Radiopaque resin microspheres, compositions thereof, and uses

Abstract

The application provides a radio-opaque resin microsphere, a composition and application thereof, loaded with radio-opaque ions and radioisotope ions, for example, bismuth ions and yttrium ions, both of which can be loaded on the resin microsphere, so that the resin microsphere is radio-opaque and can maintain its radioactivity, and the position of the resin microsphere can be observed through X-ray or other radiographic technology.

Description

[0001] This application claims priority to U.S. Patent Application No. 63 / 783,056, filed April 3, 2025, and Chinese Patent Application No. 2025110102781, filed July 21, 2025, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This application relates to the field of medical materials, and more particularly to a radiopaque resin microsphere, its composition, and its application. Background Technology

[0003] Liver cancer is a disease with a high incidence rate. As of 2024, it was the sixth most common cancer worldwide and the fourth leading cause of cancer death. Some causes of liver cancer include aflatoxin, non-alcoholic fatty liver disease, liver flukes, hepatitis B, hepatitis C, or alcoholic cirrhosis. Treatments for liver cancer include radiotherapy, surgery, targeted therapy, ablation therapy, embolization therapy, or liver transplantation. For treatments involving radiotherapy, a radionuclide, such as yttrium, may be administered to the subject.

[90] 90 Y) microspheres, for example, for administering yttrium to tumors in the liver of a subject

[90] 90 Y) Microspheres are used to achieve intratumoral radiotherapy and inhibit tumor growth. However, when using this therapy, it is difficult to determine the placement location of the radionuclide in the subject's body, making it difficult for doctors to judge the radionuclide flow and microsphere distribution during injection, affecting treatment judgment and safety. Therefore, improvements are needed. Summary of the Invention

[0004] This application generally relates to radiopaque microspheres for use in radiotherapy and other applications. The subject matter of this application, in some cases, relates to interrelated products, alternative solutions to specific problems, and / or a variety of different uses of one or more systems and / or articles.

[0005] In a first aspect, this application provides a composition containing resin microspheres, said resin microspheres comprising radiopaque ions and at least one radioactive isotope ion.

[0006] In a second aspect, this application provides a composition containing resin microspheres, said resin microspheres comprising bismuth ions and yttrium ions.

[0007] A third aspect of this application provides a suspension comprising a plurality of compositions and dispersion media described in the first or second aspect.

[0008] A fourth aspect of this application provides a method for preparing resin microspheres, comprising: Resin microspheres containing exchangeable ions are placed in a first solution containing bismuth ions, allowing at least a portion of the exchangeable ions in the ion exchange resin to exchange with bismuth ions, thereby obtaining first resin microspheres; and The negative first resin microspheres are placed in a second solution containing yttrium ions, so that at least some of the exchangeable ions are exchanged with the yttrium ions to obtain the second resin microspheres.

[0009] A fifth aspect of this application provides a method for preparing resin microspheres, comprising: Resin microspheres containing exchangeable ions are placed in a first solution containing a first ion, allowing at least a portion of the exchangeable ions in the ion exchange resin to exchange with the first ion, thereby obtaining first resin microspheres; and The first resin microspheres are placed in a second solution containing the second ions, so that at least some of the exchangeable ions are exchanged with the second ions to obtain the second resin microspheres. The first ion and the second ion are different, and the first ion or the second ion is a radiopaque ion.

[0010] A sixth aspect of this application provides a composition comprising bismuth ions and an organic solvent.

[0011] The organic solvent is selected from at least one of ethylene glycol, DMSO, and DMF.

[0012] The use of the composition of the sixth aspect above in the preparation of resin microspheres, wherein the resin microspheres are bismuth-loaded resin microspheres.

[0013] The use of the aforementioned resin microsphere composition or the aforementioned suspension in the preparation of disease therapeutic agents.

[0014] In some implementations, the disease is a tumor, such as liver cancer, pancreatic cancer, glioma, neuromeningioma, kidney cancer, etc.

[0015] This application also provides a method for treating a disease, comprising applying a composition or suspension of resin microspheres as described above to a mammal.

[0016] In some implementations, the mammal is a human.

[0017] This application provides a composition of radiopaque resin microspheres, the resin microspheres comprising radiopaque ions and radioactive isotope ions, such as bismuth ions and yttrium ions, which can be loaded simultaneously onto the resin microspheres, making the resin microspheres radiopaque while maintaining their radioactivity, and the position of the resin microspheres can be observed by X-ray or other radiographic imaging techniques. Attached Figure Description

[0018] Non-limiting embodiments of this disclosure will be described with reference to the accompanying drawings, which are schematic diagrams and not drawn to scale.

[0019] Figure 1 These are scanning electron microscope (SEM) images and energy dispersive spectroscopy (EDS) images of a resin microsphere prepared in Example 1; Figure 2 The developing effects of the resin microspheres prepared in Example 1, the blank control, and iohexol are shown. Figure 3 The radiopaque properties of resin microspheres (101) prepared by using bismuth nitrate-ethylene glycol solution at a concentration of 0.01 g / mL as the bismuth ion-loaded reaction solution in Example 1, and the radiopaque properties of resin microspheres (103) loaded with gadolinium ions in Example 3 are shown. Figure 4 The results are from an in vivo imaging experiment of the resin microspheres prepared in Example 1 (loaded with 0.04 g / mL bismuth nitrate ethylene glycol solution). Detailed Implementation

[0020] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0021] This disclosure generally relates to radiopaque materials for use in radiotherapy and other applications. Some aspects generally relate to resin materials, such as microspheres, containing radiopaque ions (e.g., bismuth) and radionuclides (e.g., yttrium-90). These microspheres can be applied to a subject, such as a tumor within the subject, where the yttrium decays to produce radiation that treats the tumor. The radiopaque ions within the microspheres can be used to determine the location of the resin microspheres within the subject, for example, during or after application. For example, techniques such as fluoroscopy can be used to determine the placement of the microspheres. Other aspects generally relate to systems and methods for manufacturing such microspheres, methods for using such microspheres, kits including such microspheres, or the like. In this document, "radioporous" and "radioisopermeable" have the same meaning.

[0022] Some aspects generally involve materials containing radionuclides that can be administered to subjects and used to treat tumors. Such materials may be in the form of microspheres or microspheres (e.g., with a diameter ≤ 500 micrometers) and may include polymers, including resins such as ion exchange resins (e.g., styrene-divinylbenzene copolymer). Radionuclides, such as yttrium-90 (… 90Beta rays (γ) can emit beta rays over relatively short distances, which can be used to destroy or kill nearby tissue, i.e., tissue within a tumor. Therefore, materials containing such radionuclides can be injected into or near a tumor as a form of targeted radiotherapy. However, these materials are not necessarily administered or delivered to the correct location within the subject's body. Furthermore, because the administration site is inside the body, it can be difficult to determine the exact location of the material within the subject.

[0023] Therefore, this application first provides a resin microsphere comprising radiopaque ions and radioactive nuclide ions. In some embodiments, the radiopaque ions and radioactive nuclide ions are bound to the same resin microsphere, that is, two types of the above-mentioned ions are bound to one resin microsphere.

[0024] In some embodiments, radiopaque ions may be added to the material to determine its location within a subject's body, for example, using fluoroscopy or other radiographic techniques. Examples of radiopaque ions include bismuth or other ions described herein, such as zirconium, tantalum, titanium, barium, etc. These ions block a portion of X-rays, making the material opaque to radiation. Radiopaque ions may be present in any suitable form, for example, separately from microspheres or other materials containing radionuclides, or in some embodiments, combined with microspheres or other materials.

[0025] In some cases, radiopaque ions can be added to microspheres or similar materials using techniques such as ion exchange. In some embodiments, resin materials (such as ion exchange resins) can be exposed to a solution containing bismuth and / or other radiopaque ions, allowing some bismuth ions to exchange with exchangeable ions in the resin material. However, some ions, such as bismuth, are poorly soluble in water, making this process challenging. We have unexpectedly discovered that certain organic solvents, such as ethylene glycol, can be used to dissolve bismuth and participate in ion exchange, for example, introducing bismuth into resin materials.

[0026] Ion exchange technology can also be used to introduce radionuclides (radioisotopes) into resin materials. For example, resins (such as ion exchange resins) can be exposed to solutions containing yttrium (such as yttrium-90) and / or other radioisotopes, and through ion exchange, some yttrium ions can exchange with exchangeable ions in the resin material.

[0027] However, because ions exchange with other ions in the ion-exchange resin during the ion-exchange process, multiple ion-exchange reactions are not expected to be used. Surprisingly, however, we have found that under certain conditions, such as those described herein, multiple types of ions can be exchanged into the resin. Therefore, as discussed herein, certain embodiments are generally directed to systems and methods for forming microspheres or other materials containing radionuclides and radiopaque ions, which can be applied to a subject, for example, for treating tumors in the subject's body, such as liver cancer, pancreatic cancer, glioma, meningioma, and kidney cancer.

[0028] The above discussion is a non-limiting example of one embodiment of this disclosure, which can be used to produce radiopaque materials for radiotherapy and other applications. However, other embodiments are also possible. Therefore, more generally, the aspects are directed to various systems and methods for producing radiopaque materials for radiotherapy and other applications.

[0029] One aspect typically addresses microspheres or other materials containing radiopaque ions (such as bismuth) and radioactive nuclides (such as yttrium). In some cases, microspheres can be microspheres, for example, with an average diameter ≤ 1 mm. Microspheres can be substantially spherical, but are not necessarily regular or symmetrical in shape. Therefore, microspheres can be spherical and / or non-spherical, and can have the same or different shapes and / or sizes. In some embodiments, the shape of the microspheres may also be free of sharp edges or points that could damage arteries or become lodged in unexpected locations. The average diameter of a non-spherical microsphere can be taken as the diameter of a perfect sphere with the same volume as the non-spherical microsphere.

[0030] In some cases, the average diameter of the microspheres can be ≤1 mm, ≤500 μm, ≤300 μm, ≤200 μm, ≤150 μm, ≤100 μm, ≤50 μm, ≤40 μm, or ≤35 μm, etc. In other cases, the average diameter of the microspheres can be at least 5 μm, at least 10 μm, at least 15 μm, at least 20 μm, at least 30 μm, or at least 50 μm. In different embodiments, any of the above can also be combined. For example, the average diameter of the microspheres can be between 5 μm and 200 μm, between 15 μm and 100 μm, between 20 μm and 50 μm, between 30 μm and 35 μm, between 20 μm and 50 μm, between 30 μm and 40 μm, etc. In some cases, the microspheres or other materials may comprise polymers. At least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% of the microspheres or other materials may comprise one or more polymers. An example of a polymer is a resin. For example, the polymer may be an ion exchange resin, such as a cation exchange resin. In some cases, ion exchange resins include aliphatic polymers, such as polystyrene, polystyrene sulfonate, polyacrylate, etc. One or more of these polymers, and / or other polymers, may be present in the microspheres or other materials. Non-limiting examples of cation exchange resins include styrene-divinylbenzene copolymer resins, or sulfonated divinylbenzene-styrene copolymers. Many such resins are commercially available, and commercially available resin microspheres may be used in other embodiments. Furthermore, in some embodiments, the polymer may be at least partially crosslinked (e.g., polystyrene crosslinked with divinylbenzene). For example, 1% to 20% crosslinking, 2% to 10% crosslinking, 3% to 5% crosslinking, etc., may be present in the microspheres or other materials. In some respects, the microspheres may contain radiopaque ions, such as bismuth (Bi). In some cases, the radiopaque ions are monatomic ions. Radiopaque ions generally do not allow the passage of X-rays or similar radiation. Other radiopaque ions that can be used in various embodiments include, but are not limited to, gadolinium (Gd), lutetium (Lu), holmium (Ho), barium (Ba), tantalum (Ta), iodine (I), titanium (Ti), tungsten (W), or zirconium (Zr). Furthermore, in some cases, two, three, or more different radiopaque ions may be present.

[0031] Radiopaque ions can be present in microspheres or other materials at any density or concentration. In some cases, the concentration of radiopaque ions can be at least 0.1 mmol / g, at least 0.2 mmol / g, at least 0.3 mmol / g, at least 0.4 mmol / g, at least 0.5 mmol / g, at least 0.6 mmol / g, at least 0.7 mmol / g, at least 0.8 mmol / g, at least 0.9 mmol / g, or at least 1.0 mmol / g. The concentration of ions can not exceed 1.0 mmol / g, not exceeding 0.9 mmol / g, not exceeding 0.8 mmol / g, not exceeding 0.7 mmol / g, not exceeding 0.6 mmol / g, not exceeding 0.5 mmol / g, not exceeding 0.4 mmol / g, not exceeding 0.3 mmol / g, not exceeding 0.2 mmol / g, or not exceeding 0.1 mmol / g. In other embodiments, any combination of the above concentrations may be used, such as 0.5 mmol / g to 0.6 mmol / g, 0.4 mmol / g to 0.7 mmol / g, 0.5 mmol / g to 0.7 mmol / g, etc. In some embodiments, the mass concentration of the radiopaque microspheres or other materials is at least 1 wt%, at least 2 wt%, at least 3 wt%, at least 4 wt%, at least 5 wt%, at least 7 wt%, at least 10 wt%, at least 12 wt%, at least 15 wt%, at least 17 wt%, at least 20 wt%, and / or not exceeding 20 wt%, not exceeding 17 wt%, not exceeding 15 wt%, not exceeding 12 wt%, not exceeding 10 wt%, not exceeding 7 wt%, not exceeding 5 wt%, etc. The molar concentration or mass concentration of radiopaque ions contained in a unit mass (e.g., per 1 g) of microspheres can be detected and calculated using the following methods: Taking the suspension formed by 1g of resin microspheres and 5mL of water as an example, the supernatant and microspheres were first separated by a filtration device, and the supernatant and microspheres were detected separately by inductively coupled plasma mass spectrometry (ICP-MS). ICP-MS testing process: (1) Preparation of standard curve solution: Use diluent (5% nitric acid solution) and standard solution of the element to be tested (such as bismuth and yttrium) to prepare linear stock solution with known concentration of the element to be tested. Then use diluent to dilute the linear stock solution to obtain standard curve solutions with different concentrations (such as 0.4%, 1%, 2%, 3%, and 4% of the linear stock solution). The concentration unit is generally ng / ml. (2) Establishing a standard curve: Place the diluent and the prepared standard curve solutions of each concentration of the element to be measured into the instrument injection tank, inject the samples one by one and obtain the response values ​​at each concentration from the instrument, thereby establishing the standard curve equation between the response value and the concentration of the element to be measured. (3) Sample concentration test: After diluting the sample solution to be tested with diluent (record the dilution ratio), the response value of the element in the sample to be tested is obtained by injecting the sample into the instrument, and the element concentration value in the sample diluent is calculated according to the standard curve equation. The concentration of the corresponding element in the sample solution to be tested can be obtained after combining the dilution ratio.

[0032] Supernatant testing process: Accurately transfer 1.0 ml into a 100 ml Grade A glass volumetric flask, dilute to the mark with 2% dilute nitric acid, shake well, and filter through a 0.45 μm filter membrane. Perform ICP-MS analysis directly on the target ions (such as bismuth and yttrium). The detection results... 100 represents the mass concentration of free ions in the original supernatant. The molar concentration of ions (mol / g) is the obtained mass concentration of ions (wt%) divided by the atomic mass of the corresponding ion element (e.g., bismuth is 209).

[0033] Microsphere testing process: (1) Weighing: Remove the supernatant from the polystyrene solid microspheres and record the initial mass of the microspheres. Dry the microspheres thoroughly at 80℃ for 10 hours. After cooling to room temperature in a desiccator, accurately weigh approximately 15-20 mg using a balance with a precision of 0.01% (the actual mass weighed is recorded as the mass of the dried microspheres). The swelling rate of these polystyrene microspheres in aqueous solution is approximately 150% (the swelling rate is calculated as: (mass after swelling - mass before swelling) / mass before swelling). 100%.

[0034] (2) Digestion: Place the weighed microspheres in a digestion vessel, add 6 ml HNO3 and 2 ml H2O2, pre-digest at room temperature for 30 min, then place on a hot plate, raise the temperature to 120℃ and hold for 60 min, continue to raise the temperature to 160℃ and hold for 60 min, and finally hold at 180℃ for 6 h until the sample is completely digested and the solution becomes a clear and transparent solution.

[0035] (3) Volume adjustment: Then transfer the digested solution to a 100ml Grade A glass volumetric flask, rinse the digestion vessel 3 times with ultrapure water and transfer all the rinsed solution to the volumetric flask, adjust the volume to the mark and shake well, filter with a 0.45μm filter membrane, then accurately transfer 0.1ml to a 100ml volumetric flask, adjust the volume to the mark with 1% dilute nitric acid, shake well and then perform ICP-MS detection.

[0036] (4) The mass concentration of the target ions (bismuth ions and yttrium ions) detected by ICP-MS, combined with the dilution factor of the digestion solution during the volume adjustment process, can be used to calculate the ion mass concentration in the microsphere digestion solution. Multiply this concentration by the volume of the digestion solution and divide by the mass of the microspheres before digestion to get the ion mass concentration loaded in the microspheres.

[0037] The molar concentration of an ion (mol / g) is the mass concentration of the obtained ion (wt%) divided by the atomic mass of the corresponding ion element (e.g., bismuth is 209).

[0038] Furthermore, in some embodiments, radiopaque ions can be stably incorporated into microspheres or other materials.

[0039] In some respects, the microspheres or other materials may contain a radionuclide, such as yttrium-90. For example, yttrium-90 can be prepared by irradiating yttrium (yttrium oxide) in a neutron beam to activate it into the isotope yttrium-90, and / or by using other techniques in certain circumstances, yttrium oxide can be dissolved, for example, as a yttrium sulfate solution, to be added to the microspheres or other materials, as described herein. Furthermore, yttrium-90 from other sources may be used in other embodiments.

[0040] However, it should be understood that this disclosure is not limited to yttrium-90 ( 90 (Y). Other radionuclides that may be used in other embodiments include, but are not limited to, lutetium-177, astatine-211, rhenium-186, rhenium-188, or actinium-225. Examples of other radionuclides include radioisotopes of holmium, samarium, iodine, phosphorus, iridium, etc. Furthermore, in some cases, two, three, or more different types of radionuclides may be present.

[0041] Radionuclides may also be present in the microspheres or other materials at any density or concentration. In some cases, the concentration of radionuclides within the microspheres may be at least 0.1 mmol / g, at least 0.2 mmol / g, at least 0.3 mmol / g, at least 0.4 mmol / g, at least 0.5 mmol / g, at least 0.6 mmol / g, at least 0.7 mmol / g, at least 0.8 mmol / g, at least 0.9 mmol / g, or at least 1.0 mmol / g. In some embodiments, the concentration of radionuclides may not exceed 1.0 mmol / g, not exceeding 0.9 mmol / g, not exceeding 0.8 mmol / g, not exceeding 0.7 mmol / g, not exceeding 0.6 mmol / g, not exceeding 0.5 mmol / g, not exceeding 0.4 mmol / g, not exceeding 0.3 mmol / g, not exceeding 0.2 mmol / g, or not exceeding 0.1 mmol / g. In other embodiments, arbitrary combinations are also possible, such as 0.5 mmol / g to 0.6 mmol / g, 0.4 mmol / g to 0.7 mmol / g, 0.5 mmol / g to 0.7 mmol / g, etc. Furthermore, in some cases, the concentration of the radionuclide in the microspheres can be at least 5 wt%, at least 7 wt%, at least 10 wt%, at least 12 wt%, at least 15 wt%, at least 17 wt%, at least 20 wt%, and / or not exceeding 20 wt%, not exceeding 17 wt%, not exceeding 15 wt%, not exceeding 12 wt%, not exceeding 10 wt%, not exceeding 7 wt%, not exceeding 5 wt%, etc. In some embodiments, the radionuclide can be stably incorporated into the microspheres or other materials.

[0042] It should also be understood that different isotopes of a radionuclide may be present in some embodiments, but not all isotopes are radioactive. For example, stable or “cold” yttrium (such as yttrium-89) may be present in some embodiments, as in partial replacement of yttrium-90. For example, controlling the ratio of stable isotopes to radioactive isotopes (such as yttrium-89 and yttrium-90) may help control the amount of radioactivity present (e.g., without altering the synthesis or preparation of the microspheres or other materials). In this way, the activity or specific activity of the microspheres or other materials can be controlled, for example, by controlling the ratio of stable isotopes to radioactive isotopes.

[0043] Therefore, for example, in some cases, at least 10 mol% of the isotopes of a radioactive nuclide are radioactive; in other cases, at least 20 mol%, 30 mol%, 40 mol%, 50 mol%, 60 mol%, 70 mol%, 80 mol%, or 90 mol% of the isotopes are radioactive. In some cases, isotopes not exceeding 90 mol%, 80 mol%, 70 mol%, 60 mol%, 50 mol%, 40 mol%, 30 mol%, 20 mol%, or 10 mol% may be radioactive. In different embodiments, any combination of the above ranges is also possible; for example, isotopes of 20 mol% to 40 mol%, 30 mol% to 50 mol%, 20 mol% to 30 mol%, etc., may be radioactive.

[0044] In some implementations, the selection of radioactive isotopes can cause the microspheres or other materials to exhibit a (total) radioactivity of at least 1 GBq, at least 2 GBq, at least 3 GBq, at least 4 GBq, or at least 5 GBq. In some cases, isotopes can be selected to cause the microspheres or other materials to exhibit a radioactivity of ≤5 GBq, ≤4 GBq, ≤3 GBq, or ≤2 GBq. In some cases, these isotopes can also be combined. In some implementations, the radioactive isotope may be selected from microspheres or other material forms and maintain a radioactivity of at least 0.1 GBq / g, at least 0.2 GBq / g, at least 0.3 GBq / g, at least 0.4 GBq / g, at least 0.5 GBq / g, at least 0.6 GBq / g, at least 0.7 GBq / g, at least 0.8 GBq / g, at least 0.9 GBq / g, or at least 1 GBq / g, and / or not exceeding 1 GBq / g, not exceeding 0.9 GBq / g, not exceeding 0.8 GBq / g, not exceeding 0.7 GBq / g, not exceeding 0.6 GBq / g, not exceeding 0.5 GBq / g, not exceeding 0.4 GBq / g, not exceeding 0.3 GBq / g, not exceeding 0.2 GBq / g, or not exceeding 0.1 GBq / g. In some cases, a combination of these parameters may also be used.

[0045] In some embodiments, a radionuclide (e.g., yttrium) and a radiopaque ion (e.g., bismuth) are bound to the same resin microsphere. That is, a single resin microsphere is simultaneously loaded with a radionuclide (e.g., yttrium) and a radiopaque ion (e.g., bismuth). In some embodiments, in a composition of multiple resin microspheres, some resin microspheres are loaded with a radionuclide (e.g., yttrium), while others are loaded with a radiopaque ion (e.g., bismuth). In some embodiments, in a composition of multiple resin microspheres, each of some resin microspheres is simultaneously loaded with a radionuclide (e.g., yttrium) and a radiopaque ion (e.g., bismuth), while others are loaded with either a radionuclide (e.g., yttrium) or a radiopaque ion (e.g., bismuth).

[0046] Depending on certain aspects, radionuclides and / or radiopaque ions can be stably incorporated into microspheres or other materials, such as resins or polymers. Stable incorporation is understood to mean that the incorporation of ions prevents them from extensively leaching from the microspheres or other materials (such as polymers or resins) under physiological conditions, such as within the subject and / or during storage. For example, leaching of radionuclides from materials can cause nonspecific radiation to the subject and damage surrounding tissues.

[0047] Therefore, in some embodiments, ions stably incorporated into microspheres or other materials may exhibit exudation (i.e., exudation of unbound ions, free ions) of less than 5 mol%, 4 mol%, 3 mol%, 2 mol%, 1 mol%, 0.7 mol%, 0.5 mol%, or 0.4 mol%. In some cases, microspheres or other materials may include unbound ions in total amounts not exceeding 1 wt%, 0.8 wt%, 0.7 wt%, 0.6 wt%, 0.5 wt%, 0.4 wt%, 0.3 wt%, 0.2 wt%, or 0.1 wt%. Further, based on the total mass of the microspheres, microspheres or other materials may include unbound ions (free ions, such as free bismuth ions and free yttrium ions) in total amounts not exceeding 0.1 wt%, 0.08 wt%, 0.07 wt%, 0.06 wt%, 0.05 wt%, 0.04 wt%, 0.03 wt%, 0.02 wt%, or 0.01 wt%.

[0048] In some implementations, the percentage of free bismuth ions in the total initial bismuth ion load does not exceed 0.01 wt%, for example, not exceeding 0.008 wt%, not exceeding 0.007 wt%, not exceeding 0.006 wt%, not exceeding 0.005 wt%, not exceeding 0.004 wt%, not exceeding 0.003 wt%, not exceeding 0.002 wt%, or not exceeding 0.001 wt%.

[0049] The percentage of free yttrium ions in the total initial yttrium ion loading does not exceed 0.01 wt%, for example, not exceeding 0.006 wt%, not exceeding 0.005 wt%, not exceeding 0.004 wt%, not exceeding 0.003 wt%, not exceeding 0.002 wt%, not exceeding 0.001 wt%, not exceeding 0.0015 wt%, not exceeding 0.0005 wt%, and not exceeding 0.0002 wt%.

[0050] One example method for assessing ion leaching is to adjust the pH of the sample containing microspheres to 7.0 and stir the microspheres in a 37°C water bath for 20 minutes. For example, a 100 μL sample can be used to determine radionuclides, and the results can be calculated using a Geiger-Muller counter. Another representative 100 μL sample can be filtered through a 0.22 μL filter, and the filtrate can be used for β-emission counting in a Geiger-Muller counter. The percentage of unbound radionuclides can be calculated as: Radionuclide count in filtrate / Radionuclide count in sample × 100% = Unbound radionuclides.

[0051] Ion exchange can be used in some respects to introduce ions, such as radioactive nuclei and / or radiopaque ions, into microspheres or other materials. In one set of embodiments, the microspheres or other materials may be exposed to a solution containing suitable dissolved ions, such as bismuth ions, yttrium ions, or any other ions described herein, and exchangeable ions within the material may exchange with such ions.

[0052] Furthermore, in certain situations, ions can be precipitated to stably bind them to microspheres or other materials. For example, ions can be precipitated in the form of phosphates, hydrogen phosphates, dihydrogen phosphates, carbonates, bicarbonates, sulfates, chlorides (hydrochlorides), etc., thereby binding the ions to the resin or other materials. Different ions (such as radionuclides and / or radiopaque ions) can be precipitated using the same salt (such as phosphates), or different salts (such as one ion precipitated using a phosphate and another using a carbonate). As a non-limiting example, phosphates can be precipitated by adding a sodium phosphate solution to a solution containing resin, carbonates can be precipitated by adding a sodium carbonate solution to a solution containing microspheres or other materials, and bicarbonates can be precipitated by adding a sodium bicarbonate solution to a solution containing microspheres or other materials, etc. In some cases, such salt precipitation results in the stable binding of ions to the microspheres or other materials, for example, causing little or no leaching of ions from the microspheres or other materials (as discussed herein).

[0053] Certain types of radionuclides and / or radiopaque ions are readily soluble (e.g., yttrium ions) and can therefore be exchanged into microspheres or other materials as described above. For example, yttrium is readily soluble, and the concentration of yttrium ions in the solution can be at least 10 g / mL, at least 20 g / mL, at least 30 g / mL, at least 40 g / mL, at least 50 g / mL, at least 60 g / mL, at least 70 g / mL, or at least 80 g / mL. Furthermore, in some embodiments, the concentration of yttrium ions may not exceed 80 g / mL, not more than 70 g / mL, not more than 60 g / mL, not more than 50 g / mL, not more than 40 g / mL, not more than 30 g / mL, not more than 20 g / mL, or not more than 10 g / mL.

[0054] However, some ions (such as bismuth ions) are insoluble and therefore cannot be exchanged into microspheres or other materials. Due to their poor solubility, these ions are almost never used in ion exchange. Surprisingly, however, we have found that certain organic solvents can dissolve bismuth ions, thus allowing bismuth to subsequently participate in ion exchange, for example, in ion exchange resins. In one embodiment, bismuth can be dissolved in organic solvents such as ethylene glycol or DMF (dimethylformamide). For example, bismuth salts (such as bismuth nitrate, Bi(NO3)3) can be dissolved in organic solvents such as ethylene glycol. In some cases, the concentration of bismuth in the organic solvent (such as Bi(NO3)3 in ethylene glycol) is 0.01 g / mL to 10 g / mL, for example, 0.01 g / mL to 5 g / mL, 0.01 g / mL to 0.5 g / mL, 0.01 g / mL to 0.2 g / mL, 0.04 g / mL to 0.2 g / mL, 0.04 g / mL to 0.15 g / mL; in some embodiments, the concentration of bismuth in the organic solvent (such as Bi(NO3)3 in ethylene glycol) is at least 0.01 g / mL, at least 0.02 g / mL, at least 0.03 g / mL, at least 0.04 g / mL, at least 0.05 g / mL, at least 0.06 g / mL, at least 0.07 g / mL, at least 0.08 g / mL, at least 0.09 g / mL, at least 0.1 g / mL, at least 0.12 g / mL, at least 0.15 g / mL, etc. In some cases, the concentration of bismuth ions may not exceed 0.15 g / mL, 0.1 g / mL, 0.12 g / mL, 0.09 g / mL, 0.08 g / mL, 0.04 g / mL, 0.05 g / mL, 0.06 g / mL, 0.07 g / mL, 0.08 g / mL, or 0.09 g / mL. In some cases, the organic solvent may be nonane. After bismuth is dissolved, microspheres or other materials can be added to the organic solvent, and then the dissolved bismuth ions can be exchanged into these materials. Furthermore, multiple ions can be exchanged into these microspheres or other materials, for example, in a manner that allows for ion co-loading. In many ion exchange processes, the addition of a second ion to the ion exchange resin displaces the first ion in the ion exchange resin, and the addition of a third ion to the ion exchange resin also displaces the second ion (this property is often used for the recharging of ion exchange resins). Therefore, surprisingly, after yttrium and bismuth ions are exchanged onto the resin microspheres and precipitated by phosphate solution, both types of ions can be loaded into the resin without causing a large displacement of other ions.

[0055] Therefore, for example, in one embodiment, bismuth ions can be exchanged into an ion exchange resin (e.g., by exposing the resin to a solution containing dissolved bismuth ions), and then the bismuth ions are converted into phosphate form and precipitated on or inside the resin using a solution such as sodium phosphate, sodium hydrogen phosphate, or disodium hydrogen phosphate. Subsequently, yttrium ions can be exchanged into the resin (e.g., by exposing the resin to a solution containing dissolved yttrium ions) without causing excessive migration of bismuth ions from the resin. In another embodiment, yttrium ions can be exchanged into the ion exchange resin first, and then bismuth ions can be exchanged. In yet another embodiment, yttrium ions and bismuth ions can be exchanged simultaneously (e.g., by exposing the resin to a solution containing both dissolved bismuth ions and dissolved yttrium ions).

[0056] In some embodiments, this may result in microspheres or other materials with a bismuth ion to yttrium ion mass ratio between 1:1 and 10:1, such as at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, not exceeding 10:1, not exceeding 9:1, not exceeding 8:1, not exceeding 7:1, not exceeding 6:1, not exceeding 5:1, not exceeding 4:1, not exceeding 3:1, not exceeding 2:1, etc. In some cases, the molar ratio of bismuth ions to yttrium ions in the microspheres can be between 0.2:1 and 10:1, such as at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, not exceeding 10:1, not exceeding 9:1, not exceeding 8:1, not exceeding 7:1, not exceeding 6:1, not exceeding 5:1, not exceeding 4:1, not exceeding 3:1, not exceeding 2:1, etc.

[0057] It is understood that the metrological measurements (e.g., molar concentration, mass concentration, radioactivity, etc.) of radiopaque ions (e.g., bismuth ions) and radionuclide ions (e.g., yttrium ions) in the resin microspheres described in this application are based on a unit mass of resin microspheres. Therefore, in some embodiments, this application also provides a composition of resin microspheres comprising a plurality of resin microspheres as described above, referring to a collection of a plurality of resin microspheres.

[0058] In some cases, the composition is a combination of one or more of the following resin microspheres: resin microspheres simultaneously loaded with radiopaque ions and radionuclide ions (loaded with both types of ions), resin microspheres loaded with only radiopaque ions or only radionuclide ions (loaded with one type of ion), and resin microspheres not loaded with either radiopaque ions or radionuclide ions (not loaded with any additional ions).

[0059] The composition is any of the following: (a) is a combination of multiple resin microspheres loaded with two types of ions; (b) is a combination of resin microspheres loaded with two types of ions and resin microspheres loaded with one type of ions; (c) is a combination of resin microspheres loaded with two types of ions and resin microspheres loaded with one type of ions; and a combination of resin microspheres not loaded with any additional ions.

[0060] Preferably, in the embodiments of this application, the composition of resin microspheres contains more resin microspheres loaded with the aforementioned two ions.

[0061] This application provides a method for preparing resin microspheres, which can be used to prepare the aforementioned resin microspheres.

[0062] Resin microspheres containing exchangeable ions are placed in a first solution containing a first ion, allowing at least a portion of the exchangeable ions in the ion exchange resin to exchange with the first ion, thereby obtaining first resin microspheres; and The first resin microspheres are placed in a second solution containing the second ions, so that at least some of the exchangeable ions are exchanged with the second ions to obtain the second resin microspheres. The first ion and the second ion are different, and the first ion or the second ion is a radiopaque ion.

[0063] In some embodiments, the first ion is a radiopaque ion, such as a bismuth ion; the second ion is a radioactive isotope ion, such as... 90 Y ions. In some embodiments, the second ion is a non-radioactive metal ion, such as... 89 Y ions.

[0064] In some embodiments, the first solution is a solution containing a bismuth salt, particularly an organic solvent containing a bismuth salt. The organic solvent is an organic solvent such as ethylene glycol, glycerol, DMF, DMSO, or a combination thereof, and the bismuth salt may be bismuth nitrate. In the first solution, the concentration of bismuth nitrate is 0.01-5 g / mL, preferably 0.04-2 g / mL or 0.04-1.5 g / mL, for example, 0.01 g / mL, 0.02 g / mL, or 0.03 g / mL.

[0065] Since microspheres or other materials may be applied to the arterial blood supply of a subject's target organ, this application also provides a suspension comprising the microspheres and dispersion medium provided in the embodiments of this application.

[0066] The dispersion medium can be of a pharmaceutically acceptable type, such as pure water, or other acceptable type. In some embodiments, the dispersion medium is primarily a nonionic solvent.

[0067] When a combination of multiple resin microspheres (e.g., 1 g) is prepared using the above method, a composition of resin microspheres as described above is obtained.

[0068] In some cases, the preparation of microspheres or other materials may result in a suspension with a pH ≤ 9. If the pH is ≥ 9, then in some embodiments, when the suspension is injected into an artery or target organ, it may cause vascular irritation. In some cases, the pH may be ≤ 8.5, ≤ 8.0, or ≤ 7.5. In one set of embodiments, the pH is 7.4, which is the physiological pH. For example, phosphate-buffered saline or other pH buffers can be used to control the pH, for example, to such a pH value.

[0069] To lower the pH of a suspension containing microspheres or other materials, in some embodiments, it may be washed, for example, to remove any unprecipitated or loosely attached radionuclides. Some embodiments are typically for suspensions with a controlled pH, for example, by precipitating yttrium with a trisodium phosphate solution containing at least three times the excess of phosphate ions, but not exceeding 30 times the excess, followed by washing the microspheres with deionized water. In another embodiment, the microspheres or other materials may be washed with a phosphate buffer solution of the desired pH.

[0070] Because microspheres or other materials may be administered to the arterial blood supply of a subject's target organ, it may be necessary to produce microspheres or other materials with specific sizes, shapes, and / or densities to facilitate distribution within the target organ. In some cases, the mass-volume concentration of microspheres or other materials in the suspension may be relatively low, for example, between 0.01 g / mL and 10 g / mL, such as 10 g / mL, 8 g / mL, 5 g / mL, 3.0 g / mL, 2.8 g / mL, 2.5 g / mL, 2.3 g / mL, 2.2 g / mL, 2.0 g / mL, 1.5 g / mL, 1.0 g / mL, 0.5 g / mL, etc.; or concentrations lower than these values. Furthermore, in some cases, microspheres or other materials may have a relatively narrow size distribution. For example, the standard deviation of the microsphere diameter may be ≤10%, ≤8%, ≤5%, ≤4%, ≤3%, or ≤2%. This may, for example, contribute to the uniform distribution of microspheres or other materials within the target organ (such as the liver of a patient with hepatocellular carcinoma).

[0071] Furthermore, certain aspects generally pertain to systems and methods for radiotherapy and other applications, such as the use of the compositions discussed herein. For example, some embodiments are for radiotherapy systems and methods for human or other mammalian subjects, including the administration of the compositions described herein to the subject. It is understood that administration can be performed in any suitable manner. For example, in some cases, the composition can be delivered into or through an artery, such as an artery associated with the treatment site of the subject. As a non-limiting example, in the treatment of liver cancer, administration can be performed by exposing the hepatic artery through open surgery or by inserting a catheter into the hepatic artery through the femoral or brachial artery. In some embodiments, pre-administration or co-administration of another agent can be used, for example, to prepare the tumor for receiving the composition. As a non-limiting example, vasoactive substances, such as angiotensin-2, can be used to redirect arterial blood flow to the treatment site. Administration of the composition can be performed using any suitable technique, for example, using single or multiple doses until the desired level of radiation or treatment is achieved.

[0072] Therefore, this document provides, in certain respects, compositions for the prevention and / or treatment of proliferative diseases (such as cancer) in humans and other mammals. Thus, the subjects of study can be humans or non-human mammals such as monkeys, cattle, sheep, goats, horses, rabbits, pigs, mice, rats, dogs, cats, etc. Cancer is typically an uncontrolled growth of cells that interferes with the normal function of the body's organs and systems. Many tumors exhibit altered metabolic requirements, and this alteration in antioxidant defense function may allow tumor growth. According to certain embodiments, the compositions discussed herein can at least partially counteract this effect. Examples of cancers that can be treated using the compositions discussed herein include liver cancer.

[0073] In some embodiments, an effective amount of the composition is administered to a subject (e.g., a mammalian subject, such as a human or non-human subject) to treat cancer. The effective amount of the composition may be based at least in part on the targeted tissue and / or cell type, the route of administration, the characteristics of the composition, or the like. Other determining factors include the subject's weight, age, height, sex, and general health condition. Generally, an effective amount of the composition can treat cancer. As used herein, "treatment" means a therapeutic or preventative measure aimed at preventing or alleviating the target pathological condition or disorder (such as cancer) described herein. Thus, in some embodiments, treatment may include directly affecting or curing, inhibiting, suppressing, preventing, reducing severity, delaying onset, alleviating symptoms associated with the disease, disorder, or symptom, or a combination thereof. In some embodiments, "treatment" means, among other things, delaying disease progression, accelerating remission, inducing remission, enhancing remission, accelerating recovery, improving the efficacy of alternative therapies, or reducing resistance to alternative therapies, or a combination thereof. In some embodiments, the compositions provided herein are used to treat cancer, for example, by enhancing the killing power of tumor cells. Compared to the control group that did not receive the composition of the present invention, receiving the composition of the present invention killed more tumor cells, thus demonstrating an enhanced killing effect on tumor cells.

[0074] In some cases, the composition can be determined in the subject, for example, before or during administration to the subject (e.g., for treating cancer in the subject). In other cases, parameters such as location, concentration, distribution, and administration rate can be determined. Various techniques can be used, such as those using radiation to generate images of the subject. Non-limiting examples include X-rays or radiography, fluoroscopy, CT scans, or similar techniques. As a non-limiting example, fluoroscopy can be used to image the subject, and then the composition, including radiopaque microspheres, can be administered to the subject, for example, to one or more specific locations within the subject's body (e.g., the liver of a liver cancer patient). This allows for monitoring of composition administration and, if necessary, corrective action (e.g., if an ideal site within the subject is unintentionally missed).

[0075] According to certain embodiments, the pharmaceutical compositions provided herein contain an inert or active carrier (such as a pharmaceutically acceptable carrier) that makes the composition particularly suitable for in vivo or in vitro diagnostic or therapeutic use. A pharmaceutically acceptable carrier is one that does not cause adverse physiological effects when administered to a subject. The carrier in the pharmaceutical composition must be "acceptable," meaning it is compatible with the active ingredient and stabilizes the active ingredient.

[0076] Pharmaceutically acceptable carriers include, but are not limited to, physiological saline, phosphate-buffered saline (PBS), biocompatible carriers, adjuvants, additives, and diluents to obtain compositions that can be used as dosage forms. In some cases, this can form suspensions, such as microspheres in a liquid. Other suitable drug carriers and the essential pharmaceutical ingredients that use these carriers are described in *Remington's Pharmaceutical Sciences*. Compositions can be formulated or administered alone or in combination with one or more other ingredients. For example, pharmaceutical compositions may further contain other ingredients such as chemotherapeutic agents, inhibitors, adjuvants, etc.

[0077] This disclosure also provides kits for any of the above-described compositions, optionally including instructions for use of the composition for treating cancer. That is, the kit may include instructions for use regarding the composition's engagement with any biological or chemical mechanism disclosed herein. The kit may further include instructions for therapeutic activity against a pathology, rather than instructions for treating pathological symptoms. That is, the kit may include instructions for use of the compositions discussed herein. The kit may also include instructions for use in combination of two or more compositions of this disclosure, or in combination of a composition of this disclosure with one or more other compounds indicated for treating cancer. Furthermore, instructions for administering the composition using any suitable technique described above may be provided.

[0078] The kits described herein may also contain one or more containers, which may contain the compositions described above and other ingredients. In some cases, the kits may also contain instructions for mixing, diluting, and / or administering the compositions disclosed herein. The kits may also include other containers containing one or more solvents, surfactants, preservatives, and / or diluents (e.g., physiological saline (0.9% NaCl) or 5% glucose), and containers for mixing, diluting, or administering the ingredients in a sample or to a subject requiring such treatment.

[0079] The compositions in the kit may be provided in any suitable form, such as a liquid solution or a dry powder. When the provided composition is a dry powder, the composition may be reconstituted by adding an appropriate liquid, or an appropriate liquid may be provided. In embodiments using liquid compositions, the liquid composition may be a concentrate or a ready-to-use solution. The added liquid depends on the composition and the method of use or administration. Liquids suitable for pharmaceutical compositions are well known, for example, as previously described, and are available from the literature. For example, the liquid will depend on the composition and the method of use or administration.

[0080] As an example, this application provides the following technical solution: A composition comprising resin microspheres, said resin microspheres comprising radiopaque ions and at least one radioactive isotope ion.

[0081] In some embodiments, the radioactive isotope ions exist in the form of phosphates, chlorides, nitrates, carbonates, bicarbonates, hydrogen phosphates, dihydrogen phosphates, or sulfates.

[0082] In some embodiments, the radiopaque ions are present in the form of phosphates, chlorides, nitrates, carbonates, bicarbonates, hydrogen phosphates, dihydrogen phosphates, or sulfates.

[0083] In some embodiments, at least some radioactive isotope ions and some radiopaque ions bind to an identical resin microsphere.

[0084] In some embodiments, the molar concentration of the radiopaque ions is at least 0.1 mmol / g based on the total mass of the resin microspheres.

[0085] In some embodiments, the mass concentration of the radiopaque ions is at least 0.1 wt% based on the total mass of the resin microspheres.

[0086] In some embodiments, the radioactivity of the resin microspheres is at least 0.1 GBq / g, based on the total mass of the resin microspheres.

[0087] In some embodiments, the radioactive isotope ion includes at least one of the following radioactive isotope ions: 90 Y、 177 Lu、 186 Re、 188 Re、 225 Ac、 221 At.

[0088] In some embodiments, the radiopaque ions include at least one of the following metal ions: bismuth ion, lutetium ion, gadolinium ion, holmium ion, tantalum ion, and barium ion.

[0089] In some embodiments, the radiopaque ions and radioactive isotope ions are stably bound to the resin microspheres via cation exchange.

[0090] In some embodiments, the radiopaque ions and radioactive isotope ions are stably bound to the resin microspheres by precipitation.

[0091] In some embodiments, the mass ratio of the radiopaque ions to the radioactive isotope ions is 1:1 to 10:1.

[0092] In some embodiments, the molar ratio of the radiopaque ions to the radioactive isotope ions is 0.2:1 to 10:1.

[0093] In some embodiments, the resin microspheres comprise bismuth ions and yttrium ions.

[0094] In some embodiments, the bismuth ions are present in the form of phosphate.

[0095] In some embodiments, the yttrium ions are present in the form of phosphate.

[0096] In some embodiments, at least some bismuth ions and some yttrium ions bind to one of the same resin microspheres.

[0097] In some embodiments, the molar concentration of bismuth ions is at least 0.1 mmol / g based on the total mass of the resin microspheres. In some embodiments, the mass concentration of bismuth ions is at least 0.1 wt% based on the total mass of the resin microspheres. In some embodiments, the molar concentration of yttrium ions is at least 0.1 mmol / g based on the total mass of the resin microspheres. In some embodiments, the mass concentration of yttrium ions is at least 0.1 wt% based on the total mass of the resin microspheres.

[0098] In some embodiments, the yttrium ions are 89 Y ions and 90 At least one of the Y ions.

[0099] In some embodiments, the yttrium ions include 90 Y ions, based on the total mass of the resin microspheres, have a specific radioactivity of at least 0.1 GBq / g.

[0100] In some embodiments, the bismuth ions and yttrium ions are stably bound to the resin microspheres via cation exchange.

[0101] In some embodiments, the bismuth ions and yttrium ions are stably bound to the resin microspheres by precipitation.

[0102] In some embodiments, the mass ratio of bismuth ions to yttrium ions is 1:1 to 10:1.

[0103] In some embodiments, the molar ratio of bismuth ions to yttrium ions is 0.2:1-10:1.

[0104] In some embodiments, it may also optionally include at least one radiopaque ion other than bismuth ions and / or at least one radioactive isotope ion other than yttrium ions.

[0105] A suspension comprising the aforementioned composition and a dispersion medium.

[0106] In some embodiments, the concentration of the resin microspheres is 0.01 g / mL to 10 g / mL, based on the total volume of the suspension.

[0107] In some embodiments, the dispersion medium is a nonionic solvent, such as pure water.

[0108] In some embodiments, the resin microspheres contain bismuth ions and yttrium ions.

[0109] In some embodiments, the resin microspheres contain no more than 0.5 wt% of free bismuth ions and free yttrium ions based on their total mass.

[0110] A method for preparing resin microspheres, comprising: Resin microspheres containing exchangeable ions are placed in a first solution containing bismuth ions, allowing at least a portion of the exchangeable ions in the ion exchange resin to exchange with bismuth ions, thereby obtaining first resin microspheres; and The negative first resin microspheres are placed in a second solution containing yttrium ions, so that at least some of the exchangeable ions are exchanged with the yttrium ions to obtain the second resin microspheres.

[0111] In some embodiments, the first solution includes an organic solvent capable of dissolving the bismuth ions.

[0112] In some embodiments, the organic solvent is selected from at least one of ethylene glycol, DMSO, and DMF.

[0113] In some embodiments, the bismuth ions are derived from bismuth nitrate.

[0114] In some embodiments, the concentration of bismuth nitrate in the first solution is 0.01-5 g / mL, preferably 0.04-2 g / mL or 0.04-1.5 g / mL.

[0115] In some embodiments, the process may optionally include washing the first resin microspheres with a phosphate solution and / or washing the second resin microspheres with a phosphate solution.

[0116] In some embodiments, the first resin microsphere is a resin microsphere loaded with bismuth ions, and the second resin microsphere is a resin microsphere loaded with bismuth ions and yttrium ions.

[0117] A method for preparing resin microspheres, comprising: Resin microspheres containing exchangeable ions are placed in a first solution containing a first ion, allowing at least a portion of the exchangeable ions in the ion exchange resin to exchange with the first ion, thereby obtaining first resin microspheres; and The first resin microspheres are placed in a second solution containing the second ions, so that at least some of the exchangeable ions are exchanged with the second ions to obtain the second resin microspheres. The first ion and the second ion are different, and the first ion or the second ion is a radiopaque ion.

[0118] In some embodiments, the first or second ion, in addition to radiopaque ions, is a radioactive isotope ion.

[0119] In some embodiments, the first or second ion, in addition to radiopaque ions, is a yttrium ion.

[0120] In some embodiments, the yttrium ions include 89 Y or 90 Y.

[0121] In some embodiments, the radiopaque ions include bismuth ions.

[0122] A composition comprising bismuth ions and an organic solvent.

[0123] In some embodiments, the bismuth ions are present in the form of Bi(NO3)3. In some embodiments, the concentration of bismuth ions is 0.01-10 g / mL.

[0124] In some embodiments, the organic solvent is selected from at least one of ethylene glycol, DMSO, DMF, N-methyl-2-pyrrolidone, dimethylacetamide, sulfolane, propylene carbonate, N-formylmorpholine, 1,3-dimethyl-2-imidazolium ketone, and propylene glycol.

[0125] The aforementioned composition containing bismuth ions and an organic solvent is used in the preparation of resin microspheres, wherein the resin microspheres are bismuth-loaded.

[0126] The use of the aforementioned resin microsphere composition or suspension in the preparation of disease therapeutic agents. The diseases include, but are not limited to, tumors, such as liver cancer, pancreatic cancer, glioma, meningioma, and kidney cancer.

[0127] A composition comprising: resin microparticles, wherein bismuth ions and yttrium ions are bound within the resin microparticles.

[0128] In some embodiments, the bismuth ions and yttrium ions are each ionically bound within the resin microparticles.

[0129] In some embodiments, the bismuth ions and yttrium ions are each physically bound within the resin particles.

[0130] In some embodiments, the yttrium ions are present in the form of yttrium phosphate. In some embodiments, the bismuth ions are present in the form of bismuth phosphate.

[0131] In some embodiments, at least a portion of bismuth ions and yttrium ions are bound to the same resin microparticle. In some embodiments, at least a portion of bismuth ions and yttrium ions are bound to different resin microparticles.

[0132] In some embodiments, the bismuth ions and yttrium ions exist within the resin particles via ion exchange.

[0133] In some embodiments, the bismuth ions and yttrium ions are stably incorporated into the resin microparticles by precipitation.

[0134] In some embodiments, the resin microparticles contain no more than 1.0 wt% unbound bismuth and yttrium ions. In some embodiments, the resin microparticles contain no more than 0.9 wt% unbound bismuth and yttrium ions. In some embodiments, the resin microparticles contain no more than 0.8 wt% unbound bismuth and yttrium ions. In some embodiments, the resin microparticles contain no more than 0.7 wt% unbound bismuth and yttrium ions. In some embodiments, the resin microparticles contain no more than 0.6 wt% unbound bismuth and yttrium ions. In some embodiments, the resin microparticles contain no more than 0.5 wt% unbound bismuth and yttrium ions. In some embodiments, the resin microparticles contain no more than 0.4 wt% unbound bismuth and yttrium ions. In some embodiments, the resin microparticles contain no more than 0.3 wt% unbound bismuth and yttrium ions. In some embodiments, the resin microparticles contain no more than 0.2 wt% unbound bismuth and yttrium ions. In some embodiments, the resin microparticles contain no more than 0.1 wt% unbound bismuth and yttrium ions. In some embodiments, the resin particles contain no more than 0.05 wt% of unbound bismuth ions and yttrium ions.

[0135] In some embodiments, at least 20 mol% of the yttrium ions are yttrium-90 ions.

[0136] In some embodiments, the specific activity of the resin microparticles is at least 1 GBq / g microparticle. In some embodiments, the specific activity of the resin microparticles is at least 3 GBq / g microparticle. In some embodiments, the specific activity of the resin microparticles is less than 10 GBq / g microparticle. In some embodiments, the specific activity of the resin microparticles is less than 5 GBq / g microparticle.

[0137] In some embodiments, the average diameter of the resin particles is less than 500 μm. In some embodiments, the average diameter of the resin particles is less than 200 μm. In some embodiments, the average diameter of the resin particles is between 5 μm and 200 μm. In some embodiments, the average diameter of the resin particles is between 10 μm and 50 μm.

[0138] In some embodiments, the resin particles comprise an ion exchange resin.

[0139] In some embodiments, the resin particles comprise a cation exchange resin.

[0140] In some embodiments, the resin particles comprise copolymers.

[0141] In some embodiments, the resin particles comprise a crosslinked polymer.

[0142] In some embodiments, the resin particles comprise a styrene-divinylbenzene copolymer.

[0143] In some embodiments, the resin particles comprise a sulfonated divinylbenzene-styrene copolymer.

[0144] In some embodiments, the resin microparticles comprise microspheres.

[0145] In some embodiments, the resin particles are present in a liquid suspension.

[0146] In some embodiments, the liquid suspension comprises physiological saline.

[0147] In some embodiments, the liquid suspension contains a pH buffer.

[0148] In some embodiments, the resin microparticles contain at least 5 wt% bismuth ions. In some embodiments, the resin microparticles contain at least 10 wt% bismuth ions. In some embodiments, the resin microparticles contain at least 20 wt% bismuth ions. In some embodiments, the resin microparticles contain at least 30 wt% bismuth ions.

[0149] A composition comprising: resin microparticles, wherein the resin microparticles are incorporating radioisotope ions and radionuclides.

[0150] In some embodiments, the radioisotope ions and the radionuclides are each bound within the resin microparticles.

[0151] In some embodiments, the radioisotope monatomic ion comprises gadolinium ions. In some embodiments, the radioisotope monatomic ion comprises lutetium ions. In some embodiments, the radioisotope monatomic ion comprises holmium ions. In some embodiments, the radioisotope monatomic ion comprises barium ions. In some embodiments, the radioisotope monatomic ion comprises tantalum ions.

[0152] In some embodiments, the radionuclide comprises yttrium-90. In some embodiments, the radionuclide comprises lutetium-177.

[0153] In some embodiments, the resin particles contain no more than 0.4 wt% of unbound radioimpermeable monatomic ions and radionuclides.

[0154] In some embodiments, the resin particles contain at least 5 wt% radioisotope monatomic ions.

[0155] A composition comprising: a plurality of resin microparticles, wherein the plurality of resin microparticles includes resin microparticles wherein bismuth ions are ionically bonded thereto and resin microparticles wherein yttrium ions are bonded thereto.

[0156] In some embodiments, the yttrium ions are ionized with the resin particles.

[0157] A composition comprising: a plurality of resin microparticles wherein bismuth ions are bound.

[0158] In some embodiments, the bismuth ions are ionized within the plurality of resin particles.

[0159] In some embodiments, the plurality of resin particles further comprise yttrium ions bound therein.

[0160] In some embodiments, the yttrium ions are ionized with the plurality of resin particles.

[0161] A composition comprising: resin microparticles containing bismuth phosphate and yttrium phosphate.

[0162] A composition comprising: resin microparticles containing bismuth ions and yttrium ions, wherein the bismuth ions and yttrium ions are present within the resin microparticles via ion exchange.

[0163] A composition comprising: resin microparticles containing bismuth ions and yttrium ions, wherein the resin microparticles contain at least 0.0 wt% and no more than 0.4 wt% of unbound bismuth ions and yttrium ions.

[0164] A composition comprising: resin microparticles, wherein the mass ratio of bismuth ions to yttrium ions is between 1:1 and 10:1.

[0165] A method comprising administering to a subject the composition of any of the preceding claims.

[0166] In some embodiments, the subject has cancer or is at risk of developing cancer.

[0167] In some embodiments, the cancer is liver cancer.

[0168] A method includes: exposing an ion exchange resin containing exchangeable ions to a first solution containing bismuth ions to exchange at least a portion of the exchangeable ions in the ion exchange resin with bismuth ions; and The ion exchange resin is exposed to a second solution containing yttrium ions to exchange at least a portion of the exchangeable ions in the ion exchange resin with yttrium ions.

[0169] In some embodiments, the first solution contains N-methyl-2-pyrrolidone.

[0170] In some embodiments, the first solution contains dimethylacetamide.

[0171] In some embodiments, the first solution contains sulfolane.

[0172] In some embodiments, the first solution contains ethylene glycol.

[0173] In some embodiments, the first solution contains dimethylformamide.

[0174] In some embodiments, the first solution contains dimethyl sulfoxide.

[0175] In some embodiments, the first solution comprises propylene carbonate.

[0176] In some embodiments, the first solution contains N-formylmorpholine.

[0177] In some embodiments, the first solution contains 1,3-dimethyl-2-imidazolone.

[0178] In some embodiments, the first solution contains propylene glycol.

[0179] A method includes: exposing an ion exchange resin containing exchangeable ions to a first solution containing a first ion to exchange at least a portion of the exchangeable ions in the ion exchange resin with the first ion; and The ion exchange resin is exposed to a second solution containing a second ion to exchange at least a portion of the exchangeable ions within the ion exchange resin with the second ion, without exchanging the first ion. The first ion is different from the second ion, and the first ion is a yttrium ion or the second ion is a yttrium ion.

[0180] The first ion contains radioactive monatomic ions.

[0181] A method includes exposing resin particles containing bismuth ions to a solution containing yttrium ions.

[0182] The present application's solution will be described in detail below with reference to specific embodiments. These embodiments are intended to illustrate certain implementations of this disclosure, but do not represent the full scope of this disclosure.

[0183] Radiopaque resin microspheres were created by loading radiopaque isotopes (such as bismuth) and yttrium onto resin microspheres via ion exchange reactions. The loading mechanism of bismuth and yttrium on resin microspheres is likely based on ion exchange.

[0184] The chemicals included: ethylene glycol (99%, GC); bismuth nitrate pentahydrate (Bi(NO3)3·5H2O, 99%); sodium phosphate (Na3PO4, 96%); yttrium oxide (Y2O3), 99.9%; sulfuric acid (H2SO4, 98%); and iohexol (350 mg iodine per mL, Onapex). All chemicals were purchased from commercial suppliers. The resin microspheres were sulfonated polystyrene microspheres from Biorad.

[0185] Nylon-6 organic filter membranes were also used in the examples.

[0186] Example 1 This embodiment provides a method for preparing bismuth and yttrium loaded onto resin microspheres, wherein the reaction for loading bismuth is carried out in an organic solvent. The preparation method specifically includes: Weigh a certain amount of Bi(NO3)3·5H2O using a balance, then transfer it to a 50 mL beaker. Add a certain volume of ethylene glycol and stir (300 rpm) for 1 hour to prepare ethylene glycol solutions of bismuth nitrate at different concentrations. The solutions of different concentrations are numbered as shown in Table 1. Collect the bismuth nitrate ethylene glycol solutions using a syringe, and then filter them using a syringe filter to obtain a clear bismuth nitrate ethylene glycol solution.

[0187] Table 1

[0188] An exemplary loading process for bismuth loaded onto resin microspheres is as follows: (B1) Weigh 1.15 grams of blank resin microspheres that are not loaded with any metal elements; (B2) Add 15 mL of filtered bismuth nitrate ethylene glycol solution; (B3) Stir the solution for 10 minutes using a magnetic stirrer at 200 rpm. (B4) Vacuum filtration of the solution: Vacuum filtration of the solution is performed using a filter membrane (nylon 6 organic filter membrane); after filtration, microspheres adhere to the surface of the filter membrane; (B5) Wash the filter membrane and the microspheres on the filter membrane with 10 ml of ethylene glycol organic solution; (B6) Rinse the filter membrane and the microspheres on the filter membrane with pure water; (B7) Wash the microspheres on the filter membrane with 15 mL of Na3PO4 solution (concentration of 1.25% by weight / volume), and then wash with pure water; (B8) Collect the microspheres and weigh them on the membrane, then transfer the microspheres to centrifuge tubes; (B9) Add 5 mL of pure water to a centrifuge tube to obtain a microsphere suspension; The above steps yielded bismuth-loaded microspheres, with approximately 1 g of bismuth-containing microspheres in 5 mL of water, which were used as a raw material for yttrium loading.

[0189] This embodiment adopts 89 The acidic solution of Y2O3 is used for the reaction of supporting yttrium, and the steps are as follows.

[0190] (Y1) 0.07 grams 89 Y₂O₃ is dissolved in 0.1M sulfuric acid until the solution becomes clear, yielding a yttrium sulfate solution; (Y2) Weigh 1 gram of bismuth-containing microspheres and then add them to a yttrium sulfate solution; (Y3) Stir the solution for 10 minutes; (Y4) Vacuum filtration of the solution: Vacuum filtration of the solution using a filter membrane; after filtration, microspheres adhere to the surface of the filter membrane; (Y5) Wash the filter membrane and microspheres with 10 mL of pure water; then wash the filter membrane with 15 mL of Na3PO4 solution (concentration of 1.25% by weight / volume), and then wash with 10 mL of pure water. (Y6) Collect the microspheres to obtain resin microspheres loaded with bismuth and yttrium; (Y7) Weigh the microspheres on the membrane and then transfer them to a 15 mL centrifuge tube. Add 5 mL of pure water to the centrifuge tube to obtain a suspension of resin microspheres loaded with bismuth and yttrium.

[0191] The resin microspheres loaded with bismuth and yttrium in a 5 mL suspension weighed approximately 1 g. The prepared resin microspheres were added to water at a mass-to-volume ratio of 0.2 g / mL and extracted at 37 °C and 60 rpm for 72 hours. The residual ethylene glycol in the extract was approximately 400 ppm.

[0192] Example 2 In this embodiment, following steps (B1)-(B9) of Example 1, the anhydrous bismuth nitrate in Example 1 was replaced with bismuth oxide (Bi2O3) or bismuth sulfate (Bi2(SO4)3), and ethylene glycol was replaced with 0.1M HCl. The concentration of bismuth oxide or bismuth sulfate in HCl was 0.5 g / mL. The ethylene glycol washing step was replaced with washing with pure water or 0.1M HCl. Other conditions and operating steps were the same as in steps (B1)-(B9) of Example 1, and resin microspheres were prepared. Yttrium was not loaded in this embodiment. The prepared resin microspheres were used to evaluate the loading effect of bismuth ions in HCl solution (aqueous phase system).

[0193] Example 3 The bismuth nitrate ethylene glycol solution in Example 1 was replaced with an aqueous solution of gadolinium chloride (GdCl3), with gadolinium chloride concentrations of 0.8 g / mL and 1 g / mL, respectively. Other conditions and operating procedures were the same as in Example 1, resulting in resin microspheres loaded with gadolinium and yttrium ions. The gadolinium ion loading concentration was approximately 0.5-0.6 mmol / g.

[0194] Gadolinium chloride (GdCl3) or lutetium chloride (LuCl3) was dissolved in water, and the gadolinium or lutetium solution was mixed with blank resin microspheres. Table 2 below shows the radiopermeability expressed as optical intensity grayscale values.

[0195] Table 2

[0196] Test case 1.1 Identification of Bismuth and Yttrium Loading in Resin Microspheres Some resin microspheres prepared in Example 1 (Bi(NO3)3 concentration of 0.1 g / mL) were selected and observed using a scanning electron microscope (FSEM high-resolution field emission scanning electron microscope). Target microspheres were located in BSE mode. The target microspheres were selected, and surface scanning was performed using EDS. Characteristic peaks of bismuth and yttrium were selected, and elemental distribution maps were acquired. The results are as follows: Figure 1 As shown.

[0197] Figure 1 In the image, A shows a SEM image of the resin microspheres prepared in Example 1; B shows the bismuth element loaded on these resin microspheres in A; and C shows the yttrium element loaded on these resin microspheres in A. According to... Figure 1 Figures A, B, and C show that the signals of bismuth and yttrium highly overlap with the morphology of the microspheres, indicating that bismuth and yttrium are simultaneously loaded onto the same microsphere.

[0198] 1.2 Bismuth loading detection The resin microspheres prepared in Example 1 were completely digested with nitric acid and hydrogen peroxide. The concentrations of bismuth ions and yttrium in the digestion solution were measured by inductively coupled plasma mass spectrometry (ICP-MS). The bismuth loading in the resin microspheres could reach about 10 wt% or higher, and the yttrium loading could reach about 2 wt% or higher. When the concentration of bismuth nitrate in ethylene glycol reached 0.04 g / mL, the bismuth loading in the resin microspheres reached about 13 wt% (about 0.6 mmol / g resin microspheres).

[0199] 1.3 Non-transmittance linearity test Digital subtraction angiography (DSA) was used to test the sample solution and observe its radiopaque properties.

[0200] The radiopaque properties of resin microspheres supported on bismuth nitrate solutions of different concentrations were investigated. The results showed that all bismuth nitrate concentrations listed in Table 1 exhibited radiopaque properties. Figure 2 The radiopaque properties of resin microspheres loaded with a 0.04 g / mL bismuth nitrate ethylene glycol solution (Bi-Y coloaded) in Example 1 are shown. Iohexol solution was used as a positive control, and blank microspheres without bismuth and yttrium ions were used as a negative control. The results show that even at a bismuth nitrate concentration as low as 0.04 g / mL in ethylene glycol, good radiopaque properties are achieved, reaching developmental effects comparable to iohexol. This indicates that excellent developmental effects can still be achieved with a lower bismuth ion loading, providing more sites for yttrium ion loading.

[0201] The radiopaque properties of the resin microspheres prepared in Example 2 were assessed by DSA. The development test showed that bismuth oxide or bismuth sulfate could be effectively dissolved in hydrochloric acid to form a homogeneous solution, maintaining the good radiopaque properties of bismuth. However, when a hydrochloric acid solution of bismuth oxide or bismuth sulfate was used as the reaction solution for bismuth ion loading of the resin microspheres, the loading efficiency was limited, and the bismuth ions dissolved in the hydrochloric acid solution could not be effectively loaded onto the microspheres.

[0202] Figure 3 The development effect of resin microspheres prepared by using a 0.01 g / mL bismuth nitrate ethylene glycol solution as a bismuth ion-loaded reaction solution in Example 1 is shown. Figure 3 The development effect of the resin microspheres loaded with Gd ions in Example 101 and Example 3 (101) and Example 3) Figure 3 (103). The results showed that the resin microspheres prepared with a 0.01 g / mL bismuth nitrate ethylene glycol solution as the reaction solution could achieve the same development effect as the resin microspheres loaded with Gd ions after the reaction with saturated GdCl3 aqueous solution, indicating that a lower bismuth ion loading can achieve good radiopaque performance.

[0203] 1.4 Load stability test This test was used to evaluate whether bismuth and yttrium ions could be stably loaded onto resin microspheres. In Example 1, 1 g of microspheres loaded with bismuth and yttrium ions were mixed with 5 mL of water to form a suspension, which was then allowed to stand at room temperature in the dark. The concentrations of free bismuth and yttrium ions in the supernatant were measured by ICP-MS on days 1, 2, 3, 5, and 7 of standing.

[0204] According to the experimental results, from day 1 to day 7, the concentrations of free bismuth ions and free yttrium ions in the supernatant did not increase significantly. Specifically, the concentration of free yttrium ions in the supernatant did not exceed 0.0002 wt% of the initial total mass of yttrium ions, and the concentration of free bismuth ions did not exceed 0.002 wt% of the initial total mass of bismuth ions. This indicates that the bismuth and yttrium ions loaded on the resin microspheres are stable and will not dissolve due to prolonged storage. During days 1-7, the concentrations of bismuth and yttrium loaded on the microspheres remained stable and did not decrease over time. This demonstrates that the resin microspheres provided in this application can stably load bismuth and yttrium ions for a relatively long period.

[0205] 1.5 Animal in vivo imaging experiment 1g of microspheres loaded with bismuth and yttrium ions prepared in Example 1 were mixed with 5mL of water to form a suspension. This suspension was injected into the splenic artery of experimental pigs, and digital subtraction angiography (DSA) was performed. The results are as follows: Figure 4 As shown. The results indicate that the resin microspheres loaded with bismuth and yttrium ions prepared in Example 1 can be clearly visualized in animals, enabling visualization of the microspheres during infusion and improving the accuracy of microsphere interventional therapy.

[0206] The foregoing embodiments employ 89 Y₂O₃, used as a reaction raw material for loading yttrium ions, produces microspheres that are radiopaque, exhibit good developmental properties, and possess radioactivity. 89 Y2O3 was replaced with 90 Y₂O₃ can be prepared to have radiopaque properties, good development effect, and [other properties]. 90 Y-radioactive resin microspheres, yttrium [ 90 Y] imparts radiotherapy properties to the microspheres, while bismuth makes them radioisotope-free, thus enabling the microspheres to be visualized in imaging examinations and facilitating in vivo visualization and interventional radiotherapy. When loaded... 90 When Y is present, the reaction can be carried out in a radiation-protected container, such as an acrylic or lead container.

[0207] The phrase “and / or” as used in the specification and claims should be understood as meaning “any or both,” that is, appearing together in some cases and not in others. Multiple elements listed with “and / or” should be understood in the same way, i.e., elements “one or more” linked together. In addition to the elements specifically indicated in the sentence containing “and / or,” other elements may be optionally present, whether related to or unrelated to the specifically indicated elements. Thus, as a non-limiting example, when “A and / or B” is used with open-ended language such as “comprising,” in one embodiment, it may refer only to A (optionally including elements other than B); in another embodiment, it may refer only to B (optionally including elements other than A); in yet another embodiment, it may refer to both A and B (optionally including other elements); and so on.

[0208] The word “or” as used herein in the specification and claims shall be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as inclusive, meaning that it includes at least one, but also includes more than one list of quantities or elements, as well as other optional unlisted items. Only terms that explicitly indicate the opposite, such as “only one” or “exclusively one,” or “consisting of…” as used in the claims, refer to exactly one element from the list of quantities or elements. Generally, terms used herein, or only when preceded by exclusive terms such as “any,” “one,” “only one,” or “exactly one,” are interpreted as indicating an exclusive choice (i.e., “one or the other but not two”).

[0209] The phrase "at least one" as used herein, when referring to one or more lists of elements, should be understood to mean that at least one element is selected from any one or more elements in the list of elements, but does not necessarily include at least one of every element specifically listed in the list of elements, nor exclude any combination of elements in the list of elements. This definition also allows for the selective presence of other elements in the list of elements referred to by the phrase "at least one," in addition to the specifically specified elements, whether or not these elements are related to the specifically specified elements. Thus, as a non-limiting example, "at least one of A and B" (or equivalent to "at least one of A or B," or equivalent to "at least one of A and / or B") may refer to at least one, optionally including more than one A, without B (optionally including elements other than B); in another embodiment, it may refer to at least one, optionally including more than one B, without A (optionally including elements other than A); in yet another embodiment, it may refer to at least one, optionally including more than one A, and at least one, optionally including more than one B (optionally including other elements); and so on.

[0210] Although embodiments of this application have been shown and described, those skilled in the art will understand that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of this application, the scope of which is defined by the claims and their equivalents.

Claims

1. A composition comprising resin microspheres, characterized in that, The resin microspheres comprise radiopaque ions and at least one radioactive isotope ion.

2. The composition according to claim 1, wherein the radioactive isotope ion is present in the form of a phosphate, chloride, nitrate, carbonate, bicarbonate, hydrogen phosphate, dihydrogen phosphate, or sulfate.

3. The composition according to claim 1 or 2, wherein the radiopaque ion is present in the form of a phosphate, chloride, nitrate, carbonate, bicarbonate, hydrogen phosphate, dihydrogen phosphate, or sulfate.

4. The composition according to any one of claims 1-3, wherein at least some radioactive isotope ions and some radiopaque ions are bound to an identical resin microsphere.

5. The composition according to any one of claims 1-4, wherein the molar concentration of the radiopaque ions is at least 0.1 mmol / g based on the total mass of the resin microspheres.

6. The composition according to any one of claims 1-5, wherein the mass concentration of the radiopaque ions is at least 0.1 wt% based on the total mass of the resin microspheres.

7. The composition according to any one of claims 1-6, wherein the radioactivity of the resin microspheres is at least 0.1 GBq / g based on the total mass of the resin microspheres.

8. The composition according to any one of claims 1-7, wherein the radioactive isotope ion comprises at least one of the following radioactive isotope ions: 90 Y、 177 Lu、 186 Re、 188 Re、 225 Ac、 221 At.

9. The composition according to any one of claims 1-8, wherein the radiopaque ions include at least one of the following metal ions: bismuth ion, lutetium ion, gadolinium ion, holmium ion, tantalum ion, and barium ion.

10. The composition according to any one of claims 1-9, wherein the radiopaque ions and radioactive isotope ions are stably bound to the resin microspheres via cation exchange.

11. The composition according to any one of claims 1-9, wherein the radiopaque ions and radioactive isotope ions are stably bound to the resin microspheres by precipitation.

12. The composition according to any one of claims 1-11, wherein the mass ratio of the radiopaque ion to the radioactive isotope ion is 1:1 to 10:

1.

13. The composition according to any one of claims 1-12, wherein the molar ratio of the radiopaque ion to the radioactive isotope ion is 0.2:1-10:

1.

14. A composition comprising resin microspheres, said resin microspheres comprising bismuth ions and yttrium ions.

15. The composition according to claim 14, wherein the bismuth ions are present in the form of phosphate.

16. The composition according to claim 14 or 15, wherein the yttrium ions are present in the form of phosphate.

17. The composition according to any one of claims 14-16, wherein at least some bismuth ions and some yttrium ions are bound to an identical resin microsphere.

18. The composition according to any one of claims 14-17, wherein the molar concentration of bismuth ions is at least 0.1 mmol / g based on the total mass of the resin microspheres.

19. The composition according to any one of claims 14-18, wherein the mass concentration of bismuth ions is at least 0.1 wt% based on the total mass of the resin microspheres.

20. The composition according to any one of claims 14-18, wherein the molar concentration of yttrium ions is at least 0.1 mmol / g based on the total mass of the resin microspheres.

21. The composition according to any one of claims 14-18, wherein the mass concentration of yttrium ions is at least 0.1 wt% based on the total mass of the resin microspheres.

22. The composition according to any one of claims 14-21, wherein the yttrium ion is 89 Y ions and 90 At least one of the Y ions.

23. The composition of claim 22, wherein the yttrium ions comprise 90 Y ions, based on the total mass of the resin microspheres, have a specific radioactivity of at least 0.1 GBq / g.

24. The composition according to any one of claims 14-23, wherein the bismuth ions and yttrium ions are stably bound to the resin microspheres via cation exchange.

25. The composition according to any one of claims 14-23, wherein the bismuth ions and yttrium ions are stably bound to the resin microspheres by precipitation.

26. The composition according to any one of claims 14-25, wherein the mass ratio of bismuth ions to yttrium ions is 1:1 to 10:

1.

27. The composition according to any one of claims 14-26, wherein the molar ratio of bismuth ions to yttrium ions is 0.2:1 to 10:

1.

28. The composition according to any one of claims 14-27, wherein it optionally comprises at least one radiopaque ion other than bismuth ions and / or at least one radioactive isotope ion other than yttrium ions.

29. A suspension comprising the composition and dispersion medium according to any one of claims 1-28.

30. The suspension according to claim 29, wherein the concentration of the resin microspheres is 0.01 g / mL to 10 g / mL based on the total volume of the suspension.

31. The suspension according to claim 29 or 38, wherein the dispersion medium is a nonionic solvent, such as pure water.

32. The suspension according to any one of claims 29-31, wherein the resin microspheres contain bismuth ions and yttrium ions.

33. The suspension according to claim 32, based on the total mass of the resin microspheres, contains no more than 0.5 wt% of free bismuth ions and free yttrium ions.

34. A method for preparing resin microspheres, comprising: Resin microspheres containing exchangeable ions are placed in a first solution containing bismuth ions, so that at least some of the exchangeable ions in the ion exchange resin are exchanged with bismuth ions to obtain the first resin microspheres. and The negative first resin microspheres are placed in a second solution containing yttrium ions, so that at least some of the exchangeable ions are exchanged with the yttrium ions to obtain the second resin microspheres.

35. The preparation method according to claim 34, wherein the first solution comprises an organic solvent capable of dissolving the bismuth ions.

36. The preparation method according to claim 35, wherein the organic solvent is selected from at least one of ethylene glycol, DMSO, and DMF.

37. The preparation method according to any one of claims 34-36, wherein the bismuth ions are derived from bismuth nitrate.

38. In the preparation method according to claim 37, the concentration of bismuth nitrate in the first solution is 0.01-5 g / mL, preferably 0.04-2 g / mL or 0.04-1.5 g / mL.

39. The preparation method according to any one of claims 34-38, optionally further comprising washing the first resin microspheres with a phosphate solution and / or washing the second resin microspheres with a phosphate solution.

40. The preparation method according to claim 34, wherein the first resin microsphere is a resin microsphere loaded with bismuth ions, and the second resin microsphere is a resin microsphere loaded with bismuth ions and yttrium ions.

41. A method for preparing resin microspheres, comprising: Resin microspheres containing exchangeable ions are placed in a first solution containing a first ion, so that at least some of the exchangeable ions in the ion exchange resin are exchanged with the first ion to obtain the first resin microspheres. and The first resin microspheres are placed in a second solution containing the second ions, so that at least some of the exchangeable ions are exchanged with the second ions to obtain the second resin microspheres. The first ion and the second ion are different, and the first ion or the second ion is a radiopaque ion.

42. In the preparation method according to claim 41, the other ion besides the radiopaque ion is a radioactive isotope ion.

43. In the preparation method according to claim 41, the other ion besides the radiopaque ion is a yttrium ion.

44. The preparation method according to claim 43, wherein the yttrium ions comprise 89 Y or 90 Y.

45. The preparation method according to any one of claims 41-44, wherein the radiopaque ions include bismuth ions.

46. ​​A composition comprising bismuth ions and an organic solvent.

47. The composition according to claim 46, wherein the bismuth ions are present in the form of Bi(NO3)3.

48. The composition according to claim 46 or 47, wherein the concentration of bismuth ions in the solution is 0.01-10 g / mL.

49. The composition according to claim 47, wherein the organic solvent is selected from at least one of ethylene glycol, DMSO, and DMF.

50. The composition according to claim 46, wherein the organic solvent is selected from at least one of ethylene glycol, DMSO, DMF, N-methyl-2-pyrrolidone, dimethylacetamide, sulfolane, propylene carbonate, N-formylmorpholine, 1,3-dimethyl-2-imidazolium ketone, and propylene glycol.

51. Use of the composition according to any one of claims 46-50 in the preparation of resin microspheres, wherein the resin microspheres are bismuth-loaded.

52. The use of the composition of resin microspheres according to any one of claims 1-28, or the suspension according to any one of claims 29-33, in the preparation of a disease treatment agent.

53. The application according to claim 52, wherein the disease is a tumor, such as liver cancer, pancreatic cancer, glioma, meningioma, kidney cancer, etc.

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