Particles functionalized with imageable radioisotopes, methods of making and use thereof

Abstract

Some embodiments relate to imageable radioisotope microspheres. In some embodiments, the imageable microspheres are radiolabeled with an imageable radioisotope. In some embodiments, the imageable radioisotope is directly chemically coupled to the surface of the microsphere matrix. In some embodiments, the imageable microspheres can be used as surrogate particles to predict the distribution of therapeutic microspheres containing radiotherapeutic isotopes.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 62 / 970,587, filed February 5, 2020, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure relates to particles functionalized with imageable radioisotopes, their use as substitutes for therapeutic particles, methods for preparing such imageable particles, and methods for performing bioimaging and dosimetry using said particles. Background Technology

[0004] Related Art

[0005] One method of treating certain cancer patients involves introducing a radioactive isotope into the patient's circulatory system. A measured amount of the radioactive isotope is injected into the patient, causing it to accumulate at the cancer site sufficiently to treat the cancer. Summary of the Invention

[0006] In one method of cancer radiotherapy, radioactive microspheres are delivered to a point in the patient's vascular system, where they are carried by the bloodstream to the target tissue. Once there, they remain in the capillaries and release a therapeutic dose of radiation. This treatment is called selective internal radiation therapy (SIRT). The goal is to deliver a sufficient dose of radiation to cause localized tissue death in the cancerous tissue.

[0007] However, because therapeutic microparticles are not easily imaged, it is difficult to determine their distribution within the body. The characteristics of these therapeutic microspheres make predicting the distribution of therapeutic doses within the body very difficult and impractical. In turn, it is difficult to track and accurately assess where therapeutic microspheres ultimately reside. If the location of these microspheres within the body cannot be accurately determined, it is difficult to predict or measure the radiation dose of the therapeutic microspheres at the target site. Furthermore, it is also difficult to measure radiation doses harmful to healthy areas of the body. Some embodiments disclosed herein relate to imageable radioisotope-modified particles (e.g., microspheres) visible when using imaging modes. In some embodiments, these imageable radioisotope particles can be used as alternatives for roughly estimating the distribution of therapeutic microspheres within the body when introduced into the body. In some embodiments, the use of imageable alternatives as disclosed herein can allow for more accurate prediction of radiation doses, more effective treatment, and / or a reduction in the incidence of side effects on patients.

[0008] As disclosed elsewhere herein, some embodiments relate to imageable particles. In some embodiments, the particles are microspheres. In some embodiments, the imageable microspheres comprise at least one imageable radioisotope. In some embodiments, the imageable microspheres further comprise a matrix. In some embodiments, the matrix provides a surface to which at least one imageable radioisotope can be bound. In some embodiments, the matrix comprises an inorganic material. In some embodiments, the inorganic material comprises metalloid or metal atoms. In some embodiments, the matrix comprises a core that extends to the surface of the particle. In some embodiments, the core comprises a first portion of metalloid or metal atoms and the surface comprises a second portion of metalloid or metal atoms.

[0009] In some embodiments, the second portion of metalloid or metal atoms is bonded to nonmetal atoms. In some embodiments, the imageable radioisotope is directly bound to the matrix through at least a portion of the nonmetal atoms at the surface of the matrix. In some embodiments, the first portion of metalloid or metal atoms is also bonded to nonmetal atoms.

[0010] In some embodiments, the matrix comprises a substantially uniform mixture of constituent elements (i.e., elements from the periodic table).

[0011] In some embodiments, the surface comprises at least a portion of the constituent elements. For example, in some embodiments, the metalloid, metal, or nonmetal atoms of the surface of the matrix comprise the same elements as those found in the core.

[0012] In some embodiments, the nonmetal atoms are oxygen atoms. In some embodiments, at least a portion of the oxygen atoms of the surface of the matrix are provided as hydroxyl groups.

[0013] Some embodiments relate to imageable microspheres comprising an inorganic matrix having a surface layer. In some embodiments, the imageable microspheres comprise at least one imageable radioisotope. In some embodiments, the inorganic matrix comprises at least one nonmetal, metalloid, or transition metal oxide. In some embodiments, the imageable radioisotope is bound to the surface of the inorganic matrix through a Lewis acid-base coordination bond (thereby providing a Lewis acid-base adduct), e.g., a Lewis acid-base coordination bond with an inorganic Lewis base.

[0014] Some embodiments disclosed herein relate to imageable microspheres comprising an inorganic matrix comprising a surface having one or more electron-donating functional groups. In some embodiments, the imageable microspheres comprise a surface layer comprising at least one imageable radioisotope. In some embodiments, the imageable radioisotope is bound to the surface of the inorganic matrix through coupling with the one or more electron-donating functional groups during preparation of the imageable microspheres.

[0015] Some embodiments relate to imageable microspheres comprising a ceramic microsphere matrix and at least one imageable radioisotope. The imageable radioisotope is coupled to the surface of the ceramic microsphere matrix, for example as a Lewis acid-base adduct (e.g., an adduct of an inorganic Lewis base).

[0016] Any of the embodiments described above or elsewhere herein can include one or more of the following features.

[0017] In some embodiments, the imageable radioisotope is bound to the matrix through a chemical bond. In some embodiments, the chemical bond is selected from an ionic bond, a covalent bond, or a coordination bond. In some embodiments, the chemical bond is a coordination bond.

[0018] In some embodiments, the imageable radioisotope is configured for imaging by an imaging modality selected from single-photon imaging and two-photon imaging. In some embodiments, the imageable radioisotope is configured for imaging 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 radioisotope is a positron emitter or a gamma emitter. In some embodiments, the at least one imageable radioisotope is selected from 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, and / or combinations thereof. In some embodiments, the at least one imageable radioisotope is a metal radioisotope. In some embodiments, the at least one imageable radioisotope is selected from 99m Tc and 89 Zr. In some embodiments, the at least one imageable radioisotope is 89 Zr. In some embodiments, the at least one imageable radioisotope is 99m Tc.

[0019] In some embodiments, the surface of the imageable microsphere comprises a structure of Formula (V):

[0020]

[0021] wherein the matrix comprises Mc And M c Independently selected from Pb, Al, Si, Y, Mn, Ga, Fe, Sr, and Ti; m is an integer selected from 1, 2, or 3; M a It is a matrix atom or a bridging atom, M a Selected from Pb, Al, Si, Y, Mn, Ga, Fe, Ti, Sr, and Sn; M b Selected from 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 combinations thereof; R is absent or H; X is selected from –OH, =O and –O. - n is an integer selected from 0, 1, 2, 3, or 4. M a It can be a matrix atom or a bridging metal atom that chemically links (through chemical bonds) the imageable radioactive isotope to the matrix. In some embodiments, M... a It is a matrix atom, M a The elements are selected from Pb, Al, Si, Y, Mn, Ga, Fe, Sr, and Ti. In some embodiments, M... a It is a matrix atom, M a The elements are selected from Pb, Al, Si, Y, Mn, Ga, Fe, and Ti. In some embodiments, M... a Sn is a bridging metal atom. In some embodiments, M c It is Al; the matrix contains M a And M a It is Si; M b yes 89 Zr; each X is independently –OH or =O; n is 1 or 2. In some embodiments, M c and M a Independently selected from Al, Si, and Y; M b yes 89 Zr; each X is independently –OH or =O; n is 1 or 2. In some embodiments, M b yes 89 Zr, X is -OH, n is 2. In some embodiments, Mc It is Si, Al, or Y; M a It is Sn; M b yes 99m Tc; each X is independently –OH or =O; n is 2 or 3. In some embodiments, M b yes 99m Tc, X is -OH, n is 2 or 3.

[0022] In some embodiments, the surface of the imageable microsphere contains a structure of type (VI):

[0023]

[0024] The matrix contains M c And M c Selected from Pb, Al, Si, Y, Mn, Ga, Fe, Sr, and Ti; the surface layer contains M b And M b Selected from 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 combinations thereof; each instance of R is absent or –H; each instance of X is independently selected from –OH, =O, and –O. - m is an integer selected from 1, 2, or 3; n is an integer selected from 0, 1, 2, 3, or 4. In some embodiments, m is 1. In some embodiments, M c It is Al; M b yes 89 Zr; X is –OH or O - n is 1 or 2. In some embodiments, M c Is it Y or Al; M b yes 89 Zr; X is –OH or O - n is 2. In some embodiments, M c Is it Y or Al; M b yes 89 Zr; X is –OH or O - n is 1 or 2. In some embodiments, M b It is AlF18 In some embodiments, M b yes 99m Tc. In some embodiments, M b yes 89 Zr. In some embodiments, X is OH.

[0025] In some embodiments, the surface of the imageable microsphere contains a structure of type (VIII):

[0026]

[0027] The matrix contains M a and M c And M a and M c 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 Selected from 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 combinations thereof; R a Each instance is independently OH, O, or –O-Sn-O. - X is selected from –OH, =O and –O - n is an integer selected from 0, 1, 2, 3, or 4. In several embodiments, M a and M c Independently selected from Sn, Pb, Al, Si, Y, Mn, Ga, Fe, Sr, and Ti; m is an integer selected from 1, 2, or 3; M b Selected from 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 combinations thereof; R a Each instance is independently OH or O; X is selected from –OH, =O, and –O. - n is an integer selected from 0, 1, 2, 3, or 4. In some embodiments, M c Independently selected from Sn, Pb, Al, Si, Y, Mn, Ga, Fe, Sr, and Ti, especially from Al, Si, Y, Mn, and Sr; M a It is Sn;R a It is O; M b yes 99m Tc, X is OH, -O- or =O, n is 2 or 3.

[0028] In some embodiments, Sn in -O-Sn-O- may have one or more OH, O-, or hydrate groups coordinated thereto. In some embodiments, M c and M a Independently, it is Si, Al, or Y; M b yes 99m Tc; Each X is independently –OH, =O, or –O. - n is 2 or 3. In some embodiments, M c and M a Independently, it is Si, Al, or Y; M b yes 99m Tc;R a At least one instance is -O-Sn-O-; each X is independently –OH, =O, or –O. - n is 2 or 3. In some embodiments, M c It is Al; M a It is Si; M b yes 99m Tc; each X is independently –OH or =O; n is 2 or 3. In some embodiments, M c It is Al; M a It is Si; M b yes 99m Tc;R a At least one instance is -O-Sn-O-, where each X is independently –OH or =O; n is 2 or 3. In some embodiments, M b yes 99m Tc;R a At least one instance is -O-Sn-O-; each X is independently –OH or =O; n is 2 or 3. In some embodiments, M byes 99m Tc;R a One example is -O-Sn-O-, R a An example is -O- or -OH-; each X is independently –OH or =O; n is 2 or 3.

[0029] In some embodiments, as disclosed elsewhere herein, the inorganic matrix may comprise a ceramic material or a glass material. In some embodiments, the ceramic material may comprise a glass material or a glass material.

[0030] The inorganic matrix, ceramic, or glass may contain at least one nonmetallic, quasi-metallic, 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 matrix, 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 matrix, ceramic, or glass contains at least one of the following: Y₂O₃, SiO₂, MnO₂, AlO₃, Ga₂O₃, Fe₂O₃, TiO₂, SrO₂, SrCO₃, or combinations thereof. In some embodiments, the inorganic matrix, ceramic, or glass may contain SiO₂ and at least one of the following: Y₂O₃, MnO₂, AlO₃, Ga₂O₃, Fe₂O₃, TiO₂, SrO₂, SrCO₃, or combinations thereof.

[0031] The inorganic matrix, ceramic, or glass may contain yttrium aluminum silicon oxide or yttrium aluminum silicon oxide. Yttrium aluminum silicon oxide is described, for example, in U.S. Patent No. 4,789,501, the entire contents of which are incorporated herein by reference.

[0032] In some embodiments, the imageable microspheres lack therapeutic radioisotopes.

[0033] In some embodiments, the diameter of the imageable microspheres is from 5 μm to 1000 μm. In some embodiments, the diameter is the average diameter of the imageable microsphere group. In some embodiments, the diameter is determined by optical or electron microscopy.

[0034] In some embodiments, the inorganic matrix is ​​non-porous. In some embodiments, the inorganic matrix is ​​porous. In some embodiments, the imageable element is confined to the surface of the microsphere and / or the core of the inorganic matrix lacks an imageable radioisotope. In some embodiments, the imageable element is confined to the surface of the non-porous microsphere.

[0035] Some embodiments relate to imageable microspheres prepared by a method comprising providing a matrix and chemically coupling at least one imageable radioisotope to the matrix, thereby providing imageable microspheres.

[0036] Some embodiments relate to imageable microspheres prepared by methods including providing a matrix comprising an inorganic material (e.g., quasi-metallic or metallic atoms bonded or unbonded to nonmetallic atoms) as described elsewhere herein. In some embodiments, the matrix comprises a core and a surface layer, the core comprising a first portion of quasi-metallic or metallic atoms and the surface layer comprising a second portion of quasi-metallic or metallic atoms. In some embodiments, at least one imageable radioisotope is provided. In some embodiments, at least one imageable radioisotope is chemically coupled to the surface layer of the matrix to provide an imageable microsphere. In some embodiments, chemical coupling is achieved through nonmetallic atoms on the surface of the inorganic material.

[0037] In some embodiments, the at least one imageable radioisotope is provided as a salt prior to chemically coupling the at least one imageable radioisotope to the surface of an inorganic matrix. In some embodiments, the salt may be water-soluble or substantially water-soluble. In some embodiments, the salt is a halogen salt (e.g., a fluoride salt, chloride salt, bromide salt, or iodide salt) and / or a polyatomic salt, or may be a salt formed from an organic acid (e.g., an oxalate).

[0038] In some embodiments, chemical functionalization is performed 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., stannous salts (e.g., stannous chloride to provide stannous ions), tin hydrates (e.g., stannous hydrate), HCl, sodium borohydride, sodium dithionite, ferrous sulfate, ferric chloride plus ascorbic acid, hypophosphite (e.g., phosphonic acid), and / or hydrazine. In some embodiments, the reducing agent is a tin salt (e.g., stannous salts (e.g., stannous chloride to provide stannous ions) or a tin hydrate (e.g., stannous hydrate).

[0039] Some embodiments relate to a process for preparing imageable ceramic microspheres, the process comprising, in the presence of a reducing agent, reacting ceramic microspheres comprising at least one nonmetallic, quasi-metallic, or transition metal oxide with... 99m Tc pertechnetate ion reaction.

[0040] Some embodiments relate to a process for preparing imageable ceramic microspheres, the process comprising mixing ceramic microspheres comprising at least one nonmetallic or transition metal oxide with... 89 Zr ions (e.g., oxalic acid) 89 Zr or chloride 89 Zr) reaction. In some embodiments, the reaction is carried out in the presence of a base. When 89 When Zr is provided in the form of a halide salt (e.g., chloride), it is typically provided in an acidic solution (e.g., in 1M HCl or 1M oxalic acid), in which case the acid can be neutralized with a base, and thus the reaction can take place in the presence of a base.

[0041] Some embodiments relate to methods for preparing imageable microspheres, the methods comprising providing an inorganic matrix and chemically functionalizing the inorganic matrix with at least one imageable radioisotope, thereby providing imageable microspheres.

[0042] In some embodiments, the at least one imageable radioisotope is provided in ionic form (e.g., a salt) prior to chemically functionalizing the at least one imageable radioisotope onto the surface of an inorganic matrix. In some embodiments, the salt may be water-soluble or substantially water-soluble. In some embodiments, the salt is 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 may be a salt formed from an organic acid (e.g., oxalate). In some embodiments, the salt is a halogen salt (e.g., chloride) and / or a polyatomic salt, or may be a salt formed from an organic acid (e.g., oxalate). In some embodiments, one or more counterions (e.g., 1, 2, 3, 4, 5, etc.) may be associated with the imageable radioisotope. In some embodiments, the at least one imageable radioisotope is provided together with a chelating agent. In some embodiments, the chelating agent is selected from one or more of 6-hydrazinonicotinamide (HYNIC), dodecanetetraacetic acid (DOTA), deferoxamine (DFO), etc.

[0043] In some embodiments, a reducing agent is added during the chemical functionalization step, for example when the imageable isotope is... 99m At Tc. In some embodiments, the reducing agent is selected from one or more of the following: tin salts (e.g., stannous salts (e.g., stannous chloride to provide stannous ions), tin hydrates (e.g., stannous hydrate), HCl, sodium borohydride, sodium dithionite, ferrous sulfate, ferric chloride plus ascorbic acid, hypophosphite, and / or hydrazine. In some embodiments, the radioactive isotope is 99m Tc reacts in the presence of a tin salt (e.g., a stannous salt (e.g., stannous chloride to provide stannous ions). In some embodiments, 99m Tc is provided in the form of pertechnetate ions.

[0044] Some embodiments relate to methods for preparing imageable microspheres as described elsewhere herein, the methods including providing microspheres comprising a ceramic microsphere matrix as described elsewhere herein, and reacting the microspheres with an imageable radioisotope as described elsewhere herein under suitable conditions, thereby coupling the imageable radioisotope to the surface of the ceramic microsphere matrix in the form of a Lewis acid-base adduct.

[0045] In some embodiments, the radioactive isotope is provided in the form of a salt. In some embodiments, the radioactive isotope is provided in ionic form (e.g., in the form of a salt). In some embodiments, the salt may be water-soluble or substantially water-soluble. In some embodiments, the salt is an alkali metal (e.g., sodium or potassium) salt, an alkaline earth metal (e.g., calcium, magnesium, barium, or strontium) salt, a halide salt (e.g., chloride), and / or a polyatomic salt, or may be a salt formed from an organic acid (e.g., oxalate).

[0046] In some embodiments, such as in 89 When Zr is an imageable isotope, the radioactive isotope can be provided in the form of a salt. This radioactive isotope can react with the microspheres in the presence of a base. The base can be, for example, selected from alkali metal or alkaline earth metal carbonates (e.g., sodium carbonate and calcium carbonate), alkali metal hydroxides, etc. In some embodiments, the base can 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 a range including and / or within the range of the above values. In some embodiments, the base is an inorganic base. In some embodiments, the imageable radioactive isotope can be... 89 Zr, for example, is provided as a salt, such as oxalic acid. 89 Zirconium or halide salts, such as chlorides 89 zirconium.

[0047] In some embodiments, the radioactive isotope is provided in the form of a salt and reacts with the ceramic microspheres in the presence of a reducing agent.

[0048] In some embodiments, the reducing agent is selected from one or more of the following: tin salts (e.g., stannous salts (e.g., stannous chloride)), tin hydrates (e.g., stannous hydrate), HCl, sodium borohydride, sodium dithionite, ferrous sulfate, ferric chloride plus ascorbic acid, hypophosphite, and / or hydrazine. In one method, the reducing agent is a tin salt, which may be a stannous salt, such as a salt containing a halogen (e.g., chlorine).

[0049] In one approach, the imageable isotope can be 99m Tc can be provided as pertechnetate. The reducing agent can be stannous ions, such as stannous chloride.

[0050] In any of the described methods, the method may be carried out in an aqueous medium and may additionally include recovering the imageable microspheres and / or washing the microspheres to remove unreacted radioisotopes. In some embodiments, the method may additionally include resuspending the imageable microspheres in a pharmaceutically acceptable injectable aqueous medium (e.g., a sterile aqueous medium).

[0051] Some embodiments involve imageable microspheres that can be obtained by any of the preparation methods described herein.

[0052] Some embodiments relate to methods for determining the amount of therapeutic microspheres to be delivered to a patient's body. In some embodiments, an imageable microsphere cluster is provided. In some embodiments, the imageable microsphere cluster is delivered to the patient by introducing it into a first location in the patient's vascular system. In some embodiments, the imageable microsphere cluster is allowed to distribute within the patient's body. In some embodiments, the distribution of at least a portion of the imageable microsphere cluster within the patient's body is determined by imaging at least one target portion of the patient's body using an imaging modality. In some embodiments, the distribution of the imageable 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 a body portion 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. In some embodiments, the target portion of the body is the patient's kidney. In some embodiments, the target portion of the body is the patient's spleen. In some embodiments, the target portion of the body is the patient's gastrointestinal tract. In some embodiments, the target portion of the body is the patient's pancreas. In some embodiments, the target portion of the body is the patient's adrenal gland. In some embodiments, the target portion of the body is the patient's gallbladder. In some embodiments, the target portion of the body is the patient's bladder. In some embodiments, the target portion of the body is the patient's muscles. In some embodiments, the target portion of the body is the patient's bones. In some embodiments, the target portion of the body is the patient's thyroid gland. In some embodiments, the target portion of the body is the patient's ovary. In some embodiments, the target portion of the body is the patient's uterus. In some embodiments, the treatment method includes treating a tumor in any of the aforementioned target portions.

[0053] In some embodiments, the imaging mode is SPECT. In some embodiments, the detection mode is PET. In some embodiments, the detection mode is gamma camera imaging. In some embodiments, the imageable microsphere is an imageable microsphere as disclosed elsewhere herein.

[0054] Some embodiments relate to a method of treating a patient. In some embodiments, an imageable microsphere cluster is provided. In some embodiments, the imageable microsphere cluster is delivered to a patient by introducing it into a first location in the vascular system of the patient's body. In some embodiments, the imageable microsphere cluster is allowed to distribute within the patient's body. In some embodiments, the distribution of at least a portion of the imageable microsphere cluster within the patient's body is determined by imaging at least one target portion of the patient's body using an imaging modality. In some embodiments, the distribution of the imageable microspheres is used to calculate the amount of therapeutic microspheres to be delivered to the patient's body. In some embodiments, data regarding the distribution of the imageable therapeutic microsphere substitute within the patient's body is obtained. In some embodiments, this data is used to determine the therapeutic amount of microspheres to be administered to the patient's body. In some embodiments, the therapeutic microsphere cluster is delivered to a patient by introducing it into a second location in the vascular system of the patient's body. In some embodiments, the therapeutic microsphere cluster is allowed to distribute within the patient's body, thereby treating 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.

[0055] In some embodiments, the imaging mode is SPECT. In some embodiments, the detection mode is PET. In some embodiments, the detection mode is gamma camera imaging. In some embodiments, the imageable microsphere is an imageable microsphere as disclosed herein.

[0056] Some embodiments relate to a method of treating a patient using therapeutic microspheres. In some embodiments, data is calculated based on the distribution of an imageable therapeutic microsphere substitute within the patient's body. In some embodiments, the data is used to determine the amount of therapeutic microspheres to be administered to the patient's body. In some embodiments, the amount of therapeutic microspheres is administered to the patient by introducing the amount of therapeutic microspheres into a first location in the patient's vascular system. In some embodiments, the therapeutic microspheres are allowed to distribute within the patient's body. In some embodiments, the therapeutic microspheres are allowed to remain within the patient's body, thereby treating the patient.

[0057] In some embodiments, an imageable microsphere cluster is provided to a patient. In some embodiments, the imageable microsphere cluster is delivered to the patient by introducing it into a first location in the vascular system of the patient's body. In some embodiments, the imageable microsphere cluster is allowed to distribute within the patient's body. In some embodiments, the distribution of at least a portion of the imageable microsphere cluster within the patient's body is determined by imaging at least one target portion of the patient's body using an imaging modality. In some embodiments, the distribution of the imageable microspheres is used to calculate the amount of therapeutic microspheres to be delivered to the patient's body.

[0058] Some embodiments relate to methods of treating a patient with malignant or benign tumors (e.g., non-malignant tumors). Some embodiments relate to methods of treating vascularized tumors with vascular connections (e.g., malignant or benign tumors), such as those found in liver cancer (e.g., liver tumors, such as hepatocellular carcinoma-HCC, and tumors derived from other tumors that have metastasized to the liver (e.g., neuroendocrine tumors and colorectal tumors)) and tumors of the brain, prostate, lung, spleen, and kidney. In some embodiments, an imageable microsphere cluster is introduced into the patient. In some embodiments, the imageable microspheres are allowed to distribute within the patient for a period of time. In some embodiments, the imageable microspheres are imaged directly after injection or in real-time (during injection). In some embodiments, the imageable microspheres are allowed to distribute within the patient for a period of time less than two half-lives of the imageable radioisotope associated with the imageable microspheres. In some embodiments, the distribution of the imageable microspheres at the cancer site within the patient is determined by imaging the imageable microspheres using an imaging modality. In some embodiments, based on the distribution of the imageable microspheres, an estimated effective dose at the cancer site is determined when therapeutic microspheres are used instead of the imageable microspheres. In some embodiments, a dose of therapeutic microspheres is administered to the patient based on an estimated effective dose (i.e., an estimated absorbed dose). In some embodiments, the imageable microsphere group comprises imageable microspheres as disclosed elsewhere herein. In some embodiments, the cancer is liver cancer.

[0059] In some embodiments, the imageable microspheres are imaged after injection. In some embodiments, the imageable microspheres are allowed to distribute in the patient for a period of time prior to imaging, said time being at least about: 2 minutes, 5 minutes, 10 minutes, 30 minutes, 1 hour, 4 hours, 6 hours, or a range including and / or within the range of said values. In some embodiments, the imageable microspheres are distributed in the body shortly after injection (e.g., within minutes). In some embodiments, the imageable microspheres are distributed in the patient (e.g., the target and / or off-target areas) for a period of time, said time being equal to or less than about: 2 minutes, 5 minutes, 10 minutes, 30 minutes, or a range including and / or within the range of said values. In some embodiments, the imageable microspheres are allowed to distribute in the patient for a period of time prior to imaging, said time being equal to or less than about: 2 minutes, 5 minutes, 10 minutes, 30 minutes, or a range including and / or within the range of said values.

[0060] Some embodiments relate to methods for predicting the extent of lung shunting (off-target delivery) in patients undergoing radioisotope cancer treatment. In some embodiments, an imageable microsphere swarm is administered to the patient. In some embodiments, the imageable microspheres are allowed to distribute within the patient for a period of time. In some embodiments, the distribution of the imageable microspheres within the patient's lungs is determined by imaging the imageable microspheres using an imaging modality. In some embodiments, an estimated radiation dose to the patient's lungs is determined by calculating the radiation dose that would be received if a specific amount of radioisotope therapeutic particles were administered instead of the imageable microspheres. In some embodiments, a dose of radioisotope therapeutic microspheres sufficient to cause clinically relevant lung changes due to lung shunting is determined. In some embodiments, it is determined whether the patient is a candidate to receive the treatment. In some embodiments, the dose of radioisotope therapeutic microspheres administered to the patient is lower than the dose of radioisotope therapeutic microspheres determined to be sufficient to cause clinically relevant lung changes due to lung shunting. In some embodiments, the imageable microsphere swarm comprises imageable microspheres as disclosed elsewhere herein.

[0061] Some embodiments relate to methods for reducing gastrointestinal damage during treatment of patients requiring radioisotope cancer therapy. In some embodiments, the method includes introducing an imageable microsphere swarm into the patient. In some embodiments, the imageable microspheres are allowed to distribute within the patient for a period of time. In some embodiments, the distribution of the imageable microspheres within the patient's gastrointestinal tract is determined by imaging the imageable microspheres using an imaging modality. In some embodiments, an estimated radiation dose in the patient's gastrointestinal tract is determined if a specific amount of the imageable microspheres were replaced by radioisotope therapeutic microspheres. In some embodiments, a dose of radioisotope therapeutic microspheres sufficient to cause gastrointestinal damage is determined. In some embodiments, it is determined whether the patient is a candidate for receiving the treatment. In some embodiments, the dose of radioisotope therapeutic microspheres administered to the patient is lower than the dose of radioisotope therapeutic microspheres determined to be sufficient to cause gastrointestinal damage. In some embodiments, the imageable microsphere swarm comprises imageable microspheres as disclosed elsewhere herein.

[0062] Some embodiments relate to kits. In some embodiments, the kit includes a non-derived version of the imageable microspheres further described herein and instructions for using imageable radioisotope-derived microspheres described herein. In some embodiments, for example, the kit includes microspheres comprising a matrix having an inorganic material comprising quasi-metallic or metallic atoms bonded to non-metallic atoms, the matrix may include a core extending to a surface, the core comprising a first portion of quasi-metallic or metallic atoms bonded to non-metallic atoms, and the surface comprising a second portion of quasi-metallic or metallic atoms bonded to the non-metallic atoms. The kit may also include instructions for reacting an imageable radioisotope with the matrix, such that the imageable radioisotope binds directly to the matrix via at least a portion of the non-metallic atoms on the matrix surface.

[0063] In some embodiments, the kit may comprise microspheres having an inorganic matrix; wherein the inorganic matrix comprises at least one nonmetallic, quasi-metallic, or transition metal oxide. The kit may additionally include instructions for binding an imageable radioisotope to the surface of the inorganic matrix via Lewis acid-base coordination bonds.

[0064] In some embodiments, the kit may include microspheres having a ceramic microsphere matrix and instructions for performing a reaction in which an imageable radioisotope is coupled to the ceramic microsphere matrix as a Lewis acid-base adduct.

[0065] In some embodiments, the kit may additionally contain a reducing agent as further described herein.

[0066] In some embodiments, the kit may additionally contain therapeutic microspheres, such as microspheres suitable for selective internal radiotherapy as further described herein.

[0067] In some embodiments, the kit includes instructions for introducing imageable microspheres into a patient using a catheter. In some embodiments, the kit includes one or more of the following: a vascular access needle, a guidewire, a vascular sheath (e.g., 4-6 Fr), a vascular catheter (4-5 Fr), a microcatheter, a syringe, and a vial. Attached Figure Description

[0068] The features of the imageable particles disclosed herein are described below with reference to the accompanying drawings of certain embodiments. The embodiments shown are intended to illustrate but are not intended to limit this disclosure.

[0069] FIG. 1 It describes the periodic table of elements.

[0070] FIG. 2 The results of the detachment study of an example of an imageable radioisotope particle are described.

[0071] FIG. 3A Described with99m Stability study results of an imageable radioisotope particle example of Tc microspheres.

[0072] FIG. 3B Described with 89 Stability study results of an imageable radioisotope particle example of Zr microspheres.

[0073] FIG. 4A The results of a stability study of a comparative imaging particle containing a large-particle polymeric protein labeled with technetium-99m are described.

[0074] FIG. 4B Results of radioisotope functionalization at different pH levels and in various buffer solutions are provided.

[0075] FIG. 5A and 5B Axial images of a marmot with bilateral large hepatocellular carcinoma are provided. FIG. 5A T2-weighted MRI imaging was used. FIG. 5B The text describes PET-CT images showing catheter-directed delivery. 89 Absorption of Zr-functionalized YAS microspheres.

[0076] FIG. 6A and 6B Images of marmots were provided. FIG. 6A Axial images of a marmot with a large, single, overt hepatocellular carcinoma are provided, as shown in T2-weighted MRI images. FIG. 6B Is delivery 89 Digital subtraction angiography of a catheter located in the common hepatic artery prior to Zr-functionalized YAS microspheres.

[0077] Figures 7A and 7B provide catheter-directed delivery at reconnaissance dose (PT1; 7A) and full dose (PT2; 7B). 89 Imaging of Zr-functionalized microspheres. Note that lung absorption is negligible, while absorption differs significantly between tumors and normal livers. Detailed Implementation

[0078] Some embodiments disclosed herein relate to particles (e.g., microspheres) comprising imageable radioisotopes, which can serve as alternatives to therapeutic particles (e.g., therapeutic radioisotope microsphere alternatives), such as those suitable for selective internal radiotherapy (SIRT), methods for preparing imageable radioisotope particles, methods for bioimaging and dosimetry using imageable radioisotope particles, and methods for treating patients using information collected by imageable radioisotope particles. In some embodiments, the imageable radioisotope is functionalized (through chemical bonding) to the particle surface to prepare the imageable radioisotope particles. In some embodiments, the chemical bond is a Lewis acid-base interaction between the imageable radioisotope and the particle matrix surface. In some embodiments, the imageable particles serve as alternatives (e.g., surrogates) to therapeutic microspheres for determining the location in the body where therapeutic microspheres will travel upon introduction and how a swarm of therapeutic microspheres will distribute in the body upon delivery to blood vessels. Some embodiments relate to therapeutic fields using microspheres, including SIRT.

[0079] As used herein, the term "chemical bond" is given its simple and general meaning as a persistent attractive force between atoms, ions, or molecules capable of forming compounds. This bond can arise from electrostatic attraction between ions with opposite charges (such as an ionic bond) or through electron sharing (such as a covalent bond). Chemical bonds include "strong bonds" or "primary bonds," such as covalent bonds, ionic bonds, and metallic bonds, as well as "weak bonds" or "secondary bonds," such as dipole-dipole interactions, London dispersion forces, and hydrogen bonds.

[0080] As used herein, the term "coordinate bond" is given its simple and common meaning as a covalent bond in which two electrons come from the same atom.

[0081] As used herein, the term "covalent bond" is given its simple and general meaning as a bond formed between atoms by sharing a pair of electrons.

[0082] As used herein, the term "Lewis acid" is given its simple and general meaning as any substance (molecule or ion) that acts as an electron pair acceptor.

[0083] As used herein, the term “Lewis base” is given its simple and general meaning as any substance (molecule or ion) that acts as an electron pair donor.

[0084] As used herein, the term "Lewis acid-base adduct" is given its simple and general meaning as a compound containing a coordinate covalent bond between a Lewis acid and a Lewis base.

[0085] As used herein, the term "half-life" or t 1 / 2It is given a simple and common meaning, referring to the time required for half of the atoms of a radioactive isotope to decay.

[0086] As used herein, the term "metalloid" refers to a class of chemical elements whose properties are intermediate between those of metals and nonmetals, or mixtures of metals and nonmetals. Metalloids include at least boron (B), silicon (Si), germanium (Ge), arsenic (As), antimony (Sb), and tellurium (Te). Metalloids in FIG. 1 The elements are shown in the periodic table.

[0087] As used herein, the term "metal" refers to a class of chemical elements in the periodic table that include alkali metals, alkaline earth metals, and transition metals. Transition metals further include late transition metals, lanthanides, and actinides. The metals in... FIG. 1 The elements are shown in the periodic table.

[0088] As used herein, the term "nonmetal" refers to a class of chemical elements in the periodic table. Nonmetals include... FIG. 1 The elements shown in the periodic table are carbon (C), nitrogen (N), oxygen (O), sulfur (S), and other elements.

[0089] As used herein, the term "ceramic microsphere matrix" refers to ceramic microspheres that form a matrix that binds to imageable radioactive isotopes.

[0090] In some embodiments, the treatment “patient” or “subject” disclosed herein is a human patient; however, it should be understood that the principles of the currently disclosed subject matter indicate that the subject matter is applicable to all vertebrate species (including mammals) intended to be included in the terms “subject” and “patient.” Suitable subjects are typically mammalian subjects. The subject matter described herein can also be used for research in 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 newborns, infants, children, adolescents, adults, and elderly subjects. Subjects may be subjects who “need” the methods disclosed herein, subjects experiencing a disease state, and the methods and compounds of the present invention are used to evaluate treatment options.

[0091] As used herein, the term "effective dose" refers to the amount of the particles and / or composition that provides a moderating effect to a subject suffering from a disorder, disease, or condition, such moderating effect being, for example, a beneficial effect including improving the subject's condition (e.g., one or more symptoms), delaying or shortening the course of a disease, preventing or delaying the onset of a disease, and / or altering clinical parameters, diseases, or conditions, as is well known in the art. For example, an effective dose may refer to an amount of composition, particles, or reagent that improves the subject's condition by at least 5%, such as 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 each active ingredient in the active compositions of the subject matter of this disclosure can be varied to administer an amount of active particles that effectively achieves the desired response in a particular subject and / or application. The chosen dose level will depend on a variety of factors, including but not limited to the activity of the composition, route of administration, composition distribution, severity of the condition being treated, and the physical condition and medical history of the subject being treated. In some embodiments, a minimum dose is administered. This document envisions the determination and adjustment of effective doses, and the assessment of when and how such adjustments should be made.

[0092] "Treatment" or "treating" or "treatmet" refers to any type of action that provides a moderating effect on a subject suffering from a disorder, disease, or condition. This moderating effect can be beneficial, such as improving the subject's condition (e.g., one or more symptoms), delaying or shortening the course of a disease, and / or altering clinical parameters, disease, or condition, curing a disease, etc.

[0093] Whenever a group is described as “optionally substituted,” the group may be unsubstituted or substituted with one or more of the shown substituents. Similarly, when a group is described as “unsubstituted or substituted,” if substituted, the substituent may be selected from one or more of the shown substituents. If no substituent is specified, it indicates that the shown “optionally substituted” or “substituted” group may be substituted by one or more groups individually and independently selected from: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, hydroxyl, alkoxy, cyano, halogen, C-amide, N-amide, C-carboxyl, O-carboxyl, haloalkyl, haloalkoxy, mercapto, amino, mono-substituted amino, and di-substituted amino.

[0094] As used in this article, "C" a To C bThe term “C1 to C4 alkyl” refers to the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, or in a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heteroaryl ring. Specifically, the rings of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heteroaryl groups can contain “a” to “b” (inclusive) carbon atoms. Therefore, for example, “C1 to C4 alkyl” refers to all alkyl groups having 1 to 4 (e.g., 1, 2, 3, or 4) carbon atoms, i.e., CH3- CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. "C1 to C6 alkyl" refers to all alkyl groups having 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbons. Where "a" and "b" are not specified for alkyl, alkenyl, ynyl, cycloalkyl, cycloalkenyl, cycloynyl, aryl, or heteroaryl, the widest range described in these definitions is assumed.

[0095] As used herein, the term "alkyl" refers to a fully saturated aliphatic hydrocarbon group. The alkyl moiety can be branched or straight-chain. Examples of branched alkyl groups include, but are not limited to, isopropyl, sec-butyl, tert-butyl, etc. Examples of straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, etc. Alkyl groups can have 1 to 30 carbon atoms (wherever it appears herein, for example, the numerical range "1 to 30" refers to each integer within a given range; for example, "1 to 30 carbon atoms" means that an alkyl group can 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, although this definition also covers the term "alkyl" where no numerical range is specified). "Alkyl" can also refer to medium-sized alkyl groups having 1 to 12 carbon atoms. "Alkyl" can also refer to lower alkyl groups having 1 to 6 carbon atoms. Alkyl groups can be substituted or unsubstituted. For example, "C1-C5 alkyl" indicates that the alkyl chain has 1-5 carbon atoms, meaning the alkyl chain is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chain), etc. Typical alkyl groups include, but are by no means limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl.

[0096] As used herein, the term "alkylene" refers to a fully saturated divalent straight-chain aliphatic hydrocarbon group. Examples of alkylenes include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, and octylene. Alkylenes can be used... Followed by the number of carbon atoms, then by an asterisk (*). For example, Represents ethylene. Alkylenes can have 1 to 30 carbon atoms (wherever they appear in this text, numerical ranges such as “1 to 30” refer to every integer within a given range; for example, “1 to 30 carbon atoms” means that an alkyl group can consist of 1, 2, 3, etc., up to and including 30 carbon atoms, although this definition also covers the term “alkylene” where no numerical range is specified). Alkylenes can also be medium-sized alkyl groups having 1 to 12 carbon atoms. Alkylenes can also be lower alkyl groups having 1 to 6 carbon atoms. Alkylenes can be substituted or unsubstituted. For example, substitution can be made by replacing one or more hydrogens of a lower alkylene group and / or by using C 3-6 Monocyclic cycloalkyl (e.g., It replaces two hydrogen atoms on the same carbon atom to replace lower alkylene groups.

[0097] As used herein, "alkenyl" refers to an alkyl group containing one or more double bonds in a straight or branched hydrocarbon chain. Alkenyl groups may be substituted or unsubstituted.

[0098] As used herein, "alkynyl" refers to an alkyl group containing one or more triple bonds in a straight-chain or branched hydrocarbon chain. The alkynyl group may or may not be substituted.

[0099] As used herein, "aryl" refers to a monocyclic or polycyclic aromatic ring system (including fused ring systems where two carbon rings share a chemical bond) that possesses a fully delocalized π-electron system in all rings. The number of carbon atoms in an aryl group can vary. For example, an aryl group can be C6-C. 14 Aryl, C6-C 10 Aryl or C6 aryl. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. Aryl groups may be substituted or unsubstituted.

[0100] As used herein, “heteroaryl” refers to a monocyclic or polycyclic aromatic ring system (a ring system with a fully 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 can vary. For example, a heteroaryl can contain 4 to 14 atoms, 5 to 10 atoms, 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 aromatic ring and at least one heteroaromatic ring, or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazolidone, 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, tetrazolium, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cyclophosphine, and triazine. The heteroaryl group may be substituted or unsubstituted.

[0101] As used herein, “cycloalkyl” refers to a fully saturated (without double or triple bonds) monocyclic or polycyclic hydrocarbon ring system. When composed of two or more rings, these rings can be fused together. A cycloalkyl group may contain 3 to 10 atoms or 3 to 8 atoms in the ring, or as otherwise noted herein. Cycloalkyl groups may be substituted or unsubstituted. Typical cycloalkyl groups include, but are by no means limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0102] As used herein, “cycloalkenyl” refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring; however, if there is more than one double bond, the double bonds cannot form a fully delocalized π-electron system in all rings (otherwise the group would be “aryl” as defined herein). When composed of two or more rings, these rings can be connected together in a fused manner. Cycloalkenyl groups may be substituted or unsubstituted.

[0103] As used herein, "heterocyclic group" or "heterocyclic alicyclic group" refers to a tri-, tetra-, penta-, hexa-, hepta-, octa-, nona-, deca-, up to 18-membered monocyclic, bicyclic, and tricyclic system in which a carbon atom, together with one to five heteroatoms, forms the ring system. However, the heterocycle may optionally contain one or more unsaturated bonds positioned such that a fully delocalized π-electron system is not present in all rings. Heteroatoms are elements other than carbon, including but not limited to oxygen, sulfur, and nitrogen. Heterocycles may further contain one or more carbonyl or thiocarbonyl functional groups, thereby including oxo and thio systems, such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. When composed of two or more rings, these rings may be fused together. Additionally, any nitrogen in the heterocyclic ring may be quaternized. Heterocyclic groups or heterocyclic alicyclic groups may be substituted or unsubstituted. Examples of such "heterocyclic groups" or "heterocyclic alicyclic groups" include, but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxothione, 1,4-oxothionediene, 1,3-oxothionediene, 1,3-dithionediene, 1,4-oxothionediene, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, and dihydrogen Uracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazoline, isoxazoline, isoxazoline, oxazoline, oxazoline, oxazoline, oxazoline, oxazoline, thiazoline, thiazoline, morpholine, ethylene oxide, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidone, 4-piperidinone, pyrzoline, pyrrolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiaran, thiomorpholine, thiomorpholine sulfoxide, thiomorpholine sulfone and their benzo[a]-fused analogues (e.g., benzimidazolone, tetrahydroquinoline, 3,4-methylenedioxyphenyl).

[0104] As used herein, the term "amino" refers to the –NH2 group.

[0105] As used herein, the term "hydroxyl group" refers to the –OH group.

[0106] As used herein, the term "cyano" refers to the "-CN" group.

[0107] As used herein, the term “thiol” refers to the “-SH” group.

[0108] As used herein, “alkoxy” refers to the formula -OR, where R is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl) group as defined herein. A non-limiting list of alkoxy groups includes methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, phenoxy, and benzoyloxy. Alkoxy groups may be substituted or unsubstituted.

[0109] As used herein, the term "C-acylamino" refers to "-C(=O)N(R)". A R B )" group, wherein R A and R B It can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heteroaryl. The C-amide may be substituted or unsubstituted.

[0110] As used in this article, "N-acylamino" refers to "RC(=O)N(R A )-” groups, wherein R and R A It can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heteroaryl. The N-amide may be substituted or unsubstituted.

[0111] As used herein, the term “O-carboxyl” refers to an “RC(=O)O-” group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heteroaryl as defined herein. The O-carboxyl group may be substituted or unsubstituted.

[0112] As used herein, the terms “ester” and “C-carboxyl” refer to the “-C(=O)OR” group, where R may be the same as defined for an O-carboxyl group. Esters and C-carboxyl groups may be substituted or unsubstituted.

[0113] As used herein, the term "halogen atom" or "halogen" refers to any radioactively stable atom in column 7 of the periodic table, such as fluorine, chlorine, bromine, and iodine.

[0114] As used herein, "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are substituted with a halogen (e.g., monohaloalkyl, dihaloalkyl, and trihaloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and 1-chloro-2-fluoromethyl, 2-fluoroisobutyl. Haloalkyl groups may be substituted or unsubstituted.

[0115] As used herein, "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are substituted with a halogen (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. Haloalkoxy groups may be substituted or unsubstituted.

[0116] As used in this article, "diamino" refers to a substance that can pass through C 1-10 Compounds with two amino groups linked by an alkyl chain, wherein the two amino groups are optionally substituted independently (e.g., optionally substituted by another C). 1-6 Alkyl-substituted di-substituted amino or tri-substituted amino).

[0117] As used in this article, "triamino" refers to a substance that has two or three carbon atoms. 1-10 Compounds of three amino groups linked by an alkyl chain (e.g., forming a cyclic structure or a straight chain), wherein the three amino groups are optionally substituted independently (e.g., optionally substituted by another C). 1-6 Alkyl-substituted di-substituted amino or tri-substituted amino).

[0118] As disclosed elsewhere herein, radioactive microspheres for SIRT can be delivered (e.g., via a catheter) to a point in the vascular system, from which they are carried by blood flow and / or injection fluid to the target tissue. Here, they remain in the capillaries and deliver a dose of therapeutic radiation, typically sufficient to cause local tissue death. The therapeutic radiation is typically delivered in the form of beta or gamma radiation emanating from a beta or gamma radioactive isotope. Various therapeutic isotopes can be used in SIRT, including but not limited to yttrium-90 and holmium-166. In one approach, SIRT employs glass microspheres containing yttrium-90 (a beta emitter). These microspheres are prepared by neutron bombardment of non-radioactive glass microspheres containing naturally occurring yttrium-89, converting the natural yttrium-89 to yttrium-90 through neutron capture.

[0119] The chapter headings used herein are for organizational purposes only and should not be construed as limiting the subject matter in any way. All references and similar materials cited in this application, including but not limited to patents, patent applications, articles, books, papers, and internet web pages, are expressly incorporated herein by reference in their entirety for any purpose. Where the definitions of terms in the included references appear to differ from those provided in this teaching, the definitions provided in this teaching shall prevail. It should be understood that the terms "about" are implied before temperature, concentration, time, etc., discussed in this teaching, thus minor and non-substantial deviations fall within the scope of the teachings herein. In this application, the singular is used to include the plural unless otherwise expressly stated. Furthermore, the use of "comprising," "including," "containing," etc., is not intended to be limiting. It should be understood that the summary of the invention and the following detailed description are merely exemplary and explanatory, and not restrictive. The term "and / or" indicates that the provided possibilities can be used together or alternatively. Therefore, the term "and / or" indicates that both options of the set of possibilities exist.

[0120] INTRODUCTION

[0121] Because circulatory systems vary greatly from person to person, patients undergoing SIRT may experience varying levels of success. This may be partly due to off-target distribution of the therapeutic radioisotope microspheres. If introduced into blood vessels, therapeutic radioisotope microspheres may distribute in unexpected ways to unintended areas of the body. For example, this could be due to blood vessels in a small percentage of the population diverting a portion of their blood supply to tissues not normally supplied by the main vascular system. These vessels can cause the radioisotope microspheres to be delivered to inappropriate tissues. Off-target distribution of the microspheres is undesirable because, for example, it can lead to radiation to non-target tissues, resulting in unintended tissue death, which can be clinically considered side effects on the patient. For example, if a pulmonary shunt exists (i.e., a blood vessel that unintentionally diverts blood from the primary target tissue, such as the liver, to the lungs), the therapeutic radioisotope particles may accumulate in the lungs and potentially damage lung tissue.

[0122] Another problem with off-target delivery is that it also reduces the number of microspheres delivered to the target tissue. Therefore, other tissues, instead of the target tissue, receive the radiation, thus reducing the radiation dose delivered to the target tissue. This can lead to ineffective cancer treatment and consequently, higher mortality rates.

[0123] Furthermore, beta radiation itself is unsuitable for precise imaging techniques. While beta radiation is well-suited for tumor treatment, its effective range is very short, and it is difficult, if not impossible, to detect in vitro. Additionally, the low bremsstrahlung radiation from the beta and positron emissions of these therapeutic microspheres results in poor imaging quality and accuracy.

[0124] Prior to treatment, the local vascular system is typically mapped using iodinated contrast agents, allowing visualization of blood vessels via X-ray-based techniques. This enables physicians to better understand the local vascular anatomy and plan the delivery of radioactive microspheres into the appropriate vessels supplying the target tissue. However, these contrast agents can be difficult to detect in small amounts for several reasons and are a poor alternative to therapeutic radioisotope microspheres. Because contrast agents can vary in shape and size and may have different properties than therapeutic radioisotope microspheres, there remains a risk that a certain percentage of the radioactive microspheres may remain at off-target sites (e.g., by penetrating the target tissue and entering vessels flowing to distal tissues). Therefore, mapping the vascular system itself has several drawbacks.

[0125] In addition to mapping the vascular system, the predicted microsphere distribution map before treatment is also beneficial. This can be achieved using an imageable microparticle substitute injected into the patient's vascular system to simulate the planned SIRT procedure. One currently used imageable microparticle substitute is a large-particle polymeric protein formulation labeled with technetium-99m before use (called...). 99m TcMAA). Technetium-99m is a short-lived gamma emitter that can be imaged using a gamma detection camera. Single-photon emission computed tomography (SPECT) combines a gamma detection camera with X-ray imaging, producing images against the background of the patient's anatomy. 99m TcMAA emits images. These images can then be used to clarify... 99m The distribution of TcMAA in the body can be analyzed, and this information can be used to predict the final possible distribution of SIRT therapeutic microspheres. In this way, the proportion of radiation dose predicted to be delivered to the target tissue can be calculated. The predicted dose can be used to adjust the treatment plan and optimize the SIRT treatment dose. The predicted distribution can also be used to classify patients suitable for SIRT treatment. For example, if a large number of microspheres are predicted to distribute to sensitive tissues (such as the lungs or intestinal wall), it may be necessary to use angiography techniques (such as coil embolization) to correct the off-target flow of particles before performing SIRT. If off-target flow cannot be corrected, the SIRT dose may need to be reduced to a safer level, or the patient may otherwise be considered unsuitable for this treatment.

[0126] Although 99m TcMAA has been widely used as an imaging microparticle substitute prior to SIRT treatment, but 99m TcMAA is not the best alternative to therapeutic microspheres. For example, the final distribution of SIRT microspheres may differ from... 99m The final distribution of TcMAA substitute particles does not match perfectly or accurately.99m When the distribution of TcMAA substitute particles and therapeutic particles differs, the patient's tissue to be treated may receive one or more inappropriate (too low or too high) radiation doses, or off-target tissues may be irradiated in a way that is not predicted. Furthermore, based on incorrect... 99m With TcMAA surrogate readings, patients may be excluded from this treatment when they are actually eligible.

[0127] One approach to this problem is to prepare a resin or crystalline ceramic core coated with imaging radioactive material. However, microspheres contain a core material with a radioactive isotope coating on the outer surface, posing a high risk of the radioactive coating separating from the underlying microsphere core. Any mechanical breakage of the coating could release unwanted radioactivity into other parts of the body, which is highly undesirable (exacerbating the aforementioned problem). Other drawbacks include the need for special handling and precautions when coating the ceramic core with radioactive isotopes.

[0128] In another application, microspheres with radioactive isotope precursors incorporated into ceramic materials can be fabricated. While incorporating radioactive isotope precursors into ceramic spheres reduces the risk of accidental release of radioactive isotopes from the radioactive coating into other parts of the body, this latter form of product is not without its drawbacks. For example, their fabrication typically requires activation of the non-radioactive element through neutron bombardment in a nuclear reactor. Furthermore, this fabrication necessitates the use of ultrapure starting materials to avoid the generation of unwanted long-lived isotopes, and their commercial distribution is hampered by the inherently short half-life of radioactive isotopes and transportation-related safety concerns. Another disadvantage is the lack of design flexibility.

[0129] Some embodiments disclosed herein address one or more of the aforementioned or other problems by providing imageable radioisotope particles (e.g., imageable radioisotope microspheres). In some embodiments, as disclosed in more detail elsewhere herein, the imageable radioisotope is chemically bonded to the particle surface, thereby providing imageable radioisotope particles.

[0130] Imagable radioisotope particles

[0131] As described above, some embodiments involve imageable radioisotope particles. In some embodiments, the imageable radioisotope is functionalized onto the surface of a supporting matrix. In some embodiments, the supporting matrix is ​​a particle. In some embodiments, the matrix provides the bulk of the particle (e.g., most of the particle's size and / or weight is attributed to the matrix). In some embodiments, the particle is a microsphere. In some embodiments, the imageable radioisotope is bound to the matrix (e.g., directly to the matrix). In some embodiments, the imageable radioisotope is bound to the matrix via irreversible or substantially irreversible bonds. In some embodiments, the imageable radioisotope is chemically bonded to the surface via one or more chemical bonds. In some embodiments, by providing particles having an imageable radioisotope chemically bonded to the surface, the risks associated with imageable radioisotope separation are reduced and / or eliminated. Furthermore, because in some embodiments the imageable radioisotope can be functionalized onto the matrix in its radioactive form, neutron activation of the imageable radioisotope is not required. For example, in some embodiments, the imageable radioisotope is bound to the matrix surface during imageable particle preparation by coupling with the matrix. However, in other embodiments, it is envisioned that non-radioactive isotopes are activated while functionalizing the particle surface to form imageable radioactive isotopes.

[0132] Imageable radioisotopes can be functionalized onto the surface of a particle matrix via chemical bonds. In some embodiments, the chemical bond is the primary bond. For example, in some embodiments, the imageable radioisotope is bonded to the surface of the particle (e.g., microsphere) via one or more covalent bonds. In some embodiments, the imageable radioisotope is bonded to the surface of the microsphere via one or more coordination bonds. In some embodiments, the imageable radioisotope is bonded to the surface of the microsphere via valence bonds. In some embodiments, the imageable radioisotope is bonded to the surface of the microsphere via covalent bonds, coordination bonds, valence bonds, ionic bonds, or combinations thereof. In some embodiments, the imageable radioisotope is bonded to the surface of the microsphere via Lewis acid-base interactions (e.g., Lewis acid-base coordination bonds). For example, in some embodiments, one or more functional groups on the particle matrix surface act as Lewis bases, forming Lewis acid-base adducts with the imageable radioisotope (acting as a Lewis acid).

[0133] As described elsewhere herein, in some embodiments, the particle matrix provides a basis for imageable radioactive isotopes to which they bind. In some embodiments, the matrix includes a core extending outward (e.g., from the particle center) to the particle surface. In some embodiments, the matrix is ​​an inorganic material.

[0134] As described elsewhere herein, the matrix can be homogeneous or substantially homogeneous. For example, the particle surface can contain a number of atoms that are found to overlap with and / or be atoms of the same element as the elements in the matrix core (e.g., atoms of the same element). In some embodiments, as disclosed elsewhere herein, a portion of the atoms providing the matrix surface can be directly bonded to an imageable radioisotope. The portion of the atoms bonded to the imageable radioisotope (e.g., chemically bonded) can be of the same type of chemical element as the atoms in the core. In some embodiments, the particles containing the imageable radioisotope lack any intermediate or different molecular species (e.g., linker groups) between the matrix and the imageable radioisotope.

[0135] In some embodiments, as disclosed elsewhere herein, the matrix comprises an inorganic material. In some embodiments, the inorganic material comprises one or more elements that are metalloids, metals, or both (as defined on the periodic table). In some embodiments, the inorganic material further comprises a nonmetallic element. In some embodiments, the inorganic material comprises at least one nonmetal, metalloid, or transition metal oxide. In some embodiments, metalloid atoms, metal atoms, or both are bonded to nonmetallic atoms to form a matrix structure. For example, in a matrix comprising a transition metal oxide, the oxygen of the oxide is considered to be a nonmetallic chemical element providing at least a portion of the matrix. In some embodiments, the matrix comprises a lattice, an amorphous structure, or a combination thereof. In some embodiments, the core of the matrix comprises a first portion of metalloids or metal atoms bonded to nonmetallic atoms, while the surface comprises a second portion of metalloids or metal atoms bonded to nonmetallic atoms. In some embodiments, as disclosed elsewhere herein, an imageable radioisotope can be directly bonded to the matrix via at least a portion of the nonmetallic atoms at the matrix surface.

[0136] Obviously, the particle matrix can be prepared from a variety of materials, such as one or more inorganic materials. In some embodiments, the matrix is ​​an inorganic material. In some embodiments, the inorganic material includes ceramic materials and / or ceramics. In some embodiments, the inorganic material contains at least one element selected from silicon, yttrium, manganese, aluminum, gallium, strontium, and titanium. In some embodiments, the inorganic material contains glass or glass. In some embodiments, the inorganic material contains 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 contains one or more of the following: SiO2, Y2O3, MnO2, AlO3, Ga2O3, Fe2O3, SrO2, SrCO3, and / or TiO2. In some embodiments, the inorganic material includes SiO2 and one or more of the following: Y2O3, MnO2, AlO3, Ga2O3, Fe2O3, SrO2, SrCO3, and / or TiO2. In some embodiments, the inorganic material comprises SiO2 and one or more of the following: Al2O3 and / or Y2O3.

[0137] In some embodiments, the matrix comprises a ceramic material and / or ceramic. In some embodiments, the matrix (e.g., a ceramic matrix) comprises at least one element selected from silicon, yttrium, manganese, aluminum, gallium, strontium, and titanium. In some embodiments, the inorganic material (e.g., the ceramic matrix) comprises glass or glass. In some embodiments, the matrix (e.g., the ceramic matrix) comprises silicon dioxide. In some embodiments, the matrix (e.g., the ceramic matrix) comprises silicon dioxide and at least one other element selected from yttrium, manganese, aluminum, gallium, boron, strontium, and titanium. In some embodiments, the matrix (e.g., the ceramic matrix) comprises one or more of the following: SiO2, Y2O3, MnO2, Al2O3, Ga2O3, Fe2O3, SrO2, SrCO3, and / or TiO2. In some embodiments, the matrix (e.g., the ceramic matrix) comprises SiO2 and one or more of the following: Y2O3, MnO2, Al2O3, Ga2O3, Fe2O3, SrO2, SrCO3, and / or TiO2. In some embodiments, the matrix (e.g., a ceramic matrix) comprises SiO2 and one or more of the following: Al2O3 and / or Y2O3.

[0138] In some embodiments, the matrix comprises yttrium aluminum silicon oxide. In some embodiments, the yttrium aluminum silicon oxide is 17Y₂O₃-19Al₂O₃-64SiO₂ (in molar percentages). As disclosed elsewhere herein, in some embodiments, the imagerable alternatives disclosed herein are used as... Alternatives to (Biocompatibles UK Ltd). It consists of insoluble glass microspheres, in which yttrium is a component of glass (i.e., (Contains yttrium aluminum silicon oxide). Yttrium in precursor particles as naturally occurring non-radioactive isotopes 89 It exists in the form of Y. 89 Y is neither a beta emitter nor a radiotherapy agent. Before being used as a radiotherapy agent, the precursor particles are first bombarded with neutrons to remove the neutrons from the particles. 89 Y is converted into yttrium in the β-emission form. 90 Y (thus generating activity) (particles). In some embodiments, the matrix used for the imageable radioisotope particles disclosed herein comprises 89 Y and lack 90 Y precursor Particles. In other words, yttrium in the yttrium aluminum silicon oxide disclosed herein exists in its abundant natural form, which does not emit beta radiation ( 89 Y) is provided. However, in some embodiments, an imageable radioisotope may be coupled to activated yttrium-containing microspheres, and the microspheres may contain 90 Y.

[0139] In some embodiments, as disclosed elsewhere herein, the matrix comprises a single material, while in other embodiments, the matrix may comprise more than one material. In the case where the matrix is ​​a substantially homogeneous material, in some embodiments, the matrix may comprise a substantially homogeneous mixture of constituent elements (e.g., Si and O in SiO2). In the case of a homogeneous matrix, the surface also comprises at least a portion of these constituent elements (e.g., Si and O atoms), although the surface may also comprise terminal atoms (e.g., -H in -OH). In some embodiments, atoms provided within the core are also provided on the surface as part of terminal functional groups (e.g., O in -OH). As described above, terminal functional groups may additionally comprise terminal atoms (e.g., -H in -OH). For illustration, the arrangement is provided below.

[0140] The particles prepared from SiO2 can be represented by the following structure (I):

[0141]

[0142] Although the structure of formula (I) contains end groups that may not be substantially present in the matrix core, the particle will still be considered homogeneous because the elements located on the surface that are not components of the core are provided as end groups.

[0143] More generally, in some embodiments, the particle can be represented by the structure of formula (II):

[0144]

[0145] Where M cEach instance is independently selected from the group consisting of Pb, Al, Si, Y, Mn, Ga, Sr, Fe, and Ti. In some embodiments, M c The group consisting of Pb, Al, Si, Y, Mn, Ga, Fe, and Ti is selected. In some embodiments, M... c Each instance is independently selected from Si, Y, and Al. In some embodiments, when the surface of the matrix is ​​functionalized, one or more OH groups on the surface may contain M as disclosed elsewhere herein. b (X) n .

[0146] In some embodiments, the terminal groups of the matrix provide functional groups that can interact with the imageable radioisotope, thereby chemically bonding the imageable radioisotope to form an imageable particle. Thus, in some embodiments, the imageable radioisotope is directly chemically bonded to the particle matrix surface. In some embodiments, as exemplified by the structures described above, the inorganic matrix may comprise a surface having one or more electron-donating functional groups (e.g., -OH) that coordinate or covalently bind to the imageable radioisotope, thereby bonding the imageable radioisotope to the surface.

[0147] As described above, imageable radioisotopes can modify the particle surface to provide imageable particles. In some embodiments, on average, each particle (e.g., a microsphere) contains multiple (e.g., 2, 3, or 4) radioisotopes bound to the matrix. In some embodiments, on average, each particle (e.g., a microsphere) contains a single radioisotope bound to the matrix.

[0148] In some embodiments, not every microsphere is labeled with an imageable radioisotope. In some embodiments, the number of imageable radioisotopes per particle (e.g., functionalized on each particle) is equal to or less than about 1 x 10-1 -6 0.0001, 0.001, 0.01, 0.1, 0.5, 1, 2, or a range including the above values ​​and / or within the range of the above values.

[0149] In some embodiments, an imageable radioisotope is characterized by emitting detectable radiation. In some embodiments, the detectable radiation is radiation that can be detected using standard medical imaging techniques. In some embodiments, the imageable radioisotope emits radiation that is directly detectable, indirectly detectable, or both (e.g., where the radiation can be detected by 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 results in another, different form of imageable radiation. For example, the imageable radioisotope may be a positron emitter. Once emitted from the imageable radioisotope, the positrons collide with electrons in the patient's body, where the positrons and electrons are annihilated, producing two gamma rays. The gamma rays can then be detected. In some embodiments, the imageable radioisotope is a positron emitter, a gamma emitter, or both. In some embodiments, radiation from the imageable radioisotope can be detected directly or indirectly by imaging modality.

[0150] In some embodiments, as disclosed elsewhere herein, an imageable isotope is an isotope configured for imaging via an imaging mode. In some embodiments, the imaging mode is selected from single-photon imaging and two-photon imaging. In some embodiments, an imageable radioisotope is configured for imaging via an imaging mode selected from positron emission tomography (PET), single-photon emission computed tomography (SPECT), and gamma camera imaging.

[0151] In some embodiments, the imageable radioactive isotope may be a metal. In some embodiments, the imageable radioactive isotope is selected from 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 combinations thereof.

[0152] As described above, in some embodiments, an imageable radioisotope is chemically bonded to the matrix surface via one or more chemical bonds. In some embodiments, the imageable radioisotope may also be functionalized to the surface of the particle matrix, at least partially, via inorganic bridges. An inorganic bridge is a series of atoms bonded together, lacking an organic portion. The term “inorganic” as used herein is used in its conventional sense and will be understood by those skilled in the art to refer to a compound (or a portion or atom thereof) lacking an organic carbon-based portion (e.g., alkyl groups). As used herein, inorganic does not include organometallic entities.

[0153] When present, the inorganic bridge comprises a metal atom or quasi-metal atom that is not a radioactive isotope (e.g., a bridging metal atom). The inorganic bridge also comprises one or more non-metallic atoms chemically bonded to a series of bridging atoms (e.g., bridging metal atoms) that bridge the imageable radioactive isotope and the matrix (in other words, bridging the imageable radioactive isotope and the matrix). In some embodiments, each atom forming the inorganic bridge is chemically bonded to another atom in the inorganic bridge, thereby connecting the matrix and the imageable radioactive isotope by chemical bonds. In some embodiments, the inorganic bridge comprises a non-metallic atom of the matrix, a bridging atom (e.g., a bridging metal atom), and a non-metallic atom that is chemically bonded to the imageable radioactive isotope. In some embodiments, a non-metallic atom of the matrix is ​​chemically bonded to a bridging atom (e.g., a bridging metal atom), and the bridging atom is chemically bonded to a non-metallic atom that is also chemically bonded to the imageable radioactive isotope.

[0154] In some embodiments, during the functionalization of the matrix with an imageable radioisotope, the bridging metal atom (e.g., Sn) initially acts as the imageable radioisotope (e.g., 99m The reducing agent is Tc. The bridging atom can then maintain a chemical bond between the imageable radioisotope and the matrix (e.g., through chemical bonds, such as covalent bonds, coordinate bonds, and / or Lewis acid-base interactions). The imageable radioisotope and the bridging metal atom can be separated by a nonmetallic atom (e.g., O), which can be chemically bonded to both the imageable radioisotope and the bridging metal atom. This nonmetallic atom can be part of an inorganic bridge. Similarly, the nonmetallic atoms of the matrix (e.g., O) can be directly bonded to the bridging metal atom connecting the bridging metal atom to the matrix. Tin (Sn) is believed to be... 99m The bridging atom of Tc acts as 99m It is part of an inorganic bridge between the Tc and the matrix, but is not bound by any particular mechanism. In some embodiments, the inorganic bridge comprises or is chemically connected to the matrix and an imageable radioisotope (e.g., 99mTc (e.g., by chemical bonding) of -O-Sn-O-. In some embodiments, such as those of formula VIII, the inorganic bridge comprising the -O-Sn-O- bridge may further be coupled with –OH, =O, and –O. - One or more bonds in (e.g., as -O-Sn(X)) n -O-, where each instance of X is –OH, =O, and –O. - (and n is 1 or 2).

[0155] In some embodiments, the imageable radioisotope can be directly bonded to the matrix simultaneously via atoms of the matrix (e.g., nonmetallic atoms, such as O) and via inorganic bridges (e.g., via non-radioactive isotope metal atoms). This configuration is illustrated in some configurations of the following formula (VIII). In other embodiments, non-radioactive isotope metal atoms form chemically bonded bridges between the radioisotope and the matrix surface, and the radioisotope itself is chemically bonded to the matrix only via bridging metal atoms (or multiple bridging metal atoms), as illustrated in some configurations of the following formula (V). For example, as shown in formula (V), the bridging metal can be chemically bonded to two nonmetals, wherein these two nonmetallic atoms (e.g., O) are further chemically bonded to the imageable radioisotope.

[0156] In some embodiments, the imageable radioisotope may be nonmetallic. In some embodiments, the imageable particle may include an imageable feature, which may be a metal bonded to the nonmetallic imageable radioisotope, for example, a complex of a metal and an imageable nonmetallic radioisotope (e.g., Al). 18 F). In some embodiments, the imageable complex is chemically bonded to the surface via aluminum atoms, wherein 18 F forms a complex with aluminum atoms. In some embodiments, the imageable complex is Al. 18 F.

[0157] As described above, in some embodiments, the radioactive isotope is coupled to the particle surface via a particle matrix. In some embodiments, the functionalization of the particle surface can be represented by the following formula (III):

[0158]

[0159] The matrix contains M c And M b It is an imageable radioactive isotope. In some embodiments, M c Selected from Si, Mn, Y, Al, Sr, Ga, Fe, Ti, and Pb (especially Si, Mn, Ti, and Pb); M b Selected from 201 Th、 51 Cr67 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 Lu; each instance of R is nonexistent or –H; each instance of X is independently selected from –OH, =O, and –O-; n is an integer selected from 0, 1, 2, 3, or 4. In some embodiments, M c Selected from Sn, Si, Mn, Al, Ga, Fe, Ti, and Pb; M b Selected from 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 Each instance of Lu;R is either nonexistent or –H;each instance of X is independently selected from –OH, =O, and –O. - n is an integer selected from 0, 1, 2, 3, or 4. In some embodiments, the matrix comprises M c And M b It is an imageable radioactive isotope, M c Selected from Si, Mn, Al, Ga, Fe, Ti, and Pb (especially Si, Mn, Ti, and Pb); M b yes 89 Each instance of Zr;R is –H; each instance of X is –OH;n is 2.

[0160] In some embodiments, the functionalization of the particle surface can be represented by the following formula (IIIa):

[0161]

[0162] The variables are as disclosed elsewhere herein. For example, in several embodiments, the matrix comprises M c And Mb It is an imageable radioactive isotope. In some embodiments, M c Selected from Si, Mn, Y, Al, Sr, Ga, Fe, Ti, and Pb (especially Si, Mn, Ti, and Pb); m is an integer selected from 1, 2, or 3; M b Selected from 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 Each instance of Lu;R is either nonexistent or –H;each instance of X is independently selected from –OH, =O, and –O. - n is an integer selected from 0, 1, 2, 3, or 4. In some embodiments, M c Selected from Sn, Si, Mn, Al, Ga, Fe, Ti, and Pb; M b Selected from 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 Each instance of Lu;R is either nonexistent or –H;each instance of X is independently selected from –OH, =O, and –O. - n is an integer selected from 0, 1, 2, 3, or 4. In some embodiments, the matrix comprises M c And M b It is an imageable radioactive isotope, M c Selected from Si, Mn, Al, Ga, Fe, Ti, and Pb (especially Si, Mn, Ti, and Pb); M b yes 89 Each instance of Zr;R is –H; each instance of X is –OH;n is 2.

[0163] In some embodiments, the imageable particle can be represented by the following structure (IV):

[0164]

[0165] The variables are as defined elsewhere herein, for example, according to Equation III. In some embodiments, as disclosed elsewhere herein, the matrix comprises M c And M b It is an imageable radioactive isotope. In some embodiments, M c Each instance was independently selected from Pb, Al, Si, Y, Mn, Ga, Fe, and Ti; M b Each instance is selected independently. 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 F, 177 Each instance of Lu;R is either nonexistent or –H;each instance of X is independently selected from –OH, =O, and –O. - n is an integer selected from 0, 1, 2, 3, or 4. In some embodiments, M c Each instance is selected from Si, Al, and Y; M b yes 89 Each instance of Zr;X is selected from –OH;n is 2 or 3. In some embodiments, M c Each instance is selected from Si, Al, and Y; M b yes 89 Each instance of Zr;X is –OH;n is 2. In some embodiments, M c It is Si; M b yes 89 Zr; X is –OH; n is 2. In some embodiments, R is -H. In several embodiments, where R is H, the structure of formula (IV) can be represented by the following formula (IVa):

[0166]

[0167] In several embodiments, where R is absent, the structure of equation (IV) can be represented by the following equation (IVb):

[0168]

[0169] In some embodiments, the particle surface can be represented by equation (V):

[0170]

[0171] M a It can be a matrix atom or a bridging metal atom that connects the imageable radioactive isotope to the matrix via chemical bonds. In some embodiments, for example, M a It is a matrix atom or a bridging atom, and M a Selected from Pb, Al, Si, Y, Mn, Ga, Fe, Ti, Sr, and Sn; the matrix contains M c And M c Independently selected from Pb, Al, Si, Y, Mn, Ga, Fe, and Ti; m is an integer selected from 1, 2, or 3; M b Selected from 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 combinations thereof; each instance of R is independently absent or –H; each instance of X is independently selected from –OH, =O, –O. - Mono-substituted amino, di-substituted amino, halogen, -CN, -CF3, optionally substituted diamino, optionally substituted triamino, wherein one or more substituents of the amino group (if present) are independently C 1-6 Alkyl, heteroaryl, or aryl; n is an integer selected from 0, 1, 2, 3, or 4; m is an integer equal to 1, 2, or 3. In some embodiments, each instance of R is absent or H; X is selected from -OH, =O, and -O. - n is an integer selected from 0, 1, 2, 3, or 4. In some embodiments, M a It is Sn, and M a It is a bridging metal atom. In some embodiments, the matrix comprises M a and M c And M bIt is an imageable radioactive isotope. In some embodiments, M a and M c Independently selected from Pb, Al, Si, Y, Mn, Ga, Fe, and Ti; M b Selected from 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 Each instance of Lu;R independently does not exist or -H;each instance of X independently selects from =O, -O - -OH, mono-substituted amino, di-substituted amino, halogen, -CN, -CF3, optionally substituted diamino, optionally substituted triamino, wherein one or more substituents of the amino group (if present) are independently C 1-6 Alkyl, heteroaryl, or aryl; n is an integer selected from 0, 1, 2, 3, or 4; m is an integer equal to 1, 2, or 3.

[0172] In some embodiments, the matrix comprises M c And M c Independently selected from Pb, Al, Si, Y, Mn, Ga, Fe, and Ti; m is an integer selected from 1, 2, and 3; M b yes 99m Tc;M a It is Sn; each instance of R is either nonexistent or H; X is –OH or =O; n is 2 or 3.

[0173] In some embodiments, M a It consists of Si, Y, and Al; M b yes 89 Zr, M c Selected from Si, Al, and Y; X is –OH; n is 2. In some embodiments, M c It is Si, Al, or Y; M a It is Sn; M b yes 99m Tc; X is independently –OH or =O; n is 2 or 3. In some embodiments, M b yes 99m Tc, X is -OH, n is 2 or 3.

[0174] Alternatively, in some embodiments, M b It can be an imageable radioactive isotope containing a host metal bonded to a non-metallic radioactive isotope. For example, a complex with a non-metallic imageable radioactive isotope (e.g., Al). 18 F). In some embodiments, the complex is chemically bonded to the surface via aluminum atoms, wherein 18 F complexes with aluminum atoms. In some embodiments, M a and M c Independently selected from Si, Al, Y, and Sn; M b Selected from 99m Tc and 89 Each instance of Zr;X is –OH;n is 2 or 3. In some embodiments, M a and M c Independently selected from Si, Al, Y, and Sn; M b yes 99m Each instance of Tc;X is –OH;n is 2 or 3. In some embodiments, M a and M c Independently selected from Si, Al, Y, and Sn; M b yes 99m Each instance of Tc;X is selected from –OH and Sn;n is 3. In some embodiments, M a and M c Independently selected from Si, Al, and Y; M b yes 89 Each instance of Zr;X is –OH;n is 2. In some embodiments, M a It is Si; M c It is Al; M b yes 89 Zr; X is –OH; n is 2. In some embodiments, M a It is Si; M c It is Al; M b yes 99m Each instance of Tc;X is independently selected from –OH and Sn;n is 3. In some embodiments, R is -H.

[0175] In some embodiments, the particle surface can be represented by formula (VI):

[0176]

[0177] Where M c M b R, X, m, and n are as disclosed elsewhere in this document. M c M b R, X, m and n can be, for example, as disclosed in equation (V).

[0178] In some embodiments, the particle surface can be represented by equation (VII):

[0179]

[0180] Where M c M b R, X, and n are as disclosed elsewhere in this document. M c M b R, X, m and n can be, for example, as disclosed in equation (V).

[0181] In some embodiments, the particle surface may be represented by formula (VIII):

[0182]

[0183] Where M c M b X and n are as disclosed elsewhere herein. In some embodiments, the matrix comprises M a and M c M a and M c 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 Selected from 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 combinations thereof; M a It is a matrix atom or a bridging atom, and M a Selected from Sn, Pb, Al, Si, Y, Mn, Ga, Fe, and Ti; R a Each instance is independently OH, O, -OSn(X). n -O or -OSnO-; each instance of X is selected from –OH, =O, and –O. - Each instance of n is an integer selected from 0, 1, 2, 3, or 4. In some embodiments, M c It is Al; M a It is Si; Mb yes 99m Each instance of Tc;X is independently –OH or =O;n is 2 or 3. In some embodiments, M c It is Al; M a It is Si; M b yes 99m Tc;R a At least one instance is -O-Sn-O-, where each X is independently –OH or =O; n is 2 or 3. In some embodiments, M c It is Al; M a It is Si; M b yes 99m Tc;R a At least one instance is -O-Sn(X). n -O-, each X is independently –OH or =O; each instance of n is independently 2 or 3. In some embodiments, M b yes 99m Tc;R a At least one instance is -O-Sn-O-, where each X is independently –OH or =O; n is 2 or 3. In some embodiments, M b yes 99m Tc;R a At least one instance is -O-Sn(X). n -O-, each X is –OH; n is 2. In some embodiments, M b yes 99m Tc;R a One example is -O-Sn-O-, R a One example is -O- or -OH-; each X is independently –OH or =O; n is 2 or 3. In some embodiments, M b yes 99m Tc;R a One example is -O-Sn(X). n -O-,R a An example is -O- or -OH-; each X is independently –OH or =O; n is 2 or 3.

[0184] In some embodiments, the imageable particle can be represented by the structure described by equation (IX):

[0185]

[0186] The variables are defined elsewhere in this document.

[0187] In some embodiments, the imageable particle can be represented by the structure described by equation (X):

[0188]

[0189] The variables are defined elsewhere in this document.

[0190] In some embodiments, the imageable radioisotope may be selected based on its half-life. For example, in some embodiments, an imageable radioisotope with a shorter half-life is selected, resulting in shorter periods of bodily exposure to the imageable radioisotope radiation. In some embodiments, the half-life of the imageable radioisotope is less than or equal to about: 1 day, 3 days, 7 days, 2 weeks, 1 month, 2 months, or a range including and / or within the range of the above values.

[0191] In some embodiments, as disclosed elsewhere herein, the imageable element is confined to the surface of the microsphere. In some embodiments, the matrix lacks imageable radioisotopes.

[0192] As described elsewhere herein, in some embodiments the matrix is ​​porous. In other embodiments, the matrix is ​​non-porous. In some embodiments, the porosity of the particles described herein is determined by their surface area per unit weight. In some embodiments, the surface area of ​​the particle matrix as disclosed herein is less than or equal to about: 1 m² 2 / g, 0.5m 2 / g, 0.25m 2 / g, 0.1m 2 / g, 0.05m 2 / g, or a range including and / or within the range of values ​​described above. In some embodiments, where the particles are substantially non-porous or lack pores, the radioactive isotope may bind to the peripheral surface of the particle (e.g., a surface not within a pore and not inside the periphery of the particle). In other embodiments where the particles are porous, the radioactive isotope may bind to any surface of the particle, including cavities or pores within the particle and / or the peripheral surface of the particle.

[0193] In some embodiments, the particles are microspheres. Microspheres are particles having microscale dimensions. In some embodiments, the average size of the microspheres is 5 μm to 1000 μm. In some embodiments, the particles are microspheres with 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 about: 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 a range including and / or within the range of the above values.

[0194] The diameter of the microspheres can be easily determined using optical or scanning electron microscopy.

[0195] In some embodiments, the matrix of the imageable particles is chosen because of its similarity to particles currently used for SIRT, such as similarity in size, shape, density, and / or chemical composition, and therefore they are used as substitutes (except for their lack of therapeutic radioisotopes). For example, TheraSphere consists of insoluble glass microspheres in which yttrium-90 is a component of the glass. These radioactive glass microspheres have a diameter of about 20 μm to 30 μm. By providing imageable particles with similar size and properties to therapeutic particles, imageable particles can serve as more accurate substitutes for therapeutic particles. In some embodiments, the composition of the imaging particles is chosen such that the density of the imaging microspheres is the same as or close to the density of the therapeutic microspheres, so that the motion and distribution of the imaging particles will be similar to the motion and distribution of the therapeutic microspheres. In some embodiments, each milligram of imageable radioisotope particles contains equal to or less than about: 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 within the range of the above values.

[0196] While the use of microspheres is mentioned in several embodiments disclosed herein, the term particle broadly includes microspheres and other particles to which an imageable radioisotope can be bound. For example, the size and shape of particles can vary (e.g., cylindrical, cubic, pyramidal, box-shaped, etc.). In some embodiments, the shape of the imageable particle is selected according to the appropriate size and shape of the therapeutic particle, which serves as its substitute.

[0197] As described elsewhere herein, in some embodiments, the imageable microspheres lack therapeutic radioisotopes. In some embodiments, the imageable isotope and / or the imageable microspheres are non-therapeutic (e.g., the dose it emits is sufficient and / or configured for imaging but 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 bombardment and / or neutron activation, which convert non-imageable isotopes of the element into imageable radioisotopes of the imageable microspheres. In some embodiments, the imageable radioisotope is imageable due to its radioactivity rather than due to paramagnetism. In some embodiments, the imager is not a paramagnetic material and / or is not an imager selected from the group consisting of: H-1, He-3, Li-7, B-7, B-9, N-15, O-17, F-19, Mg-27, Al-27, Si-29, S-33, Cl-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, 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 imageable microspheres lack one or more of strontium phosphate, phosphate, or phosphorus. In some embodiments, the imageable microspheres do not contain a layer of strontium phosphate and / or phosphate on a matrix to which imageable isotopes are bound. In some embodiments, the matrix is ​​not organic, lacks organic materials, and / or is not a resin. In some embodiments, the imageable radioisotope is not bound to the matrix via any of the carboxylic acid groups, bisphosphonic acid groups, or sulfonic acid groups. In some embodiments, the imageable radioisotope is not bound to the matrix via any alkyl linker and / or via a non-metallic bridge.

[0198] Manufacturing methods and products made thereby

[0199] Some embodiments relate to imageable radioisotope particles prepared by methods including obtaining particles as disclosed elsewhere herein. As disclosed herein, in some embodiments, the particles comprise a matrix material. In some embodiments, the matrix material comprises a Lewis basic component surrounding the matrix surface (and / or the entire matrix). In some embodiments, the radioisotope is bound to the matrix, and a chemical bond is formed between the matrix and the radioisotope of the particle. In some embodiments, the imageable radioisotope is bound to the matrix, and a chemical bond is formed between the imageable radioisotope, nonmetallic atoms, bridging atoms, nonmetallic atoms, and the particle matrix. In some embodiments, a chemical bond is also formed between the nonmetallic atoms and the radioisotope, thereby providing a bridge from the radioisotope to the matrix. In some embodiments, the constituent atoms of the bridge are bonded to each other by chemical bonds as disclosed herein (e.g., coordination, covalent bonding, etc.).

[0200] Some embodiments relate to imageable microspheres prepared by a method comprising providing a matrix comprising an inorganic material, said inorganic material comprising a quasi-metallic or metallic atom. In some embodiments, the core of the matrix comprises a first portion of quasi-metallic or metallic atoms bonded to nonmetallic atoms, while the surface comprises a second portion of quasi-metallic or metallic atoms bonded to nonmetallic atoms. In some embodiments, as disclosed elsewhere herein, an imageable radioisotope is directly bonded to the matrix by bridging metallic atoms or chemical bonds or both (e.g., bonded to at least a portion of nonmetallic atoms on the matrix surface). In some embodiments, the method further comprises obtaining at least one imageable radioisotope. In some embodiments, the method further comprises chemically coupling said at least one imageable radioisotope to the surface layer of the matrix to provide the imageable microsphere.

[0201] In some embodiments, the method includes providing at least one imageable radioisotope in ionic form (e.g., salt form) prior to chemically coupling at least one imageable radioisotope to an inorganic matrix surface. In some embodiments, the imageable radioisotope (e.g., in the form of a radioisotope salt) has an oxidation number equal to or greater than 1, 2, 3, 4, or 5. In some embodiments, the imageable radioisotope salt has one or more associated counterions. In some embodiments, the counterion has an oxidation number equal to or greater than -1 or -2. In some embodiments, the salt is a halide salt or a polyatomic salt.

[0202] In some embodiments, chemical functionalization is performed in the presence of a reducing agent. In some embodiments, the matrix is ​​contacted with a radioactive isotope 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., stannous salts, providing stannous ions), HCl, sodium borohydride, sodium dithionite, ferrous sulfate, ferric chloride plus ascorbic acid, hypophosphite, and / or hydrazine.

[0203] In some embodiments, the imageable radioisotope can be any imageable radioisotope disclosed elsewhere herein. In some embodiments, the imageable ceramic microspheres can be formed by reacting the ceramic microspheres with a reducing agent (e.g., stannous ions, such as stannous halides, e.g., stannous chloride) in the presence of a reducing agent. 99m It is obtained by the reaction of Tc (e.g., in the form of pertechnetate ions).

[0204] Some embodiments relate to a process for preparing imageable ceramic microspheres, the process comprising mixing a ceramic microsphere matrix (e.g., comprising at least one nonmetallic, quasi-metallic, or transition metal oxide) with... 99m Tc ions, for example 99m Tc pertechnetate or other Tc(VII) ions react in the presence of a reducing agent as described elsewhere herein. The ceramic microspheres may be in the form of glass microspheres as described elsewhere herein.

[0205] Some embodiments relate to a process for preparing imageable ceramic microspheres, the process including reacting a ceramic microsphere matrix with a zirconium salt (e.g., oxalic acid). 89 Zr or chloride 89 The Zr reaction can be carried out in the presence of a base.

[0206] Some embodiments relate to methods for preparing imageable microspheres, the methods comprising providing an inorganic matrix and chemically functionalizing the inorganic matrix with at least one imageable radioisotope, thereby providing imageable microspheres.

[0207] Some embodiments relate to methods for preparing imageable radioisotope particles. In some embodiments, the method includes the step of providing at least one imageable radioisotope as a salt before chemically functionalizing at least one imageable radioisotope onto an inorganic matrix surface. In some embodiments, the salt is an alkali metal salt, an alkaline earth metal salt (e.g., when the imageable isotope is...). 18 (F time), halogen salts or polyatomic salts (e.g., when the imageable isotope is...) 89 (Zr). In some embodiments, the method includes adding a reducing agent during a chemical functionalization step. In some embodiments, (e.g., an imageable isotope is...) 99m When Tc is present, the reducing agent is selected from at least one or more of the following: tin salts (e.g., stannous salts (e.g., stannous halides, providing stannous ions), HCl, sodium borohydride, sodium dithionite, ferrous sulfate, ferric chloride plus ascorbic acid, hypophosphorous acid, and / or hydrazine. In some embodiments, the reducing agent is a reducing agent capable of reducing Tc(VII) to Tc(V).

[0208] In several embodiments, the radioactive isotope is added to the matrix (e.g., microspheres) by adding a radioactive isotope (or a salt thereof) to a solution containing the matrix. In several embodiments, the radioactive isotope is added to the matrix (e.g., microspheres) by adding the matrix to a solution containing the radioactive isotope (or a salt thereof). In several embodiments, the solution contains water. In several embodiments, the solution contains a brine solution. In several embodiments, the pH of the solution is greater than or equal to about: 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 within the range of the above values. In several embodiments, the solution contains a buffer solution. In several embodiments, the buffer solution is selected from the group consisting of phosphate-buffered saline (PBS), citrate, acetate, or combinations thereof. In several embodiments, the solution lacks a buffer solution. Suitable pH ranges include pH 3 to pH 10 and pH 5 to pH 8.

[0209] Some embodiments provide imageable microspheres that are obtained or available through the methods or processes described herein.

[0210] Methods of using imagable radioisotope particles

[0211] As disclosed elsewhere herein, in some embodiments, methods for using imageable radioisotope particles are provided. In some embodiments, imageable radioisotope particles can be used as an alternative to therapeutic radioisotope particles without exposing the patient to harmful therapeutic radiation. For example, as described above, in SIRT, therapeutic radioisotope particles are introduced into the blood vessels of a patient via a catheter. These therapeutic particles are commonly used to treat vascularized tumors, such as liver cancer (e.g., liver tumors (e.g., hepatocellular carcinoma-HCC) and tumors derived from other tumors that have metastasized to the liver (e.g., neuroendocrine tumors and colorectal tumors), as well as tumors of the brain, prostate, lung, spleen, and kidney.

[0212] Initially, patients often have different vascular systems, and the blood vessels surrounding the tumor also vary from person to person. Therefore, a drug that works for one person may not work for another or may be harmful. In some patients, therapeutic particles may travel to areas of the body that are not desired (off-target delivery), causing damage to off-target tissues. For example, when treating the liver, atypical vascular systems can lead to off-target localization of microspheres, causing gastrointestinal damage, lung damage, or other undesirable side effects. Delivery or shunting to off-target tissues (e.g., when a liver tumor is the intended target) – specifically, the portion of microspheres delivered to the lungs – is called a lung shunt fraction or pulmonary shunt portion. Furthermore, although surrogate therapeutic particles exist, they are not well-matched and do not resemble actual therapeutic particles. Therefore, candidates with a high actual success rate may be excluded from treatment, while less successful candidates may be treated, causing unnecessary harm to other parts of the body.

[0213] However, the particles disclosed herein are a good match for SIRT therapeutic particles (including TheraSphere). These particles can serve as more effective predictors of in vivo therapeutic distribution. Therefore, some methods disclosed herein involve using the imageable radioisotope particles disclosed herein to predict the distribution of therapeutic radioisotope particles in a patient's body. In some embodiments, as disclosed elsewhere herein, an imageable particle swarm is administered to a patient to obtain images of a specific area. As disclosed elsewhere herein, different regions of the body (target and off-target sites) can then be imaged using imaging modalities. In some embodiments, the imageable particle swarm may comprise particles having one imageable radioisotope type. In other embodiments, the particle swarm may comprise particles having multiple different radioisotope types (e.g., 2, 3, 4, or more). For example, in some embodiments, only one radioisotope is present in the particle swarm (e.g., ...). 99m Tc). In other embodiments, the particle swarm contains multiple types of imageable radioactive isotopes (e.g., Tc). 99m Tc and 89 Zr). Some embodiments disclosed herein relate to imageable particle swarms comprising one or more imageable radioisotopes as disclosed.

[0214] In some embodiments, imageable radioisotope particles can be used in methods of treating cancer because 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 can be used in methods of avoiding damage to off-target tissues caused by therapeutic radioisotope particles. In some embodiments, off-target tissues are normal and / or healthy tissues. In some embodiments, off-target areas may include the lungs or gastrointestinal tract (e.g., when treating liver cancer). In some embodiments, imageable radioisotope particles can be used in methods of calculating an appropriate radiation dose of therapeutic radioisotope particles. In some embodiments, imageable radioisotope particles can be used in methods of determining whether treatment with therapeutic radioisotope particles is likely to 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 be applied.

[0215] In some embodiments, imageable radioisotope particles are used to determine the amount of therapeutic microspheres to be delivered to a patient's body. In some embodiments of the method, an imageable particle swarm is obtained. In some embodiments, the signal intensity of the imageable radioisotope particles per unit dose is calculated. In some embodiments, patient-relative calibration is used, for example, where only treatment volume and expected therapeutic activity are required. In some embodiments, the imageable microsphere swarm is then administered to the patient by introducing the imageable microsphere swarm into a first location in the patient's vascular system. In some embodiments, the microspheres are injected into multiple locations within the vascular system that may overlap or not.

[0216] In some embodiments, after the imaging microspheres are injected into a patient (e.g., via a catheter), the particles are allowed to distribute within the patient for a period of time, typically at least until the particles reach their destination in the capillaries. In some embodiments, the time allowed for the imaging radioisotope particles to distribute within the body is less than or equal to about: 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, or a range including and / or within the range of the aforementioned values. In some embodiments, the time allowed for the imaging radioisotope particles to distribute within the body is equal to or at least about: 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, or a range including and / or within the range of the aforementioned values.

[0217] In some embodiments, once imageable radioisotope particles are distributed within the patient's body, their location and / or abundance within the body can be mapped. For example, one or more parts or sites of the patient's body can be imaged using imaging modalities (e.g., gamma camera imaging, PET, e.g., for...). 89 Zr particles), SPECT scanner (e.g., for use with Zr particles), 99m(Tc particles) or techniques disclosed elsewhere herein. Those parts of the body may include target sites for treatment. Additionally, off-target sites of the body (e.g., sites where treatment is not required and / or radiation damage is not desired) can be imaged to determine whether damaging amounts of particles will reach these sites. The relative dose of imageable radioisotope particles for each target and / or off-target area can be determined, for example, by comparing the signal intensity of each region. In some embodiments, the dose of a particular site (e.g., an organ or part of the body) is determined by comparing the radiation signal intensity of the site with the total radiation intensity in the body or other regions or treatment areas. The relative dose of imageable radioisotope particles for each target and / or off-target area can be determined, for example, by comparing the signal intensity of each region. In some embodiments, the dose of therapeutic particles to be delivered to a particular region is calculated by comparing the radiation signal intensity of imageable particles in the target and / or off-target areas with the signal intensity per unit dose of imageable radioisotope particles.

[0218] In some embodiments, the predicted dose of therapeutic particles to be delivered to the target area is calculated by determining the proportion of the total imageable signal obtained from the target area and any off-target areas, based on the total imageable signal from the target area and any off-target areas. This proportion can then be used to determine the total dose of therapeutic particles to be delivered so as to deliver the desired dose of therapeutic particles to the target area. This method can also be used to determine the proportion of therapeutic particle dose to be delivered to any off-target tissue (e.g., lungs, gastrointestinal tract, brain, reproductive tissue, mucous membranes, or any other radiation-sensitive organ). In some embodiments, these calculations can be performed on a volumetric basis, that is, based on the signal obtained from a given volume of target and / or off-target tissue. For example, when 60% of the signal comes from the radioisotope at the target site and 40% from the off-target site, the approximate radiation dose at the target site can be calculated to be 60% of the total dose. Similarly, the radiation dose at the off-target site can be calculated to be 40%.

[0219] In some embodiments, off-target areas or portions of the body may include those areas or portions most susceptible to damage from therapeutic radioisotope particles. Examples include the lungs and gastrointestinal system (although other parts of the body may also be imaged, such as reproductive tissues, mucous membranes or any other radiosensitive organs, the brain, kidneys, heart, etc., or any other radiosensitive organ or tissue). Target portions of the body are those parts selected for treatment (e.g., the liver of a patient suffering from liver cancer). Target areas may include malignant or benign tumors in the patient requiring treatment. Target areas may include vascularized tumors (e.g., cancerous or benign tumors), such as those found in liver cancer (e.g., liver tumors (e.g., hepatocellular carcinoma (HCC)) and other tumors that have metastasized to the liver (e.g., neuroendocrine tumors and colorectal tumors)) and tumors of the brain, prostate, lungs, spleen, and kidneys.

[0220] In some embodiments, once the relative dose to one or more target or off-target areas is determined, a patient's suitability as a treatment candidate can be determined. For example, if the dose of therapeutic particles required to treat a patient's liver cancer is too high, potentially causing lung or gastrointestinal damage, the patient's eligibility for treatment can be revoked. Such damage could occur, for example, if there is a vascular system that could shun the radioactive microspheres to the lungs or gastrointestinal tract. If the dose of therapeutic microspheres required to treat the liver is insufficient to cause side effects (such as lung or gastrointestinal damage), the patient can be selected for treatment.

[0221] In some embodiments, the distribution of imageable radioisotope particles can also be used to calculate the amount of therapeutic microspheres to be delivered to a patient. For example, when the amount of therapeutic radiation per unit dose of therapeutic particles is known, the amount of radiation per unit dose of imageable particles at the site (target or off-target) can be used to determine the amount of therapeutic particles administered. In some embodiments, using the imageable particles described herein, a target radiation dose of 80 Gy to 150 Gy can be achieved on the liver. In some embodiments, using the imageable particles described herein, a target radiation dose of 80 Gy to 300 Gy can be achieved on the liver. In some embodiments, using the imageable particles described herein, a target radiation dose of 200 Gy to 300 Gy can be achieved on the liver.

[0222] In some embodiments, the method includes obtaining data regarding the distribution of an imageable therapeutic microsphere substitute within a patient. In some embodiments, the method includes using the data to determine the amount of therapeutic microspheres to be administered to the patient. In some embodiments, the method includes allowing a cluster of therapeutic microspheres to distribute within the patient, thereby treating the patient.

[0223] Some embodiments relate to methods for predicting the extent of off-target tissue damage (e.g., lung or gastrointestinal damage) or liver treatment during the treatment of patients requiring radioisotope cancer therapy. In some embodiments, the method includes introducing a cluster of imageable microspheres into the patient's body. In some embodiments, the method includes allowing the imageable microspheres to distribute within the patient's body for a period of time. In some embodiments, the method includes determining the distribution of the 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 an estimated radiation dose in the patient's lungs, gastrointestinal tract, or liver when the imageable microspheres have been replaced by radioisotope therapeutic microspheres. In some embodiments, the method includes determining the dose of radioisotope therapeutic microspheres sufficient to cause clinically relevant lung changes due to off-target delivery of the microspheres to the lungs. In some embodiments, the method includes administering a dose of radioisotope therapeutic microspheres to the patient that is lower than the dose of the 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 would be sufficient to cause clinically relevant harm due to off-target delivery of the microspheres into the gastrointestinal tract. In some embodiments, the method includes administering to a patient a dose of radioisotope therapeutic microspheres lower than a dose of radioisotope therapeutic microspheres determined to be sufficient to cause clinically relevant gastrointestinal damage due to off-target delivery.

[0224] Some embodiments provide the imageable particles and microspheres described herein for determining or estimating the distribution of therapeutic microspheres or for determining a therapeutic dose of the therapeutic microspheres described herein.

[0225] In some embodiments, at the time of injection, a microsphere dose with a radioactivity intensity equal to or less than about 50 microcuries (μCi), 100 μCi, 150 μCi, 250 μCi, 1000 μCi, 2000 μCi, or 4000 μCi (or a range including and / or within the range of the above values) is injected. In some embodiments, a dose of microspheres from 10 mg to 100 mg is injected. In some embodiments, a smaller dose of microspheres (in mg) is administered to the subject that is less than or equal to about: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 250 mg, 500 mg, or a range including and / or within the range of the above values.

[0226] Kits and methods of using the same

[0227] Some embodiments relate to kits containing imageable radioisotope particles as disclosed herein. In some embodiments, the kit comprises underivative microspheres as described herein and instructions for performing the method herein to react the imageable radioisotope with the microspheres.

[0228] In some embodiments, the kit comprises microspheres having a matrix of inorganic material containing quasi-metallic or metallic atoms bonded to non-metallic atoms. The matrix comprises a core extending to a surface and a specification, the core containing a first portion of quasi-metallic or metallic atoms bonded to non-metallic atoms, and the surface containing a second portion of quasi-metallic or metallic atoms bonded to non-metallic atoms. The specification is used to enable an imageable radioisotope to react with the matrix such that the imageable radioisotope binds directly to the matrix through at least a portion of the non-metallic atoms on the matrix surface.

[0229] In some embodiments, the kit comprises: microspheres containing an inorganic matrix, wherein the inorganic matrix contains at least one nonmetallic, quasi-metallic, or transition metal oxide; and instructions for binding an imageable radioisotope to the surface of the inorganic matrix via Lewis acid-base coordination bonds.

[0230] In some embodiments, the kit may comprise: microspheres comprising a ceramic microsphere matrix; and instructions for performing a reaction that couples an imageable radioisotope to the ceramic microsphere matrix. In some embodiments, the instructions are for performing a reaction in which the imageable radioisotope is coupled to the ceramic microsphere matrix as a Lewis acid-base adduct.

[0231] In some embodiments, the kit contains microspheres in a sealed unit at a volume of 50 μl to 2 ml. In some embodiments, the sealed unit may be a container, such as a vial (e.g., a glass vial); in other embodiments, the sealed unit may be a syringe. The microspheres may be provided aseptically.

[0232] In some embodiments, the kit may additionally contain a reducing agent.

[0233] In some embodiments, the kit includes instructions for introducing imageable microspheres into a patient using a catheter. In some embodiments, the kit includes therapeutic microspheres. In some embodiments, the kit contains 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.

[0234] In some embodiments, an imageable radioisotope particle delivery kit is obtained. In some embodiments, the delivery kit includes a sterile, disposable tubing kit and an empty sterile vial. In some embodiments, the tubing kit is manufactured from pre-assembled sterile components and is for single use only. In some embodiments, the pre-assembled tubing kit includes a needle plunger assembly and an integrated 20cc syringe. In some embodiments, a one-way valve incorporated in the delivery kit controls the flow of fluid, ensuring it flows only in the appropriate direction. In some embodiments, pulling back the syringe plunger fills the syringe from a fluid source. In some embodiments, pushing the syringe plunger moves fluid toward the needle plunger assembly. In some embodiments, prior to infusion, the delivery kit is manually pre-filled to purge air from the tubing by pushing a sterile flushing solution through the kit.

[0235] In some embodiments, a drug delivery accessory kit is obtained. In some embodiments, the drug delivery accessory kit includes reusable accessories, including one or more of an acrylic case base, a top shield, removable side shields, and a hanging bag hook. In some embodiments, the drug delivery accessory kit facilitates monitoring of the infusion process and provides beta radiation protection. In some embodiments, the drug delivery accessory kit should be placed on a stable cart or table next to the patient, near the infusion catheter inlet Luer connector. In some embodiments, an extension arm on the accessory kit facilitates the alignment and positioning of the drug delivery device / patient catheter connection.

[0236] In some embodiments, the imageable radioisotope particle dosing vial remains sealed within a transparent acrylic vial housing throughout the dosing procedure. In some embodiments, a removable stopper at the top of the acrylic vial housing provides access to a septum of the imageable radioisotope particle dosing vial. In some embodiments, the needle plunger assembly is designed to snap into the top of the acrylic housing and is not easily removed once in place. In some embodiments, this provides stability and alignment for the needle inserted through the septum when the tab is pushed down on the plunger assembly.

[0237] In some embodiments, a constant syringe pressure should be maintained for the duration of each flush, with a flow rate equal to or greater than 20 cc per minute. Each flush should contain 20 cc as indicated on the syringe barrel. In some embodiments, using a flow rate less than 20 cc per minute (i.e., flow suitable for natural blood vessels) may reduce the delivery efficiency of the drug delivery system. In some embodiments, flushing should continue until optimal delivery of imageable radioisotope particles is achieved. In some embodiments, it is recommended to flush at least three times, for a total of 60 cc. In some embodiments, the infusion pressure should not exceed 30 psi during any flush. In some embodiments, a pressure reducing valve is included in the drug delivery device to prevent overpressure.

[0238] In some embodiments, to minimize the possibility of high radiation doses to the hands, hemostatic forceps, tweezers, or towels / gauze are used when handling parts of the administration device after infusion. In some embodiments, the dose contained in the acrylic protective shield is measured at a distance of 30 cm from the detector prior to administration.

[0239] Some embodiments provide a sealing unit containing 50 μl to 2 ml of the underivatively derived microspheres described herein, based on a fill volume. For example, the sealing unit may be a vial or a syringe.

[0240] In some embodiments, the underivative microspheres comprise a matrix having an inorganic material comprising quasi-metallic or metallic atoms bonded to non-metallic atoms, the matrix comprising: a core extending to a surface, the core comprising a first portion of quasi-metallic or metallic atoms bonded to non-metallic atoms, and the surface comprising a second portion of quasi-metallic or metallic atoms bonded to non-metallic atoms.

[0241] In some embodiments, the underivative microspheres comprise a matrix having an inorganic material comprising quasi-metallic or metallic atoms bonded to non-metallic atoms, the matrix comprising: a core extending to a surface, the core comprising a first portion of quasi-metallic or metallic atoms bonded to non-metallic atoms, and the surface comprising a second portion of quasi-metallic or metallic atoms bonded to non-metallic atoms as described herein.

[0242] In some embodiments, the underrivatized microspheres comprise a ceramic microsphere matrix as described herein. The microspheres may be provided aseptically.

[0243] Enumerated examples

[0244] Various exemplary embodiments of the particles, microspheres, and methods disclosed herein can be found in the following non-limiting provisions:

[0245] 1. An imageable microsphere, comprising:

[0246] At least one imageable radioactive isotope; and

[0247] A matrix comprising inorganic materials, said inorganic materials comprising quasi-metallic or metallic atoms bonded to nonmetallic atoms, said matrix comprising:

[0248] A core extending to the surface, the core comprising a first portion of quasi-metallic or metallic atoms bonded to nonmetallic atoms, and the surface comprising a second portion of quasi-metallic or metallic atoms bonded to nonmetallic atoms;

[0249] The imageable radioactive isotope is directly bonded to the matrix through at least a portion of the non-metallic atoms on the matrix surface.

[0250] 2. An imageable microsphere, comprising:

[0251] At least one imageable radioactive isotope; and

[0252] A matrix comprising inorganic materials, said inorganic materials comprising quasi-metallic or metallic atoms bonded to nonmetallic atoms, said matrix comprising:

[0253] A core extending to a surface, wherein the core and the surface comprise a matrix of quasi-metallic or metallic atoms and non-metallic atoms;

[0254] The imageable radioisotope is directly bound to the matrix via non-metallic atoms on the matrix surface and / or the imageable radioisotope is bound to the matrix via an inorganic bridge containing non-metallic atoms on the matrix surface.

[0255] 3. An imageable microsphere, comprising:

[0256] At least one imageable radioactive isotope; and

[0257] A matrix comprising inorganic materials, said inorganic materials comprising quasi-metallic or metallic atoms bonded to nonmetallic atoms, said matrix comprising:

[0258] A core extending to a surface, wherein the core and the surface comprise a matrix of quasi-metallic or metallic atoms and non-metallic atoms;

[0259] The imageable radioisotope is directly bound to the matrix via non-metallic atoms on the matrix surface and / or the imageable radioisotope is bound to the matrix via an inorganic bridge containing non-metallic atoms on the matrix surface.

[0260] 4. The imageable microsphere according to any one of Examples 1 to 3, wherein the non-metallic atom is an oxygen atom.

[0261] 5. The imageable microsphere according to Example 4, wherein at least a portion of the oxygen atoms on the surface of the matrix are provided in the form of hydroxyl groups.

[0262] 6. An imageable microsphere comprising:

[0263] An inorganic matrix with a surface layer; and

[0264] At least one imageable radioactive isotope;

[0265] The matrix comprises at least one nonmetal, quasi-metallic, or transition metal oxide; and

[0266] The imageable radioisotope is bound to the matrix surface via Lewis acid-base coordination bonds.

[0267] 7. An imageable microsphere comprising:

[0268] Inorganic matrix comprising a surface having one or more electron-donating functional groups; and

[0269] A surface layer containing at least one imageable radioactive isotope;

[0270] The imageable radioisotope is bound to the matrix surface during the fabrication of the imageable microspheres by chemical coupling with one or more electron-donating functional groups.

[0271] 8. The imageable microspheres according to any one of Examples 1 to 7, wherein the imageable radioactive isotopes are bonded by chemical bonds selected from ionic bonds, covalent bonds or coordinate bonds.

[0272] 9. The imageable microsphere according to Example 8, wherein the imageable radioactive isotopes are bound by coordination bonds.

[0273] 10. An imageable microsphere, comprising:

[0274] A ceramic microsphere matrix and at least one imageable radioactive isotope;

[0275] The imageable radioactive isotope is coupled to the surface of the ceramic microsphere matrix as a Lewis acid-base adduct.

[0276] 11. An imageable microsphere, comprising:

[0277] At least one imageable radioactive isotope; and

[0278] A matrix comprising inorganic materials, said inorganic materials comprising quasi-metallic or metallic atoms bonded to nonmetallic atoms, said matrix comprising:

[0279] A core extending to the surface, the core comprising a first portion of quasi-metallic or metallic atoms bonded to nonmetallic atoms, and the surface comprising a second portion of quasi-metallic or metallic atoms bonded to nonmetallic atoms;

[0280] The imageable radioisotope is directly bound to the matrix via non-metallic atoms on the matrix surface and / or the imageable radioisotope is bound to the matrix via an inorganic bridge containing non-metallic atoms on the matrix surface.

[0281] 12. The imageable microspheres according to Examples 1 to 11, wherein the imageable radioactive isotope is directly bonded to the matrix through non-metallic atoms on the matrix surface.

[0282] 13. The imageable microspheres according to Examples 1 to 12, wherein the matrix is ​​bonded to the matrix by non-metallic atoms on the matrix surface through inorganic bridges.

[0283] 14. The imageable microsphere according to any one of Examples 1 to 13, wherein the matrix comprises a substantially homogeneous mixture of constituent chemical elements.

[0284] 15. The imageable microsphere according to Example 14, wherein the surface contains at least a portion of the constituent chemical elements.

[0285] 16. The imageable microsphere according to any one of Examples 1 to 15, wherein the non-metallic atom is an oxygen atom.

[0286] 17. The imageable microsphere according to Example 16, wherein at least a portion of the oxygen atoms on the surface of the matrix are hydroxyl groups.

[0287] 18. An imageable microsphere comprising:

[0288] Inorganic matrix with surface; and

[0289] At least one imageable radioactive isotope;

[0290] The matrix comprises at least one nonmetal and at least one quasi-metal or metal; and

[0291] The imageable radioisotope is bound to the matrix surface via Lewis acid-base coordination bonds with inorganic Lewis bases.

[0292] 19. An imageable microsphere comprising:

[0293] Inorganic matrix with surface; and

[0294] At least one imageable radioactive isotope;

[0295] The matrix comprises at least one nonmetal and at least one quasi-metal or metal; and

[0296] The imageable radioactive isotope is bound to the matrix surface through chemical bonds with oxygen in the inorganic material.

[0297] 20. An imageable microsphere, comprising:

[0298] Inorganic matrix comprising a surface having one or more electron-donating functional groups; and

[0299] At least one imageable radioactive isotope;

[0300] The imageable radioisotope is directly bonded to the surface and / or bonded to the surface via an inorganic bridge during the fabrication of the imageable microspheres by chemical coupling with one or more electron-donating functional groups.

[0301] 21. The imageable microsphere according to Example 20, wherein the imageable radioactive isotope is directly bonded to the matrix surface.

[0302] 22. The imageable microsphere according to any one of Examples 1 to 21, wherein the matrix comprises a metal oxide, a transition metal oxide, a quasi-metal oxide, or a combination thereof.

[0303] 23. The imageable microsphere according to any one of Examples 1 to 22, wherein the imageable radioisotope is bonded to the matrix by a chemical bond selected from ionic bonds, covalent bonds or coordination bonds.

[0304] 24. The imageable microsphere according to Example 23, wherein the imageable radioactive isotopes are bound by coordination bonds.

[0305] 25. An imageable microsphere, comprising:

[0306] A ceramic microsphere matrix and at least one imageable radioactive isotope;

[0307] The imageable radioactive isotope is coupled to the surface of the ceramic microsphere matrix as a Lewis acid-base adduct of an inorganic Lewis base.

[0308] 26. The imageable microsphere according to Example 25, wherein the inorganic Lewis base is a component of the matrix, and the imageable isotope is directly coupled to the matrix surface via the inorganic Lewis base.

[0309] 27. The imageable microsphere according to Example 26, wherein the imageable radioisotope is coupled to the surface of the ceramic microsphere matrix via an inorganic binder comprising a Lewis base.

[0310] 28. The imageable microsphere according to Example 27, wherein the inorganic binder is a metal oxide.

[0311] 29. The imageable microsphere according to Example 28, wherein the metal oxide is tin oxide.

[0312] 30. The imageable microsphere according to any one of Examples 25 to 29, wherein the Lewis base is oxygen of a metal oxide or a quasi-metal oxide.

[0313] 31. The imageable microsphere according to any one of Examples 18 to 30, wherein the Lewis base is oxygen in tin oxide.

[0314] 32. The imageable microsphere according to any one of Examples 1 to 31, wherein the imageable isotope is configured for imaging via an imaging mode selected from single-photon imaging and two-photon imaging.

[0315] 33. The imageable microsphere according to any one of Examples 1 to 32, wherein the imageable radioisotope is configured for imaging via an imaging mode selected from positron emission tomography (PET), single-photon emission computed tomography (SPECT), and gamma camera imaging.

[0316] 34. The imageable microsphere according to any one of Examples 1 to 33, wherein the at least one imageable radioactive isotope is a positron emitter or a gamma emitter.

[0317] 35. The imageable microsphere according to any one of Examples 1 to 34, wherein the at least one imageable radioactive isotope is a metallic radioactive isotope.

[0318] 36. The imageable microsphere according to any one of Examples 1 to 34, wherein the at least one imageable radioactive isotope is selected from... 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 F and / or combinations thereof.

[0319] 37. The imageable microsphere according to any one of Examples 1 to 34, wherein the at least one imageable radioactive isotope is selected from 99mTc and 89Zr.

[0320] 38. The imageable microsphere according to any one of Examples 1 to 34, comprising a structure of formula (V):

[0321]

[0322] in

[0323] The matrix contains M c And M c Selected from Pb, Al, Si, Y, Mn, Ga, Fe, Sr, and Ti;

[0324] m is an integer selected from 1, 2, or 3;

[0325] M bSelected from 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 F and / or combinations thereof;

[0326] M a It is a matrix atom or a bridging metal atom, and M a Selected from Sn, Pb, Al, Si, Y, Mn, Ga, Fe, Sr, and Ti;

[0327] Each instance of R either does not exist or is -H;

[0328] X is selected from –OH, =O, and –O. - ;and

[0329] n is an integer selected from 0, 1, 2, 3 or 4.

[0330] 39. The imageable microsphere according to Example 38, wherein:

[0331] M c It is Al;

[0332] The matrix contains M a And M a It is Si;

[0333] M b yes 89 Zr;

[0334] Each X is independently –OH or –O-; and

[0335] n is 1 or 2.

[0336] 40. The imageable microsphere according to Example 38 or 39, wherein M b yes 89 Zr, X is -OH, n is 2.

[0337] 41. The imageable microsphere according to Example 38, wherein:

[0338] M cIt is Si;

[0339] M a It is Sn;

[0340] M b yes 99m Tc;

[0341] Each X is independently –OH or –O-; and

[0342] n is 2 or 3.

[0343] 42. The imageable microsphere according to Example 38, wherein M b yes 99m Tc, X is -OH, n is 3.

[0344] 43. The imageable microsphere according to any one of Examples 1 to 34, comprising the structure of formula (VIII):

[0345]

[0346] The matrix contains M a and M c And M a and M c Independently selected from Pb, Al, Si, Y, Mn, Ga, Fe, and Ti;

[0347] m is an integer selected from 1, 2, or 3;

[0348] M b Selected from 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 combinations thereof;

[0349] R a Each instance is independently OH, O, or –O-Sn(X). n -O-;

[0350] X is selected from –OH, =O, and –O. - ;and

[0351] n is an integer selected from 0, 1, 2, 3 or 4.

[0352] 44. The imageable microsphere according to Example 43, wherein M c It is Al; M a It is Si; M b yes 99m Tc; each X is independently –OH or =O; n is 2 or 3.

[0353] 45. The imageable microsphere according to Example 43, wherein M b yes 99m Tc;R a At least one instance is -O-Sn(X). n -O-, each X is independently –OH or =O; n is 2 or 3.

[0354] 46. ​​The imageable microsphere according to Example 43, wherein M b yes 99m Tc;R a One example is -O-Sn-O-;R a An example is -O- or -OH-; each X is independently –OH or =O; n is 2 or 3.

[0355] 47. The imageable microsphere according to any one of Examples 1 to 46, wherein the matrix comprises at least one nonmetal and quasi-metal, transition metal and metal.

[0356] 48. The imageable microsphere according to any one of Examples 1 to 47, wherein the matrix comprises a ceramic material.

[0357] 49. The imageable microsphere according to Example 48, wherein the ceramic comprises at least one element selected from silicon, yttrium, manganese, aluminum, gallium and titanium.

[0358] 50. The imageable microsphere according to any one of Examples 1 to 49, wherein the matrix comprises glass.

[0359] 51. The imageable microsphere according to any one of Examples 1 to 50, wherein the matrix comprises silicon dioxide and at least one other element selected from manganese, aluminum, gallium, yttrium, boron and titanium.

[0360] 52. The imageable microsphere according to any one of Examples 1 to 51, wherein the matrix comprises SiO2, Y2O3, MnO2, AlO3, Ga2O3, Fe2O3, TiO2, SrCO3, SrO2 or combinations thereof.

[0361] 53. The imageable microsphere according to any one of Examples 1 to 52, wherein the matrix comprises at least one of SiO2 and Y2O3, MnO2, AlO3, Ga2O3, Fe2O3, TiO2, SrCO3 and SrO2.

[0362] 54. The imageable microsphere according to any one of Examples 1 to 53, wherein the matrix comprises yttrium aluminum silicon oxide.

[0363] 55. The imageable microsphere according to any one of Examples 1 to 54, wherein the imageable microsphere lacks a therapeutic radioisotope.

[0364] 56. The imageable microsphere according to any one of Examples 1 to 55, wherein the diameter of the imageable microsphere is from 5 μm to 1000 μm.

[0365] 57. The imageable microsphere according to any one of Examples 1 to 56, wherein the matrix is ​​non-porous.

[0366] 58. The imageable microsphere according to any one of Examples 1 to 56, wherein the matrix is ​​porous.

[0367] 59. The imageable microsphere according to any one of Examples 1 to 58, which is prepared by a method comprising the following steps:

[0368] Provide the matrix;

[0369] The at least one imageable radioactive isotope is chemically coupled to the matrix to provide imageable microspheres.

[0370] 60. An imageable microsphere, prepared by a method comprising the following steps:

[0371] A matrix is ​​provided, the matrix comprising:

[0372] Inorganic materials, wherein the inorganic materials contain metal or quasi-metal atoms bonded to non-metallic atoms;

[0373] Core, the core comprising a first portion of nonmetallic atoms; and

[0374] Surface, the surface comprising a second portion of nonmetallic atoms;

[0375] Provide at least one imageable radioactive isotope; and

[0376] Imageable microspheres are provided by chemically coupling the at least one imageable radioactive isotope to the surface of the matrix via a second portion of non-metallic atoms.

[0377] 61. The imageable microspheres according to Example 59 or 60 further include providing at least one imageable radioisotope as a salt prior to chemically coupling the at least one imageable radioisotope to the surface of the inorganic matrix.

[0378] 62. The imageable microsphere according to Example 61, wherein the salt is an alkali metal salt, an alkaline earth metal salt, a halide salt, a polyatomic salt, or a salt formed from an organic acid.

[0379] 63. The imageable microspheres according to Examples 59 to 62, wherein the chemical functionalization is carried out in the presence of a reducing agent.

[0380] 64. The imageable microsphere according to Example 63, wherein the reducing agent is selected from one or more of the following: stannous salt, stannous hydrate, concentrated HCl, sodium borohydride, sodium dithionite, ferrous sulfate, ferric chloride plus ascorbic acid, hypophosphite and / or hydrazine.

[0381] 65. The imageable microspheres according to Examples 59 to 63, wherein the radioactive isotope is 99m Tc undergoes the aforementioned chemical functionalization in the presence of tin salts.

[0382] 66. The imageable microsphere according to Example 65, wherein the radioactive isotope is... 99m The form of Tc pertechnetate is provided, and the chemical functionalization is carried out in the presence of stannous ions.

[0383] 67. The imageable microspheres according to Examples 59 to 62, wherein 89 Zr with oxalic acid 89 Provided in Zr form.

[0384] 68. The imageable microsphere according to Example 67, wherein 89 Zr with oxalic acid 89 Provided in Zr form.

[0385] 69. A method for preparing imageable microspheres, comprising providing a ceramic microsphere matrix and reacting the ceramic microsphere matrix with an imageable radioactive isotope under conditions suitable for coupling the radioactive isotope to the surface of the ceramic microspheres.

[0386] 70. The method according to Example 69, wherein the imageable radioisotope is coupled to the surface of the ceramic microspheres in the form of a Lewis acid-base adduct.

[0387] 71. The method according to Example 69 or Example 70, wherein the radioactive isotope is a metallic radioactive isotope.

[0388] 72. The method according to any one of Examples 59 to 61, wherein the radioactive isotope is selected from... 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 F and / or combinations thereof.

[0389] 73. The method according to any one of Examples 69 to 72, wherein the radioactive isotope is provided in the form of a salt.

[0390] 74. The method according to any one of Examples 69 to 73, wherein the radioactive isotope reacts with the ceramic microspheres in the presence of a reducing agent.

[0391] 75. The method according to Example 74, wherein the reducing agent is selected from one or more of the following: stannous salt, stannous hydrate, HCl, sodium borohydride, sodium dithionite, ferrous sulfate, ferric chloride plus ascorbic acid, hypophosphorous acid and / or hydrazine.

[0392] 76. The method according to any one of Examples 69 to 75, wherein the radioactive isotope is 99m Tc.

[0393] 77. The method according to embodiment 76, wherein 99m Tc is provided in the form of pertechnetate.

[0394] 78. The method according to embodiment 76, wherein 99m Tc is provided in the form of pertechnetate, and the reaction is carried out in the presence of stannous ions.

[0395] 79. The method according to any one of Examples 69 to 75, wherein the radioactive isotope is 89 Zr.

[0396] 80. The method according to Example 79, wherein 89Zr is in the form of oxalic acid 89 Provided in Zr form.

[0397] 81. The method according to Example 79 or 80, wherein the reaction is carried out in the presence of a base.

[0398] 82. The method for preparing imageable microspheres according to any one of Examples 1 to 68, the method comprising:

[0399] Provide an inorganic matrix; and

[0400] The inorganic matrix is ​​chemically functionalized using at least one imageable radioactive isotope to provide imageable microspheres.

[0401] 83. The method according to Example 82 further includes providing at least one imageable radioisotope as a salt before chemically functionalizing at least one imageable radioisotope onto the surface of an inorganic matrix.

[0402] 84. The method according to Example 83, wherein the salt is an alkali metal salt, an alkaline earth metal salt, a halide salt, a polyatomic salt, or a salt formed with an organic acid.

[0403] 85. The method according to Example 83 or 84 further includes adding a reducing agent during the chemical functionalization step.

[0404] 86. The method according to Example 85, wherein the reducing agent is selected from one or more of the following: stannous salt, stannous hydrate, HCl, sodium borohydride, sodium dithionite, ferrous sulfate, ferric chloride plus ascorbic acid, hypophosphorous acid and / or hydrazine.

[0405] 87. The method according to any one of Examples 82 to 86, wherein the radioactive isotope is 99m Tc.

[0406] 88. The method according to embodiment 87, wherein 99m Tc is provided in the form of pertechnetate.

[0407] 89. The method according to embodiment 87, wherein 99m Tc is provided in the form of pertechnetate, and the reaction is carried out in the presence of stannous ions.

[0408] 90. The method according to any one of Examples 82 to 89, wherein the radioactive isotope is 89 Zr.

[0409] 91. The method according to embodiment 90, wherein 89 Zr with oxalic acid 89 Provided in Zr form.

[0410] 92. The method according to Example 90 or 91, wherein the reaction is carried out in the presence of a base.

[0411] 93. The method according to any one of Examples 69 to 92, which is carried out under aqueous conditions.

[0412] 94. The method according to any one of Examples 69 to 93 further includes recovering the imageable microspheres and / or washing the microspheres to remove unreacted radioisotopes.

[0413] 95. The method according to any one of Examples 69 to 94 further includes resuspending the imageable microspheres in a pharmaceutically acceptable injectable aqueous medium.

[0414] 96. An imageable microsphere, which can be obtained according to any one of Examples 69 to 95.

[0415] 97. A method for determining the amount of therapeutic microspheres to be delivered to a patient's body, the method comprising:

[0416] Provides imageable microsphere clusters;

[0417] The imageable microspheres are delivered to the patient by introducing them into the first location in the patient's vascular system.

[0418] Allowing the imageable microspheres to distribute within the patient's body;

[0419] By using imaging modalities to image a portion of a patient's body, the distribution of at least a portion of the imageable microsphere population within the patient's body can be determined.

[0420] The amount of therapeutic microspheres to be delivered to a patient can be calculated by using the distribution of imageable microspheres.

[0421] 98. The method according to Example 97, wherein the part of the body is the patient's off-target area, and the off-target area is the patient's lungs.

[0422] 99. The method according to Example 97, wherein the part of the body is the patient's target area, and the target area is the patient's liver.

[0423] 100. The method according to any one of Examples 97 to 99, wherein the target area is divided into tumor tissue and non-tumor tissue.

[0424] 101. The method according to any one of Examples 97 to 100, wherein the amount of therapeutic microspheres to be delivered to the patient is calculated.

[0425] 102. The method according to Example 91, wherein the calculated amount is delivered to the patient.

[0426] 103. The method according to any one of Examples 97 to 102, wherein the imaging mode is SPECT.

[0427] 104. The method according to any one of Examples 97 to 102, wherein the detection mode is PET.

[0428] 105. The method according to any one of Examples 97 to 102, wherein the detection mode is gamma camera imaging.

[0429] 106. The method according to any one of Examples 97 to 102, wherein the imageable microsphere is the imageable microsphere according to any one of Examples 1 to 68.

[0430] 107. A method of treating a patient, the method comprising:

[0431] Provide imageable microspheres;

[0432] The imageable microspheres are delivered to the patient by introducing them into a first location in the vascular system of the patient's body.

[0433] Allowing the imageable microspheres to distribute within the patient's body;

[0434] By using imaging modalities to image target portions of the patient's body, the distribution of at least a portion of the imageable microsphere population within the patient's body can be determined.

[0435] The amount of therapeutic microspheres to be delivered to the patient can be calculated by utilizing the distribution of imageable microspheres.

[0436] To obtain data on the distribution of imageable therapeutic microsphere substitutes in patients;

[0437] This data was used to determine the dosage of therapeutic microspheres to be administered to the patient.

[0438] The therapeutic microspheres are delivered to the patient by introducing them into a second location in the patient's vascular system.

[0439] The therapeutic microspheres are allowed to distribute within the patient's body, thereby treating the patient.

[0440] 108. The method according to Example 107, wherein the second location in the patient's vascular system is the same as the first location in the patient's vascular system.

[0441] 109. The method according to embodiment 107 or 108, wherein the imaging mode is SPECT.

[0442] 110. The method according to Example 107 or 108, wherein the detection mode is PET.

[0443] 111. The method according to embodiment 107 or 108, wherein the detection mode is gamma camera imaging.

[0444] 112. The method according to any one of Examples 107 or 111, wherein the imageable microsphere is the imageable microsphere according to any one of Examples 1 to 68.

[0445] 113. A method for treating a patient using therapeutic microspheres, the method comprising:

[0446] Data were calculated from the distribution of imageable therapeutic microsphere substitutes in patients;

[0447] The data is used to determine the amount of therapeutic microspheres to be administered to the patient.

[0448] The therapeutic microspheres are delivered to the patient by introducing the amount of therapeutic microspheres into a first location in the patient's vascular system;

[0449] Allowing the therapeutic microspheres to distribute within the patient; and

[0450] The therapeutic microspheres are allowed to remain in the patient's body, thereby treating the patient.

[0451] 114. The method according to Example 113 further includes providing the patient with an imageable cluster of microspheres.

[0452] 115. The method according to embodiment 114 further includes delivering the imageable microspheres to the patient by introducing the imageable microspheres into a first location in the vascular system of the patient's body.

[0453] 116. The method according to Example 115 further includes allowing the imageable microsphere cluster to distribute within the patient.

[0454] 117. The method according to Example 116 further includes imaging a target portion of the patient's body using an imaging mode to determine the distribution of at least a portion of the imageable microsphere cluster within the patient's body.

[0455] 118. The method according to Example 117 further includes calculating the amount of therapeutic microspheres to be delivered to the patient body using the distribution of the imageable microspheres.

[0456] 119. A method of treating a tumor in a patient requiring treatment, the method comprising:

[0457] Introduce imageable microsphere clusters to the patient;

[0458] Allows imageable microspheres to distribute within the patient's body for a period of time;

[0459] The distribution of imageable microspheres at specific sites within a patient was determined by imaging microspheres using imaging modalities.

[0460] Based on the distribution of imageable microspheres, determine the estimated effective dose at the site when the imageable microspheres are replaced by therapeutic microspheres; and

[0461] Based on the estimated effective dose, a certain amount of therapeutic microspheres is administered to the patient.

[0462] 120. The method according to Example 119, wherein the imageable microsphere group comprises any one of Examples 1 to 68.

[0463] 121. The method according to Example 119 or 120, wherein the site is a malignant or benign tumor and / or non-tumor tissue.

[0464] 122. The method according to Example 119 or 120, wherein the site is a malignant tumor.

[0465] 123. The method according to Example 122, wherein the site is a malignant tumor.

[0466] 124. A method for predicting the extent of off-target delivery to the lungs or gastrointestinal tract during treatment in a patient requiring radioisotope cancer therapy, the method comprising:

[0467] Introduce imageable microsphere clusters to the patient;

[0468] Allows imageable microspheres to distribute within the patient's body for a period of time;

[0469] The distribution of imageable microspheres in a patient's lungs was determined by imaging microspheres using imaging modalities.

[0470] Determine the estimated radiation dose to the lungs or gastrointestinal tract of a patient if the imaging microspheres are replaced by radioactive isotope therapeutic microspheres;

[0471] Determine the dose of radioisotope therapeutic microspheres that, due to off-target delivery, would be sufficient to cause clinically relevant pulmonary or gastrointestinal changes; and

[0472] A dose of radioactive isotope therapeutic microspheres is administered to a patient, the dose being lower than that of radioactive isotope therapeutic microspheres that have been determined to cause clinically relevant lung or gastrointestinal changes due to off-target delivery.

[0473] 125. The method according to Example 124, wherein the imageable microsphere group comprises any one of Examples 1 to 68.

[0474] 126. A method for reducing lung or gastrointestinal damage during treatment of a patient requiring radioisotope cancer therapy, the method comprising:

[0475] Introduce imageable microsphere clusters to the patient;

[0476] Allows imageable microspheres to distribute within the patient's body for a period of time;

[0477] By using imaging modalities to image imageable microspheres, the distribution of imageable microspheres in the patient's gastrointestinal tract or lungs can be determined.

[0478] Determine the estimated radiation dose to the patient's gastrointestinal tract or lungs if the imaging microspheres are replaced by radioactive isotope therapeutic microspheres;

[0479] Determine the dose of radioactive isotope therapeutic microspheres sufficient to cause gastrointestinal damage; and

[0480] A dose of radioactive isotope therapeutic microspheres is administered to the patient, the dose being lower than that of radioactive isotope therapeutic microspheres determined to be sufficient to cause gastrointestinal damage.

[0481] 127. The method according to Example 126, wherein the imageable microsphere group comprises any one of Examples 1 to 68.

[0482] 128. A reagent kit comprising:

[0483] Microspheres, comprising:

[0484] A matrix comprising inorganic materials, said inorganic materials comprising quasi-metallic or metallic atoms bonded to nonmetallic atoms, said matrix comprising:

[0485] A core extending to the surface, the core comprising a first portion of quasi-metallic or metallic atoms bonded to nonmetallic atoms, and the surface comprising a second portion of quasi-metallic or metallic atoms bonded to nonmetallic atoms; and

[0486] The specification is for causing an imageable radioactive isotope to react with a matrix, thereby causing the imageable radioactive isotope to directly bind to the matrix through at least a portion of the non-metallic atoms on the matrix surface.

[0487] 129. A reagent kit comprising:

[0488] Microspheres, comprising:

[0489] Inorganic matrix; wherein the inorganic matrix comprises at least one nonmetallic, quasi-metallic, or transition metal oxide; and

[0490] The instruction manual is for binding an imageable radioisotope to an inorganic matrix surface via Lewis acid-base coordination bonds.

[0491] 130. A kit comprising microspheres having a ceramic microsphere matrix and instructions for carrying out a reaction in which an imageable radioisotope is coupled to the ceramic microsphere matrix as a Lewis acid-base adduct.

[0492] 131. The kit according to any one of Examples 128 to 130, wherein the sealed unit contains 10 μl to 2 ml of microspheres based on the fill volume.

[0493] 132. The kit according to any one of Examples 128 to 131, wherein the microspheres are provided in a vial or syringe.

[0494] 133. The kit according to any one of Examples 128 to 132, wherein the imageable radioisotope is selected from... 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 One or more of F.

[0495] 134. The kit according to any one of Examples 128 to 133, further comprising a reducing agent.

[0496] 135. The kit according to Example 134, wherein the reducing agent is selected from one or more of the following: stannous salt, stannous hydrate, concentrated HCl, sodium borohydride, sodium dithionite, ferrous sulfate, ferric chloride plus ascorbic acid, hypophosphite and / or hydrazine.

[0497] 136. The kit according to Example 134 or 135, wherein the reducing agent is a stannous salt and the radioactive isotope is 99m Tc, and the radioactive isotope is in the form of pertechnetate.

[0498] 137. The kit according to any one of Examples 128 to 133, wherein the radioactive isotope is 89 Zr.

[0499] 138. The kit according to Example 137, wherein the radioactive isotope is 89 Zr exists in the form of zirconium oxalate or zirconium chloride.

[0500] 139. The kit according to any one of Examples 128 to 138 further comprises therapeutic microspheres.

[0501] 140. The kit according to Example 139, wherein the therapeutic microspheres comprise a therapeutic radioisotope.

[0502] 141. The kit according to Example 140, wherein the therapeutic microspheres comprise 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 Pb.

[0503] 142. The kit according to any one of Examples 139 to 141, wherein the therapeutic microspheres have the same chemical composition as the imaging microspheres.

[0504] 143. The kit according to any one of Examples 139 to 142, wherein the therapeutic microspheres comprise yttrium aluminum silicon oxide.

[0505] 144. The kit according to any one of Examples 128 to 143 further comprises 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.

[0506] 145. An imageable microsphere comprising:

[0507] At least one imageable radioactive isotope; and

[0508] A matrix comprising inorganic materials, said inorganic materials comprising quasi-metallic or metallic atoms bonded to nonmetallic atoms, said matrix comprising:

[0509] A core extending to the surface, the core comprising a first portion of quasi-metallic or metallic atoms bonded to nonmetallic atoms, and the surface comprising a second portion of quasi-metallic or metallic atoms bonded to nonmetallic atoms;

[0510] The imageable radioisotope is directly bound to the matrix via non-metallic atoms on the matrix surface and / or the imageable radioisotope is bound to the matrix via an inorganic bridge containing non-metallic atoms on the matrix surface.

[0511] 146. The imageable microsphere according to Example 145, wherein the imageable radioactive isotope is directly bonded to the matrix via non-metallic atoms on the matrix surface.

[0512] 147. The imageable microsphere according to Example 145 or 146, wherein the matrix is ​​bonded to the matrix by non-metallic atoms on the matrix surface via inorganic bridges.

[0513] 148. The imageable microsphere according to any one of Examples 145 to 147, wherein the matrix comprises a substantially homogeneous mixture of constituent chemical elements.

[0514] 149. The imageable microsphere according to Example 148, wherein the surface contains at least a portion of the constituent chemical elements.

[0515] 150. The imageable microsphere according to any one of Examples 145 to 149, wherein the non-metallic atom is an oxygen atom.

[0516] 151. The imageable microsphere according to Example 150, wherein at least a portion of the oxygen atoms on the surface of the matrix are hydroxyl groups.

[0517] 152. An imageable microsphere, comprising:

[0518] Inorganic matrix with surface; and

[0519] At least one imageable radioactive isotope;

[0520] The matrix comprises at least one nonmetal and at least one quasi-metal or metal; and

[0521] The imageable radioisotope is bound to the matrix surface via Lewis acid-base coordination bonds with inorganic Lewis bases.

[0522] 153. An imageable microsphere comprising:

[0523] Inorganic matrix with surface; and

[0524] At least one imageable radioactive isotope;

[0525] The matrix comprises at least one nonmetal and at least one quasi-metal or metal; and

[0526] The imageable radioactive isotope is bound to the matrix surface through chemical bonds with oxygen in the inorganic material.

[0527] 154. An imageable microsphere comprising:

[0528] Inorganic matrix comprising a surface having one or more electron-donating functional groups; and

[0529] At least one imageable radioactive isotope;

[0530] The imageable radioisotope is directly bonded to the surface and / or bonded to the surface via an inorganic bridge during the fabrication of the imageable microspheres by chemical coupling with one or more electron-donating functional groups.

[0531] 155. The imageable microsphere according to Example 154, wherein the imageable radioactive isotope is directly bonded to the matrix surface.

[0532] 156. The imageable microsphere according to any one of Examples 145 to 155, wherein the matrix comprises a metal oxide, a transition metal oxide, a quasi-metal oxide, or a combination thereof.

[0533] 157. The imageable microsphere according to any one of Examples 145 to 156, wherein the imageable radioisotope is bonded to the matrix by a chemical bond selected from ionic bonds, covalent bonds or coordination bonds.

[0534] 158. The imageable microsphere according to Example 157, wherein the imageable radioactive isotopes are bound by coordination bonds.

[0535] 159. An imageable microsphere comprising:

[0536] A ceramic microsphere matrix and at least one imageable radioactive isotope;

[0537] The imageable radioactive isotope is coupled to the surface of the ceramic microsphere matrix as a Lewis acid-base adduct of an inorganic Lewis base.

[0538] 160. The imageable microsphere according to Example 159, wherein the inorganic Lewis base is a component of the matrix, and the imageable isotope is directly coupled to the matrix surface via the inorganic Lewis base.

[0539] 161. The imageable microsphere according to any one of Examples 159 to 160, wherein the imageable radioisotope is coupled to the surface of the ceramic microsphere matrix via an inorganic binder comprising a Lewis base.

[0540] 162. The imageable microsphere according to Example 161, wherein the inorganic binder is a metal oxide.

[0541] 163. The imageable microsphere according to Example 162, wherein the metal oxide is tin oxide.

[0542] 164. The imageable microsphere according to any one of Examples 159 to 163, wherein the Lewis base is oxygen of a metal oxide or a quasi-metal oxide.

[0543] 165. The imageable microsphere according to any one of Examples 152 to 164, wherein the Lewis base is oxygen in tin oxide.

[0544] 166. The imageable microsphere according to any one of Examples 145 to 165, wherein the imageable isotope is configured for imaging via an imaging mode selected from single-photon imaging and two-photon imaging.

[0545] 167. The imageable microsphere according to any one of Examples 145 to 166, wherein the imageable radioisotope is configured for imaging via an imaging mode selected from positron emission tomography (PET), single-photon emission computed tomography (SPECT), and gamma camera imaging.

[0546] 168. The imageable microsphere according to any one of Examples 145 to 167, wherein the at least one imageable radioactive isotope is a positron emitter or a gamma emitter.

[0547] 169. The imageable microsphere according to any one of Examples 145 to 168, wherein the at least one imageable radioactive isotope is a metallic radioactive isotope.

[0548] 170. The imageable microsphere according to any one of Examples 145 to 168, wherein the at least one imageable radioactive isotope is selected from... 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 F and / or combinations thereof.

[0549] 171. The imageable microsphere according to any one of Examples 145 to 168, wherein the at least one imageable radioisotope is selected from... 99m Tc and 89 Zr.

[0550] 172. The imageable microsphere according to any one of Examples 145 to 168, comprising a structure of formula (V):

[0551]

[0552] in

[0553] The matrix contains M c And M c Selected from Pb, Al, Si, Y, Mn, Ga, Fe, Sr, and Ti;

[0554] m is an integer selected from 1, 2, or 3;

[0555] M b Selected from 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 F and / or combinations thereof;

[0556] M a It is a matrix atom or a bridging metal atom, and M a Selected from Sn, Pb, Al, Si, Y, Mn, Ga, Fe, Sr, and Ti;

[0557] Each instance of R either does not exist or is -H;

[0558] X is selected from –OH, =O, and –O. - ;and

[0559] n is an integer selected from 0, 1, 2, 3 or 4.

[0560] 173. The imageable microsphere according to Example 172, wherein:

[0561] M c It is Al;

[0562] The matrix contains M a And M a It is Si;

[0563] M b yes 89 Zr;

[0564] Each X is independently –OH or –O. - ;and

[0565] n is 1 or 2.

[0566] 174. The imageable microsphere according to Example 172 or 173, wherein M b yes 89 Zr, X is -OH, n is 2.

[0567] 175. The imageable microsphere according to Example 172, wherein:

[0568] M c It is Si;

[0569] M a It is Sn;

[0570] M b yes 99m Tc;

[0571] Each X is independently –OH or –O. - ;

[0572] And n is 2 or 3.

[0573] 176. The imageable microsphere according to Example 172, wherein M b yes 99m Tc, X is -OH, n is 3.

[0574] 177. The imageable microsphere according to any one of Examples 145 to 168, comprising the structure of formula (VIII):

[0575] (VIII)

[0576] The matrix contains M a and M c And M a and M c Independently selected from Pb, Al, Si, Y, Mn, Ga, Fe, Sr, and Ti;

[0577] m is an integer selected from 1, 2, or 3;

[0578] M b Selected from 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 combinations thereof;

[0579] R a Each instance is independently OH, O, or –O-Sn(X). n -O-;

[0580] X is selected from –OH, =O, and –O-; and

[0581] n is an integer selected from 0, 1, 2, 3 or 4.

[0582] 178. The imageable microsphere according to Example 177, wherein M c It is Al; M a It is Si; M b yes 99m Tc; each X is independently –OH or =O; n is 2 or 3.

[0583] 179. The imageable microsphere according to Example 177, wherein M b yes 99m Tc;R a At least one instance is -O-Sn(X). n -O-, each X is independently –OH or =O; n is 2 or 3.

[0584] 180. The imageable microsphere according to Example 177, wherein M b yes 99m Tc;R a One example is -O-Sn-O-;R a An example is -O- or -OH-; each X is independently –OH or =O; n is 2 or 3.

[0585] 181. The imageable microsphere according to any one of Examples 145 to 180, wherein the matrix comprises at least one nonmetal and quasi-metal, transition metal and metal.

[0586] 182. The imageable microsphere according to any one of Examples 145 to 181, wherein the matrix comprises a ceramic material.

[0587] 183. The imageable microsphere according to Example 182, wherein the ceramic comprises at least one element selected from silicon, yttrium, manganese, aluminum, gallium and titanium.

[0588] 184. The imageable microsphere according to any one of Examples 145 to 183 or 182, wherein the matrix comprises glass.

[0589] 185. The imageable microsphere according to any one of Examples 145 to 184, wherein the matrix comprises silicon dioxide and at least one other element selected from manganese, aluminum, gallium, yttrium, boron and titanium.

[0590] 186. The imageable microsphere according to any one of Examples 145 to 185, wherein the matrix comprises SiO2, Y2O3, MnO2, AlO3, Ga2O3, Fe2O3, TiO2, SrO2, SrCO3 or combinations thereof.

[0591] 187. The imageable microsphere according to any one of Examples 145 to 186, wherein the matrix comprises at least one of SiO2 and the following: Y2O3, MnO2, AlO3, Ga2O3, Fe2O3, TiO2, SrCO3 and SrO2.

[0592] 188. The imageable microsphere according to any one of Examples 145 to 187, wherein the matrix comprises yttrium aluminum silicon oxide.

[0593] 189. The imageable microsphere according to any one of Examples 145 to 188, wherein the imageable microsphere lacks a therapeutic radioisotope.

[0594] 190. The imageable microsphere according to any one of Examples 145 to 189, wherein the diameter of the imageable microsphere is from 5 μm to 1000 μm.

[0595] 191. The imageable microsphere according to any one of Examples 145 to 190, wherein the matrix is ​​non-porous.

[0596] 192. The imageable microsphere according to any one of Examples 145 to 190, wherein the matrix is ​​porous.

[0597] 193. The imageable microsphere according to any one of Examples 145 to 192, which is prepared by a method comprising the following steps:

[0598] Provide the matrix;

[0599] The at least one imageable radioactive isotope is chemically coupled to the matrix to provide imageable microspheres.

[0600] 194. An imageable microsphere, prepared by a method comprising the following steps:

[0601] A matrix is ​​provided, the matrix comprising:

[0602] Inorganic materials, wherein the inorganic materials contain metal or quasi-metal atoms bonded to non-metallic atoms;

[0603] Core, the core comprising a first portion of nonmetallic atoms; and

[0604] Surface, the surface comprising a second portion of nonmetallic atoms;

[0605] Provide at least one imageable radioactive isotope; and

[0606] Imageable microspheres are provided by chemically coupling the at least one imageable radioactive isotope to the surface of the matrix via the second portion of non-metallic atoms.

[0607] 195. The imageable microspheres according to Examples 193 or 194 further include providing at least one imageable radioisotope as a salt prior to chemically coupling the at least one imageable radioisotope to the surface of the inorganic matrix.

[0608] 196. The imageable microsphere according to Example 195, wherein the salt is an alkali metal salt, an alkaline earth metal salt, a halide salt, a polyatomic salt, or a salt formed with an organic acid.

[0609] 197. The imageable microspheres according to Examples 193 to 196, wherein the chemical functionalization is carried out in the presence of a reducing agent.

[0610] 198. The imageable microsphere according to Example 197, wherein the reducing agent is selected from one or more of the following: stannous salt, stannous hydrate, concentrated HCl, sodium borohydride, sodium dithionite, ferrous sulfate, ferric chloride plus ascorbic acid, hypophosphite and / or hydrazine.

[0611] 199. The imageable microspheres according to Examples 193 to 197, wherein the radioactive isotope is 99m Tc undergoes the aforementioned chemical functionalization in the presence of tin salts.

[0612] 200. The imageable microsphere according to Example 199, wherein the radioactive isotope is... 99m The form of Tc pertechnetate is provided, and the chemical functionalization is carried out in the presence of stannous ions.

[0613] 201. The imageable microsphere according to any one of Examples 193 to 196, wherein the radioactive isotope is 89 Zr.

[0614] 202. The imageable microsphere according to Example 201, wherein 89 Zr with oxalic acid 89 Provided in Zr form.

[0615] 203. A method for preparing imageable microspheres, comprising providing a ceramic microsphere matrix and reacting the ceramic microsphere matrix with an imageable radioisotope under conditions suitable for coupling the radioisotope to the surface of the ceramic microspheres.

[0616] 204. The method according to Example 203, wherein the radioactive isotope is bonded to the surface of the ceramic microspheres in the form of a Lewis acid-base adduct.

[0617] 205. The method according to Example 203 or Example 204, wherein the radioactive isotope is a metallic radioactive isotope.

[0618] 206. The method according to any one of Examples 203 to 205, wherein the radioactive isotope is selected from... 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 F and / or combinations thereof.

[0619] 207. The method according to any one of Examples 203 to 206, wherein the radioactive isotope is provided in the form of a salt.

[0620] 208. The method according to any one of Examples 203 to 207, wherein the radioactive isotope reacts with the ceramic microspheres in the presence of a reducing agent.

[0621] 209. The method according to Example 208, wherein the reducing agent is selected from one or more of the following: stannous salt, stannous hydrate, HCl, sodium borohydride, sodium dithionite, ferrous sulfate, ferric chloride plus ascorbic acid, hypophosphorous acid and / or hydrazine.

[0622] 210. The method according to any one of Examples 203 to 209, wherein the radioactive isotope is 99m Tc.

[0623] 211. The method according to embodiment 210, wherein 99m Tc is provided in the form of pertechnetate.

[0624] 212. The method according to embodiment 210, wherein 99m Tc is provided in the form of pertechnetate, and the reaction is carried out in the presence of stannous ions.

[0625] 213. The method according to any one of Examples 203 to 209, wherein the radioactive isotope is 89 Zr.

[0626] 214. The method according to embodiment 213, wherein 89 Zr with oxalic acid 89 Provided in Zr form.

[0627] 215. The method according to Example 213 or 214, wherein the reaction is carried out in the presence of a base.

[0628] 216. The method for preparing imageable microspheres according to any one of Examples 145 to 192, the method comprising:

[0629] Provide inorganic matrix; and

[0630] The inorganic matrix is ​​chemically functionalized using at least one imageable radioactive isotope to provide imageable microspheres.

[0631] 217. The method according to Example 216, wherein at least one imageable radioisotope as a salt is provided prior to chemically functionalizing at least one imageable radioisotope onto the surface of an inorganic matrix.

[0632] 218. The method according to Example 217, wherein the salt is an alkali metal salt, an alkaline earth metal salt, a halogen salt, a polyatomic salt, or a salt formed with an organic acid.

[0633] 219. The method according to Examples 217 to 218, wherein the reaction is carried out in the presence of a reducing agent.

[0634] 220. The method according to Example 219, wherein the reducing agent is selected from one or more of the following: stannous salt, stannous hydrate, HCl, sodium borohydride, sodium dithionite, ferrous sulfate, ferric chloride plus ascorbic acid, hypophosphite and / or hydrazine.

[0635] 221. The method according to any one of Examples 216 to 220, wherein the radioactive isotope is 99m Tc.

[0636] 222. The method according to embodiment 221, wherein 99m Tc is provided in the form of pertechnetate.

[0637] 223. The method according to embodiment 221, wherein 99m Tc is provided in the form of pertechnetate, and the reaction is carried out in the presence of stannous ions.

[0638] 224. The method according to any one of Examples 216 to 223, wherein the radioactive isotope is 89 Zr.

[0639] 225. The method according to embodiment 224, wherein 89 Zr with oxalic acid 89 Provided in Zr form.

[0640] 226. The method according to Example 224 or 225, wherein the reaction is carried out in the presence of a base.

[0641] 227. The method according to any one of Examples 203 to 226, which is carried out under aqueous conditions.

[0642] 228. The method according to any one of Examples 203 to 227 further includes recovering the imageable microspheres and / or washing the microspheres to remove unreacted radioisotopes.

[0643] 229. The method according to any one of Examples 203 to 228 further includes resuspending the imageable microspheres in a pharmaceutically acceptable injectable aqueous medium.

[0644] 230. An imageable microsphere, which can be obtained by any one of Examples 203 to 229.

[0645] 231. A method for determining the amount of therapeutic microspheres to be provided to a patient's body, the method comprising:

[0646] Provides imageable microsphere clusters;

[0647] The imageable microspheres are delivered to the patient by introducing them into the first location in the patient's vascular system.

[0648] Allowing the imageable microspheres to distribute within the patient's body;

[0649] By using imaging modalities to image a portion of a patient's body, the distribution of at least a portion of the imageable microsphere population within the patient's body can be determined.

[0650] The distribution of imageable microspheres is used to calculate the dose of therapeutic microspheres to be delivered to the patient.

[0651] 232. The method according to Example 231, wherein the part of the body is the patient's off-target area, and the off-target area is the patient's lungs.

[0652] 233. The method according to Example 231, wherein the part of the body is the patient's target area, and the target area is the patient's liver.

[0653] 234. The method according to any one of Examples 231 to 233, wherein the target area is divided into tumor tissue and non-tumor tissue.

[0654] 235. The method according to any one of Examples 231 to 234, wherein the amount of therapeutic microspheres to be delivered to the patient is calculated.

[0655] 236. The method according to Example 235, wherein the calculated amount is delivered to the patient.

[0656] 237. The method according to any one of Examples 231 to 236, wherein the imaging mode is SPECT.

[0657] 238. The method according to any one of Examples 231 to 236, wherein the detection mode is PET.

[0658] 239. The method according to any one of Examples 231 to 236, wherein the detection mode is gamma camera imaging.

[0659] 240. The method according to any one of Examples 231 to 239, wherein the imageable microsphere is the imageable microsphere according to any one of Examples 145 to 202.

[0660] 241. A method of treating a patient, the method comprising:

[0661] Provides imageable microsphere clusters;

[0662] The imageable microspheres are delivered to the patient by introducing them into the first location in the patient's vascular system.

[0663] Allowing the imageable microspheres to distribute within the patient's body;

[0664] By using imaging modalities to image target portions of the patient's body, the distribution of at least a portion of the imageable microsphere population within the patient's body can be determined.

[0665] The amount of therapeutic microspheres to be delivered to a patient can be calculated by utilizing the distribution of imageable microspheres.

[0666] To obtain data on the distribution of imageable therapeutic microsphere substitutes in patients;

[0667] This data was used to determine the dosage of therapeutic microspheres to be administered to the patient.

[0668] The therapeutic microspheres are delivered to the patient by introducing them into a second location in the patient's vascular system.

[0669] The therapeutic microspheres are allowed to distribute within the patient's body, thereby treating the patient.

[0670] 242. The method according to embodiment 241, wherein the second position in the patient's vascular system is the same as or approximately the same as the first position in the patient's vascular system.

[0671] 243. The method according to embodiment 241 or 242, wherein the imaging mode is SPECT.

[0672] 244. The method according to embodiment 241 or 242, wherein the imaging mode is PET.

[0673] 245. The method according to embodiment 241 or 242, wherein the imaging mode is gamma camera imaging.

[0674] 246. The method according to any one of Examples 241 to 245, wherein the imageable microsphere is the imageable microsphere according to any one of Examples 145 to 202.

[0675] 247. A method for treating a patient using therapeutic microspheres, the method comprising:

[0676] Data were calculated from the distribution of imageable therapeutic microsphere substitutes in patients;

[0677] The data is used to determine the amount of therapeutic microspheres to be administered to the patient.

[0678] The therapeutic microspheres are delivered to the patient by introducing the amount of therapeutic microspheres into a first location in the patient's vascular system;

[0679] Allowing the therapeutic microspheres to distribute within the patient; and

[0680] The therapeutic microspheres are allowed to remain in the patient's body, thereby treating the patient.

[0681] 248. The method according to Example 247 further includes providing the patient with an imageable cluster of microspheres.

[0682] 249. The method according to embodiment 248 further includes delivering the imageable microspheres to the patient by introducing the imageable microspheres into a first location in the vascular system of the patient's body.

[0683] 250. The method according to Example 249 further includes allowing the imageable microspheres to distribute within the patient.

[0684] 251. The method according to Example 250 further includes imaging a target portion of the patient's body using an imaging mode to determine the distribution of at least a portion of the imageable microsphere cluster within the patient's body.

[0685] 252. The method according to Example 251 further includes calculating the amount of therapeutic microspheres to be delivered to the patient's body using the distribution of the imageable microspheres.

[0686] 253. A method for treating a tumor in a patient requiring treatment, the method comprising:

[0687] Introduce imageable microsphere clusters to the patient;

[0688] Allow the imageable microspheres to distribute within the patient for a period of time;

[0689] The distribution of imageable microspheres at specific sites within a patient was determined by imaging microspheres using imaging modalities.

[0690] Based on the distribution of imageable microspheres, determine the estimated effective dose at the site when the imageable microspheres are replaced by therapeutic microspheres; and

[0691] Based on the estimated effective dose, a certain amount of therapeutic microspheres is administered to the patient.

[0692] 254. The method according to Example 253, wherein the imageable microsphere group comprises any one of Examples 145 to 202.

[0693] 255. The method according to Example 253 or 254, wherein the site is a malignant or benign tumor and / or non-tumor tissue.

[0694] 256. The method according to Example 253 or 254, wherein the site is a malignant tumor.

[0695] 257. The method according to Example 256, wherein the site is a malignant tumor.

[0696] 258. A method for predicting the extent of off-target delivery to the lungs or gastrointestinal tract during treatment in a patient requiring radioisotope cancer therapy, the method comprising:

[0697] Introduce imageable microsphere clusters to the patient;

[0698] Allows imageable microspheres to distribute within the patient's body for a period of time;

[0699] The distribution of imageable microspheres in a patient's lungs was determined by imaging microspheres using imaging modalities.

[0700] Determine the estimated radiation dose to the lungs or gastrointestinal tract of a patient if the imaging microspheres are replaced by radioactive isotope therapeutic microspheres;

[0701] Determine the dose of radioisotope therapeutic microspheres that, due to off-target delivery, would be sufficient to cause clinically relevant pulmonary or gastrointestinal changes; and

[0702] A dose of radioactive isotope therapeutic microspheres is administered to a patient, the dose being lower than that of radioactive isotope therapeutic microspheres that have been determined to cause clinically relevant lung or gastrointestinal changes due to off-target delivery.

[0703] 259. The method according to Example 258, wherein the imageable microsphere comprises any one of Examples 145 to 202.

[0704] 260. A method for reducing lung or gastrointestinal damage during treatment of a patient requiring radioisotope cancer therapy, the method comprising:

[0705] Introduce imageable microsphere clusters to the patient;

[0706] Allows imageable microspheres to distribute within the patient's body for a period of time;

[0707] By using imaging modalities to image imageable microspheres, the distribution of imageable microspheres in the patient's gastrointestinal tract or lungs can be determined.

[0708] Determine the estimated radiation dose to the patient's gastrointestinal tract or lungs if the imaging microspheres are replaced by radioactive isotope therapeutic microspheres;

[0709] Determine the dose of radioactive isotope therapeutic microspheres sufficient to cause gastrointestinal damage; and

[0710] A dose of radioactive isotope therapeutic microspheres is administered to the patient, the dose being lower than that of radioactive isotope therapeutic microspheres determined to be sufficient to cause gastrointestinal damage.

[0711] 261. The method according to Example 260, wherein the imageable microsphere comprises any one of Examples 145 to 202.

[0712] 262. A reagent kit comprising:

[0713] Microspheres, comprising:

[0714] A matrix comprising inorganic materials, said inorganic materials comprising quasi-metallic or metallic atoms bonded to nonmetallic atoms, said matrix comprising:

[0715] A core extending to the surface, the core comprising a first portion of quasi-metallic or metallic atoms bonded to nonmetallic atoms, and the surface comprising a second portion of quasi-metallic or metallic atoms bonded to nonmetallic atoms; and

[0716] The specification is for causing an imageable radioactive isotope to react with a matrix, thereby causing the imageable radioactive isotope to directly bind to the matrix through at least a portion of the non-metallic atoms on the matrix surface.

[0717] 263. A reagent kit comprising:

[0718] Microspheres, comprising:

[0719] Inorganic matrix; wherein the inorganic matrix comprises at least one nonmetallic, quasi-metallic, or transition metal oxide; and

[0720] The instruction manual is for binding an imageable radioisotope to an inorganic matrix surface via Lewis acid-base coordination bonds.

[0721] 264. A kit comprising microspheres having a ceramic microsphere matrix and instructions for carrying out a reaction in which an imageable radioisotope is coupled to the ceramic microsphere matrix as a Lewis acid-base adduct.

[0722] 265. The kit according to any one of Examples 262 to 264, wherein the sealed unit contains 10 μl to 2 ml of microspheres based on the fill volume.

[0723] 266. The kit according to Example 110, wherein the microspheres are provided in a vial or syringe.

[0724] 267. The kit according to any one of Examples 262 to 266, wherein the imageable radioisotope is selected from... 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 Cr18 F, Al 18 F.

[0725] 268. The kit according to any one of Examples 262 to 267, further comprising a reducing agent.

[0726] 269. The kit according to Example 268, wherein the reducing agent is selected from one or more of the following: stannous salt, stannous hydrate, concentrated HCl, sodium borohydride, sodium dithionite, ferrous sulfate, ferric chloride plus ascorbic acid, hypophosphite and / or hydrazine.

[0727] 270. The kit according to Example 268 or 269, wherein the reducing agent is a stannous salt and the radioactive isotope is 99m Tc, and the radioactive isotope is in the form of pertechnetate.

[0728] 271. The kit according to any one of Examples 262 to 267, wherein the radioactive isotope is 89 Zr.

[0729] 272. The kit according to Example 271, wherein the radioactive isotope is 89 Zr exists in the form of zirconium oxalate or zirconium chloride.

[0730] 273. The kit according to any one of Examples 262 to 272 further comprises therapeutic microspheres.

[0731] 274. The kit according to Example 273, wherein the therapeutic microspheres comprise a therapeutic radioisotope.

[0732] 275. The kit according to Example 274, wherein the therapeutic microspheres comprise 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 B and / or 212 Pb.

[0733] 276. The kit according to any one of Examples 273 to 275, wherein the therapeutic microspheres have the same chemical composition as the imaging microspheres.

[0734] 277. The kit according to any one of Examples 273 to 276, wherein the therapeutic microspheres comprise yttrium aluminum silicon oxide.

[0735] 278. The kit according to any one of Examples 262 to 277 further comprises 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.

[0736] Example

[0737] The following examples illustrate some embodiments disclosed herein and are not intended to be limiting. It will be readily understood by those skilled in the art that this disclosure is well-suited for carrying out the objectives and obtaining the mentioned purposes and advantages, as well as those objectives, purposes, and advantages naturally derived from the embodiments disclosed herein. Various variations and uses will occur to those skilled in the art as defined by the characteristic attributes of this disclosure, as defined by the scope of the claims.

[0738] Example 1 : Preparation of zirconium-89 coupled yttrium aluminum silicate (YAS) microspheres

[0739] Yttrium aluminum silicon oxide (YAS) glass beads ( Biocompatibles UK Ltd provides it in the form of non-radioactive spheres that have not been exposed to neutron bombardment; therefore, Y₂O₃ is naturally occurring. 89 The sample (Y form) was placed into a 4 mL glass vial and suspended in 300 μL of deionized water. Next, 2 μL of a 1 M oxalic acid aliquot of zirconium-89 (3D Imaging, Little Rock, Alaska) (approximately 100 microcuries (μCi)) was added to the reactor vial, followed by 2 μL of 2 M sodium carbonate, and then... - Coated magnetic stir bar. The reaction mixture was stirred and heated on an aluminum heating block at 120°C for 2 hours, then removed from the heating block and cooled to room temperature. The microspheres were suspended in 3.0 mL of deionized water and collected through a 0.22 μm syringe filter for labeling analysis. The glass vial was rinsed with 4 mL of deionized water, and then the deionized water was passed through a syringe filter. The syringe filter (containing labeled microspheres), glass vial, and deionized water filtrate were analyzed by a gamma well counter, and the results are summarized in Table 1 below.

[0740] Table 1.

[0741]

[0742] *The reaction flask did not contain a Teflon-coated magnetic stir bar.

[0743] Example 2: 99m Preparation of Tc-labelled yttrium-aluminium-silicate microspheres

[0744] Add 1 mg of stannous chloride (II) dihydrate to a 1-drench vial and dissolve it in 400 μL of deionized water. In a separate 1-drench vial, add yttrium aluminum silicate glass beads (…). 89 Y, non-radioactive TheraSphere-TS), then add 100 μL of [ 99m [Tc] Sodium pertechnetate (>30 mCi / mL). Add stannous chloride (II) dihydrate solution to the TheraSphere vial, mix briefly (approximately 3 seconds), cap the vial, and allow it to react at room temperature for 60 minutes. Suspend the microspheres in 3.0 mL of deionized water and collect them through a 0.22 μm syringe filter for labeling analysis. Rinse the glass vial with 4 mL of deionized water, then pass the deionized water through a syringe filter. Analyze the syringe filter (containing labeled microspheres), glass vial, and deionized water filtrate using a gamma well counter. The results are summarized in the table below.

[0745] Table 2.

[0746]

[0747] All radiochemical yield (RCY) data are reported as the average of n=3 runs.

[0748] *The reaction flask did not contain a Teflon-coated magnetic stir bar.

[0749] Example 3: Attack with DFO chelate 89 Zr] microspheres ligand

[0750] YAS microspheres (e.g., Therasphere) (suspended in 200 μL sterile saline, pH 7–8) were mixed with progressively increasing concentrations of deferroamine (DFO) from 0.05 mM to 5 mM and incubated with stirring at 37 °C. At each time point, 5 μL of the solution was transferred to a 0.45 μm rotary filter and diluted with 100 μL of deionized water. The rotary filter was centrifuged at 13,200 x G for 60 seconds, and 100 μL of deionized water was added back to the rotary filter, and the centrifugation was repeated. The rotary filter was removed from the microcentrifuge tube, and the supernatant was analyzed by gamma spectroscopy and then counted in a gamma counter to detect possible... 89 Zr-DFO formation. Negligible levels were detected within 48 hours. 89 Zr-TS 89 Zr detachment indicates 89 Zr and TS have a strong binding affinity. The results are as follows... FIG. 2 As shown.

[0751] Example 4: Testing specificity of tin (II) chloride as reducing agent

[0752] Having understood the specificity of the reaction between tin(II) chloride and TheraSphere, several oxidizing and reducing agents were tested. Tin was not only expected to actively reduce Tc(VII) to Tc(V), but also appeared to actively participate in… 99m The integration of Tc with TheraSphere. Several methods were explored to facilitate TheraSphere / 99m Reducing agents coupled with Tc: FeCl2 / ascorbic acid (pH=2); sodium borohydride; and zinc metal. No reducing agent was produced. 99m The Tc-TheraSphere had a large radiochemical yield, so it was not considered further. This indicates that tin in... 99m Tc plays a role in the combination of Tc and TheraSphere.

[0753] Example 5: Effect of reaction volume on 99M yield of Tc conjugated microspheres

[0754] Add 1 mg of stannous chloride (II) dihydrate to a 1-drench vial and dissolve it in the deionized water shown in Table 3. In a separate 1-drench vial, add 10 mg of yttrium aluminum silicate glass beads (TheraSphere), followed by 100 μL of […]. 99m [Tc] Sodium pertechnetate (>30 mCi / mL). Add stannous chloride (II) dihydrate solution to the TheraSphere vial, mix briefly (approximately 3 seconds), cap the vial, and allow it to react at room temperature for 60 minutes. Suspend the microspheres in 3.0 mL of deionized water and collect them through a 0.22 μm syringe filter for labeling analysis. Rinse the glass vial with 4 mL of deionized water, then pass the deionized water through a syringe filter. Analyze the syringe filter (containing labeled microspheres), glass vial, and deionized water filtrate using a gamma well counter. The results are summarized in the table below.

[0755] Table 3.

[0756] Reaction volume (μL) Filter (microspheres) Residual in reaction vial Deionized water filtrate Radiochemical yield 100 0.44 mCi 0.01 mCi 0.003 mCi 95％ 200 0.055 mCi 0.015 mCi 0.01 mCi 75％ 500 0.033 mCi 0.022 mCi 0.026 mCi 41％

[0757] Example 6: Coupling with alternative ceramic microparticles

[0758] Examples 1 and 2 were repeated using silica and aluminosilicate microspheres. The aluminosilicate microspheres were purchased from SteagEnergo Mineral. The silica microspheres were purchased from EPRUI Biotech Co. Limited (product #: EPRUI-SI-20), which consisted of SiO2 and were monodisperse microspheres with a diameter of 20 μm.

[0759] Table 4.

[0760]

[0761] Table 5.

[0762]

[0763] Table 6.

[0764]

[0765] Table 7.

[0766]

[0767] Example 7: Testing interdependence of tin on 99mTc and TheraSphere for product formation

[0768] Several reactions were carried out under the conditions shown below.

[0769] Under typical reaction conditions, 10 mg TheraSphere, 0.5-1.0 mg SnCl2, and 3 mCi are used. 99m Tc and 400 μL of deionized water.

[0770] Under normal reaction conditions, using 10 mg TheraSphere and 3 mCi 99m Tc and 400 μL of deionized water. No SnCl2.

[0771] Under normal reaction conditions, using 25 mg TheraSphere and 3 mCi 99m Tc and 400 μL of deionized water. No SnCl2.

[0772] Under normal reaction conditions, use 0.5-1.0 mg SnCl2 and 3 mCi 99m Tc and 400 μL of deionized water. No TheraSphere.

[0773] Table 8.

[0774] Reaction Filter (microspheres) Residual in reaction vial Deionized water filtrate Radiochemical yield 1 2.1 mCi 0.35 mCi 0.23 mCi 80％ 2 0.1 mCi 0 mCi 2.3 mCi <1％ 3 0.1 mCi 0.03 mCi 2.3 mCi <1％ 4 1.2 mCi 0.2 mCi 1.1 mCi 48％

[0775] As shown in reaction 4, tin and 99m There are correlations between certain oxidation states of Tc. However, under the test conditions, in the absence of TheraSphere, the product degraded in solution for over 120 minutes, as was evident in reaction 1. Furthermore, when... 99m When Tc is mixed with TheraSphere alone in the absence of tin, no reaction occurs. This combination of three reagents produces a stable product, as demonstrated in our in vitro stability analysis below.

[0776] Example 8: 99M Tc and 89 Solution stability analysis of Zr-coupled yttrium-aluminum-silicate oxide spheres.

[0777] Preparation of sample solution

[0778] Prepare three separate solutions as follows: 1) #1 vial: Add 10 mL of PBS and 3-5 mL of Ci 99m Tc-TheraSphere or 100-150μCi 89 1) Mix Zr-TheraSphere thoroughly; 2) #2 vial: Add 10mL goat serum and 4±1mCi 99m Tc-TheraSphere (suspended in 100 μL PBS for easy transfer) or 125 ± 25 μCi 89 Zr-TheraSphere is mixed thoroughly; 3) #3 vial: Add 10 mL of goat serum (other serums can be used, such as horse, goat, or other mammal serums), 4 ± 1 mCi 99m Tc-TheraSphere (suspended in 100 μL PBS for easy transfer) or 125 ± 25 μCi 89 Zr-TheraSphere, 100 μL 0.1M HCl (check that the pH is below 4; if not, add more 0.1M HCl until <4. It is acceptable to over-adjust the pH to between 1 and 3, just be mindful of the final pH), mix thoroughly. Incubate each vial at 37°C for 8 hours. From each vial: remove 100 μL, centrifuge, and aliquot 10 μL of the supernatant into a single vial or microcentrifuge tube for activity assay. To determine any effect of time, sample at selected time points.

[0779] Preparation of standard samples for gamma counters

[0780] Add 4±1mCi to a 100mL volumetric flask 99m Tc-TheraSphere (suspended in 100 μL PBS for easy transfer) or 125 ± 25 μCi 89 Zr-TheraSphere. Dilute the solution to 100 mL with deionized water and mix. Take 5 x 1 mL aliquots from the volumetric flask and add them to 5 separate vials. Stability data are as follows. FIG. 3A and 3B As shown.

[0781] For comparison 99m Tc- and 89 Regarding the industry-standard in vitro stability of Zr-TheraSphere, we use... 99m The same serum analysis was performed on Tc-MAA. Three separate solutions were prepared as follows: 1) #1 vial (buffer solution): 10 mL PBS, 4 ± 1 mCi 99mTc-MAA, mix well; 2) #2 vial (serum): 10mL goat serum, 4±1mCi 99m Tc-MAA, mix well; 3) #3 vial (serum and acid): 10mL goat serum; 4±1mCi 99m Tc-MAA; 100 μL 0.1 M HCl (check that the pH is below 4; if not, add more 0.1 M HCl until <4. Adjusting the pH to between 1 and 3 is acceptable; just be mindful of the final pH). Mix thoroughly. Incubate each vial at 37°C for 8 hours. From each vial: remove 100 μL, centrifuge, and aliquot 10 μL of the supernatant into a single-pass vial or microcentrifuge tube for activity assay. To determine any effect of time, samples were taken at selected time points. Results are shown in Figure 4.

[0782] The relative stability of all imaging substitutes is summarized in the table below.

[0783] Table 9.

[0784]

[0785] Table 10.

[0786]

[0787] Example 9: Buffer solution and pH study

[0788] Add 0.5–1.0 mg SnCl2 to a vial. Add 500 μL of buffer solution to the vial. Filter the solution into a clean 1-dozen-blue vial. In a separate 1-dozen-blue vial (reaction flask), add 10 mg of YAS microspheres and 20 μL of Tc-99m stock solution. Add 380 μL of SnCl2 solution to the reaction flask, bringing the total reaction volume to 400 μL. Cap the reaction flask and mix by hand for 3–5 seconds, then react without stirring at room temperature for 1 hour. Then mix the vials and aspirate the reaction mixture into a syringe with an 18 G x 1.5” needle. The labeled YAS microspheres are trapped on a 0.2 μm syringe filter. Rinse the reaction flask with 400 μL of DI H2O and trap the mixture on the syringe filter.

[0789] Vial labels and list of buffer solutions:

[0790] 1. Salt water (pH 5)

[0791] 2. PBS (pH 7.4)

[0792] 3. Acetate saline buffer solution (pH 5)

[0793] 4. Citrate buffer solution (pH 3)

[0794] 5. Citrate buffer solution (pH 4)

[0795] 6. Citrate buffer solution (pH 5)

[0796] Analysis: The initial activity in reaction flask (I), waste bottle (W), syringe filter (SF), and reaction flask (V) was calculated, and the background value (BKG) was recorded. Table 11 provides the results.

[0797] Table 11.

[0798] Vial I W SF 1 2.70 mCi @ 1317 42 uCi @ 1327 2.27 mCi @ 1327 2a 2.63 mCi @ 1328 118.6 uCi @ 1331 2.51 mCi @ 1330 2b 1.96 mCi @ 1556 1.06 mCi @ 1558 726 uCi @ 1558 2c 1.95 mCi @ 1600 870 uCi @ 1602 885 uCi @ 1603 3 2.60 mCi @ 1333 4 uCi @ 1336 2 mCi @ 1336 4 2.57 mCi @ 1337 2.17 mCi @ 1341 230 uCi @ 1341 5 2.58 mCi @ 1343 2.29 mCi @ 1346 263 uCi @ 1346 6 2.53 mCi @ 1348 2.30 mCi @ 1350 206 uCi @ 1350

[0799] Table 11, continued

[0800] Vial V BKG 1 420 uCi @ 1327 3 uCi @ 1328 2a 124 uCi @ 1332 3 uCi @ 1332 2b 174 uCi @ 1559 3.8 uCi @ 1559 2c 197 uCi @ 1602 2.6 uCi @ 1603 3 642 uCi @ 1336 3 uCi @ 1337 4 10 uCi @ 1341 3 uCi @ 1342 5 12 uCi @ 1346 3 uCi @ 1347 6 37 uCi @ 1350 2.5 uCi @ 1351

[0801] like FIG. 4B As shown, the buffer solution may negatively impact the production of [99mTc]YAS microspheres. Optimal radiochemical yields were achieved using brine as the reaction solvent. Any attempt to use an analyte buffer solution or to change the pH resulted in a decrease in yield.

[0802] Example 10: Predictive Al 18 F embodiment

[0803] Fluoride ions bind to most metals, but form particularly strong bonds with aluminum(III), which has historically been shown to form complexes with metal-bonded chelates; forming highly stable (670 kJ / mol) Al-F bonds. Aluminum forms octahedral complexes; therefore, pentadentate coordination is preferred to form stable 18F substitutes both in vitro and in vivo. [18F]fluoride is readily available in aqueous solution; therefore, for practical use in a hospital setting, the reagents and reaction conditions should be compatible with aqueous reaction conditions. YAS glass (10 mg) and [18F]fluoride (provided in aqueous solution) are mixed with aluminum trichloride hydrate (monohydrate, hexahydrate, or other hydrated species to indicate compatibility with aqueous solution) in pH 4 acetate buffer and a suitable chelating agent (NOTA, NODA, trimethyltriazolidine, or other chelating agent substances to support octahedral aluminum-fluoride complexes). The solution was heated at 100°C for 15-30 minutes. During this time, the [18F]Al-YAS material was removed from the heat source and purified for use.

[0804] Example 11 : In vivo animal study

[0805] Radioembolization involves the intravascular delivery of particles with embedded radiogenerating material through the arterial vascular system to treat malignant tumors. Currently, FDA-approved radioembolization methods focus on treating primary or metastatic liver cancer, but other organ systems may also be therapeutic targets. Safe and effective treatment delivery requires generating a dose tailored to the treatment target area. Various dose calculation methods exist, which may include variables such as the target liver volume (in some cases, the liver tumor volume). No approved method currently considers patient-specific vascular flow preferentially to the tumor or the number of radioembolization particles required to completely cover the tumor. Addressing these last two variables may be best achieved through radioembolization dose calculation alternatives that are initially administered in a manner as close as possible to the actual therapeutic radioembolization device in terms of size distribution, geometry, and specific gravity. Boston Scientific manufactures radioembolization devices consisting of particles with embedded radiogenerating material... 89 Y is composed of glass microspheres. 89 Y can be converted to 90 Y, the latter being a primary β-emitting particle. An alternative to optimal dose calculation would involve labeling the surface of glass microspheres with a radioisotope, which can be visualized by positron emission tomography (PET) or single-photon emission computed tomography (SPECT). This particle can be administered intravascularly during the initial planning procedure of the therapy and subsequently visualized by a PET or SPECT scanner to determine the optimal dose parameters for subsequent administration of the therapy.

[0806] A series of proof-of-concept experiments were conducted at the University of Virginia to explore... 89 Distribution of Zr-labeled iSpheres (YAS microspheres; prepared as in Example 1) after targeted delivery of the reagent via catheter. The current protocol was used in a marmot hepatocellular carcinoma model. 89 Zr-labeled microspheres were used to explore: (i) distribution, (ii) in vivo stability, and (iii) visualization of microspheres administered via the hepatic artery in a catheter-directed manner. Specific procedures included: (i) magnetic resonance imaging (MRI) of the abdomen and pelvis at multiple stages of intravascular angiography. FIG. 5A and 6A (ii) Angiography of microcatheters located within the hepatic artery ( FIG. 6B (iii) the detection dose (1.3 mg) and the full dose (13 mg). 89 Positron emission tomography (PET-CT) of Zr-labeled microspheres FIG. 5B (iv) Fusion of PET-CT and MRI image datasets with quantitative analysis of tumor and normal liver uptake (Figures 7A and 7B).

[0807] In short, marmots infected with WHV (marmot hepatitis virus) were identified by the supplier, Northeastern Wildlife (Harrison, Idaho), using an immunoassay. Blood samples were collected every 3-4 months by the supplier to assess WHV DNA levels to verify whether the animals were still virus carriers. Serum gamma-glutamyl transferase (GGT), a serum marker for the presence of hepatocellular tumors, was also determined. Animals with GGT levels greater than 50 IU / dL were provided by the supplier. The marmots were evaluated using ultrasound to look for liver tumors and to assess their size and location. Each animal underwent an ultrasound US session before being transported to UVA to confirm the presence of tumors.

[0808] Prior to embolization, the marmots were brought to a preparation area and anesthetized by a veterinarian. Ketamine (25-50 mg / kg) and toluidine (1-5 mg / kg) were administered intramuscularly. Atropine [0.04 mg / kg] was administered before intubation. The animals were intubated and kept on an oxygen ventilator with 1.5-2.5% isoflurane. The animals were placed on a heating pad to maintain body temperature. Angiography was performed ( FIG. 6B Previously, the animals underwent MRI scans on a Siemens 3 Tesla Prisma scanner (Erlangen, Germany). FIG. 5A and 6A For MRI procedures, use 1 mg / kg of pharmaceutical-grade Magnevist.

[0809] After the MRI is completed (e.g.) FIG. 5A and 6A (As shown), immediately take the animal to the angiography room. Using a 4F micro-puncture kit (Cook Medical, Bloomington, Indiana), obtain an access to the right common femoral artery using ultrasound. Place a 4F Glidesheath Slender Sheath (Terumo Medical, Somerset County, NJ) and introduce a 4F tilting tip catheter (Cook Medical, Bloomington, Indiana) into the abdominal aorta via a guide wire. Perform digital subtraction angiography (e.g., using approximately 10cc of Omnipaque 350 contrast agent (GE Healthcare, Chicago, Illinois)). FIG. 6B(As shown in the image) to depict the origin of the celiac artery. Next, the Headway Duo microcatheter (Microvention, Aristotle, California) is advanced into the hepatic artery system, followed by an injection of 3–5 cc of Omnipaque 350 contrast agent to depict the tumor supply visualized on previous ultrasound and MRI. The microcatheter is then positioned in the appropriate hepatic artery, left hepatic artery, or right hepatic artery for subsequent injections. 89 iSpheres marked with Zr (using 89 Zr-labeled YAS microspheres). After establishing an entrance to the intended delivery site, the catheter is secured in place, and the animal is transferred to the PET / CT area under anesthesia.

[0810] PET / CT imaging was initiated within 5 minutes of iSphere infusion, and the same imaging protocol was followed for each animal. Results were as follows: FIG. 5B As shown. Two separate injections were performed within the PET / CT area. Injections were performed using a custom-designed injection device (Boston Scientific, Marlborough, Massachusetts) that allows for controlled delivery of iSpheres. The first injection was a "reconnaissance dose" of up to 1.3 mg of microspheres. The results are shown in Figure 7A. The second injection was a dose up to 13 mg of particles, designed to simulate the number of particles required for the treatment procedure. FIG. 5B (and 7B). Similar to human imaging procedures, the second dose is not expected to cause significant embolism. PET / CT imaging will be performed 90 minutes after each injection. FIG. 5B Note that lung absorption is negligible, while there is a significant difference in absorption between tumor-bearing and normal liver tissue (indicating that the patient is a candidate for SIRT).

[0811] A dedicated PET scanner, interfaced with multimodal CT, was used for preclinical imaging studies. Dynamic and static scans were acquired starting one hour post-injection. Animals were kept anesthetized using 1-5% isoflurane. CT images were acquired for photon attenuation correction and image registration with PET imaging data. Reconstruction algorithms for PET and CT were provided by the scanner manufacturer. CT acquisition parameters were 120 rotational steps within 220°, continuous acquisition, 80kVp tube voltage, 500μA tube current, and 175ms exposure. Image display and analysis were performed using the software packages MiM (Cleveland, Ohio) and Simple90Y (Mirada Medical, Denver, Colorado, USA) (Figures 7A and 7B). Target areas (VOIs) were plotted on registered MRI images of tumors and other target organs. The VOIs were adjusted to include apparent partial volume overflows used for organ uptake calculations.

[0812] This study notes that A) 89Zr-Spheres were successfully delivered to the liver via catheter-directed delivery; B) absorption was successfully visualized using PET-CT; C) as previously suggested by contrast-enhanced cross-sections and angiography, absorption followed different patterns of flow distribution within the liver.

[0813] Example 12: Predictive animal study

[0814] Animals carrying liver tumors are used as models to study diagnostic and treatment methods for managing this condition. One example is the marmot developing liver tumors due to chronic infection with marmot hepatocellular carcinoma virus. After catheterization of the appropriate hepatic artery in the marmot carrying the liver tumor using a microcatheter, imageable radioisotope microspheres are administered. These microspheres are distributed and remain within the small arteries of the liver in a flow-guided manner. The imageable radioisotope microspheres are visualized via PET or SPECT and used as... 90 A replacement for the Y-Therasphere, thus allowing direct access to... 90 The expected distribution of the Y-Therasphere within the liver is mapped. This mapping informs the choice of dose that will maximize [the effect of the Y-Therasphere]. 90 Y-Therasphere delivers a lethal dose to liver tumor cells while minimizing damage to normal liver cells.

[0815] Example 13: Predicting dose of therapeutic particles using surrogates

[0816] Based on the inventor's experience, the following predictions were made using a controlled study program.

[0817] A group of 30 patients with liver cancer were selected for SIRT treatment with TheraSphere. Prior to treatment, patients were given a certain dose of... 99m Tc-functionalized yttrium aluminum silicon oxide microspheres (such as the imageable radioisotope microspheres disclosed herein) as... 90 Y TheraSphere alternative.

[0818] The average diameter of the imageable microspheres is 20-30 μm. The prescribed dose of imageable microspheres was dispersed in 0.6 mL of pyrogen-free water, and the dosage was calculated to be approximately 150 MBq. The imageable microspheres were injected into the hepatic artery and allowed to distribute for 15 minutes. During this time, the patient's liver, lungs, and gastrointestinal tract were imaged using SPECT. From this imaging, the number of microspheres reaching each of the liver, lungs, and gastrointestinal tract was determined. Due to the risk of pulmonary shunt, patients were classified as either treated with TheraSphere or not. Seven patients were excluded from treatment. For 23 patients as treatment candidates, a dose of TheraSphere to deliver 300 Gy to the tumor while maintaining a dose of <60 Gy to normal tissues was administered, based on the ratio of imageable microspheres delivered to tumor and normal tissue. For patients as treatment candidates, a dose of 300 Gy of TheraSphere to deliver to the liver was calculated based on the ratio of imageable microspheres delivered to the liver. Typically, the target dose of TheraSphere can be between 80 Gy and 300 Gy. Then, based on the distribution of the imageable radioisotope microspheres, a dose of TheraSphere up to 300 Gy was calculated for the treatment candidates. No patients experienced a significant distribution of pulmonary shunts or gastrointestinal damage.

[0819] For the second group of 30 patients, Tc-99m MAA was administered intrahepaticly to determine the extent of pulmonary AV shunt and to confirm the absence of gastric and duodenal flow. Imaging of the liver, lungs, and gastrointestinal tract was performed at this time. The number of microspheres reaching each of the liver, lungs, and gastrointestinal tract was determined from the imaging. Patients were categorized as receiving or not receiving TheraSphere treatment due to the risk of pulmonary shunt. Twelve patients were excluded from treatment. Treatment candidates were then given a calculated dose of TheraSphere up to 300 Gy. Four patients experienced pulmonary shunt, and three patients had a significant distribution of gastrointestinal damage. Based on post-treatment evaluation, two patients were found to have received insufficient treatment.

[0820] Based on the Tc-99m MAA results, 12 patients excluded from the treatment pool were administered imageable radioisotope microspheres as disclosed in Group 1. Of these patients, 8 were identified as actual candidates for TheraSphere treatment. TheraSphere doses up to 300 Gy were then administered to these candidates based on the distribution of the imageable radioisotope microspheres. No patients experienced a significant distribution of pulmonary shunts or gastrointestinal injury.

[0821] For the third group of 30 patients, TheraSphere was administered to the liver at a dose equivalent to 300 Gy. Eight of these patients experienced pulmonary shunts, and six had significant gastrointestinal involvement. Based on post-treatment evaluation, five of these patients received insufficient treatment.

Claims

1. An imageable microsphere comprising: At least one imageable radioactive isotope; and A matrix comprising inorganic materials, said inorganic materials comprising quasi-metallic or metallic atoms bonded to nonmetallic atoms, said matrix comprising: A core extending to the surface, the core comprising a first portion of quasi-metallic or metallic atoms bonded to nonmetallic atoms, and the surface comprising a second portion of quasi-metallic or metallic atoms bonded to nonmetallic atoms; The imageable radioisotope is directly bound to the matrix through non-metallic atoms on the matrix surface and / or the imageable radioisotope is bound to the matrix through an inorganic bridge containing non-metallic atoms on the matrix surface. The at least one imageable radioactive isotope is selected from 99m Tc and / or 89 Zr; and The matrix comprises yttrium aluminum silicon oxide TheraSphere microspheres.

2. The imageable microsphere according to claim 1, wherein... 89 Zr is directly bonded to the matrix through non-metallic atoms on the matrix surface.

3. The imageable microsphere according to claim 1, wherein the imageable radioactive isotope is bonded to the matrix via inorganic bridges through non-metallic atoms on the matrix surface.

4. The imageable microsphere according to claim 1, wherein the non-metallic atom is an oxygen atom.

5. The imageable microsphere of claim 4, wherein at least a portion of the oxygen atoms on the matrix surface are provided in the form of hydroxyl groups.

6. An imageable microsphere comprising: Inorganic matrix with surface; and At least one imageable radioactive isotope; The matrix comprises at least one nonmetal and at least one quasi-metal or metal; The imageable radioactive isotope is bound to the matrix surface via Lewis acid-base coordination bonds with inorganic Lewis bases; The at least one imageable radioactive isotope is selected from 99m Tc and / or 89 Zr; and The matrix comprises yttrium aluminum silicon oxide TheraSphere microspheres.

7. An imageable microsphere comprising: Inorganic matrix with surface; and At least one imageable radioactive isotope; The matrix comprises at least one nonmetal and at least one quasi-metal or metal; The imageable radioactive isotope is bound to the matrix surface through chemical bonds with oxygen in inorganic materials. The at least one imageable radioactive isotope is selected from 99m Tc and / or 89 Zr; and The matrix comprises yttrium aluminum silicon oxide TheraSphere microspheres.

8. An imageable microsphere comprising: An inorganic matrix comprising a surface having one or more electron-donating functional groups; and At least one imageable radioactive isotope; The imageable radioactive isotope is directly bound to the surface and / or bound to the surface via an inorganic bridge during the fabrication of the imageable microspheres by chemical coupling with one or more electron-donating functional groups. The at least one imageable radioactive isotope is selected from 99m Tc and / or 89 Zr; and The matrix comprises yttrium aluminum silicon oxide TheraSphere microspheres.

9. The imageable microsphere according to claim 8, wherein... 89 Zr binds directly to the matrix surface.

10. The imageable microsphere of claim 9, wherein the imageable radioisotope is bound by a coordination bond.

11. An imageable microsphere, comprising: A ceramic microsphere matrix and at least one imageable radioactive isotope; The imageable radioactive isotope is coupled to the surface of the ceramic microsphere matrix as a Lewis acid-base adduct of an inorganic Lewis base. The at least one imageable radioactive isotope is selected from 99m Tc and / or 89 Zr; and The matrix comprises yttrium aluminum silicon oxide TheraSphere microspheres.

12. The imageable microsphere according to claim 11, wherein the inorganic Lewis base is a component of the matrix, and the imageable radioisotope is directly coupled to the matrix surface via the inorganic Lewis base.

13. The imageable microsphere of claim 11, wherein the imageable radioisotope is coupled to the surface of the ceramic microsphere matrix via an inorganic binder comprising a Lewis base.

14. The imageable microsphere according to claim 13, wherein the inorganic binder is a metal oxide.

15. The imageable microsphere of claim 14, wherein the metal oxide is tin oxide.

16. The imageable microsphere of claim 11, wherein the Lewis base is oxygen in a metal oxide or quasi-metal oxide.

17. The imageable microsphere according to any one of claims 6 and 11, wherein the imageable radioactive isotope is 99m Tc, where the Lewis base is the oxygen of tin oxide.

18. The imageable microsphere according to any one of claims 1, 6-8 and 11, wherein the imageable radioisotope is configured for imaging via an imaging mode selected from single-photon imaging and two-photon imaging.

19. The imageable microsphere according to any one of claims 1, 6-8 and 11, wherein the imageable radioisotope is configured for imaging via an imaging mode selected from positron emission tomography, single-photon emission computed tomography and gamma camera imaging.

20. The imageable microsphere according to any one of claims 1, 6-8 and 11, wherein the at least one imageable radioactive isotope is a positron emitter or a gamma emitter.

21. The imageable microsphere according to claim 1, comprising a structure of formula (V): （V） in The matrix contains M c And M c Selected from Al, Si, and Y; m is an integer selected from 1, 2, or 3; M b Selected from 99m Tc and / or 89 Zr; M a It is a matrix atom or a bridging metal atom, and M a Selected from Sn, Al, Si, and Y; Each instance of R either does not exist or is -H; X is selected from –OH, =O, and –O. - ;and n is an integer selected from 0, 1, 2, 3 or 4.

22. The imageable microsphere according to claim 21, wherein: M c It is Al; The matrix contains M a And M a It is Si; M b is 89 Zr; Each X is independently –OH or –O. - ;and n is 1 or 2.

23. The imageable microsphere according to claim 21, wherein M b yes 89 Zr, X is -OH, n is 2.

24. The imageable microsphere according to claim 21, wherein: M c It is Si; M a It is Sn; M b yes 99m Tc; Each X is independently –OH or –O. - ; And n is 2 or 3.

25. The imageable microsphere according to claim 21, wherein M b yes 99m Tc, X is -OH, n is 3.

26. The imageable microsphere according to claim 1, comprising the structure of formula (VIII): (VIII) The matrix contains M a and M c And M a and M c Independently selected from Al, Si, and Y; m is an integer selected from 1, 2, or 3; M b Selected from 99m Tc and / or 89 Zr; R a Each instance is independently OH, O, or –O-Sn(X). n -O-; X is selected from –OH, =O, and –O. - ;and n is an integer selected from 0, 1, 2, 3 or 4.

27. The imageable microsphere according to claim 26, wherein M c It is Al; M a It is Si; M b yes 99m Tc; each X is independently –OH or =O; n is 2 or 3.

28. The imageable microsphere of claim 26, wherein M b yes 99m Tc;R a At least one instance is -O-Sn(X). n -O-, each X is independently –OH or =O; n is 2 or 3.

29. The imageable microsphere according to claim 26, wherein M b yes 99m Tc;R a One example is -O-Sn-O-;R a An example is -O- or -OH-; each X is independently –OH or =O; n is 2 or 3.

30. The imageable microsphere according to any one of claims 1 to 29, wherein it is prepared by a method comprising the following steps: Provide the matrix; The at least one imageable radioactive isotope is chemically coupled to the matrix to provide imageable microspheres.

31. The imageable microsphere according to any one of claims 1 to 29, wherein it is prepared by a method comprising the following steps: A matrix is ​​provided, the matrix comprising: Inorganic materials, wherein the inorganic materials contain metal or quasi-metal atoms bonded to non-metallic atoms; The core comprises a first portion of non-metallic atoms; and Surface, the surface comprising a second portion of nonmetallic atoms; Provide at least one imageable radioactive isotope; and Imageable microspheres are provided by chemically coupling the at least one imageable radioactive isotope to the surface of the matrix via the second portion of non-metallic atoms.

32. The imageable microsphere of claim 30, further comprising providing at least one imageable radioisotope as a salt prior to chemically coupling the at least one imageable radioisotope to the surface of the inorganic matrix.

33. A method for preparing imageable microspheres according to any one of claims 1 to 32, comprising providing a ceramic microsphere matrix and reacting the ceramic microsphere matrix with an imageable radioisotope under conditions suitable for coupling the radioisotope to the surface of the ceramic microsphere.

34. The method of claim 33, wherein the radioactive isotope is coupled to the surface of the ceramic microspheres in the form of a Lewis acid-base adduct.

35. The method according to claim 33 or 34, wherein the radioactive isotope is selected from... 99m Tc and / or 89 Zr; The reaction is carried out in the presence of a reducing agent selected from one or more of the following: stannous salts, stannous hydrates, HCl, sodium borohydride, sodium dithionite, ferrous sulfate, ferric chloride plus ascorbic acid, hypophosphorous acid, and / or hydrazine.

36. An imageable microsphere, which can be obtained by the method of any one of claims 33 to 35.

37. Use of imageable microspheres in the preparation of a product for determining the amount of therapeutic microspheres to be administered to a patient, wherein the step of determining the amount of therapeutic microspheres to be administered to the patient includes: Provide an imageable microsphere cluster according to any one of claims 1 to 32; The imageable microspheres are delivered to the patient by introducing them into the first location in the patient's vascular system. Allowing the imageable microspheres to distribute within the patient's body; By using imaging modalities to image a portion of a patient's body, the distribution of at least a portion of the imageable microsphere population within the patient's body can be determined. The amount of therapeutic microspheres to be delivered to a patient can be calculated by using the distribution of imageable microspheres.

38. The use according to claim 37, wherein the part of the body is the patient's off-target area, and the off-target area is the patient's lungs.

39. The use according to claim 37, wherein the part of the body is the patient's target area, and the target area is the patient's liver.

40. The use according to claim 39, wherein the target area is divided into tumor tissue and non-tumor tissue.

41. The use according to claim 37, wherein the amount of therapeutic microspheres to be delivered to the patient is calculated.

42. The use according to claim 41, wherein the calculated amount is delivered to the patient.

43. The use according to any one of claims 37 to 42, wherein the imaging mode is SPECT.

44. The use according to any one of claims 37 to 42, wherein the imaging mode is PET.

45. The use according to any one of claims 37 to 42, wherein the imaging mode is gamma camera imaging.

46. ​​Use of imageable microspheres and therapeutic microspheres in the preparation of products for treating patients, wherein the steps for treating patients include: Provide an imageable microsphere cluster according to any one of claims 1 to 32; The imageable microspheres are delivered to the patient by introducing them into the first location in the patient's vascular system. Allowing the imageable microspheres to distribute within the patient's body; By using imaging modalities to image target portions of the patient's body, the distribution of at least a portion of the imageable microsphere population within the patient's body can be determined. and The amount of therapeutic microspheres to be delivered to a patient can be calculated by utilizing the distribution of imageable microspheres. To obtain data on the distribution of imageable therapeutic microsphere substitutes in patients; This data was used to determine the dosage of therapeutic microspheres to be administered to the patient. The therapeutic microspheres are delivered to the patient by introducing them into a second location in the patient's vascular system. The therapeutic microspheres are allowed to distribute within the patient's body, thereby treating the patient.

47. The use according to claim 46, wherein the second location in the patient's vascular system is the same as or approximately the same as the first location in the patient's vascular system.

48. The use according to claim 46 or 47, wherein the imaging mode is SPECT.

49. The use according to claim 46 or 47, wherein the imaging mode is PET.

50. The use according to claim 46 or 47, wherein the imaging mode is gamma camera imaging.

51. Use of imageable therapeutic microsphere substitutes and therapeutic microspheres in the preparation of products for treating patients, wherein the steps for treating patients include: Data were calculated from the distribution of imageable therapeutic microsphere substitutes in patients; The data is used to determine the amount of therapeutic microspheres to be administered to the patient. The therapeutic microspheres are delivered to the patient by introducing the amount of therapeutic microspheres into a first location in the patient's vascular system; Allowing the therapeutic microspheres to distribute within the patient's body; and The therapeutic microspheres are allowed to remain in the patient's body, thereby treating the patient; The imageable therapeutic microsphere alternatives described herein include imageable microspheres according to any one of claims 1 to 32.

52. The use according to claim 51 further includes providing the patient with an imageable cluster of microspheres.

53. The use according to claim 52 further includes delivering the imageable microspheres to a patient by introducing the imageable microspheres into a first location in the vascular system of the patient's body.

54. The use according to claim 53 further includes allowing the imageable microsphere cluster to distribute within the patient.

55. The use according to claim 54 further includes determining the distribution of at least a portion of the imageable microsphere cluster within the patient body by imaging a target portion of the patient body using an imaging mode.

56. The use according to claim 55 further includes calculating the amount of therapeutic microspheres to be delivered to a patient using the distribution of the imageable microspheres.

57. Use of imageable microspheres in the preparation of products for treating tumors in patients requiring treatment, wherein the steps of treating the tumor include: Introduce an imageable microsphere cluster according to any one of claims 1 to 32 into the patient; Allows imageable microspheres to distribute within the patient's body for a period of time; The distribution of imageable microspheres at specific sites within a patient was determined by imaging microspheres using imaging modalities. Based on the distribution of the imageable microspheres, determine the estimated effective dose at the site when the imageable microspheres are replaced by therapeutic microspheres; and administer a certain amount of therapeutic microspheres to the patient based on the estimated effective dose.

58. The use according to claim 57, wherein the site is a malignant or benign tumor and / or non-tumor tissue.

59. The use according to claim 57, wherein the site is a malignant tumor.

60. The use according to claim 59, wherein the site is a malignant liver tumor.

61. Use of imageable microspheres in the preparation of a product for predicting the extent of off-target delivery to the lungs or gastrointestinal tract during treatment in patients requiring radioisotope cancer therapy, wherein the step of using imageable microspheres to predict the extent of off-target delivery to the lungs or gastrointestinal tract during treatment in patients requiring radioisotope cancer therapy includes: Introduce an imageable microsphere cluster according to any one of claims 1 to 32 into the patient; Allows imageable microspheres to distribute within the patient's body for a period of time; The distribution of imageable microspheres in a patient's lungs was determined by imaging microspheres using imaging modalities. Determine the estimated radiation dose to the lungs or gastrointestinal tract of a patient if the imaging microspheres are replaced by radioactive isotope therapeutic microspheres; Determine the dose of radioactive isotope therapeutic microspheres that, due to off-target delivery, are sufficient to cause clinically relevant pulmonary or gastrointestinal changes; and A dose of radioactive isotope therapeutic microspheres is administered to a patient, the dose being lower than that of radioactive isotope therapeutic microspheres that have been determined to cause clinically relevant lung or gastrointestinal changes due to off-target delivery.

62. Use of imageable microspheres in the preparation of products for reducing lung or gastrointestinal damage during treatment of patients requiring radioisotope cancer therapy, wherein the steps of the method of using imageable microspheres to reduce lung or gastrointestinal damage during treatment of patients requiring radioisotope cancer therapy include: Introduce an imageable microsphere cluster according to any one of claims 1 to 32 into the patient; Allows imageable microspheres to distribute within the patient's body for a period of time; By using imaging modalities to image imageable microspheres, the distribution of imageable microspheres in the patient's gastrointestinal tract or lungs can be determined. Determine the estimated radiation dose to the patient's gastrointestinal tract or lungs if the imaging microspheres are replaced by radioactive isotope therapeutic microspheres; Determine the dose of radioactive isotope therapeutic microspheres sufficient to cause gastrointestinal damage; and A dose of radioactive isotope therapeutic microspheres is administered to the patient, the dose being lower than that of radioactive isotope therapeutic microspheres determined to be sufficient to cause gastrointestinal damage.

63. A reagent kit comprising: Microspheres, comprising: A matrix comprising inorganic materials, said inorganic materials comprising quasi-metallic or metallic atoms bonded to nonmetallic atoms, said matrix comprising: A core extending to the surface, the core comprising a first portion of quasi-metallic or metallic atoms bonded to non-metallic atoms, and the surface comprising a second portion of quasi-metallic or metallic atoms bonded to non-metallic atoms; wherein the matrix comprises yttrium aluminum silicon oxide TheraSphere microspheres; and This specification provides instructions for binding an imageable radioisotope to a matrix, wherein the imageable radioisotope is directly bound to the matrix via non-metallic atoms on the matrix surface and / or the imageable radioisotope is bound to the matrix via an inorganic bridge comprising non-metallic atoms on the matrix surface, and the imageable radioisotope is selected from... 99m Tc and / or 89 Zr.

64. A reagent kit comprising: Microspheres, comprising: Inorganic matrix; wherein the inorganic matrix comprises At least one nonmetallic, quasi-metallic, or transition metal oxide; wherein the matrix comprises yttrium aluminum silicon oxide TheraSphere microspheres; and This specification provides instructions for binding an imageable radioisotope to an inorganic matrix surface, wherein the imageable radioisotope is bound to the inorganic matrix surface via Lewis acid-base coordination bonds, and the imageable radioisotope is selected from... 99m Tc and / or 89 Zr.

65. A system for determining the amount of therapeutic microspheres to be administered to a patient, comprising: Imageable microspheres according to any one of claims 1 to 32; Provides elements for providing the imageable microsphere group; The introducing element delivers the imageable microspheres to the patient by introducing the imageable microspheres into a first location in the patient's vascular system; And allow the imageable microspheres to distribute within the patient's body; An imaging element that images a portion of a patient’s body using an imaging modality to determine the distribution of at least a portion of an imageable microsphere population within the patient’s body. The computing element uses the distribution of imageable microspheres to calculate the amount of therapeutic microspheres to be delivered to the patient's body.

66. The system of claim 65, wherein the part of the body is the patient's off-target area, and the off-target area is the patient's lungs.

67. The system of claim 65, wherein the part of the body is the patient's target area, and the target area is the patient's liver.

68. The system of claim 67, wherein the target area is divided into tumor tissue and non-tumor tissue.

69. The system of claim 65, wherein the amount of therapeutic microspheres to be delivered to the patient is calculated.

70. The system of claim 69 further includes an application element that delivers a calculated amount of therapeutic microspheres to the patient.

71. The system according to any one of claims 65 to 70, wherein the imaging mode is SPECT.

72. The system according to any one of claims 65 to 70, wherein the imaging mode is PET.

73. The system according to any one of claims 65 to 70, wherein the imaging mode is gamma camera imaging.

74. Systems for treating patients, including: Imageable microspheres according to any one of claims 1 to 32; Provides elements for providing the imageable microsphere group; An introducing element is used to deliver the imageable microspheres to the patient by introducing the imageable microspheres into a first location in the vascular system of the patient's body. And allow the imageable microspheres to distribute within the patient's body; An imaging element that images a target portion of a patient's body using an imaging mode to determine the distribution of at least a portion of the imageable microsphere population within the patient's body. The computing element uses the distribution of imageable microspheres to calculate the amount of therapeutic microspheres to be delivered to the patient's body; Determine the element used to obtain data on the distribution of imageable therapeutic microsphere substitutes in a patient; This data will be used to determine the dosage of therapeutic microspheres to be administered to the patient. and The application element delivers the therapeutic microspheres to the patient by introducing the therapeutic microspheres into a second location in the patient's vascular system; And allows the therapeutic microspheres to distribute within the patient's body, thereby treating the patient.

75. The system of claim 74, wherein the second position in the patient's vascular system is the same as or approximately the same as the first position in the patient's vascular system.

76. The system according to claim 74 or 75, wherein the imaging mode is SPECT.

77. The system of claim 74 or 75, wherein the imaging mode is PET.

78. The system according to claim 74 or 75, wherein the imaging mode is gamma camera imaging.

79. Systems for treating tumors in patients requiring treatment, including: Imageable microspheres according to any one of claims 1 to 32; An introducing element is used to introduce the imageable microsphere cluster into the patient; allowing the imageable microspheres to distribute within the patient for a period of time; An imaging element that uses imaging modes to image imageable microspheres and determine the distribution of imageable microspheres at specific sites within a patient's body; A computing element for determining, based on the distribution of imageable microspheres, the estimated effective dose at the site when the imageable microspheres are replaced by therapeutic microspheres; and An application element, used to administer a specific amount of therapeutic microspheres to a patient based on an estimated effective dose.

80. The system of claim 79, wherein the site is a malignant or benign tumor and / or non-tumor tissue.

81. The system of claim 79, wherein the site is a malignant tumor.

82. The system of claim 81, wherein the site is a malignant liver tumor.

83. A system for predicting the extent of off-target delivery to the lungs or gastrointestinal tract during treatment in patients requiring radioisotope cancer therapy, comprising: Imageable microspheres according to any one of claims 1 to 32; An introducing element is used to introduce the imageable microsphere cluster into the patient; allowing the imageable microspheres to distribute within the patient for a period of time; An imaging element used to determine the distribution of imageable microspheres in a patient's lungs by imaging microspheres using imaging modes; Computational elements are used to determine the estimated radiation dose to a patient's lungs or gastrointestinal tract if the imageable microspheres are replaced by radioactive isotope therapeutic microspheres, respectively. Determining element, which is used to determine the dose of radioisotope therapeutic microspheres that are sufficient to cause clinically relevant lung or gastrointestinal changes due to off-target delivery; and An application element for administering a dose of radioisotope therapeutic microspheres to a patient, the dose being lower than that of radioisotope therapeutic microspheres determined to be sufficient to cause clinically relevant lung or gastrointestinal changes due to off-target delivery.

84. Systems for reducing lung or gastrointestinal damage during treatment in patients requiring radioisotope cancer therapy, including: Imageable microspheres according to any one of claims 1 to 32; An introducing element is used to introduce the imageable microsphere cluster into the patient; allowing the imageable microspheres to distribute within the patient for a period of time; Imaging elements that use imaging modes to image imageable microspheres to determine the distribution of imageable microspheres in a patient's gastrointestinal tract or lungs; A computational element used to determine the estimated radiation dose to a patient's gastrointestinal tract or lungs if the imageable microspheres were replaced by radioactive isotope therapeutic microspheres; A determining element for determining the dose of radioactive isotope therapeutic microspheres sufficient to cause gastrointestinal damage; and An application element for administering a dose of radioactive isotope therapeutic microspheres to a patient, the dose being lower than that of radioactive isotope therapeutic microspheres determined to be sufficient to cause gastrointestinal damage.

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