Embolism microsphere and preparation method thereof
By bonding AIE-performance tetrastyrene compounds with polyvinyl alcohol microspheres, embolized microspheres with fluorescence development capabilities were prepared, which solved the problem of unvisible existing microspheres under clinical detection and achieved the operation. Accurate embolization and postoperative evaluation, and drug delivery performance was maintained.
Patent Information
- Application Number
- CN202411337145.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-24
- Publication Date
- 2024-12-27
AI Technical Summary
Existing embolization microspheres are difficult to visualize under clinical testing equipment, affecting surgical accuracy and postoperative evaluation, and have limited fluorescence development capabilities, affecting drug loading and delivery performance.
By chemically bonding tetrastyrene compounds with AIE properties with polyvinyl alcohol microspheres, embolizing microspheres with fluorescence development capabilities are prepared, combined with loaded drugs, accurate intraoperative embolization and postoperative evaluation, and maintain good suspension Performance and elasticity.
The visual operation of microspheres under fluorescent equipment is realized, which improves surgical accuracy and evaluation accuracy, while maintaining drug delivery performance and particle size and surface performance suitable for clinical use.
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Figure CN119185629A_ABST
Abstract
Description
Technical Field
[0001] The present application relates to the technical field of embolic materials, and in particular to an embolic microsphere and a preparation method thereof. Background Art
[0002] At present, TACE therapy has become the main treatment for advanced liver cancer. Embolic microspheres are the most widely used embolic materials in clinical TAE and TACE surgeries. However, the embolic microspheres currently commonly used in clinical practice cannot be visualized under conventional clinical detection equipment, making it difficult to accurately control their positioning during interventional surgery. Although exogenous contrast agents can assist in the visualization of microspheres, the exogenous contrast agents quickly diffuse in the bloodstream, and the specific location of the embolic microspheres cannot be confirmed after surgery.
[0003] The reported X-ray visualized embolic microspheres, such as DC Bead LUMI developed by Biocompatibles UK and marketed overseas, modify iodine-containing compounds on polyvinyl alcohol microspheres and use the high absorption of iodine to X-rays to achieve in vivo visualization of high-iodine-content microspheres under X-ray detection equipment (CT, DSA, etc.), thereby achieving intraoperative and postoperative traceability of embolic microspheres, which is convenient for improving surgical accuracy and postoperative evaluation. In the literature, there are many methods that use physical coating or in-situ deposition of ferromagnetic compounds, such as ferroferric oxide particles, to synthesize MRI or multimodal visualized embolic microspheres, but no related products have been marketed. It may be due to the addition of ferromagnetic particles that the good surface properties of the microspheres cannot be guaranteed, which seriously affects surgical delivery.
[0004] Although X-ray detection equipment is currently a commonly used device in clinical surgery, it causes radiation damage to the human body, affecting the health of patients and surgeons. MRI imaging technology has high precision and is harmless to the human body, but it requires high magnetic field conditions. There is currently no intraoperative equipment, and it can only be used for preoperative diagnosis and postoperative evaluation. Fluorescence imaging, as a rapidly developing in vivo imaging mode, does not involve ionizing radiation, has no radiotoxicity, and is safer. It also has good imaging characteristics (including fast feedback, high sensitivity, low detection limit, and high temporal and spatial resolution, etc.), can visualize the anatomical structure and function of living tissues and organs, and can dynamically monitor changes in the pathophysiological microenvironment of tumors, and is expected to play an important role in tumor diagnosis and surgical guidance. Therefore, the preparation of embolic microspheres with fluorescent imaging function can realize the visualization operation of microspheres through fluorescent equipment during surgery, which has great clinical and economic value.
[0005] Existing fluorescent microspheres are generally surface-modified on microspheres with greater hardness (such as styrene resins and silica microspheres), giving the microspheres surface fluorescent properties, but with limited fluorescence visualization capabilities, and seriously changing the surface properties of the microspheres, affecting drug loading and delivery performance. Moreover, the surface-modified compounds are easy to fall off, resulting in loss of fluorescence. In addition, the particle size of clinically used embolic microspheres is generally 30-2000 microns, while the existing fluorescent microspheres have a size between tens of nanometers and tens of microns, which cannot meet the needs of embolization surgery. Summary of the invention
[0006] The present application provides an embolic microsphere and a preparation method thereof, which has the ability of fluorescent imaging while being loaded with drugs, so as to facilitate precise embolization during surgery and postoperative evaluation.
[0007] The embodiment of the present application is implemented as follows:
[0008] In a first aspect, the present application provides an embolic microsphere, which includes polyvinyl alcohol microspheres and a compound with AIE properties modified on the polyvinyl alcohol microspheres, wherein the compound with AIE properties is a tetraphenylethylene compound.
[0009] In the above technical scheme, the present application chemically bonds polyvinyl alcohol microspheres to modify organic molecular compounds with AIE (aggregation-induced emission) properties, and the organic molecular compounds with AIE properties are tetraphenylethylene compounds, so as to realize embolic microspheres with controllable fluorescence intensity. The embolic microspheres of the present application have fluorescence development capabilities while loading drugs, which facilitates precise intraoperative embolization and postoperative evaluation. In addition, the embolic microspheres have a lower density, better suspension performance and elasticity, and a suitable particle size, which is conducive to convenient delivery in embolic surgery.
[0010] In some possible embodiments, the chemical formula of the embolic microspheres is as follows:
[0011]
[0012] Wherein, R1, R2 and R3 are independently selected from hydrogen or an electron-donating group, and m and n are 1000 to 100000 respectively.
[0013] In the above technical scheme, the tetraphenylethylene compound in the embolic microspheres of the present application is bonded to the polyvinyl alcohol microspheres through acetal bonds, and the tetraphenylethylene compound molecules with aggregation-induced emission function are closely arranged on the polyvinyl alcohol chain. Due to the restricted molecular movement, it has fluorescent development performance.
[0014] In some possible embodiments, the electron donating group includes a methoxy group or a dimethylamino group.
[0015] In the above technical solution, the electron-donating group includes a methoxy group or a dimethylamino group, so that the embolization microspheres have a fluorescent development property.
[0016] In some possible embodiments, the chemicals having AIE properties include:
[0017]
[0018]
[0019] In the above technical solution, by making the chemical with AIE property include the above structure, the embolic microspheres have fluorescence development property.
[0020] In some possible embodiments, the mass of the compound having AIE performance in the embolic microspheres accounts for 30% to 70% of the total mass of the embolic microspheres.
[0021] In the above technical solution, by making the mass of the compound having AIE performance in the embolic microspheres account for the total mass of the embolic microspheres within the above range, the embolic microspheres have better fluorescence development performance.
[0022] In some possible embodiments, the particle size of the embolic microspheres is 50 μm to 1000 μm.
[0023] In the second aspect, the present application provides a method for preparing the embolic microspheres in the above embodiment, which comprises mixing a compound having AIE properties of polyvinyl alcohol microspheres and a raw material of a first solvent, heating under stirring to completely swell the polyvinyl alcohol microspheres, adding methanesulfonic acid to the raw material, and reacting to obtain a crude product. The mass ratio of the polyvinyl alcohol microspheres to the compound having AIE properties is 1:0.5-1.3.
[0024] In the above technical scheme, the preparation method of the embolic microspheres of the present application is simple, the prepared embolic microspheres have a stable structure, and have the ability to develop fluorescence while loading drugs, which is convenient for accurate intraoperative embolization and postoperative evaluation. In addition, the embolic microspheres have a low density, good suspension performance and elasticity, and a suitable particle size, which is conducive to convenient delivery during embolic surgery.
[0025] In some possible embodiments, the reaction temperature is 50°C to 80°C.
[0026] In some possible implementation schemes, the mass volume ratio of polyvinyl alcohol microspheres and methanesulfonic acid is 1:1 to 5 g / mL.
[0027] In some possible embodiments, the crude product is washed with dimethyl sulfoxide, sodium bicarbonate solution and purified water in sequence to prepare embolic microspheres.
[0028] In the above technical solution, the crude product is washed with dimethyl sulfoxide, sodium bicarbonate solution and purified water in sequence, so as to remove the impurities and acid remaining in the crude product, thereby preparing embolic microspheres. BRIEF DESCRIPTION OF THE DRAWINGS
[0029] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings required for use in the embodiments will be briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present application and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without paying creative work.
[0030] Figure 1 A schematic diagram of the embolic microspheres of the present application embodiment;
[0031] Figure 2 This is a scanning electron microscope image of blank polyvinyl alcohol microspheres prepared in Example 1 of the present application;
[0032] Figure 3 This is a schematic diagram of the process for preparing embolic microspheres in Example 1 of the present application;
[0033] Figure 4 This is a scanning electron microscope image of the embolic microspheres prepared in Example 1 of the present application;
[0034] Figure 5 A schematic diagram of the process for preparing embolic microspheres in Example 2 of the present application;
[0035] Figure 6 This is a scanning electron microscope image of the embolic microspheres prepared in Example 2 of the present application;
[0036] Figure 7 This is a schematic diagram of the process for preparing embolic microspheres in Example 3 of the present application;
[0037] Figure 8 This is a scanning electron microscope image of the embolic microspheres prepared in Example 3 of the present application;
[0038] Fig. 9 Fluorescence microscopic images of the blank polyvinyl alcohol microspheres prepared in Example 1 of the present application and the embolic microspheres prepared in Examples 1 to 3. DETAILED DESCRIPTION
[0039] The embodiments of the present application will be described in detail below in conjunction with the examples, but it will be appreciated by those skilled in the art that the following examples are only used to illustrate the present application and should not be considered as limiting the scope of the present application. In the examples, if specific conditions are not specified, they are carried out according to normal conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be purchased commercially.
[0040] The following is a detailed description of an embolic microsphere and its preparation method according to an embodiment of the present application:
[0041] See also Figure 1 The present application provides an embolic microsphere, comprising polyvinyl alcohol microspheres and a compound with AIE properties modified on the polyvinyl alcohol microspheres, wherein the compound with AIE properties is a tetraphenylethylene compound.
[0042] The chemical formula of embolic microspheres is as follows:
[0043]
[0044] Wherein, R1, R2 and R3 are independently selected from hydrogen or an electron-donating group, and m and n are 1000 to 100000 respectively.
[0045] In some exemplary embodiments, R1, R2 and R3 may all be hydrogen; or R1 is hydrogen, and R2 and R3 are electron-donating groups; or R2 is hydrogen, and R1 and R3 are electron-donating groups; or R3 is hydrogen, and R1 and R2 are electron-donating groups; or R1 and R2 are hydrogen, and R3 is an electron-donating group; or R1 and R3 are hydrogen, and R2 is an electron-donating group; or R2 and R3 are hydrogen, and R1 is an electron-donating group; or R1, R2 and R3 are all electron-donating groups.
[0046] It should be noted that the values of m and n can be the same or different. For example, m and n can be 1000, 2000, 5000, 10000, 20000, 50000 or 100000 at the same time; or m is 1000 and n is 2000; or m is 1000 and n is 10000; or m is 1000 and n is 1000; or m is 5000 and n is 10000; or m is 10000 and n is 20000.
[0047] The tetraphenylethylene compound in the embolic microspheres of the present application is bonded to the polyvinyl alcohol microspheres through acetal bonds, and the tetraphenylethylene compound molecules with aggregation-induced emission function are closely arranged on the polyvinyl alcohol chain, and due to the restricted molecular motion, it has fluorescent development performance.
[0048] In some exemplary embodiments, the electron donating group includes a methoxy group (—OMe) or a dimethylamino group (—NMe2).
[0049] By making the electron-donating group include methoxy or dimethylamino, the embolic microspheres have fluorescent imaging properties.
[0050] Chemicals with AIE properties include:
[0051]
[0052] By making the chemical with AIE property include the above structure, the embolic microspheres have fluorescence imaging property.
[0053] In some exemplary embodiments, the mass of the compound having AIE property in the embolic microspheres accounts for 30% to 70% of the total mass of the embolic microspheres.
[0054] As an example, the mass of the compound having AIE properties in the embolic microspheres accounts for 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65% or 70% of the total mass of the embolic microspheres.
[0055] By making the mass of the compound having AIE performance in the embolic microspheres account for the total mass of the embolic microspheres within the above range, the embolic microspheres have better fluorescence development performance.
[0056] In some exemplary embodiments, the particle size of the embolic microspheres is 50 μm to 1000 μm.
[0057] As an example, the particle size of the embolic microspheres may be 50 μm, 80 μm, 100 μm, 200 μm, 500 μm, 800 μm or 1000 μm.
[0058] The present application uses polyvinyl alcohol microspheres to chemically bond and modify organic molecular compounds with AIE (aggregation-induced emission) properties. The organic molecular compounds with AIE properties are tetraphenylethylene compounds, and embolic microspheres with controllable fluorescence intensity are realized. The embolic microspheres of the present application have fluorescence development capabilities while loading drugs, which facilitates precise intraoperative embolization and postoperative evaluation. In addition, the embolic microspheres have a lower density, better suspension performance and elasticity, and a suitable particle size, which is conducive to convenient delivery during embolic surgery.
[0059] The present application also provides a method for preparing the embolic microspheres in the above embodiment, which comprises the following steps:
[0060] S1. Preparation of polyvinyl alcohol dry balls
[0061] S11. Preparation of polyvinyl alcohol macromonomer
[0062] In a 25 mL three-necked flask equipped with an overhead mechanical stirrer, add 100 mL of purified water, add about 15 g of PVA (model 1799), heat to 95 ° C to dissolve, and cool to room temperature; add 1.65 g of N-(2,2-dimethoxyethyl)-2-acrylamide (NAAADA), followed by 10 mL of concentrated hydrochloric acid, react at room temperature for 14 hours, and then use 2.5 M sodium hydroxide solution to neutralize to pH = 7 to obtain a macromolecular polyvinyl alcohol monomer solution.
[0063] S12, Synthesis of Polyvinyl Alcohol Microspheres by Inverse Suspension Polymerization
[0064] In a 1L three-necked flask equipped with an overhead mechanical stirrer, add 600mL of butyl acetate, add 18g of cellulose acetate butyrate to dissolve, and obtain an oil phase; 8.61g of acrylamido-2-methylpropanesulfonic acid sodium salt (AMPS sodium) is dissolved in 60mL of water, 160g of macromolecular polyvinyl alcohol monomer solution is added, and 1.5g of potassium persulfate is added to obtain an aqueous phase. The speed is set to 400rpm, and the aqueous phase is added dropwise to the oil phase; after the addition is completed, the temperature is raised to 55°C, 2.2mL of tetramethylethylenediamine is added, and the reaction is carried out for 8h. After washing with 5% sodium bicarbonate solution and purified water, the blank polyvinyl alcohol microspheres are obtained.
[0065] S13, wet bulb drying
[0066] Under stirring, slowly add 3 volumes of acetone to the wet ball prepared above, the microspheres shrink and settle, then continue stirring for 30 minutes and pour out the upper solution. Repeat this process 3 times, and pour out all the solvent as much as possible in the last time. Transfer the microspheres to a vacuum drying oven and heat at 80℃ for 3 hours to obtain powdered polyvinyl alcohol dry balls.
[0067] S2. Preparation of embolic microspheres
[0068] Add polyvinyl alcohol microspheres, compounds with AIE properties and solvents to a three-necked flask equipped with a mechanical stirring paddle at the top, adjust the stirring speed to 100 rpm / min, and heat at 50°C to 80°C. After the microspheres are completely swollen, add methanesulfonic acid and keep the temperature at 50°C to 80°C for 24 hours. After the reaction, wash the microspheres with DMSO, 10% sodium bicarbonate and purified water in turn to remove residual impurities and acid to obtain embolic microspheres.
[0069] In some exemplary embodiments, the mass ratio of the polyvinyl alcohol microspheres to the compound having AIE properties is 1:0.5-1.3.
[0070] As an example, the mass ratio of the polyvinyl alcohol microspheres to the compound having AIE properties can be 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2 or 1:1.3.
[0071] In some exemplary embodiments, the mass volume ratio of polyvinyl alcohol microspheres to methanesulfonic acid is 1:1-5 g / mL.
[0072] As an example, the mass volume ratio of the polyvinyl alcohol microspheres and the methanesulfonic acid may be 1 g:1 mL, 1 g:2 mL, 1 g:3 mL, 1 g:4 mL, or 1 g:5 mL.
[0073] The preparation method of the embolic microspheres of the present application is simple, the prepared embolic microspheres have a stable structure, and have the ability to develop fluorescence while loading drugs, which is convenient for accurate intraoperative embolization and postoperative evaluation. In addition, the embolic microspheres have a low density, good suspension performance and elasticity, and a suitable particle size, which is conducive to convenient delivery during embolic surgery.
[0074] The following is a further detailed description of an embolic microsphere and a preparation method thereof of the present application in conjunction with examples.
[0075] Example 1
[0076] The present invention provides an embolic microsphere and a preparation method thereof, which comprises the following steps:
[0077] S1. Preparation of polyvinyl alcohol dry balls
[0078] S11. Preparation of polyvinyl alcohol macromonomer
[0079] In a 25 mL three-necked flask equipped with an overhead mechanical stirrer, add 100 mL of purified water, add about 15 g of PVA (model 1799), heat to 95 ° C to dissolve, and cool to room temperature; add 1.65 g of N-(2,2-dimethoxyethyl)-2-acrylamide (NAAADA), followed by 10 mL of concentrated hydrochloric acid, react at room temperature for 14 hours, and then use 2.5 M sodium hydroxide solution to neutralize to pH = 7 to obtain a macromolecular polyvinyl alcohol monomer solution.
[0080] S12, Synthesis of Polyvinyl Alcohol Microspheres by Inverse Suspension Polymerization
[0081] In a 1L three-necked flask equipped with an overhead mechanical stirrer, add 600mL of butyl acetate, add 18g of cellulose acetate butyrate to dissolve and obtain an oil phase; 8.61g of acrylamido-2-methylpropanesulfonic acid sodium salt (AMPS sodium) is dissolved in 60mL of water, 160g of macromolecular polyvinyl alcohol monomer solution is added, and 1.5g of potassium persulfate is added to obtain an aqueous phase. The speed is set to 400rpm, and the aqueous phase is added dropwise to the oil phase; after the addition is completed, the temperature is raised to 55°C, 2.2mL of tetramethylethylenediamine is added, and the reaction is carried out for 8h. After washing with 5% sodium bicarbonate solution and purified water, polyvinyl alcohol blank microspheres are obtained. The scanning electron microscope image of the obtained polyvinyl alcohol blank microspheres is shown as follows Figure 2 As shown, the blank polyvinyl alcohol microspheres are typical hydrogels with a particle size of 20 μm to 1400 μm.
[0082] S13, wet bulb drying
[0083] Under stirring, slowly drop 3 volumes of acetone into the wet ball prepared above, the microspheres shrink and settle, then continue stirring for 30 minutes and pour out the upper solution. Repeat this process 3 times, and pour out all the solvent as much as possible in the last time. Transfer the microspheres to a vacuum drying oven and heat at 80℃ for 3 hours to obtain powdered polyvinyl alcohol dry balls with a dryness of ≥95%.
[0084] S2. Preparation of embolic microspheres
[0085] like Figure 3 As shown, 5g of polyvinyl alcohol dry balls, 10g of 1,1,2-triphenyl-2-(4-formaldehyde phenyl)ethylene and 120mL of DMSO (dimethyl sulfoxide) were added to a three-necked flask equipped with a mechanical stirring paddle at the top, the stirring speed was adjusted to 100rpm / min, and heated at 60°C. After the microspheres were completely swollen, 5mL of methanesulfonic acid was added and the reaction was maintained at 60°C for 24h. After the reaction, the microspheres were washed with DMSO, 10% sodium bicarbonate and purified water in turn to remove residual impurities and acid to obtain embolic microspheres. The scanning electron microscope image of the prepared embolic microspheres is shown in Figure 4 shown.
[0086] Example 2
[0087] The present invention provides an embolic microsphere and a preparation method thereof, which comprises the following steps:
[0088] S1. Preparation of polyvinyl alcohol dry balls
[0089] Same as Example 1.
[0090] S2. Preparation of embolic microspheres
[0091] like Figure 5 As shown, 5g of polyvinyl alcohol dry balls, 8g of 4-(2,2-bis(4-methoxyphenyl)-1-phenylvinyl)benzaldehyde and 120mL of DMSO (dimethyl sulfoxide) were added to a three-necked flask equipped with a mechanical stirring paddle at the top, the stirring speed was adjusted to 100rpm / min, and heated at 60°C. After the microspheres were completely swollen, 5mL of methanesulfonic acid was added and the reaction was maintained at 60°C for 24h. After the reaction, the microspheres were washed with DMSO, 10% sodium bicarbonate and purified water in turn to remove residual impurities and acid to obtain embolic microspheres. The scanning electron microscope image of the prepared embolic microspheres is shown in Figure 6 shown.
[0092] Example 3
[0093] The present invention provides an embolic microsphere and a preparation method thereof, which comprises the following steps:
[0094] S1. Preparation of polyvinyl alcohol dry balls
[0095] Same as Example 1.
[0096] S2. Preparation of embolic microspheres
[0097] like Figure 7 As shown, 5g of polyvinyl alcohol dry balls, 9.5g of 4-(2,2-bis(4-methoxyphenyl)-1-phenylvinyl)benzaldehyde and 120mL of DMSO (dimethyl sulfoxide) were added to a three-necked flask equipped with a mechanical stirring paddle at the top, the stirring speed was adjusted to 100rpm / min, and heated at 60°C. After the microspheres were completely swollen, 5mL of methanesulfonic acid was added and the reaction was maintained at 60°C for 24h. After the reaction, the microspheres were washed with DMSO, 10% sodium bicarbonate and purified water in turn to remove residual impurities and acid to obtain embolic microspheres. The scanning electron microscope image of the prepared embolic microspheres is shown in Figure 8 shown.
[0098] Example 4
[0099] The present application example provides an embolic microsphere and a preparation method thereof. The present application example changes the mass ratio of polyvinyl alcohol dry ball and 4-(2,2-bis(4-methoxyphenyl)-1-phenylvinyl)benzaldehyde to 1:0.5 based on Example 1.
[0100] Example 5
[0101] The present application example provides an embolic microsphere and a preparation method thereof. The present application example changes the mass ratio of polyvinyl alcohol dry ball and 4-(2,2-bis(4-methoxyphenyl)-1-phenylvinyl)benzaldehyde to 1:1 based on Example 1.
[0102] Example 6
[0103] The present embodiment provides an embolic microsphere and a preparation method thereof. Based on Example 1, the present embodiment changes the mass ratio of polyvinyl alcohol dry ball and 4-(2,2-bis(4-methoxyphenyl)-1-phenylvinyl)benzaldehyde to 1:3.
[0104] Comparative Example 1
[0105] The comparative example of the present application provides an embolic microsphere and a preparation method thereof. The present application example changes the mass ratio of polyvinyl alcohol dry ball and 4-(2,2-bis(4-methoxyphenyl)-1-phenylvinyl)benzaldehyde to 1:0.2 on the basis of Example 1.
[0106] Comparative Example 2
[0107] The comparative example of the present application provides an embolic microsphere and a preparation method thereof. The present application example changes the mass ratio of polyvinyl alcohol dry ball and 4-(2,2-bis(4-methoxyphenyl)-1-phenylvinyl)benzaldehyde to 1:0.4 on the basis of Example 1.
[0108] Comparative Example 3
[0109] The comparative example of the present application provides an embolic microsphere and a preparation method thereof. The present application example changes the mass ratio of polyvinyl alcohol dry ball and 4-(2,2-bis(4-methoxyphenyl)-1-phenylvinyl)benzaldehyde to 1:4 on the basis of Example 1.
[0110] Comparative Example 4
[0111] The comparative example of the present application provides an embolic microsphere and a preparation method thereof. The present application example replaces the organic molecule compound having AIE performance with indole[3,2-b]carbazole on the basis of Example 1.
[0112] Test Example 1
[0113] The blank polyvinyl alcohol microspheres prepared in Example 1, the embolic microspheres prepared in Examples 1 to 6 and Comparative Examples 1 to 3 were divided into eleven levels of 0 to 10 according to the fluorescence visualization intensity to evaluate the fluorescence ability of the microspheres. The results are shown in Table 1. The fluorescence microscopic images of 1,1,2-triphenyl-2-(4-formaldehydephenyl)ethylene powder, the blank polyvinyl alcohol microspheres prepared in Example 1, and the embolic microspheres prepared in Examples 1 to 3 are shown in Table 1. Fig. 9 shown.
[0114] Among them, scores of 5 and above were considered to have good fluorescence development ability.
[0115] Table 1 Visualization levels of blank polyvinyl alcohol microspheres prepared in Example 1 and embolic microspheres prepared in Examples 1 to 6 and Comparative Examples 1 to 3
[0116]
[0117] It can be seen from Table 1 that the blank polyvinyl alcohol microspheres prepared in Example 1 have no fluorescence imaging ability, and the embolic microspheres prepared in Examples 1 to 3 all show good fluorescence imaging ability.
[0118] From the comparison of the performance of the embolic microspheres in Examples 1, 4 to 6 and Comparative Examples 1 to 3, it can be seen that when the mass ratio of polyvinyl alcohol microspheres to the compound with AIE properties is 1:0.5 to 1.3, the mass of the compound with AIE properties in the embolic microspheres accounts for 30% to 70% of the total mass of the embolic microspheres, and the embolic microspheres exhibit good fluorescence development ability.
[0119] Depend on Fig. 9 It can be seen that Fig. 9 From left to right in the figure are fluorescence microscopic images of 1,1,2-triphenyl-2-(4-formaldehydephenyl)ethylene powder, blank polyvinyl alcohol microspheres prepared in Example 1, and embolic microspheres prepared in Examples 1 to 3. The blank polyvinyl alcohol microspheres prepared in Example 1 have no fluorescence development ability, while the embolic microspheres prepared in Examples 1 to 3 all show good fluorescence development ability.
[0120] Test Example 2
[0121] The blank polyvinyl alcohol microspheres prepared in Example 1 and the embolic microspheres prepared in Examples 1 to 3 were tested for strength and elasticity. The results are shown in Table 2.
[0122] Strength and elasticity test methods are as follows:
[0123] The test was performed using a TA.XT.plus C texture analyzer system, with a 6 mm probe and a trigger force of 0.1 g. The microspheres were compressed to 0% and held for 60 seconds.
[0124] Table 2 Strength and elastic properties of the blank polyvinyl alcohol microspheres prepared in Example 1 and the embolic microspheres prepared in Examples 1 to 3
[0125]
[0126] As shown in Table 2, the density of the embolic microspheres of the present application after development modification and radiation modification increases very little, much lower than that of existing microspheres. The microspheres also have excellent suspension properties and are easy to deliver through a catheter. The microspheres still maintain their original elasticity when their strength increases.
[0127] Test Example 3
[0128] The blank polyvinyl alcohol microspheres prepared in Example 1 and the embolic microspheres prepared in Examples 1 to 3 were tested for their drug loading performance. The results are shown in Table 3.
[0129] The test method for drug loading performance of microspheres is as follows:
[0130] Prepare 20 mg / mL doxorubicin hydrochloride solution and 20 mg / mL irinotecan hydrochloride solution respectively. Take 1 mL of wet bulb and add 2 mL of drug solution. Determine the drug concentration in the solution after 30 minutes by liquid phase measurement, and calculate the drug loading amount and loading rate.
[0131] Table 3 Drug loading properties of blank polyvinyl alcohol microspheres prepared in Example 1 and embolic microspheres prepared in Examples 1 to 3
[0132]
[0133] As can be seen from the above, the embolic microspheres of the present application are negatively charged, and thus can be efficiently loaded with cationic drugs such as doxorubicin hydrochloride and irinotecan hydrochloride.
[0134] The above description is only a specific embodiment of the present application and is not intended to limit the present application. For those skilled in the art, the present application may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.
Claims
1. An embolic microsphere, characterized in that: The embolic microspheres include polyvinyl alcohol microspheres and a compound with AIE properties modified on the polyvinyl alcohol microspheres; Wherein, the compound with AIE performance is a tetraphenylethylene compound.
2. The embolic microsphere according to claim 1, characterized in that: The chemical formula of the embolic microspheres is as follows: Wherein, R1, R2 and R3 are independently selected from hydrogen or an electron-donating group, and m and n are 1000 to 100000 respectively.
3. The embolic microsphere according to claim 2, characterized in that: The electron donating group includes a methoxy group or a dimethylamino group.
4. The embolic microsphere according to claim 1, characterized in that: The chemicals having AIE properties include:
5. The method for preparing embolic microspheres according to claim 1, characterized in that: The mass of the compound with AIE performance in the embolic microspheres accounts for 30% to 70% of the total mass of the embolic microspheres.
6. The method for preparing embolic microspheres according to claim 1, characterized in that: The particle size of the embolic microspheres is 50 μm to 1000 μm.
7. A method for preparing embolic microspheres according to any one of claims 1 to 6, characterized in that: The preparation method of the embolic microspheres comprises mixing the polyvinyl alcohol microspheres, the compound having AIE performance and a raw material of a first solvent, heating under stirring to completely swell the polyvinyl alcohol microspheres, and then adding methanesulfonic acid to the raw material to react and obtain a crude product; The mass volume ratio of the polyvinyl alcohol microspheres to the methanesulfonic acid is 1:1-5 g / mL.
8. The method for preparing embolic microspheres according to claim 7, characterized in that: The mass ratio of the polyvinyl alcohol microspheres to the compound having AIE performance is 1:0.5-1.
3.
9. The method for preparing embolic microspheres according to claim 7, characterized in that: The reaction temperature is 50°C to 80°C.
10. The method for preparing embolic microspheres according to claim 7, characterized in that: The crude product was washed with dimethyl sulfoxide, sodium bicarbonate solution and purified water in sequence to obtain embolic microspheres.