Microsphere and preparing method thereof

Abstract

To provide a microsphere and a preparing method thereof.SOLUTION: The present invention relates to a microsphere which has a plurality of pores, which have a gradient feature of gradually decreasing along a direction from a surface to a center of the microsphere, wherein the microsphere includes: first nuclide which is distributed in the microsphere and whose concentration is greater in the center than in the surface of the microsphere, and second nuclide gradually decreasing from the surface toward the center of the microsphere, wherein the first nuclide and the second nuclide are capable of being radioactive through neutron activation to produce β rays, γ rays or a combination thereof. The present disclosure also provides a method of preparing the microsphere. The microsphere can have functions of radiotherapy, imaging and tracking by introducing the first nuclide and second nuclide into the microsphere, and can increase in adhesion to a shell layer by increasing a surface area through the plurality of pores.SELECTED DRAWING: Figure 1C

Description

Technical Field

[0001] The present disclosure relates to therapeutic microspheres and a method for preparing the same, and particularly to microspheres that can be used for brachytherapy and a method for preparing the same.

Background Art

[0002] Brachytherapy is a form of radiotherapy. Different from conventional external radiotherapy, which irradiates tumors in the body by penetrating the body with high-energy radiation from outside the body, brachytherapy accurately places a radiation source inside the site that requires treatment. For example, when treating a tumor, the radiation source can be placed inside or around the tumor. The greatest feature of brachytherapy is that since the radiation source is very close to the target, high-dose treatment can be performed. Furthermore, since the irradiation only affects a very limited area around it, the radiation dose received by normal tissues farther away from the radiation source can be significantly reduced. On the other hand, brachytherapy does not require a large external irradiation device, so patients can reduce the number of hospital visits, improving the convenience of medical treatment.

Summary of the Invention

Problems to be Solved by the Invention

[0003] However, since brachytherapy requires placing a radiation source inside the body, precise control of the position of the radiation source inside the body is extremely important. The previously reported yttrium-90 glass microspheres, although having good stability, are relatively difficult to track their positions after being administered into the body, causing some concerns.

Means for Solving the Problems

[0004] The present disclosure provides microspheres having a plurality of holes, wherein the plurality of holes have a gradient feature that gradually decreases along the direction from the surface of the microspheres to the center, and the microspheres A first nuclide distributed within the microspheres and having a higher concentration at the center of the microspheres than on the surface of the microspheres, and a second nuclide that gradually decreases in the direction from the surface to the center of the microspheres, and the first nuclide and the second nuclide are radioactive by neutron activation and can generate beta rays, gamma rays, or a combination thereof, to provide microspheres.

[0005] Also, the present disclosure is a method for preparing microspheres, comprising: providing a first raw material of a first nuclide and a second raw material of a second nuclide; mixing the first raw material and the second raw material to form a mixed powder; heating the mixed powder to obtain an intermediate; forming molten droplets by melting and spheroidizing the intermediate; contacting the molten droplets with a cooling source to obtain microspheres; contacting the microspheres with a treatment solution to form a plurality of pores; and both the first raw material and the second raw material are powders, the first nuclide is distributed within the microspheres, the concentration of the first nuclide at the center of the microspheres is higher than that on the surface of the microspheres, the distribution of the second nuclide gradually decreases in the direction from the surface to the center of the microspheres, the plurality of pores have a gradient feature that gradually decreases along the direction from the surface to the center of the microspheres, the first nuclide and the second nuclide are radioactive by neutron activation and can generate beta rays, gamma rays, or a combination thereof, to provide a method.

[0006] Also, the present disclosure is a method for preparing microspheres, comprising: providing a first raw material of a first nuclide; heating the first raw material to obtain an intermediate; A step of forming molten droplets by melting and spheroidizing the intermediate; A step of obtaining microspheres by bringing the molten droplets into contact with a cooling source; A step of forming a plurality of pores by bringing the microspheres into contact with a treatment solution comprising: The first raw material is a powder, The cooling source is a second raw material of a second nuclide, The second raw material is a liquid, By allowing the second nuclide to enter from the surface of the molten droplet or the microsphere and diffuse into it, or by depositing it on the surface, the first nuclide is distributed in the microsphere, and the concentration of the first nuclide at the center of the microsphere is higher than that on the surface of the microsphere, and the distribution of the second nuclide gradually decreases in the direction from the surface to the center of the microsphere. The plurality of pores have a gradient feature that gradually decreases in the direction from the surface to the center of the microsphere. The first nuclide and the second nuclide are radioactive by neutron activation and can generate β-rays, γ-rays or a combination thereof, providing a method.

Advantages of the Invention

[0007] According to the present disclosure, by introducing the first nuclide and the second nuclide into the microspheres, the microspheres can have the functions of radiotherapy, imaging and tracking. Furthermore, since the microspheres have a plurality of pores, the surface area of the microspheres can be increased and the surface morphology can be complicated. Moreover, a shell layer with excellent adhesion to the microspheres can be easily installed on the surface of the microspheres, and various changes can be made to the shell layer. For example, the shell layer can be made hydrophilic or hydrophobic, or ligands capable of targeting specific molecules can be supported, or drugs or other reagents can be supported, greatly enhancing the usefulness.

Brief Description of the Drawings

[0008]

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Modes for Carrying Out the Invention

[0009] The following describes the embodiments of the present disclosure according to specific specific embodiments. Those skilled in the art can easily understand the advantages and effects by reading the disclosure content of this specification.

[0010] The structures, ratios, dimensions, etc. shown in the drawings attached to this specification are merely described in accordance with the specification so that those skilled in the art can understand and read them easily. It should be noted that these contents are not intended to be the limiting conditions of the present disclosure, so they have no substantial technical meaning. Also, any structural modification, change in ratio relationship, adjustment of dimensions, change or adjustment of relative relationship, as long as it does not affect the effects produced in this specification and the achieved purpose, is included within the scope disclosed in this specification.

[0011] The terms such as "first", "second", "upper" and "lower" described in this specification are merely for making the description clearer and easier to understand. The change or adjustment of their relative relationship is also regarded as within the scope where the present disclosure can be implemented as long as there is no change in the substantial technical content. Also, all ranges and numerical values described in this specification are inclusive and combinable. The present disclosure describes many ranges, and any numerical value or endpoint within the ranges described in this specification is included in the present disclosure, and any numerical value or endpoint included within the ranges described in this specification can be used as the minimum value or the maximum value to derive sub-ranges and the like.

[0012] First, the first form of the present disclosure is A microsphere having a plurality of pores, The plurality of holes have a gradient feature that gradually decreases along the direction from the surface to the center of the microsphere, The microsphere, includes a first nuclide distributed within the microsphere and having a higher concentration at the center of the microsphere than on the surface of the microsphere, and a second nuclide that gradually decreases in the direction from the surface to the center of the microsphere, The first nuclide and the second nuclide are microspheres that are radioactive by neutron activation and can generate beta rays, gamma rays, or a combination thereof.

[0013] In one specific embodiment, the gradient feature includes the diameter of the holes, the distribution of the holes, or a combination thereof. Specifically, the definition of gradually decreasing along the direction from the surface to the center of the microsphere can also mean that the diameter of the holes or the distribution of the holes tends to gradually become smaller / less in the direction from the surface to the center of the microsphere. For example, if three regions are arbitrarily taken from the surface to the center, and the diameter of the holes or the distribution of the holes within these three regions satisfy the above conditions, it indicates that the microsphere has a gradient feature in which the holes gradually decrease along the direction from the surface to the center of the microsphere. For example, the diameter of the holes on the surface of the microsphere is larger than the diameter of the holes between the surface and the center of the microsphere, and the diameter of the holes between the surface and the center of the microsphere is larger than the diameter of the holes at the center of the microsphere.

[0014] In one specific embodiment, the plurality of pores of the microspheres of the present disclosure can have a distribution that gradually decreases along the direction from the surface to the center of the microspheres. This embodiment can be referred to FIG. 1A of the present application. The microsphere 10 has a plurality of pores 20. The distribution of pores on the surface of the microsphere is relatively large, and the distribution of pores decreases as it approaches the center 100 of the microsphere. That is, the distribution of pores gradually decreases along the direction I from the surface of the microsphere to the center 100. In another specific embodiment, the microspheres of the present disclosure do not necessarily have a pore distribution throughout the microspheres. Referring to FIG. 1A again, since there are no pores in the region close to the center 100, the microsphere 10 can be considered to have a pore gradient characteristic region 110, and the pores 20 are distributed only within the pore gradient characteristic region 110. The definition of the pore distribution may be the ratio of the total area of all pores to the total surface area at different depths of the microspheres. The higher the ratio, the larger the pore distribution.

[0015] In another specific embodiment, the diameters of the plurality of pores of the microspheres of the present disclosure can gradually decrease along the direction from the surface to the center of the microspheres. This embodiment can be referred to FIG. 1B of the present application. The microsphere 10 has a plurality of pores 20, 21, 22. The pore 20 has a relatively large diameter and is located on the surface of the microsphere or relatively close to the surface. The pore 22 has a relatively small diameter and is located relatively close to the center 100 of the microsphere. The pore 21 has a diameter and distribution that are also between those of the pore 20 and the pore 22, which indicates that the diameters of the pores gradually decrease along the direction I from the surface of the microsphere to the center 100. In yet another specific embodiment, similarly, the microspheres of the present disclosure do not necessarily have a pore distribution throughout the microspheres. Referring to FIG. 1B again, since there are no pores in the region close to the center 100, the microsphere 10 can be considered to have a pore gradient characteristic region 110, and the pores 20 are distributed only within the pore gradient characteristic region 110.

[0016] In another specific embodiment, the plurality of pores of the microspheres of the present disclosure can have their pore diameters and pore distributions gradually decreasing along the direction from the surface to the center of the microspheres. This embodiment can be referred to FIG. 1C of the present application. Since FIG. 1C is a combination of two specific embodiments, namely FIG. 1A and FIG. 1B, the same content will be omitted here.

[0017] Also, the fact that the second nuclide gradually decreases in the direction from the surface to the center of the microsphere can be referred to FIG. 2. The colored portion of the microsphere 10 shows the distribution of the second nuclide, which gradually decreases along the direction I from the surface to the center 100 of the microsphere.

[0018] In one specific embodiment, the pores do not penetrate the microspheres.

[0019] In one specific embodiment, the plurality of holes includes macropores and micropores. The diameter of the macropores is 10 - 30 micrometers (μm), or 10 - 25μm, 10 - 20μm, 15 - 30μm, 20 - 30μm, for example, 10, 15, 20, 25, 30μm. The diameter of the micropores is 0.1 - 10μm, or 0.1 - 5μm, 0.5 - 10μm, 0.5 - 5μm, for example, 0.1, 0.5, 1, 5, 10μm. This embodiment can be referred to FIG. 1C. Since the diameter of hole 20 is relatively large, it is a macropore, and since the diameter of hole 22 is relatively small, it is a micropore. In another specific embodiment, the plurality of holes includes macropores, mesopores and micropores. The diameter of the macropores is 20 - 30μm, or 15 - 25μm, 20 - 25μm, for example, 15, 20, 25, 30μm. The diameter of the mesopores is 5 - 20μm, or 5 - 15μm, 5 - 10μm, 10 - 20μm, for example, 5, 10, 15, 20μm. Also, the diameter of the micropores is 0.1 - 5μm, or 0.5 - 5μm, 0.1 - 1μm, 0.1 - 10μm, for example, 0.1, 0.5, 1, 5, 10μm. This embodiment can be referred to FIG. 1C. Since the diameter of hole 20 is relatively large, it is a macropore, and since the diameter of hole 22 is relatively small, it is a micropore, and since the diameter of hole 21 is between that of hole 20 and hole 22, it can be a mesopore. In one specific embodiment, some of the holes are connected to each other, and some of the holes are not connected to each other. For example, the macropores are not connected to each other, but some of the macropores and some of the micropores are connected to each other.

[0020] In one specific embodiment, the microspheres are glass microspheres.

[0021] The first nuclide and the second nuclide are not limited in the present disclosure, and may be any that can have radioactivity by neutron activation and generate β-rays, γ-rays or a combination thereof.

[0022] In one specific embodiment, the first nuclide can provide a β (beta) radioactive isotope, may be derived from the first raw material, and the first nuclide includes, for example, those selected from yttrium, aluminum, silicon, or a combination thereof. In one specific embodiment, the first nuclide includes yttrium, and may further include other things, such as aluminum, silicon, or a combination thereof, but is not limited thereto. In one specific embodiment, the first raw material forming the first nuclide may be in powder form, for example, oxides, but is not limited thereto, and for example, yttrium oxide, aluminum oxide, silicon oxide, but is not limited thereto.

[0023] In one specific embodiment, the second nuclide can provide a γ (gamma) radioactive isotope and may be derived from the second raw material. Also, the second nuclide can be potassium, barium, molybdenum, tellurium, indium, antimony, gallium, zinc, zirconium, palladium, rhodium, tantalum, tungsten, iridium, platinum, niobium, technetium, strontium, titanium, vanadium, phosphorus, calcium, sodium, rhenium, scandium, lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, lutetium, copper, gold, silver, iron, tin, cobalt, nickel, manganese, aluminum, carbon, boron, iodine, actinium-225, antimony-127, arsenic-74, barium-140, bismuth-210, bismuth-213, californium-246, calcium-46, calcium-47, carbon-11, carbon-14, cesium-131, cesium-137, chromium-51, cobalt-57, cobalt-58, cobalt-60, dysprosium-165, dysprosium-166, erbium-169, erbium-109, fluorine-18, gallium-67, gallium-68, gold-198, holmium-166, hydrogen-3, indium-111, indium-113m, iodine-123, iodine-125, iodine-131, iridium-192, iridium-194, iron-59, iron-82, krypton-81m, lanthanum-140, lutetium-177, molybdenum-99, nitrogen-13, oxygen-15, palladium-103, phosphorus-32, radon-222, radium-224, radium-223, rhenium-186, rhenium-188, rhodium-82, samarium-153, selenium-75, sodium-22, sodium-24, strontium-89, strontium-90, technetium-99m, thallium-201, xenon-127, xenon-133, cerium-137, actinium-225, zirconium-89, terbium-149, astatine-211, thorium-227, thorium-201, bismuth-212, bismuth-213, copper-64, ytterbium-169, ytterbium-175, lead-212, potassium-42, rubidium-82,It can contain at least one selected from the group consisting of titanium-45, scandium-44, and yttrium-90. In one specific embodiment, the second raw material for forming the second nuclide may be in powder form, for example, including hydrated oxides and hydroxides containing oxides and their crystal water forms, such as, but not limited to, yttrium oxide, iron oxide, calcium oxide, aluminum oxide, copper oxide, etc. In another specific embodiment, the second raw material may be in liquid form, for example, copper sulfate containing crystal water form, copper sulfate aqueous solution, iron chloride aqueous solution, calcium chloride aqueous solution, calcium hydroxide aqueous solution, calcium carbonate containing crystal water form, aluminum sulfate aqueous solution, yttrium acetate aqueous solution, phosphoric acid aqueous solution, etc., but not limited to these.

[0024] The nuclides used in the present disclosure can be used for radiotherapy when generating β-rays by neutron activation. When generating γ-rays by neutron activation, the position signal of the nuclide can be captured by a device capable of detecting γ-rays. When generating both β-rays and γ-rays by neutron activation, it is suitable for the above two applications simultaneously. Therefore, after administering the microspheres of the present disclosure into the body of the subject, not only can radiotherapy be performed on the target tissue using the β-rays generated by the microspheres, but also the distribution and metabolic status of the microspheres in the body can be observed by the generated γ-rays being captured by imaging devices (such as γ-ray cameras, positron emission tomography devices, etc.). Through the integrated operation of these imaging devices and computers, images can be displayed and more information can be obtained through calculation and analysis.

[0025] On the other hand, since the nuclides contained in the microspheres of the present disclosure are located within the structure, problems such as damage to non-target tissues caused by easy leakage, like carriers that carry nuclides or drugs in voids, do not occur.

[0026] In one specific embodiment, the microsphere further includes a shell layer, and the shell layer covers the surface of the microsphere and fills the plurality of pores.

[0027] Since the microspheres of the present disclosure have a plurality of pores, in order to increase the surface area of the microspheres and complicate the surface morphology, a shell layer with excellent adhesion to the microspheres can be easily installed on the surface of the microspheres. Thereby, various changes can be made to the shell layer. For example, the shell layer can be made hydrophilic or hydrophobic, or carry ligands that can target specific molecules, or carry drugs or other reagents, greatly enhancing the usefulness.

[0028] In one specific embodiment, the shell layer comprises a material selected from organic materials, inorganic materials, or combinations thereof. In another specific embodiment, the organic material is selected from polyvinylpyrrolidone, polyvinyl alcohol, carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyethylene glycol, gum arabic, polylactic acid, polylactic acid-glycolic acid, or combinations thereof. In another specific embodiment, the inorganic material is selected from phosphates, sulfates, chloride salts, nitrates, tellurium compounds, tellurates, iodides, iodates, xenonates, tungstates, rhenates, platinates, chloroaurates, mercurates, plumbates, bismuthates, astatates, uranates, polonides, osmates, antimonates, stannates, tin compounds, technetates, molybdates, niobates, bromates, bromides, selenates, selenides, arsenates, zincates, cuprates, cobaltates, ferrates, nickelates, manganates, chromates, vanadates, titanates, chlorates, sulfides, fluorophosphates, fluorosilicates, silicates, aluminates, fluorides, oxides, peroxides, superoxides, cyanates, carbonates, or borates.

[0029] In one specific embodiment, the diameter of the microspheres is 2 to 1000 micrometers (μm). In another specific embodiment, the diameter of the microspheres is 2 to 500 μm, 5 to 100 μm, or 5 to 50 μm, for example, 2, 3, 4, 5, 6, 7, 9, 10, 15, 20, 25, 30, 35, 37, 40, 45, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000 μm.

[0030] In one specific embodiment, the etching resistance of the first nuclide is higher than that of the second nuclide.

[0031] The second aspect of the present disclosure is A method for preparing microspheres, comprising: providing a first raw material of a first nuclide and a second raw material of a second nuclide; mixing the first raw material and the second raw material to form a mixed powder; heating the mixed powder to obtain an intermediate; forming molten droplets by melting and spheroidizing the intermediate; contacting the molten droplets with a cooling source to obtain microspheres; contacting the microspheres with a treatment solution to form a plurality of pores; and both the first raw material and the second raw material are powders; the first nuclide is distributed within the microspheres; the concentration of the first nuclide at the center of the microspheres is higher than that on the surface of the microspheres; the distribution of the second nuclide gradually decreases in the direction from the surface to the center of the microspheres; the plurality of pores have a gradient feature that gradually decreases in the direction from the surface to the center of the microspheres; the first nuclide and the second nuclide have radioactivity by neutron activation and can generate β-rays, γ-rays, or a combination thereof; A method.

[0032] A third aspect of the present disclosure is a method for preparing microspheres, comprising: providing a first raw material of a first nuclide; heating the first raw material to obtain an intermediate; forming molten droplets by melting and spheroidizing the intermediate; contacting the molten droplets with a cooling source to obtain microspheres; contacting the microspheres with a treatment solution to form a plurality of pores; wherein the first raw material is in powder form; the cooling source is a second raw material of a second nuclide; the second raw material is in liquid form; the second nuclide is introduced from the surface of the molten droplets or the microspheres and diffused into the interior thereof, or deposited on the surface thereof, so that the first nuclide is distributed within the microspheres, and the concentration of the first nuclide at the center of the microspheres is higher than that on the surface of the microspheres, and the distribution of the second nuclide gradually decreases in the direction from the surface to the center of the microspheres; the plurality of pores have a gradient feature that gradually decreases in the direction from the surface to the center of the microspheres; the first nuclide and the second nuclide are radioactive by neutron activation and can generate beta rays, gamma rays, or a combination thereof; and a method.

[0033] In one specific embodiment, the first raw material and the second raw material may be glass raw material powders. In one specific embodiment, the first raw material (glass raw material powder) of the first nuclide and / or the second raw material (glass raw material powder) of the second nuclide are combined with other glass raw material powders to form a glass raw material powder mixture (i.e., batch material). After uniformly mixing, melting, and rapidly quenching this glass raw material powder mixture, glass is formed. The formed glass can also be further pulverized to obtain glass powder. For example, the glass raw material powder mixture is placed in a crucible (e.g., a platinum crucible), the crucible is placed in an electric furnace, and the glass raw material powder mixture is melted (the melting time varies depending on the components of the powder mixture and usually takes 2 to 8 hours to be completely melted). During this time, it is stirred and mixed as needed to improve chemical uniformity. Then, the crucible is taken out, and the melt is brought into contact with a cooling source (e.g., poured onto a cold steel plate or into cold water). At this time, the melt is rapidly quenched to form glass. There may be a possibility of fragmentation during the process of forming glass, which helps to simplify the subsequent glass pulverization process. Finally, the glass is pulverized (e.g., crushed, mechanically polished, ball mill polished) to obtain glass powder.

[0034] In one specific embodiment, in the steps of heating the first raw material in powder form (or the mixed powder of the first raw material and the second raw material) to obtain an intermediate, melting the intermediate to form a sphere, and bringing the molten droplets into contact with a cooling source, for example, the flame spraying method can be employed. For example, the powder is filled into a feeder, and the powder is made to enter a pipe by forced air transportation, thereby guiding the powder into a gas flame. At this time, the powder is melted into a molten liquid state by the heating of the gas flame and is simultaneously ejected and scattered by the gas flame. During this time, the molten droplets are formed into a sphere under the influence of multiple factors such as rotation, surface tension, and gravity. Then, the spherical molten droplets come into contact with a cooling source and are rapidly quenched to become glass.

[0035] As described above, when contacting the cooling source, the rotating spherical molten droplet entraps a part of the cooling source. On the other hand, the components in the cooling source also diffuse and penetrate from its surface while quenching the spherical molten droplet into glass. Therefore, when the cooling source is the second raw material of the second nuclide, that is, when the second raw material is liquid, the second nuclide is introduced into the microsphere by the above phenomenon, and the distribution of the second nuclide gradually decreases from the surface to the center of the microsphere as shown in FIG. 2.

[0036] In one specific embodiment, the step of forming a plurality of pores by bringing the microspheres into contact with a treatment solution uses the treatment solution for etching treatment. Generally, the etching treatment starts from the surface of the microspheres. In particular, in the present disclosure, the microspheres exhibit excellent corrosion resistance to the treatment solution, and the treatment solution enhances corrosion only at the positions where the second nuclide is present. When the distribution of the second nuclide gradually decreases from the surface to the center of the microsphere as described above, the degree of corrosion also gradually weakens from the surface to the center of the microsphere. As a result, the plurality of pores have a gradient feature of gradually decreasing along the direction from the surface to the center of the microsphere. In another specific embodiment, this gradient feature includes, as shown in FIGS. 1A to 1C, the diameter of the pores, the distribution of the pores, or a combination thereof.

[0037] In one specific embodiment, the processing solution contains an etching agent. In another specific embodiment, the etching agent is a combination of any one of an acid and a base and an oxidizing agent, and the acid is citric acid, lactic acid, oxalic acid, acetic acid, permanganic acid, p-toluenesulfonic acid, phosphoric acid, aqua regia, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, perchloric acid, chloric acid (HClO3), bromic acid (HBrO3), perbromic acid (HBrO4), iodic acid (HIO3), periodic acid (HIO4), metaperiodic acid (HIO4), selenic acid (H2SeO4), hexafluorosilicic acid (H2SiF6), chloro-plumbic acid (H2PbCl6), ferrate (H2FeO4), tetrafluoroboric acid (HBF4), fluorosulfonic acid (HSO3F), cyanic acid (HOCN), thiocyanic acid (HSCN), 2,4,6-trinitrophenol (HC6H2N3O7), 2,4,6-trinitrobenzoic acid (HC7H2N3O8), trifluoroacetic acid (CF3COOH), trichloroacetic acid (CCl3COOH), methanesulfonic acid (CH3SO3H), benzenesulfonic acid (C6H5SO3H), cyclohexanethiol sulfonic acid (C6H 10 (SH)SO3H), 2-chloroethanethiol (CH3CHClSH), fluoroantimonic acid (HSbF6), fluoroantimonosulfonic acid (SbF6SO3H), perfluorosulfonic acid resin (Nafion-H), chlorofluoroaluminate (HAlCl3F), carboranic acid (H[CHB 11 Cl 11) and at least one selected from the group consisting of FeCl3·HClO4·SiO2·nH2O, and the base is sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonia, lithium hydroxide, rubidium hydroxide, cesium hydroxide, francium hydroxide, strontium hydroxide, barium hydroxide, radium hydroxide, thallium(I) hydroxide, diamminesilver(I) hydroxide, choline, quaternary ammonium base, butyllithium, lithium diisopropylamine, benzyllithium, Grignard reagent, alkylcopper lithium, sodium methoxide, sodium ethoxide, potassium ethoxide and sodium tert-butoxide, and the oxidizing agent is at least one selected from the group consisting of amphoteric compounds, hydrogen peroxide, permanganate, hypochlorite, chromate, dichromate and chromium trioxide.

[0038] In another specific embodiment, the treatment solution contains nitric acid and hydrogen peroxide, or the treatment solution contains sodium hydroxide and hydrogen peroxide. In another specific embodiment, the treatment solution is 1 to 37 wt% nitric acid (e.g., 1N) and 1 to 25 wt% hydrogen peroxide (e.g., 25 wt%), or the treatment solution is 0.1 to 10N sodium hydroxide (e.g., 0.1N, 0.5N, 1N, 2N, 5N, 10N) and 1 to 25 wt% hydrogen peroxide (e.g., 25 wt%).

[0039] In one specific embodiment, the step of bringing the microspheres into contact with the treatment solution to form a plurality of pores is heated according to the situation. For example, the etching treatment is carried out in a temperature range of 25°C to 100°C, such as 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 95, 100°C. In one specific embodiment, the step of bringing the microspheres into contact with the treatment solution to form a plurality of pores continues for 10 minutes (min) to 3 hours (hr), such as 10 min, 20 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr.

[0040] In one specific embodiment, the pores do not penetrate the microspheres as described in the first embodiment.

[0041] In one specific embodiment, the plurality of pores include macropores and micropores as described in the first embodiment, the diameter of the macropores being 10 - 30 μm, or 10 - 20 μm, 10 - 25 μm, 15 - 30 μm, 20 - 30 μm, for example, 10, 15, 20, 25, 30 μm, and the diameter of the micropores being 0.1 - 10 μm, or 0.1 - 5 μm, 0.5 - 10 μm, 0.5 - 5 μm, for example, 0.1, 0.5, 1, 5, 10 μm.

[0042] In one specific embodiment, it further includes a shell layer covering the surface of the microspheres.

[0043] In one specific embodiment, the shell layer includes a material selected from organic materials, inorganic materials, or a combination thereof. In another specific embodiment, the organic material is selected from polyvinylpyrrolidone, polyvinyl alcohol, carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyethylene glycol, gum arabic, polylactic acid, poly(lactic - glycolic acid), or a combination thereof. In another specific embodiment, the inorganic material is selected from phosphates, sulfates, chloride salts, nitrates, or borates.

Examples

[0044] Furthermore, the present disclosure will be described in more specific detail through the following examples. However, the interpretation of the present disclosure should not be limited by the description of the following examples.

[0045] Example 1

[0046] 35 g of Y2O3 powder, 35 g of Al2O3 powder, 20 g of SiO2 powder and 10 g of CuO powder were taken. After uniformly mixing these powders, they were put into a crucible and placed in an electric furnace heated to 1600 °C to melt the powder mixture. The direct addition of copper helped lower the melting temperature of the entire glass bulk material by about 100 °C. During this period, after the start of melting, it was sufficiently stirred to improve chemical uniformity. After melting and stirring were completed, the crucible was taken out, and the melt was poured onto a cold steel plate, and rapid quenching was performed to form glass, and at the same time, it was crushed to form glass fragments. Next, using a mortar and pestle, the glass fragments were crushed to a particle size of about 100 mesh, and further polished using a mechanical mortar and pestle or a ball mill until they passed through a 400-mesh (37 μm in diameter) sieve to obtain glass powder.

[0047] Next, the glass powder was put into a forced-air transport feeder located above an acetylene / oxygen burner, and the glass powder was made to enter the pipe by forced-air transport, thereby guiding the glass powder into the flame of the acetylene / oxygen burner. The feeding rate into the flame was set within the range of 5 - 25 g / hr. The glass powder was melted by the high temperature of the flame and formed spherical molten droplets during the process of rotation and scattering. The spherical molten droplets were brought into contact with deionized water, which was a cooling source, to obtain glass microspheres of Mode 1. Microspheres with diameters in the range of 5 - 30 μm were selected, and the dimensions and appearance of the microspheres after the selection were analyzed by a scanning electron microscope (SEM) as shown in Figure 3, and then used for subsequent experiments. Also, three microspheres were randomly selected as samples from the selected microspheres, and energy-dispersive X-ray spectroscopy (EDS) analysis was performed. The results are as shown in Table 1, which shows the atomic percentages of each sample.

[0048]

Table 1

[0049] Example 2

[0050] 35 g of Y2O3 powder, 35 g of Al2O3 powder, and 20 g of SiO2 powder were taken. After uniformly mixing these powders, they were placed in a crucible and put into an electric furnace heated to 1700 °C to melt the powder mixture. During this process, after the start of melting, it was sufficiently stirred to improve chemical uniformity. After melting and stirring were completed, the crucible was taken out, and the melt was poured onto a cold steel plate and rapidly quenched to form glass, and at the same time, it was crushed to form glass fragments. Next, using a mortar and pestle, the glass fragments were crushed to a particle size of about 100 mesh, and further polished using a mechanical mortar and pestle or a ball mill until they passed through a 400-mesh (37 μm in diameter) sieve to obtain glass powder.

[0051] Next, the glass powder was put into a forced-air transport feeder located above an acetylene / oxygen burner, and the glass powder was made to enter the pipe by forced-air transport, thereby guiding the glass powder into the flame of the acetylene / oxygen burner. The feeding rate into the flame was set within the range of 5 - 25 g / hr. The glass powder was melted by the high temperature of the flame and formed spherical molten droplets during the process of rotation and scattering. The spherical molten droplets were brought into contact with a CuSO4·5H2O solution (10 M supersaturated state) as a cooling source to obtain glass microspheres of Mode 2. Glass microspheres with diameters in the range of 5 - 30 μm were selected and used for subsequent experiments.

[0052] Example 3

[0053] Glass microspheres of Mode 3 were obtained in the same manner as the preparation method described in Example 2, except that the powder mixture was changed to 35 g of Y2O3 powder, 35 g of Al2O3 powder, 20 g of SiO2 powder, and 10 g of CuO powder.

[0054] Example 4

[0055] The same preparation method as described in Example 2 was carried out, except that the concentration of the CuSO4·5H2O solution was changed to 1 M (unsaturated).

[0056] Example 5

[0057] The preparation method was the same as that described in Example 2, except that the concentration of the CuSO4·5H2O solution was changed to 3 M (saturated).

[0058] Examples 3 to 5 were observed with a scanning electron microscope (SEM). The results are as shown in Fig. 4, where (A) to (C) therein respectively show Example 4, Example 5 and Example 2. According to Fig. 4, when the glass microspheres were brought into contact with an unsaturated CuSO4·5H2O solution, no deposition of substances was observed on the surface of the glass microspheres. However, when the glass microspheres were brought into contact with a saturated or supersaturated CuSO4·5H2O solution, deposition of substances was observed on the surface of the glass microspheres.

[0059] Example 6

[0060] Regarding the glass microspheres of Example 2, five microspheres were randomly taken as samples and subjected to EDS analysis. The results are as shown in Table 2, which shows the atomic percentages of each sample. According to Table 2, it was confirmed that the substance deposited on the surface of the glass microspheres contained copper.

[0061]

Table 2

[0062] In addition, the glass microspheres of Example 2 were brought into contact with a treatment solution containing 1 N nitric acid and 25 wt% hydrogen peroxide, and subjected to an etching treatment at 75°C for 1 hour. Then, five microspheres were randomly taken as samples and subjected to EDS analysis. The results are as shown in Table 3, which shows the atomic percentages of each sample. According to Table 3, although the copper deposited on the surface of the glass microspheres was still observed, the concentration of copper decreased from an average value of 8.67 to 6.80, indicating that some copper was etched.

[0063]

Table 3

[0064] Example 7

[0065] The glass microspheres of Example 2 were brought into contact with a treatment solution containing 1N nitric acid and 25 wt% hydrogen peroxide, and an etching treatment was carried out at 75°C for 24 hours. As shown in (A), (B), (C), and (D) of FIG. 5, the SEM photograph results showed that the glass microspheres were etched and a plurality of holes were formed. Also, for the glass microspheres etched in this example, two microspheres were randomly taken as samples and subjected to EDS analysis. The results are as shown in Table 4 and Table 5 respectively, showing the atomic percentage and weight percentage of each sample.

[0066] [Table 4]

[0067] [Table 5]

[0068] Next, 100 milligrams (mg) of the etched glass microspheres were taken. Further, a double-sided carbon tape was placed flat on a conductive substrate, the double-sided carbon tape was dried, the glass microspheres were laid flat on the double-sided carbon tape, and air was blown with an air gun. If the glass microspheres with sufficient carbon paste adhered, they adhered to the substrate, and the glass microspheres etched in this example adhered sufficiently to the substrate even after air blowing with an air gun.

[0069] In order to observe the cross-section of the glass microspheres etched in Example 7, the etched glass microspheres were subjected to processes such as embedding, polishing, finishing, washing, and conductive layer plating. The SEM photographs of the cross-section of the glass microspheres are shown in (A) to (F) of FIG. 6. The above processing steps are as follows. 1. Cold embedding After washing 100 mg of glass microspheres (refer to Step 4), they were placed in a mold, then a mixture of resin and curing agent was poured, cured at room temperature and normal pressure, and then the embedded test piece was taken out. The embedded test piece was cut to appropriate dimensions. 2. Polishing The embedded test specimens were polished using SiC sandpaper, with rough polishing and fine polishing carried out according to the grit numbers 240 → 400 → 600 → 800 → 1200 → 2400 → 4000. 3. Polishing The surface of the test specimen was polished to a mirror finish (a state without scratches when observed under an optical microscope). As the polishing solution, a diamond suspension was adopted, and the diamond abrasive grains in it enabled the rapid removal of the material, flattening the surface of the test specimen. 4. Cleaning The test specimens were immersed in alcohol and deionized water in sequence and vibrated with ultrasonic waves to remove the substances remaining on the test specimens during the polishing and polishing steps, thus avoiding interference with the analysis results. 5. Conductive layer plating The non-conductive glass microsphere material and the resin embedding it needed to be plated with a conductive layer to prevent the concentration of the charged electron beam. The conductive layer was, for example, a continuous thin film of Au.

[0070] Example 8

[0071] Glass microspheres having a plurality of holes with an etching treatment for 24 hours in Example 7 were collected. Next, the glass microspheres having a plurality of holes were spray granulated and coated with the materials listed in Table 6 below. After uniformly wetting and mixing the material solution of 0.1 - 10 wt% and the glass microspheres at a ratio of 1:1, the coating was carried out using a spray dryer. Here, the flow rate was 357 L / h, the outlet temperature was between 180 - 245 °C, and all groups were able to form a shell layer on the surface of the glass microspheres. As shown in Figure 7, the SEM photos of the glass microspheres coated with PVP (A) or the glass microspheres coated with CMC (B) show that a clear shell layer was formed on the surface of the glass microspheres.

[0072]

Table 6

[0073] Example 9

[0074] To verify whether the positron signals generated by the decay of yttrium-90 and copper-64 in glass microspheres can be effectively detected by using positron emission tomography (PET) / computed tomography (CT), the glass microspheres of Example 3 were taken and contacted with a treatment solution containing 1N nitric acid and 25 wt% hydrogen peroxide, and a corrosion treatment was carried out at 75 °C for 1 hour to form glass microspheres with a plurality of pores. 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, and 200 mg of glass microspheres were taken in two groups respectively, placed in 0.5 mL Eppendorf tubes, irradiated with a neutron activation beam for 6 hours, and then decayed overnight. Among them, one group of samples was measured for radioactivity with a dose calibrator every 6 hours, and positron emission tomography / computed tomography (PET / CT) was performed. Another group of samples was placed in a columnar agar gel phantom and imaged in the same way. Figure 8 is a PET / CT image of the sample placed in the Eppendorf tube, and Figure 9 is a PET / CT image of the sample placed in the agar gel phantom.

[0075] According to the results of Figures 8 and 9, regardless of whether the samples were placed in test tube racks or in agar gel phantoms, complete overlap of the CT image and PET image of the glass microspheres was observed in the images at different time points. However, only the positron signal of the PET image decayed with time, and the positron signal intensity at each time point showed a correlation with the weight of the glass microspheres.

[0076] Next, the regions of interest (ROIs) in Figures 8 and 9 were circled with a circle using image analysis software, and the photon signal intensity in the ROI was calculated for quantitative analysis to obtain the half-life. In Figures 10(A) and 10(B), the relationship diagrams (TAC) of time-residual activity A t were plotted, and as a result, it was shown that the positron signal decayed with time and exhibited a linear relationship, which was consistent with the decay function of the radioactive substance.

[0077] Calculation formula:

Number

[0078] Taking the natural logarithm of both sides of the equation in [Equation 1] in the same way gives a linear function.

Equation

Equation

[0079] Also, as described above, yttrium-90 / copper-64 dinuclear glass microspheres with different weights were placed in test tube racks and agar gel phantoms respectively, and PET / CT imaging was performed at different time points to calculate the photon signal intensity of the ROI in the images. In (A) and (B) of Figure 11, the relationship diagrams (TAC) of weight - residual activity A t were plotted, and among them, the linear correlation coefficient (R 2 ) of each curve is greater than 0.99, indicating that the positron signal intensity at each time point and the weight of the glass microspheres show a high linear correlation.

[0080] In this example, furthermore, the decay function of the above radioactive substance was inferred as follows. That is, both sides of the equation in [Equation 1] were divided by A0 in the same way, and then the natural logarithm was taken to obtain the following result.

Equation

[0081] Based on Equation 4, time - ln(A tThe relational diagram of / A0) is as shown in FIG. 12. In FIGS. 12(A) and 12(B), the half-lives of the radioactive substances contained in the glass microspheres placed in the test tube stand and the agar gel phantom are shown respectively. Each curve in the figure is subjected to linear regression using GraphPad Prism software. After obtaining the slope of each curve, that is, the decay constant λ of Equation 4, if the numerical value is applied to Equation 5, the half-life of the radioactive substance can be calculated, as shown in Table 7 below.

[0082]

Table 7

[0083] According to these results, regardless of whether the glass microspheres of each group are placed in a test tube stand or an agar gel phantom, the average half-life is 12.7 hours, which is the same as the known half-life of copper-64. Thus, when performing contrast imaging of yttrium-90 / copper-64 glass microspheres with PET / CT, it was confirmed that the positron decay signal of copper-64 can be detected. Without being bound by theory, PET imaging devices have options for coincidence circuits and energy windows, and only pairs of 511 keV energy photons generated by positron-electron annihilation are detected, while all other photon signals of non-positron decay are excluded. Also, yttrium-90 undergoes very little positron decay, and the ratio is about 3.18×10 -5 which is extremely low and the influence is extremely small.

[0084] Example 10

[0085] In order to further verify that in addition to the copper-64 radionuclide, the yttrium-90 radionuclide also exists in the yttrium-90 / copper-64 dual-nuclide glass microspheres, in this example, a dose calibrator was used to read the activity of the yttrium-90 / copper-64 dual-nuclide glass microspheres, and the device can detect γ-rays and β-rays with relatively high energy. First, the measurement period was set to 250 hours (about 4 times the half-life of yttrium-90), and the reading results of the dose calibrator were plotted as time-A as shown in FIG. 13 tPlotted as a relational diagram of / A0. For the curve, a two-phase decay curve regression analysis was performed using GraphPad Prism software, and the half-lives of the two radioactive substances were obtained: 66.3 hours and 12.7 hours, which are close to or the same as the half-life of known yttrium-90 (64.1 hours) and the half-life of copper-64 (12.7 hours), respectively. Therefore, it was confirmed that the glass microspheres after neutron activation mainly contain two radionuclides, yttrium-90 and copper-64.

[0086] Example 11

[0087] In this example, it was observed whether there were changes in the dimensions and appearance of the glass microspheres before and after neutron activation. An appropriate amount of yttrium-90 / copper-64 two-nuclide glass microspheres before neutron activation and yttrium-90 / copper-64 two-nuclide glass microspheres that had been neutron-activated and decayed (completely decayed) to the environmental background value were each taken and placed on a slide glass, and sample images with magnifications of 10 times and 40 times were taken using a positive fluorescence microscope (Olympus BX61) as shown in Figure 14. After calculating the diameter of each microsphere in the image using MetaMorph (registered trademark) image processing software, the data was imported into GraphPad Prism software for analysis, and a microsphere diameter distribution diagram was plotted as shown in Figure 15.

[0088] According to Figure 14, the appearances of the glass microspheres before and after neutron activation both exhibit smooth spherical shapes, indicating that neutron activation does not significantly change the appearance of the glass microspheres. According to Figure 15, the diameters of the glass microspheres before and after neutron activation are 31.6 ± 3.8 μm and 30.5 ± 0.5 μm, respectively, indicating that there is no significant difference in the diameter distribution before and after neutron activation.

[0089] Example 12

[0090] Analysis of the in vitro stability of yttrium-90 / copper-64 dual-radionuclide glass microspheres was performed. Twenty-four test tubes were taken, and after adding glass microspheres with fixed activity and phosphate buffer solution (PBS) or fetal bovine serum (FBS) respectively, they were placed in incubators at 4 °C and 37 °C respectively. At each selected time point (1 hour, 2 hours, 4 hours, 8 hours, 24 hours, and 48 hours), three test tubes were taken each time, and the radiochemical purity was measured. 200 μL of the sample was taken, passed through a 0.45 μm filter, the filter was washed with 2 mL of physiological saline to collect the filtrate, and the residual activities of the filtrate and the filter were measured respectively. The radiochemical purity was calculated using the following formula, and a relationship diagram of time-radiochemical purity (Figure 16) was plotted.

Number

[0091] According to Figure 16, after standing in PBS / 4 °C and FBS / 37 °C for 48 hours, the radiochemical purity of yttrium-90 / copper-64 dual-radionuclide glass microspheres can still be maintained as high as over 98%. This indicates that yttrium-90 / copper-64 dual-radionuclide glass microspheres have extremely excellent stability. From this, it is speculated that the glass microspheres are less likely to be chelated by proteins in the blood after being administered in vivo.

[0092] Example 13

[0093] Analysis of the in vivo stability of yttrium-90 / copper-64 dual-radionuclide glass microspheres was performed. Sprague-Dawley (SD) rats aged 8 - 10 weeks were gas anesthetized with isoflurane / oxygen (2%) and then fixed on the table. 300 μL of the liquid containing yttrium-90 / copper-64 glass microspheres was injected through the tail vein, and the weight of the glass microspheres in it was about 500 μCi / 50 mg. PET / CT imaging was performed at each selected time point (1 hour, 4 hours, 24 hours, and 48 hours), the left and right lung lobes were circled as ROIs, and quantitative analysis was performed using image analysis software to calculate the photon signal intensity in the ROIs.

[0094] In the PET / CT imaging results of Figure 17, one hour after intravenous injection of glass microspheres, the pulmonary capillaries were almost completely embolized, showing high activity in the lungs (both the left and right lung lobes) (simply indicating that the lung region is a high-activity (H) region). On the other hand, except for a small amount of glass microspheres remaining in the caudal vein, which is the injection site, there was little accumulation in other parts of the body, indicating extremely low activity, almost close to zero. Four hours after injection, the activity of the glass microspheres in the lungs and the caudal vein, which is the injection site, only decreased slightly and still maintained a high activity level. As time passed, 24 hours after injection, the activity of the glass microspheres in the lungs and the caudal vein, which is the injection site, decreased. Also, for clarity, the lung region at this time was defined as a medium-activity (M) region. 48 hours after injection, the glass microspheres in the lungs and the caudal vein, which is the injection site, decreased more significantly. The lung region at this time was defined as a low-activity (L) region, and its activity was almost the same as that of other parts of the body where the glass microspheres were not accumulated.

[0095] In Figures 18(A) and 18(B), the time-residual activity A t curve diagram and the time-ln(A t / A0) curve diagram are shown when the left and right lung lobes of the rat or the reference line source are used as the ROI. According to the calculation method described in Example 8, the effective half-lives of yttrium-90 and copper-64 contained in the glass microspheres in the left and right lung lobes of the rat in the body were obtained as 12.48 hours and 53.23 hours, respectively. Also, from the group using the reference line source as the ROI, the physical half-lives of yttrium-90 and copper-64 were obtained as 12.48 hours and 67.35 hours, respectively, which are close to the known half-lives.

[0096] Furthermore, the physiological half-life of the yttrium-90 / copper-64 dual-radionuclide glass microspheres calculated from the following [Equation 6] was also long.

Equation

[0097] When comprehensively considering the in vitro and in vivo stability results of Example 12 and Example 13, the glass microspheres of the present disclosure can continuously exist within the glass microspheres without any leakage of the radionuclides yttrium-90 and copper-64 during the test period. In addition, after intravenous administration into the body, the glass microspheres can continuously embolize the lungs and can be considered to have a permanent embolization effect. Therefore, it can be applied to specific internal radiotherapy.

Explanation of Signs

[0098] 10: Microsphere 20, 21, 22: Hole 100: Center 110: Hole gradient characteristic region I: Direction from the surface to the center H: High activity M: Medium activity L: Low activity

Claims

1. A microsphere having a plurality of holes, wherein the plurality of holes have a gradient characteristic that gradually decreases along the direction from the surface to the center of the microsphere, and the microsphere includes a first nuclide distributed within the microsphere and having a higher concentration at the center of the microsphere than on the surface thereof, and a second nuclide that gradually decreases in the direction from the surface to the center of the microsphere, and the first nuclide and the second nuclide are radioactive by neutron activation and can generate beta rays, gamma rays, or a combination thereof. Microsphere.

2. The microsphere according to claim 1, wherein the gradient characteristic includes the diameter of the holes, the distribution of the holes, or a combination thereof.

3. The microsphere according to claim 1, wherein the holes do not penetrate the microsphere.

4. The plurality of holes include macropores and micropores, the diameter of the macropores is 10 to 30 μm, and the diameter of the micropores is 0.1 to 10 μm. The microsphere according to claim 1.

5. The microsphere according to claim 1, wherein the first nuclide includes those selected from yttrium, aluminum, silicon, or a combination thereof.

6. The second nuclide includes at least one selected from the group consisting of potassium, barium, molybdenum, tellurium, indium, antimony, gallium, zinc, zirconium, palladium, rhodium, tantalum, tungsten, iridium, platinum, niobium, technetium, strontium, titanium, vanadium, phosphorus, calcium, sodium, rhenium, scandium, lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, lutetium, copper, gold, silver, iron, tin, cobalt, nickel, manganese, aluminum, carbon, boron, iodine, actinium-225, antimony-127, arsenic-74, barium-140, bismuth-210, bismuth-213, californium-246, calcium-46, calcium-47, carbon-11, carbon-14, cesium-131, cesium-137, chromium-51, cobalt-57, cobalt-58, cobalt-60, dysprosium-165, dysprosium-166, erbium-169, erbium-109, fluorine-18, gallium-67, gallium-68, gold-198, holmium-166, hydrogen-3, indium-111, indium-113m, iodine-123, iodine-125, iodine-131, iridium-192, iridium-194, iron-59, iron-82, krypton-81m, lanthanum-140, lutetium-177, molybdenum-99, nitrogen-13, oxygen-15, palladium-103, phosphorus-32, radon-222, radium-224, radium-223, rhenium-186, rhenium-188, rhodium-82, samarium-153, selenium-75, sodium-22, sodium-24, strontium-89, strontium-90, technetium-99m, thallium-201, xenon-127, xenon-133, cerium-137, actinium-225, zirconium-89, terbium-149, astatine-211, thorium-227, thorium-201, bismuth-212, bismuth-213, copper-64, ytterbium-169, ytterbium-175, lead-212, potassium-42, rubidium-82, titanium-45, scandium-44 and yttrium-90.The microspheres according to claim 1.,

7. further includes a shell layer, the shell layer covers the surface of the microsphere and fills the plurality of holes, and the shell layer includes a material selected from an organic material, an inorganic material, or a combination thereof. The microsphere according to claim 1.

8. The organic material is selected from polyvinylpyrrolidone, polyvinyl alcohol, carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyethylene glycol, gum arabic, polylactic acid, poly(lactic-co-glycolic acid), or a combination thereof. The microsphere according to claim 7.

9. The inorganic material of the microspheres according to claim 7 is selected from phosphates, sulfates, chloride salts, nitrates, tellurium compounds, tellurates, iodides, iodates, xenonates, tungstates, rhenates, platinates, chloroaurates, mercurates, plumbates, bismuthates, astatates, uranates, polonides, osmates, antimonates, stannates, tin compounds, technetiumates, molybdates, niobates, bromates, bromides, selenates, selenides, arsenates, zincates, cuprates, cobaltates, ferrites, nickelates, manganates, chromates, vanadates, titanates, chlorates, sulfides, fluorophosphates, fluorosilicates, silicates, aluminates, fluorides, oxides, peroxides, superoxides, cyanates, carbonates or borates.

10. The microspheres according to claim 1, having a diameter of 2 to 1000 μm.

11. The microspheres according to claim 1, wherein the etching resistance of the first nuclide is higher than that of the second nuclide.

12. A method for preparing microspheres, comprising: providing a first raw material of a first nuclide and a second raw material of a second nuclide; mixing the first raw material and the second raw material to form a mixed powder; heating the mixed powder to obtain an intermediate; forming molten droplets by melting and spheroidizing the intermediate; contacting the molten droplets with a cooling source to obtain microspheres; contacting the microspheres with a treatment solution to form a plurality of pores; and both the first raw material and the second raw material are powders; the first nuclide is distributed within the microspheres; the concentration of the first nuclide at the center of the microspheres is higher than that on the surface of the microspheres; the distribution of the second nuclide gradually decreases in the direction from the surface to the center of the microspheres; the plurality of pores have a gradient feature that gradually decreases in the direction from the surface to the center of the microspheres; the first nuclide and the second nuclide are radioactive by neutron activation and can generate beta rays, gamma rays or a combination thereof.

13. A method for preparing microspheres, comprising: providing a first raw material of a first nuclide; heating the first raw material to obtain an intermediate; forming molten droplets by melting and spheroidizing the intermediate; contacting the molten droplets with a cooling source to obtain microspheres; A step of bringing the microspheres into contact with a treatment solution to form a plurality of pores including the first raw material is in powder form the cooling source is a second raw material of a second nuclide the second raw material is in liquid form by allowing the second nuclide to enter from the surface of the molten droplets or the microspheres and diffuse into them or precipitate on the surface, distributing the first nuclide within the microspheres such that the concentration of the first nuclide at the center of the microspheres is higher than that at the surface of the microspheres, and the distribution of the second nuclide gradually decreases in the direction from the surface to the center of the microspheres the plurality of pores have a gradient feature that gradually decreases in the direction from the surface to the center of the microspheres the first nuclide and the second nuclide are radioactive by neutron activation and can generate beta rays, gamma rays, or a combination thereof, a method

14. the cooling source is a second raw material of a second nuclide the second raw material is in liquid form the method according to claim 12, wherein the second nuclide is allowed to enter from the surface of the plurality of molten droplets or the microspheres and diffuse into them or precipitate on the surface

15. the method according to claim 12 or 13, wherein the treatment solution contains an etching agent

16. the etching agent is a combination of any one of an acid and a base and an oxidizing agent The acids include citric acid, lactic acid, oxalic acid, acetic acid, permanganic acid, p-toluenesulfonic acid, phosphoric acid, aqua regia, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, perchloric acid, chloric acid (HClO ３ ), bromic acid (HBrO ３ ), perbromic acid (HBrO ４ ), iodic acid (HIO ３ ), periodic acid (HIO ４ ), metaperiodic acid (HIO ４ ), selenic acid (H ２ SeO ４ ), hexafluorosilicic acid (H ２ SiF ６ ), chloroplumbic acid (H ２ PbCl ６ ), ferrate (H ２ FeO ４ ), tetrafluoroboric acid (HBF ４ ), fluorosulfonic acid (HSO ３ F), cyanic acid (HOCN), thiocyanic acid (HSCN), 2,4,6-trinitrophenol (HC ６ H ２ N ３ O ７ ), 2,4,6-trinitrobenzoic acid (HC ７ H ２ N ３ O ８ ), trifluoroacetic acid (CF ３ COOH), trichloroacetic acid (CCl ３ COOH), methanesulfonic acid (CH ３ SO ３ H), benzenesulfonic acid (C ６ H ５ SO ３ H), cyclohexanethiol sulfonic acid (C ６ H １０ (SH)SO ３ H), 2-chloroethanethiol (CH ３ CHClSH), fluoroantimonic acid (HSbF ６ ), fluoroantimonosulfonic acid (SbF ６ SO ３ H), perfluorosulfonic acid resin (Nafion-H), chlorofluoroaluminate (HAlCl ３ F), carboranic acid (H[CHB １１ Cl １１ ), and FeCl ３ ·HClO ４ ·SiO ２ ·nH ２ O, and is at least one selected from the group consisting of the base is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonia, lithium hydroxide, rubidium hydroxide, cesium hydroxide, francium hydroxide, strontium hydroxide, barium hydroxide, radium hydroxide, thallium(I) hydroxide, diamminesilver(I) hydroxide, choline, quaternary ammonium bases, butyllithium, lithium diisopropylamine, benzyllithium, Grignard reagents, alkyllithium coppers, sodium methoxide, sodium ethoxide, potassium ethoxide, and sodium tert-butoxide the oxidizing agent is at least one selected from the group consisting of amphoteric compounds, hydrogen peroxide, permanganates, hypochlorites, chromates, dichromates, and chromium trioxide, the method according to claim 15

17. the method according to claim 12 or 13, wherein etching is performed at the position of the second nuclide in the treatment solution

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