Particles functionalized with imageable radioisotopes, and methods for producing and using them.

Abstract

This disclosure relates to particles functionalized with imaging radioisotopes, their use as substitutes for therapeutic particles, methods for producing such imaging particles, and methods for using particles for biological imaging and dosimetry. In one method for radiotherapy of cancer, radioactive microspheres are delivered to a point in the patient's vascular system so that they are carried to the target tissue by the bloodstream. Once delivered to the target tissue, the radioactive microspheres remain in the capillaries and deliver a dose of therapeutic radiation. This treatment method is called selective internal radiation therapy (SIRT). The goal is to have a dose of radiation sufficient to cause localized tissue death in the cancerous tissue. [Solution] Some embodiments relate to imageable radioisotope microspheres. In some embodiments, the imageable microspheres are radiolabeled with imageable radioisotopes. In some embodiments, the imageable radioisotopes are directly bonded to the surface of the substrate of the microspheres. In some embodiments, the imageable microspheres can be used as surrogate particles to predict the distribution of therapeutic microspheres containing radiotherapeutic isotopes.

Description

Technical Field

[0001] Cross - reference to related applications This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 970,587, filed on February 5, 2020, the entire content of which is incorporated herein by reference.

[0002] Field The present disclosure relates to particles functionalized with an imageable radioisotope, their use as surrogates for therapeutic particles, methods of making such imageable particles, and methods of using the particles for biological imaging and dosimetry.

Background Art

[0003] Description of related art One approach to treating a patient having a particular cancer is to introduce a radioisotope into the patient's circulatory system. A measured amount of the radioisotope is injected into the patient, and a sufficient amount to treat the cancer accumulates at the site of the cancer.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] In one method for radiation therapy of cancer, radioactive microspheres are delivered to a point in the patient's vascular system so as to be carried by the blood flow to the target tissue. Once carried to the target tissue, the radioactive microspheres remain in the capillaries and deliver a dose of therapeutic radiation. This treatment is called selective internal radiation therapy (SIRT). The goal is to have a sufficient dose of radiation to cause local tissue death of the cancerous tissue.

Means for Solving the Problems

[0006] However, because therapeutic microparticles are not easily imaged, determining their distribution within the body is difficult. The characteristics of these therapeutic microspheres make predicting the distribution of therapeutic doses within the body difficult and impractical. Furthermore, tracking and accurately evaluating where the therapeutic microspheres ultimately remain is difficult. Without the ability to accurately determine where the microparticles are located within the body, it is difficult to predict or measure the radiation dose at the target location of the therapeutic microspheres. Moreover, it is difficult to determine the harmful radiation dose to healthy areas of the body. Some embodiments disclosed herein relate to particles (e.g., microspheres) decorated with imageable radioisotopes that can be viewed using imaging modalities. In some embodiments, these imageable radioisotope particles, once introduced into the body, can be used as surrogates that approximate the distribution of therapeutic microspheres within the body. In some embodiments, the use of the imageable surrogates disclosed herein can lead to more accurate prediction of radiation delivery, more effective treatment, and / or a reduction in the incidence of adverse effects in patients.

[0007] As disclosed elsewhere in this specification, some embodiments relate to imageable particles. In some embodiments, the particles are microspheres. In some embodiments, the imageable microspheres contain at least one imageable radioisotope. In some embodiments, the imageable microspheres also include a substrate. In some embodiments, the substrate provides a surface to which at least one imageable radioisotope can be bonded. In some embodiments, the substrate includes an inorganic material. In some embodiments, the inorganic material includes a metalloid or metal atom. In some embodiments, the substrate includes a core extending over the surface of the particles. In some embodiments, the core includes a first portion of the metalloid or metal atom, and the surface includes a second portion of the metalloid or metal atom. In some embodiments, the second portion of the metalloid or metal atom is bonded to a nonmetallic atom. In some embodiments, the imageable radioisotope is directly bonded to the substrate through at least a portion of the nonmetallic atoms on the surface of the substrate. In some embodiments, the first portion of the metalloid or metal atom is also bonded to the nonmetallic atom.

[0008] In some embodiments, the substrate comprises a substantially homogeneous mixture of constituent elements (i.e., elements from the periodic table). In some embodiments, the surface comprises at least a portion of the constituent elements. For example, in some embodiments, metalloid, metallic, or nonmetallic atoms on the surface of the substrate comprise the same elements as those metalloid, metallic, or nonmetallic atoms found in the core.

[0009] In some embodiments, the nonmetallic atom is an oxygen atom. In some embodiments, at least a portion of the oxygen atoms on the surface of the substrate are provided as hydroxyl groups.

[0010] Some embodiments relate to imageable microspheres comprising an inorganic substrate having a surface layer. In some embodiments, the imageable microspheres contain at least one imageable radioisotope. In some embodiments, the inorganic substrate contains at least one nonmetal, metalloid, or transition metal oxide. In some embodiments, the imageable radioisotope is bonded to the surface of the inorganic substrate, for example, by a Lewis acid-base coordination bond to an inorganic Lewis base (to provide a Lewis acid-base adduct).

[0011] Some embodiments disclosed herein relate to imageable microspheres comprising an inorganic substrate having a surface having one or more electron-donating functional groups. In some embodiments, the imageable microsphere includes a surface layer containing at least one imageable radioisotope. In some embodiments, the imageable radioisotope is bonded to the surface of the inorganic substrate during the preparation of the imageable microsphere via bonding with one or more electron-donating functional groups.

[0012] Some embodiments relate to imageable microspheres and include a ceramic microsphere substrate and at least one imageable radioisotope. The imageable radioisotope is bonded to the surface of the ceramic microsphere substrate, for example, as a Lewis acid-base adduct (e.g., of an inorganic Lewis base).

[0013] Any embodiment described above or elsewhere in this specification may include one or more of the following features:

[0014] In some embodiments, the imageable radioisotopes are bonded to the substrate via chemical bonds. In some embodiments, the chemical bonds are selected from ionic bonds, covalent bonds, or coordinate bonds. In some embodiments, the chemical bonds are coordinate bonds.

[0015] In some embodiments, the imageable isotope is configured to be imaged by an imaging modality selected from single photon imaging and two photon imaging. In some embodiments, the imageable radioactive isotope is configured to be imaged by an imaging modality selected from positron emission tomography (PET), single photon emission computed tomography (SPECT), and gamma camera imaging. In some embodiments, the imageable radioactive isotope is a positron emitter or a gamma emitter. In some embodiments, at least one imageable radioactive isotope is 89 , 68 , 51 Tc, 201 Th, 51 Cr, 67 Ga, 68 Ga, 111 In, 64 Cu, 89 Zr, 59 Fe, 42 K, 82 Rb, 24 Na, 45 Ti, 44 Sc, 51 Cr, 18 F, and / or a combination thereof. In some embodiments, at least one imageable radioactive isotope is a metallic radioactive isotope. In some embodiments, at least one imageable radioactive isotope is 99m Tc and 89 Zr. In some embodiments, at least one imageable radioactive isotope is 89 Zr. In some embodiments, at least one imageable radioactive isotope is 99m Tc.

[0016] In some embodiments, the surface of the imageable microspheres comprises the structure of formula (V),

[0017]

Chemical formula

[0018] The substrate is M cIncludes M c m is independently selected from Pb, Al, Si, Y, Mn, Ga, Fe, Sr, and Ti, and m is an integer selected from 1, 2, or 3. a M is either an atom of the substrate or a crosslinking atom. a It is selected from Pb, Al, Si, Y, Mn, Ga, Fe, Ti, Sr and Sn, M b teeth, 99m Tc, 201 Th, 51 Cr, 67 Ga, 68 Ga, 111 In, 64 Cu, 89 Zr, 59 Fe, 42 K, 82 Rb, 24 Na, 45 Ti, 44 Sc, 51 Cr, 177 Lu, Al 18 F and / or any combination thereof are selected, and each appearing R is either absent or H, and X is -OH, =O and -O - n is an integer selected from 0, 1, 2, 3, or 4. a This may be either atoms of the substrate or bridging metal atoms that chemically (through chemical bonding) connect the imageable radioisotopes to the substrate. In some embodiments, M a If M is an atom of the substrate, a The material is selected from Pb, Al, Si, Y, Mn, Ga, Fe, Sr, and Ti. In some embodiments, M a If M is an atom of the substrate, a The material is selected from Pb, Al, Si, Y, Mn, Ga, Fe, and Ti. In some embodiments, M a is a Sn-bridged metal atom. In some embodiments, M c It is Al, and the base material is M a Includes M a is Si, M b teeth 89 Zr, where each X is independently -OH or =O, and n is 1 or 2. In some embodiments, Mc and M a It is independently selected from Al, Si, and Y, and M b teeth 89 Zr, where each X is independently -OH or =O, and n is 1 or 2. In some embodiments, M b teeth 89 Zr is -OH, and n is 2. In some embodiments, M c is Si, Al, or Y, and M a is Sn, and M b teeth 99m Tc is such that each X is independently -OH or =O, and n is 2 or 3. In some embodiments, M b teeth 99m Tc is -OH, and n is 2 or 3.

[0019] In some embodiments, the surface of an imageable microsphere includes the structure of formula (VI),

[0020] [ka]

[0021] The base material is M c Includes M c The material is selected from Pb, Al, Si, Y, Mn, Ga, Fe, Sr, and Ti, and the surface layer is M b Includes M b teeth, 201 Th, 51 Cr, 67 Ga, 68 Ga, 111 In, 64 Cu, 89 Zr, 59 Fe, 42 K, 82 Rb, 24 Na, 45 Ti, 44 Sc, 51 Cr, Al 18 F, 177 Lu and / or any combination thereof are selected, and each R that appears is either nonexistent or -H, and each X that appears is -OH, =O, and -O- Selected independently from, m is an integer selected from 1, 2 or 3, and n is an integer selected from 0, 1, 2, 3 or 4. In some embodiments, m is 1. In some embodiments, M c is Al, M b is 89 Zr, X is -OH or O - and n is 1 or 2. In some embodiments, M c is Y or Al, M b is 89 Zr, X is -OH or O - and n is 2. In some embodiments, M c is Y or Al, M b is 89 Zr, X is -OH or O - and n is 1 or 2. In some embodiments, M b is AlF 18 In some embodiments, M b is 99m Tc. In some embodiments, M b is 89 Zr. In some embodiments, X is OH.

[0022] In some embodiments, the surface layer of the imageable microspheres comprises the structure of formula (VIII),

[0023]

Chemical formula

[0024] The substrate comprises M a and M c , M a and M c are independently selected from Pb, Al, Si, Y, Mn, Ga, Fe, Sr and Ti, m is an integer selected from 1, 2 or 3, M b is 99m Tc, 201 Th, 51 Cr, 67 Ga, 68 Ga,111 In, 64 Cu, 89 Zr, 59 Fe, 42 K, 82 Rb, 24 Na, 45 Ti, 44 Sc, 51 Cr, 177 Lu, Al 18 Each R that appears is selected from F and / or a combination thereof. a These are independently OH, O or -O-Sn-O-, and X is -OH, =O and -O - n is an integer selected from 0, 1, 2, 3, or 4. In some embodiments, M a and M c m is an integer selected independently from Sn, Pb, Al, Si, Y, Mn, Ga, Fe, Sr, and Ti, and m is an integer selected from 1, 2, or 3. b teeth, 99m Tc, 201 Th, 51 Cr, 67 Ga, 68 Ga, 111 In, 64 Cu, 89 Zr, 59 Fe, 42 K, 82 Rb, 24 Na, 45 Ti, 44 Sc, 51 Cr, 177 Lu, Al 18 Each R that appears is selected from F and / or a combination thereof. a OH and O are independent of each other, and X is -OH, =O and -O - n is an integer selected from 0, 1, 2, 3, or 4. In some embodiments, M c It is independently selected from Sn, Pb, Al, Si, Y, Mn, Ga, Fe, Sr and Ti, and in particular selected from Al, Si, Y, Mn and Sr, M a is Sn, and R a is O, M b teeth 99mTc is OH, -O-, or =O, and n is 2 or 3.

[0025] In some embodiments, the Sn in -O-Sn-O- may have one or more OH, O-, or hydrate groups coordinated to the Sn. In some embodiments, M c and M a These are independently Si, Al, or Y, and M b teeth 99m Tc is such that each X is independently -OH, =O, or -O - And n is 2 or 3. In some embodiments, M c and M a These are independently Si, Al, or Y, and M b teeth 99m Tc and at least one R appear a is -O-Sn-O-, and each X is independently -OH, =O, or -O - And n is 2 or 3. In some embodiments, M c Al is M a is Si, M bは99m Tc is such that each X is independently -OH or =O, and n is 2 or 3. In some embodiments, M c Al is M a is Si, M b teeth 99m Tc and at least one R appear a is -O-Sn-O-, where each X is independently -OH or =O, and n is 2 or 3. In some embodiments, M b teeth 99m Tc and at least one R appear a is -O-Sn-O-, where each X is independently -OH or =O, and n is 2 or 3. In some embodiments, M b teeth 99m Tc, and one R appears. a It is -O-Sn-O- and one R appears a x is -O- or -OH-, each X is independently -OH or =O, and n is 2 or 3.

[0026] In some embodiments, as disclosed elsewhere in this specification, the inorganic substrate may include or may be a ceramic material. In some embodiments, the ceramic material may include or may be glass.

[0027] The inorganic substrate, ceramic, or glass may contain at least one nonmetal, metalloid, or transition metal oxide. In some embodiments, the ceramic material or glass may contain at least one element selected from yttrium, silicon, manganese, aluminum, gallium, strontium, and titanium. In some embodiments, the inorganic substrate, ceramic, or glass contains silicon dioxide and at least one other element selected from yttrium, manganese, aluminum, gallium, boron, strontium, and titanium. In some embodiments, the inorganic substrate, ceramic, or glass contains at least one of Y2O3, SiO2, MnO2, AlO3, Ga2O3, Fe2O3, TiO2, SrO2, SrCO3, or a combination thereof. In some embodiments, the inorganic substrate, ceramic, or glass may contain SiO2 and at least one of Y2O3, MnO2, AlO3, Ga2O3, Fe2O3, TiO2, SrO2, SrCO3, or a combination thereof.

[0028] The inorganic substrate, ceramic, or glass may contain yttrium aluminum silicon oxide, or may be yttrium aluminum silicon oxide. Yttrium aluminum silicon oxide is described, for example, in U.S. Patent No. 4,789,501, which is incorporated herein by reference in whole.

[0029] In some embodiments, the imageable microspheres lack therapeutic radioisotopes.

[0030] In some embodiments, the imageable microspheres have a diameter of 5 μm to 1000 μm. In some embodiments, the diameter is the average diameter of the group of imageable microspheres. In some embodiments, the diameter is measured by light or electron microscopy.

[0031] In some embodiments, the inorganic substrate is non-porous. In some embodiments, the inorganic substrate is porous. In some embodiments, the imageable elements are limited to the surface of the microspheres, and / or the core of the inorganic substrate lacks imageable radioisotopes. In some embodiments, the imageable elements are limited to the surface of the non-porous microspheres.

[0032] Some embodiments relate to imageable microspheres prepared by a method that includes preparing a substrate and chemically bonding at least one imageable radioisotope to the substrate to obtain imageable microspheres.

[0033] Some embodiments relate to imageable microspheres produced by a method comprising preparing a substrate containing an inorganic material (e.g., a bonded metalloid or metal atom which may or may not be bonded to a nonmetallic atom) as described elsewhere in this specification. In some embodiments, the substrate includes a core containing a first portion of a metalloid or metal atom and a surface layer containing a second portion of a metalloid or metal atom. In some embodiments, at least one imageable radioisotope is provided. In some embodiments, at least one imageable radioisotope is chemically bonded to the surface layer of the substrate to obtain imageable microspheres. In some embodiments, the chemical bonding is carried out through a nonmetallic atom on the surface of the inorganic material.

[0034] In some embodiments, at least one imageable radioisotope is prepared as a salt before chemically bonding the at least one imageable radioisotope to the surface of an inorganic substrate. In some embodiments, the salt may be water-soluble or substantially water-soluble. In some embodiments, the salt may be a halogen salt (e.g., a fluoride, chloride, bromide, or iodide salt) and / or a polyatomic salt, or a salt having an organic acid (e.g., an oxalate).

[0035] In some embodiments, chemical functionalization is carried out in the presence of a reducing agent. In some embodiments, the reducing agent is selected from one or more of the following: tin salts (e.g., tin salts such as tin chloride to prepare tin ions), tin hydrates (e.g., tin hydrate), HCl, sodium borohydride, sodium diotionate, ferrous sulfate, ferric chloride + ascorbic acid, hypophosphorous acid (e.g., phosphinic acid), and / or hydrazine. In some embodiments, the reducing agent is a tin salt (e.g., tin salts such as tin chloride to prepare tin ions) or a tin hydrate (e.g., tin hydrate).

[0036] Some embodiments describe a ceramic microsphere containing at least one nonmetal, metalloid, or transition metal oxide in the presence of a reducing agent. 99m This invention relates to a method for preparing imageable ceramic microspheres, which includes reacting them with Tc pertechnetate ions.

[0037] Some embodiments include ceramic microspheres containing at least one nonmetallic or transition metal oxide, 89 Zr ions, for example 89 Zr oxalate or 89 The present invention relates to a method for preparing imageable ceramic microspheres, which includes reacting them with Zr chloride. In some embodiments, the reaction is carried out in the presence of a base. 89 When Zr is provided as a halide salt such as a chloride, it is generally provided in an acidic solution (for example, in 1M HCl or 1M oxalic acid), in which case the acid may be neutralized with a base, and therefore the reaction can proceed in the presence of a base.

[0038] Some embodiments relate to a method for producing imageable microspheres, which includes preparing an inorganic substrate and chemically functionalizing the inorganic substrate with at least one imageable radioisotope to obtain imageable microspheres.

[0039] In some embodiments, at least one imageable radioisotope is provided in ionic form, for example, as a salt, before chemically functionalizing the surface of an inorganic substrate with the at least one imageable radioisotope. In some embodiments, the salt may be water-soluble or substantially water-soluble. In some embodiments, the salt may be an alkali metal (e.g., sodium or potassium) salt, an alkaline earth metal (e.g., calcium magnesium barium or strontium) salt, a halogen salt (e.g., chloride), and / or a polyatomic salt, or a salt having an organic acid such as oxalate. In some embodiments, the salt may be a halogen salt (e.g., chloride), and / or a polyatomic salt, or a salt having an organic acid such as oxalic acid. In some embodiments, one or more counterions (e.g., 1, 2, 3, 4, 5, etc.) may associate with the imageable radioisotope. In some embodiments, at least one imageable radioisotope is provided in combination with a chelating agent. In some embodiments, the chelating agent is selected from one or more of the following: 6-hydrazinonicotinyl (HYNIC), dodecanetetraacetic acid (DOTA), deferoxamine (DFO), etc.

[0040] In some embodiments, the reducing agent is an imageable isotope. 99m In cases such as when Tc is used, it is added during the chemical functionalization process. In some embodiments, the reducing agent is selected from one or more of the following: tin salts (e.g., tin chloride or other tin salts to prepare tin ions), tin hydrates (e.g., tin hydrate), HCl, sodium borohydride, sodium diotionate, ferrous sulfate, ferric chloride + ascorbic acid, hypophosphorous acid, and / or hydrazine. In some embodiments, radioisotopes are used. 99mThe reaction is carried out in the presence of Tc and a tin salt (for example, a tin salt such as tin chloride to prepare tin ions). In some embodiments, 99m Tc is provided in the form of pertechnetium ions.

[0041] Some embodiments relate to a method for preparing imageable microspheres as described elsewhere in this specification, the method comprising preparing microspheres comprising a ceramic microsphere substrate as described elsewhere in this specification, and reacting the microspheres with an imageable radioisotope as described elsewhere in this specification under conditions suitable for bonding the imageable radioisotope to the surface of the ceramic microsphere substrate in the form of a Lewis acid-base adduct.

[0042] In some embodiments, the radioactive isotope is provided in the form of a salt. In some embodiments, the radioactive isotope is provided in an ionic form, such as a salt. In some embodiments, the salt may be water-soluble or substantially water-soluble. In some embodiments, the salt may be an alkali metal (e.g., sodium or potassium) salt, an alkaline earth metal (e.g., calcium magnesium barium or strontium) salt, a halogen salt (e.g., chloride), and / or a polyatomic salt, or a salt having an organic acid such as an oxalate.

[0043] 89In some embodiments, such as when Zr is an imageable isotope, the radioactive isotope may be prepared in the form of a salt. The radioactive isotope may be reacted with microspheres in the presence of a base. The base may be selected from, for example, alkali or alkaline earth metal carbonates (such as sodium carbonate and calcium carbonate), alkali hydroxides, etc. In some embodiments, the base may be selected from NaOH, KOH, etc. In some embodiments, the base is a weak base. In some embodiments, the base is a weak base whose conjugate acid has a pKa equal to or greater than about 3, 5, 7, 9, 11, 13, 14 or the aforementioned values ​​and / or spanning that range. In some embodiments, the base is an inorganic base. In some embodiments, the imageable radioactive isotope is, 89 It may also be Zr, for example, oxalic acid 89 As a salt of zirconium, etc., or as a chloride 89 It may also be prepared as a halide salt such as zirconium.

[0044] In some embodiments, the radioactive isotope is prepared in the form of a salt and reacts with ceramic microspheres in the presence of a reducing agent. In some embodiments, the reducing agent is selected from one or more of the following: tin salts (e.g., tin chloride), tin hydrates (e.g., tin hydrate), HCl, sodium borohydride, sodium diotionate, ferrous sulfate, ferric chloride + ascorbic acid, hypophosphorous acid, and / or hydrazine. In one approach, the reducing agent is a tin salt, which may also be a tin salt having a halogen, such as chlorine.

[0045] In one approach, the imageable isotopes are 99m It may also be Tc, which may be prepared as a pertechnetium salt. The reducing agent may be a tin ion such as tin chloride.

[0046] In any of the described methods, the method may be carried out in an aqueous medium and may further include recovering the imageable microspheres and / or washing the microspheres to remove unreacted radioisotopes. In some embodiments, the method may further include resuspending the imageable microspheres in a pharmaceutically acceptable injectable aqueous medium, such as a sterile aqueous medium.

[0047] Some embodiments relate to imageable microspheres obtained by any of the preparative methods described herein.

[0048] Some embodiments relate to a method for determining the amount of therapeutic microspheres to be delivered to a patient's body. In some embodiments, a population of imagingable microspheres is prepared. In some embodiments, the population of imagingable microspheres is delivered to the patient by introducing it to a first location in the patient's vascular system. In some embodiments, the population of imagingable microspheres is distributed within the patient's body. In some embodiments, the distribution of at least a portion of the population of imagingable microspheres within the patient's body is determined by imaging at least a target portion of the patient's body using an imaging modality. In some embodiments, the distribution of imagingable microspheres is used to calculate the amount of therapeutic microspheres to be delivered to the patient's body. In some embodiments, the target portion of the body is the portion of the body having a tumor to be treated. In some embodiments, the target portion of the body is the patient's liver. In some embodiments, the target portion of the body is the patient's brain. In some embodiments, the target portion of the body is the patient's lungs. In some embodiments, the target portion of the body is the patient's prostate gland. In some embodiments, the target portion of the body is the patient's kidneys. In some embodiments, the target portion of the body is the patient's spleen. In some embodiments, the target body part is the patient's gastrointestinal tract. In some embodiments, the target body part is the patient's pancreas. In some embodiments, the target body part is the patient's adrenal gland. In some embodiments, the target body part is the patient's gallbladder. In some embodiments, the target body part is the patient's bladder. In some embodiments, the target body part is the patient's muscles. In some embodiments, the target body part is the patient's bones. In some embodiments, the target body part is the patient's thyroid gland. In some embodiments, the target body part is the patient's ovaries. In some embodiments, the target body part is the patient's uterus. In some embodiments, the treatment method includes treating a tumor in any of the aforementioned target body parts.

[0049] In some embodiments, the imaging modality is SPECT. In some embodiments, the detection modality is PET. In some embodiments, the detection modality is gamma camera imaging. In some embodiments, the imageable microspheres are imageable microspheres disclosed elsewhere in this specification.

[0050] Some embodiments relate to methods for treating a patient. In some embodiments, a population of imageable microspheres is prepared. In some embodiments, the population of imageable microspheres is delivered to the patient by introducing the population of imageable microspheres to a first location in the vascular system of the patient's body. In some embodiments, the population of imageable microspheres is distributed within the patient's body. In some embodiments, the distribution of at least a portion of the population of imageable microspheres within the patient's body is determined by imaging at least a target portion of the patient's body using an imaging modality. In some embodiments, the distribution of imageable microspheres is used to calculate the amount of therapeutic microspheres to be delivered to the patient's body. In some embodiments, data is obtained regarding the distribution of the imageable therapeutic microsphere substitute in the patient. In some embodiments, this data is used to determine the therapeutic dose of microspheres to be administered to the patient's body. In some embodiments, the population of therapeutic microspheres is delivered to the patient by introducing the population of therapeutic microspheres to a second location in the vascular system of the patient's body. In some embodiments, the population of therapeutic microspheres is distributed within the patient's body to treat the patient. In some embodiments, the second location in the patient's vascular system is the same as the first location in the patient's vascular system.

[0051] In some embodiments, the imaging modality is SPECT. In some embodiments, the detection modality is PET. In some embodiments, the detection modality is gamma camera imaging. In some embodiments, the imageable microspheres are imageable microspheres disclosed herein.

[0052] Some embodiments relate to methods for treating patients with therapeutic microspheres. In some embodiments, data is obtained from the distribution of imagingable therapeutic microsphere substitutes in the patient. In some embodiments, this data is used to determine the amount of therapeutic microspheres to be administered to the patient's body. In some embodiments, the amount of imagingable microspheres is administered to the patient by introducing the therapeutic microspheres to a first location in the patient's vascular system. In some embodiments, the therapeutic microspheres are distributed within the patient's body. In some embodiments, the therapeutic microspheres are left in the patient's body to treat the patient.

[0053] In some embodiments, a population of imageable microspheres is provided to a patient. In some embodiments, the population of imageable microspheres is delivered to the patient by introducing the population of imageable microspheres to a first location in the vascular system of the patient's body. In some embodiments, the population of imageable microspheres is distributed within the patient's body. In some embodiments, the distribution of at least a portion of the population of imageable microspheres within the patient's body is determined by imaging at least a target portion of the patient's body using an imaging modality. In some embodiments, the distribution of imageable microspheres is used to calculate the amount of therapeutic microspheres to be delivered to the patient's body.

[0054] Some embodiments relate to methods for treating malignant or benign tumors (e.g., non-malignant tumors) in patients requiring treatment. Some embodiments relate to methods for treating vascularized tumors (e.g., malignant or benign tumors) with vascular supply, such as liver cancer (e.g., liver tumors such as hepatocellular carcinoma - HCC, and tumors resulting from metastases of other tumors to the liver such as neuroendocrine tumors and colorectal tumors), and tumors of the brain, prostate, lungs, spleen, and kidneys, for example. In some embodiments, a population of imageable microspheres is introduced into the patient. In some embodiments, the imageable microspheres are distributed to the patient over a period of time. In some embodiments, the imageable microspheres are imaged post-injection or directly in real time (during injection). In some embodiments, the imageable microspheres are distributed to the patient over a period of time in which the half-life of the imageable radioisotope associated with the imageable microspheres is less than 2. In some embodiments, the distribution of imageable microspheres in the patient's cancer site is determined by imaging the imageable microspheres using an imaging modality. In some embodiments, when imaging microspheres are replaced with therapeutic microspheres, the estimated effective dose at the cancer site is determined based on the distribution of imaging microspheres. In some embodiments, the amount of therapeutic microspheres is administered to the patient based on the estimated effective dose (i.e., estimated absorbed dose). In some embodiments, the population of imaging microspheres includes imaging microspheres disclosed elsewhere in this specification. In some embodiments, the cancer is liver cancer.

[0055] In some embodiments, the imageable microspheres are imaged after injection. In some embodiments, before imaging, the imageable microspheres are distributed to the patient for a period of time including and / or spanning the aforementioned values, at least about 2 minutes, 5 minutes, 10 minutes, 30 minutes, 1 hour, 4 hours, 6 hours, or the aforementioned values. In some embodiments, the imageable microspheres are distributed in the body immediately after injection (e.g., within just a few minutes). In some embodiments, the imageable microspheres are distributed to the patient (e.g., in a target or off-target area) for a period of time including and / or spanning the aforementioned values, at least about 2 minutes, 5 minutes, 10 minutes, 30 minutes, or the aforementioned values. In some embodiments, before imaging, the imageable microspheres are distributed to the patient for a period including and / or spanning the aforementioned values, at least about 2 minutes, 5 minutes, 10 minutes, 30 minutes, or the aforementioned values.

[0056] Some embodiments relate to a method for predicting the extent of pulmonary shunt (off-target delivery) to a patient for radioisotope cancer therapy. In some embodiments, a population of imageable microspheres is administered to the patient. In some embodiments, the imageable microspheres are distributed to the patient over a period of time. In some embodiments, the distribution of imageable microspheres in the patient's lungs is determined by imaging the imageable microspheres using an imaging modality. In some embodiments, the estimated radiation dose to the patient's lungs is determined by calculating the radiation dose that would have been received if a specific amount of radioisotope therapy particles had been administered instead of imageable microspheres. In some embodiments, a dose of radioisotope therapy microspheres sufficient to cause clinically relevant lung changes due to pulmonary shunt is determined. In some embodiments, a determination is made as to whether the patient is a candidate for treatment. In some embodiments, a dose of radioisotope therapy microspheres is administered to the patient that is less than or equal to the dose of radioisotope therapy microspheres determined to be sufficient to cause clinically relevant lung changes due to pulmonary shunt. In some embodiments, the collection of imageable microspheres includes imageable microspheres disclosed elsewhere in this specification.

[0057] Some embodiments relate to methods for mitigating gastrointestinal tract damage during treatment for patients requiring radioisotope cancer therapy. In some embodiments, the method includes introducing a population of imageable microspheres into a patient. In some embodiments, the imageable microspheres are distributed to the patient over a period of time. In some embodiments, the distribution of imageable microspheres in the patient's gastrointestinal tract is determined by imaging the imageable microspheres using an imaging modality. In some embodiments, the estimated dose of radiation in the patient's gastrointestinal tract is determined when the imageable microspheres are replaced with a specific amount of radioisotope therapeutic microspheres. In some embodiments, a dose of radioisotope therapeutic microspheres sufficient to cause damage to the gastrointestinal tract is determined. In some embodiments, a determination is made as to whether the patient is a candidate for treatment. In some embodiments, a dose of radioisotope therapeutic microspheres is administered to the patient that is less than or equal to the dose of radioisotope therapeutic microspheres determined to be sufficient to cause damage to the gastrointestinal tract. In some embodiments, the collection of imageable microspheres includes imageable microspheres disclosed elsewhere in this specification.

[0058] Some embodiments relate to kits. In some embodiments, the kit further includes a de-derivative version of the imageable microspheres described herein and instructions for derivatizing the microspheres with imageable radioisotopes described herein. In some embodiments, for example, the kit includes microspheres comprising a substrate comprising an inorganic material containing metalloid or metal atoms bonded to nonmetal atoms, the substrate may include a core extending to a surface, the core comprising a first portion of metalloid or metal atoms bonded to the nonmetal atoms, and the surface comprising a second portion of metalloid or metal atoms bonded to the nonmetal atoms. The kit may also include instructions for reacting the imageable radioisotopes with the substrate such that the imageable radioisotopes bond directly to the substrate through at least a portion of the nonmetal atoms on the surface of the substrate.

[0059] In some embodiments, the kit may include microspheres containing an inorganic substrate, the inorganic substrate containing at least one nonmetal, metalloid, or transition metal oxide. The kit additionally includes instructions for bonding an imageable radioisotope to the surface of the inorganic substrate via Lewis acid-base coordination bonds.

[0060] In some embodiments, the kit may include instructions for carrying out a reaction in which microspheres containing a ceramic microsphere substrate and an imageable radioisotope are bonded to the ceramic microsphere substrate as a Lewis acid-base adduct.

[0061] In some embodiments, the kit may further contain reducing agents as described herein.

[0062] In some embodiments, the kit may additionally include therapeutic microspheres, which may be microspheres suitable for selective internal radiotherapy as further described herein.

[0063] In some embodiments, the kit includes instructions for using a catheter to introduce imagingable microspheres into a patient. In some embodiments, the kit includes one or more of the following: a vascular access needle, a vascular guidewire, a vascular sheath (e.g., 4-6 Fr), a vascular catheter (4-5 Fr), a microcatheter, a syringe, and a vial.

[0064] The features of the imageable particles disclosed herein are described below with reference to the drawings of specific embodiments. The exemplary embodiments are intended to demonstrate the disclosure, but not to limit it. [Brief explanation of the drawing]

[0065] [Figure 1] This is a diagram representing the periodic table. [Figure 2] This figure shows the results of a study on exfoliation in an embodiment of radioactive isotope particles that can be imaged. [Figure 3A]This figure shows the results of stability tests in an embodiment of imageable radioisotope particles using 99mTc microspheres. [Figure 3B] This figure shows the results of a stability test in an embodiment of imageable radioisotope particles using 89Zr microspheres. [Figure 4A] This figure shows the results of a stability test using imageable particles as a reference, containing coarsely aggregated albumin labeled with technitium-99m. [Figure 4B] This figure shows the results of radioisotope functionalization performed at various pH levels and with various buffers. [Figure 5A] This figure shows an axial view of Woodchuck with large bilateral liver cancers. Figure 5A was obtained using T2-weighted MRI imaging. [Figure 5B] This figure shows an axial view of Woodchuck with large bilateral liver cancers. Figure 5B shows a PET-CT image demonstrating the uptake of 89Zr-functionalized YAS microspheres following catheter-guided delivery. [Figure 6A] This figure shows images of Woodchuck. Figure 6A shows an axial view of Woodchuck with one large, major liver cancer, as shown in the T2-weighted MRI image. [Figure 6B] This figure shows an image of a woodchuck. Figure 6B is a digital subtraction angiography of a catheter placed in the common hepatic artery immediately before delivery of 89Zr-functionalized YAS microspheres. [Figure 7A] This figure shows imaging following catheter-guided delivery of 89Zr-functionalized microspheres at scout doses (PT1;7A) and total doses (PT2;7B). [Figure 7B] This figure shows imaging following catheter-guided delivery of 89Zr-functionalized microspheres at scout doses (PT1;7A) and total doses (PT2;7B). A small amount of pulmonary uptake is observed, along with a recognizable difference in uptake between tumors and normal liver tissue. [Modes for carrying out the invention]

[0066] Some embodiments disclosed herein relate to particles (e.g., microspheres) containing imaging radioisotopes that can be used as substitutes for therapeutic particles (e.g., substitutes for therapeutic radioisotope microspheres), such as those suitable for use in selective internal radiotherapy (SIRT), and relate to methods for producing imaging radioisotope particles, methods for using imaging radioisotope particles for biological imaging and dosimetry, and methods for treating patients using information collected using imaging radioisotope particles. In some embodiments, imaging radioisotope particles are prepared by functionalizing the surface of the particles (via chemical bonding) with the imaging radioisotope. In some embodiments, the chemical bonding is a Lewis acid-base interaction between the imaging radioisotope and the surface of the particle substrate. In some embodiments, imagingable particles are used as proxies (e.g., substitutes) for therapeutic microspheres to determine where the therapeutic microspheres will migrate within the body and how the population of therapeutic microspheres will be distributed within the body once delivered to the blood vessels, upon introduction of the therapeutic microspheres. Some embodiments relate to the field of microsphere-based therapy, including SIRT.

[0067] As used herein, the term “chemical bond” is given its plain and ordinary meaning and refers to the persistent attractive force between atoms, ions, or molecules that enables the formation of a compound. This bond may arise from electrostatic attraction between oppositely charged ions, such as in ionic bonds, or through the sharing of electrons, such as in covalent bonds. Chemical bonds include “strong” or “primary bonds,” such as covalent bonds, ionic bonds, and metallic bonds, and “weak” or “secondary bonds,” such as dipole-dipole interactions, London dispersion forces, and hydrogen bonds.

[0068] As used herein, the term “coordinate bond” is given its plain and common sense meaning and refers to a covalent bond in which both electrons originate from the same atom.

[0069] As used herein, the term “covalent bond” is given its plain and common sense meaning and refers to a bond between atoms formed by the sharing of a pair of electrons.

[0070] As used herein, the term “Lewis acid” is given its plain and ordinary meaning and refers to any species (molecule or ion) that is an electron pair acceptor.

[0071] As used herein, the term “Lewis base” is given its plain and ordinary meaning and refers to any species (molecule or ion) that is an electron pair donor.

[0072] As used herein, “Lewis acid-base adduct” is given its plain and common sense meaning and refers to a compound containing a coordinate covalent bond between a Lewis acid and a Lewis base.

[0073] As used herein, the term "half-life" or t 1 / 2 In its simple and ordinary sense, it refers to the time it takes for half of the atoms of a radioactive isotope to decay.

[0074] As used herein, the term “metalloid” refers to a type of chemical element that possesses properties between those of both metals and nonmetals, or is a mixture thereof. Metalloids include, at a minimum, boron (B), silicon (Si), germanium (Ge), arsenic (As), antimony (Sb), and tellurium (Te). Metalloids are shown in the periodic table in Figure 1.

[0075] As used herein, the term “metal” refers to a group of chemical elements in the periodic table, including alkali metals, alkaline earth metals, and transition metals. Further examples of transition metals include post-transition metals, lanthanides, and actinides. The metals are shown in the periodic table in Figure 1.

[0076] As used herein, the term “nonmetal” refers to one of the chemical elements of the periodic table. Examples of nonmetals include (C), nitrogen (N), oxygen (O), sulfur (S), and others, as shown in the periodic table in Figure 1.

[0077] As used herein, the term “ceramic microsphere substrate” refers to ceramic microspheres forming a substrate to which imageable radioisotopes are bonded.

[0078] While “patients” or “subjects” as disclosed herein are, in some embodiments, human patients, it should be understood that the principles of the subject matter of this disclosure are effective for all vertebrate species, including mammals, and are intended to be included in the terms “subjects” and “patients.” Appropriate subjects are generally mammalian subjects. The subject matter described herein finds use in research and veterinary and medical applications. The term “mammal” as used herein includes, but is not limited to, humans, non-human primates, cattle, sheep, goats, pigs, horses, cats, dogs, rabbits, rodents (e.g., rats or mice), monkeys, etc. Human subjects include neonates, infants, children, adolescents, adults, and elderly subjects. Subjects may be subjects who “need” the methods disclosed herein and may be subjects experiencing a disease state, and the methods and compounds of the present invention are used to evaluate therapeutic options.

[0079] As used herein, the term “effective amount” means the amount of any listed particles and / or composition that imparts a modulating effect, which may be, for example, a beneficial effect on a subject suffering from a disorder, disease or illness, and which includes, as is well known in the Art, improvement of the subject’s condition (e.g., in one or more symptoms), delay or reduction of the progression of the condition, prevention or delay of the onset of the disorder, and / or changes in clinical parameters, disease or illness, etc. For example, an effective amount may mean the amount of a composition, particle or agent that improves the condition in the subject by at least 5%, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. The actual dose level of the active ingredient in the active compositions of the subject matter of this disclosure can be varied to administer an amount of active particles effective in achieving a desired response for a particular subject and / or application. The selected dose level depends on a variety of factors, including but not limited to the activity of the composition, the route of administration, the distribution of the composition, the severity of the condition being treated, and the physical condition and prior medical history of the subject being treated. In some embodiments, a minimum dose is administered. Determination and adjustment of the effective dose, as well as evaluation of when and how such adjustments should be made, are intended herein.

[0080] "To treat" or "to treat" or "treatment" refers to any type of activity that imparts a modulating effect, which may be a beneficial effect on an object suffering from a disorder, disease or illness, and may include, for example, improvement of the object's condition (e.g., in one or more symptoms), delay or reduction of the progression of the condition and / or changes in clinical parameters, disease or illness, or cure of the disease.

[0081] Whenever a group is described as "optionally substituted," it may be unsubstituted or substituted with one or more of the substituents shown. Similarly, if a group is described as "unsubstituted or substituted," and it is substituted, the substituent may be selected from one or more of the substituents shown. If no substituent is shown, a shown "may be substituted" or "substituted" group means that it may be substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, hydroxy, alkoxy, cyano, halogen, C-amide, N-amide, C-carboxy, O-carboxy, haloalkyl, haloalkoxy, mercapto, amino, monosubstituted amino, and disubstituted amino groups.

[0082] In this specification, "a" and "b" are integers. a ~C b "C1-C4 alkyl" refers to the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, or the number of carbon atoms in a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heteroaryl ring. That is, an alkyl, alkenyl, alkynyl, cycloalkyl ring, cycloalkenyl ring, cycloalkynyl ring, aryl ring, or heteroaryl ring can contain "a" to "b" carbon atoms, including "a" and "b". Therefore, for example, a "C1-C4 alkyl" group refers to all alkyl groups having 1 to 4 carbon atoms (e.g., 1, 2, 3, or 4), i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. A "C1-C6 alkyl" group refers to all alkyl groups having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6). If "a" and "b" are not specified with respect to alkyl, alkenyl, alkynyl, cycloalkylcycloalkenyl, cycloalkynyl, aryl, or heteroaryl groups, the broadest range described in those definitions should be assumed.

[0083] As used herein, the term "alkyl" refers to a fully saturated aliphatic hydrocarbon group. The alkyl group may be branched or linear. Examples of branched alkyl groups include, but are not limited to, isopropyl, sec-butyl, and t-butyl. Examples of linear alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and n-heptyl. Alkyl groups may have 1 to 30 carbon atoms (wherever they appear herein, numerical ranges such as “1 to 30” mean each integer within a given range; for example, “1 to 30 carbon atoms” means that the alkyl group may consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 carbon atoms, but this definition also includes appearances of the term “alkyl” where no numerical range is specified). The “alkyl” group may also be a medium alkyl group having 1 to 12 carbon atoms. The “alkyl” group may also be a lower alkyl group having 1 to 6 carbon atoms. Alkyl groups may be substituted or unsubstituted. As merely an example, "C1-C5 alkyl" indicates that the alkyl chain contains 1 to 5 carbon atoms. That is, the alkyl chain is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and linear), etc. Typical alkyl groups, though not limiting, include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl.

[0084] As used herein, the term "alkylene" refers to a divalent fully saturated linear aliphatic hydrocarbon group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, and octylene. Alkylene groups are,

[0085] [ka]

[0086] Next, the number of carbon atoms, followed by " * It may be represented by ". For example, to represent ethylene

[0087] [ka]

[0088] The alkylene group may have 1 to 30 carbon atoms (wherever it appears herein, the numerical range such as "1 to 30" refers to each integer within the given range; for example, "1 to 30 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to a maximum of 30 carbon atoms; however, this definition also includes appearances of the term "alkylene" where no numerical range is specified). The alkylene group may also be a medium alkyl having 1 to 12 carbon atoms. The alkylene group may also be a lower alkyl having 1 to 6 carbon atoms. The alkylene group may be substituted or unsubstituted. For example, a lower alkylene group may be substituted by replacing one or more hydrogens of the lower alkylene group and / or both hydrogens on the same carbon. 3~6 Monocyclic cycloalkyl groups (for example,

[0089] [ka]

[0090] It can be replaced by substituting with ).

[0091] In this specification, "alkenyl" refers to an alkyl group containing one or more double bonds in a straight or branched hydrocarbon chain. The alkenyl group may be unsubstituted or substituted.

[0092] As used herein, "alkynyl" refers to an alkyl group containing one or more triple bonds in a straight or branched hydrocarbon chain. The alkynyl group may be unsubstituted or substituted.

[0093] As used herein, "aryl" refers to a carbocyclic (all-carbon) monocyclic or polycyclic aromatic ring system (including fused ring systems in which two carbocyclic rings share a chemical bond) having a π-electron system that is completely delocalized across all rings. The number of carbon atoms in an aryl group can vary. For example, an aryl group may be C6~C 14 Aryl group, C6~C 10 The group may be an aryl group or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. The aryl group may be substituted or unsubstituted.

[0094] As used herein, “heteroaryl” refers to a monocyclic or polycyclic aromatic ring system (a ring system having a completely delocalized π-electron system) containing one or more heteroatoms, i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur. The number of atoms in the ring of a heteroaryl group can vary. For example, a heteroaryl group may contain 4 to 14 atoms in the ring, 5 to 10 atoms in the ring, or 5 to 6 atoms in the ring. Furthermore, the term “heteroaryl” includes fused ring systems in which two rings, such as at least one aryl ring and at least one heteroaryl ring or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings, though not limited to them, include furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. The heteroaryl group may be substituted or unsubstituted.

[0095] As used herein, “cycloalkyl” refers to a fully saturated (non-double or triple bonded) monocyclic or polycyclic hydrocarbon ring system. If it consists of two or more rings, the rings may be condensed and joined together. A cycloalkyl group may contain 3 to 10 atoms in the ring or 3 to 8 atoms in the ring, as otherwise stated herein. A cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0096] As used herein, “cycloalkenyl” refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring, but where there are multiple double bonds, the double bonds cannot form a π-electron system that is completely delocalized across all rings (otherwise the group becomes “aryl” as defined herein). If it consists of two or more rings, the rings may be fused together. The cycloalkenyl group may be unsubstituted or substituted.

[0097] As used herein, “heterocyclyl” or “heteroalicyclic” refers to monocyclic, bicyclic, and tricyclic ring systems of 3, 4, 5, 6, 7, 8, 9, 10, and up to 18 members, where a carbon atom, together with 1 to 5 heteroatoms, constitutes this ring system. A heterocycle may optionally contain one or more unsaturated bonds in this position, but a completely delocalized π-electron system does not necessarily occur across all rings. Heteroatoms are elements other than carbon, including but not limited to oxygen, sulfur, and nitrogen. A heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so the definition includes oxo and thio systems, such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. If composed of two or more rings, the rings may be condensed and joined together. Furthermore, any nitrogen in a heteroalicyclic ring may be quaternized. Heterocyclic or heteroalicyclic groups may be unsubstituted or substituted. Examples of such "heterocyclic" or "heteroalicyclic" groups include, but are not limited to, 1,3-dioxine, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxatian, 1,4-oxathiolane, 1,3-dithiol, 1,3-dithiolane, 1,4-oxatian, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, and Examples include midazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidinone, morpholine, oxiran, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, and their benzo-condensed analogs (e.g., benzimidazolidinone, tetrahydroquinoline, 3,4-methylenedioxyphenyl).

[0098] As used herein, the term "amino" refers to the -NH2 group.

[0099] As used herein, the term "hydroxy" refers to the -OH group.

[0100] As used herein, the term "cyano" refers to the "-CN" group.

[0101] As used herein, the term "mercapto" refers to the "-SH" group.

[0102] As used herein, “alkoxy” refers to the formula -OR, where R is defined herein as alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). A non-exclusive list of alkoxys is methoxy, ethoxy, n-propoxy, 1-methylethoxy(isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy, and benzoxy. Alkoxys may be substituted or unsubstituted.

[0103] As used herein, the term "C-amide" means R A and R B "-C(=O)N(R)" can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heteroaryl. A R B This refers to the ) group. The C-amide may be substituted or unsubstituted.

[0104] The "N-amide" group is R and R A "RC(=O)N(R)" can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heteroaryl. A This refers to the )- group. N-amides may be substituted or unsubstituted.

[0105] As used herein, the term “O-carboxy” refers to the “RC(=O)O-” group where R may be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heteroaryl, as defined herein. The O-carboxy may be substituted or unsubstituted.

[0106] As used herein, the terms “ester” and “C-carboxy” refer to the “-C(=O)OR” group, which may be the same as R defines with respect to O-carboxy. Esters and C-carboxys may be substituted or unsubstituted.

[0107] As used herein, the terms “halogen atom” or “halogen” refer to any one of the radioactively stable atoms in column 7 of the periodic table, such as fluorine, chlorine, bromine, and iodine.

[0108] In this specification, "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen (e.g., monohaloalkyl, dihaloalkyl, and trihaloalkyl). Examples of such groups, but not limited to, include chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and 1-chloro-2-fluoromethyl and 2-fluoroisobutyl. Haloalkyls may be substituted or unsubstituted.

[0109] As used herein, "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced by halogens (e.g., monohaloalkoxy, dihaloalkoxy, and trihaloalkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 1-chloro-2-fluoromethoxy, 2-fluoroisobutoxy. Haloalkoxys may be substituted or unsubstituted.

[0110] As used herein, “diamino group” means C 1~10 This refers to a compound having two amino groups linked by an alkyl chain, where the two amino groups are independently and arbitrarily substituted (e.g., an additional C 1~6 (A disubstituted or trisubstituted amino group optionally substituted with an alkyl group).

[0111] As used herein, “triamino group” means two or three C groups. 1~10 This refers to a compound having three amino groups linked by an alkyl chain (e.g., a cyclic or linear structure), where the three amino groups are independently and arbitrarily substituted (e.g., an additional C 1~6 (A disubstituted or trisubstituted amino group optionally substituted with an alkyl group).

[0112] As disclosed elsewhere in this specification, radioactive microspheres for use in SIRT can be delivered to a point in the vascular system (e.g., via a transcatheter pathway) where they are carried to the tissue of interest by blood flow and / or injected fluid. Here, the radioactive microspheres remain in the capillaries and deliver a dose of therapeutic radiation that is generally sufficient to cause localized tissue death. Therapeutic radiation is typically delivered in the form of beta or gamma radiation from beta or gamma-emitting radioactive isotopes. A variety of therapeutic isotopes, including but not limited to yttrium-90 and holmium-166, can be used in SIRT. In one approach, glass microspheres containing yttrium-90 (beta emitter) are used in SIRT. The glass microspheres are prepared by neutron collision of naturally occurring non-radioactive glass microspheres containing yttrium-89, which is converted to yttrium-90 by neutron capture.

[0113] Section headings used herein are for organizational purposes only and should not be construed in any way as limiting the subject matter described herein. All documents and similar materials cited herein, including but not limited to patents, patent applications, articles, books, papers, and internet web pages, are expressly incorporated by reference in their entirety for any purpose. If the definitions of terms in incorporated references appear to differ from those provided in these instructions, the definitions provided in these instructions shall prevail. It is understood that there are implicit "approximates" preceding temperatures, concentrations, times, etc., discussed in these instructions, and such minor and insubstantial deviations are within the scope of these instructions herein. In this application, the use of singular forms includes plural forms unless otherwise specified. Furthermore, the use of "comprise, comprises," "comprising," "contain, contains," "containing," "include, includes," and "including" is not intended to be limiting. Please understand that both the general explanation and the detailed explanation below are illustrative and descriptive, and not limiting. The terms "and / or" indicate that the possible items provided can be used together or substituted for each other. Therefore, the terms "and / or" indicate that both options exist for that set of possible items.

[0114] introduction Because different individuals' circulatory systems can vary greatly, patients undergoing SIRT may experience varying levels of success. This may be partly due to the off-target distribution of therapeutic radioisotope microspheres. When introduced into the bloodstream, therapeutic radioisotope microspheres can be distributed in unexpected ways and to unintended areas of the body, which may be due, for example, to the presence of a low percentage of vessels in the population that replace a proportion of blood supply to tissues not normally supplied by the main vascular trunks. These vessels can result in the delivery of radioisotopes to inappropriate tissues. Off-target distribution of microspheres is undesirable because it can lead to irradiation of non-target tissues, for example, resulting in unintended tissue death that can be clinically observed as an adverse effect on the patient. For example, if a pulmonary shunt (i.e., a vessel that unintentionally directs blood from a major tissue of interest, such as the liver, to the lungs) is present, therapeutic radioisotope particles may aggregate in the lungs and damage lung tissue.

[0115] Furthermore, another problem with off-target delivery is that it also reduces the number of microspheres delivered to the target tissue. Consequently, other tissues receive radiation instead of the target tissue, reducing the dose of radiation delivered to that target tissue. This can lead to ineffective cancer treatment and a higher mortality rate.

[0116] Furthermore, beta radiation is not suitable for precise imaging techniques. While beta radiation is highly desirable for tumor treatment, its effective range is very limited, making it difficult, if not impossible, to detect outside the body. In addition, the low bremsstrahlung emissions from beta emission and the low positron emissions from these therapeutic microspheres lead to reduced imaging quality and accuracy.

[0117] Prior to treatment, it is common practice to map the local vascular system using iodized contrast agents, which allows for visualization of the vessels using X-ray-based techniques. This enables physicians to better understand local vascular anatomy and plan the delivery of radioactive microspheres to the appropriate vessels supplying the target tissue. However, for several reasons, these contrast agents can be difficult to detect in small amounts and are a poor substitute for therapeutic radioisotope microspheres. Because contrast agents differ in shape and size and may have different properties than therapeutic radioisotope microspheres, there remains a risk that a certain percentage of radioactive microspheres may remain at off-target locations (e.g., by passing through the target tissue to vessels supplying distant tissues). Therefore, mapping the vascular system alone suffers from several drawbacks.

[0118] In addition to mapping the vascular system, it would also be beneficial to map the predictive distribution of microspheres before treatment. This can be achieved using imaging microparticle substitutes injected into the patient's vascular system to mimic a planned SIRT procedure. One imaging microparticle substitute currently in use is technetium-99m( 99m It is a coarse aggregated egg white preparation labeled with (known as TcMAA). Technetium-99m is a short-lived gamma emitter that can be imaged using a gamma detection camera. Single-photon emission computed tomography (SPECT) imaging combines a gamma detection camera with X-ray images to visualize the patient's anatomical structure in relation to the patient's anatomical structure. 99m This generates images of TcMAA radiation within the body. 99mTcMAA can be used to elucidate the distribution of microspheres, and this information can be used to predict the final possible distribution of SIRT-treated microspheres. In this way, it is possible to calculate the proportion of delivered radiation dose that is expected to be delivered to the target tissue. Predicted dose measurements can be used to adjust the treatment plan to optimize SIRT treatment dosage. Predicted distributions can also be used to triage patients who are suitable for SIRT treatment. For example, if a large number of microspheres are expected to be distributed to sensitive tissues such as the lungs or intestinal walls, it may be necessary to correct the flow of particles over the target tissue using angiography techniques (e.g., coil embolization) before proceeding with SIRT. If it is not possible to correct the flow of non-target tissues, it may be necessary to reduce the SIRT dosage to a safer level, or the patient may be considered unsuitable for treatment.

[0119] 99m TcMAA has been widely used as an image particle substitute before SIRT treatment, 99m TcMAA is not the best substitute for therapeutic microspheres. For example, the final distribution of SIRT microspheres is: 99m The distribution may not perfectly or accurately match that of TcMAA substitute particles. 99m If the distribution differs between TcMAA surrogate particles and therapeutic particles, the patient may receive one or more inappropriate doses of radiation to the tissue to be treated (too low or too high) or radiation to unpredictable non-target tissue. Furthermore, the patient may receive incorrect radiation even if it was actually appropriate. 99m Treatment may be refused based on TcMAA surrogate readings.

[0120] One approach to solving this problem was to prepare a resin or crystalline ceramic core with a coated imaging radioactive material. However, the microspheres contain a core material with an outer surface coating containing radioactive isotopes, which presents a high risk of the radioactive coating separating from the underlying microsphere core. Any mechanical damage to the coating could release unwanted radioactivity to other parts of the human body, which is highly undesirable (exacerbating the above problem). Further drawbacks are presented by the special handling and precautions required to coat the ceramic core with radioactive isotopes.

[0121] In yet another application, microspheres containing precursors for radioisotopes incorporated into ceramic materials can be prepared. While the inadvertent release of radioisotopes from a radioactive coating to other parts of the human body is reduced by incorporating the radioisotope precursors into ceramic spheres, the latter product form is still not without its drawbacks. For example, these preparations generally require the activation of non-radioactive elements by neutron bombardment within a nuclear reactor. Furthermore, the preparations require the use of ultra-high-purity starting materials to avoid the formation of undesirable long-lived isotopes, and their commercial distribution is hindered by the inherently short half-lives of radioisotopes and safety issues associated with their transport. An additional drawback is the lack of design flexibility.

[0122] Some embodiments disclosed herein address one or more of the above-mentioned problems by providing imageable radioisotope particles (e.g., imageable radioisotope microspheres). In some embodiments, as disclosed in more detail elsewhere herein, imageable radioisotopes are chemically bonded to the surface of particles to obtain imageable radioisotope particles.

[0123] Imageable radioactive isotope particles As previously mentioned, some embodiments relate to imageable radioisotope particles. In some embodiments, the imageable radioisotopes are functionalized on the surface of a supporting substrate. In some embodiments, the supporting substrate is particles. In some embodiments, the substrate provides the majority of the particles (e.g., the majority of the particle size and / or weight may be attributed to the substrate). In some embodiments, the particles are microspheres. In some embodiments, the imageable radioisotopes are bonded to the substrate (e.g., directly bonded to the substrate). In some embodiments, the imageable radioisotopes are bonded to the substrate via irreversible or substantially irreversible bonding. In some embodiments, the imageable radioisotopes are chemically bonded to the surface via one or more chemical bonds. In some embodiments, by providing particles having imageable radioisotopes chemically bonded to the surface, the risks associated with the detachment of the imageable radioisotopes are reduced and / or eliminated. Furthermore, in some embodiments, the imageable radioisotopes can be functionalized to the substrate in their radioactive form, thus eliminating the need for neutron activation of the imageable radioisotopes. For example, in some embodiments, the imageable radioisotopes are bonded to the substrate surface during the preparation of imageable particles via bonding to the substrate. However, in other embodiments, activation of non-radioactive isotopes that form the imageable radioisotopes while functionalizing the particle surface is envisioned.

[0124] Imagingable radioisotopes may be functionalized to the surface of the particle substrate via chemical bonds. In some embodiments, the chemical bonds are primary bonds. For example, in some embodiments, imagingable radioisotopes are bonded to the surface of particles (e.g., microspheres) through one or more covalent bonds. In some embodiments, imagingable radioisotopes are bonded to the surface of microspheres through one or more coordination bonds. In some embodiments, imagingable radioisotopes are bonded to the surface of microspheres through donor bonds. In some embodiments, imagingable radioisotopes are bonded to the surface of microspheres through covalent bonds, coordination bonds, donor bonds, ionic bonds, or a combination thereof. In some embodiments, imagingable radioisotopes are bonded to the surface of microspheres through Lewis acid-base interactions (e.g., Lewis acid-base coordination bonds). For example, in some embodiments, one or more functional groups on the surface of the particle substrate act as Lewis bases to form a Lewis acid-base adduct having an imagingable radioisotope (acting as a Lewis acid).

[0125] As described elsewhere in this specification, in some embodiments, the particle substrate provides a base to which imageable radioisotopes can be bound. In some embodiments, the substrate includes a particle core extending outward relative to the particle surface (e.g., from the center of the particle). In some embodiments, the substrate is an inorganic material.

[0126] As described elsewhere in this specification, the substrate may be homogeneous or substantially homogeneous. For illustrative purposes, the surface of a particle may contain several atoms of overlapping elements and / or the same element (e.g., atoms of the same element), as found in the core of the substrate. In some embodiments, as disclosed elsewhere in this specification, a portion of the atoms providing the surface of the substrate may be directly bonded to an imageable radioisotope. The portion of atoms bonded to (e.g., chemically bonded to) the imageable radioisotope may be of the same type of chemical element as the atom in the core of the particle. In some embodiments, the particle contains an imageable radioisotope that lacks any intervening molecular species or different molecular species (e.g., a linker group) between the substrate and the imageable radioisotope.

[0127] In some embodiments, as disclosed elsewhere in this specification, the substrate comprises an inorganic material. In some embodiments, the inorganic material comprises one or more elements that are metalloids, metals, or both (as defined in the periodic table). In some embodiments, the inorganic material further comprises elements that are nonmetals. In some embodiments, the inorganic material comprises at least one nonmetal, metalloid, metal oxide, or transition metal oxide. In some embodiments, metalloid atoms, metal atoms, or both are bonded to nonmetal atoms to form the substrate structure. For example, in a substrate comprising a transition metal oxide, the oxygen of the oxide is considered a nonmetallic chemical element that provides at least a portion of the substrate. In some embodiments, the substrate comprises a crystal lattice, an amorphous structure, or a combination thereof. In some embodiments, the core of the substrate comprises a first portion of metalloid or metal atoms bonded to nonmetal atoms, and the surface comprises a second portion of metalloid or metal atoms bonded to nonmetal atoms. In some embodiments, as disclosed elsewhere in this specification, an imageable radioisotope is directly bonded to the substrate through at least a portion of nonmetal atoms on the surface of the substrate.

[0128] As will be readily apparent, the particle substrate may be made from various materials, such as one or more inorganic materials. In some embodiments, the substrate is an inorganic material. In some embodiments, the inorganic material includes and / or is a ceramic material. In some embodiments, the inorganic material includes at least one element selected from silicon, yttrium, manganese, aluminum, gallium, strontium, and titanium. In some embodiments, the inorganic material includes or is glass. In some embodiments, the inorganic material includes silicon dioxide. In some embodiments, the inorganic material includes silicon dioxide and at least one other element selected from yttrium, manganese, aluminum, gallium, boron, strontium, and titanium. In some embodiments, the inorganic material includes one or more of SiO2, Y2O3, MnO2, AlO3, Ga2O3, Fe2O3, SrO2, SrCO3, and / or TiO2. In some embodiments, the inorganic material includes SiO2 and one or more of Y2O3, MnO2, AlO3, Ga2O3, Fe2O3, SrO2, SrCO3, and / or TiO2. In some embodiments, the inorganic material includes SiO2 and one or more of Al2O3 and / or Y2O3.

[0129] In some embodiments, the substrate includes and / or is a ceramic material. In some embodiments, the substrate (e.g., a ceramic substrate) includes at least one element selected from silicon, yttrium, manganese, aluminum, gallium, strontium, and titanium. In some embodiments, the inorganic material (e.g., a ceramic substrate) includes or is glass. In some embodiments, the substrate (e.g., a ceramic substrate) includes silicon dioxide. In some embodiments, the substrate (e.g., a ceramic substrate) includes silicon dioxide and at least one other element selected from yttrium, manganese, aluminum, gallium, boron, strontium, and titanium. In some embodiments, the substrate (e.g., a ceramic substrate) includes one or more of SiO2, Y2O3, MnO2, Al2O3, Ga2O3, Fe2O3, SrO2, SrCO3, and / or TiO2. In some embodiments, the substrate (e.g., a ceramic substrate) comprises SiO2 and one or more of Y2O3, MnO2, Al2O3, Ga2O3, Fe2O3, SrO2, SrCO3, and / or TiO2. In some embodiments, the substrate (e.g., a ceramic substrate) comprises SiO2 and one or more of Al2O3 and / or Y2O3.

[0130] In some embodiments, the substrate contains yttrium aluminum silicon oxide. In some embodiments, the yttrium aluminum silicon oxide is 17Y2O3-19Al2O3-64SiO2 in mol%. As disclosed elsewhere in this specification, in some embodiments, the imageable substitutes disclosed herein are used as substitutes for TheraSphere® (Biocompatibles UK Ltd.). TheraSphere® consists of insoluble glass microspheres in which yttrium is an essential component of glass (i.e., TheraSphere® contains yttrium aluminum silicon oxide). Yttrium in the precursor particles of TheraSphere® is a naturally occurring non-radioactive isotope. 89 It is in the form of Y. 89Y is not a beta emitter and is not for radiation therapy. Before being used as a radiotherapy drug, the precursor particles are bombarded with neutrons to break down the particles. 89 Y is yttrium, 90 Convert to the beta-emitting form of Y (thus obtaining activated TheraSphere® particles). In some embodiments, the substrate used for the imageable radioisotope particles disclosed herein is 89 Including Y, 90 These are precursor TheraSphere® particles lacking Y. In other words, the yttrium in the yttrium aluminum silicon oxide disclosed herein is in its abundant natural form. 89 Provided in Y), which does not emit beta radiation. However, in some embodiments, the imageable radioisotopes may be bound to active yttrium-containing microspheres, and the microspheres 90 It may include Y.

[0131] In some embodiments, as disclosed elsewhere in this specification, the substrate comprises a single substance, while in other embodiments, the substrate may comprise multiple substances. If the substrate is substantially homogeneous, in some embodiments, the substrate may comprise a substantially homogeneous mixture of constituent elements (e.g., Si and O in SiO2). If the substrate is homogeneous, the surface also comprises at least a portion of these constituent elements (e.g., Si and O atoms), but the surface may also comprise terminal atoms (e.g., -H in -OH). In some embodiments, atoms provided within the core are also provided to the surface as part of a terminal functional group (e.g., O in -OH). As stated above, the terminal functional group may further comprise terminal atoms (e.g., -H in -OH). Such arrangements are shown below for illustrative purposes.

[0132] When particles are made from SiO2, they can be represented by the following structure (I):

[0133] [ka]

[0134] The structure of formula (I) includes terminal groups that do not necessarily need to be present in the core of the substrate, but the particle is still considered homogeneous because the terminal groups are provided by surface elements that are not components of the core.

[0135] More generally, in some embodiments, the particles may be represented as a structure having formula (II),

[0136] [ka]

[0137] Each M that appears c The element is independently selected from the group consisting of Pb, Al, Si, Y, Mn, Ga, Sr, Fe, and Ti. In some embodiments, M c The element is selected from the group consisting of Pb, Al, Si, Y, Mn, Ga, Fe, and Ti. In some embodiments, each M that appears is selected from the group consisting of Pb, Al, Si, Y, Mn, Ga, Fe, and Ti. c The element is independently selected from Si, Y, and Al. In some embodiments, when the surface of the substrate is functionalized, one or more OH groups on the surface are M as disclosed elsewhere in this specification. b (X) n It can include...

[0138] In some embodiments, the terminal groups of the substrate provide functional groups that can interact with and chemically bond to the imageable radioisotope, thereby forming imageable particles. Thus, in some embodiments, the imageable radioisotope is directly chemically bonded to the surface of the particle substrate. In some embodiments, as illustrated in the above structure, the inorganic substrate may include a surface having one or more electron-donating functional groups (e.g., -OH) that coordinate or covalently bond to the imageable radioisotope, thereby bonding it to the surface.

[0139] As described above, imageable radioisotopes may be used to decorate the surface of particles to provide imageable particles. In some embodiments, on average, each particle (e.g., microsphere) contains multiple radioisotopes (e.g., 2, 3, or 4) bound to the substrate. In some embodiments, on average, each particle (e.g., microsphere) contains a single radioisotope bound to the substrate. In some embodiments, not all microspheres are labeled with imageable radioisotopes. In some embodiments, the number of imageable radioisotopes per particle (e.g., functionalized on each particle) is about 1 x 10⁻¹⁶. -6 , 0.0001, 0.001, 0.01, 0.1, 0.5, 1, 2 or the range including and / or spanning the aforementioned values.

[0140] In some embodiments, an imageable radioisotope is characterized by the emission of detectable radiation. In some embodiments, the detectable radiation is one that is detectable by standard medical imaging techniques. In some embodiments, an imageable radioisotope emits radiation that is directly detectable, indirectly detectable, or both (e.g., the radiation is detectable by the imaging modality). For example, directly detectable radiation may include gamma rays from a gamma-emitting radioisotope. In other embodiments, the radiation itself may not be detectable, but instead may result in the generation of another imageable form of radiation. For illustrative purposes, an imageable radioisotope may be a positron emitter. When emitted from an imageable radioisotope, a positron collides with an electron in the patient's body, causing the positron and electron to annihilate and produce two gamma rays. The gamma rays can then be detected. In some embodiments, an imageable radioisotope is a positron emitter or a gamma emitter or both. In some embodiments, radiation from imageable radioisotopes can be detected directly or indirectly by imaging modalities.

[0141] In some embodiments, as disclosed elsewhere in this specification, the imageable isotope is configured to be imaged by an imaging modality. In some embodiments, the imaging modality is selected from single-photon imaging and two-photon imaging. In some embodiments, the imageable radioisotope is configured to be imaged by an imaging modality selected from positron emission tomography (PET), single-photon emission computed tomography (SPECT), and gamma camera imaging.

[0142] In some embodiments, the imageable radioisotope may be a metal. In some embodiments, the imageable radioisotope may be technetium-99m( 99m Tc), Thallium-201 ( 201 Th), Chromium-51 ( 51 Cr), Gallium-67( 67 Ga), Gallium-68( 68 Ga), Indium-111( 111 In), Copper-64( 64 Cu), Zirconium-89( 89 Zr), Iron-59( 59 Fe), potassium-42( 42 K), Rubidium-82 82 Rb), sodium-24( 24 Na), Titanium-45 45 Ti), Scandium-44 ( 44 Sc), Chromium-51 ( 51 Cr), Fluorine-18( 18 F), Lutetium-177( 177 Lu), and / or a combination thereof, are selected.

[0143] As described above, in some embodiments, the imageable radioisotopes are chemically bonded to the surface of the substrate via one or more chemical bonds. In some embodiments, the imageable radioisotopes may also be functionalized (or alternatively) to the surface of the particle substrate at least partially via inorganic crosslinking. Inorganic crosslinking is a series of atoms bonded together, lacking an organic moiety. As used herein, the term inorganic is used in its conventional sense and will be understood by those skilled in the art to refer to compounds (or parts or atoms thereof) lacking an organic carbon-based moiety (e.g., alkyl). As used herein, inorganic does not include organometallic entities.

[0144] If present, the inorganic crosslink includes a metal atom or metalloid atom that is not a radioisotope (e.g., a crosslinking metal atom). The inorganic crosslink also includes one or more nonmetallic atoms that are chemically bonded to a series of crosslinking atoms (e.g., crosslinking metal atoms) that span between the imageable radioisotope and the substrate, in other words, that crosslink between the imageable radioisotope and the substrate. In some embodiments, each atom forming the inorganic crosslink is chemically bonded to another atom in the inorganic crosslink, thereby linking the substrate and the imageable radioisotope through chemical bonding. In some embodiments, the inorganic crosslink includes a nonmetallic atom of the substrate, a crosslinking atom (e.g., a crosslinking metal atom), and a nonmetallic atom that is then chemically bonded to the imageable radioisotope. In some embodiments, the nonmetallic atom of the substrate is chemically bonded to a crosslinking atom (e.g., a crosslinking metal atom), and the crosslinking atom is chemically bonded to a nonmetallic atom that is chemically bonded to the imageable radioisotope.

[0145] In some embodiments, a crosslinked metal atom (e.g., Sn) is used during the functionalization of a substrate having an imageable radioisotope, first to image the radioisotope (e.g., 99mIt acts as a reducing agent for Tc). The bridging atoms may then remain chemically bonded between the imageable radioisotope and the substrate (e.g., through chemical bonds such as covalent bonds, coordination bonds and / or Lewis acid-base interactions). The imageable radioisotope and the bridging metal atom may be separated by a nonmetallic atom (e.g., O) which may be chemically bonded to both the imageable radioisotope and the bridging metal atom. This nonmetallic atom may be part of the inorganic bridge. Similarly, a nonmetallic atom (e.g., O) of the substrate may be directly bonded to the bridging metal atom that connects the bridging metal atom to the substrate. Although not constrained to any particular mechanism, tin (Sn) 99m It is a Tc bridging atom, 99m It is thought to act as part of the inorganic crosslink between Tc and the substrate. In some embodiments, the inorganic crosslink is an imageable radioisotope (e.g., 99m It contains or is composed of -O-Sn-O- which is chemically (e.g., through a chemical bond) connected to Tc). In some embodiments, for example in formula VIII, the inorganic bridge containing the -O-Sn-O- bridge is -OH,=O and -O - It may be further coupled to one or more of these (for example, -O-Sn(X) n Each X that appears, such as -O-, is -OH, =O, and -O - (where n is 1 or 2).

[0146] In some embodiments, the imageable radioisotope may be directly bonded to the substrate through atoms of the substrate (e.g., nonmetallic atoms such as O) and simultaneously bonded via inorganic crosslinks (e.g., via metal atoms that are not radioisotopes). Such configurations are shown in certain configurations of formula (VIII) below. In other embodiments, metal atoms that are not radioisotopes form chemically bonded crosslinks between the radioisotope and the surface of the substrate, and the radioisotope itself is chemically bonded to the substrate only through the crosslinking metal atoms (or multiple crosslinking metal atoms), as shown in some configurations of formula (V) below. For example, as shown in formula (V), the crosslinking metal can be chemically bonded to two nonmetals, and the two nonmetallic atoms (e.g., O) are further both chemically bonded to the imageable radioisotope.

[0147] In some embodiments, the imageable radioisotopes may be nonmetals. In some embodiments, the imageable particles may include imageable features that are metals bonded to imageable radioisotopes that are not metals. For example, metals and Al 18 There are complexes with imageable nonmetallic radioisotopes such as F. In some embodiments, this imageable complex is chemically bonded to the surface via aluminum atoms. 18 F is complexed with aluminum atoms. In some embodiments, the imageable complex is Al 18 It is F.

[0148] As described above, in some embodiments, radioactive isotopes are linked to the surface of the particles via the particle substrate. In some embodiments, the functionalization of the particle surface can be represented by the following formula (III),

[0149] [ka]

[0150] The base material is M cand M b It contains and is an imageable radioactive isotope. In some embodiments, M c It is selected from Si, Mn, Y, Al, Sr, Ga, Fe, Ti, and Pb (especially Si, Mn, Ti, and Pb), M b teeth, 201 Th, 51 Cr, 67 Ga, 68 Ga, 111 In, 64 Cu, 89 Zr, 59 Fe, 42 K, 82 Rb, 24 Na, 45 Ti, 44 Sc, 51 Cr, Al 18 F and 177 Selected from Lu, each appearing R is either nonexistent or -H, and each appearing X is -OH, =O, and -O - n is an integer selected independently from 0, 1, 2, 3, or 4. In some embodiments, M c It is selected from Sn, Si, Mn, Al, Ga, Fe, Ti and Pb, M b teeth, 201 Th, 51 Cr, 67 Ga, 68 Ga, 111 In, 64 Cu, 89 Zr, 59 Fe, 42 K, 82 Rb, 24 Na, 45 Ti, 44 Sc, 51 Cr, Al 18 F and 177 Selected from Lu, each appearing R is either nonexistent or -H, and each appearing X is -OH, =O, and -O - n is independently selected from 0, 1, 2, 3, or 4. In some embodiments, the substrate is M c Includes M b M is an imageable radioactive isotope. cIt is selected from Si, Mn, Al, Ga, Fe, Ti and Pb (especially Si, Mn, Ti and Pb), M b teeth 89 Zr is such that each R is -H, each X is -OH, and n is 2.

[0151] In some embodiments, the functionalization of the particle surface can be expressed by the following formula (IIIa):

[0152] [ka]

[0153] The variable groups are as disclosed elsewhere in this specification. For example, in some embodiments, the substrate is M c Includes M b is an imageable radioactive isotope. In some embodiments, M c m is selected from Si, Mn, Y, Al, Sr, Ga, Fe, Ti, and Pb (especially Si, Mn, Ti, and Pb), and m is an integer selected from 1, 2, or 3. b teeth, 201 Th, 51 Cr, 67 Ga, 68 Ga, 111 In, 64 Cu, 89 Zr, 59 Fe, 42 K, 82 Rb, 24 Na, 45 Ti, 44 Sc, 51 Cr, Al 18 F and 177 Selected from Lu, each appearing R is either nonexistent or -H, and each appearing X is -OH, =O, and -O - n is an integer selected independently from 0, 1, 2, 3, or 4. In some embodiments, M c It is selected from Sn, Si, Mn, Al, Ga, Fe, Ti and Pb, M b teeth, 201 Th, 51Cr, 67 Ga, 68 Ga, 111 In, 64 Cu, 89 Zr, 59 Fe, 42 K, 82 Rb, 24 Na, 45 Ti, 44 Sc, 51 Cr, Al 18 F and 177 Selected from Lu, each appearing R is either nonexistent or -H, and each appearing X is -OH, =O, and -O - n is independently selected from 0, 1, 2, 3, or 4. In some embodiments, the substrate is M c Includes M b M is an imageable radioactive isotope. c It is selected from Si, Mn, Al, Ga, Fe, Ti and Pb (especially Si, Mn, Ti and Pb), M b teeth 89 Zr is such that each R is -H, each X is -OH, and n is 2.

[0154] In some embodiments, imageable particles can be represented by the following structure (IV):

[0155] [ka]

[0156] The variable group is as defined elsewhere in this specification, for example, in Formula III. In some embodiments, as disclosed elsewhere in this specification, the substrate is M c Includes M b is an imageable radioactive isotope. In some embodiments, each M that appears c The elements are independently selected from Pb, Al, Si, Y, Mn, Ga, Fe, and Ti, and each M that appears is selected. b teeth, 201 Th, 51 Cr, 67 Ga, 68Ga, 111 In, 64 Cu, 89 Zr, 59 Fe, 42 K, 82 Rb, 24 Na, 45 Ti, 44 Sc, 51 Cr, Al 18 F and 177 Selected independently of Lu, each appearing R is either nonexistent or -H, and each appearing X is -OH, =O, and -O - n is an integer selected independently from 0, 1, 2, 3, or 4. In some embodiments, each M that appears c It is selected from Si, Al and Y, M b teeth 89 Zr, each X that appears is selected from -OH, and n is 2 or 3. In some embodiments, each M that appears c It is selected from Si, Al and Y, M b teeth 89 Zr, where each X that appears is -OH, and n is 2. In some embodiments, M c is Si, M b teeth 89 Zr is -OH, and n is 2. In some embodiments, R is -H. In some embodiments, when R is H, the structure of formula (IV) may be represented by the following formula (IVa).

[0157] [ka]

[0158] In some embodiments, when R is absent, the structure of formula (IV) may be represented by the following formula (IVb).

[0159] [ka]

[0160] In some embodiments, the surface of a particle can be represented by formula (V),

[0161] [ka]

[0162] M a This may be either a substrate atom or a crosslinking metal atom that chemically connects an imageable radioisotope to the substrate through chemical bonding. In some embodiments, for example, M a M is either an atom of the substrate or a crosslinking atom. a The material is selected from Pb, Al, Si, Y, Mn, Ga, Fe, Ti, Sr, and Sn, and the substrate is M c Includes M c m is independently selected from Pb, Al, Si, Y, Mn, Ga, Fe, and Ti, m is an integer selected from 1, 2, or 3, and Mb is 99m Tc, 201 Th, 51 Cr, 67 Ga, 68 Ga, 111 In, 64 Cu, 89 Zr, 59 Fe, 42 K, 82 Rb, 24 Na, 45 Ti, 44 Sc, 51 Cr, 177 Lu, Al 18 Selected from F and / or combinations thereof, each appearing R is independently either nonexistent or -H, and each appearing X is -OH, =O, -O - A substituent is independently selected from a monosubstituted amino group, a disubstituted amino group, a halogen, -CN, -CF3, an optionally substituted diamino group, or an optionally substituted triamino group, and the substituents of the amino group, if present, are independently C 1~6The R is alkyl, heteroaryl, or aryl, where n is an integer selected from 0, 1, 2, 3, or 4, and m is an integer equal to 1, 2, or 3. In some embodiments, each R that appears is either absent or H, and X is -OH, =O, and -O - Selected from, where n is an integer selected from 0, 1, 2, 3, or 4. In some embodiments, M a is Sn, and M a is a crosslinked metal atom. In some embodiments, the substrate is M a and M c Includes M b is an imageable radioactive isotope. In some embodiments, M a and M c It is independently selected from Pb, Al, Si, Y, Mn, Ga, Fe, and Ti, M b teeth, 201 Th, 51 Cr, 67 Ga, 68 Ga, 111 In, 64 Cu, 89 Zr, 59 Fe, 42 K, 82 Rb, 24 Na, 45 Ti, 44 Sc, 51 Cr, Al 18 F and 177 Selected from Lu, each appearing R is independently either nonexistent or -H, and each appearing X is either =O or -O - -OH, monosubstituted amino group, disubstituted amino group, halogen, -CN, -CF3, optionally substituted diamino group, optionally substituted triamino group, and the substituents of the amino group, if present, are independently C 1~6 It is an alkyl, heteroaryl, or aryl group, where n is an integer selected from 0, 1, 2, 3, or 4, and m is an integer equal to 1, 2, or 3.

[0163] In some embodiments, the substrate is M c Includes M cm is independently selected from Pb, Al, Si, Y, Mn, Ga, Fe, and Ti, and m is an integer selected from 1, 2, or 3. b teeth 99m Tc and M a is Sn, each R that appears is either nonexistent or H, X is -OH or =O, and n is 2 or 3.

[0164] In some embodiments, M a These are Si, Y, and Al, and M b teeth 89 Zr and M c is selected from Si, Al and Y, X is -OH, and n is 2. In some embodiments, M c is Si, Al, or Y, and M a is Sn, and M b teeth 99m Tc is such that each X is independently -OH or =O, and n is 2 or 3. In some embodiments, M b teeth 99m Tc is -OH, and n is 2 or 3.

[0165] Alternatively, in some embodiments, M b This may be an imageable radioisotope containing a host metal bonded to a non-metallic radioisotope. For example, Al 18 Examples include composites having nonmetallic, imageable radioisotopes such as F. In some embodiments, this composite is chemically bonded to the surface via aluminum atoms. 18 F is complexed with an aluminum atom. In some embodiments, M a and M c It is independently selected from Si, Al, Y, and Sn, and M b teeth, 99m Tc and 89 Selected from Zr, each X that appears is -OH, and n is 2 or 3. In some embodiments, M a and M c It is independently selected from Si, Al, Y, and Sn, and M b teeth 99mTc, where each X is -OH, and n is 2 or 3. In some embodiments, M a and M c It is independently selected from Si, Al, Y, and Sn, and M b teeth 99m Tc, where each X is selected from -OH and Sn, and n is 3. In some embodiments, M a and M c It is independently selected from Si, Al, and Y, and M b teeth 89 Zr, where each X that appears is -OH, and n is 2. In some embodiments, M a is Si, M c Al is M b teeth 89 Zr is -OH, and n is 2. In some embodiments, M a is Si, M c Al is M b teeth, 99m Tc is where each X that appears is independently selected from -OH and Sn, and n is 3. In some embodiments, R is -H.

[0166] In some embodiments, the surface of a particle can be represented by formula (VI),

[0167] [ka]

[0168] M c M b R, X, m, and n are as disclosed elsewhere in this specification. c M b R, X, m, and n may be as disclosed, for example, in relation to formula (V).

[0169] In some embodiments, the surface of a particle can be represented by formula (VII),

[0170] [ka]

[0171] M c M b R, X, and n are as disclosed elsewhere in this specification. c M b R, X, m, and n may be as disclosed, for example, in relation to formula (V).

[0172] In some embodiments, the surface of a particle can be represented by formula (VIII),

[0173] [ka]

[0174] M c M b X and n are as disclosed elsewhere in this specification. In some embodiments, the substrate is M a and M c Includes M a and M c m is independently selected from Pb, Al, Si, Y, Mn, Ga, Fe, Sr, and Ti, and m is an integer selected from 1, 2, or 3. b teeth, 99m Tc, 201 Th, 51 Cr, 67 Ga, 68 Ga, 111 In, 64 Cu, 89 Zr, 59 Fe, 42 K, 82 Rb, 24 Na, 45 Ti, 44 Sc, 51 Cr, 177 Lu, Al 18 F and / or a combination thereof, selected from M a These are atoms of the substrate or crosslinking atoms, M aThe element is selected from Sn, Pb, Al, Si, Y, Mn, Ga, Fe, and Ti, and each R that appears a is OH, O, -O-Sn(X) n Selected from -O or -OSnO-, each X that appears is -OH, =O, and -O - Selected from, each n is an integer selected from 0, 1, 2, 3, or 4. In some embodiments, M c Al is M a is Si, M b teeth 99m Tc is such that each X is independently -OH or =O, and n is 2 or 3. In some embodiments, M c Al is M a is Si, M b teeth 99m Tc and at least one R appear a is -O-Sn-O-, where each X is independently -OH or =O, and n is 2 or 3. In some embodiments, M c Al is M a is Si, M b teeth 99m Tc and at least one R appear a is -O-Sn(X) n It is -O-, and each X is independently -OH or =O, and each n that appears is 2 or 3. In some embodiments, M b teeth 99m Tc and at least one R appear a is -O-Sn-O-, where each X is independently -OH or =O, and n is 2 or 3. In some embodiments, M b teeth 99m Tc and at least one R appear a is -O-Sn(X) n It is -O-, where each X is -OH, and n is 2. In some embodiments, M b teeth 99m Tc, and one R appears. a It is -O-Sn-O- and one R appears a is -O- or -OH-, each X is independently -OH or =O, and n is 2 or 3. In some embodiments, Mb teeth 99m Tc, and one R appears. a is -O-Sn(X) n -O- and one R appears a x is -O- or -OH-, each X is independently -OH or =O, and n is 2 or 3.

[0175] In some embodiments, imageable particles can be represented by the structure shown in the following formula (IX):

[0176] [ka]

[0177] Variable groups are defined elsewhere in this specification.

[0178] In some embodiments, imageable particles can be represented by the structure shown in the following formula (X):

[0179] [ka]

[0180] Variable groups are defined elsewhere in this specification.

[0181] In some embodiments, the imageable radioisotopes may be selected based on their half-lives. For example, in some embodiments, imageable radioisotopes with shorter half-lives are selected, resulting in the body being exposed to radiation from the imageable radioisotopes for a shorter period of time. In some embodiments, the imageable radioisotopes have half-lives of approximately 1 day, 3 days, 7 days, 2 weeks, 1 month, 2 months, or a range including and / or spanning the aforementioned values.

[0182] In some embodiments, as disclosed elsewhere in this specification, the imageable elements are limited to the surface of the microspheres. In some embodiments, the substrate lacks imageable radioisotopes.

[0183] As described elsewhere in this specification, in some embodiments the substrate is porous. In other embodiments the substrate is non-porous. In some embodiments the porosity of particles as disclosed herein is measured by their surface area per unit weight. In some embodiments the surface area of ​​the substrate of particles disclosed herein is about 1 m² 2 / g, 0.5m 2 / g, 0.25m 2 / g, 0.1m 2 / g, 0.05m 2 The value is less than or equal to the range including and / or spanning the aforementioned values ​​of / g. In some embodiments, if the particles are substantially non-porous or lack porosity, the radioisotopes may be bonded to the circumferential surfaces of the particles (e.g., surfaces that are not within pores and are not internal to the outer periphery of the particles). In other embodiments, if the particles are porous, the radioisotopes may be bonded to any surfaces of the particles, including cavities or pores of the particles and / or the circumferential surfaces of the particles.

[0184] In some embodiments, the particles are microspheres. Microspheres are particles having microscale dimensions. In some embodiments, the microspheres have an average size of 5 μm to 1000 μm. In some embodiments, the particles are microspheres having an average size of 20 μm to 30 μm, or 15 μm to 100 μm. In some embodiments, the average size of the imageable particles is less than or equal to the range including and / or spanning approximately 500 nm, 1000 nm, 5 μm, 20 μm, 25 μm, 30 μm, 40 μm, 50 μm, 100 μm, 250 μm, 500 μm, 750 μm, 1000 μm, or the aforementioned values.

[0185] The diameter of the microspheres can be easily determined by light or scanning electron microscopy.

[0186] In some embodiments, the substrate for the imaging particles is selected for similarity, for example, in size, shape, density, and / or chemical composition, to particles currently used in SIRT and used as substitutes (except that these particles lack therapeutic radioisotopes). For example, TheraSphere consists of insoluble glass microspheres in which yttrium-90 is an essential component of the glass. These radioactive glass microspheres are approximately 20 μm to 30 μm in diameter. By providing imaging particles with similar dimensions and properties to therapeutic particles, the imaging particles can act as more accurate substitutes for therapeutic particles. In some embodiments, the composition of the imaging particles is selected such that the density of the imaging microspheres is the same as or close to the density of the therapeutic microspheres, and as a result, the motion and distribution of the imaging particles are similar to those of the therapeutic microspheres. In some embodiments, each milligram of imageable radioisotope particles contains approximately 5,000 particles, 10,000 particles, 20,000 particles, 30,000 particles, 50,000 particles, 70,000 particles, 80,000 particles, 100,000 particles, or a range including and / or spanning the aforementioned values.

[0187] While some embodiments disclosed herein refer to the use of microspheres, the term "particle" broadly includes microspheres and other particles to which imageable radioisotopes may be bound. For example, particles may vary in size and shape (e.g., cylindrical, cubic, pyramidal, box-shaped, etc.). In some embodiments, the shape of the particle is selected in accordance with the corresponding size and shape of the therapeutic particle, meaning that the imageable particle acts as a surrogate.

[0188] As described elsewhere in this specification, in some embodiments, the imageable microspheres lack therapeutic radioisotopes. In some embodiments, the imageable isotopes and / or imageable microspheres are non-therapeutic (e.g., they release a sufficient dose and / or a configured dose for imaging, but are insufficient to treat a patient). In some embodiments, the imageable microspheres are configured not to be delivered simultaneously with therapeutic microspheres. In some embodiments, the imageable microspheres are not exposed to neutron shock and / or neutron activation, and non-imageable isotopes of elements are converted into imageable radioisotopes of the imageable microspheres. In some embodiments, the imageable radioisotopes are imageable due to their radioactivity and not due to paramagnetism. In some embodiments, the image-forming agent is not a paramagnetic material and / or H-1, He-3, Li-7, B-7, B-9, N-15, O-17, F-19, Mg-27, Al-27, Si-29, S-33, C1-37, Ca-43, Ti-47, V-51, Cr-53, Mn-55, Fe-57, Ni-61, Cu-63, Zn-67, Ga-69, Ge-73, Kr-83, Sr-87, Y-89, Zr-91, Mo-95 It is not an imaging agent selected from the group consisting of Mo-97, Ru-99, Rh-103, Pd-105, Cd-11, Sn-115, Te-125, I-127, Ba-135, Ba-137, Xe-129, Xe-131, Nd-145, Gd-155, Dy-161, Er-167, Yb-171, W-183, Os-187, Pt-195, Hg-199, Tl-205, Pb-207, Pt-198, and H-2. In some embodiments, the imaging microspheres lack one or more of strontium phosphate, phosphates, or phosphorus. In some embodiments, the imaging microspheres do not contain a strontium phosphate and / or phosphorus layer on a substrate to which imaging isotopes are bonded. In some embodiments, the substrate is not organic, lacks organic matter, and / or is not a resin. In some embodiments, the imageable radioisotopes are not bonded to the substrate by any one of the following: a carboxylic acid group, a diphosphonic acid group, or a sulfonic acid group.In some embodiments, the imageable radioisotopes are not bonded to the substrate via any alkyl linker and / or nonmetallic crosslinking.

[0189] Manufacturing method and the resulting product Some embodiments relate to imageable radioisotope particles prepared by methods including obtaining particles as disclosed elsewhere in this specification. As disclosed herein, in some embodiments the particles include a substrate material. In some embodiments the substrate material includes a Lewis base component around the surface of the substrate (and / or throughout the substrate). In some embodiments the radioisotope is bonded to the substrate, and a chemical bond is formed between the substrate and the radioisotope of the particle. In some embodiments the imageable radioisotope is bonded to the substrate, and a chemical bond is formed between the imageable radioisotope, a nonmetallic atom, a bridging atom, a nonmetallic atom and the substrate of the particle. In some embodiments the chemical bond between the nonmetallic atom and the radioisotope is also formed to provide bridging from the radioisotope to the substrate. In some embodiments the constituent atoms of the bridging are bonded to each other through chemical bonds disclosed herein (e.g., coordination bonds, covalent bonds, etc.).

[0190] Some embodiments relate to imageable microspheres produced by a method comprising preparing a substrate comprising an inorganic material including a metalloid or metal. In some embodiments, the core of the substrate comprises a first portion of metalloid or metal atoms bonded to nonmetal atoms, and the surface comprises a second portion of metalloid or metal atoms bonded to nonmetal atoms. In some embodiments, as disclosed elsewhere in this specification, the imageable radioisotopes are directly bonded to the substrate (e.g., at least a portion of the nonmetal atoms on the surface of the substrate) via bridging metal atoms, through chemical bonding, or both. In some embodiments, the method further comprises obtaining at least one imageable radioisotope. In some embodiments, the method further comprises chemically bonding at least one imageable radioisotope to the surface of the substrate to obtain imageable microspheres.

[0191] In some embodiments, the method includes preparing at least one imageable radioisotope in ionic form, such as a salt, before chemically bonding at least one imageable radioisotope to the surface of an inorganic substrate. In some embodiments, the imageable radioisotope (e.g., in a radioisotope salt) has an oxidation state of 1, 2, 3, 4, or 5 or higher. In some embodiments, the imageable radioisotope salt has one or more counterions associated with the imageable radioisotope salt. In some embodiments, the counterions have an oxidation state of -1 or -2 or higher. In some embodiments, the salt is a halogen salt or a polyatomic salt.

[0192] In some embodiments, chemical functionalization is carried out in the presence of a reducing agent. In some embodiments, the substrate is in contact with a radioisotope in the presence of a reducing agent. In some embodiments, the reducing agent is selected from one or more of the following: tin salts (e.g., tin salts to prepare tin ions), HCl, sodium borohydride, sodium diotionate, ferrous sulfate, ferric chloride + ascorbic acid, hypophosphorous acid, and / or hydrazine.

[0193] In some embodiments, the imageable radioisotope may be any imageable radioisotope as disclosed elsewhere in this specification. In some embodiments, the imageable ceramic microspheres are ceramic microspheres 99m It can be obtained by reacting with Tc, 99m Tc may also be in the form of pertechnetium ions in the presence of a reducing agent such as tin ions (e.g., tin halides such as tin chloride).

[0194] Some embodiments involve reducing a ceramic microsphere substrate (e.g., including at least one nonmetal, metalloid, or transition metal oxide) in the presence of a reducing agent as described elsewhere in this specification. 99m Tc pertechnetium acid or other Tc(VII) ions, etc. 99mThe present invention relates to a method for preparing imageable ceramic microspheres, including reacting them with Tc ions. The ceramic microspheres may be in the form of glass microspheres, as described elsewhere in this specification.

[0195] In some embodiments, the ceramic microsphere substrate is 89 Zr oxalate or 89 This invention relates to a method for preparing imageable ceramic microspheres, which includes reacting them with a zirconium salt such as Zr chloride. This reaction may be carried out in the presence of a base.

[0196] Some embodiments relate to a method for producing imageable microspheres, which includes preparing an inorganic substrate and chemically functionalizing the inorganic substrate with at least one imageable radioisotope to prepare imageable microspheres.

[0197] Some embodiments relate to a method for producing imageable radioisotope particles. In some embodiments, the method includes a step of preparing at least one imageable radioisotope as a salt before a step of chemically functionalizing at least one imageable radioisotope on the surface of an inorganic substrate. In some embodiments, the salt is an alkali metal salt, an alkaline earth metal salt (imageable isotope is 18 (if F), halogen salts or polyatomic salts (for example, if the imageable isotope is 89 (If Zr) In some embodiments, the method includes adding a reducing agent during the chemical functionalization step. In some embodiments, (for example, if the imageable isotope is 99m (In the case of Tc) The reducing agent is selected from one or more of the following: tin salts (for example, tin halides or other tin salts to prepare tin ions), HCl, sodium borohydride, sodium diotionate, ferrous sulfate, ferric chloride + ascorbic acid, hypophosphorous acid, and / or hydrazine. In some embodiments, the reducing agent is capable of reducing Tc(VII) to Tc(V).

[0198] In some embodiments, the radioisotope (or a salt thereof) is added to the substrate (e.g., microspheres) by adding the radioisotope (or a salt thereof) to a solution containing the substrate. In some embodiments, the solution contains water. In some embodiments, the solution contains saline. In some embodiments, the solution has a pH of approximately 3.0, 4.0, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 9.0, 10.0 or a range including and / or spanning the aforementioned values. In some embodiments, the solution contains a buffer. In some embodiments, the buffer is selected from the group consisting of phosphate-buffered saline (PBS), citrate, acetate, or a combination thereof. In some embodiments, the solution lacks a buffer. Suitable pH ranges include pH 3 to pH 10 and pH 5 to pH 8.

[0199] Some embodiments provide imageable microspheres that can be obtained or obtained by the methods or processes described herein.

[0200] Method for using imageable radioactive isotope particles As disclosed elsewhere in this specification, some embodiments provide methods for using imagingable radioisotope particles. In some embodiments, imagingable radioisotope particles can be used as a substitute for therapeutic radioisotope particles without requiring the patient to be exposed to harmful therapeutic radiation. For example, as described above, in SIRT, therapeutic radioisotopes are introduced into the blood vessels of the patient's body through a catheter. These therapeutic particles are often used to treat liver cancer (e.g., hepatocellular carcinoma - HCC, as well as tumors resulting from metastases to the liver of other tumors such as neuroendocrine tumors and colorectal tumors) and vascular tumors such as cancers of the brain, prostate, lung, spleen, and kidneys.

[0201] Firstly, patients generally have different vascular systems, and the blood vessels surrounding tumors also differ from person to person. Therefore, what is therapeutic for one person may not be therapeutic, or even harmful, for another. In some patients, therapeutic particles may travel to undesirable areas of the body (off-target delivery), causing damage to off-target tissues. For example, when treating the liver, atypical vascularity may also result in off-target localization of microspheres, causing gastrointestinal tract damage, lung damage, or other undesirable site effects. A portion of microspheres delivered to or shunted to the lungs as off-target tissue (e.g., when a liver tumor is the intended target) is known, for example, as the pulmonary shunt portion or pulmonary shunt fraction. Furthermore, while surrogates for therapeutic particles exist, they do not closely match or resemble the actual therapeutic particles. Therefore, candidates who appear to have a high success rate may be rejected for treatment, while candidates who appear to have a low success rate may be able to receive treatment, potentially causing undesirable damage to other parts of the body.

[0202] However, the particles disclosed herein are well matched to SIRT therapeutic particles (including TheraSphere). These particles serve as more effective predictors of therapeutic distribution within the body. For that purpose, some of the methods disclosed herein relate to the use of imagingable radioisotope particles disclosed herein to predict the distribution of therapeutic radioisotope particles in a patient. In some embodiments, as disclosed elsewhere herein, a population of imagingable particles is administered to a patient to achieve imaging of a site in the patient. Different areas of the body (target and non-target sites) can then be imaged using an imaging modality, as disclosed elsewhere herein. In some embodiments, the population of imagingable particles may include particles having one imagingable radioisotope type. In other embodiments, the population may include particles having multiple different radioisotope types (e.g., 2, 3, 4 or more). For example, in some embodiments, a single radioisotope (e.g.,99m Only Tc) is present in the particle population. In other embodiments, multiple types of imageable radioisotopes (e.g., 99m Tc and 89 Zr) is present in the particle population. Some embodiments disclosed herein relate to a disclosed population of imageable particles comprising one or more imageable radioisotopes.

[0203] In some embodiments, imageable radioisotope particles can be used in methods of treating cancer, in which an appropriate dose of therapeutic radioisotope particles can be calculated based on the distribution of the imageable radioisotope particles. In some embodiments, imageable radioisotope particles may be used in methods of avoiding damage to off-target tissue from therapeutic radioisotope particles. In some embodiments, off-target tissue is normal and / or healthy tissue. In some embodiments, the off-target area may include the lungs or gastrointestinal tract (for example, when treating liver cancer). In some embodiments, imageable radioisotope particles can be used in methods of calculating an appropriate dose of radiation from therapeutic radioisotope particles. In some embodiments, imageable radioisotope particles can be used in methods of determining whether a treatment with therapeutic radioisotope particles will be successful for a patient. In some embodiments, imageable radioisotope particles can be used in methods of treating cancer by calculating the dose of therapeutic particles to administer.

[0204] In some embodiments, imageable radioisotope particles are used in a method to determine the amount of therapeutic microspheres to be delivered to a patient's body. In some embodiments of the method, a population of imageable particles is acquired. In some embodiments, the signal intensity per unit dose of imageable radioisotope particles is calculated. In some embodiments, patient-relative calibration is used, for example, when only therapeutic volume and expected therapeutic activity are required. In some embodiments, the population of imageable particles is then administered to the patient by introducing the population of imageable microspheres to a first location in the patient's vascular system. In some embodiments, the microspheres are injected to multiple locations in the vascular system, which may or may not overlap.

[0205] In some embodiments, after injecting a population of imageable microspheres into a patient (e.g., via a transcatheter), the particles are distributed within the patient's body for a certain period, generally until the particles are retained in the capillaries of their intended destinations. In some embodiments, the imageable radioisotope particles are distributed within the body for a period of about 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour or less, or a range including and / or spanning the aforementioned values.

[0206] In some embodiments, when imageable radioisotope particles are distributed in a patient's body, the location and / or abundance of these particles in the body can be mapped. For example, one or more parts or portions of the patient's body can be mapped using an imaging modality (e.g., gamma camera imaging, PET). 89 Zr particles, etc.), SPECT scanner ( 99mThese can be imaged using Tc particles (or other techniques as disclosed elsewhere in this specification). These parts of the body may include target areas of the body where treatment is desired. Furthermore, off-target areas of the body (e.g., areas where treatment and / or radiation damage is undesirable) can be imaged to determine whether a damaging amount of particles reaches those areas. The relative dose of imageable radioisotope particles in each target and / or off-target area can be determined, for example, by comparing the signal intensity in each area. In some embodiments, the dose in a particular area (e.g., an organ or part of the body) is determined by comparing the intensity of the radiation signal in that area with the total radiation intensity in the body or several other areas of the body, or in the treatment volume. The relative dose of imageable radioisotope particles in each target and / or off-target area can be determined, for example, by comparing the signal intensity in each area. In some embodiments, the dose of therapeutic particles that are believed to be delivered to a particular region is calculated by comparing the intensity of the radiation signal from the imaging particles in the target region and / or off-target region with the signal intensity per unit dose of imaging radioisotope particles.

[0207] In some embodiments, the predicted dose of therapeutic particles expected to be delivered to a target region is calculated by totaling the imagingable signals from the target region and any off-target regions and determining the proportion of the total signal obtained from the target region. This proportion may then be used to determine the total dose of therapeutic particles to be delivered in order to deliver the required dose of therapeutic particles to the target region. This approach may also be used to determine the proportion of the dose of therapeutic particles delivered to any off-target tissue (e.g., lungs, gastrointestinal tract, brain, reproductive tissue, mucosa, or any other radiosensitive organ). In some embodiments, these calculations may be performed on a volume basis, in other words, based on the signals obtained from the volume of the target and / or off-target tissue. For example, if 60% of the signal from the radioisotope is at the target site and 40% is at the off-target site, the approximate radiation dose at the target site can be calculated to be 60% of the given total dose. Similarly, the radiation dose at the off-target site can be calculated to be 40%.

[0208] In some embodiments, off-target areas or parts of the body may include those most sensitive to undesirable damage from therapeutic radioisotope particles. Examples include the lungs and gastrointestinal system (other parts of the body may also be imaged, such as reproductive tissue, mucous membranes or other radiosensitive organs, the brain, kidneys, heart, or any other radiosensitive organs or tissues). Target areas of the body are selected for treatment (e.g., the liver of a patient with liver cancer). Target areas may include malignant or benign tumors in patients requiring treatment. Examples of target areas include liver cancer (e.g., hepatocellular carcinoma (HCC), as well as tumors resulting from metastases to the liver from other tumors such as neuroendocrine tumors and colorectal tumors) and vascular tumors (e.g., malignant or benign tumors), such as tumors found in brain, prostate, lung, spleen, and kidney cancers.

[0209] In some embodiments, once relative doses in one or more target or off-target regions are determined, a decision can be made as to whether the patient is a good candidate for treatment. For example, if the dose of therapeutic particles required to treat the patient's liver cancer is so high that it could cause lung or gastrointestinal damage, the patient may be withdrawn from treatment. Such damage may occur, for example, if there is a vascular system that could shunt the radioactive microspheres to the lungs or gastrointestinal tract. If the dose of therapeutic microspheres required to treat the liver is not sufficient to cause side effects (such as lung or gastrointestinal damage), the patient may be selected for treatment.

[0210] In some embodiments, the amount of therapeutic microspheres delivered to the patient's body can also be calculated using the distribution of imageable radioisotope particles. For example, the amount of therapeutic particles to administer can be determined using the radiation dose per unit dose of imageable particles at a site (target or off-target) if the therapeutic radiation dose per unit dose of therapeutic particles is known. In some embodiments, a target radiation dose of 80 Gy to 150 Gy can be achieved to the liver using the imageable particles described herein. In some embodiments, a target radiation dose of 80 Gy to 300 Gy can be achieved to the liver using the imageable particles described herein. In some embodiments, a target radiation dose of 200 Gy to 300 Gy can be achieved to the liver using the imageable particles described herein.

[0211] In some embodiments, the method includes obtaining data relating to the distribution of imageable therapeutic microsphere substitutes in a patient. In some embodiments, the method includes using the data to determine a therapeutic dose of microspheres to be administered to the patient's body. In some embodiments, the method includes distributing a population of therapeutic microspheres within the patient's body to treat the patient.

[0212] Some embodiments relate to methods for predicting the extent of damage to off-target tissues such as the lungs or gastrointestinal tract, or the extent of treatment of the liver, during treatment of a patient requiring radioisotope cancer therapy. In some embodiments, the method includes introducing a population of imageable microspheres into a patient. In some embodiments, the method includes distributing the imageable microspheres into the patient over a period of time. In some embodiments, the method includes determining the distribution of imageable microspheres in the patient's lungs, gastrointestinal tract, or liver by imaging the imageable microspheres using an imaging modality. In some embodiments, the method includes determining the estimated dose of radiation in the patient's lungs, gastrointestinal tract, or liver if the imageable microspheres are replaced with radioisotope therapy microspheres. In some embodiments, the method includes determining a dose of radioisotope therapy microspheres sufficient to cause clinically relevant lung changes due to off-target delivery of microspheres to the lungs. In some embodiments, the method includes administering to a patient a dose of radioisotope therapeutic microspheres that is less than or equal to a dose of radioisotope therapeutic microspheres determined to be sufficient to cause clinically relevant lung changes due to off-target delivery. In some embodiments, the method includes determining a dose of radioisotope therapeutic microspheres that is sufficient to cause clinically relevant damage due to off-target delivery of the microspheres to the gastrointestinal tract. In some embodiments, the method includes administering to a patient a dose of radioisotope therapeutic microspheres that is less than or equal to a dose of radioisotope therapeutic microspheres determined to be sufficient to cause clinically relevant gastrointestinal damage due to off-target delivery.

[0213] Some embodiments provide imagingable particles and microspheres as described herein for use in a method for determining or estimating the distribution of therapeutic microspheres, or in a method for determining the therapeutic dose of therapeutic microspheres as described herein.

[0214] In some embodiments, at the time of injection, a dose of microspheres having a radioactivity intensity of approximately 50 microcuries (μCi), 100 μCi, 150 μCi, 250 μCi, 1000 μCi, 2000 μCi, or 4000 μCi (or a range including and / or spanning the aforementioned values) or less is injected. In some embodiments, a dose of 10 mg to 100 mg of microspheres is injected. In some embodiments, a smaller dose of microspheres (mg) of approximately 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 250 mg, 500 mg, or a range including and / or spanning the aforementioned values ​​or less is administered to the subject.

[0215] Kit and instructions for use Some embodiments relate to kits comprising imageable radioisotope particles, such as those disclosed herein.

[0216] In some embodiments, the kit includes instructions for carrying out the method described herein to react the de-derivatized microspheres and imageable radioisotopes with the microspheres.

[0217] In some embodiments, the kit includes a microsphere comprising a substrate made of an inorganic material containing metalloid or metal atoms bonded to nonmetal atoms, the substrate comprising a core extending to a surface, the core comprising a first portion of metalloid or metal atoms bonded to nonmetal atoms, and the surface comprising a second portion of metalloid or metal atoms bonded to nonmetal atoms, and instructions for reacting an imageable radioisotope with the substrate in order to directly bond an imageable isotope to the substrate through at least a portion of the nonmetal atoms on the surface of the substrate.

[0218] In some embodiments, the kit includes microspheres containing an inorganic substrate, and instructions for bonding an imageable radioisotope to the surface of the inorganic substrate via Lewis acid-base coordination bonds, wherein the inorganic substrate comprises at least one nonmetal, metalloid, or transition metal oxide.

[0219] In some embodiments, the kit includes microspheres containing a ceramic microsphere substrate and instructions for carrying out a reaction in which an imageable radioisotope is bonded to the ceramic microsphere substrate. In some embodiments, the instructions are for carrying out a reaction in which the imageable radioisotope is bonded to the ceramic microsphere substrate as a Lewis acid-base adduct.

[0220] In some embodiments, the kit contains microspheres in a sealed unit with a filling volume of 50 μl to 2 ml. In some embodiments, the sealed unit may be a container such as a vial, for example, a glass vial, and in other embodiments, the sealed unit may be a syringe. The microspheres can be prepared sterile.

[0221] In some embodiments, the kit may contain additional reducing agents.

[0222] In some embodiments, the kit includes instructions for using a catheter to introduce imagingable microspheres into a patient. In some embodiments, the kit includes therapeutic microspheres. In some embodiments, the kit includes one or more of the following: a vascular access needle, a vascular guidewire, a vascular sheath (e.g., 4-6 Fr), a vascular catheter (4-5 Fr), a microcatheter, a syringe, and a vial.

[0223] In some embodiments, an imageable radioisotope particle dosing set is obtained. In some embodiments, the set includes a sterile disposable tubing set and one empty sterile vial. In some embodiments, the tubing set is made from pre-assembled sterile components and is intended for single use only. In some embodiments, the pre-assembled tubing set includes a needle plunger assembly and an integrated 20cc syringe. In some embodiments, a one-way valve incorporated into the dosing set controls the flow of fluid so that it flows only in the appropriate direction. In some embodiments, the syringe is filled from the fluid source by retracting the syringe plunger. In some embodiments, pushing the syringe plunger moves the fluid toward the needle plunger assembly. In some embodiments, prior to injection, the dosing set is manually pre-primed by pushing a sterile flushing solution through the set to purge air from the line.

[0224] In some embodiments, a management accessory kit is provided. In some embodiments, the management accessory kit includes reusable accessories, including one or more acrylic box bases, top shields, removable side shields, and bag hooks. In some embodiments, the administration accessory kit facilitates monitoring of the infusion process and provides beta radiation shielding. In some embodiments, the administration accessory kit should be positioned on a sturdy cart or table next to the patient, near the infusion catheter inlet Luer fitting. In some embodiments, an extension arm on the accessory kit facilitates alignment and positioning of the administration set / patient catheter connection.

[0225] In some embodiments, the imageable radioisotope particle dose vial remains sealed within the supplied transparent acrylic vial shield throughout the entire administration procedure. In some embodiments, a removable plug on top of the acrylic vial shield provides access to the septum of the imageable radioisotope particle dose vial. In some embodiments, the needle plunger assembly is designed to snap onto the top of the acrylic shield and, once snapped into place, cannot be easily removed. In some embodiments, the needle plunger assembly provides stability and alignment of the needle as it is inserted through the septum when the tab is pressed down on the plunger assembly.

[0226] In some embodiments, a constant syringe pressure should be maintained at a flow rate of 20 cc / min or more for the duration of each flush. One flush is 20 cc as indicated on the syringe barrel. In some embodiments, using a flow rate of less than 20 cc / min (i.e., appropriate for the original vascular flow) may reduce the delivery efficiency of the administration system. In some embodiments, flushing should be continued until optimal delivery of imageable radioisotope particles is achieved. In some embodiments, a minimum of three flushes for a total of 60 cc is recommended. In some embodiments, the injection pressure should not exceed 30 psi in any flush. In some embodiments, a pressure relief valve in the administration set is included to prevent overpressurization.

[0227] In some embodiments, to minimize the possibility of high radiation doses reaching the hands, hemostatic agents, forceps, or towels / gauze are used when handling parts of the administration set after injection. In some embodiments, before administration, the acrylic shield containing the dose is measured at a distance of 30 cm from the detector.

[0228] Some embodiments include a sealed unit containing 50 μl to 2 ml of the non-derivative microspheres described herein in a filled volume. The sealed unit may be, for example, a vial or a syringe.

[0229] In some embodiments, the non-derivative microspheres include a substrate comprising an inorganic material containing metalloid or metal atoms bonded to nonmetal atoms, the substrate comprising a core extending to a surface, the core comprising a first portion of metalloid or metal atoms bonded to nonmetal atoms, and the surface comprising a second portion of metalloid or metal atoms bonded to nonmetal atoms.

[0230] In some embodiments, the non-derivative microspheres include a substrate comprising an inorganic material containing a metalloid or metal atom bonded to a nonmetal atom, the substrate comprising a core extending to a surface, the core comprising a first portion of a metalloid or metal atom bonded to a nonmetal atom, and the surface comprising a second portion of a metalloid or metal atom bonded to a nonmetal atom as described herein.

[0231] In some embodiments, the non-derivative microspheres include a ceramic microsphere substrate as described herein. The microspheres can be prepared sterile.

[0232] Listed embodiments Various embodiments of particles, microspheres, and methods disclosed herein can be found in the following non-limiting sections.

[0233] 1. At least one imageable radioactive isotope, A substrate comprising an inorganic material containing a metalloid or metal atom bonded to a nonmetal atom, wherein the substrate is A substrate comprising a core extending to the surface, the core comprising a first portion of a metalloid or metal atom bonded to a nonmetal atom, and the surface comprising a second portion of a metalloid or metal atom bonded to a nonmetal atom, and A microsphere that can be imaged, Imageable microspheres in which imageable radioisotopes are directly bonded to a substrate through at least a portion of nonmetallic atoms on the substrate surface.

[0234] 2. At least one imageable radioactive isotope, A substrate comprising an inorganic material containing a metalloid or metal atom bonded to a nonmetal atom, wherein the substrate is A substrate and a surface comprising a core extending to the surface, wherein the core and surface comprise a semimetallic or metallic atom and a nonmetallic atom of the substrate. A microsphere that can be imaged, Imageable microspheres in which imageable radioisotopes are directly bonded to the substrate through nonmetallic atoms on the substrate surface, and / or imageable radioisotopes are bonded to the substrate through inorganic crosslinks containing nonmetallic atoms on the substrate surface.

[0235] 3. At least one imageable radioactive isotope, A substrate comprising an inorganic material containing a metalloid or metal atom bonded to a nonmetal atom, wherein the substrate is A substrate and a surface comprising a core extending to the surface, wherein the core and surface comprise a semimetallic or metallic atom and a nonmetallic atom of the substrate. A microsphere that can be imaged, Imageable microspheres in which imageable radioisotopes are directly bonded to the substrate through nonmetallic atoms on the substrate surface, and / or imageable radioisotopes are bonded to the substrate through inorganic crosslinks containing nonmetallic atoms on the substrate surface.

[0236] 4. An imageable microsphere according to any one of Embodiments 1 to 3, wherein the nonmetallic atom is an oxygen atom.

[0237] 5. The imageable microsphere according to Embodiment 4, wherein at least a portion of the oxygen atoms on the surface of the substrate are provided as hydroxyl groups.

[0238] 6. An inorganic substrate having a surface layer, At least one imageable radioactive isotope and A microsphere that can be imaged, The substrate comprises at least one nonmetal, metalloid, or transition metal oxide. Imageable microspheres in which imageable radioisotopes are bonded to the surface of a substrate via Lewis acid-base coordination bonds.

[0239] 7. An inorganic substrate having a surface having 1 or more electron-donating functional groups, A surface containing at least one imageable radioactive isotope and A microsphere that can be imaged, Imageable microspheres in which imageable radioisotopes are bonded to the surface of a substrate via chemical bonding with one or more electron-donating functional groups during the preparation of imageable microspheres.

[0240] 8. An imageable microsphere according to any one of embodiments 1 to 7, wherein imageable radioisotopes are bonded via chemical bonds selected from ionic bonds, covalent bonds, or coordinate bonds.

[0241] 9. The imageable microsphere according to Embodiment 8, wherein imageable radioisotopes are bonded via coordination bonds.

[0242] 10. An imaging microsphere comprising a ceramic microsphere substrate and at least one imaging radioactive isotope, Imageable microspheres in which imageable radioisotopes are bonded as Lewis acid-base adducts to the surface of a ceramic microsphere substrate.

[0243] 11. At least one imageable radioactive isotope, A substrate comprising an inorganic material containing a metalloid or metal atom bonded to a nonmetal atom, wherein the substrate is A substrate comprising a core extending to the surface, the core comprising a first portion of a metalloid or metal atom bonded to a nonmetal atom, and the surface comprising a second portion of a metalloid or metal atom bonded to a nonmetal atom, and A microsphere that can be imaged, Imageable microspheres in which imageable radioisotopes are directly bonded to the substrate through nonmetallic atoms on the substrate surface, and / or imageable radioisotopes are bonded to the substrate through inorganic crosslinks containing nonmetallic atoms on the substrate surface.

[0244] 12. Imageable microspheres according to embodiments 1 to 11, wherein imageable radioisotopes are directly bonded to the substrate through nonmetallic atoms on the surface of the substrate.

[0245] 13. Imageable microspheres according to embodiments 1 to 12, wherein the substrate is bonded to the substrate through nonmetallic atoms on the surface of the substrate via inorganic metal crosslinking.

[0246] 14. An imageable microsphere according to any one of Embodiments 1 to 13, wherein the substrate comprises a substantially homogeneous mixture of constituent chemical elements.

[0247] 15. An imageable microsphere according to Embodiment 14, wherein the surface comprises at least a portion of the constituent chemical elements.

[0248] 16. An imageable microsphere according to any one of Embodiments 1 to 15, wherein the nonmetallic atom is an oxygen atom.

[0249] 17. An imageable microsphere according to Embodiment 16, wherein at least a portion of the oxygen atoms on the surface of the substrate are hydroxyl groups.

[0250] 18. An inorganic substrate having a surface, At least one imageable radioactive isotope and A microsphere that can be imaged, The base material includes at least one nonmetal and at least one metalloid or metal, Imageable microspheres in which imageable radioisotopes are bonded to the surface of a substrate via Lewis acid-base coordination bonds to an inorganic Lewis base.

[0251] 19. An inorganic substrate having a surface, At least one imageable radioactive isotope and A microsphere that can be imaged, The base material includes at least one nonmetal and at least one metalloid or metal, Imageable microspheres in which imageable radioactive isotopes are bonded to the surface of a substrate by chemical bonding to inorganic oxygen.

[0252] 20. An inorganic substrate having a surface with 1 or more electron-donating functional groups, At least one imageable radioactive isotope and A microsphere that can be imaged, Imageable microspheres in which imageable radioisotopes are directly bonded to the surface and / or bonded to the surface via inorganic crosslinking during the preparation of imageable microspheres, through chemical bonding with one or more electron-donating functional groups.

[0253] 21. The imageable microsphere according to Embodiment 20, wherein an imageable radioisotope is directly bonded to the surface of a substrate.

[0254] 22. An imageable microsphere according to any one of Embodiments 1 to 21, wherein the substrate comprises a metal oxide, a transition metal oxide, a metalloid oxide, or a combination thereof.

[0255] 23. An imageable microsphere according to any one of embodiments 1 to 22, wherein an imageable radioisotope is bonded to a substrate via a chemical bond selected from ionic, covalent, or coordinate bonds.

[0256] 24. The imageable microsphere according to Embodiment 23, wherein imageable radioisotopes are bonded via coordination bonds.

[0257] 25. An imaging microsphere comprising a ceramic microsphere substrate and at least one imaging radioisotope, Imageable microspheres in which imageable radioisotopes are bonded to the surface of a ceramic microsphere substrate as Lewis acid-base adducts of inorganic Lewis bases.

[0258] 26. The imageable microsphere according to Embodiment 25, wherein an inorganic Lewis base is a component of the substrate, and imageable isotopes are directly bonded to the surface of the substrate via the inorganic Lewis base.

[0259] 27. The imageable microsphere according to Embodiment 26, wherein an imageable radioisotope is bonded to the surface of a ceramic microsphere substrate via an inorganic linker containing a Lewis base.

[0260] 28. An imageable microsphere according to Embodiment 27, wherein the inorganic linker is a metal oxide.

[0261] 29. An imageable microsphere according to Embodiment 28, wherein the metal oxide is tin oxide.

[0262] 30. An imageable microsphere according to any one of embodiments 25 to 29, wherein the Lewis base is oxygen of a metal oxide or metalloid oxide.

[0263] 31. An imageable microsphere according to any one of embodiments 18 to 30, wherein the Lewis base is oxygen tin oxide.

[0264] 32. An imageable microsphere according to any one of embodiments 1 to 31, wherein an imageable isotope is configured to be imaged by an imaging modality selected from single-photon imaging and two-photon imaging.

[0265] 33. The imageable microsphere according to any one of embodiments 1 to 32, wherein the imageable radioisotopes are configured to be imaged by an imaging modality selected from positron emission tomography (PET), single-photon emission computed tomography (SPECT), and gamma camera imaging.

[0266] 34. An imageable microsphere according to any one of embodiments 1 to 33, wherein at least one imageable radioisotope is a positron emitter or a gamma emitter.

[0267] 35. An imageable microsphere according to any one of embodiments 1 to 34, wherein at least one imageable radioisotope is a metallic radioisotope.

[0268] 36. At least one imageable radioactive isotope, 99m Tc, 201 Th, 51 Cr, 67 Ga, 68 Ga, 111 In, 64 Cu, 89 Zr, 59 Fe, 42 K, 82 Rb, 24 Na, 45 Ti, 44 Sc, 51 Cr, 18 F, 177 Lu, Al 18 An imageable microsphere according to any one of embodiments 1 to 34, selected from F and / or a combination thereof.

[0269] 37. An imageable microsphere according to any one of Embodiments 1 to 34, wherein at least one imageable radioisotope is selected from 99mTc and 89Zr. 38. Structure of equation (V):

[0270] [ka]

[0271] (In the formula, The base material is M c Includes M c It is selected from Pb, Al, Si, Y, Mn, Ga, Fe, Sr and Ti. m is an integer selected from 1, 2, or 3. M bteeth, 99m Tc, 201 Th, 51 Cr, 67 Ga, 68 Ga, 111 In, 64 Cu, 89 Zr, 59 Fe, 42 K, 82 Rb, 24 Na, 45 Ti, 44 Sc, 51 Cr, 18 F, 177 Lu, Al 18 Selected from F and / or a combination thereof, M a This is either an atom of the substrate or a crosslinking metal atom, M a It is selected from Sn, Pb, Al, Si, Y, Mn, Ga, Fe, Sr, and Ti. Each R that appears is either nonexistent or -H. X is -OH, =O and -O - Selected from, n is an integer selected from 0, 1, 2, 3, or 4. An imageable microsphere according to any one of embodiments 1 to 34, including the imageable microsphere described above.

[0272] 39.M c Al is, The base material is M a Includes M a is Si, M b but 89 It is Zr, Each X independently becomes -OH or -O - And, An imageable microsphere according to embodiment 38, wherein n is 1 or 2.

[0273] 40.M b but 89 An imageable microsphere according to embodiment 38 or 39, wherein Zr is -OH and n is 2.

[0274] 41.M cis Si, M a Sn is, M b but 99m Tc, Each X independently becomes -OH or -O - And, An imageable microsphere according to embodiment 38, wherein n is 2 or 3.

[0275] 42.M b but 99m An imageable microsphere according to Embodiment 38, wherein Tc is -OH and n is 3.

[0276] 43. Structure of equation (VIII):

[0277] [ka]

[0278] (In the formula, The base material is M a and M c Includes M a and M c It is independently selected from Pb, Al, Si, Y, Mn, Ga, Fe, and Ti. m is an integer selected from 1, 2, or 3. M b teeth, 99m Tc, 201 Th, 51 Cr, 67 Ga, 68 Ga, 111 In, 64 Cu, 89 Zr, 59 Fe, 42 K, 82 Rb, 24 Na, 45 Ti, 44 Sc, 51 Cr, 177 Lu, Al 18 Selected from F and / or a combination thereof, Each R that appears a These are independently OH, O, or -O-Sn(X)n -O-, X is -OH, =O, and -O - Selected from, n is an integer selected from 0, 1, 2, 3, or 4. An imageable microsphere according to any one of embodiments 1 to 34, including the imageable microsphere described above.

[0279] 44.M c Al is M a is Si, M b but 99m An imageable microsphere according to Embodiment 43, wherein Tc is and each X is independently -OH or =O, and n is 2 or 3.

[0280] 45.M b but 99m Tc and at least one R appear a -O-Sn(X) n An imageable microsphere according to Embodiment 43, wherein each X is independently -OH or =O, and n is 2 or 3.

[0281] 46.M b but 99m Tc, and one R appears. a is -O-Sn-O-, and one R appears a An imageable microsphere according to Embodiment 43, wherein is -O- or -OH-, and each X is independently -OH or =On, and n2 or 3.

[0282] 47. An imageable microsphere according to any one of Embodiments 1 to 46, wherein the substrate comprises at least one nonmetal, metalloid, transition metal, and metal.

[0283] 48. An imageable microsphere according to any one of Embodiments 1 to 47, wherein the substrate comprises a ceramic material.

[0284] 49. The imageable microsphere according to Embodiment 48, wherein the ceramic comprises at least one element selected from silicon, yttrium, manganese, aluminum, gallium, and titanium.

[0285] 50. An imageable microsphere according to any one of Embodiments 1 to 49, wherein the substrate includes glass.

[0286] 51. An imageable microsphere according to any one of Embodiments 1 to 50, wherein the substrate comprises silicon dioxide and at least one other element selected from manganese, aluminum, gallium, yttrium, boron, and titanium.

[0287] 52. An imageable microsphere according to any one of Embodiments 1 to 51, wherein the substrate comprises SiO2, Y2O3, MnO2, AlO3, Ga2O3, Fe2O3, TiO2, SrCO3, SrO2, or a combination thereof.

[0288] 53. The substrate is SiO2 and Y2O3, MnO2, AlO3, Ga2O3, Fe2O3, TiO 2、 An imageable microsphere according to any one of Embodiments 1 to 52, comprising at least one of SrCO3 and SrO2.

[0289] 54. Imagingable microspheres according to any one of Embodiments 1 to 53, wherein the substrate comprises yttrium aluminum silicon oxide.

[0290] 55. An imageable microsphere according to any one of Embodiments 1 to 54, wherein the imageable microsphere lacks a therapeutic radioisotope.

[0291] 56. An imageable microsphere according to any one of Embodiments 1 to 55, wherein the imageable microsphere has a diameter of 5 μm to 1000 μm.

[0292] 57. An imageable microsphere according to any one of Embodiments 1 to 56, wherein the substrate is nonporous.

[0293] 58. An imageable microsphere according to any one of Embodiments 1 to 56, wherein the substrate is porous.

[0294] 59. The process of preparing the base material, A step of obtaining imageable microspheres by chemically bonding at least one imageable radioactive isotope to a substrate, and An imageable microsphere according to any one of embodiments 1 to 58, produced by a method including the above.

[0295] 60. Inorganic materials containing metal or metalloid atoms bonded to nonmetal atoms, A core containing a first portion of nonmetallic atoms, and Substrate including a surface containing a second portion of nonmetallic atoms The process of preparing, A step of preparing at least one imageable radioactive isotope, A step of obtaining imageable microspheres by chemically bonding at least one imageable radioactive isotope to the surface of a substrate through a second portion of a nonmetallic atom. Microspheres that can be imaged, produced by a method including [a specific method].

[0296] 61. The imageable microsphere according to Embodiment 59 or 60, further comprising the step of preparing at least one imageable radioactive isotope as a salt before the step of chemically bonding at least one imageable radioactive isotope to the surface layer of an inorganic substrate.

[0297] 62. The imageable microsphere according to Embodiment 61, wherein the salt is an alkali metal salt, an alkaline earth metal salt, a halogen salt, a polyatomic salt, or a salt having an organic acid.

[0298] 63. Imagingable microspheres according to embodiments 59 to 62, wherein chemical functionalization is carried out in the presence of a reducing agent.

[0299] 64. The imageable microspheres according to Embodiment 63, wherein the reducing agent is selected from one or more of tin salts, tin hydrate, concentrated HCl, sodium borohydride, sodium dithionite, ferrous sulfate, ferric chloride + ascorbic acid, hypophosphorous acid, and / or hydrazine.

[0300] 65. Radioactive isotopes 99m The imageable microspheres according to embodiments 59 to 63, wherein the microsphere is Tc and chemical functionalization is carried out in the presence of a tin salt.

[0301] 66. Radioactive isotopes 99m Imageable microspheres according to Embodiment 65, prepared in the form of Tc pertechnetium acid and chemically functionalized in the presence of tin ions.

[0302] 67. 89 Zr 89 Imagingable microspheres according to embodiments 59-62, provided in the form of Zr oxalate.

[0303] 68. 89 Zr 89 The imageable microspheres described in Embodiment 67 are provided in the form of Zr oxalate.

[0304] 69. A method for preparing imageable microspheres, comprising the steps of: preparing a ceramic microsphere substrate; and reacting the ceramic microsphere substrate with an imageable radioisotope under conditions suitable for bonding the radioisotope to the surface of the ceramic microspheres.

[0305] 70. The method according to embodiment 69, wherein a radioactive isotope is bonded to the surface of a ceramic microsphere in the form of a Lewis acid-base adduct.

[0306] 71. The method according to Embodiment 69 or 70, wherein the radioactive isotope is a metallic radioactive isotope.

[0307] 72. Radioactive isotopes, 99m Tc, 201 Th,51 Cr, 67 Ga, 68 Ga, 111 In, 64 Cu, 89 Zr, 59 Fe, 42 K, 82 Rb, 24 Na, 45 Ti, 44 Sc, 51 Cr, 18 F, Al 18 The method according to any one of embodiments 59 to 61, selected from F and / or a combination thereof.

[0308] 73. The method according to any one of embodiments 69 to 72, wherein the radioactive isotope is prepared in the form of a salt.

[0309] 74. The method according to any one of embodiments 69 to 73, wherein a radioactive isotope is reacted with ceramic microspheres in the presence of a reducing agent.

[0310] 75. The method according to Embodiment 74, wherein the reducing agent is selected from one or more of tin salts, tin hydrate, HCl, sodium borohydride, sodium dithionite, ferrous sulfate, ferric chloride + ascorbic acid, hypophosphorous acid, and / or hydrazine.

[0311] 76. Radioactive isotopes 99m The method according to any one of embodiments 69 to 75, wherein Tc is...

[0312] 77. 99m The method according to embodiment 76, wherein Tc is provided in the form of a pertechnetium salt.

[0313] 78. 99m The method according to Embodiment 76, wherein Tc is prepared in the form of a pertechnetium salt and the reaction is carried out in the presence of tin ions.

[0314] 79. Radioactive isotopes 89 The method according to any one of embodiments 69 to 75, wherein Zr is Zr.

[0315] 80. 89 Zr 89 The method according to embodiment 79, provided in the form of Zr oxalate.

[0316] 81. The method according to Embodiment 79 or 80, wherein the reaction is carried out in the presence of a base.

[0317] 82. The process of preparing an inorganic substrate, A process to obtain imageable microspheres by chemically functionalizing an inorganic substrate with at least one imageable radioactive isotope. A method for producing imageable microspheres according to any one of embodiments 1 to 68, including the above.

[0318] 83. The method according to Embodiment 82, further comprising the step of preparing at least one imageable radioisotope as a salt before chemically functionalizing the surface of an inorganic substrate with at least one imageable radioisotope.

[0319] 84. The method according to Embodiment 83, wherein the salt is an alkali metal salt, an alkaline earth metal salt, a halogen salt, a polyatomic salt, or a salt having an organic acid.

[0320] 85. The method according to Embodiment 83 or 84, further comprising adding a reducing agent during the chemical functionalization step.

[0321] 86. The method according to Embodiment 85, wherein the reducing agent is selected from one or more of tin salts, tin hydrate, HCl, sodium borohydride, sodium dithionite, ferrous sulfate, ferric chloride + ascorbic acid, hypophosphorous acid, and / or hydrazine.

[0322] 87. Radioactive isotopes 99m The method according to any one of embodiments 82 to 86, wherein Tc is...

[0323] 88. 99m The method according to Embodiment 87, wherein Tc is provided in the form of a pertechnetium salt.

[0324] 89. 99m The method according to Embodiment 87, wherein Tc is prepared in the form of a pertechnetium salt and the reaction is carried out in the presence of tin ions.

[0325] 90. Radioactive isotopes 89 The method according to any one of embodiments 82 to 89, wherein Zr is Zr.

[0326] 91. 89 Zr 89 The method according to embodiment 90, provided in the form of Zr oxalate.

[0327] 92. The method according to Embodiment 90 or 91, wherein the reaction is carried out in the presence of a base.

[0328] 93. The method according to any one of embodiments 69 to 92, carried out under aqueous conditions.

[0329] 94. The method according to any one of embodiments 69 to 93, further comprising the steps of recovering imageable microspheres and / or washing the microspheres to remove unreacted radioisotopes.

[0330] 95. The method of any one of embodiments 69 to 94, further comprising resuspending the imageable microspheres in a pharmaceutically acceptable injectable aqueous medium.

[0331] 96. Imagingable microspheres that can be obtained by the method described in any of embodiments 69 to 95.

[0332] 97. A method for determining the amount of therapeutic microspheres to be provided to a patient's body, The process of preparing a collection of microspheres that can be imaged, The process involves delivering a population of imageable microspheres to a patient by introducing the population of imageable microspheres to a first location in the patient's vascular system, A process of distributing a group of imageable microspheres within the patient's body, A step of determining the distribution of at least a portion of the population of imageable microspheres within a patient's body by imaging a portion of the patient's body using an imaging modality, The process involves calculating the amount of therapeutic microspheres delivered into the patient's body using the distribution of microspheres that can be imaged. Methods that include...

[0333] 98. The method according to embodiment 97, wherein a portion of the body is the patient's off-target area, and the off-target area is the patient's lungs.

[0334] 99. The method according to embodiment 97, wherein a part of the body is the target region of the patient, and the target region is the patient's liver.

[0335] 100. The method according to any one of embodiments 97 to 99, wherein the target region is divided into tumor tissue and non-tumor tissue.

[0336] 101. The method according to any one of embodiments 97 to 100, wherein the amount of therapeutic microspheres to be delivered to the patient is calculated.

[0337] 102. The method according to Embodiment 91, wherein the calculated amount is delivered to the patient.

[0338] 103. The method according to any one of embodiments 97 to 102, wherein the imaging modality is SPECT.

[0339] 104. The method according to any one of embodiments 97 to 102, wherein the detection modality is PET.

[0340] 105. The method according to any one of embodiments 97 to 102, wherein the detection modality is a gamma camera image.

[0341] 106. The method according to any one of embodiments 97 to 102, wherein the imageable microsphere is an imageable microsphere described in any one of embodiments 1 to 68.

[0342] 107. A method of treating a patient, The process of preparing a collection of microspheres that can be imaged, The process involves delivering a population of imageable microspheres to a patient by introducing the population of imageable microspheres to a first location in the patient's vascular system, A process of distributing a group of imageable microspheres within the patient's body, The process involves determining the distribution of at least a portion of the population of imageable microspheres within a patient's body by imaging a target area of ​​the patient's body using an imaging modality, A process of calculating the amount of therapeutic microspheres delivered into the patient's body using the distribution of microspheres that can be imaged, A process to obtain data on the distribution of imagingable therapeutic microsphere substitutes in patients, A process of determining the therapeutic dose of microspheres to be administered to the patient's body using data, The process involves delivering a population of therapeutic microspheres to a patient by introducing the population of therapeutic microspheres to a second location in the patient's vascular system, The process involves distributing a group of therapeutic microspheres within the patient's body to treat the patient. Methods that include...

[0343] 108. The method according to Embodiment 107, wherein the second location in the patient's vascular system is the same as the first location in the patient's vascular system.

[0344] 109. The method according to Embodiment 107 or 108, wherein the imaging modality is SPECT.

[0345] 110. The method according to embodiment 107 or 108, wherein the detection modality is PET.

[0346] 111. The method according to Embodiment 107 or 108, wherein the detection modality is a gamma camera image.

[0347] 112. The method according to either embodiment 107 or 111, wherein the imageable microsphere is an imageable microsphere described in any one of embodiments 1 to 68.

[0348] 113. A method of treating a patient with therapeutic microspheres, A process to obtain data calculated from the distribution of imageable therapeutic microsphere substitutes in patients, A process of determining the amount of therapeutic microspheres to be administered to the patient's body using data, A process of delivering a quantity of therapeutic microspheres to a patient by introducing the quantity of therapeutic microspheres to a first location in the patient's vascular system, The process of distributing therapeutic microspheres within the patient's body, The process involves leaving therapeutic microspheres in the patient's body to treat the patient. Methods that include...

[0349] 114. The method according to embodiment 113, further comprising the step of preparing a population of imageable microspheres in a patient.

[0350] 115. The method according to Embodiment 114, further comprising the step of delivering a population of imageable microspheres to a patient by introducing the population of imageable microspheres to a first location in the vascular system of the patient's body.

[0351] 116. The method according to embodiment 115, further comprising the step of distributing a population of imageable microspheres within the body of a patient.

[0352] 117. The method according to Embodiment 116, further comprising the step of determining the distribution of at least a portion of a population of imageable microspheres within a patient's body by imaging a target portion of the patient's body using an imaging modality.

[0353] 118. The method according to Embodiment 117, further comprising the step of calculating the amount of therapeutic microspheres to be delivered to the patient's body using the distribution of imageable microspheres.

[0354] 119. A method for treating a tumor in a patient requiring treatment, The process involves introducing a population of microspheres that can be imaged into a patient, A process of distributing imageable microspheres to a patient over a certain period of time, The process involves determining the distribution of imageable microspheres in a patient's area by imaging imageable microspheres using an imaging modality, and A step of determining the estimated effective dose at a site when the imageable microspheres are replaced with therapeutic microspheres, based on the distribution of imageable microspheres, The process involves administering a quantity of therapeutic microspheres to the patient based on the estimated effective dose. Methods that include...

[0355] 120. The method according to Embodiment 119, wherein the population of imageable microspheres includes imageable microspheres described in any one of Embodiments 1 to 68.

[0356] 121. The method according to Embodiment 119 or 120, wherein the site is a malignant or benign tumor and / or non-tumorous tissue.

[0357] 122. The method according to Embodiment 119 or 120, wherein the site is a malignant tumor.

[0358] 123. The method according to Embodiment 122, wherein the site is a malignant tumor.

[0359] 124. A method for predicting the extent of off-target delivery to the lungs or gastrointestinal tract during treatment of a patient requiring radioisotope cancer therapy, The process involves introducing a population of microspheres that can be imaged into a patient, A process of distributing imageable microspheres to a patient over a certain period of time, The process involves determining the distribution of imageable microspheres within a patient's lungs by imaging imageable microspheres using an imaging modality, When imaging microspheres are replaced with radioisotope therapy microspheres, the process involves determining the estimated radiation dose in the patient's lungs or gastrointestinal tract, respectively. A step of determining a dose of radioisotope therapy microspheres sufficient to cause clinically relevant pulmonary or gastrointestinal changes due to off-target delivery, The process involves administering to a patient a dose of radioisotope therapeutic microspheres that is less than or equal to the dose of radioisotope therapeutic microspheres determined to be sufficient to cause clinically relevant pulmonary or gastrointestinal changes due to off-target delivery. Methods that include...

[0360] 125. The method according to Embodiment 124, wherein the population of imageable microspheres includes imageable microspheres described in any one of Embodiments 1 to 68.

[0361] 126. A method for reducing lung or gastrointestinal tract damage during treatment for patients requiring radioisotope cancer therapy, The process involves introducing a population of microspheres that can be imaged into a patient, A process of distributing imageable microspheres to a patient over a certain period of time, A step of determining the distribution of imageable microspheres within a patient's gastrointestinal tract or lungs by imaging imageable microspheres using an imaging modality, When imagingable microspheres are replaced with radioisotope therapy microspheres, the process involves determining the estimated radiation dose in the patient's gastrointestinal tract or lungs. A step of determining the dose of radioactive isotope therapy microspheres sufficient to cause damage to the gastrointestinal tract, The process of administering to a patient a dose of radioisotope therapy microspheres that is less than or equal to the dose of radioisotope therapy microspheres determined to be sufficient to cause damage to the gastrointestinal tract. Methods that include...

[0362] 127. The method according to Embodiment 126, wherein the population of imageable microspheres includes imageable microspheres described in any one of Embodiments 1 to 68.

[0363] 128. It is a kit, A microsphere comprising a substrate containing an inorganic material that includes metalloid or metal atoms bonded to nonmetal atoms, wherein the substrate is The surface includes a core extending to the surface, the core includes a first portion of a metalloid or metal atom bonded to a nonmetal atom, and the surface includes a second portion of a metalloid or metal atom bonded to a nonmetal atom. Microspheres and, Instructions for reacting an imageable radioisotope with a substrate such that the imageable radioisotope directly bonds to the substrate through at least a portion of the nonmetallic atoms on the substrate surface. A kit that includes this.

[0364] 129. It is a kit, Microspheres comprising an inorganic substrate containing at least one nonmetal, metalloid, or transition metal oxide, Instructions for bonding imageable radioisotopes to the surface of an inorganic substrate via Lewis acid-base coordination bonds. A kit that includes this.

[0365] 130. A kit including instructions for carrying out a reaction in which microspheres containing a ceramic microsphere substrate and an imageable radioisotope are bonded to the ceramic microsphere substrate as a Lewis acid-base adduct.

[0366] 131. A kit according to any one of embodiments 128 to 130, comprising a sealed unit containing microspheres in a packed volume of 10 μl to 2 ml.

[0367] 132. A kit according to any one of embodiments 128 to 131, wherein microspheres are provided in a vial or syringe.

[0368] 133. Imageable radioactive isotopes, 99m Tc, 201 Th, 51 Cr, 67 Ga, 68 Ga, 111 In, 64Cu, 89 Zr, 59 Fe, 42 K, 82 Rb, 24 Na, 45 Ti, 44 Sc, 51 Cr, 18 F, Al 18 A kit according to any one of embodiments 128 to 132, selected from one or more types of F.

[0369] 134. A kit according to any one of embodiments 128 to 133, further comprising a reducing agent.

[0370] 135. The kit according to Embodiment 134, wherein the reducing agent is selected from one or more of tin salts, tin hydrate, concentrated HCl, sodium borohydride, sodium dithionite, ferrous sulfate, ferric chloride + ascorbic acid, hypophosphorous acid, and / or hydrazine.

[0371] 136. The reducing agent is a tin salt, and the radioactive isotope is 99m The kit according to Embodiment 134 or 135, wherein the radioactive isotope is Tc and is in the form of a pertechnetium salt.

[0372] 137. Radioactive isotopes 89 A kit according to any one of embodiments 128 to 133, wherein the material is Zr.

[0373] 138. Radioactive isotopes 89 The kit according to Embodiment 137, in the form of zirconium oxalate or zirconium chloride.

[0374] 139. A kit according to any one of embodiments 128 to 138, further comprising therapeutic microspheres.

[0375] 140. The kit according to Embodiment 139, wherein the therapeutic microspheres contain a therapeutic radioisotope.

[0376] 141. Therapeutic microspheres, 90 Y, 166 Ho,177 Lu, 131 I, 89 Sr, 153 Sm, 223 Ra, 224 Ra, 211 At, 225 Ac, 227 Th, 212 Bi, 213 Bi and / or 212 The kit according to embodiment 140, which includes Pb.

[0377] 142. The kit according to any one of embodiments 139 to 141, wherein the therapeutic microspheres have the same chemical composition as the imaging microspheres.

[0378] 143. A kit according to any one of Embodiments 139 to 142, wherein the therapeutic microspheres contain yttrium aluminum silicon oxide.

[0379] 144. A kit according to any one of embodiments 128 to 143, further comprising one or more of a vascular access needle, a vascular guidewire, a vascular sheath (e.g., 4-6 Fr), a vascular catheter (4-5 Fr), a microcatheter, a syringe, and a vial.

[0380] 145. At least one imageable radioactive isotope, An imageable microsphere comprising a substrate containing an inorganic material that includes metalloid or metal atoms bonded to nonmetal atoms, wherein the substrate is A substrate comprising a core extending to the surface, the core comprising a first portion of a metalloid or metal atom bonded to a nonmetal atom, and the surface comprising a second portion of a metalloid or metal atom bonded to a nonmetal atom, and A microsphere that can be imaged, Imageable microspheres in which imageable radioisotopes are directly bonded to the substrate through nonmetallic atoms on the substrate surface, and / or imageable radioisotopes are bonded to the substrate through inorganic crosslinks containing nonmetallic atoms on the substrate surface.

[0381] 146. The imageable microsphere according to Embodiment 145, wherein an imageable radioisotope is directly bonded to the substrate through nonmetallic atoms on the surface of the substrate.

[0382] 147. An imageable microsphere according to Embodiment 145 or 146, wherein the substrate is bonded to the substrate through nonmetallic atoms on the surface of the substrate via inorganic metal crosslinking.

[0383] 148. Imagingable microspheres according to any one of embodiments 145 to 147, wherein the substrate comprises a substantially homogeneous mixture of constituent chemical elements.

[0384] 149. An imageable microsphere according to Embodiment 148, wherein the surface comprises at least a portion of the constituent chemical elements.

[0385] 150. An imageable microsphere according to any one of embodiments 145 to 149, wherein the nonmetallic atom is an oxygen atom.

[0386] 151. An imageable microsphere according to Embodiment 150, wherein at least a portion of the oxygen atoms on the surface of the substrate are hydroxyl groups.

[0387] 152. An inorganic substrate having a surface, At least one imageable radioactive isotope and A microsphere that can be imaged, The base material includes at least one nonmetal and at least one metalloid or metal, Imageable microspheres in which imageable radioisotopes are bonded to the surface of a substrate via Lewis acid-base coordination bonds to an inorganic Lewis base.

[0388] 153. An inorganic substrate having a surface, At least one imageable radioactive isotope and A microsphere that can be imaged, The base material includes at least one nonmetal and at least one metalloid or metal, Imageable microspheres in which imageable radioactive isotopes are bonded to the surface of a substrate by chemical bonding to inorganic oxygen.

[0389] 154. An inorganic substrate having a surface having 1 or more electron-donating functional groups, At least one imageable radioactive isotope and A microsphere that can be imaged, Imageable microspheres in which imageable radioisotopes are directly bonded to the surface and / or bonded to the surface via inorganic crosslinking during the preparation of imageable microspheres, through chemical bonding with one or more electron-donating functional groups.

[0390] 155. The imageable microsphere according to Embodiment 154, wherein an imageable radioisotope is directly bonded to the surface of a substrate.

[0391] 156. An imageable microsphere according to any one of Embodiments 145 to 155, wherein the substrate comprises a metal oxide, a transition metal oxide, a metalloid oxide, or a combination thereof.

[0392] 157. An imageable microsphere according to any one of embodiments 145 to 156, wherein an imageable radioisotope is bonded to a substrate via a chemical bond selected from ionic, covalent, or coordinate bonds.

[0393] 158. An imageable microsphere according to Embodiment 157, wherein imageable radioisotopes are bonded via coordination bonds.

[0394] 159. An imaging microsphere comprising a ceramic microsphere substrate and at least one imaging radioactive isotope, Imageable microspheres in which imageable radioisotopes are bonded to the surface of a ceramic microsphere substrate as Lewis acid-base adducts of inorganic Lewis bases.

[0395] 160. The imageable microsphere according to Embodiment 159, wherein an inorganic Lewis base is a component of the substrate, and imageable isotopes are directly bonded to the surface of the substrate via the inorganic Lewis base.

[0396] 161. An imageable microsphere according to any one of embodiments 159 to 160, wherein an imageable radioisotope is bonded to the surface of a ceramic microsphere substrate via an inorganic linker containing a Lewis base.

[0397] 162. An imageable microsphere according to Embodiment 161, wherein the inorganic linker is a metal oxide.

[0398] 163. An imageable microsphere according to Embodiment 162, wherein the metal oxide is tin oxide.

[0399] 164. An imageable microsphere according to any one of embodiments 159 to 163, wherein the Lewis base is oxygen of a metal oxide or metalloid oxide.

[0400] 165. An imageable microsphere according to any one of embodiments 152 to 164, wherein the Lewis base is oxygen tin oxide.

[0401] 166. An imageable microsphere according to any one of embodiments 145 to 165, wherein an imageable isotope is configured to be imaged by an imaging modality selected from single-photon imaging and two-photon imaging.

[0402] 167. An imageable microsphere according to any one of embodiments 145 to 166, wherein an imageable radioisotope is configured to be imaged by an imaging modality selected from positron emission tomography (PET), single-photon emission computed tomography (SPECT), and gamma camera imaging.

[0403] 168. An imageable microsphere according to any one of embodiments 145 to 167, wherein at least one imageable radioisotope is a positron emitter or a gamma emitter.

[0404] 169. An imageable microsphere according to any one of embodiments 145 to 168, wherein at least one imageable radioisotope is a metallic radioisotope.

[0405] 170. At least one imageable radioactive isotope, 99m Tc, 201 Th, 51 Cr, 67 Ga, 68 Ga, 111 In, 64 Cu, 89 Zr, 59 Fe, 42 K, 82 Rb, 24 Na, 45 Ti, 44 Sc, 51 Cr, 18 F, Al 18 Imageable microspheres according to any one of embodiments 145 to 168, selected from F and / or a combination thereof.

[0406] 171. At least one imageable radioactive isotope 99m Tc and 89 An imageable microsphere according to any one of embodiments 145 to 168, selected from Zr.

[0407] 172. Structure of equation (V):

[0408] [ka]

[0409] (In the formula, The base material is M c Includes M c It is selected from Pb, Al, Si, Y, Mn, Ga, Fe, Sr and Ti. m is an integer selected from 1, 2, or 3. M b teeth, 99m Tc, 201Th, 51 Cr, 67 Ga, 68 Ga, 111 In, 64 Cu, 89 Zr, 59 Fe, 42 K, 82 Rb, 24 Na, 45 Ti, 44 Sc, 51 Cr, 18 F, 177 Lu, Al 18 Selected from F and / or a combination thereof, M a This is either an atom of the substrate or a crosslinking metal atom, M a However, it is selected from Sn, Pb, Al, Si, Y, Mn, Ga, Fe, Sr, and Ti. Each R that appears is either nonexistent or -H. X is -OH, =O, and -O - Selected from, n is an integer selected from 0, 1, 2, 3, or 4. An imageable microsphere according to any one of embodiments 145 to 168, including the above.

[0410] 173. M c Al is, The base material is M a Includes M a is Si, M b but 89 It is Zr, Each X independently becomes -OH or -O - And, n is either 1 or 2. An imageable microsphere as described in Embodiment 172.

[0411] 174.M b but 89 An imageable microsphere according to embodiment 172 or 173, wherein Zr is -OH and n is 2.

[0412] 175.M c is Si, M a Sn is, M b but 99m Tc, Each X independently becomes -OH or -O - And, n is 2 or 3. An imageable microsphere as described in Embodiment 172.

[0413] 176.M b but 99m An imageable microsphere according to Embodiment 172, wherein Tc is -OH and n is 3.

[0414] 177. Structure of equation (VIII): (VIII) (In the formula, the base material is M a and M c Includes M a and M c It is independently selected from Pb, Al, Si, Y, Mn, Ga, Fe, Sr, and Ti. m is an integer selected from 1, 2, or 3. M b teeth, 99m Tc, 201 Th, 51 Cr, 67 Ga, 68 Ga, 111 In, 64 Cu, 89 Zr, 59 Fe, 42 K, 82 Rb, 24 Na, 45 Ti, 44 Sc, 51 Cr, 177 Lu, Al 18 Selected from F and / or a combination thereof, Each R that appears a These are independently OH, O, or -O-Sn(X) n -O-, X is -OH, =O, and -O - Selected from, n is an integer selected from 0, 1, 2, 3, or 4. An imageable microsphere according to any one of embodiments 145 to 168, including the imageable microsphere described above.

[0415] 178.M c Al is M a is Si, M b but 99m An imageable microsphere according to Embodiment 177, wherein Tc is and each X is independently -OH or =O, and n is 2 or 3.

[0416] 179.M b but 99m Tc and at least one R appear a -O-Sn(X) n An imageable microsphere according to Embodiment 177, wherein each X is independently -OH or =O, and n is 2 or 3.

[0417] 180.M b but 99m Tc, and one R appears. a is -O-Sn-O-, and one R appears a An imageable microsphere according to Embodiment 177, wherein is -O- or -OH-, each X independently is -OH or =On, and n is 2 or 3.

[0418] 181. An imageable microsphere according to any one of embodiments 145 to 180, wherein the substrate comprises at least one nonmetal, metalloid, transition metal, and metal.

[0419] 182. An imageable microsphere according to any one of embodiments 145 to 181, wherein the substrate comprises a ceramic material.

[0420] 183. The imageable microsphere according to Embodiment 182, wherein the ceramic comprises at least one element selected from silicon, yttrium, manganese, aluminum, gallium, and titanium.

[0421] 184. An imageable microsphere according to any one of embodiments 145 to 183 or 182, wherein the substrate includes glass.

[0422] 185. An imageable microsphere according to any one of embodiments 145 to 184, wherein the substrate comprises silicon dioxide and at least one other element selected from manganese, aluminum, gallium, yttrium, boron, and titanium.

[0423] 186. Imagingable microspheres according to any one of Embodiments 145 to 185, wherein the substrate comprises SiO2, Y2O3, MnO2, AlO3, Ga2O3, Fe2O3, TiO2, SrO2, SrCO3, or a combination thereof.

[0424] 187. An imageable microsphere according to any one of Embodiments 145 to 186, wherein the substrate comprises SiO2 and at least one of Y2O3, MnO2, AlO3, Ga2O3, Fe2O3, TiO2, SrCO3, and SrO2.

[0425] 188. Imagingable microspheres according to any one of embodiments 145 to 187, wherein the substrate comprises yttrium aluminum silicon oxide.

[0426] 189. Imagingable microspheres according to any one of embodiments 145 to 188, wherein the imagingable microspheres lack therapeutic radioisotopes.

[0427] 190. An imageable microsphere according to any one of embodiments 145 to 189, wherein the imageable microsphere has a diameter of 5 μm to 1000 μm.

[0428] 191. An imageable microsphere according to any one of embodiments 145 to 190, wherein the substrate is nonporous.

[0429] 192. An imageable microsphere according to any one of embodiments 145 to 190, wherein the substrate is porous.

[0430] 193. The process of preparing the base material, A step of obtaining imageable microspheres by chemically bonding at least one imageable radioactive isotope to a substrate, and An imageable microsphere according to any one of embodiments 145 to 192, prepared by a method including the above.

[0431] 194. Inorganic materials containing metal or metalloid atoms bonded to nonmetal atoms, A core containing the first portion of nonmetallic atoms and surface containing the second portion of nonmetallic atoms A step of preparing a substrate containing, A step of preparing at least one imageable radioactive isotope, A step of obtaining imageable microspheres by chemically bonding at least one imageable radioactive isotope to the surface of a substrate through a second portion of a nonmetallic atom. Microspheres that can be imaged, produced by a method including [a specific method].

[0432] 195. The imageable microsphere according to Embodiment 193 or 194, further comprising the step of preparing at least one imageable radioactive isotope as a salt before chemically bonding at least one imageable microsphere to the surface layer of an inorganic substrate.

[0433] 196. The imageable microsphere according to Embodiment 195, wherein the salt is an alkali metal salt, an alkaline earth metal salt, a halogen salt, a polyatomic salt, or a salt having an organic acid.

[0434] 197. Imageable microspheres according to embodiments 193 to 196, wherein chemical functionalization is carried out in the presence of a reducing agent.

[0435] 198. The imaging microspheres according to Embodiment 197, wherein the reducing agent is selected from one or more of tin salts, tin hydrate, concentrated HCl, sodium borohydride, sodium dithionite, ferrous sulfate, ferric chloride + ascorbic acid, hypophosphorous acid, and / or hydrazine.

[0436] 199. Radioactive isotopes 99m Imageable microspheres according to embodiments 193 to 197, wherein the microsphere is Tc and chemical functionalization is carried out in the presence of a tin salt.

[0437] 200. Radioactive isotopes 99m Imageable microspheres according to Embodiment 199, prepared in the form of Tc pertechnetium acid and chemically functionalized in the presence of tin ions.

[0438] 201. Radioactive isotopes 89 Imageable microspheres, which are Zr, as described in embodiments 193 to 196.

[0439] 202. 89 Zr 89 Imageable microspheres according to Embodiment 201, provided in the form of Zr oxalate.

[0440] 203. A method for preparing imageable microspheres, comprising the steps of: preparing a ceramic microsphere substrate; and reacting the ceramic microsphere substrate with an imageable radioisotope under conditions suitable for bonding the radioisotope to the surface of the ceramic microspheres.

[0441] 204. The method according to embodiment 203, wherein a radioactive isotope is bonded to the surface of a ceramic microsphere in the form of a Lewis acid-base adduct.

[0442] 205. The method according to Embodiment 203 or 204, wherein the radioactive isotope is a metallic radioactive isotope.

[0443] 206. Radioactive isotopes, 99m Tc, 201 Th, 51 Cr, 67 Ga, 68 Ga, 111 In, 64 Cu, 89 Zr, 59 Fe, 42 K, 82 Rb, 24 Na,45 Ti, 44 Sc, 51 Cr, 18 F, Al 18 The method according to any one of embodiments 203 to 205, selected from F and / or a combination thereof.

[0444] 207. The method according to any one of embodiments 203 to 206, wherein the radioactive isotope is prepared in the form of a salt.

[0445] 208. The method according to any one of embodiments 203 to 207, wherein a radioactive isotope is reacted with ceramic microspheres in the presence of a reducing agent.

[0446] 209. The method according to Embodiment 208, wherein the reducing agent is selected from one or more of tin salts, tin hydrate, HCl, sodium borohydride, sodium dithionite, ferrous sulfate, ferric chloride + ascorbic acid, hypophosphorous acid, and / or hydrazine.

[0447] 210. Radioactive isotopes 99m The method according to any one of embodiments 203 to 209, wherein Tc is the same.

[0448] 211. 99m The method according to Embodiment 210, wherein Tc is provided in the form of a pertechnetium salt.

[0449] 212. 99m The method according to Embodiment 210, wherein Tc is prepared in the form of a pertechnetium salt and the reaction is carried out in the presence of tin ions.

[0450] 213. Radioactive isotopes 89 The method according to any one of embodiments 203 to 209, wherein Zr is Zr.

[0451] 214. 89 Zr 89 The method according to Embodiment 213, provided in the form of Zr oxalate.

[0452] 215. The method according to Embodiment 213 or 214, wherein the reaction is carried out in the presence of a base.

[0453] 216. The process of preparing an inorganic substrate, A process to obtain imageable microspheres by chemically functionalizing an inorganic substrate with at least one imageable radioactive isotope. A method for producing an imageable microsphere according to any one of embodiments 145 to 192, including the above.

[0454] 217. The method according to Embodiment 216, wherein at least one imageable radioisotope is provided as a salt before chemically functionalizing the surface of an inorganic substrate with at least one imageable radioisotope.

[0455] 218. The method according to Embodiment 217, wherein the salt is an alkali metal salt, an alkaline earth metal salt, a halogen salt, a polyatomic salt, or a salt having an organic acid.

[0456] 219. The method of Embodiment 217 or 218, wherein the reaction is carried out in the presence of a reducing agent.

[0457] 220. The method of Embodiment 219, wherein the reducing agent is selected from one or more of tin salts, tin hydrate, HCl, sodium borohydride, sodium dithionite, ferrous sulfate, ferric chloride + ascorbic acid, hypophosphorous acid, and / or hydrazine.

[0458] 221. Radioactive isotopes 99m The method according to any one of embodiments 216 to 220, wherein Tc is...

[0459] 222. 99m The method according to Embodiment 221, wherein Tc is provided in the form of a pertechnetium salt.

[0460] 223. 99m The method according to Embodiment 221, wherein Tc is prepared in the form of a pertechnetium salt and the reaction is carried out in the presence of tin ions.

[0461] 224. Radioactive isotopes 89 The method according to any one of embodiments 216 to 223, wherein Zr is Zr.

[0462] 225. 89 Zr 89 The method according to Embodiment 224, provided in the form of Zr oxalate.

[0463] 226. The method according to Embodiment 224 or 225, wherein the reaction is carried out in the presence of a base.

[0464] 227. The method according to any one of embodiments 203 to 226, carried out under aqueous conditions.

[0465] 228. The method according to any one of embodiments 203 to 227, further comprising the steps of recovering imageable microspheres and / or washing the microspheres to remove unreacted radioisotopes.

[0466] 229. The method according to any one of embodiments 203 to 228, further comprising the step of resuspending the imageable microspheres in a pharmaceutically acceptable injectable aqueous medium.

[0467] 230. Imagingable microspheres that can be obtained by the method described in any of embodiments 203 to 229.

[0468] 231. A method for determining the amount of therapeutic microspheres to be provided to a patient's body, The process of preparing a collection of microspheres that can be imaged, The process involves delivering a population of imageable microspheres to a patient by introducing the population of imageable microspheres to a first location in the patient's vascular system, A process of distributing a group of imageable microspheres within the patient's body, A step of determining the distribution of at least a portion of the population of imageable microspheres within a patient's body by imaging a portion of the patient's body using an imaging modality, The process involves calculating the amount of therapeutic microspheres delivered into the patient's body using the distribution of microspheres that can be imaged. Methods that include...

[0469] 232. The method according to embodiment 231, wherein a portion of the body is the patient's off-target area, and the off-target area is the patient's lungs.

[0470] 233. The method according to Embodiment 231, wherein a portion of the body is the target region of the patient, and the target region is the patient's liver.

[0471] 234. The method according to any one of embodiments 231 to 233, wherein the target region is divided into tumor tissue and non-tumor tissue.

[0472] 235. The method according to any one of embodiments 231 to 234, wherein the amount of therapeutic microspheres to be delivered to the patient is calculated.

[0473] 236. The method according to embodiment 235, wherein the calculated amount is delivered to the patient.

[0474] 237. The method according to any one of embodiments 231 to 236, wherein the imaging modality is SPECT.

[0475] 238. The method according to any one of embodiments 231 to 236, wherein the detection modality is PET.

[0476] 239. The method according to any one of embodiments 231 to 236, wherein the detection modality is a gamma camera image.

[0477] 240. The method according to any one of embodiments 231 to 239, wherein the imageable microsphere is an imageable microsphere described in any one of embodiments 145 to 202.

[0478] 241. A method of treating a patient, The process of preparing a collection of microspheres that can be imaged, The process involves delivering a population of imageable microspheres to a patient by introducing the population of imageable microspheres to a first location in the patient's vascular system, A process of distributing a group of imageable microspheres within the patient's body, The process involves determining the distribution of at least a portion of the population of imageable microspheres within a patient's body by imaging a target area of ​​the patient's body using an imaging modality, A process of calculating the amount of therapeutic microspheres delivered into the patient's body using the distribution of microspheres that can be imaged, A process to obtain data on the distribution of imagingable therapeutic microsphere substitutes in patients, A process of determining the therapeutic dose of microspheres to be administered to the patient's body using data, The process involves delivering a population of therapeutic microspheres to a patient by introducing the population of therapeutic microspheres to a second location in the patient's vascular system, The process involves distributing a group of therapeutic microspheres within the patient's body to treat the patient. Methods that include...

[0479] 242. The method according to Embodiment 241, wherein the second location in the patient's vascular system is the same as, or substantially the same as, the first location in the patient's vascular system.

[0480] 243. The method according to Embodiment 241 or 242, wherein the imaging modality is SPECT.

[0481] 244. The method according to Embodiment 241 or 242, wherein the imaging modality is PET.

[0482] 245. The method according to Embodiment 241 or 242, wherein the imaging modality is a gamma camera image.

[0483] 246. The method according to any one of embodiments 241 to 245, wherein the imageable microsphere is an imageable microsphere described in any one of embodiments 145 to 202.

[0484] 247. A method of treating a patient with therapeutic microspheres, A process to obtain data calculated from the distribution of imageable therapeutic microsphere substitutes in patients, A process of determining the amount of therapeutic microspheres to be administered to the patient's body using data, A process of delivering a quantity of therapeutic microspheres to a patient by introducing the quantity of therapeutic microspheres to a first location in the patient's vascular system, The process of distributing therapeutic microspheres within the patient's body, The process involves leaving therapeutic microspheres in the patient's body to treat the patient. Methods that include...

[0485] 248. The method according to embodiment 247, further comprising the step of preparing a population of imageable microspheres in a patient.

[0486] 249. The method according to Embodiment 248, further comprising the step of delivering a population of imageable microspheres to a patient by introducing the population of imageable microspheres to a first location in the vascular system of the patient's body.

[0487] 250. The method according to Embodiment 249, further comprising the step of distributing a population of imageable microspheres within the body of a patient.

[0488] 251. The method according to Embodiment 250, further comprising the step of determining the distribution of at least a portion of a population of imageable microspheres within a patient's body by imaging a target portion of the patient's body using an imaging modality.

[0489] 252. The method according to Embodiment 251, further comprising the step of calculating the amount of therapeutic microspheres to be delivered to the patient's body using the distribution of imageable microspheres.

[0490] 253. A method for treating a tumor in a patient requiring treatment, The process involves introducing a population of microspheres that can be imaged into a patient, A process of distributing imageable microspheres to a patient over a certain period of time, The process involves determining the distribution of imageable microspheres in a patient's area by imaging imageable microspheres using an imaging modality, and A step of determining the estimated effective dose at a site when the imageable microspheres are replaced with therapeutic microspheres, based on the distribution of imageable microspheres, The process involves administering a quantity of therapeutic microspheres to the patient based on the estimated effective dose. Methods that include...

[0491] 254. The method according to Embodiment 253, wherein the population of imageable microspheres includes imageable microspheres described in any one of Embodiments 145 to 202.

[0492] 255. The method according to Embodiment 253 or 254, wherein the site is a malignant or benign tumor and / or non-tumorous tissue.

[0493] 256. The method according to Embodiment 253 or 254, wherein the site is a malignant tumor.

[0494] 257. The method according to Embodiment 256, wherein the site is a malignant tumor.

[0495] 258. A method for predicting the extent of off-target delivery to the lungs or gastrointestinal tract during treatment of a patient requiring radioisotope cancer therapy, The process involves introducing a population of microspheres that can be imaged into a patient, A process of distributing imageable microspheres to a patient over a certain period of time, A process to determine the distribution of imageable microspheres within a patient's lungs by imaging imageable microspheres using an imaging modality. When imaging microspheres are replaced with radioisotope therapy microspheres, the process involves determining the estimated radiation dose in the patient's lungs or gastrointestinal tract, respectively. A step of determining a dose of radioisotope therapy microspheres sufficient to cause clinically relevant pulmonary or gastrointestinal changes due to off-target delivery, The process involves administering to a patient a dose of radioisotope therapeutic microspheres that is less than or equal to the dose of radioisotope therapeutic microspheres determined to be sufficient to cause clinically relevant pulmonary or gastrointestinal changes due to off-target delivery. Methods that include...

[0496] 259. The method according to Embodiment 258, wherein the population of imageable microspheres includes imageable microspheres described in any one of Embodiments 145 to 202.

[0497] 260. A method for reducing lung or gastrointestinal tract damage during treatment for patients requiring radioisotope cancer therapy, The process involves introducing a population of microspheres that can be imaged into a patient, A process of distributing imageable microspheres to a patient over a certain period of time, A step of determining the distribution of imageable microspheres within a patient's gastrointestinal tract or lungs by imaging imageable microspheres using an imaging modality, When imagingable microspheres are replaced with radioisotope therapy microspheres, the process involves determining the estimated radiation dose in the patient's gastrointestinal tract or lungs. A step of determining the dose of radioactive isotope therapy microspheres sufficient to cause damage to the gastrointestinal tract, The process of administering to a patient a dose of radioisotope therapy microspheres that is less than or equal to the dose of radioisotope therapy microspheres determined to be sufficient to cause damage to the gastrointestinal tract. Methods that include...

[0498] 261. The method according to Embodiment 260, wherein the population of imageable microspheres includes imageable microspheres described in any one of Embodiments 145 to 202.

[0499] 262. It is a kit, A microsphere comprising a substrate containing an inorganic material that includes metalloid or metal atoms bonded to nonmetal atoms, wherein the substrate is A microsphere comprising a core extending to the surface, the core comprising a first portion of a metalloid or metal atom bonded to a nonmetal atom, and the surface comprising a second portion of a metalloid or metal atom bonded to a nonmetal atom, A kit including instructions for reacting an imageable radioisotope with a substrate such that the imageable radioisotope directly bonds to the substrate through at least a portion of nonmetallic atoms on the substrate surface.

[0500] 263. It is a kit, Microspheres comprising an inorganic substrate containing at least one nonmetal, metalloid, or transition metal oxide, A kit including instructions for bonding imageable radioisotopes to the surface of an inorganic substrate via Lewis acid-base coordination bonds.

[0501] 264. A kit including instructions for carrying out a reaction in which microspheres containing a ceramic microsphere substrate and an imageable radioisotope are bonded to the ceramic microsphere substrate as a Lewis acid-base adduct.

[0502] 265. A kit according to any one of embodiments 262 to 264, comprising a sealed unit containing microspheres in a packed volume of 10 μl to 2 ml.

[0503] 266. The kit according to Embodiment 110, wherein microspheres are provided in a vial or syringe.

[0504] 267. Radioactive isotopes, 99m Tc, 201 Th, 51 Cr, 67 Ga, 68 Ga, 111 In, 64 Cu, 89 Zr, 59 Fe, 42 K, 82 Rb, 24 Na, 45 Ti,44 Sc, 51 Cr, 18 F, Al 18 A kit according to any one of embodiments 262 to 266, selected from F.

[0505] 268. A kit according to any one of embodiments 262 to 267, further comprising a reducing agent.

[0506] 269. The kit according to Embodiment 268, wherein the reducing agent is selected from one or more of tin salts, tin hydrate, concentrated HCl, sodium borohydride, sodium dithionite, ferrous sulfate, ferric chloride + ascorbic acid, hypophosphorous acid, and / or hydrazine.

[0507] 270. The reducing agent is a tin salt, and the radioactive isotope is 99m The kit according to Embodiment 268 or 269, wherein the radioactive isotope is Tc and is in the form of a pertechnetium salt.

[0508] 271. Radioactive isotopes 89 A kit according to any one of embodiments 262 to 267, wherein the material is Zr.

[0509] 272. Radioactive isotopes 89 The kit according to Embodiment 271, which is in the form of zirconium oxalate or zirconium chloride.

[0510] 273. A kit according to any one of embodiments 262 to 272, further comprising therapeutic microspheres.

[0511] 274. The kit according to Embodiment 273, wherein the therapeutic microspheres contain a therapeutic radioisotope.

[0512] 275. Therapeutic microspheres, 90 Y, 166 Ho, 177 Lu, 131 I, 89 Sr, 153 Sm, 223 Ra, 224 Ra, 211At, 225 Ac, 227 Th, 212 Bi, 213 Bi and / or 212 The kit according to embodiment 274, which includes Pb.

[0513] 276. The kit according to any one of embodiments 273 to 275, wherein the therapeutic microspheres have the same chemical composition as the imaging microspheres.

[0514] 277. A kit according to any one of embodiments 273 to 276, wherein the therapeutic microspheres contain yttrium aluminum silicon oxide.

[0515] 278. A kit according to any one of embodiments 262 to 277, further comprising one or more of a vascular access needle, a vascular guidewire, a vascular sheath (e.g., 4-6 Fr), a vascular catheter (4-5 Fr), a microcatheter, a syringe, and a vial. [Examples]

[0516] The following examples illustrate, and are not intended to limit, some embodiments of those disclosed herein. Those skilled in the art will readily recognize that this disclosure is well adapted not only to achieve the objectives and benefits mentioned, but also to achieve objectives, results, and benefits that naturally arise from the embodiments disclosed herein. The problems and other uses that are characteristic attributes of the disclosure as defined by the claims will be conceivable to those skilled in the art.

[0517] (Example 1) Preparation of zirconium-89 bonded yttrium aluminum silicon oxide (YAS) microspheres Yttrium aluminum silicon oxide (YAS) glass beads (supplied as non-radioactive spheres that have not been subjected to neutron bombardment, TheraSphere®, Biocompatibles UK Ltd) are supplied in 4 mL glass vials. Therefore, Y2O3 is natural. 89The microspheres (in the form of Y) were loaded and suspended in 300 μL of deionized water. Next, 2 μL aliquots of zirconium-89 in 1 M oxalic acid (3D imaging, Little Rock, AK) (approximately 100 microcuries (μCi)) were added to the reactor vial, followed by 2 μL of 2 M sodium carbonate, and then a Teflon® coated magnetic stirring rod. The reaction mixture was stirred and heated on an aluminum heating block at 120°C for 2 hours, then removed from the block and cooled to room temperature. The microspheres were suspended in 3.0 mL of deionized water and collected for labeling analysis by passing them through a 0.22 μm syringe filter. The glass vial was rinsed with an additional 4 mL of deionized water and then passed through a syringe filter. The syringe filter (containing the labeled microspheres), glass vial, and deionized water filtrate were analyzed using a gamma well counter, and the results are summarized in Table 1 below.

[0518] [Table 1]

[0519] (Example 2) 99m Preparation of Tc-bonded yttrium aluminum silicon oxide microspheres 1 mg of tin(II) chloride dihydrate was added to one drum vial and dissolved in 400 μL of deionized water. In another drum vial, yttrium aluminum silicon oxide glass beads were added. 89 Y, non-radioactive TheraSphere-TS) is added, followed by 100 μL of [ 99mSodium pertechnetiumate (>30 mCi / mL) [Tc] was added. Tin(II) chloride dihydrate solution was added to the TheraSphere vial, mixed briefly (approximately 3 seconds), the vial was capped, and the mixture was allowed to react at room temperature for 60 minutes. The microspheres were suspended in 3.0 mL of deionized water and passed through a 0.22 μm syringe filter to collect the microspheres for labeling analysis. The glass vial was rinsed with an additional 4 mL of deionized water and then passed through a syringe filter. The syringe filter (containing the labeled microspheres), glass vial, and deionized water filtrate were analyzed using a gamma well counter, and the results are summarized in the table below.

[0520] [Table 2]

[0521] (Example 3) Using DFO chelate [ 89 Zr] Microsphere Ligand Challenge YAS microspheres (e.g., Therasphere) (suspended in 200 μL sterile saline at pH 7-8) were mixed with increasing concentrations of desferrioxamine (DFO) ranging from 0.05 to 5 mM and incubated at 37°C with constant stirring. At each time point, 5 μL of the solution was taken out, added to a 0.45 μm spin filter, and diluted with 100 μL of deionized water. The spin filter was centrifuged at 13,200 × G for 60 seconds, 100 μL of deionized water was added back to the spin filter, and the centrifugation was repeated. The spin filter was removed from the microcentrifuge tube, and the supernatant was analyzed by gamma spectroscopy and then measured with a gamma counter to determine the possible values. 89 The formation of Zr-DFO was detected. 89 In Zr-TS, within 48 hours, a very small amount 89 Zr peeling was detected. 89 We demonstrated the strong binding affinity of Zr to TS. The results are shown in Figure 2.

[0522] (Example 4) Testing the specificity of tin(II) chloride as a reducing agent. On the premise of understanding the specificity of tin (II) chloride in reducing pertechnetate for reaction with TheraSphere, several oxidizing and reducing agents were tested. Tin is predicted not only to actively reduce Tc(VII) to Tc(V), but 99m is also thought to actively participate in the binding of Tc to TheraSphere. TheraSphere / 99m To promote the TheraSphere / Tc coupling, several reducing agents: FeCl2 / ascorbic acid (pH = 2); sodium borohydride; and zinc metal were attempted. None of the reducing agents 99m resulted in a substantial radiochemical yield of Tc-TheraSphere and were not further investigated. This suggests 99m that tin plays a role in the binding of Tc to TheraSphere.

[0523] (Example 5) 99M Effect of reaction volume on the yield of Tc-binding microspheres Tin (II) chloride dihydrate (1 mg) was added to a 1 dram vial and dissolved in deionized water as shown in Table 3. In another 1 dram vial, 10 mg of yttrium aluminum silicate glass beads (TheraSphere) were added, followed by 100 μL of 99m Tc] sodium pertechnetate (>30 mCi / mL). The tin (II) chloride dihydrate solution was added to the TheraSphere vial, mixed briefly (approximately 3 seconds), capped, and reacted at room temperature for 60 minutes. The microspheres were suspended in 3.0 mL of deionized water and passed through a 0.22 μm syringe filter to collect the microspheres for radiolabeling analysis. The glass vial was rinsed with an additional 4 mL of deionized water and then passed through the syringe filter. The syringe filter (containing the radiolabeled microspheres), glass vial, and deionized water filtrate were analyzed by a gamma well counter and the results were summarized in the following table.

[0524] [Table 3]

[0525] (Example 6) Bonding to alternative ceramic microparticles Examples 1 and 2 were repeated using silicon dioxide and silicon-aluminum oxide microparticles. Silicon-aluminum oxide microspheres were obtained from Steag Energo Mineral. Silica microspheres were purchased from EPRUI Biotech Co. Limited (product number: EPRUI-SI-20), which consisted of SiO2 as monodisperse microspheres with a diameter of 20 μm.

[0526] [Table 4]

[0527] [Table 5]

[0528] [Table 6]

[0529] [Table 7]

[0530] (Example 7) Tests on the interdependence of 99mTc and TheraSphere on tin in product formation. Several reactions were carried out under the various conditions shown below.

[0531] 10mg TheraSphere, 0.5-1.0mg SnCl2, 3mCi 99m Typical reaction conditions using Tc and 400 μL of deionized water.

[0532] 10mg TheraSphere, 3mCi 99mGeneral reaction conditions using 25 mg of TheraSphere, 3 mCi of

[0533] 25 mg of TheraSphere, 3 mCi of 99m Tc, and 400 μL of deionized water. Without SnCl2.

[0534] 0.5 - 1.0 mg of SnCl2, 3 mCi of 99m Tc, and 400 μL of deionized water. Without TheraSphere.

[0535]

Table 8

[0536] As demonstrated by Reaction 4, there is a relationship between some oxidation state of tin and 99m Tc. However, under the conditions tested, without the presence of TheraSphere, the product deteriorates in solution over 120 minutes, as is clear in Reaction 1. Without tin and 99m Tc mixed only with TheraSphere also does not react. The combination of the three reagents results in a stable product, as demonstrated in the inventors' in vitro stability assay below.

[0537] (Example 8) 99M Tc and 89 Assay for solution stability of yttrium aluminum silicon oxide spheres bound with Preparation of sample solutions Three separate solutions were prepared as follows: 1) Vial #1: 10 mL of PBS and 3 - 5 mCi of 99m Tc - TheraSphere or 100 - 150 μCi of 89 Zr - TheraSphere, mix to homogenize; 2) Vial #2: 10 mL of goat serum, 4 ± 1 mCi of 99mTc-TheraSphere (suspended in 100 μL of PBS to make it easier to transfer) or 125 ± 25 μCi 89 Zr-TheraSphere, mix to homogenize; 3) Vial #3: 10 mL of goat serum (other serums may be used, e.g., horse, goat, or other mammal), 4 ± 1 mCi 99m Tc-TheraSphere (suspended in 100 μL of PBS to make it easier to transfer) or 125 ± 25 μCi 89 Mix Zr-TheraSphere with 100 μL of 0.1 M HCl (check the pH; it must be less than 4. If it is not less than 4, add more 0.1 M HCl until it is <4. It is acceptable to exceed pH 1-3, only pay attention to the final pH) to homogenize. Incubate each vial at 37°C for 8 hours. Take 100 μL from each vial, centrifuge, and collect 10 μL of the supernatant into a drum vial or microcentrifuge tube for activity measurement. Samples were taken at several selected time points to determine the effect of time.

[0538] Preparation of gamma counter standard samples 4±1 mCi in a 100 mL volumetric flask 99m Tc-TheraSphere (suspended in 100 μL of PBS to make it easier to transfer) or 125 ± 25 μCi 89 Zr-TheraSphere was added. The solution was diluted to 100 mL with deionized water and mixed. 5 × 1 mL aliquots were taken from the flask and added to five separate vials. Stability data are shown in Figures 3A and 3B.

[0539] Regarding industrial standards 99m Tc- and 89 To compare the relative stability of Zr-TheraSpheres in vitro, the inventors 99m The same serum assay was performed using Tc-MAA. Three separate solutions were prepared as follows: 1) Vial #1 (buffer): 10 mL of PBS, 4 ± 1 mCi 99m1) Tc-MAA, mixed to homogenize; 2) Vial #2 (serum): 10 mL of goat serum, 4 ± 1 mCi 99m Tc-MAA, mixed to homogenize; 3) Vial #3 (serum and acid): 10 mL goat serum; 4 ± 1 mCi 99m Tc-MAA; 100 μL of 0.1 M HCl (check the pH and it must be less than 4. If it is not less than 4, add more 0.1 M HCl until it is <4. It is acceptable to exceed pH 1-3, only pay attention to the final pH), mixed to homogenize. Each vial was incubated at 37°C for 8 hours. 100 μL was taken from each vial, centrifuged, and 10 μL of the supernatant was collected in a drum vial or microcentrifuge tube for activity measurement. Samples were taken at several selected time points to determine the effect of time. The results are shown in Figure 4.

[0540] The relative stability of all image substitutes is summarized in the table below.

[0541] [Table 9]

[0542] [Table 10]

[0543] (Example 9) Buffering agent and pH testing 0.5–1.0 mg of SnCl2 was added to the vial. 500 μL of buffer solution was added to the vial. The solution was filtered and transferred to a clean 1-drum vial. 10 mg of YAS microspheres were added to another 1-drum vial (reaction vial) along with 20 μL of Tc-99m stock solution. 380 μL of SnCl2 solution was added to the reaction vial to make a total reaction volume of 400 μL. The reaction vial was capped and mixed manually for 3–5 seconds, then allowed to react at room temperature for 1 hour without stirring. The vial was then mixed, and the reaction mixture was withdrawn into a syringe using an 18G × 1.5" needle. Labeled YAS microspheres were captured on a 0.2 μm syringe filter. The reaction vial was rinsed with 400 μL of deionized water and captured on the syringe filter.

[0544] List of vial labeling and buffering materials: 1. Saltwater (pH 5) 2. PBS (pH 7.4) 3. Acetate buffer in saline solution (pH 5) 4. Citrate buffer (pH 3) 5. Citrate buffer (pH 4) 6. Citrate buffer (pH 5)

[0545] Analysis: Measure the initial activity (I) of the reaction vial, the waste vial (W), the syringe filter (SF), and the reaction vial (V), paying attention to the background (BKG). Table 11 shows the results.

[0546] [Table 11]

[0547] As shown in Figure 4B, buffer solutions may have a negative effect on the formation of [99mTc]YAS microspheres. The best radiochemical yield was obtained using saline solution as the reaction solvent. Attempts to treat the analyte-containing solution with buffers and variations in pH both resulted in low yields.

[0548] (Example 10) Predictive Al 18 Embodiment F Fluoride ions bind to most metals, but historically, they have been shown to form complexes with metal-binding chelates, forming a particularly strong bond with aluminum(III), resulting in a very stable (670 kJ / mol) Al-F bond. Since aluminum forms an octahedral complex, pentadentate coordination is preferred to form a stable 18F substitute in vitro and in vivo. [18F]fluoride is readily available commercially as an aqueous solution, and therefore, for practical use in hospitals, the reagents and reaction conditions should be suitable for aqueous reaction conditions. Mix YAS glass (10 mg) and [18F]fluoride (supplied as an aqueous solution) with aluminum trichloride hydrate (monohydrate, hexahydrate, or other hydrate species that are compatible with aqueous solution) and a suitable chelating agent (NOTA, NODA, trimethyltriazonane, or other chelating agent species that support the octahedral aluminum fluoride complex) in an acetate buffer at pH 4. The solution is heated at 100°C for 15-30 minutes, at which point the [18F]Al-YAS material is removed from the heat and purified for use.

[0549] (Example 11) In vivo animal studies Radioembolization involves intravascular delivery of particles embedded with radioactive materials through the vascular structure of arteries to treat malignant tumors. Current FDA-approved methods in radioembolization focus on the treatment of primary or metastatic liver cancer, although other organ systems may also act as targets for therapy. Safe and effective delivery of the therapy requires delivering a customized dose to the target area of ​​treatment. Various dosing methodologies currently exist, which may involve variables such as the target liver volume and, in some cases, the liver tumor volume. None of the currently approved methodologies take into account patient-specific considerations, such as preferential blood flow to the tumor or the number of radioembolic particles needed to completely cover the tumor. Addressing these latter two variables can best be achieved by an initial dose of a radioembolization dosing substitute that is as close as possible to the actual therapeutic radioembolization device in terms of size distribution, shape, and specific gravity. Boston Scientific has developed a primary beta radioactive particle. 90 Converted to Y 89 We are manufacturing a radioembolization device consisting of glass microspheres embedded with Y. The optimal drug delivery involves labeling the surface of the glass microspheres with a radioactive isotope that can be visualized by positron emission tomography (PET) or single-photon emission computed tomography (SPECT). Such particles can be administered intravascularly during the initial planning procedure of this therapy and subsequently visualized by a PET or SPECT scanner to determine the optimal drug delivery parameters for subsequent administrations of this therapy.

[0550] 89 Following catheter-guided delivery of Zr-labeled iSpheres 89 A series of proof-of-concept experiments were conducted at the University of Virginia to investigate the distribution of Zr-labeled iSpheres (YAS microspheres; prepared in Example 1). This protocol was used in the Woodchuck liver cancer model. 89Using Zr-labeled microspheres, we investigated (i) distribution, (ii) in vivo stability, and (iii) visualization of microspheres administered via the hepatic artery using a catheter-guided method. The specific procedure included (i) multiphase magnetic resonance imaging (MRI) of the abdomen and pelvis (Figures 5A and 6A), (ii) angiography to position the microcatheter in the hepatic artery (Figure 6B), and (iii) scout dose (1.3 mg) and total dose (13 mg) (Figure 5B). 89 The study included positron emission tomography-computed tomography (PET-CT) imaging of Zr-labeled microspheres, and (iv) fusion of PET-CT and MRI image datasets, including quantitative analysis of uptake in tumors and normal liver (Figures 7A and 7B).

[0551] In short, woodchucks infected with WHV (Woodchuck Hepatitis Virus) were identified by immunoassay by the supplier, Northeastern Wildlife (Harrison, ID). Blood samples were obtained by the supplier every 3-4 months to assess WHV DNA levels and confirm that the animals remained virus carriers. Serum gamma-glutamine transferase (GGT), a serum marker for the presence of hepatocellular tumors, was also determined. Animals with GGT levels above 50 IU / dL were sent by the supplier. Woodchucks were evaluated by ultrasound to look for liver tumors and assess their size and location. One ultrasound (US) session was performed per animal before shipment to UVA to confirm the presence of tumors.

[0552] Prior to embolization, the woodchucks were brought into the preparation area and anesthetized by veterinary staff. They were intramuscularly administered ketamine (25-50 mg / kg) and xylazine (1-5 mg / kg). Atropine [0.04 mg / kg] was administered before intubation. The animals were intubated and maintained on a ventilator using 1.5-2.5% isoflurane in oxygen. The animals were placed on a heating pad to maintain body temperature. Before angiography (Figure 6B), the animals underwent MRI using a Siemens 3 Tesla Prisma scanner (Erlangen, Germany) (Figures 5A and 6A). 1 mg / kg of pharmaceutical-grade Magnevist was used during the MRI procedure.

[0553] Immediately after the completion of the MRI (shown in Figures 5A and 6A), the animal was brought to the angiography room. Ultrasound was used to access the right common femoral artery using a 4F micropuncture kit (Cook Medical, Bloomington, IN). A 4F Glidesheath Slender Sheath (Terumo Medical, Somerset, NJ) was placed, and a 4F angled tip catheter (Cook Medical, Bloomington, IN) was introduced into the abdominal aorta along the wire. Digital subtraction angiography (shown in Figure 6B) was performed using approximately 10cc of Omnipaque 350 contrast agent (GE Healthcare, Chicago, IL) to outline the origin of the celiac artery. Next, a Headway Duo microcatheter (Microvention, Aliso Viejo, CA) was inserted into the hepatic artery system, followed by the injection of 3-5cc of Omnipaque 350 contrast agent to outline the supply to the tumor visualized by the ultrasound and MRI. 89 Zr-labeled iSpheres ( 89 For the injection of Zr-labeled YAS microspheres, a microcatheter was then placed in the proper hepatic artery, left hepatic artery, or right hepatic artery. After establishing access to the intended delivery site, the catheter was secured in place, and the animal was moved to the PET / CT area under anesthesia.

[0554] PET / CT imaging was initiated within 5 minutes of iSpheres injection, following the same imaging protocol for each animal. The results are shown in Figure 5B. Two separate injections were performed within the PET / CT area. A custom-made injector (Boston Scientific, Marlborough, MA) was used to enable controlled delivery of iSpheres. The first injection was a "scout dose" of 1.3 mg or less of iSpheres. The results are shown in Figure 7A. The second injection was a particle dose of 13 mg or less, designed to model the number of particles required for the treatment procedure (Figures 5B and 7B). Similar to the human imaging procedure, this second dose was not expected to be significantly embolic. PET / CT imaging was performed for 90 minutes after each injection (Figure 5B). Very slight pulmonary uptake was observed, along with a recognizable difference in uptake within the tumor and normal liver (indicating that the patient is a candidate for SIRT).

[0555] A dedicated PET scanner docked with a multimodality CT scanner was used for preclinical imaging studies. Dynamic and static scans were acquired, starting within 1 hour of injection. Animals were maintained under anesthesia using 1–5% isoflurane. CT images were acquired for photon attenuation correction and for image co-registration with PET imaging data. Reconstruction algorithms for both PET and CT were provided by the scanner manufacturer. Parameters for CT acquisition were 120 rotation steps over 220°, continuous acquisition, tube voltage of 80kVp, tube current of 500μA, and exposure of 175ms. Image visualization and analysis were performed using the software packages MiM (Cleveland, OH) and Simplicit90Y (Mirada Medical, Denver, CO) (Figures 7A and 7B). Volumes of Interest (VOIs) of interest were plotted on co-registration MRI images of the tumor and other organs of interest. VOIs were adjusted to include obvious partial volume overflows for organ uptake calculations.

[0556] Through this research, A) 89We noticed that Zr spheres could be successfully delivered to the liver using a catheter-guided method, that uptake could be clearly visualized using PET-CT, and that uptake following different patterns of flow distribution within the liver, as suggested by the contrast agent, improved tomographic and angiographic images.

[0557] (Example 12) Predictive animal testing Animals with liver tumors were used as models to study diagnostic and therapeutic methods for managing this disease. Woodchucks with liver tumors resulting from chronic infection with woodchuck hepatocarcinoma virus are one such model. After inserting a microcatheter into the proper hepatic artery of woodchucks with liver tumors, microspheres of imaginable radioisotopes are administered. These are distributed in a flow-guided manner and remain within the small arteries of the liver. The imaginable radioisotope microspheres are visualized by PET or SPECT. 90 It functions as a substitute for Y-Therasphere, and therefore predicts the presence of Y-Therasphere in the liver. 90 This enables direct mapping of the Y-Therasphere distribution to hepatoma cells while minimizing damage to normal liver cells. 90 This provides information on selecting the dose that will maximize the lethal dose in the Y-Therasphere.

[0558] (Example 13) Predicting the dosage of therapeutic particles using substitutes. Based on the inventors' experience, the following predictive results can be estimated using controlled tests.

[0559] A group of 30 patients with liver cancer will be selected for treatment using TheraSphere-assisted SIRT. Before treatment, patients will be given the following information: 90 As a substitute for Y TheraSphere, one use 99m This provides Tc-functionalized yttrium aluminum silicon oxide microspheres (imagingable radioisotope microspheres disclosed herein).

[0560] Imagingable microspheres have an average diameter of 20–30 μm. The dose of imagingable microspheres is calculated to be approximately 150 MBq, dispersed in 0.6 mL of pyrogen-free water. Imagingable microspheres are injected into the hepatic artery and allowed to distribute for 15 minutes. At that time, the patient's liver, lungs, and gastrointestinal tract are imaged using SPECT. From these images, the amount of microspheres reaching each of the liver, lungs, and gastrointestinal tract is measured. Patients are classified into either TheraSphere treatment or non-treatment due to the risk of pulmonary shunt. Seven patients are excluded from the treatment category. For the 23 patients who are candidates for treatment, the TheraSphere dose that will deliver 300 Gy to the tumor while maintaining a dose to normal tissue <60 Gy is calculated based on the proportion of imagingable microspheres delivered to the tumor and normal tissue. For the patients who are candidates for treatment, the TheraSphere dose that will deliver 300 Gy to the liver is calculated based on the proportion of imagingable microspheres delivered to the liver. Typically, the target dose for TheraSphere may range from 80 Gy to 300 Gy. A single dose of TheraSphere, calculated to obtain 300 Gy based on the distribution of imageable radioisotope microspheres, is administered to the treatment candidate. None of the patients experience significant distribution of pulmonary shunt or gastrointestinal tract damage.

[0561] In the second group of 30 patients, Tc-99m MAA was administered intrahepatic artery to determine the extent of AV shunt to the lung and to confirm the absence of flow to the stomach and duodenum. At that time, the patients' liver, lungs, and gastrointestinal tract were imaged. From these images, the dose of microspheres reaching the liver, lungs, and gastrointestinal tract was measured. Patients were classified into either treatment with TheraSphere or non-treatment due to the risk of pulmonary shunt. Twelve patients were excluded from the treatment category. Candidates for treatment were then given a single dose of TheraSphere calculated to obtain 300 Gy. Four of the patients experienced pulmonary shunt, and three had a significant distribution of gastrointestinal damage. Two of the patients received inadequate treatment based on post-treatment evaluation.

[0562] Twelve patients who were excluded from the treatment category based on the Tc-99m MAA results were administered the disclosed imagingable radioisotope microspheres in Group 1. Of these patients, eight were found to be candidates for TheraSphere treatment. These treatment candidates were then given a single dose of TheraSphere calculated to yield 300 Gy based on the distribution of imagingable radioisotope microspheres. None of the patients experienced significant distribution of pulmonary shunt or gastrointestinal tract damage.

[0563] In the third group of 30 patients, a single dose of TheraSphere equivalent to 300 Gy was administered to the liver. Eight of the patients experienced pulmonary shunts, and six had a significant distribution of gastrointestinal damage. Five of the patients received inadequate treatment based on post-treatment evaluation.

Claims

1. At least one imageable radioactive isotope, A substrate comprising an inorganic material containing a metalloid or metal atom bonded to a nonmetal atom, wherein the substrate is A substrate comprising a core extending to the surface, wherein the core comprises a first portion of the metalloid or metal atom bonded to the nonmetal atom, and the surface comprises a second portion of the metalloid or metal atom bonded to the nonmetal atom, and A microsphere that can be imaged, Imageable microspheres wherein the imageable radioisotope is directly bonded to the substrate through nonmetallic atoms on the surface of the substrate, and / or the imageable radioisotope is bonded to the substrate through inorganic crosslinks containing nonmetallic atoms on the surface of the substrate.

2. The imageable microsphere according to claim 1, wherein the imageable radioactive isotope is directly bonded to the substrate through nonmetallic atoms on the surface of the substrate.

3. The imageable microsphere according to claim 1, wherein the substrate is bonded to the substrate through nonmetallic atoms on the surface of the substrate via inorganic crosslinking.

4. The imageable microsphere according to claim 1, wherein the substrate comprises a substantially homogeneous mixture of constituent chemical elements.

5. The imageable microsphere according to claim 4, wherein the surface comprises at least a portion of the constituent chemical elements.

6. The imageable microsphere according to claim 1, wherein the nonmetallic atom is an oxygen atom.

7. The imageable microsphere according to claim 6, wherein at least a portion of the oxygen atoms on the surface of the substrate are hydroxyl groups.

8. An inorganic substrate having a surface, At least one imageable radioactive isotope and A microsphere that can be imaged, The substrate comprises at least one nonmetal and at least one metalloid or metal, An imageable microsphere in which the imageable radioactive isotope is bonded to the surface of the substrate by a Lewis acid-base coordination bond to an inorganic Lewis base.

9. An inorganic substrate having a surface, At least one imageable radioactive isotope and A microsphere that can be imaged, The substrate comprises at least one nonmetal and at least one metalloid or metal, Imageable microspheres in which the imageable radioactive isotope is bonded to the surface of the substrate by chemical bonding to inorganic oxygen.

10. An inorganic substrate having a surface having one or more electron-donating functional groups, At least one imageable radioactive isotope and A microsphere that can be imaged, Imageable microspheres wherein the imageable radioisotopes are directly bonded to the surface and / or bonded to the surface via inorganic crosslinking during the preparation of the imageable microspheres, through chemical bonding with one or more electron-donating functional groups.

11. The imageable microsphere according to claim 10, wherein the imageable radioactive isotope is directly bonded to the surface of the substrate.

12. The imageable microsphere according to any one of claims 1 to 11, wherein the substrate comprises a metal oxide, a transition metal oxide, a metalloid oxide, or a combination thereof.

13. The imageable microsphere according to any one of claims 1 to 12, wherein the imageable radioisotope is bonded to the substrate via a chemical bond selected from ionic bonds, covalent bonds, or coordination bonds.

14. The imageable microsphere according to claim 13, wherein the imageable radioactive isotopes are bonded via coordination bonds.

15. An imageable microsphere comprising a ceramic microsphere substrate and at least one imageable radioactive isotope, An imageable microsphere in which the imageable radioactive isotope is bonded to the surface of the ceramic microsphere substrate as a Lewis acid-base adduct of an inorganic Lewis base.

16. The imageable microsphere according to claim 15, wherein the inorganic Lewis base is a component of the substrate, and the imageable isotope is directly bonded to the surface of the substrate through the inorganic Lewis base.

17. The imageable microsphere according to claim 15 or 16, wherein the imageable radioisotope is bonded to the surface of the ceramic microsphere substrate via an inorganic linker containing the Lewis base.

18. The imageable microsphere according to claim 17, wherein the inorganic linker is a metal oxide.

19. The imageable microsphere according to claim 18, wherein the metal oxide is tin oxide.

20. The imageable microsphere according to any one of claims 15 to 19, wherein the Lewis base is oxygen of a metal oxide or metalloid oxide.

21. The imageable microsphere according to any one of claims 8 to 20, wherein the Lewis base is oxygen of tin oxide.

22. The imageable microsphere according to any one of claims 1 to 21, wherein the imageable isotope is configured to be imaged by an imaging modality selected from single-photon imaging and two-photon imaging.

23. The imageable microsphere according to any one of claims 1 to 22, wherein the imageable radioisotope is configured to be imaged by an imaging modality selected from positron emission tomography (PET), single-photon emission computed tomography (SPECT), and gamma camera imaging.

24. The imageable microsphere according to any one of claims 1 to 23, wherein the at least one imageable radioactive isotope is a positron emitter or a gamma emitter.

25. The imageable microsphere according to any one of claims 1 to 24, wherein the at least one imageable radioisotope is a metallic radioisotope.

26. the at least one imageable radioactive isotope is 99m Tc, 201 Th, 51 Cr, 67 Ga, 68 Ga, 111 In, 64 Cu, 89 Zr, 59 Fe, 42 K, 82 Rb, 24 Na, 45 Ti, 44 Sc, 51 Cr, 18 F, Al 18 the imageable microspheres according to any one of claims 1 to 24, selected from F and / or combinations thereof.

27. The aforementioned at least one imageable radioactive isotope, 99m Tc and 89 An imageable microsphere according to any one of claims 1 to 24, selected from Zr.

28. Structure of equation (V): 【Chemistry 1】 (In the formula, The aforementioned substrate is M c Includes M c It is selected from Pb, Al, Si, Y, Mn, Ga, Fe, Sr and Ti. m is an integer selected from 1, 2, or 3. M b teeth, 99m Tc, 201 Th, 51 Cr, 67 Ga, 68 Ga, 111 In, 64 Cu, 89 Zr, 59 Fe, 42 K, 82 Rb, 24 Na, 45 Ti, 44 Sc, 51 Cr, 18 F, 177 Lu, Al 18 Selected from F and / or a combination thereof, M a This is either an atom of the substrate or a crosslinking metal atom, M a It is selected from Sn, Pb, Al, Si, Y, Mn, Ga, Fe, Sr, and Ti. Each R that appears is either nonexistent or -H. X is -OH, =O and -O - Selected from, n is an integer selected from 0, 1, 2, 3, or 4. An imageable microsphere according to claim 1, including the imageable microsphere described in claim 1.

29. M c Al is, The base material is M a Includes M a is Si, M b but 89 It is Zr, Each X independently becomes -OH or -O - And, n is 1 or 2. The imageable microsphere according to claim 28.

30. M b but 89 The imageable microsphere according to claim 28 or 29, wherein Zr, X is -OH, and n is 2.

31. M c is Si, M a is Sn, M b but 99m Tc, Each X independently becomes -OH or -O - And, n is 2 or 3. The imageable microsphere according to claim 28.

32. M b but 99m An imageable microsphere according to claim 28, wherein Tc is -OH and n is 3.

33. Structure of equation (VIII): 【Chemistry 2】 (In the formula, The aforementioned substrate is M a and M c Includes M a and M c It is independently selected from Pb, Al, Si, Y, Mn, Ga, Fe, Sr, and Ti. m is an integer selected from 1, 2, or 3. M b teeth, 99m Tc, 201 Th, 51 Cr, 67 Ga, 68 Ga, 111 In, 64 Cu, 89 Zr, 59 Fe, 42 K, 82 Rb, 24 Na, 45 Ti, 44 Sc, 51 Cr, 177 Lu, Al 18 Selected from F and / or a combination thereof, Each R that appears a These are independently OH, O, or -O-Sn(X) n -O-, X is -OH, =O, and -O - Selected from, n is an integer selected from 0, 1, 2, 3, or 4. An imageable microsphere according to claim 1, including the imageable microsphere described in claim 1.

34. M c Al is M a is Si, M b but 99m The imageable microsphere according to claim 33, wherein Tc is, each X is independently -OH or =O, and n is 2 or 3.

35. M b is 99m Tc, and at least one R that appears a is -O-Sn(X) n -O-, where each X is independently -OH or =O, and n is 2 or 3, the imaging microspheres according to claim 33.

36. M b but 99m Tc, and one R appears. a is -O-Sn-O-, and one R appears a The imageable microsphere according to claim 33, wherein is -O- or OH-, each X is independently -OH or =O, and n is 2 or 3.

37. The process of preparing the aforementioned substrate, A step of chemically bonding at least one imageable radioactive isotope to the substrate to obtain the imageable microspheres. A microsphere that can be imaged according to any one of claims 1 to 36, produced by a method comprising the above.

38. Inorganic materials containing metal or metalloid atoms bonded to nonmetal atoms, A core comprising the first portion of the nonmetallic atoms, and surface including the second portion of the nonmetallic atoms A step of preparing a substrate containing, A step of preparing at least one imageable radioactive isotope, A step of obtaining imageable microspheres by chemically bonding at least one imageable radioactive isotope to the surface of the substrate through the second portion of the nonmetallic atom. Microspheres that can be imaged, produced by a method including [a specific method].

39. The imageable microsphere according to claim 37 or 38, further comprising the step of preparing the at least one imageable radioactive isotope as a salt before the step of chemically bonding the at least one imageable radioactive isotope to the surface layer of the inorganic substrate.

40. A method for preparing imageable microspheres, comprising the steps of: preparing a ceramic microsphere substrate; and reacting the ceramic microsphere substrate with an imageable radioactive isotope under conditions suitable for bonding the radioactive isotope to the surface of the ceramic microspheres.

41. The method according to claim 40, wherein the radioactive isotope is bonded to the surface of the ceramic microsphere in the form of a Lewis acid-base adduct.

42. The method according to claim 40 or 41, wherein the radioactive isotope is a metallic radioactive isotope.

43. the radioactive isotope is 99m Tc, 201 Th, 51 Cr, 67 Ga, 68 Ga, 111 In, 64 Cu, 89 Zr, 59 Fe, 42 K, 82 Rb, 24 Na, 45 Ti, 44 Sc, 51 Cr, 18 F, Al 18 selected from F and / or combinations thereof The method according to any one of claims 40 to 42, wherein the reducing agent is selected from one or more of tin salts, tin hydrate, HCl, sodium borohydride, sodium dithionite, ferrous sulfate, ferric chloride + ascorbic acid, hypophosphorous acid, and / or hydrazine.

44. An imageable microsphere that can be obtained by the method described in any one of claims 40 to 43.

45. A method for determining the amount of therapeutic microspheres to be delivered to a patient's body, The process of preparing a collection of microspheres that can be imaged, The process involves delivering the population of imageable microspheres to a patient by introducing the population of imageable microspheres to a first location in the patient's vascular system, A step of distributing the group of imageable microspheres within the patient's body, A step of determining the distribution of at least a portion of the population of imageable microspheres within the patient's body by imaging a portion of the patient's body using an imaging modality, A method comprising the step of calculating the amount of therapeutic microspheres to be delivered into the patient's body using the distribution of the imageable microspheres.

46. The method according to claim 45, wherein the portion of the body is an off-target area of ​​the patient, and the off-target area is the patient's lungs.

47. The method according to claim 45, wherein the portion of the body is the target region of the patient, and the target region is the liver of the patient.

48. The method according to any one of claims 45 to 47, wherein the target region is divided into tumor tissue and non-tumor tissue.

49. The method according to any one of claims 45 to 48, wherein the amount of therapeutic microspheres to be delivered to the patient is calculated.

50. The method according to claim 49, wherein the calculated amount is delivered to the patient.

51. The method according to any one of claims 45 to 50, wherein the imaging modality is SPECT.

52. The method according to any one of claims 45 to 50, wherein the detection modality is PET.

53. The method according to any one of claims 45 to 50, wherein the detection modality is a gamma camera image.

54. The method according to any one of claims 45 to 53, wherein the imageable microsphere is the imageable microsphere described in any one of claims 1 to 39.

55. A method of treating patients, The process of preparing a collection of microspheres that can be imaged, The process involves delivering the population of imageable microspheres to a patient by introducing the population of imageable microspheres to a first location in the vascular system of the patient's body, A step of distributing the group of imageable microspheres within the patient's body, A step of determining the distribution of at least a portion of the population of imageable microspheres within the patient's body by imaging a target portion of the patient's body using an imaging modality, A step of calculating the amount of therapeutic microspheres delivered into the patient's body using the distribution of the imageable microspheres, A process to obtain data on the distribution of imagingable therapeutic microsphere substitutes in patients, Using the aforementioned data, a step is to determine the therapeutic dose of microspheres to be administered to the patient's body. A step of delivering a group of therapeutic microspheres to a patient by introducing the group of therapeutic microspheres to a second location in the vascular system of the patient's body, A method comprising the steps of distributing the population of therapeutic microspheres within the body of the patient, thereby treating the patient.

56. The method according to claim 55, wherein the second position in the vascular system of the patient is the same as, or substantially the same as, the first position in the vascular system of the patient.

57. The method according to claim 55 or 56, wherein the imaging modality is SPECT.

58. The method according to claim 55 or 56, wherein the imaging modality is PET.

59. The method according to claim 55 or 56, wherein the imaging modality is a gamma camera image.

60. The method according to any one of claims 55 to 59, wherein the imageable microsphere is the imageable microsphere according to any one of claims 1 to 39.

61. A method of treating patients with therapeutic microspheres, A process to obtain data calculated from the distribution of imageable therapeutic microsphere substitutes in patients, Using the aforementioned data, a step is made to determine the amount of therapeutic microspheres to be administered to the patient's body. A step of delivering the amount of therapeutic microspheres to the patient by introducing the amount of therapeutic microspheres to a first location in the patient's vascular system, The steps include distributing the therapeutic microspheres within the patient's body, A method comprising the step of leaving the therapeutic microspheres in the patient's body to treat the patient.

62. The method according to claim 61, further comprising the step of providing the patient with a population of imageable microspheres.

63. The method according to claim 62, further comprising the step of delivering the population of imageable microspheres to a patient by introducing the population of imageable microspheres to a first location in the vascular system of the patient's body.

64. The method according to claim 63, further comprising the step of distributing the population of imageable microspheres within the body of the patient.

65. The method according to claim 64, further comprising the step of determining the distribution of at least a portion of the population of imageable microspheres within the patient's body by imaging a target portion of the patient's body using an imaging modality.

66. The method according to claim 65, further comprising the step of calculating the amount of therapeutic microspheres to be delivered to the patient's body using the distribution of the imageable microspheres.

67. A method for treating tumors in patients requiring treatment, A step of introducing a group of microspheres that can be imaged into the patient, The steps include distributing the imageable microspheres to the patient over a certain period of time, A step of determining the distribution of the imageable microspheres in the patient's area by imaging the imageable microspheres using an imaging modality, A step of determining an estimated effective dose at the site when the imageable microspheres are replaced with therapeutic microspheres, based on the distribution of the imageable microspheres; A method comprising the step of administering to the patient an amount of the therapeutic microspheres based on the estimated effective dose.

68. The method according to claim 67, wherein the group of imageable microspheres includes imageable microspheres according to any one of claims 1 to 39.

69. The method according to claim 67 or 68, wherein the said site is a malignant or benign tumor and / or non-tumorous tissue.

70. The method according to claim 67 or 68, wherein the site is a malignant tumor.

71. The method according to claim 70, wherein the aforementioned site is a malignant liver tumor.

72. A method for predicting the extent of off-target delivery to the lungs or gastrointestinal tract during treatment of patients requiring radioisotope cancer therapy, A step of introducing a group of microspheres that can be imaged into the patient, The steps include distributing the imageable microspheres to the patient over a certain period of time, A step of determining the distribution of imageable microspheres within the patient's lungs by imaging the imageable microspheres using an imaging modality, A step of determining the estimated radiation dose in the patient's lungs or gastrointestinal tract, respectively, when the imageable microspheres are replaced with radioisotope therapy microspheres, A step of determining a dose of the radioisotope therapeutic microspheres that is sufficient to cause clinically relevant pulmonary or gastrointestinal changes due to off-target delivery, A method comprising the step of administering to a patient a dose of the radioisotope therapeutic microspheres that is less than or equal to the dose of the radioisotope therapeutic microspheres determined to be sufficient to cause clinically relevant changes in the lungs or gastrointestinal tract due to off-target delivery.

73. The method according to claim 72, wherein the group of imageable microspheres includes imageable microspheres according to any one of claims 1 to 39.

74. A method for reducing lung or gastrointestinal tract damage during treatment for patients requiring radioisotope cancer therapy, A step of introducing a group of microspheres that can be imaged into the patient, The steps include distributing the imageable microspheres to the patient over a certain period of time, A step of determining the distribution of imageable microspheres within the gastrointestinal tract or lungs of the patient by imaging the imageable microspheres using an imaging modality, A step of determining the estimated radiation dose in the patient's gastrointestinal tract or lungs when the imagingable microspheres are replaced with radioisotope therapy microspheres, A step of determining a dose of the radioactive isotope therapeutic microspheres that is sufficient to cause damage to the gastrointestinal tract, A method comprising the step of administering to a patient a dose of radioisotope therapeutic microspheres that is less than or equal to the dose of radioisotope therapeutic microspheres determined to be sufficient to cause damage to the gastrointestinal tract.

75. The method according to claim 74, wherein the group of imageable microspheres includes imageable microspheres according to any one of claims 1 to 39.

76. It's a kit, A microsphere comprising a substrate containing an inorganic material which includes a metalloid or metal atom bonded to a nonmetal atom, wherein the substrate is A microsphere comprising a core extending to the surface, wherein the core comprises a first portion of the metalloid or metal atom bonded to the nonmetal atom, and the surface comprises a second portion of the metalloid or metal atom bonded to the nonmetal atom, Instructions for reacting an imageable radioisotope with a substrate such that the imageable radioisotope directly bonds to the substrate through at least a portion of the nonmetallic atoms on the surface of the substrate, and A kit that includes this.

77. Microspheres comprising an inorganic substrate containing at least one nonmetal, metalloid, or transition metal oxide, Instructions for bonding an imageable radioisotope to the surface of an inorganic substrate via Lewis acid-base coordination bonds. A kit that includes this.

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