Suspensions containing radioactive microspheres, methods of making and using the same

Abstract

This invention provides a suspension containing radioactive microspheres, a method for preparing the same, and its applications. The radioactive microspheres comprise resin microspheres and a radionuclide loaded on the resin microspheres. The resin microspheres are made of at least one of polystyrene, polyethylene, or divinylbenzene, or a cross-linked polymer thereof. The average particle size of the radioactive microspheres is 25 μm to 40 μm. By controlling the non-spherical ratio of the radioactive microspheres to within 5%, the distribution density of the microspheres in the tumor region is increased, thereby enhancing the tumor-killing effect; furthermore, it can reduce the incidence of adverse events.

Description

Technical Field

[0001] This application relates to the medical field, specifically to suspensions containing radioactive microspheres, their preparation methods, and applications. Background Technology

[0002] There are currently various treatment options for malignant tumors, including chemotherapy, radiotherapy, interventional therapy, and biological immunotherapy. Since most patients are diagnosed at an advanced stage, losing the opportunity for surgical treatment, and become less sensitive to chemotherapy drugs after multiple rounds of chemotherapy, radiotherapy has become a key treatment method for some cancers.

[0003] Radioactive microsphere therapy involves preparing radioactive materials into microspheres of regular size, which are then injected into the arterial blood supply of the target organ to emit high-dose, high-energy beta rays to kill tumor tissue. Due to the limited tissue penetration depth of the rays, nearby healthy tissue can be protected simultaneously. Radioactive microspheres mainly consist of a carrier and the nuclide loaded on the carrier. Currently discovered nuclides include yttrium [90Y], phosphorus [32P], iodine [131I], iodine [125I], technetium [99mTc], rhenium [188Re], and holmium [166Ho]. The carrier is primarily resin microspheres, using polystyrene-divinylbenzene polymer as the carrier. Its density is close to that of blood, and it does not easily settle. It has been widely used clinically, especially in the treatment of hepatocellular carcinoma (HCC). Recently, other forms of carrier microspheres, such as carbon microspheres and silicon microspheres, have also emerged, but there is limited public information on them, indicating they are in the early stages of development.

[0004] Although radioactive microsphere therapy causes less damage to the patient's normal tissues, some patients still experience adverse reactions after use. Furthermore, existing radioactive microspheres are more effective for small tumors with a volume of <10cc, but the distribution of radioactive microspheres within the boundaries of large tumors with a volume of >10cc, especially deep within the tumor, needs to be improved. Summary of the Invention

[0005] In view of this, this application provides a suspension of radioactive microspheres, a method for preparing the same, and their applications, aiming to improve the adverse reactions and therapeutic effects of existing radioactive microspheres.

[0006] In a first aspect, this application provides a suspension containing radioactive microspheres, the radioactive microspheres comprising resin microspheres and a radionuclide loaded on the resin microspheres, the resin microspheres being made of at least one of polystyrene, polyethylene or polydivinylbenzene, or a cross-linked polymer thereof, the radioactive microspheres having an average particle size of 25 μm to 40 μm and a non-spherical ratio of less than 5%.

[0007] Optionally, the non-spherical ratio refers to the proportion of non-spherical radioactive microspheres to the total number of radioactive microspheres in the suspension, wherein the non-spherical radioactive microspheres are radioactive microspheres with a minimum radius lower than 75% of the original microsphere radius.

[0008] Optionally, based on the number of radioactive microspheres, the proportion of radioactive microspheres with a diameter of 20 μm to 60 μm in the suspension is greater than 85%; and / or the non-spherical ratio of the radioactive microspheres is less than 2%; and / or the material of the resin microspheres is selected from cross-linked polystyrene microspheres with a cross-linking degree of 2% to 10%.

[0009] Optionally, the resin microspheres are resin microspheres that have undergone sulfonation, nitration, or carbonization.

[0010] Optionally, the radionuclide is selected from at least one isotope of yttrium, lutetium, indium, holmium, samarium, iodine, phosphorus, iridium, or rhenium.

[0011] Optionally, the radionuclide is selected from yttrium [ 90 [Y], the resin microspheres are selected from sulfonated polystyrene partially crosslinked with divinylbenzene, and the suspension also contains water for injection, with each 1 mL containing yttrium [ 90 The activity of Y is 300–700 MBq.

[0012] Secondly, this application provides a method for preparing a suspension containing radioactive microspheres, the method comprising: mixing resin microspheres and a radioactive nuclide compound in a solution, and reacting to obtain the suspension containing the radioactive microspheres; wherein the resin microspheres are made of at least one of polystyrene, polyethylene or polydivinylbenzene, or a cross-linked polymer thereof, and the average particle size of the radioactive microspheres is 25 μm to 40 μm, and the non-spherical ratio is less than 5%.

[0013] Optionally, the resin microspheres are subjected to sulfonation, nitration, or carbonization before being mixed with the radioactive nuclide compound.

[0014] Thirdly, this application provides the use of the suspension as described in the first aspect or the suspension prepared by the method described in the second aspect in the preparation of a drug for treating tumors.

[0015] Optionally, the tumor is primary or secondary liver cancer.

[0016] Beneficial effects:

[0017] This application provides a suspension of radioactive microspheres, the radioactive microspheres comprising resin microspheres and a radionuclide loaded on the resin microspheres, the resin microspheres being made of at least one of polystyrene, polyethylene, or divinylbenzene, or their cross-linked polymers, the radioactive microspheres having an average particle size of 25 to 40 μm, thereby increasing the distribution density of microspheres in the tumor region by controlling the non-spherical ratio of the radioactive microspheres to within 5%, improving the therapeutic effect, reducing the incidence of adverse reactions, and improving safety. Attached Figure Description

[0018] To more clearly illustrate the technical solutions in the embodiments of this application, the accompanying drawings used in the description of the embodiments will be briefly introduced below.

[0019] Figure 1 The minimum radius (R) of the microspheres in the embodiments of this application min A schematic diagram showing the relationship between the radius of the microsphere and the original radius (R). Figure 1 In the diagram, A represents an example of a spherical microsphere, while B, C, and D each represent an example of a non-spherical microsphere.

[0020] Figure 2 This is a microscope photograph of a non-spherical radioactive polystyrene microsphere contained in an embodiment of this application.

[0021] Figure 3 This is a schematic diagram of the implantation site of the test sample or control sample in the embodiments of this application. Detailed Implementation

[0022] To make the technical problems, solutions, and effects of this invention clearer, the invention will be further described in detail below with reference to specific embodiments. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0023] Existing technologies for radioactive microspheres have revealed adverse reactions and limitations in therapeutic efficacy during experiments. These include radioactive polystyrene microspheres prepared from commercially available sulfonated polystyrene microspheres, or radioactive polystyrene or carbon microspheres prepared using methods provided in CN202211592412X, CN2022116010239, and CN2022116017505. However, extensive and long-term research by the inventors has revealed that the non-spherical ratio of the radioactive microspheres ultimately produced by the aforementioned existing technologies is consistently high, generally exceeding 10%. Even when the non-spherical ratio is relatively reduced during sulfonation by controlling the stirring speed, uneven sulfonation persists, and the non-spherical ratio of the final radioactive microspheres remains greater than 10%. Furthermore, existing technologies do not investigate the non-spherical ratio in suspensions containing radioactive microspheres.

[0024] The inventors unexpectedly discovered that controlling the non-spherical ratio in a suspension containing radioactive microspheres to below 5% not only increases the distribution density of microspheres within tumors, indicating a better tumor-killing effect, but also significantly reduces irritation and inflammation, thereby lowering the incidence of adverse reactions such as fever, pain, and liver damage. The study found that the non-spherical ratio of microspheres is one of the key factors affecting distribution density, ultimately influencing efficacy and safety.

[0025] Therefore, this application first provides a suspension containing radioactive microspheres for radiotherapy of malignant tumors. The radioactive microspheres comprise resin microspheres and a radionuclide loaded on the resin microspheres. The average particle size of the radioactive microspheres is 25 to 40 μm, and the non-spherical ratio of the radioactive microspheres is less than 5%. Compared to existing technologies, controlling the non-spherical ratio of the radioactive microspheres within this range not only improves the therapeutic effect but also enhances safety.

[0026] In this paper, "non-spherical ratio" refers to the proportion of non-spherical microspheres in a suspension to the total number of microspheres. Non-spherical microspheres are defined as microspheres with a minimum radius less than 75% of the original microsphere radius. Correspondingly, "spherical ratio" refers to the proportion of spherical microspheres in a given amount of suspension, where spherical microspheres are defined as those with a minimum radius (R... min Microspheres with a radius (R) greater than 75% of the original microspheres. min This refers to the shortest distance from the center to the edge of the microsphere under orthographic projection. The center of the microsphere is the center of the two points with the longest straight-line distance on the microsphere under orthographic projection (if the distance from the center to any point on the edge of the microsphere is equal, non-spherical microspheres are not considered); R refers to the average radius of the microsphere, which is relative to the average diameter. The average diameter refers to the average particle size, and the average radius is half of the average particle size. Figure 1 As shown, Figure 1 The minimum radius (R) of the microsphere is shown.min A schematic diagram showing the relationship between the radius of the microsphere (R) and the radius of the original microsphere. Figure 1 In this context, A is an example of a spherical microsphere, and R... min Equal to R. B, C, and D represent examples of non-spherical microspheres, i.e., R min Less than 0.75 times R. It should also be noted that the sphericity ratio and mean sphericity in this article have different meanings and are calculated differently. Therefore, the values ​​of the sphericity ratio and mean sphericity for the same microsphere will also be different.

[0027] The non-spherical ratio can be any value within 5%, such as 0.1% to 5%, 1% to 4%, 2% to 3%, etc.; for example, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0%, etc.

[0028] The average particle size of the radioactive microspheres can be any value within the range of 25 to 40 μm, for example, 30 to 35 μm. Within this range, the distribution of the microspheres in the target organ is beneficial, helping to improve the therapeutic effect and reduce side effects. It is understood that the average particle size can be any value within the range of 25 to 40 μm, such as 25 μm, 28 μm, 30 μm, 32.5 μm, 35 μm, 40 μm, etc.

[0029] In some embodiments, the suspension contains more than 85% radioactive microspheres with a diameter of 20 μm to 60 μm, for example, more than 90% or more, and even more than 95%. Within this range, the distribution of microspheres in the target organ is beneficial, helping to improve therapeutic efficacy and reduce side effects. It is understood that the percentage of radioactive microspheres with a diameter of 20 μm to 60 μm can be any value greater than 85%, such as 85%, 88%, 90%, 95%, 98%, etc. It should be noted that the percentage of radioactive microspheres with a diameter of 20 μm to 60 μm refers to the ratio of microspheres with a diameter within this range to the total number of microspheres, where the total number of microspheres includes both spherical and non-spherical microspheres. Therefore, microspheres in the 20 μm to 60 μm range include both spherical and non-spherical microspheres, and microspheres outside this range also include both spherical and non-spherical microspheres.

[0030] In some embodiments, to better load radionuclides, the resin microspheres are selected from, but are not limited to, sulfonated, nitrated, or carbonized resin microspheres. When the resin microspheres are sulfonated or nitrated, their surface has sulfonic acid groups or nitrate groups, and the radionuclides are linked to the sulfonic acid groups or nitrate groups and are mostly distributed on the surface of the microspheres. When the resin microspheres are carbonized, they are specifically carbon microspheres. The surface of the carbon microspheres contains mesopores, and the radionuclides are distributed in the pores of the mesopores in the form of complexes. Because carbon microspheres are non-degradable, non-spherical carbon microspheres are more likely to induce inflammatory responses. Therefore, compared with microspheres made of other materials, controlling the non-spherical particles of carbon microspheres to less than 5% is more effective in reducing irritation and inflammatory responses, as well as reducing the incidence of adverse reactions.

[0031] In some embodiments, the resin microspheres are selected from, but not limited to, at least one of polystyrene, polyethylene, or divinylbenzene, or their crosslinked polymers. In some embodiments, the resin microspheres include phenolic resin microspheres. In some embodiments, the resin microspheres are crosslinked polystyrene microspheres with a crosslinking degree of 2% to 10%, for example, 4%, 6%, or 8%. Within this range, the requirements for microsphere strength and loading rate can be met. In some embodiments, the resin microspheres are selected from sulfonated or nitrated crosslinked polystyrene. In some embodiments, the resin microspheres are selected from polystyrene partially crosslinked with divinylbenzene. In some embodiments, the resin microspheres are selected from sulfonated polystyrene partially crosslinked with divinylbenzene.

[0032] In some embodiments, the radionuclide is an isotope of at least one of yttrium, lutetium, indium, holmium, samarium, iodine, phosphorus, iridium, or rhenium. In some embodiments, the radionuclide is yttrium. 90 Y].

[0033] In some embodiments, the radionuclide is yttrium. 90 [Y], wherein the resin microspheres are selected from sulfonated polystyrene partially crosslinked with divinylbenzene, and the suspension further contains water for injection. In some embodiments, yttrium [ 90 The activity of yttrium (Y) is 300–700 MBq, preferably 500–700 MBq. In some embodiments, each 1 mL of the suspension contains 2–3 mg of resin microspheres. In some embodiments, the suspension also contains yttrium chloride and / or yttrium sulfate. In some embodiments, the suspension also contains sulfate, wherein the sulfate is present in a small amount in an aqueous solution. In some embodiments, the sulfate is sodium sulfate. In some embodiments, the suspension also contains a buffer solution, such as phosphate buffer.

[0034] This application also provides a suspension containing radioactive carbon microspheres, wherein the radioactive carbon microspheres include carbon microspheres and radionuclides loaded on the carbon microspheres, the average particle size of the radioactive carbon microspheres is 25 to 40 μm (micrometers), and the non-spherical ratio of the radioactive microspheres is less than 5%.

[0035] Accordingly, embodiments of this application also provide a method for preparing a suspension of radioactive microspheres, comprising: mixing resin microspheres and radioactive nuclide compounds in a solution and reacting to obtain the suspension containing radioactive microspheres; wherein the average particle size of the radioactive microspheres is 25 μm to 40 μm, and the non-spherical ratio is less than 5%.

[0036] In some embodiments, the resin microspheres are further subjected to sulfonation, nitration, or carbonization before being mixed with the radionuclide compound.

[0037] In some embodiments, when resin microspheres undergo sulfonation treatment, the preparation method of the suspension of radioactive microspheres includes the following steps:

[0038] S10. The resin microspheres are placed in concentrated sulfuric acid to undergo a sulfonation reaction, resulting in sulfonated resin microspheres.

[0039] S20. The sulfonated microspheres and the radioactive nuclide compound are mixed in solution and reacted to obtain the suspension containing the radioactive microspheres.

[0040] In some embodiments, in step S10, the sulfonation reaction is carried out under an inert atmosphere or nitrogen, such as nitrogen or argon. This prevents the oxidation reaction during preparation from affecting the morphology of the microspheres and facilitates control of the non-spherical ratio of the radioactive microspheres.

[0041] In some embodiments, in step S10, the sulfonation reaction temperature is 35–80°C, for example: 35°C, 40°C, 50°C, 60°C, 70°C, or 80°C. The time is 3 to 6 hours, for example: 4 hours, 5 hours, or 6 hours. Based on the above embodiments, in some embodiments, the concentrated sulfuric acid is added in batches during the sulfonation reaction. Specifically, the resin microspheres are first mixed with a small amount of concentrated sulfuric acid, and the temperature is slowly increased to a specific temperature at a rate of 1–3°C / min while stirring. Then, the remaining concentrated sulfuric acid is added for sulfonation. In some embodiments, during the mixing of the microspheres and the small amount of concentrated sulfuric acid, the mass ratio of the resin microspheres to the volume of the concentrated sulfuric acid is 1 g: (1.5–2) mL. After adding the remaining concentrated sulfuric acid, the mass ratio of the resin microspheres to the volume of the concentrated sulfuric acid is 1 g: (3–6) mL. Thus, by adding concentrated sulfuric acid in batches, not only can a better sulfonation effect be achieved, but the problem of excessive heat affecting the morphology of microspheres during the sulfonation reaction can also be improved, thereby controlling the non-spherical ratio of radioactive microspheres.

[0042] In some embodiments, in step S10, the sulfonation reaction is carried out under an inert atmosphere or nitrogen, and concentrated sulfuric acid is added in batches during the sulfonation process. Under these conditions, it is advantageous to control the non-spherical ratio of the radioactive microspheres to be within 5%.

[0043] In some embodiments, in step S20, the concentration of the yttrium chloride solution is 1 to 3 mg / mL, for example: 1 mg / mL, 1.5 mg / mL, 2 mg / mL, 2.5 mg / mL, etc.

[0044] In some embodiments, during the reaction of sulfonated, nitrated, or carbonized resin microspheres with radioactive nuclide compounds, the reaction temperature is 25 to 40°C, for example 25°C, 30°C, 35°C, or 40°C, and the reaction time is 1 to 2 hours, for example 1 hour, 1.5 hours, 1.8 hours, or 2 hours.

[0045] In some embodiments, when resin microspheres undergo carbonization, the preparation method of the suspension of radioactive microspheres includes the following steps:

[0046] S100. Carbon microspheres are obtained by calcining resin microspheres under an inert or nitrogen atmosphere.

[0047] S200. The carbon microspheres and the radioactive nuclide compound are mixed in solution and reacted to obtain the suspension containing the radioactive microspheres.

[0048] In some embodiments, the calcination temperature of the microspheres in step S100 is 400–800°C, for example: 400°C, 500°C, 600°C, 700°C, 800°C, etc., particularly 400–600°C; the time is 3–6 hours, for example: 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, etc., particularly 3–4 hours. Based on the above embodiments, in some embodiments, the calcination heating process adopts a stepped heating method, specifically: first, the temperature is rapidly increased from room temperature to 150°C–200°C at a rate of 4–12°C / min, and then the temperature is slowly increased to a specific calcination temperature above 150°C–200°C at a rate of 1–2°C / min (°C / minute), and then calcination is carried out. In another specific embodiment, the temperature is first rapidly increased from room temperature to 150°C–200°C, then slowly increased to 300°C at a rate of 1.6–2°C / min above 150°C–200°C, and then slowly increased to a specific calcination temperature at a rate of 1–1.5°C / min. This step-heating method not only improves production efficiency but also allows for control of the non-spherical ratio of the radioactive microspheres.

[0049] In some embodiments, in step S100, the calcined carbon microspheres further undergo a cleaning step and a drying step. For example, the cleaning step may use dilute nitric acid and deionized water. The drying step may use vacuum drying or a forced-air drying oven.

[0050] In some embodiments, to achieve better complexation, a precipitant is added before or after mixing the carbon microspheres and the radionuclide compound in solution in step S200. For example, in some specific embodiments, the method for preparing the radioactive carbon microspheres includes any one of the following methods:

[0051] Method 1: After mixing carbon microspheres with a solution containing a radioactive nuclide compound, a solution containing a precipitant is added, and radioactive carbon microspheres are obtained through reaction.

[0052] Method 2: After mixing carbon microspheres with a solution containing a precipitant, a solution containing a radioactive nuclide compound is added, and radioactive carbon microspheres are obtained through reaction.

[0053] In this way, radionuclides can be generated and grown in the mesopores of carbon microspheres, resulting in radioactive carbon microspheres with high loading stability. Based on this, the inventors discovered that excessively rapid or excessive generation of radionuclides in the mesopores of carbon microspheres can cause the mesoporous structure to collapse, thereby increasing the non-spherical ratio of the carbon microspheres. Therefore, the generation rate and amount of radionuclides in the mesopores are controlled by adjusting the concentrations of the precipitant and the radionuclides. Accordingly, in some embodiments, the concentration of the precipitant is 5 mg / mL to 10 mg / mL (mg / mL). For example, 5 mg / mL, 6 mg / mL, 8 mg / mL, 10 mg / mL, etc. In some embodiments, the concentration of the radionuclides is 3 mg / mL to 6 mg / mL, for example, 3 mg / mL, 5 mg / mL, 6 mg / mL, etc. Controlling the precipitant and radionuclides within this range not only satisfies the radionuclide loading requirement but also slows down the generation rate and amount of radionuclides in the mesopores, which is beneficial for controlling the non-spherical ratio of the carbon microspheres.

[0054] In some embodiments, in step S100, the microsphere carbonization process first rapidly heats from room temperature to 150°C–200°C at a rate of 4–12°C / min, and then slowly heats to 400–600°C at a rate of 1–2°C / min, calcining for 3–4 hours; in step S200, the concentration of the precipitant is 5 mg / mL to 10 mg / mL, and the concentration of the radionuclide is 3 mg / mL to 6 mg / mL. This allows the non-spherical ratio of the carbon microspheres to be controlled within 5%.

[0055] In some embodiments, the radionuclide compound is selected from, but not limited to, yttrium sulfate or yttrium chloride. The precipitant is selected from, but not limited to, at least one of tartaric acid, EDTA, and sodium phosphate, for example, one or two. For example:

[0056] When the precipitant is selected from one, such as EDTA, and the radionuclide compound is selected from yttrium chloride. For example, a method for preparing radioactive carbon microspheres includes: washing the carbon microspheres, mixing them uniformly with a YCl3 solution, allowing them to stand for 12 hours, then adding EDTA to the mixture, shaking in a shaker for 1 hour, washing, and drying to obtain carbon microspheres loaded with EDTA complex.

[0057] When the precipitant is selected from one such substance, such as tartaric acid, and the radioactive nuclide compound is selected from yttrium chloride. For example, a method for preparing carbon microspheres includes: washing the carbon microspheres, mixing them uniformly with a YCl3 solution, allowing them to stand for 12 hours, then adding tartaric acid to the mixture, shaking in a shaker for 1 hour, washing, and drying to obtain carbon microspheres loaded with tartaric acid complexes.

[0058] When the precipitant is selected from two, such as tartaric acid and sodium phosphate, and the radionuclide compound is selected from yttrium chloride. For example, a method for preparing carbon microspheres includes: adding porous carbon microspheres supported on a γ-tartaric acid complex to a sodium phosphate solution, shaking in a shaker for 1 hour, washing, and drying to obtain porous carbon microspheres supported on a γ-PO4 complex.

[0059] This application also provides a method for preparing a suspension of radioactive carbon microspheres, the method comprising: mixing carbon microspheres and a radionuclide compound in a solution, and reacting to obtain the suspension containing the radioactive carbon microspheres; wherein the average particle size of the radioactive carbon microspheres is 25 μm to 40 μm, and the non-spherical ratio is less than 5%.

[0060] Accordingly, this application also provides the use of the above suspension in the preparation of drugs for treating tumors.

[0061] In some embodiments, the tumor is an vascularized solid tumor; in other embodiments, the tumor is primary or secondary liver cancer.

[0062] The technical solutions of this disclosure will be illustrated more clearly and explicitly below with reference to embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of protection of this disclosure. The scope of protection of this disclosure is defined only by the claims.

[0063] Unless otherwise stated, all reagents and instruments used in the following examples are commercially available conventional products. Unless otherwise stated, experiments were conducted under conventional conditions or conditions recommended by the manufacturer. The polystyrene microspheres used for sulfonation in the following examples were commercially available DuPont AmberChrom™ XT30 cross-linked polystyrene-divinylbenzene polymer microspheres with an average particle size of 30 μm and a cross-linking degree ranging from 2% to 10%. The polystyrene microspheres used for carbonization were commercially available cross-linked polystyrene-divinylbenzene polymer microspheres from Qingdao Hongpu Biotechnology Co., Ltd. with an average particle size of 50 μm and a cross-linking degree ranging from 2% to 10% (hereinafter referred to as "polystyrene microspheres"). The sulfonated polystyrene microspheres had an average particle size of 30 μm, and the cation exchange resin was Aminex 50W-X4 (Biorad, Hercules, CA). Yttrium chloride [ 90 Y] and yttrium sulfate 90 Y] was obtained through the decay of Strontium-90. The activity of the radionuclide was measured using a Capintec (CRC-55TW) activity meter.

[0064] I. Preparation Examples

[0065] Example 1

[0066] This embodiment provides a radioactive polystyrene microsphere, the preparation steps of which are as follows:

[0067] (1) After washing and drying the polystyrene microspheres with anhydrous ethanol, they were ultrasonically dispersed in a small amount of concentrated sulfuric acid (1g:2mL) under Ar atmosphere. The temperature was increased to 75℃ at a rate of 1℃ / min under stirring at 300r / min, and then the remaining concentrated sulfuric acid (to 1g:6mL) was added. The reaction was carried out for 6h to obtain sulfonated polystyrene microspheres, which were then washed and dried.

[0068] (2) A yttrium chloride solution with an activity of 5 GBq (yttrium chloride [ 90 A mixture of Y and yttrium chloride (total 2 mg / mL) was stirred and mixed with 2 g of sulfonated polystyrene microspheres. The mixture was then loaded and reacted at 40 °C for 2 h. After washing, the microspheres were resuspended in 10 mL of water to obtain radioactive polystyrene microspheres.

[0069] Example 2

[0070] This embodiment provides a radioactive polystyrene microsphere, the preparation steps of which are as follows:

[0071] (1) After washing and drying the polystyrene microspheres with anhydrous ethanol, they were ultrasonically dispersed in a small amount of concentrated sulfuric acid (1g:2mL) under Ar atmosphere. The temperature was increased to 75℃ at a rate of 2℃ / min under stirring at 300r / min, and then the remaining concentrated sulfuric acid was added (to 1g:6mL). The reaction was carried out for 6h to obtain sulfonated polystyrene microspheres, which were then washed and dried.

[0072] (2) A yttrium chloride solution with an activity of 5 GBq (yttrium chloride [ 90 A mixture of Y and yttrium chloride (total 2.25 mg / mL) was mixed with 2 g of sulfonated polystyrene microspheres by stirring until homogeneous. The mixture was then subjected to a loading reaction at 40 °C for 2 h. After washing, the microspheres were resuspended in 10 mL of water to obtain radioactive polystyrene microspheres.

[0073] Example 3

[0074] This embodiment provides a radioactive polystyrene microsphere, the preparation steps of which are as follows:

[0075] (1) After washing and drying the polystyrene microspheres with anhydrous ethanol, they were ultrasonically dispersed in a small amount of concentrated sulfuric acid (1g:2mL). Under stirring conditions of 300r / min, the temperature was increased to 75℃ at a rate of 2℃ / min, and then the remaining concentrated sulfuric acid was added (to 1g:6mL). The reaction was carried out for 6h to obtain sulfonated polystyrene microspheres, which were then washed and dried.

[0076] (2) A yttrium chloride solution with an activity of 5 GBq (yttrium chloride [ 90 A mixture of Y and yttrium chloride (total 2.25 mg / mL) was mixed with 2 g of sulfonated polystyrene microspheres by stirring until homogeneous. The mixture was then subjected to a loading reaction at 40 °C for 2 h. After washing, the microspheres were resuspended in 10 mL of water to obtain radioactive polystyrene microspheres.

[0077] Example 4

[0078] This embodiment provides a radioactive polystyrene microsphere, the preparation steps of which are as follows:

[0079] (1) After washing and drying the polystyrene microspheres with anhydrous ethanol, they were ultrasonically dispersed in a small amount of concentrated sulfuric acid (1g:1.5mL) under a nitrogen atmosphere. The mixture was stirred at 300r / min and then heated to 80℃ at a rate of 3℃ / min. The remaining concentrated sulfuric acid was then added (to a ratio of 1g:3mL). The mixture was reacted for 6h to obtain sulfonated polystyrene microspheres, which were then washed and dried.

[0080] (2) A yttrium chloride solution with an activity of 5 GBq (yttrium chloride [ 90A mixture of Y and yttrium chloride (total 1 mg / mL) was mixed with 2 g of sulfonated polystyrene microspheres by stirring until homogeneous. The mixture was then loaded and reacted at 40 °C for 2 h. After washing, the microspheres were resuspended in 10 mL of water to obtain radioactive polystyrene microspheres.

[0081] Example 5

[0082] This embodiment provides a radioactive polystyrene microsphere, the preparation steps of which are as follows:

[0083] (1) After washing and drying the polystyrene microspheres with anhydrous ethanol, they were ultrasonically dispersed in a small amount of concentrated sulfuric acid (1g:2mL) under Ar atmosphere. The mixture was stirred at 300r / min and then heated to 80℃ at a rate of 1℃ / min. The remaining concentrated sulfuric acid was then added (to a total of 1g:3mL). The mixture was reacted for 3h to obtain sulfonated polystyrene microspheres, which were then washed and dried.

[0084] (2) A yttrium chloride solution with an activity of 5 GBq (yttrium chloride [ 90 A mixture of Y and yttrium chloride (total 3 mg / mL) was mixed with 2 g of sulfonated polystyrene microspheres by stirring until homogeneous. The mixture was then loaded and reacted at 40 °C for 2 h. After washing, the microspheres were resuspended in 10 mL of water to obtain radioactive polystyrene microspheres.

[0085] Example 6

[0086] This embodiment provides a radioactive carbon microsphere, the preparation steps of which are as follows:

[0087] (1) Carbon microspheres were prepared by calcining polystyrene microspheres at 400℃ for 4h under Ar atmosphere (heating from room temperature to 200℃ at 10℃ / min, then to 300℃ at 2℃ / min, then to 400℃ at 1℃ / min, holding for 4h, and then cooling down at 10℃ / min). Then, the microspheres were washed twice with 0.3mol / L dilute nitric acid and deionized water, dried, and sieved.

[0088] (2) After mixing 2g of carbon microspheres with tartaric acid solution (5mg / mL) and letting stand for 12h, 5GBq of yttrium chloride solution (yttrium chloride [ 90 A mixture of Y and yttrium chloride (3 mg / mL) was prepared and shaken in a constant temperature shaker at 25°C for 1 h (total solution volume 20 mL) to obtain radioactive carbon microspheres.

[0089] Example 7

[0090] This embodiment provides a radioactive carbon microsphere, the preparation steps of which are as follows:

[0091] (1) Carbon microspheres were prepared by calcining polystyrene microspheres at 400℃ for 4h under Ar atmosphere (heating from room temperature to 200℃ at 10℃ / min, then heating to 400℃ at 2℃ / min, holding for 4h, and then cooling down at 10℃ / min). Then, the microspheres were washed twice with 0.3mol / L dilute nitric acid and deionized water, dried, and sieved.

[0092] (2) Mix 2g of carbon microspheres with tartaric acid solution (10mg / mL) until homogeneous, let stand for 12h, and then add 5GBq of yttrium chloride solution (yttrium chloride [ 90 A mixture of Y and yttrium chloride (6 mg / mL) was prepared and shaken in a constant temperature shaker at 25 °C for 1 h (total solution volume 20 mL) to obtain radioactive carbon microspheres.

[0093] Example 8

[0094] This embodiment provides a radioactive carbon microsphere, the preparation steps of which are as follows:

[0095] (1) Carbon microspheres were prepared by calcining polystyrene microspheres at 400℃ for 4h under Ar atmosphere (heating from room temperature to 200℃ at 10℃ / min, then heating to 400℃ at 2℃ / min, holding for 4h, and then cooling down at 10℃ / min). Then, the microspheres were washed twice with 0.3mol / L dilute nitric acid and deionized water, dried, and sieved.

[0096] (2) Mix 2g of carbon microspheres with tartaric acid solution (25mg / mL) until homogeneous, let stand for 12h, and then add 5GBq of yttrium chloride solution (yttrium chloride [ 90 A mixture of Y and yttrium chloride (12.5 mg / mL) was prepared and shaken in a constant temperature shaker at 25 °C for 1 h (total solution volume 20 mL) to obtain radioactive carbon microspheres.

[0097] Example 9

[0098] This embodiment provides a radioactive carbon microsphere, the preparation steps of which are as follows:

[0099] (1) Carbon microspheres were prepared by calcining polystyrene microspheres at 600℃ for 3h under Ar atmosphere (the temperature was increased to 150℃ at 10℃ / min at room temperature, then increased to 600℃ at 2℃ / min, held for 3h, and then cooled at a rate of 10℃ / min). The microspheres were then washed twice with 0.3mol / L dilute nitric acid and deionized water, dried, and sieved.

[0100] (2) Mix 2g of carbon microspheres with tartaric acid solution (10mg / mL) until homogeneous, let stand for 12h, and then add 5GBq of yttrium chloride solution (yttrium chloride [ 90A mixture of Y and yttrium chloride (5 mg / mL) was prepared and shaken in a constant temperature shaker at 25 °C for 1 h (total solution volume 20 mL) to obtain radioactive carbon microspheres.

[0101] Example 10

[0102] This embodiment provides a radioactive carbon microsphere, the preparation steps of which are as follows:

[0103] (1) Carbon microspheres were prepared by calcining polystyrene microspheres at 500℃ for 3h under Ar atmosphere (the temperature was increased to 200℃ at 10℃ / min at room temperature, then increased to 500℃ at 2℃ / min, held for 3h, and then cooled at a rate of 10℃ / min). The microspheres were then washed twice with 0.3mol / L dilute nitric acid and deionized water, dried, and sieved.

[0104] (2) 2g of carbon microspheres were reacted with 5g of yttrium chloride solution (yttrium chloride [ 90 After mixing the mixture of Y and yttrium chloride (4 mg / mL) thoroughly, let it stand for 12 h. Then, add tartaric acid solution (8 mg / mL) to the mixture and shake it in a constant temperature shaker at 25 °C for 1 h (total solution volume is 20 mL) to obtain radioactive carbon microspheres.

[0105] Comparative Example 1

[0106] This embodiment provides a radioactive polystyrene microsphere, the preparation steps of which are as follows:

[0107] (1) After washing and drying the polystyrene microspheres with anhydrous ethanol, they were ultrasonically dispersed in an appropriate amount of concentrated sulfuric acid (1g:6mL), stirred at 300r / min, and reacted at 75℃ for 6h to obtain sulfonated polystyrene microspheres, which were then washed and dried.

[0108] (2) A yttrium chloride solution with an activity of 5 GBq (yttrium chloride [ 90 A mixture of Y and yttrium chloride (2.25 mg / mL) was mixed with 2 g of sulfonated polystyrene microspheres by stirring and reacted at 40 °C for 2 h. After washing, the mixture was resuspended in 10 mL of water to obtain radioactive polystyrene microspheres.

[0109] Comparative Example 2

[0110] A radioactive polystyrene microsphere is provided, and its preparation steps are as follows:

[0111] (1) Add 2g of commercially available sulfonated polystyrene microspheres to water and then react with 5g of yttrium sulfate solution (yttrium chloride) at 40°C. 90 A mixture of Y and yttrium chloride (total 2.25 mg / mL) was loaded and reacted for 2 hours.

[0112] (2) Wash the microspheres with phosphate buffer solution and then resuspend them in 10 mL of water to obtain radioactive polystyrene microspheres.

[0113] Comparative Example 3

[0114] A radioactive carbon microsphere is provided, and its preparation steps are as follows:

[0115] (1) Carbon microspheres were prepared by calcining polystyrene microspheres at 400℃ for 4h under Ar atmosphere (heating from room temperature to 200℃ at 10℃ / min, then heating to 400℃ at 3℃ / min, holding for 4h, and then cooling down at a rate of 10℃ / min). Then, the microspheres were washed twice with 0.3mol / L dilute nitric acid and deionized water, dried, and sieved.

[0116] (2) Mix 2g of carbon microspheres with tartaric acid solution (25mg / mL) until homogeneous, let stand for 12h, and then add 5GBq of yttrium chloride solution (yttrium chloride [ 90 A mixture of Y and yttrium chloride (12.5 mg / mL) was prepared and shaken in a constant temperature shaker at 25 °C for 1 h (total solution volume 20 mL) to obtain radioactive carbon microspheres.

[0117] II. Effect Test Examples

[0118] Experimental Example 1

[0119] Determination of the non-sphericity ratio, particle size, and particle size distribution of radioactive microspheres.

[0120] (1) Non-spherical ratio: The morphology of radioactive microspheres was observed under a microscope, and the proportion of non-spherical microspheres was calculated. The specific measurement method is as follows:

[0121] Assay method: Take an appropriate amount of the sulfonated polymer from each example onto a disposable hemocytometer, place the cap on the sample with the grid facing down (the text facing up) and examine it under a trinocular microscope. On the disposable hemocytometer, randomly select four suitable square areas of equal size, observe and photograph them at a magnification of 20 to 40 times, and count the total number of non-spherical microspheres and microspheres in the four selected areas (including spherical and non-spherical microspheres).

[0122] Calculation method: Non-spherical ratio = Non-spherical microspheres / Total number of microspheres * 100% (The final result is the average of the four regions).

[0123] Judgment criteria: Non-spherical microspheres are defined as irregular particles with a minimum radius less than 75% of the original microsphere radius, but do not include concave particles. See details. Figure 2 , Figure 2 The images show actual microscopic observations of an embodiment containing non-spherical microspheres, where the framed area represents the non-spherical microspheres.

[0124] (2) Particle size and particle size distribution: The determination method is the same as that for non-spherical ratio. The particle size is calculated by observing and photographing with a disposable counting plate and a trinocular microscope, and the number of particles in the range of 20μm to 60μm and the total number of particles in the four selected regions are counted based on the results.

[0125] Calculation method: Percentage of particles in the 20μm to 60μm range = Number of particles in the 20μm to 60μm range / Total number of particles * 100% (The final result is the average of the four regions).

[0126] Judgment criteria: Both non-spherical microspheres and spherical particles are included in the statistics. The particle size of non-spherical microspheres is calculated based on the straight-line distance between the two farthest endpoints on the microsphere.

[0127] (3) Average particle size: The average particle size of the radioactive microspheres was determined using a Malvern laser particle size analyzer (Mastersizer 3000).

[0128] All of the above tests were conducted after the radioactive microspheres had completed their decay.

[0129] The final results are shown in Table 1 below. The average particle size of the radioactive polystyrene microspheres and carbon microspheres provided in each example and comparative example is in the range of 25 to 40 μm, and the proportion of radioactive microspheres with a diameter of 20 μm to 60 μm is greater than 85%. At the calibration time, the yttrium content per mL... 90 The activity range of Y] was all within 500–700 MBq, and there was no significant difference.

[0130] Table 1

[0131] serial number Microsphere types Non-spherical ratio Example 1 polystyrene 1.4％ Example 2 polystyrene 5.0％ Example 3 polystyrene 7.2％ Example 4 polystyrene 4.6％ Example 5 polystyrene 2.2％ Example 6 carbon microspheres 1.5％ Example 7 carbon microspheres 4.8％ Example 8 carbon microspheres 9.4％ Example 9 carbon microspheres 4.5％ Example 10 carbon microspheres 3.4％ Comparative Example 1 polystyrene 15.2％ Comparative Example 2 polystyrene 8.0％ Comparative Example 3 carbon microspheres 15.1％

[0132] As shown in Table 1, using the method provided in this application, the non-spherical ratio of the radioactive polystyrene microspheres and radioactive carbon microspheres in Examples 1-10 can all be controlled within 10%. Specifically, the non-spherical ratio of Examples 1-2, 4-7, and 9-10 can all be controlled within 5%.

[0133] Experimental Example 2

[0134] To determine and evaluate whether and to what extent radioactive microspheres lodged in the tumor microcirculation stimulate mammals.

[0135] Test samples: radioactive microspheres provided in Examples 1-3, Examples 6-8, and Comparative Examples 1 and 3.

[0136] Reference standard: High-density polyethylene film (HDPE) (Hatano Research Institute, FDSC, lot number C-212).

[0137] Laboratory animals: New Zealand white rabbits, ordinary grade, male; weight: 2.5-3.5 kg.

[0138] Experimental methods:

[0139] (1) The rabbits were divided into 8 groups of 3 each. The 8 groups corresponded to Examples 1-3, Examples 6-8, and Comparative Examples 1 and 3, respectively. The fur on both sides of the back of the animals was removed 24 hours before the experiment. The anesthetized animals were placed prone on the operating table. Isoflurane anesthesia was used during the operation to prevent muscle tremors.

[0140] (2) After the test sample has decayed, centrifuge to remove the liquid from the suspension.

[0141] (3) Make a longitudinal incision along the midline of the skin on the animal's back, separate the fascia to expose the paraspinal muscles, and make a small incision in the muscle with a scalpel. Using hemostatic forceps, place a certain amount of the treated test sample or control sample (approximately 0.5g of resin microspheres or approximately 0.3g of carbon microspheres) into the appropriate container. Figure 3 The incision is shown. Four test specimens (T1, T2, T3, T4) were implanted into the left paraspinal muscle of each animal, and four control specimens (C1, C2, C3, C4) were implanted into the same muscle on the opposite side.

[0142] (4) The day of implantation is defined as Day 1. All implants are positioned approximately 25mm to 50mm from the midline and are parallel to the midline, with a spacing of approximately 2.5cm between each implant. After implantation, the muscles and skin are sutured with medical sutures. Aseptic procedures are ensured during the implantation process, and the implantation cycle is 13 weeks.

[0143] (5) After the implantation period, the animals were euthanized, and a longitudinal incision was made downward along the center of the rabbit's back to expose the paradorsolateral muscles. The sufficiently large, unaffected paradorsolateral muscles that encased the implant were removed. All implantation sites were collected and fixed for gross observation and histopathological evaluation.

[0144] Evaluation criteria:

[0145] The experimental results are primarily evaluated based on histopathological examination results, and the specific rating process is as follows:

[0146] (1) Evaluate and record the cellular and tissue responses of the surrounding tissues of each implant.

[0147] (2) Calculate the cell response (score in Table 2) and tissue response score (score in Table 3) at each implantation site.

[0148] (3) Calculate the total integral for each site: total integral of cell response × 2 + total integral of tissue response.

[0149] (4) Average score of test sample for each animal = total score of test sample for that animal / number of effective implanted test samples. The total average score of test sample is obtained by adding the average scores of test sample for each animal and dividing by the number of animals. The total average score of control sample is calculated in the same way.

[0150] (5) Final response score = total average score of test sample - total average score of reference sample (negative numbers are recorded as 0).

[0151] Based on the final response score, the degree of implantation response of the test sample is graded according to Table 4.

[0152] Table 2 Histological Evaluation System - Cell Type / Response

[0153]

[0154] phf-high magnification (400×) field of view

[0155] Table 3 Histological Evaluation System - Tissue Response

[0156]

[0157]

[0158] Table 4 Grading of Local Reaction After Implantation

[0159] Final reaction score Classification 0～2.9 No irritation or very slight irritation 3.0～8.9 mild irritation 9.0～15.0 moderate stimulation ＞15.0 Severe stimulation

[0160] The experimental results are as follows:

[0161] No animals were observed to be near death or dead during the experiment. A planned necropsy revealed no gross changes relevant to the test samples.

[0162] The final response scores of the test sample compared with the reference sample are shown in Table 5 below.

[0163] Table 5. Implantation Experiment Results

[0164]

[0165] Table 5 shows that at 13 weeks post-implantation, Examples 1, 2, 6, and 7 had lower scores, all below 2.9, while Examples 3 and 8 had higher scores, and Comparative Examples 1 and 3 had even higher scores, approaching 9.0. This indicates that microspheres with less than 5% non-spherical microspheres were considered non-irritating, while those exceeding 5% caused irritation or even moderate irritation. This suggests that keeping the proportion of non-spherical microspheres below 5% can significantly reduce local inflammatory responses and improve safety.

[0166] Experimental Example 3

[0167] To determine and evaluate the distribution of microspheres in rabbit liver tumors.

[0168] Test samples: radioactive microspheres provided in Examples 1-3, Examples 6-8, and Comparative Examples 1 and 3.

[0169] Laboratory animals: New Zealand white rabbits, ordinary grade, male; weight: 2.5-3.5 kg.

[0170] Experimental methods:

[0171] (1) Establishing a tumor model

[0172] A VX2 rabbit liver transplantation cancer model was established using New Zealand white rabbits. A 2mm diameter VX2 tumor mass was inserted to the lower edge of the central lobe of the rabbit liver. A CT scan was performed 7 days later to record the location and size of the tumor mass. Modeling was considered successful when the maximum tumor diameter reached 1-2cm.

[0173] (2) Group administration

[0174] Animals were anesthetized preoperatively (2.5% sodium pentobarbital, 30 mg / kg). The groin area was shaved, the groin skin was cut, and the femoral artery was bluntly dissected. Under direct vision, the femoral artery was punctured, and a 5F arterial sheath was inserted. The femoral artery and sheath were fixed with absorbable sutures. Under digital subtraction angiography (DSA) guidance, a 2.7F microcatheter was inserted into the common hepatic artery, and radioactive microspheres were injected through the microcatheter, minimizing microsphere reflux. After embolization, the catheter and arterial sheath were removed, the area above the femoral artery puncture site was ligated, and the muscle and skin were sutured layer by layer.

[0175] Rabbits were randomly divided into 8 groups of 3 each, corresponding to Examples 1-3, Examples 6-8, and Comparative Examples 1 and 3, respectively. After 1 GBq of the test sample had decayed, it was perfused into the liver. After 24 hours, the animals were euthanized and dissected. The liver was fixed in formalin, embedded in paraffin, sectioned, stained with hematoxylin and eosin, and subjected to pathological examination. The distribution and density of the microspheres were calculated using the following methods.

[0176] The observed area is divided into four parts:

[0177] 0-1 mm outside the tumor boundary, 0-1 mm inside the tumor boundary, non-tumor tissue, and deep tumor tissue (more than 1 mm inside the tumor boundary).

[0178] Within the microscope's field of view (3mm × 3mm), calculate the distribution density of radioactive microspheres in each region (unit: particles / mm). 2 The average distribution density of the corresponding region for each test sample is calculated using the following formula:

[0179] Average distribution density = total distribution density within the corresponding area / number of animals.

[0180] The experimental results are shown in Table 6 below.

[0181] Table 6

[0182]

[0183] As shown in Table 6, compared to Examples 3 and 8 and Comparative Examples 1 and 3, Examples 1, 2, 6, and 7 generally exhibited higher average distribution density within the tumor. The density outside the tumor and in non-tumor tissues decreased; for example, the distribution density of non-tumor tissue in Example 1 was 0.1, while in Comparative Example 1 it was 1.4. The distribution density deep within the tumor in Example 1 was 1.8, while in Comparative Example 1 it was 0.5. This indicates that controlling the non-sphericity ratio to within 5% can increase the distribution density within the tumor while reducing the distribution density outside the tumor boundary.

[0184] Test Example 4

[0185] To determine and evaluate the therapeutic effect of radioactive microspheres on rabbit liver tumors.

[0186] Test materials: radioactive microspheres provided in Examples 2 and 7, and Comparative Examples 1 and 3.

[0187] Laboratory animals: New Zealand white rabbits, ordinary grade, male; weight: 2.5-3.5 kg.

[0188] Experimental methods:

[0189] (1) Establishing a tumor model

[0190] A VX2 rabbit liver transplantation cancer model was established using New Zealand white rabbits. A 2mm diameter VX2 tumor mass was inoculated into the lower margin of the central lobe of the rabbit liver. A CT scan was performed seven days later to record the tumor's location and size. Successful modeling was considered achieved when the tumor diameter reached 1-2cm.

[0191] (2) Group administration

[0192] Rabbits were randomly divided into 5 groups of 3 each. The 5 groups corresponded to Examples 2 and 7, Comparative Examples 1 and 3, and the model group, respectively. Examples 2 and 7 and Comparative Examples 1 and 3 were assigned to the treatment group.

[0193] Model group: Animals were anesthetized preoperatively (2.5% sodium pentobarbital, 30 mg / kg). The groin area was shaved, the groin skin was cut, and the femoral artery was bluntly dissected. The femoral artery was punctured under direct vision, and a 5F arterial sheath was inserted. The femoral artery and sheath were fixed with absorbable sutures. Under digital subtraction angiography (DSA) guidance, a 2.7F microcatheter was inserted into the common hepatic artery, and saline was injected through the microcatheter, minimizing microsphere reflux. After embolization, the catheter and arterial sheath were removed, the area above the femoral artery puncture site was ligated, and the muscle and skin were sutured layer by layer.

[0194] Insert a catheter into the rabbit's hepatic artery and slowly inject physiological saline through the catheter.

[0195] Treatment group: Each animal was given radioactive embolization microspheres via surgical intervention at a dose of 1 GBq, using the same intervention method as the model group.

[0196] Two weeks after drug administration, a CT scan was performed to record the location and size of the tumor. The animals were then euthanized, the tumors were removed, and weighed. The tumor growth inhibition rate was calculated, and the results are shown in Table 7.

[0197] The tumor growth inhibition rate is calculated using the following formula:

[0198] Tumor growth inhibition rate = (average tumor weight of model group animals - average tumor weight of treatment group animals) / average tumor weight of model group animals * 100%.

[0199] Table 7

[0200] Group Example 2 Example 7 Comparative Example 1 Comparative Example 3 Tumor growth inhibition rate 85.0％ 81.0％ 61.6％ 58.0％

[0201] As shown in Table 7, compared to Comparative Examples 1 and 3, Examples 2 and 7 generally exhibited higher tumor growth inhibition rates against liver tumors. For example, the tumor growth inhibition rate of Example 2 was 85.0%, while that of Comparative Example 1 was only 61.6%. This indicates that controlling the non-spherical ratio to within 5% resulted in better tumor suppression. This is because controlling the non-spherical ratio to within 5% increased the distribution density of microspheres within the tumor, thereby enhancing the tumor-killing ability.

[0202] The above provides a detailed description of a suspension containing radioactive microspheres, its preparation method, and its applications. Specific examples have been used to illustrate the principles and implementation methods of this application. The descriptions of the embodiments above are merely for the purpose of helping to understand the technical solutions and core ideas of this application. 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 of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions in the embodiments of this application.

Claims

1. A suspension containing radioactive microspheres, characterized in that, The radioactive microspheres comprise resin microspheres and a radionuclide loaded on the resin microspheres. The resin microspheres are made of at least one of polystyrene, polyethylene, or divinylbenzene, or a cross-linked polymer thereof, and the surface of the resin microspheres also has sulfonate groups. The resin microspheres are sulfonated resin microspheres obtained by sulfonating the resin microspheres in concentrated sulfuric acid in a batch-by-batch manner. The average particle size of the radioactive microspheres is 25 μm to 40 μm. Based on the number of radioactive microspheres, the proportion of radioactive microspheres with a diameter of 20 μm to 60 μm in the suspension is greater than 85%, and the non-spherical ratio is less than 4%. The non-spherical ratio refers to the proportion of non-spherical radioactive microspheres to the total number of radioactive microspheres in the suspension. Non-spherical radioactive microspheres are those with a minimum radius less than 75% of the original microsphere radius. The original microsphere radius refers to the average radius of the radioactive microspheres in the suspension. The radionuclide is selected from yttrium. 90 Y], each 1 mL of suspension contains yttrium [ 90 The activity of Y] ranges from 500 to 700 MBq.

2. The suspension according to claim 1, characterized in that, The non-spherical ratio of the radioactive microspheres is less than 2%.

3. The suspension according to claim 1, characterized in that, The resin microspheres are made of cross-linked polystyrene with a cross-linking degree of 2% to 10%.

4. The suspension according to claim 1, characterized in that, Based on the number of radioactive microspheres, the proportion of radioactive microspheres with a size of 20 μm to 60 μm in the suspension is greater than 95%.

5. The suspension according to claim 1, characterized in that, The resin microspheres are made of sulfonated polystyrene partially crosslinked with divinylbenzene, and the suspension also contains water for injection.

6. The use of the suspension according to any one of claims 1 to 5 in the preparation of a medicament for treating primary or secondary liver cancer.

Images