Microsphere and preparation method thereof

Abstract

The invention relates to a microsphere which is provided with a plurality of holes and has a gradient characteristic which is gradually reduced from the surface to the center of the microsphere, and the microsphere comprises a first nuclide which is distributed in the microsphere, and the concentration of the first nuclide at the center of the microsphere is greater than the concentration of the first nuclide at the surface of the microsphere; the first nuclide is gradually reduced from the surface of the microsphere to the center of the microsphere, the second nuclide is gradually reduced from the surface of the microsphere to the center of the microsphere, and the first nuclide and the second nuclide can be activated by neutrons to have radioactivity and generate beta-rays, gamma-rays or a combination of beta-rays and gamma-rays. The invention also provides a method for preparing the microspheres. The first nuclide and the second nuclide are introduced into the microsphere, so that the microsphere has the functions of radiotherapy, radiography and tracking, and the plurality of holes can increase the surface area of the microsphere so as to increase the adhesive force between the microsphere and the shell layer.

Description

Technical Field

[0001] The present invention relates to a microsphere for treatment and a method for preparing the same, and more particularly to a microsphere for internal radiotherapy and a method for preparing the same. Background Art

[0002] Internal radiotherapy is a form of radiotherapy. Different from traditional external radiotherapy (which irradiates tumors in the body by penetrating the body with high-energy rays from outside), internal radiotherapy places the radiation source accurately inside the part to be treated. For example, to treat a tumor, the radiation source can be placed inside or around the tumor. The biggest feature of internal radiotherapy is that the radiation source is very close to the target, so high-dose treatment can be achieved; moreover, the irradiation only affects a very limited area around, so the irradiation dose received by normal tissues far from the radiation source can be significantly reduced. On the other hand, internal radiotherapy does not require large external irradiation instruments, and patients can reduce the number of hospital visits, thus enhancing medical convenience.

[0003] However, for internal radiotherapy, since the radiation source needs to be placed inside the body, the position control of the radiation source in the body is crucial. The previously reported yttrium-90 glass microspheres, although having good stability, are difficult to track their positions after being administered into the body, leading to some concerns. Summary of the Invention

[0004] The present invention provides a microsphere having a plurality of pores with a gradient feature that gradually decreases in the direction from the surface to the center of the microsphere. The microsphere includes:

[0005] A first radionuclide distributed inside the microsphere with a concentration at the center of the microsphere greater than that at the surface of the microsphere; and

[0006] A second radionuclide that gradually decreases in the direction from the surface to the center of the microsphere,

[0007] wherein the first radionuclide and the second radionuclide can be neutron-activated to have radioactivity and generate β-rays, γ-rays, or a combination thereof.

[0008] The present invention also provides a method for preparing a microsphere, which includes:

[0009] Providing a first raw material of a first radionuclide and a second raw material of a second radionuclide, wherein both the first raw material and the second raw material are powders;

[0010] Mixing the first raw material and the second raw material to form a mixed powder;

[0011] Heating the mixed powder to obtain an intermediate;

[0012] Melting and spheroidizing the intermediate to form molten droplets;

[0013] Contacting molten droplets with a cooling source to obtain microspheres, wherein a first nuclide is distributed within the microspheres and its concentration at the center of the microspheres is greater than that at the surface of the microspheres, and the distribution of a second nuclide decreases gradually in the direction from the surface to the center of the microspheres; and

[0014] Contacting the microspheres with a treatment solution to form a plurality of pores, wherein the plurality of pores have a gradient feature that decreases gradually in the direction from the surface to the center of the microspheres,

[0015] wherein the first nuclide and the second nuclide can be activated by neutrons to have radioactivity and generate β-rays, γ-rays or a combination thereof.

[0016] The present invention further provides a method for preparing microspheres, which includes:

[0017] Providing a first raw material of a first nuclide, wherein the first raw material is in powder form;

[0018] Heating the first raw material to obtain an intermediate;

[0019] Melting and spheroidizing the intermediate to form molten droplets;

[0020] Contacting the molten droplets with a cooling source to obtain microspheres, wherein the cooling source is a second raw material of a second nuclide, and the second raw material is in liquid form, so that the second nuclide enters from the surface of the molten droplets or the microspheres and diffuses into the interior thereof or precipitates on the surface, thereby enabling the first nuclide to be distributed within the microspheres and its concentration at the center of the microspheres to be greater than that at the surface of the microspheres, and the distribution of the second nuclide decreases gradually in the direction from the surface to the center of the microspheres; and

[0021] Contacting the microspheres with a treatment solution to form a plurality of pores, wherein the plurality of pores have a gradient feature that decreases gradually in the direction from the surface to the center of the microspheres,

[0022] wherein the first nuclide and the second nuclide can be activated by neutrons to have radioactivity and generate β-rays, γ-rays or a combination thereof.

[0023] According to the present invention, by introducing the first and second nuclides into the microspheres, they can have the functions of radiotherapy, imaging and tracking; and, since the microspheres have a plurality of pores, the surface area of the microspheres is increased and the surface topography is complicated, so that a shell layer can be easily further added on the surface of the microspheres, and the adhesion between the shell layer and the microspheres is excellent, thereby various changes can be made to the shell layer, for example, making the shell layer hydrophilic, hydrophobic, carrying ligands that can target specific molecules, carrying drugs or other reagents, etc., greatly improving the usability. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figures 1A to 1C It is a schematic structural diagram of the microspheres of the present invention.

[0025] Figure 2Schematic diagram of the distribution of the second radionuclide in the microspheres of the present invention.

[0026] Figure 3 SEM photograph of the glass microspheres of Example 1.

[0027] Figure 4 SEM photographs of the glass microspheres of Examples 3 to 5.

[0028] Figure 5 SEM photograph of the glass microspheres of Example 7.

[0029] Figure 6 SEM photograph of the cross-section of the glass microspheres of Example 7.

[0030] Figure 7 SEM photograph of the glass microspheres of Example 8.

[0031] Figure 8 Positron emission tomography (PET) / computed tomography (CT) photograph of the glass microspheres of Example 9 placed in an Eppendorf tube.

[0032] Figure 9 PET / CT photograph of the glass microspheres of Example 9 placed in an agar phantom.

[0033] Figure 10 Time-residual activity A of the glass microspheres of Example 9 in an Eppendorf tube and an agar phantom t Relationship diagram.

[0034] Figure 11 Weight-residual activity A of the glass microspheres of Example 9 in an Eppendorf tube and an agar phantom t Relationship diagram.

[0035] Figure 12 Time-ln(A t / A0) relationship diagram of the glass microspheres of Example 9 in an Eppendorf tube and an agar phantom.

[0036] Figure 13 Time-A t / A0 relationship diagram of the glass microspheres of Example 10.

[0037] Figure 14 Positive-phase fluorescence microscope photograph of the glass microspheres of Example 11.

[0038] Figure 15 Diameter distribution of the glass microspheres of Example 11.

[0039] Figure 16 Time-radiochemical purity diagram of the glass microspheres of Example 12.

[0040] Figure 17 PET / CT images of the rats in Example 13, showing the distribution and remaining activity A of the glass microspheres in the rats t .

[0041] Figure 18 Time-remaining activity A of the glass microspheres in the rats in Example 13 t relationship diagram and time-ln(A t / A0) relationship diagram.

[0042] Among them, the reference numerals are as follows:

[0043] 10: microspheres 20, 21, 22: holes

[0044] 100: center 110: hole gradient characteristic region

[0045] I: direction from the surface to the center H: high activity

[0046] M: medium activity L: low activity Detailed implementation manners

[0047] The following specific implementation manners illustrate the implementation manners of the present invention. After reading the disclosure content of this specification, those of ordinary skill in the art can easily understand its advantages and effects.

[0048] It should be noted that the structures, ratios, dimensions, etc. shown in the drawings of this specification are only for matching the content described in the specification, so that those of ordinary skill in the art can understand and read, rather than intending to make these contents the limiting conditions of the present invention. Therefore, they do not have technical substantial significance. Moreover, any modification of the structure, change of the proportional relationship, adjustment of the dimension, change or adjustment of the relative relationship, without affecting the effects that can be produced by this specification and the purposes that can be achieved, should be included in the scope disclosed in this specification.

[0049] The terms "first", "second", "upper", and "lower" used in this specification are only for the convenience of narration and clarity. The change or adjustment of their relative relationships, without substantial change in the technical content, should also be regarded as the scope in which the present invention can be implemented. In addition, all ranges and values in this article are inclusive and combinable. The present invention describes many ranges, and any numerical value or point falling within the ranges described in this article is also covered by the present invention, and any numerical value or point falling within the ranges described in this article can be used as the minimum value or the maximum value to derive sub-ranges, etc.

[0050] First, a first aspect of the present invention is a kind of microsphere, which has a plurality of holes, and the plurality of holes have a gradient characteristic that gradually decreases along the direction from the surface of the microsphere to the center. Among them, the microsphere includes:

[0051] A first radionuclide, which is distributed within the microsphere and has a higher concentration at the center of the microsphere than at the surface of the microsphere; and

[0052] A second radionuclide, which decreases gradually from the surface to the center of the microsphere,

[0053] wherein the first radionuclide and the second radionuclide can be activated by neutrons to become radioactive and generate β-rays, γ-rays or a combination thereof.

[0054] In a specific embodiment, the gradient feature includes the pore diameter, the pore distribution or a combination thereof. Specifically, the definition of gradually decreasing from the surface to the center of the microsphere can mean that the pore diameter or the pore distribution has a tendency to become smaller / less from the surface to the center of the microsphere. For example, if three regions are randomly selected from the surface to the center, and the pore diameter or the pore distribution in these three regions meets the above conditions, it means that the microsphere has a gradient feature of gradually decreasing from the surface to the center of the microsphere. For example, the pore diameter on the surface of the microsphere is larger than the pore diameter between the surface and the center of the microsphere, and the pore diameter between the surface and the center of the microsphere is larger than the pore diameter at the center of the microsphere.

[0055] In a specific embodiment, for the multiple pores of the microsphere of the present invention, their distribution can gradually decrease from the surface to the center of the microsphere. The embodiment can refer to this case Figure 1A , the microsphere 10 has multiple pores 20. The pore distribution on the surface of the microsphere is relatively large, while the closer to the center 100 of the microsphere, the less the pore distribution, that is, the pore distribution gradually decreases along the direction I from the surface to the center 100 of the microsphere. In another specific embodiment, for the microsphere of the present invention, not the entire microsphere has a pore distribution. Referring again to Figure 1A , there are no pores in the area close to the center 100. Therefore, it can be considered that the microsphere 10 has a pore gradient feature area 110, and the pores 20 are only distributed within the pore gradient feature area 110. The definition of the pore distribution can also be the proportion of the total area of all pores in the total surface area of the microsphere at different depths. The higher the proportion, the greater the pore distribution.

[0056] In another specific embodiment, for the multiple pores of the microsphere of the present invention, their pore diameters can gradually decrease from the surface to the center of the microsphere. The embodiment can refer to this case Figure 1B , the microsphere 10 has multiple pores 20, 21, 22. The diameter of the pore 20 is larger and it is located at or closer to the surface of the microsphere. The diameter of the pore 22 is smaller and it is closer to the center 100 of the microsphere. The diameter and distribution of the pore 21 are both between those of the pore 20 and the pore 22, which shows that the pore diameters gradually decrease along the direction I from the surface to the center 100 of the microsphere. In another specific embodiment, similarly, for the microsphere of the present invention, not the entire microsphere has a pore distribution. Referring again to Figure 1B, there are no holes in the area near the center 100. Therefore, the microsphere 10 can be regarded as having a hole gradient characteristic region 110, and the holes 20 are only distributed within the hole gradient characteristic region 110.

[0057] In another specific embodiment, for the multiple holes of the microsphere of the present invention, the hole diameter and hole distribution can gradually decrease along the direction from the microsphere surface to the center. The embodiments can refer to this case Figure 1C , which is Figure 1A and Figure 1B a combination of two specific embodiments. Therefore, the same content will not be repeated here.

[0058] In addition, for the second nuclide to gradually decrease along the direction from the microsphere surface to the center, reference can be made to Figure 2 , the colored part of the microsphere 10 represents the distribution of the second nuclide, which gradually decreases along the direction I from the microsphere surface to the center 100.

[0059] In a specific embodiment, the holes do not penetrate the microsphere.

[0060] In a specific embodiment, the multiple holes include large holes and small holes. The diameter of the large holes is 10 to 30 micrometers (μm), or 10 to 25 μm, 10 to 20 μm, 15 to 30 μm, 20 to 30 μm, such as 10, 15, 20, 25, 30 μm; and the diameter of the small holes is 0.1 to 10 μm, or 0.1 to 5 μm, 0.5 to 10 μm, 0.5 to 5 μm, such as 0.1, 0.5, 1, 5, 10 μm. The embodiments can refer to Figure 1C , the diameter of the hole 20 is larger and serves as a large hole, and the diameter of the hole 22 is smaller and serves as a small hole. In another specific embodiment, the multiple holes include large holes, medium holes and small holes. The diameter of the large holes is 20 to 30 μm, or 15 to 25 μm, 20 to 25 μm, such as 15, 20, 25, 30 μm; the diameter of the medium holes is 5 to 20 μm, or 5 to 15 μm, 5 to 10 μm, 10 to 20 μm, such as 5, 10, 15, 20 μm; and the diameter of the small holes is 0.1 to 5 μm, or 0.5 to 5 μm, 0.1 to 1 μm, 0.1 to 10 μm, such as 0.1, 0.5, 1, 5, 10 μm. The embodiments can refer to Figure 1C , the diameter of the hole 20 is larger and serves as a large hole, the diameter of the hole 22 is smaller and serves as a small hole, and the diameter of the hole 21 is between that of the hole 20 and the hole 22 and thus can serve as a medium hole. In a specific embodiment, some of the holes are connected to each other and some are not, for example: the large holes are not connected to each other but the large holes are connected to some small holes.

[0061] In a specific embodiment, the microsphere is a glass microsphere.

[0062] The first nuclide and the second nuclide are not limited in the present invention, as long as they can be neutron-activated to have radioactivity and generate β-rays, γ-rays or a combination thereof.

[0063] In a specific embodiment, the first nuclide can provide a β (beta) radioactive isotope, which can be derived from a first raw material, and the first nuclide includes, for example, those selected from yttrium, aluminum, silicon or a combination thereof. In a specific embodiment, the first nuclide contains yttrium, and may also contain others, such as but not limited to aluminum, silicon or a combination thereof. In a specific embodiment, the first raw material forming the first nuclide can be in the form of a powder, such as but not limited to oxides, such as but not limited to yttrium oxide, aluminum oxide, silicon oxide.

[0064] In a specific embodiment, the second radionuclide may provide a gamma (γ) radioactive isotope, which may be derived from a second raw material, and the second radionuclide may include at least one selected from the group consisting of potassium, barium, molybdenum, tellurium, indium, hassium, gallium, zinc, zirconium, palladium, rhodium, tantalum, tungsten, iridium, platinum, niobium, technetium, strontium, titanium, vanadium, zinc, 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. In a specific embodiment, the second raw material for forming the second radionuclide may be in the form of a powder, such as, but not limited to, oxides and hydrated oxides and hydroxides containing crystal water, 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 the form of a liquid, such as, but not limited to, copper sulfate containing crystal water, aqueous copper sulfate solution, aqueous ferric chloride solution, aqueous calcium chloride solution, aqueous calcium hydroxide solution, calcium carbonate containing crystal water, aqueous aluminum sulfate solution, aqueous yttrium acetate solution, aqueous phosphoric acid solution, etc.

[0065] When the radionuclide used in the present invention generates β-rays through neutron activation, it can be used for radiotherapy; when it generates γ-rays through neutron activation, the position signal of the radionuclide can be captured by a device capable of detecting γ-rays; and when it generates both β-rays and γ-rays through neutron activation, it is suitable for both of the above applications. Therefore, after the microspheres of the present invention are administered to a subject, not only can the β-rays generated by the microspheres be used for radiotherapy of target tissues, but also the γ-rays generated can be captured by imaging devices (such as γ-ray cameras, positron emission tomography scanners, etc.) to observe the distribution and metabolism of the microspheres in the body. The integrated use of these imaging devices and a computer can display images and obtain more information through calculation and analysis.

[0066] On the other hand, the radionuclide contained in the microspheres of the present invention is located within the framework and does not have the problem of easy leakage and damage to non-target tissues like other carriers that load radionuclides or drugs in pores.

[0067] In a specific embodiment, the microsphere further includes a shell layer that coats the surface of the microsphere and fills a plurality of pores.

[0068] Due to the presence of a plurality of pores, the surface area of the microspheres of the present invention is increased and the surface topography is complicated. Therefore, a shell layer can be easily added to the surface of the microspheres, and the adhesion between the shell layer and the microspheres is excellent, enabling various modifications to the shell layer. For example, the shell layer can be hydrophilic, hydrophobic, carry ligands that can target specific molecules, carry drugs or other reagents, etc., greatly enhancing usability.

[0069] In a specific embodiment, the shell layer includes a material selected from organic materials, inorganic materials, or a combination thereof. In another specific embodiment, the organic materials are selected from polyvinylpyrrolidone, polyvinyl alcohol, carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyethylene glycol, gum arabic, polylactic acid, poly(lactic-co-glycolic acid), or a combination thereof. In another specific embodiment, the inorganic materials are selected from phosphates, sulfates, chlorides, nitrates, tellurides, tellurates, iodides, iodates, xenates, tungstates, rhenates, platinates, chloroaurates, mercurates, leadates, bismuthates, astatates, uranates, polonides, osmates, antimonates, stannates, stannides, technetates, 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.

[0070] In a 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, such as 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.

[0071] In a specific embodiment, the etching resistance of the first radionuclide is greater than that of the second radionuclide.

[0072] The second aspect of the present invention is a method for preparing microspheres, which includes:

[0073] Providing a first raw material of a first radionuclide and a second raw material of a second radionuclide, wherein both the first raw material and the second raw material are powders;

[0074] Mixing the first raw material and the second raw material to form a mixed powder;

[0075] Heating the mixed powder to obtain an intermediate;

[0076] Melting and spheroidizing the intermediate to form molten droplets;

[0077] Bringing the molten droplets into contact with a cooling source to obtain microspheres, wherein the first radionuclide is distributed within the microspheres and its concentration at the center of the microspheres is greater than that at the surface of the microspheres, and the distribution of the second radionuclide gradually decreases in the direction from the surface to the center of the microspheres; and

[0078] Bringing the microspheres into contact with a treatment solution to form a plurality of holes, wherein the plurality of holes have a gradient characteristic that gradually decreases in the direction from the surface to the center of the microspheres,

[0079] Wherein, the first radionuclide and the second radionuclide can be activated by neutrons to become radioactive and generate β-rays, γ-rays, or a combination thereof.

[0080] The third aspect of the present invention provides a method for preparing microspheres, which includes:

[0081] Providing a first raw material of a first radionuclide, wherein the first raw material is a powder;

[0082] Heating the first raw material to obtain an intermediate;

[0083] Melting and spheroidizing the intermediate to form molten droplets;

[0084] Obtaining microspheres by bringing molten droplets into contact with a cooling source, where the cooling source is the second raw material of the second nuclide and the second raw material is a liquid, so that the second nuclide enters from the surface of the molten droplets or microspheres and diffuses into their interior or precipitates on the surface, thereby enabling the first nuclide to be distributed within the microspheres with a concentration at the center of the microspheres greater than that at the surface of the microspheres, and the distribution of the second nuclide decreasing gradually in the direction from the surface to the center of the microspheres; and

[0085] Bringing the microspheres into contact with a treatment solution to form a plurality of pores, where the plurality of pores have a gradient characteristic of decreasing gradually in the direction from the surface to the center of the microspheres,

[0086] wherein the first nuclide and the second nuclide can be neutron-activated to have radioactivity and generate β-rays, γ-rays or a combination thereof.

[0087] In a specific embodiment, the first raw material and the second raw material can be glass raw material powders. In a 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, together with other glass raw material powders, serve as a glass raw material powder mixture (i.e., batch), and the glass raw material powder mixture forms glass after being uniformly mixed, melted, and rapidly quenched. The formed glass can also be pulverized to obtain glass powder. For example, the glass raw material powder mixture is placed in a crucible (such as a platinum crucible), and the crucible is placed in an electric furnace to melt the glass raw material powder mixture (the melting time depends on the composition of the powder mixture and usually takes 2 to 8 hours for complete melting), during which stirring and mixing are optionally carried out to improve chemical uniformity; then the crucible is taken out, and the melt is brought into contact with a cooling source, such as being poured onto a cold steel plate or into cold water, at which time the melt is rapidly quenched to form glass. It may break during the process of forming glass, which helps to simplify the subsequent step of pulverizing the glass. Finally, the glass is pulverized (such as crushed, mechanically ground, or ground in a ball mill) to obtain glass powder.

[0088] In a specific embodiment, the steps of heating the first raw material in powder form (or the mixed powder of the first and second raw materials) to obtain an intermediate, melting and spheroidizing the intermediate, and bringing the molten droplets into contact with a cooling source can be carried out, for example, by flame spraying. For example, the powder is filled into a feeder, and the powder is forcedly pneumatically conveyed into a pipeline, which guides the powder into a gas flame. At this time, the powder is melted into a molten liquid state by the gas flame and is simultaneously ejected by the gas flame and flies. During this period, the molten droplets form spheres 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 into glass.

[0089] When the above-mentioned comes into contact with the cooling source, the rotating spherical molten droplets will entrain a part of the cooling source; on the other hand, the components in the cooling source will also diffuse and penetrate from its surface during the quenching of the spherical molten droplets into glass. Therefore, when the cooling source is the second raw material of the second nuclide, that is, when the second raw material is a liquid, the second nuclide will be introduced into the microspheres due to the above-mentioned phenomenon, and its distribution gradually decreases from the surface to the center of the microspheres, as Figure 2 shown.

[0090] In the step of bringing the microspheres into contact with the treatment solution to form a plurality of holes, in a specific embodiment, the treatment solution is used for etching treatment, and generally, the etching treatment starts from the surface of the microspheres. In particular, in the present invention, the microspheres exhibit excellent corrosion resistance to the treatment solution, and the treatment solution only intensively corrodes the positions where the second nuclide is located. Therefore, when the distribution of the second nuclide gradually decreases from the surface to the center of the microspheres as described above, the degree of corrosion also gradually weakens from the surface to the center of the microspheres, resulting in a gradient characteristic that the plurality of holes gradually decreases in the direction from the surface to the center of the microspheres. In another specific embodiment, such a gradient characteristic includes the hole diameter, the hole distribution, or a combination thereof, as Figures 1A to 1C shown.

[0091] In a specific embodiment, the treatment solution includes an etchant. In another specific embodiment, the etchant is a combination of any one of an acid and a base and an oxidant. The acid is selected from 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), chloroplumbic acid (H2PbCl6), ferrate acid (H2FeO4), fluoboric 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-chloroethyl mercaptan (CH3CHClSH), fluoroantimonic acid (HSbF6), fluoroantimonosulfonic acid (SbF6SO3H), perfluorosulfonic acid resin (Nafion-H), chloroaluminum fluoride acid (HAlCl3F), carborane acid (H[CHB 11 Cl 11) and at least one of the group consisting of solid superacids (FeCl3·HClO4·SiO2·nH2O); the base is selected from at least one of 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, thallous hydroxide, silver diamine hydroxide, choline, quaternary ammonium base, butyllithium, lithium diisopropylamide, benzyllithium, Grignard reagent, organocopper lithium, sodium methoxide, sodium ethoxide, potassium ethoxide, and sodium tert-butoxide; the oxidant is selected from at least one of the group consisting of amphoteric compounds, hydrogen peroxide, permanganate, hypochlorite, chromate, and chromium trioxide of dichromate.

[0092] In yet another specific embodiment, the treatment solution includes nitric acid and hydrogen peroxide, or the treatment solution includes sodium hydroxide and hydrogen peroxide. In yet 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%).

[0093] In a specific embodiment, the step of contacting the microspheres with the treatment solution to form a plurality of pores is optionally heated, for example, the etching treatment is carried out in the temperature range of 25°C to 100°C, for example, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 95, 100°C. In a specific embodiment, the step of contacting the microspheres with the treatment solution to form a plurality of pores lasts for 10 minutes (min) to 3 hours (hr), for example, 10 min, 20 min, 30 min, 1 hr, 1.5 hr, 2 hr, 3 hr.

[0094] In a specific embodiment, the pores do not penetrate the microspheres as described in the first aspect.

[0095] In a specific embodiment, the plurality of pores includes macropores and micropores as described in the first aspect. The diameter of the macropores is 10 to 30 μm, or 10 to 20 μm, 10 to 25 μm, 15 to 30 μm, 20 to 30 μm, for example, 10, 15, 20, 25, 30 μm; and the diameter of the micropores is 0.1 to 10 μm, or 0.1 to 5 μm, 0.5 to 10 μm, 0.5 to 5 μm, for example, 0.1, 0.5, 1, 5, 10 μm.

[0096] In a specific embodiment, it further includes a shell layer that coats the surface of the microspheres.

[0097] In a specific embodiment, the shell layer comprises a material selected from organic materials, inorganic materials, or a combination thereof. In yet another specific embodiment, the organic materials are selected from polyvinylpyrrolidone, polyvinyl alcohol, carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyethylene glycol, gum arabic, polylactic acid, poly(lactic-co-glycolic acid), or a combination thereof. In yet another specific embodiment, the inorganic materials are selected from phosphates, sulfates, chlorides, nitrates, or borates.

[0098] The present invention is further illustrated in more detail by way of the following examples. However, the interpretation of the present invention should not be limited to the description of the following examples.

[0099] Example 1

[0100] Take 35 g of Y2O3 powder, 35 g of Al2O3 powder, 20 g of SiO2 powder, and 10 g of CuO powder. After mixing these powders evenly, load them into a crucible and place the crucible in an electric furnace heated to 1600 °C to melt the powder mixture. Since the direct addition of copper will help reduce the melting temperature of the overall glass mass by about 100 °C. During this period, stir thoroughly after melting starts to improve chemical homogeneity. After melting and stirring are completed, take out the crucible, pour the melt onto a cold steel plate and quickly quench it into glass, while breaking it into glass fragments. Then, use a mortar and pestle to crush the glass fragments to a particle size of about 100 mesh, and then grind them using a mechanical mortar and pestle or a ball mill until they pass through a 400-mesh (37 μm in diameter) sieve to obtain glass powder.

[0101] Next, put the glass powder into a forced air-feed feeder located above an acetylene / oxygen burner. The glass powder passes through a forced air-feed pipe, which guides the glass powder into the flame of the acetylene / oxygen burner. The feeding rate into the flame is set within the range of 5 to 25 g / hr. The glass powder melts due to the high temperature of the flame and forms spherical molten droplets during rotation and flight, and the spherical molten droplets are made to contact deionized water as a cooling source to obtain glass microspheres of the first aspect. Select microspheres with diameters falling within the range of 5 to 30 μm. The size and appearance of the microspheres after the above selection are analyzed by scanning electron microscopy (SEM), as Figure 3 shown, for subsequent experiments. In addition, randomly select three from the selected microspheres as samples for energy-dispersive X-ray spectroscopy (EDS) analysis. The results are shown in Table 1, which shows the atomic percentages of each sample.

[0102] Table 1

[0103] C O Al Si Cu Y Total Sample 1 41.26 8.74 16.92 3.52 29.56 100.00 Sample 2 7.29 42.46 8.06 14.48 3.81 23.90 100.00 Sample 3 9.06 40.73 8.08 14.26 3.62 24.25 100.00

[0104] Example 2

[0105] Take 35 g of Y2O3 powder, 35 g of Al2O3 powder, and 20 g of SiO2 powder. After mixing these powders evenly, load them into a crucible and place the crucible in an electric furnace heated to 1700 °C to melt the powder mixture. During this process, stir thoroughly after melting starts to improve chemical uniformity. After melting and stirring are completed, take out the crucible, pour the melt onto a cold steel plate to rapidly quench it into glass, and at the same time break it into glass fragments. Then, use a mortar and pestle to crush the glass fragments to a particle size of about 100 mesh, and then grind them using a mechanical mortar and pestle or a ball mill until they pass through a 400-mesh (37 μm in diameter) sieve to obtain glass powder.

[0106] Next, put the glass powder into a forced air-feed feeder located above an acetylene / oxygen burner. The glass powder passes through a forced air-feed pipe, which guides the glass powder into the flame of the acetylene / oxygen burner. The feeding rate into the flame is set within the range of 5 to 25 g / hr. The glass powder melts due to the high temperature of the flame and forms spherical molten droplets during rotation and flight. Then, make the spherical molten droplets contact a CuSO4·5H2O solution (in a supersaturated state with a concentration of 10 M) as a cooling source to obtain glass microspheres in the second aspect. Screen out the glass microspheres with diameters falling within the range of 5 to 30 μm for subsequent experiments.

[0107] Example 3

[0108] Using the same preparation method as described in Example 2, the difference is that the powder mixture is changed to 35 g of Y2O3 powder, 35 g of Al2O3 powder, 20 g of SiO2 powder, and 10 g of CuO powder to obtain glass microspheres in the third aspect.

[0109] Example 4

[0110] Using the same preparation method as described in Example 2, the difference is that the concentration of the CuSO4·5H2O solution is changed to 1 M (unsaturated).

[0111] Example 5

[0112] Using the same preparation method as described in Example 2, the difference is that the concentration of the CuSO4·5H2O solution is changed to 3 M (supersaturated).

[0113] Observed Examples 3 to 5 with a scanning electron microscope (SEM), and the results are as Figure 4 shown, where (A) to (C) respectively represent Examples 4, 5, and 2. According to Figure 4 , when the glass microspheres contact an unsaturated CuSO4·5H2O solution, no substance is observed to precipitate on the surface of the glass microspheres; while when the glass microspheres contact a saturated or supersaturated CuSO4·5H2O solution, a substance is observed to precipitate on the surface of the glass microspheres.

[0114] Example 6

[0115] For the glass microspheres of Example 2, five microspheres were randomly selected as samples for EDS analysis. The results are shown in Table 2, which shows the atomic percentages of each sample. According to Table 2, it was confirmed that the substance precipitated on the surface of the glass microspheres contained copper.

[0116] Table 2

[0117] O Al Si Cu Y Total Sample 1 47.84 14.87 14.26 10.63 12.40 100.00 Sample 2 48.67 14.69 14.16 10.05 12.43 100.00 Sample 3 49.69 14.02 13.24 10.93 12.12 100.00 Sample 4 46.24 15.77 15.07 9.22 13.70 100.00 Sample 5 51.21 28.25 13.41 2.54 4.59 100.00 Average 48.73 17.52 14.03 8.67 11.05 Standard Deviation 1.87 6.03 0.74 3.49 3.66

[0118] In addition, the glass microspheres of Example 2 were contacted with a treatment solution containing 1 N nitric acid and 25 wt% hydrogen peroxide, and after etching treatment at 75 °C for 1 hour, five microspheres were randomly selected as samples for EDS analysis. The results are shown in Table 3, which shows the atomic percentages of each sample. According to Table 3, copper precipitated was still observed on the surface of the glass microspheres, but the concentration of copper decreased from an average value of 8.67 to 6.80, indicating that part of the copper had been etched away.

[0119] Table 3

[0120] O Al Si Cu Y Total Sample 1 44.14 9.26 16.21 5.92 24.47 100.00 Sample 2 43.80 8.91 14.30 6.48 26.51 100.00 Sample 3 41.03 8.78 14.36 6.87 28.96 100.00 Sample 4 40.87 8.91 14.84 6.62 28.76 100.00 Sample 5 41.78 8.41 14.00 8.10 27.71 100.00 Average 42.32 8.85 14.74 6.80 27.28 Standard Deviation 1.55 0.31 0.87 0.81 1.85

[0121] Example 7

[0122] The glass microspheres of Example 2 were contacted with a treatment solution containing 1 N nitric acid and 25 wt% hydrogen peroxide, and etched at 75 °C for 24 hours. The SEM photo results are as shown in (A), (B), (C), and (D) of Figure 5 Multiple holes were etched on the glass microspheres. And, for the etched glass microspheres of this example, two microspheres were randomly selected as samples for EDS analysis. The results are shown in Table 4 and Table 5 respectively, which show the atomic percentages and weight percentages of each sample.

[0123] Table 4

[0124]

[0125]

[0126] Table 5

[0127] Sample 2 O Al Si Cu Y Total wt% 46.04 8.35 15.99 2.48 27.14 100.00 at% 70.18 7.55 13.88 0.95 7.44 100.00 Standard <![CDATA[SiO2]]> <![CDATA[Al2O3]]> <![CDATA[SiO2]]> Cu Y

[0128] Next, 100 mg of the etched glass microspheres were taken. Additionally, a double-sided carbon tape was laid flat on a conductive substrate. After the double-sided carbon tape was dried, the glass microspheres were flattened on the double-sided carbon tape and blown with an air gun. The glass microspheres that could be fully adhered to the carbon tape would adhere to the substrate, and the etched glass microspheres of this example still adhered to the substrate fully after being blown with an air gun.

[0129] To observe the cross-section of the etched glass microspheres in Example 7, the etched glass microspheres were further processed by embedding, grinding, polishing, cleaning, and coating with a conductive layer. The SEM photographs of the cross-section of the glass microspheres are as shown in Figure 6 (A) to (F) of

[0130] 1. Cold embedding

[0131] After washing 100 mg of glass microspheres (reference can be made to Step 4), they were placed in a mold, and then a mixture of resin and hardener was poured in. After hardening at room temperature and normal pressure, the embedded specimen was taken out. The embedded specimen was cut into a suitable size.

[0132] 2. Grinding

[0133] The embedded specimen was ground using SiC sandpaper, and rough grinding and fine grinding were carried out according to the following grit numbers: 240 → 400 → 600 → 800 → 1200 → 2400 → 4000.

[0134] 3. Polishing

[0135] The surface of the specimen was polished to a mirror finish (without scratches when observed with an optical microscope). The polishing liquid used was diamond suspension, and the diamond abrasive grains in it could quickly remove materials and flatten the surface of the specimen.

[0136] 4. Cleaning

[0137] The specimen was successively immersed in alcohol and deionized water and ultrasonically vibrated to remove the substances remaining on the specimen during the grinding and polishing stages and avoid interfering with the analysis results.

[0138] 5. Coating with a conductive layer

[0139] The non-conductive glass microsphere material and the resin embedding it need to be coated with a conductive layer to prevent the concentration of charge electron beams. The conductive layer is, for example, a continuous film of Au.

[0140] Example 8

[0141] Take the glass microspheres with multiple holes obtained by etching for 24 hours in Example 7. Then, the glass microspheres with multiple holes were spray granulated and coated with the materials listed in Table 6 below. After uniformly wetting and mixing a 0.1 to 10 wt% material solution and the glass microspheres in a ratio of 1:1, coating was carried out using a spray dryer, where the flow rate was set at 357 L / h and the outlet temperature was between 180 and 245 °C. A shell layer could be formed on the surface of the glass microspheres in all groups. As shown in Figure 7 The SEM photographs of the glass microspheres coated with PVP (A) or the glass microspheres coated with CMC (B) show that an obvious shell layer is formed on the surface of the glass microspheres.

[0142] Table 6

[0143] Shell Material Can a shell be formed? Polyvinylpyrrolidone PVP Yes Polyvinyl alcohol PVA Yes Carboxymethyl cellulose CMC Yes Polyethylene glycol PEG6000 Yes Methyl cellulose MC Yes Hydroxypropyl methyl cellulose HPMC Yes Hydroxypropyl cellulose HPC Yes Gum arabic Yes Polylactic-co-glycolic acid PLA / PGA Yes <![CDATA[Ca3(PO4)2]]> Yes

[0144] Example 9

[0145] To verify whether positron emission tomography (PET) / computed tomography (CT) can effectively detect the positron signals generated by the decay of yttrium-90 and copper-64 in glass microspheres, the glass microspheres of Example 3 were taken and contacted with a treatment solution containing 1N nitric acid and 25 wt% hydrogen peroxide, and subjected to a corrosion treatment at 75 °C for 1 hour to form glass microspheres with multiple pores. Two groups of 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, and 200 mg of glass microspheres were taken and placed in 0.5 mL Eppendorf tubes respectively, and after being irradiated with a neutron activation beam for 6 hours, they were decayed overnight. One group of samples was measured for radioactivity with a dose calibrator every 6 hours and subjected to positron emission tomography / computed tomography (PET / CT), and the other group of samples was placed in a cylindrical agar phantom and imaged in the same manner. Figure 8 is the PET / CT image of the sample placed in the Eppendorf tube, while Figure 9 is the PET / CT image of the sample placed in the agar phantom.

[0146] Figure 8 and Figure 9 The results show that whether placed in a test tube rack or an agar phantom, the CT and PET images of the glass microspheres can be observed to completely overlap at different time points, but only the positron signal of the PET image decays with time, and the positron signal intensity at each time point shows a correlation with the weight of the glass microsphere body.

[0147] Next, the regions of interest (ROIs) of Figure 8 and Figure 9 were circled with image analysis software, and the photon signal intensity in the ROI was calculated for quantitative analysis and to obtain the half-life. Figure 10 The (A) and (B) of t respectively plotted the time-residual activity A t relationship diagram (TAC), and the results show that the positron signal decays with time and shows a linear relationship, which is consistent with the decay function of the radioactive substance.

[0148] Calculation formula:

[0149] A t = A0 × e -λt (1)

[0150] where, A t is the residual activity of the radioactive substance after decaying for time t;

[0151] A0 is the activity of the radioactive substance at the starting time;

[0152] t is the elapsed time; and

[0153] λ is the decay constant.

[0154] Taking the natural logarithm on both sides of the equal sign in the above formula (1) can obtain a linear function:

[0155] ln A t = -λt + ln A0 (2)

[0156] lnA = 2.303×logA

[0157] 2.303log A t = -λt + 2.303log A0 (3)

[0158] In addition, as described above, yttrium-90 / copper-64 dual-isotope glass microspheres with different weights are respectively placed in a test tube rack and an agar phantom, and PET / CT imaging is performed at different time points, and the photon signal intensity of the ROI in the image is calculated. Figure 11 (A) and (B) respectively plot the weight-residual activity A t relationship diagram (TAC), where the linear correlation coefficient (R 2 ) of each curve is greater than 0.99, indicating that the positron signal intensity at each time point has a high linear correlation with the weight of the glass microspheres.

[0159] In this embodiment, the above radioactive substance decay function is further derived as follows. Divide both sides of the equal sign in the above formula (1) by A0 and then take the natural logarithm to obtain:

[0160]

[0161] And when t = t 1 / 2 , when (t 1 / 2 represents the radioactive nuclide half-life):

[0162]

[0163] According to the time-ln(A t / A0) relationship diagram of formula (4) as Figure 12 shown, where (A) and (B) respectively show the half-lives of the radioactive substances contained in the glass microspheres placed in the test tube rack and the agar phantom. The curves in the figure are linearly regressed with GraphPad Prism software to obtain the slopes of the curves, that is, the decay constant λ in formula (4), and then substituting this value into formula (5) can calculate the half-life of the radioactive substance, which is listed in Table 7 below.

[0164] Table 7

[0165]

[0166] Based on these results, for each group of glass microspheres, whether placed in a test tube rack or an agar phantom, the average half-life was 12.7 hours, the same as the known half-life of copper-64. Thus, it was confirmed that when performing yttrium-90 / copper-64 glass microsphere imaging with PET / CT, the positron decay signal of copper-64 could be detected. Without being bound by theory, the PET imaging instrument has coincidence circuitry and energy window selection, and only detects the paired 511 keV energy photons generated by the annihilation of positrons and electrons. Other photon signals from non-positron decays are filtered out. Additionally, although yttrium-90 also has a very small amount of positron decay, its proportion is very low, approximately 3.18×10 -5 , and the impact is very small.

[0167] Example 10

[0168] To further verify that in addition to the copper-64 radionuclide, there is also a yttrium-90 radionuclide in the yttrium-90 / copper-64 dual-radionuclide glass microspheres, in this example, the activity of the yttrium-90 / copper-64 dual-radionuclide glass microspheres was read with a dose calibrator, which can detect γ-rays and β-rays with higher 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 a time-A t / A0 relationship diagram, as Figure 13 shown. The curve was subjected to a two-phase decay curve regression analysis using GraphPad Prism software to obtain the half-lives of the two radioactive substances: 66.3 hours and 12.7 hours, which are close to or the same as the known half-life of yttrium-90 (64.1 hours) and copper-64 (12.7 hours), respectively. Therefore, it was confirmed that the glass microspheres after neutron activation mainly contained two radionuclides, yttrium-90 and copper-64.

[0169] Example 11

[0170] In this example, it was observed whether there were changes in the size and appearance of the glass microspheres before and after neutron activation. Appropriate volumes of the yttrium-90 / copper-64 dual-radionuclide glass microspheres before neutron activation and the yttrium-90 / copper-64 dual-radionuclide glass microspheres after neutron activation and with the activity decayed to the environmental background value (complete decay) were placed on a glass slide, and the sample images at 10-fold and 40-fold magnifications were taken using a normal-phase fluorescence microscope (Olympus BX61), as Figure 14 shown. The diameter of each microsphere on the image was calculated through image processing software, and then the data was imported into GraphPad Prism software for analysis and a microsphere diameter distribution diagram was plotted, as Figure 15 shown.

[0171] According toFigure 14 , the appearance of the glass microspheres before and after neutron activation both presented a smooth spherical shape, indicating that neutron activation did not significantly change the appearance morphology of the glass microspheres. Moreover, according to Figure 15 , the diameters of the glass microspheres before and after neutron activation were 31.6 ± 3.8 μm and 30.5 ± 0.5 μm respectively, indicating that there was no significant difference in the diameter distribution before and after neutron activation.

[0172] Example 12

[0173] In vitro stability analysis of yttrium-90 / copper-64 dual-isotope glass microspheres was carried out. Twenty-four test tubes were taken and fixed-activity glass microspheres and phosphate buffered saline (PBS) or fetal bovine serum (FBS) were added respectively, and then they were placed in an incubator at 4 °C and 37 °C respectively. And at each selected time point (1, 2, 4, 8, 24, and 48 hours), 3 tubes were taken for radiochemical purity determination. Take 200 μL of the sample, pass it through a 0.45 μm filter, then rinse the filter with 2 mL of physiological saline and collect the filtrate, measure the residual activities of the filtrate and the filter respectively, calculate its radiochemical purity according to the following formula, and draw a time-radiochemical purity relationship graph ( Figure 16 ):

[0174] Radiochemical purity (%) = [residual activity of the filter / (residual activity of the filter + activity of the filtrate)] × 100%.

[0175] According to Figure 16 , after standing for 48 hours in PBS / 4 °C and FBS / 37 °C, the radiochemical purity of yttrium-90 / copper-64 dual-isotope glass microspheres could still be maintained at >98%, which indicated that yttrium-90 / copper-64 dual-isotope glass microspheres had excellent stability. It can be inferred therefrom that the glass microspheres are not easily chelated by proteins in the blood after being administered into the body.

[0176] Example 13

[0177] In vivo stability analysis of yttrium-90 / copper-64 dual-isotope glass microspheres was carried out. Sprague-Dawley (SD) rats aged 8 to 10 weeks were anesthetized with isoflurane / oxygen (2%), and then fixed on the stage. Inject 300 μL of a liquid containing yttrium-90 / copper-64 glass microspheres through the tail vein, where the weight of the glass microspheres was about 500 μCi / 50 mg. PET / CT imaging was performed at each selected time point (1, 4, 24, and 48 hours), the left and right lung lobes were circled as the ROI, and quantitative analysis was carried out using image analysis software to calculate the photon signal intensity in the ROI.

[0178] Figure 17The PET / CT imaging results showed that almost all the glass microspheres were embolized in the pulmonary microvasculature 1 hour after intravenous injection, resulting in high activity in the lungs (both the left and right lung lobes) (simply marked as high-activity (H) regions in the lung area); in other parts of the body, there was almost no accumulation except for residual micro glass microspheres at the caudal vein injection site, with very low activity, approaching 0. At 4 hours after injection, the activity of the glass microspheres in the lungs and at the caudal vein injection site only slightly decreased and remained at a high-activity level. As time passed, at 24 hours after injection, the activity of the glass microspheres in the lungs and at the caudal vein injection site decreased, and for simplicity, the lung area was then considered a medium-activity (M) region at this time; at 48 hours after injection, the activity of the glass microspheres in the lungs and at the caudal vein injection site decreased more significantly, and at this time, the lung area was considered a low-activity (L) region, with activity almost the same as that in other parts of the body where no glass microspheres had accumulated.

[0179] Figure 18 (A) and (B) of which are the time-remaining activity A t curve graph and time-ln(A t / A0) curve graph for the ROI of the left and right lung lobes of the rat or the reference radiation source. 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 animal body were 12.48 hours and 53.23 hours respectively. Moreover, from the group with the reference radiation source as the ROI, the physical half-lives of yttrium-90 and copper-64 were 12.48 and 67.35 hours respectively, which were close to the known half-lives.

[0180] Moreover, the physiological half-life of the yttrium-90 / copper-64 dual-radionuclide glass microspheres calculated by the following formula (6) was also very long,

[0181]

[0182] where T E is the effective half-life, T R is the physical half-life, and T B is the physiological half-life.

[0183] Based on the in vitro and in vivo stability results of Examples 12 and 13, neither yttrium-90 nor copper-64, the radionuclides of the glass microspheres of the present invention, leaked during the test period and could continuously exist in the glass microspheres; after intravenous administration into the body, the glass microspheres were continuously embolized in the lungs, which could be regarded as having a permanent embolization effect and could thus be applied to specific in vivo radiotherapy.

Claims

1. A microsphere, characterized in that: There are a plurality of holes, and the plurality of holes have a gradient characteristic that decreases from the surface of the microsphere to the center, wherein the microsphere comprises: A first nuclide distributed within the microsphere and having a concentration at the center of the microsphere greater than a concentration at the surface of the microsphere; and The second nuclide decreases gradually from the surface to the center of the microsphere, The first nuclide and the second nuclide may be radioactive through neutron activation and generate β-rays, γ-rays or a combination thereof.

2. The microsphere according to claim 1, characterized in that The gradient characteristics include pore diameter, pore distribution or a combination thereof.

3. The microsphere according to claim 1, characterized in that The pores do not penetrate the microspheres.

4. The microsphere according to claim 1, characterized in that The plurality of holes include large holes and small holes, the large holes have a diameter of 10 to 30 micrometers, and the small holes have a diameter of 0.1 to 10 micrometers.

5. The microsphere according to claim 1, characterized in that The first nuclide is selected from yttrium, aluminum, silicon or a combination thereof.

6. The microsphere according to claim 1, characterized in that The second nuclide comprises at least one selected from the group consisting of potassium, barium, molybdenum, tellurium, indium, thulium, gallium, zinc, zirconium, palladium, rhodium, tantalum, tungsten, iridium, platinum, niobium, technetium, strontium, titanium, vanadium, zinc, 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, arsine-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.

7. The microsphere according to claim 1, characterized in that It also includes a shell layer, which covers the surface of the microsphere and fills the multiple holes, and the shell layer includes a material selected from organic materials, inorganic materials or a combination thereof.

8. The microsphere according to claim 7, characterized in that: The organic material is selected from polyvinyl pyrrolidone, polyvinyl alcohol, carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyethylene glycol, gum arabic, polylactic acid, polylactic acid-glycolic acid or a combination thereof.

9. The microsphere according to claim 7, characterized in that: The inorganic material is selected from phosphates, sulfates, chlorides, nitrates, tellurides, tellurates, iodides, iodates, xenates, tungstates, rhenates, platinates, chloroaurates, mercurates, plumbicates, bismuthates, aurinates, uranates, polonides, osmates, antimonates, stannates, tinides, technetium salts, 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 microsphere according to claim 1, characterized in that: The diameter of the microspheres is 2 to 1000 microns.

11. The microsphere according to claim 1, characterized in that: The first nuclear species has a greater etching resistance than the second nuclear species.

12. A method for preparing microspheres, characterized in that: include: Providing a first raw material of a first nuclide and a second raw material of a second nuclide, wherein the first raw material and the second raw material are both powders; mixing the first raw material and the second raw material to form a mixed powder; heating the mixed powder to obtain an intermediate; Melting and spheroidizing the intermediate to form molten droplets; The molten droplet is brought into contact with a cooling source to obtain a microsphere, wherein the first nuclide is distributed in the microsphere and its concentration at the center of the microsphere is greater than its concentration at the surface of the microsphere, and the distribution of the second nuclide decreases gradually from the surface to the center of the microsphere; and The microspheres are contacted with a treatment solution to form a plurality of pores, wherein the plurality of pores have a gradient characteristic that decreases from the surface of the microspheres to the center thereof, The first nuclide and the second nuclide may be radioactive through neutron activation and generate β-rays, γ-rays or a combination thereof.

13. The method according to claim 12, characterized in that The cooling source is a second raw material of a second nuclide, and the second raw material is a liquid, so that the second nuclide enters from the plurality of molten droplets or the surface of the microspheres and diffuses into the inside thereof or precipitates on the surface.

14. The method according to claim 12, characterized in that The processing solution includes an etchant.

15. The method according to claim 14, characterized in that The etchant is a combination of any one of an acid and a base and an oxidant, and the acid is selected from 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, bromic acid, perbromic acid, iodic acid, periodic acid, metaperiodic acid, selenic acid, fluorosilicic acid, chlorolead acid, ferric acid, fluoroboric acid, fluorosulfonic acid, cyanic acid, thiocyanic acid, 2,4,6-trinitrophenol, 2,4,6-trinitrobenzoic acid, trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid, benzenesulfonic acid, cyclohexanethiolsulfonic acid, 2-chloroethanethiol, fluoroantimonic acid, fluoroantimonysulfonic acid, perfluorosulfonic acid resin, chlorofluoroaluminic acid, carborane acid and FeCl3·HClO4·SiO2·nH2O; the base is selected from at least one of 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 hydroxide, diammine silver hydroxide, choline, quaternary ammonium base, butyl lithium, lithium diisopropylamide, benzyl lithium, Grignard reagent, alkyl copper lithium, sodium methoxide, sodium ethoxide, potassium ethoxide and sodium tert-butoxide; the oxidant is selected from at least one of the group consisting of amphoteric compounds, hydrogen peroxide, permanganate, hypochlorite, chromate, dichromate and chromium trioxide.

16. The method according to claim 12, wherein: The processing solution etches at the location of the second species.

17. A method for preparing microspheres, characterized in that: include: Providing a first raw material of a first nuclide, wherein the first raw material is a powder; heating the first raw material to obtain an intermediate; Melting and spheroidizing the intermediate to form molten droplets; The molten droplet is brought into contact with a cooling source to obtain a microsphere, wherein the cooling source is a second raw material of a second nuclide, and the second raw material is a liquid, so that the second nuclide enters from the molten droplet or the surface of the microsphere and diffuses into the interior thereof or precipitates on the surface, so that the first nuclide is distributed in the microsphere and its concentration at the center of the microsphere is greater than that at the surface of the microsphere, and the distribution of the second nuclide decreases gradually from the surface to the center of the microsphere; and The microspheres are contacted with a treatment solution to form a plurality of pores, wherein the plurality of pores have a gradient characteristic that decreases from the surface of the microspheres to the center thereof, The first nuclide and the second nuclide may be radioactive through neutron activation and generate β-rays, γ-rays or a combination thereof.

18. The method according to claim 17, characterized in that The processing solution includes an etchant.

19. The method according to claim 18, characterized in that The etchant is a combination of any one of an acid and a base and an oxidant, and the acid is selected from 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, bromic acid, perbromic acid, iodic acid, periodic acid, metaperiodic acid, selenic acid, fluorosilicic acid, chlorolead acid, ferric acid, fluoroboric acid, fluorosulfonic acid, cyanic acid, thiocyanic acid, 2,4,6-trinitrophenol, 2,4,6-trinitrobenzoic acid, trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid, benzenesulfonic acid, cyclohexanethiolsulfonic acid, 2-chloroethanethiol, fluoroantimonic acid, fluoroantimonysulfonic acid, perfluorosulfonic acid resin, chlorofluoroaluminic acid, carborane acid and FeCl3·HClO4·SiO2·nH2O; the base is selected from at least one of 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 hydroxide, diammine silver hydroxide, choline, quaternary ammonium base, butyl lithium, lithium diisopropylamide, benzyl lithium, Grignard reagent, alkyl copper lithium, sodium methoxide, sodium ethoxide, potassium ethoxide and sodium tert-butoxide; the oxidant is selected from at least one of the group consisting of amphoteric compounds, hydrogen peroxide, permanganate, hypochlorite, chromate, dichromate and chromium trioxide.

20. The method according to claim 17, characterized in that The processing solution etches at the location of the second species.

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