the number of iodine substituent groups in the iodine-substituted tyrosine derivative, thereby regulating the imaging performance of the imaging embolization microspheres.

[0020] It should be noted that, in the present application, the iodine-substituted tyrosine derivative includes a carboxylic acid group, and thus can load cationic drugs through electrostatic interaction.

[0021] In an alternative embodiment, the crosslinking agent includes a glycidyl ether compound with an end group of propylene oxide.

[0022] Alternatively, the molar ratio of the crosslinking agent to the iodine-substituted tyrosine derivative in the present application is 1: (1-10), and by regulating the content of the iodine-substituted tyrosine derivative added, the imaging performance of the imaging embolization microspheres can be controlled. At the same time, since the imaging embolization microspheres include a carboxylic acid group, the content of the loaded cationic drugs can also be regulated.

[0023] Alternatively, the crosslinking agent includes one or more of glycerol diglycidyl ether, polypropylene glycol diglycidyl ether, polyethylene glycol diglycidyl ether, 1,4-butanediol diglycidyl ether, glycerol triglycidyl ether, resorcinol diglycidyl ether, bisphenol A diglycidyl ether, 1,6-hexanediol diglycidyl ether, neopentyl glycol diglycidyl ether, and derivatives thereof.

[0024] In the present application, a glycidyl ether compound with an end group of propylene oxide is selected as the crosslinking agent. Different crosslinking agents have different chain lengths, and by selecting crosslinking agents with different chain lengths, the size of the porous structure in the synthesized imaging embolization microspheres can be regulated, specifically: When a crosslinking agent with a shorter chain length, such as glycerol triglycidyl ether, is selected, the size of the porous structure in the polymeric network structure of the embolization microspheres is smaller, resulting in greater steric hindrance of the benzene ring structure in the iodine-substituted tyrosine derivative in the smaller porous structure, which cannot effectively produce phase separation through coupling.

[0025] When a crosslinking agent with a longer chain length, such as polyethylene glycol diacrylate ((C2H4O)nC6H6O3, n selected from 10-20), is selected, the size of the porous structure in the polymeric network structure of the embolization microspheres is larger, resulting in less steric hindrance of the benzene ring structure in the iodine-substituted tyrosine derivative in the larger porous structure, which can effectively produce phase separation through coupling.

[0026] In the present application, the iodine-substituted tyrosine derivative produces a phase separation effect as shown in the following structural formula one, which is exemplary:

[0027] Structural formula one After the iodine-substituted tyrosine derivative and the crosslinking agent in the present application form a polymer network structure through ring-opening polymerization, the unreacted free iodine-substituted tyrosine derivative enters the porous structure of the polymer network structure. The product space steric hindrance of the polymer network structure synthesized by the crosslinking agent with a short chain length is large, and the phase separation effect cannot effectively occur in the small porous structure. The polymer network structure synthesized by the crosslinking agent with a long chain length has a large porous structure, and the space steric hindrance of the phase separation product is small, thus facilitating the generation of the phase separation.

[0028] The present application regulates the amount of iodine-substituted tyrosine derivative and the chain length of the crosslinking agent, thereby regulating the degree of phase separation caused by the coupling of the iodine-substituted tyrosine derivative. The greater the degree of phase separation in the developed embolization microspheres, the more the microphase structures in the microspheres, which is not only beneficial to the loading of hydrophobic drugs, but also effectively prolongs the drug release path and improves the sustained-release effect.

[0029] The present application also provides a preparation method of developed embolization microspheres, comprising: After the alkaline catalyst is added to water to configure an alkaline aqueous solution, the iodine-substituted tyrosine derivative and the crosslinking agent with an epoxy propane end group are sequentially added, and a water phase solution is obtained after pre-crosslinking for a period of time; The oil phase solvent and the dispersant are mixed to obtain an oil phase solution; The oil phase solution is added to the water phase solution to obtain a water-in-oil reverse suspension system, and the developed embolization microspheres are obtained by heating reaction.

[0030] By means of "one-pot method", the iodine-substituted tyrosine and the epoxy crosslinking agent with good biological safety are prepared through epoxy ring-opening reaction to obtain developed microspheres. The microspheres have good development performance, and also have good cationic drug loading capacity due to the presence of carboxyl groups, which takes into account the dual effects of "development" and "drug loading and release". In addition, the unique "porous structure" of the microspheres can further enhance the drug loading capacity, which is beneficial to the treatment of DEB-TACE.

[0031] In an alternative embodiment, the iodine-substituted tyrosine derivative includes at least one of 3-iodo-L-tyrosine, 3,5-diiodo-L-tyrosine, triiodothyronine, and thyroxine; and / or, The crosslinking agent includes glycidyl ether compounds with an epoxy propane end group; Optionally, the crosslinking agent includes one or more of glycerol diglycidyl ether, polypropylene glycol diglycidyl ether, polyethylene glycol diglycidyl ether, 1,4-butanediol diglycidyl ether, glycerol triglycidyl ether, resorcinol diglycidyl ether, bisphenol A diglycidyl ether, 1,6-hexanediol diglycidyl ether, neopentyl glycol diglycidyl ether, and derivatives thereof; and / or, The molar ratio of crosslinking agent, iodine-substituted tyrosine derivative and basic catalyst is 1:(1~10):(2~10).

[0032] By adjusting the dosage of each substance, especially the amount of crosslinking agent, the chain length of the crosslinking agent can be adjusted, thereby regulating the pore spacing and controlling the degree of microsphere phase separation, which is beneficial for multi-type drug loading and enhancing sustained-release effect.

[0033] In an optional embodiment, the method for preparing the imaging embolization microspheres satisfies one or more of the following conditions: (1) Alkaline catalysts include sodium hydroxide and / or potassium hydroxide; (2) The alkaline catalyst is prepared in advance as an aqueous solution with a mass concentration of 10-40% (which can be any value between 10%, 20%, 30%, 40% or 10-40%). (3) The pre-crosslinking temperature is 20-80℃, and the time is 0.5-2h; Optionally, the pre-crosslinking temperature can be any value between 20℃, 30℃, 40℃, 50℃, 60℃, 70℃, 80℃ or 20-80℃, and the time can be any value between 0.5h, 1h, 1.5h, 2h or 0.5-2h. (4) The temperature of the heating reaction is 30-70℃ and the time is 12-18h.

[0034] Optionally, the temperature of the heating reaction can be any value between 30℃, 40℃, 50℃, 60℃, 70℃ or 30-70℃, and the time can be any value between 12h, 14h, 16h, 18h or 12-18h.

[0035] In an optional embodiment, the oil phase solvent includes one or more of butyl acetate, liquid paraffin, dimethyl silicone oil, soybean oil, cycloalkanes, and alkanes; and / or, The dispersants include one or more of the following: cellulose acetate butyrate, OP dispersants (alkylphenol polyoxyethylene ether), Span dispersants, Tween dispersants, AEO dispersants (high carbon fatty alcohol polyoxyethylene ether), PEG dispersants (polyethylene glycol), and PVA dispersants (polyvinyl alcohol).

[0036] For example, cycloalkane compounds may be cyclohexane, alkanes may be n-decane, OP dispersants may be OP-10 and / or OP-20, Span dispersants may be Span-80 and / or Span-60, Tween dispersants may be Tween-60 and / or Tween-80, AEO dispersants may be AEO-7 and / or AEO-9, PEG dispersants may be PEG-400 and / or PEG-8000, and PVA dispersants may be PVA-1788 and / or PVA-1799.

[0037] Regarding dosage, for example, the mass-volume ratio of dispersant to oil phase solvent can be 1g / 100ml, 2g / 100ml, 3g / 100ml, 4g / 100ml, 5g / 100ml, 6g / 100ml, 7g / 100ml, 8g / 100ml, 9g / 100ml, 10g / 100ml or any value between 1 and 10g / 100ml.

[0038] This application also provides a drug-loaded radioactive embolization microsphere, comprising radioactive embolization microspheres, wherein the radioactive embolization microspheres are loaded with cationic drugs via anionic groups, the anionic groups including carboxyl groups on the radioactive embolization microspheres.

[0039] In one alternative embodiment, the cationized drug includes at least one of doxorubicin, arubibin, epirubibin, idarubibin, penrubibin, irinotecan, topotecan, vinorelbine, vindesin, gemcitabine, capecitabine, sorafenib, regorafenib, donafenib, cabozantinib, cunvatinib, sunitinib, osimertinib, and apatinib.

[0040] Normally, the aforementioned drugs are uploaded to the imaging embolization microspheres provided in this application using ordinary means in the art, such as mixing and impregnating the microspheres with a solution containing the aforementioned drugs.

[0041] The implementation schemes of this application will be described in detail below with reference to specific embodiments. However, those skilled in the art will understand that the following embodiments are only for illustrating this application and should not be regarded as limiting the scope of this application. Unless otherwise specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments used without specified manufacturers are all conventional products that can be purchased commercially.

[0042] Example 1 This embodiment provides a radioactive embolization microsphere, the general formula of which is shown below: ; Where X and Y represent the degree of aggregation.

[0043] The preparation method of the above-mentioned imaging embolization microspheres is as follows: Under magnetic stirring, NaOH was added to water to prepare a 20wt% NaOH solution. Then, 2g (4.6 mmol) of iodotyrosine was dissolved in 2 mL of 20wt% NaOH solution (9.7 mmol). 1.2g (4.6 mmol) of glycerol triglycidyl ether was added to the mixed solution and pre-crosslinked at 25°C for 1 h to obtain an aqueous solution.

[0044] Weigh 100 mL of butyl acetate, add 3 g of cellulose acetate butyrate and dissolve it completely to obtain the oil phase system required for the reaction.

[0045] Finally, the aqueous solution is added dropwise to the oil phase system to form a water-in-oil reverse suspension system. The mixture is reacted at 60°C for 16 hours. After the reaction is completed, the oil phase is separated, cleaned and purified, and sieved to obtain the developing microspheres with a unique "sphere-in-sphere" structure.

[0046] Example 2 This embodiment provides a radioactive embolization microsphere, the general formula of which is shown below: ; Where X and Y represent the degree of aggregation.

[0047] Compared with Example 1, the preparation method of the above-mentioned imaging embolization microspheres is modified by increasing the amount of iodotyrosine and 20wt% NaOH solution to 4g (9.2mmol) and 4mL (19.4mmol), respectively, while keeping other conditions unchanged.

[0048] Example 3 This embodiment provides a radioactive embolization microsphere, the general formula of which is shown below: ; Where X, Y, and n represent the degree of aggregation.

[0049] Compared with Example 2, the above method for preparing the imaging embolism microspheres differs in that 1.2 g (4.6 mmol) of glycerol triglycidyl ether is replaced with 2.93 g (4.6 mmol) of polyethylene glycol diacrylate ((C2H4O)). n (C6H6O3, n=10), other conditions remain unchanged.

[0050] Optical micrographs of the obtained embolized microspheres are shown below. Figure 1 As shown, from Figure 1 The obtained embolic microspheres can be clearly seen to have a unique "sphere-within-a-sphere" structure.

[0051] Example 4 This embodiment provides a radioactive embolization microsphere, the general formula of which is shown below: ; Where X, Y, and m represent the degree of polymerization.

[0052] The above-described method for preparing the imaging embolic microspheres, compared to Example 3, involves using 2.93 g (4.6 mmol) of polyethylene glycol diacrylate ((C2H4O) n (C6H6O3, n=10) was changed to 4.63 g (4.6 mmol) of polyethylene glycol diacrylate ((C2H4O) m (C6H6O3, m=20), other conditions remain unchanged.

[0053] Comparative Example 1 DC Bead microspheres (Biocompatibles, UK) were used as a control.

[0054] Comparative Example 2 Iohexol 150 was used as a control.

[0055] The following tests demonstrate the technical specifications and advantages of the solution provided in this application, as detailed below: Development performance test The radioactivity of the 100-300 μm microspheres in Examples 1-4 and Comparative Example 1 was evaluated using Micro-CT testing. The specific testing protocol is as follows: Microspheres were suspended in 0.5% agarose gel in 5 mL centrifuge tubes. Using a micro-CT imaging system scanner equipped with a tungsten anode, the X-ray radioactivity of the microspheres was tested using micro-computed tomography (micro-CT imaging system). The HU values ​​of each sample are shown in Table 1. Table 1. HU values ​​of microspheres in each group

[0056] As shown in Table 1 above, the microspheres prepared in Examples 1-4 all exhibited high HU values ​​under the same testing conditions, significantly higher than those of Comparative Example 1 (which lacked imaging ability) and the clinically commonly used Comparative Example 2. Furthermore, a comparison of the examples reveals that, with the same amount of iodotyrosine, Examples 3 and 4, using a long-chain crosslinking agent, had higher HU values ​​than Example 2, which used a short-chain crosslinking agent. This is presumably because the microscopic spatial structure of the microspheres in Examples 3 and 4 was more relaxed, making it easier for free iodotyrosine to undergo coupling reactions with the iodotyrosine on the molecular chain, thus increasing the iodine content of the microspheres. In contrast, Examples 1 and 2, using a short-chain crosslinking agent, had the lowest HU values ​​due to their more compact microscopic spatial structure and greater steric hindrance, making it difficult for iodotyrosine to undergo coupling reactions. Under the same crosslinking agent, Example 2, with a higher amount of iodotyrosine, had a higher HU value than Example 1. This may be because the iodotyrosine reacted with the remaining epoxy groups, increasing the iodine content and thus the HU value (due to excess iodotyrosine).

[0057] Drug loading performance test Two groups (1 mL each) of the embolic microspheres from Examples 1-4 and Comparative Example 1 were taken and numbered. Moisture was removed from the surface of the microspheres using filter paper. The microspheres were then transferred to vials, and 10 mL of irinotecan hydrochloride solution (20 mg / mL) was added to each vial. The mixture was shaken, and the solution concentration was tested and the drug loading of the microspheres was calculated at 5 min, 15 min, and 30 min. The results are shown in Table 2 below. Table 2 Summary of drug loading data for irinotecan on microspheres

[0058] As shown in Table 2, the microspheres in Examples 1-4 all exhibited faster drug loading rates and higher maximum drug loading capacities than the DC Bead. It is speculated that the unique "sphere-within-a-sphere" porous structure of the microspheres promotes material exchange between the entire microsphere and the drug solution, thus increasing the maximum drug loading capacity. In contrast, the DC Bead, due to its uniform structure, allows the drug to easily accumulate on the surface of the microspheres, resulting in a lower maximum drug loading capacity. Furthermore, the maximum drug loading capacity of each microsphere follows the order "Example 1 < Examples 2-3-4". The specific analysis is as follows: ① The drug loading capacity of Example 2 is higher than that of Example 1 because the microspheres in Example 2 contain more iodotyrosine, increasing the carboxyl group density of the microspheres, thus resulting in a higher drug loading capacity. ② There is no significant difference in the maximum drug loading capacity among Examples 2, 3, and 4, possibly because the carboxyl group content is similar among the three.

[0059] Microsphere drug release test The drug-loaded microspheres were added to a dialysis bag, which was then placed in a beaker. Physiological saline (20 mL) was added to the beaker, and the bag was sealed. Samples were taken every 5 min, 30 min, and 60 min to measure the drug concentration in the dialysis bag solution. The drug release rate of the microspheres was obtained by dividing the concentration by the drug loading data of the microspheres.

[0060] Table 3 Summary of Iritex release rate data for microspheres

[0061] Table 3 shows that the drug release rate of the microspheres is ranked as follows: "Example 3 < Example 4 < Example 1 < Example 2 < Comparative Example 1". The specific analysis is as follows: ① Example 2 has a stronger drug release capacity than Example 1, possibly because Example 2 contains more iodotyrosine amino acids, making the microspheres denser. The drug cannot penetrate the interior of the microspheres but accumulates on the surface, resulting in a higher release rate. ② The drug release rate of the long crosslinking agent group is lower than that of the short crosslinking agent group. This is because the microspheres in the long crosslinking agent group have a looser spatial structure, which is conducive to the coupling reaction of iodotyrosine molecules. The internal phase separation and porous structure density of the microspheres are higher, extending the drug release pathway and thus providing a better sustained-release effect. However, an excessively long crosslinking agent can negatively impact the sustained-release effect due to the overly loose microsphere structure.

[0062] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of this application, and are not intended to limit them. Although this application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of this application.

Claims

1. A type of radiopaque embolic microsphere, characterized in that, The invention comprises a polymer network structure formed by crosslinking polymerization of an iodine-substituted tyrosine derivative and a crosslinking agent having a propylene oxide end group, wherein the iodine-substituted tyrosine derivative includes at least two active groups that can react with the propylene oxide end group.

2. The imaging embolization microspheres according to claim 1, characterized in that, The two active groups include an amino group and a phenolic hydroxyl group, wherein the amino group includes at least one of a primary amine and a secondary amine; and / or, The molar ratio of the crosslinking agent to the iodine-substituted tyrosine derivative is 1:(1-10).

3. The imaging embolization microspheres according to claim 1, characterized in that, The iodine-substituted tyrosine derivatives include at least one of monoiodotyrosine derivatives, diiodotyrosine derivatives, and polyiodotyrosine derivatives. Optionally, the iodine-substituted tyrosine derivatives include at least one of 3-iodo-L-tyrosine, 3,5-diiodo-L-tyrosine, triiodothyronine, and thyroxine.

4. The imaging embolization microspheres according to claim 1, characterized in that, The crosslinking agent includes glycidyl ether compounds with propylene oxide end groups; Optionally, the crosslinking agent includes one or more of the following: glycerol diglycidyl ether, polypropylene glycol diglycidyl ether, polyethylene glycol diglycidyl ether, 1,4-butanediol diglycidyl ether, glycerol triglycidyl ether, resorcinol diglycidyl ether, bisphenol A diglycidyl ether, 1,6-hexanediol diglycidyl ether, neopentyl glycol diglycidyl ether, and their derivatives.

5. A method for preparing the imaging embolic microspheres as described in any one of claims 1-4, characterized in that, include: After adding an alkaline catalyst to water to prepare an alkaline aqueous solution, an iodine-substituted tyrosine derivative and a crosslinking agent with propylene oxide end groups are added sequentially. After pre-crosslinking for a period of time, an aqueous solution is obtained. The oil phase solvent and dispersant are mixed to obtain an oil phase solution; The oil phase solution is added to the aqueous phase solution to obtain a water-in-oil reversed-phase suspension system, and the reaction is heated to obtain the imaging embolism microspheres.

6. The method for preparing the imaging embolic microspheres according to claim 5, characterized in that, The iodine-substituted tyrosine derivatives include at least one of 3-iodo-L-tyrosine, 3,5-diiodo-L-tyrosine, triiodothyronine, and thyroxine; and / or, The crosslinking agent comprises glycidyl ether compounds with glycidyl oxide end groups; optionally, the crosslinking agent comprises one or more of the following: glycerol diglycidyl ether, polypropylene glycol diglycidyl ether, polyethylene glycol diglycidyl ether, 1,4-butanediol diglycidyl ether, glycerol triglycidyl ether, resorcinol diglycidyl ether, bisphenol A diglycidyl ether, 1,6-hexanediol diglycidyl ether, neopentyl glycol diglycidyl ether, and their derivatives; and / or, The molar ratio of the crosslinking agent, the iodine-substituted tyrosine derivative, and the basic catalyst is 1:(1~10):(2~10).

7. The method for preparing the radiopaque embolic microspheres according to claim 5, characterized in that, One or more of the following conditions must be met: (1) The alkaline catalyst includes sodium hydroxide and / or potassium hydroxide; (2) The alkaline catalyst is prepared in advance as an aqueous solution with a mass concentration of 10-40%; (3) The pre-crosslinking temperature is 20-80℃ and the time is 0.5-2h; (4) The heating reaction is carried out at a temperature of 30-70℃ for 12-18h.

8. The method for preparing the radiopaque embolic microspheres according to any one of claims 5-7, characterized in that, The oil phase solvent includes one or more of butyl acetate, liquid paraffin, dimethyl silicone oil, soybean oil, cycloalkanes, and alkanes; and / or, The dispersant includes one or more of the following: cellulose acetate butyrate, OP type dispersants, Span type dispersants, Tween type dispersants, AEO type dispersants, PEG type dispersants, and PVA type dispersants.

9. A drug-loaded contrast-enhancing embolism microsphere, comprising the contrast-enhancing embolism microsphere according to any one of claims 1 to 4, characterized in that, The contrast-enhancing embolization microspheres are loaded with cationic drugs via anionic groups, the anionic groups including carboxyl groups on the contrast-enhancing embolization microspheres.

10. The drug-loaded contrast-enhancing microspheres according to claim 9, characterized in that, The cationic drugs include at least one of doxorubicin, arubibin, epirubibin, idarubibin, penrubibin, irinotecan, topotecan, vinorelbine, vindesin, gemcitabine, capecitabine, sorafenib, regorafenib, donafenib, cabozantinib, cunvatinib, sunitinib, osimertinib, and apatinib.

Images