Radioembolic beads and methods for the treatment of tumor cells - Patents.com

Abstract

Disclosed are methods, devices and systems including embolic particles for use in treating tumor cells. The embolic particles may include an inner core and an outer layer. The inner core may have a volume capable of housing a radioisotope therein, and the inner core may include a surface onto which a layer may be disposed. The outer layer may have a thickness capable of housing a therapeutic agent therein, and the outer layer may be disposed on a surface of the inner core. The inner core and the outer layer may have a combined density sufficient to allow the embolic particles to move along a pathway with fluid flow, and the embolic particles include dimensions large enough to engage the pathway and restrict fluid flow to the tumor cells.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This patent application claims the benefit of U.S. Provisional Application No. 63 / 330,389, filed April 13, 2022, entitled "Radioembolic Beads for Treating Cancer," and U.S. Provisional Application No. 63 / 337,773, filed May 3, 2022, entitled "Radioembolic Beads for Treating Cancer," each of which is incorporated herein by reference in its entirety.

[0002] FIELD OF THEINVENTION The present invention relates to injectable particles for intravascular embolization of tumor cells, with or without localized delivery of radiation or therapeutic agents. [Background technology]

[0003] Malignant tumors of the liver include primary tumors such as hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma, with HCC being the most common primary liver tumor. Metastatic tumors from sites such as the intestine, breast, lung, and esophagus may also involve the liver. In some patients, surgical resection of liver tumors may provide therapeutic treatment. However, many patients with primary or metastatic liver cancer have underlying medical comorbidities or liver dysfunction that preclude curative liver surgery. Also, the anatomical location or extent of the liver tumor may make it technically unresectable. Summary of the Invention

[0004] An alternative treatment method for inoperable patients with liver tumors includes selective intra-arterial embolization of tumors with microsphere particles. Liver tumors receive an alternative blood supply from normal liver parenchyma. Most primary and metastatic liver tumors receive the majority of their blood supply from the systemic arterial circulation through a branch of the celiac artery. However, normal liver cells receive their blood supply through the portal venous circulation. By taking advantage of this difference in blood supply, intra-arterial embolization selectively targets tumor vasculature while preserving the majority of the blood supply to normal liver cells. Also, similar to the liver, the lungs are supplied with blood from two different sources, the pulmonary artery and the bronchial artery. Most lung tumors receive their blood supply from the bronchial artery, but the majority of the lung parenchyma receives its blood supply from the pulmonary artery. Thus, much like the liver, the branches of the bronchial artery can be embolized with a low risk of damaging the surrounding normal lung parenchyma. Furthermore, the present disclosure includes the applicability of treatments such as brain or spinal gliomas and prostate tumors.

[0005] Microspheres used for embolization of liver tumors may contain drug-eluting materials used to deliver chemotherapy drugs. Alternatively, the microspheres may contain radioactivity for a procedure commonly known as radioembolization. The most commonly used radioisotope is yttrium-90 (Y-90), a pure beta-emitting isotope. Y-90 has a half-life of 64.1 hours and the energy of the emitted beta particles is 2.28 MeV. Y-90 is produced by the decay of strontium-90, a fission product of uranium in nuclear reactors, which decays to zirconium-90. Currently available Y-90 microspheres are only two types. Currently available glass spheres are microspheres composed of glass with a size of 20-30 μm. Currently available resin spheres are resin spheres with a size of 20-60 μm.

[0006] Low linear energy delivery forms of radiation, including 2.28 MeV beta particles produced by the decay of Y-90, kill cancer cells through what is known as the indirect effect. The indirect effect causes strand breaks in the phospho-ribose backbone of DNA in chromosomes. While single-strand breaks are easily repaired, double-strand DNA breaks often result in cell death during mitosis. The indirect effect is mediated by the formation of hydroxyl and peroxide free radicals, which are produced as ionizing radiation passes through the body. The formation of these free radicals requires the presence of oxygen, and therefore, the indirect effect is enhanced in well-oxygenated tissues. This can be expressed mathematically as the oxygen enhancement ratio (OER), with the OER being higher in tissues with a robust vascular supply of well-oxygenated blood. Embolization of small arteries that feed the tumor places the cancer cells in a more hypoxic environment, lowering the OER and decreasing the level of tumor cell death.

[0007] Radiosensitizers are chemicals that enhance radiation-associated cell death. Hypoxic cell radiosensitizers selectively enhance the death of hypoxic cells but have little effect on cells with normal oxygenation. Nitroimidazoles are a class of antibiotic drugs that also provide hypoxic cell radiosensitization (metronidazole is the most widely used antibacterial drug). Misonidazole is a second-generation 2-nitroimidazole that has been shown in a Dutch randomized trial (DAHANCA 2) to improve outcomes when used with radiation therapy to treat patients with head and neck cancer. More recently, DAHANCA 5-85 showed that the addition of nimorazole to radiation therapy in the treatment of head and neck cancer improved both local control and overall survival. Unfortunately, the systemic use of drugs such as misonidazole and nimorazole is limited by their side effects, including central nervous system toxicity, and the logistics of precise timing of drug administration with radiation therapy.

[0008] Local delivery of hypoxic cell radiosensitizers may increase the therapeutic ratio of radioembolization by enhancing tumor cell killing while also reducing the systemic side effects of the radiosensitizer. In 1992, Wang et al. published the results of an animal study involving intrahepatic arterial infusion of misonidazole in rabbits bearing VX2 hepatoma cells. Hepatic arterial infusion of misonidazole was then followed by 15 Gray of external radiation therapy. Compared with rabbits that did not receive misonidazole, rabbits that received hepatic arterial infusion showed the greatest tumor response, showing extensive fibrosis and necrosis.

[0009] In addition to hypoxic cell radiosensitization, many other chemicals and pharmaceuticals have been shown to have radiosensitizing properties. Chemotherapeutic drugs are often delivered simultaneously with external radiation therapy, taking advantage of the synergistic cell killing effect of radiosensitization. Alkylating and antimetabolite chemotherapy drugs inhibit DNA repair pathways that cells utilize to repair nonlethal damage from ionizing radiation. Accumulation of nonlethal damage that is not properly repaired leads to increased cell death. Taxane chemotherapy drugs and other microtubule inhibitors arrest the cell cycle at the G2-M phase boundary where cells are most sensitive to radiotherapy. There is also a well-documented synergy between ionizing radiation and immunotherapy used to upregulate immune targeting of cancer cells through radiation-induced upregulation of antigen-presenting cells (such as dendritic cells) and other proinflammatory effects. These drugs include anti-CTLA4 drugs, anti-PD-1 and anti-PDL-1 drugs / checkpoint inhibitors, chimeric antigen receptor T cell (CAR-T) therapy, and other immunomodulatory drugs.

[0010] Novel embolic beads are disclosed that combine radioactive embolic beads with drug-containing and deliverable moieties, including radiosensitizers. The disclosure described herein takes advantage of the enhanced radiation cell killing of radiosensitizers while minimizing the systemic effects of the drugs. By combining both on a single embolic bead, they can be delivered together in a single injection, ensuring their co-location and maximizing their combined efficacy.

[0011] The present disclosure relates to an embolic particle for use in treating tumor cells, the embolic particle comprising an inner core having a volume capable of accommodating a radioisotope therein and including a surface upon which a layer can be disposed, an outer layer having a thickness capable of accommodating a therapeutic agent therein and disposed on the surface of the inner core, the inner core and outer layer having a sufficient density to allow the embolic particle to move along a pathway with fluid flow, the embolic particle including dimensions large enough to engage the pathway and restrict fluid flow to the tumor cells.

[0012] In some embodiments, the size of the embolic particles may be sufficient to substantially block fluid flow through a pathway to tumor cells. The embolic particles may treat at least one of the following tumors: liver, lung, prostate, or brain or spinal cord glioma.

[0013] In some embodiments, therapeutic agents can be injected into the outer layer. The outer layer can release therapeutic agents to tumor cells, and the embolic particles can restrict the flow of fluid to tumor cells. The embolic particles can treat at least one of primary or metastatic tumors of the liver, lung, brain or spinal cord, prostate, breast, esophagus, upper aerodigestive tract, including nasopharynx, nasal cavity, oral cavity, oropharynx, hypopharynx, larynx, neck, thyroid, lung, mediastinum, stomach, small intestine, large intestine, pancreas, spine, kidney, ureter, bladder, urethra, vagina, uterus, cervix, ovary, lymph node, muscle and bone.

[0014] In some embodiments, the inner core can be embedded with a radioisotope.The inner core can emit radiation, and the embolic particle can restrict fluid flow to irradiate tumor cells.The embolic particle can treat at least one of the primary or metastatic tumors of the liver, lung, brain or spinal cord, prostate, breast, esophagus, upper aerodigestive tract, including nasopharynx, nasal cavity, oral cavity, oropharynx, hypopharynx, larynx, neck, thyroid, lung, mediastinum, stomach, small intestine, large intestine, pancreas, spine, kidney, ureter, bladder, urethra, vagina, uterus, cervix, ovary, lymph node, muscle and bone.

[0015] In some embodiments, the radioisotope can be embedded in the inner core and the therapeutic agent can be impregnated in the outer layer. The embolic particle can restrict the flow of fluid to tumor cells, the inner core can emit radiation to kill tumor cells, and the outer layer can emit therapeutic agent to treat remaining tumor cells. The radioisotope can be yttrium-90 (Y-90). The embolic particle can treat at least one of primary or metastatic tumors of the liver, lung, brain or spinal cord, prostate, breast, esophagus, upper aerodigestive tract, including nasopharynx, nasal cavity, oral cavity, oropharynx, hypopharynx, larynx, neck, thyroid, lung, mediastinum, stomach, small intestine, large intestine, pancreas, spine, kidney, ureter, bladder, urethra, vagina, uterus, cervix, ovary, lymph node, muscle and bone.

[0016] In some embodiments, the inner core may be formed from at least one of a polymer, a ceramic, a glass, and a glass-ceramic composite. The inner core may be sintered with a porosity of about 10% to about 75%. The outer layer may form a uniform shape around the inner core. The outer layer may be formed from a polymer. The outer layer may be formed from a polymer. A radiopaque material may be embedded in the outer layer. The embolic particle may have a substantially spherical shape. The size of the embolic particle may be about 15 μm to about 1000 μm. The embolic particle may further include at least one additional layer, and the at least one additional layer may be different from the inner core and the outer layer.

[0017] In one embodiment, a kit for treating tumor cells is provided. The kit includes a plurality of embolic particles, each embolic particle including an inner core having a volume capable of accommodating a radioisotope therein and including a surface on which a layer can be disposed; an outer layer having a thickness capable of accommodating a therapeutic agent therein and disposed on the surface of the inner core; wherein the inner core and the outer layer have a density sufficient to allow the embolic particles to move along a pathway with a fluid flow, and the embolic particles include dimensions large enough to engage the pathway and restrict the flow of fluid to tumor cells; a liquid including a therapeutic agent, into which the plurality of embolic particles can be immersed to inject the therapeutic agent into the outer layer; and a vial for containing the liquid.

[0018] In some embodiments, a liquid may be disposed in the vial. When the embolic particles are disposed in the liquid, a therapeutic agent may be injected into an outer layer of the embolic particles. The liquid may include saline. When the embolic particles are disposed in the liquid, the size of the embolic particles may increase. When the embolic particles are disposed in the liquid, the embolic particles may remain the same size.

[0019] A method of making an embolic particle is disclosed, the method comprising the steps of providing an inner core having a volume therein capable of accommodating a radioisotope and including a surface onto which a layer can be disposed; providing a composition into which a therapeutic agent can be injected; and disposing the composition on the surface of the inner core to create an outer layer.

[0020] In some embodiments, the inner core may include a hollow inner chamber that can accommodate a radioisotope or a therapeutic agent. The method may further include the step of injecting a radioisotope into the inner core. The method may further include the step of activating the radioisotope such that the embolic particle emits radiation. The method may further include the step of injecting a therapeutic agent into the outer layer. The therapeutic agent may be premixed with the outer layer prior to the step of disposing.

[0021] A method for treating tumor cells with embolic particles is provided, the method including providing a plurality of embolic particles, each having an inner core with a volume capable of accommodating a radioisotope therein and an outer layer with a thickness capable of accommodating a therapeutic agent therein; identifying a target site containing tumor cells to be treated; and delivering the embolic particles to a lumen, allowing the plurality of embolic particles to travel along a pathway with a fluid flow to the target site, the embolic particles engaging the pathway to restrict the flow of fluid to the tumor cells.

[0022] In some embodiments, the method may further include activating a radioisotope in the inner core. The method may further include irradiating tumor cells at the target site. The method may further include impregnating an outer layer of each of the plurality of embolic particles with a therapeutic agent. The impregnation step may further include disposing the plurality of embolic particles in a fluid containing a therapeutic agent to inject the therapeutic agent into at least the outer layer. The dimensions of each embolic particle may limit the movement of each embolic particle through the lumen of the target site to prevent the plurality of embolic particles from moving away from the target site. The delivery step may include delivering the plurality of embolic particles through an arterial branch that supplies nutrients to the tumor cells. The method may further include treating at least one of a tumor of the liver, lung, prostate, or brain or spinal cord glioma with the plurality of embolic particles. [Brief description of the drawings]

[0023] [Figure 1A] FIG. 1A is a perspective view, partially cut away, of an embolic bead according to an embodiment of the present disclosure.

[0024] [Figure 1B] FIG. 1B is a perspective, partially cut away view of an embolic bead having an inner core containing radioisotope particles surrounded by an outer layer containing a radiosensitizing drug.

[0025] [Figure 1C] FIG. 1C is a cross-sectional view of an embolic bead according to one embodiment of the present disclosure.

[0026] [Figure 2A] FIG. 2A is a partially cut-away perspective view of an embolic bead comprised of a single uniform sphere according to an embodiment of the present disclosure.

[0027] [Figure 2B] FIG. 2B is a partially cut-away perspective view of an embolic bead having a single homogenous sphere containing both a radioisotope and a radiosensitizing drug.

[0028] [Diagram 3] 3A-3C are cross-sectional views of embolic beads according to embodiments of the present disclosure.

[0029] [Figure 4] 4A and 4B are diagrams of an injection method according to an embodiment of the present disclosure.

[0030] [Diagram 5] FIG. 5 is a cross-sectional view of an embolic bead according to one embodiment of the present disclosure.

[0031] [Figure 6] FIG. 6 illustrates an injection method according to an embodiment of the present disclosure.

[0032] [Figure 7] 7A and 7B are diagrams of an injection method according to an embodiment of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] The present invention overcomes the shortcomings of the current devices described above by providing, in one embodiment, embolic beads or particles with co-administration of radioembolic and therapeutic agents, such as radiosensitizers. The embolic beads can first increase tumor cell death by irradiation of the tumor. The embolic beads can combine a radiation source with a drug eluting component that includes a therapeutic agent, such as a radiosensitizer, to administer radiation therapy in some embodiments, either simultaneously with or after administration of the radiosensitizer. In some embodiments, the embolic beads can simultaneously administer both therapeutic agents to the same location in the tumor microvasculature. Delivery of the drug from the outer layer can depend on the formulation of the outer layer that allows either immediate release of the drug upon delivery (by dissolving the outer layer) or delayed / timed release of the drug (slow dissolution of the outer layer). Advantageously, the embolic beads minimize tumor cell radioresistance due to hypoxia or other cellular and molecular processes, provide optimized activity, and have favorable flow properties while enabling multi-modality therapy for interventional oncology. Such devices allow therapeutic treatment of various tumors, such as liver tumors, on an outpatient basis.

[0034] In other words, the present embolic beads can advantageously provide at least a dual treatment for specific tumor cells in various embodiments. For example, by providing a single particle type with a radiation source for radiation treatment of liver cancer and a drug eluting component with a therapeutic agent, the present embolic beads provide a more effective treatment than a single treatment alone. The present embolic beads provide a significant advantage not found in prior art treatments. That is, in contrast to prior art treatments that use only either radiation or radiosensitizing drugs, the present disclosure provides a more comprehensive treatment than has been previously provided.

[0035] In general, liver cancer can be treated with embolization. Embolization can be used for tumors that cannot be removed by conventional surgery. For example, embolization can be used when the tumor is too large to be treated by resection, for example, when the tumor is more than 5 cm in diameter and the liver function is adequate. Embolization may not be a good option for some patients whose livers have been damaged by diseases such as hepatitis or cirrhosis, as it may reduce the blood supply to normal liver tissue. However, because the liver has two sources of blood supply, the portal vein may be able to supply blood to healthy liver cells while the hepatic artery, which often supplies blood to liver cancer, is blocked or otherwise restricted. In addition, like the liver, the lungs are supplied with blood from two different sources, from the pulmonary artery and the bronchial artery. Just as liver tumors attach to the hepatic artery, nearly all lung tumors attach to the bronchial artery. Therefore, much like the liver, the branches of the bronchial artery can be embolized without damaging the remaining healthy tissue in the lungs. Other organs or anatomical sites in the human body can have radiation sources directly implanted in interstitial tissue or in body cavities, a procedure known as interstitial or intracavitary brachytherapy. The embolic beads of the present invention can further be used for interstitial or intracavitary near-brachytherapy, providing a means for simultaneous anatomically localized delivery of therapeutic radiation and therapeutic agents, such as radiosensitizers, through routes other than arterial embolization. Thus, the present disclosure includes applicability for the treatment of primary or metastatic tumors in the brain or spinal cord, prostate, breast, esophagus, upper aerodigestive tract, including the nasopharynx, nasal cavity, oral cavity, oropharynx, hypopharynx, larynx, neck, thyroid, lung, mediastinum, stomach, small intestine, large intestine, spine, kidney, ureter, bladder, urethra, vagina, uterus, cervix, ovary, lymph nodes, muscle and bone, etc.

[0036] According to an embodiment of the present disclosure, the embolic bead comprises a radioembolic or radiotherapeutic portion and a drug or radiosensitizer eluting portion. In one embodiment, the radioembolic portion can be the inner portion of the embolic and can be composed of a substantially hard material, such as a polymer, glass, ceramic, or glass-ceramic composite. To provide the inner portion with radiotherapeutic capabilities, in one embodiment, the inner portion can be infused or embedded with Y-90 or a resin containing Y-90. Alternatively, similar radioisotopes can be utilized as sources of radiotherapy. Thus, substantially hard particulate materials similar to glass or resin can also be used as substrates for radioisotopes. In some embodiments, the radiation-emitting portion can be a homogeneous mixture of glass, polymer, or hydrogel, ceramic, glass-ceramic composite, or other material that contains a radiation-emitting radioisotope. Alternatively, the radiation-emitting portion can be a heterogeneous mixture of glass, polymer, or hydrogel, ceramic, or glass-ceramic composite, or other material that contains a radiation-emitting radioisotope.

[0037] In some embodiments, radioembolic beads can be coated, encapsulated or otherwise combined with drug-eluting compounds that can carry therapeutic agents or drugs for slow release after or during the irradiation period. For example, in one embodiment, the therapeutic agent can be released after the irradiation period to ensure the removal of tumor cells that were not killed by the irradiation. Drug-eluting emboli can include polyvinyl alcohol (PVA) polymers doped with sulfonyl groups that bind electrostatic charges with polarized molecules. Examples include DC / LC beads and QuadraSphere beads. Additional embolic beads used in chemoembolization can include Lipiodol, gelatin sponge, polymethylmethacrylate (Oncozene), degradable starch (Spherex). However, it should be understood that these embolic beads do not have the same drug-eluting properties as PVA polymers.

[0038] In one embodiment, the radioembolic beads may comprise a radioembolic core of glass, ceramic or resin containing Y-90, which may be coated with a drug-eluting shell, such as a PVA polymer or other polymer. It is within the scope and spirit of the present disclosure to include other drug-eluting coatings, known or unknown, or other methods of incorporating drugs into or on the microparticles. For example, a PVA polymer may carry a hypoxic cell radiosensitizer drug, which may slowly elute into the irradiated area.

[0039] In some embodiments, the embolic beads 1 of the present disclosure may be larger than about 15 μm in diameter to pass through small arteriovenous shunts and prevent non-target organ embolization, biliary ischemia, hepatobiliary infarction, or other adverse effects. In one embodiment, the embolic beads may include an upper size threshold of 1,000 μm, since larger sizes may cause blockage of commonly used microcatheters. Furthermore, larger particles may cause more proximal arterial blockage, promote hypoxia, and subselect more resistant cancer cell populations. However, in practice, the embolic particles can be any size that meets the clinical requirement of reaching the desired anatomical distribution.

[0040] The present invention will now be described in detail with reference to the accompanying drawings, in which: The present disclosure is not intended to be limited to the described embodiments, but rather, this detailed description is provided to enable those skilled in the art to make and practice the present invention.

[0041] With reference to FIG. 1A and FIG. 1B, in one embodiment, the embolic bead 1 can be composed of an inner core 2 and an outer layer 3. The embolic bead 1 can have an overall size of about 5 μm to about 1000 μm. The term size or dimension as used herein can refer to the outer dimensions, including width, length, diameter, and the like. The embolic bead 1 can be any regular or irregular 3D shape, including but not limited to spherical, hemispherical, cubic, conical, cylindrical, octahedral, and the like. The figures presented in this disclosure are shown as spherical or circular. These are purely for illustrative purposes only and do not reflect the only possible embodiments that the particles may take. In some embodiments, at least a portion of the embolic bead 1 can have a radiopaque material embedded therein. The radiopaque material can advantageously allow visualization of the delivery of one or more embolic beads 1 to a target site, such as the location of a tumor, within a patient.

[0042] According to one embodiment, the inner core 2 can be made of a polymer, glass, ceramic, glass-ceramic composite, resin, or a combination thereof. It is also within the scope of the present disclosure to have a core composed of other biocompatible materials that can accommodate a radioisotope. In one embodiment, the inner core 2 of the embolic bead 1 can comprise a volume in which a radioisotope 7 can be placed that can deliver localized radiotherapy to the surrounding tumor when the embolic bead 1 is placed at the tumor site. An example of a radioisotope used in such a procedure can be yttrium-90 (Y-90) or holmium-166, but it is within the scope of the present disclosure to use any beta or gamma emitting radioisotope, known or unknown. In some embodiments, as shown in Figures 1A and 1B, the inner core 2 can be a solid, for example a solid sphere. Alternatively, as shown in Figure 1C, the inner core 2 can be porous, with a number of holes 11 arranged randomly or regularly, and can include a hollow inner section 10 for containing additional drugs or radiosensitizing compounds, including those mentioned above. In some cases, the inner core 2 can be a solid or hollow core sintered to a porosity of about 10-75%. Deposition of a fluid into the hollow inner section 10 can be accomplished by immersing the embolic beads 1 in a bath of a particular fluid and allowing the fluid to deposit inside the particle, e.g., through the pores 11. The particle can then be filtered to separate it from the liquid bath. Filtering the embolic beads 1 from the liquid bath can occur before or during injection of the embolic beads 1. In some embodiments, the inner core 2 can be coated with at least one outer layer, e.g., outer layer 3.

[0043] In one embodiment, the outer layer 3 can comprise a drug-eluting or releasing glass, ceramic, ceramic / glass, resin, polymer, metal, or other biocompatible material that can be deposited, bonded, coated, or otherwise attached to the inner core 2 and deliver and elute drugs when placed in the body. In one embodiment, the outer layer 3 can be deposited or coated on the inner core 2 to ensure that the resulting embolic bead 1 does not have rough or jagged edges and prevents the embolic bead 1 from damaging healthy tissues that it comes into contact with during administration. In some embodiments, the outer layer 3 of the embolic bead 1 can have a thickness, resulting volume, that can accommodate a therapeutic agent, such as a radiosensitizing compound, hypoxic cell toxin, immunotherapy, CAR-T therapy, etc., that can diffuse or be released from the embolic bead into the surrounding tumor and body tissues at the same time or at a different time as the radioisotope compound is treating the tumor. In one embodiment, the compound can be a hypoxic cell radiosensitizing drug, such as a nitroimidazole. However, it is within the scope of this disclosure to use any therapeutic compound, known or unknown. In some embodiments, the outer core 3 may remain intact after delivery to the target site within the patient, or the outer core 3 may be absorbed by the body after delivery. Also, while the figures show the radioisotope in the core 2 and the drug eluting portion in the outer layer 3, the positions of the two layers may be reversed, with the drug eluting portion in the core and the radioisotope in the outer layer. In this configuration, the materials that make up the core and outer layer may also need to be reversed. Alternatively, as shown in Figures 2A and 2B, in some embodiments, the embolic bead 4 may be a homogenous material 5, such as a resin, glass, polymer, or ceramic-glass composite that forms the entire bead. Within the embolic bead 4, the radioisotope 9 and the radiosensitizing drug 8 may be mixed.

[0044] In some embodiments, the therapeutic agent may be a radiosensitizing agent, which may be a nitroimidazole hypoxic cell radiosensitizer. Alternatively, the drug eluting moiety may contain other therapeutic compounds, including, but not limited to, non-nitroimidazole hypoxic cell radiosensitizers, radiosensitizing chemotherapeutic drugs such as taxanes (e.g., paclitaxel) or platinum-containing compounds (e.g., cisplatin), or other radiosensitizing compounds yet to be identified.

[0045] In some embodiments, the embolic bead 1 comprises an inner core 2 and an outer layer 3, where the inner core 2 does not contain radioactive material and the outer layer does not contain therapeutic agent. In such a case, the embolic bead 1 can perform TAE or harmless embolization of tumors to deplete the tumor's energy source. Alternatively, in some cases, the embolic bead 1 can be used for transarterial chemoembolization (TACE). TACE is often the first type of embolization used for large liver cancers that cannot be treated by surgery or resection, and combines embolization with chemotherapy (chemo). When treating metastatic tumors derived from hepatocellular carcinoma (HCC), the drug-eluting moiety may include certain systemic drugs, including Atezolizumab, Bevacizumab, Tremelimumab-actl, Darvalumab, Sorafenib, Lenvatinib, Pembrolizumab, Nivolumab, Ipilimumab, Regorafenib, Cabozantinib, Ramucirumab, Dostallimab, or Selpercatinib. In some embodiments, when treating metastatic tumors derived from colorectal cancer, the drug eluting moiety may comprise 5FU, oxaliplatin, leucovorin, capecitabine, irinotecan, bevacizumab, panitumumab, nivolumab, ipilimumab, pembrolizumab, trastuzumab, pertuzumab, lapatinib, tucatinib, ramucirumab, Ziv-aflibercept, cetuximab, panitumumab, encorafenib, dostallimab-gxly, lapatinib, Fam-trastuzumab (trastuzumab) deruxtecan, regorafenib, trifluridine or tipiracil.

[0046] In some embodiments, when treating metastatic tumors derived from cholangiocarcinoma, the drug-eluting portion may include drugs commonly treated with TACE, including doxorubicin, cisplatin, epirubicin, miriplatin, carboplatin, mitomycin C, gemcitabine or 5FU. Alternatively, the drug eluting portion may comprise any of 5FU, capecitabine, oxaliplatin, leucovorin, gemcitabine, cisplatin, durvalumab, paclitaxel and NAB-paclitaxel, regorafenib, irinotecan, lenvatinib, pembrolizumab, entrectinib, larotrectinib, nivolumab, ipilimumab, pralsetinib, selpercatinib, dostallimab-gxly, dabrafenib, trametinib, futibatinib, pemigatinib, ivosidenib, traztuzumab, or pertuzumab.

[0047] In some embodiments, when treating metastatic tumors derived from breast cancer, the drug eluting moiety may comprise adriamycin, cyclophosphamide, paclitaxel, docetaxel, olaparib, pembrolizumab, carboplatin, epirubicin, methotrexate, 5FU, capecitabine, trastuzumab, pertuzumab, neratinib, TDM-1, tamoxifen, anastrozole, letrozole, ribociclib, abemaciclib, palbociclib, fulvestrant, exemestane, or everolimus. In some embodiments, when treating metastatic tumors derived from non-small cell lung cancer, the drug-eluting portion can comprise carboplatin, paclitaxel, cisplatin, pemetrexed, gemcitabine, docetaxel, vinorelbine, etoposide, nivolumab, osimertinib, atezolizumab, pembrolizumab or durvalumab.In some embodiments, when treating metastatic tumors derived from prostate cancer, the drug-eluting portion can comprise nilutamide, flutamide, bicalutamide, abiraterone, enzalutamide, apalutamide, darolutamide, docetaxel, ketoconazole, cabazitaxel, carboplatin, mitoxantrone, pembrolizumab. In some embodiments, when treating metastatic tumors derived from pancreatic cancer, the drug eluting moiety may include 5FU, oxaliplatin, irinotecan, leucovorin, gemcitabine, paclitaxel, Nab-paclitaxel, cisplatin, erlotinib, dabrafenib, trametinib, pembrolizumab, larotrectinib, entrectinib, dabrafenib, olaparib, rucaparib.

[0048] Combining radioisotopes and a drug-eluting layer infused with a therapeutic agent on the same embolic bead or particle can enhance tumor cell killing while maintaining a simplified procedure that requires only one hepatic artery cannulation and one injection of the therapeutic agent. Also, the range of Y-90 emitting beta particles is only about 1 mm in tissue. Therefore, it is important to ensure co-location of the radioactive source and the elution of the radiosensitizing agent. This can be achieved by co-administration of the same embolic bead, since combining a radioactive embolic bead with another drug-eluting particle does not guarantee that both therapeutic agents are delivered to the same anatomical location. In some embodiments, the embolic bead can be used for TAE (or harmless embolization), TACE (or chemoembolization) and TARE (or radioembolization), in addition to bioradioembolization with simultaneous delivery of a therapeutic agent. In the case of TARE, the embolic bead can have the ability to deliver drugs if the physician chooses. In some embodiments for TARE, the embolic beads 1 may have radioactive material embedded in the activated inner core 2 without a therapeutic agent embedded in the outer layer 3. In such embodiments, the embolic beads 1 may be injected into a patient such that the embolic beads 1 can treat a tumor at a target site by emitting radiation alone. In some embodiments, a therapeutic agent may be injected into the outer layer 3 after delivery to a hospital or medical facility, but before injection into a patient. In some embodiments, the embolic beads may provide a specific combination of a specific drug and a radiation-emitting bead. In some cases, the embolic beads may not have an activated radioisotope, resulting in a particle with a core and an outer polymer coating, which also serves the TAE and TACE markets. Thus, the embolic beads allow for embolic beads that can have radiation emission, drug delivery and embolization capabilities, while some embolic beads can only have drug delivery and embolization (no radiation).

[0049] In some embodiments, the radiosensitizer can be used to treat multiple metastatic tumors that affect the liver.For example, the radiosensitizer can be a nitroimidazole hypoxic cell radiosensitizer.Alternatively, the drug-eluting portion can contain other radiosensitizer compounds, including but not limited to non-nitroimidazole hypoxic cell radiosensitizers, radiosensitizer chemotherapeutic drugs such as taxanes (e.g., paclitaxel) or platinum-containing compounds (e.g., cisplatin), or other radiosensitizer compounds that have not yet been identified. For example, in some embodiments, when treating metastatic tumors in the liver resulting from colorectal cancer, the drug eluting portion or outer layer 3 may be infused with 5FU, oxaliplatin, leucovorin, capecitabine, irinotecan, bevacizumab, panitumumab, nivolumab, ipilimumab, pembrolizumab, trastuzumab, pertuzumab, lapatinib, tucatinib, ramucirumab, Ziv-aflibercept, cetuximab, panitumumab, encorafenib, dostallimab-gxly, lapatinib, Fam-trastuzumab deruxtecan, regorafenib, trifluridine or tipiracil.

[0050] In some embodiments, the inner core 2 may have a first material density and the outer layer 3 may have a second material density. In some embodiments, the first material density may be denser than the second material density. However, advantageously, the embolic bead 1, which is composed of the inner core 2 and the outer layer 3, may have a lower overall or combined density than the inner core 2 alone, so that the embolic bead 1 may be buoyant or neutrally buoyant in a fluid, and thus the embolic bead 1 may have favorable flow properties in a fluid, such as human blood. Favorable flow properties may be understood to mean that the embolic bead 1 can flow in a fluid without sinking or clogging in a lumen, such as a human artery or vein. The lower density of the embolic bead 1 may be a function of the volume ratio of the inner core 2 to the outer layer 3. In some embodiments, the lower density may also be a function of the physical properties of the inner core 2. For example, an inner core 2 having holes or hollow cavities may be more buoyant than a solid inner core of the same dimensions.

[0051] In some embodiments, the embolic bead 1 may be comprised of any combination of layers, such as an inner core 2 of radiation-emitting material 7 and an outer layer 3 of drug-eluting material 6, as shown in Figures 1A and 1B. Alternatively, the embolic bead 1 may be formed of any multiple layers, having a combination of one radiation-emitting layer 2 and one drug-eluting layer 3, as shown in Figure 3A. In some embodiments, the embolic bead 1 may incorporate a bonding layer 20, which bonds the drug-eluting layer 3 to other layers, such as the radiation-emitting layer 2, as shown in Figure 3B. The bonding layer 20 may be incorporated at the interface of any of the various layers. The bonding layer may be polymeric in nature or may be a bonding agent that utilizes some form of ionic bonding. The embolic bead 1 may incorporate a sacrificial encapsulation layer 30, which contains an eluting drug relative to the remainder of the particle, as shown in Figure 3C. The sacrificial layer dissolves and disappears upon administration of the particle to a patient, exposing the drug-eluting layer 3 at the desired target location.

[0052] In the method of use, activation of drug elution may be required. For example, initiating delivery of drug at the target site may include removing sacrificial layer 30 to expose drug eluting layer 3 or activating an already exposed drug layer, as shown in FIG. 3C. Activation may be achieved in a number of ways, including exposing embolic beads 1 to bodily fluids; exposing embolic beads 1 to bodily heat; exposing embolic beads 1 to an external energy source, such as radiation, heat, MRI or ultrasound; exposing embolic beads 1 to fluids, such as saline, outside the patient before administration of the particles; exposing embolic beads 1 to light; exposing embolic beads 1 to magnetism; injecting CO2 that can react with the drug; and / or emitting radiation from an isotope that cleaves in core 2 to convert the drug. In some embodiments, the method may include delivering an energy delivery device, such as ablation / heat, percutaneously to the target site after delivery of embolic beads 1, and delivering energy at the target site using an energy delivery device, such as ablation / heat. In one embodiment, a method of activating a drug may involve the use of an internal gas source within an embedded particle that expands and bursts or creates a hole when exposed to body heat or other energy source.

[0053] In some embodiments, a method is provided for delivering radiation-emitting micron-sized embolic beads 1 that can be mixed into a fluid 40. For example, the embolic beads 1 and the fluid 40 can be injected into a patient simultaneously, as shown in FIG. 4A. In some embodiments, the fluid 40 can be a chemotherapy drug, a hypoxic radiosensitizer, or other drug used to treat tumor cells. The term radiosensitizer as used herein can refer to a hypoxic cell radiosensitizer, a bioreductive drug, a radiosensitizing chemotherapy drug, an immunotherapeutic drug, or other radiosensitizing chemicals, proteins, drugs, or compounds known now or in the future. The embolic beads 1 and the fluid 40 can be contained in a single vial 100 and delivered directly to a clinician for use. For example, the embolic beads 1 can be bromide with the drug eluting layer 3 being free of any therapeutic agent. In such a case, the hospital can mix the embolic beads 1 with a therapeutic agent via the fluid 40 before administering the embolic beads 1 to the patient.

[0054] In some embodiments, the embolic beads 1 may require a fluid 40 to "activate" the drug eluting layer 3, which may be a polymer layer. In the case of a polymer layer or coating, the fluid 40 may be about 100% NaCl 0.9% aqueous solution, a non-ionic contrast agent, or about a 50 / 50 mixture of NaCl 0.9% aqueous solution and a contrast agent. Alternatively, the fluid 40 may be any of the therapeutic agents disclosed herein. When the polymer layer, e.g., the drug eluting layer 3, is exposed to the fluid 40, the embolic beads 1 may expand and increase in diameter. Alternatively, exposure of the fluid 40 to the embolic beads may activate the drug eluting layer 3 without expanding the embolic beads 1. In some embodiments, the introduction of the embolic beads 1 into the fluid 40 may occur before or after the embolic beads 1 are shipped to the hospital. In another embodiment, the radiation-emitting micron-sized embolic beads 1 are delivered in a separate vial 100 from the fluid 40, as shown in FIG. 4B, and the two are mixed and injected through a delivery mechanism.

[0055] In some embodiments, the embolic beads may be radiation-emitting and drug-eluting embolic beads. Compared to the embolic beads 1 of FIG. 1A and FIG. 1B, for example, the particles 50 may be a single mixture of base material 52, radiation-emitting isotope 54, and drug 56, as shown in FIG. 5. Once the base material is absorbed into the body, the drug may be time-released, advantageously allowing for greater amounts of the drug 56 and radiation-emitting isotope 54 to be provided to the patient without causing adverse side effects. The particles 50 may be as large as about 5 μm to about 1000 μm in overall size. The particles 50 may be made from any material that is bioabsorbable, such as polymers, hydrogels, etc. The particles 50 may be any regular or irregular 3D shape, including spheres, hemispheres, cubes, cones, cylinders, octahedrons, etc. Although the figures presented in this disclosure show the particles 50 as spherical or circular, these are purely for illustrative purposes only and do not reflect the only possible embodiments the particles may take.

[0056] In the method of delivering the embolic beads of the present invention, according to one embodiment, the method may include non-co-delivery of radioactive embolic particles 1 and fluid 40 (e.g., chemotherapeutic drugs, hypoxic radiosensitizers, or other drugs used to treat tumor cells), as shown in FIG. 6. In some embodiments, the fluid 40 may first be delivered to the arterial branch 200 that feeds the tumor 300 by a microcatheter 400. Immediately or later, the method may include delivery of radioactive embolic beads 1 to the same arterial branch 200. The idea is that the fluid 40 or drug is delivered to the tumor 300, and the radioactive embolic beads 1 can occlude the lumen, trapping the drug at a location and preventing the drug from migrating throughout the body. Advantageously, the radioactive embolic beads 1 may also deliver the radiation required to treat the tumor 300. Alternatively, the method may include using ultrasound-guided percutaneous methods to deliver the drug directly to the tumor, followed by delivery of the radioembolic material using standard techniques of placing a microcatheter in the appropriate blood vessel.

[0057] Some embodiments may include combining two separate particles. One particle 70 is a micron-sized embolic bead that emits radiation, and the other particle 80 is a micron-sized drug-eluting particle. Drug elution may be accomplished in any manner described in the above embodiments. In some embodiments, the drug may be a chemotherapeutic drug, a hypoxic radiosensitizer, or other drug used to treat tumor cells, such as those disclosed herein. The particles 70, 80 may be of any shape or material, as in other embodiments above. The two particles 70, 80 may be of the same or different materials, and may be of the same or different density. In some embodiments, the two particles 70, 80 may be of the same size and shape, or may be of two different sizes and shapes. The two particles 70, 80 may be already mixed together, as shown in FIG. 7A, or may be mixed upon injection into the patient via a delivery mechanism, as shown in FIG. 7B. Alternatively, in some embodiments, the delivery method may involve first injecting the drug-eluting particles 80 into the patient, followed by the radiation-emitting particles 70, or vice versa. The ratio of one grain to the other may vary considerably.

[0058] In some embodiments, in addition to the drugs added to the embolic beads 1, there may be the addition of CAR-T therapy or other cell therapy as an additional element. Cell therapy, including CAR-T, typically requires the extraction of the patient's natural cells, genetic modification of those cells, and reintroduction of the modified cells into the patient. In the case of CAR-T, the patient's T cells (both CD4 and CD8) may be harvested from the patient. The T cells are then genetically engineered to recognize and target tumor-specific antigens by gene editing techniques such as CRISPR / Cas9. The modified T cells may then be reintroduced into the patient's body by infusion to stimulate an immune response that targets cancer cells. CAR-T may include targeting specific antigens and proteins, but may also be tailored to target hypoxic cancer cells. This differs from hypoxic cell radiosensitization in that CAR-T is more similar to bioreductive drugs that are directly toxic to hypoxic cells. Thus, CAR-T therapy may be introduced in addition to hypoxic cell radiosensitizing drugs, not necessarily replacing them. Systemic administration of CAR-T therapy often leads to cytokine release syndrome (CRS), a potentially life-threatening inflammatory response to treatment. Localized delivery of CAR-T cells directly to tumors, for example using the present embolic beads, may reduce the severity of CRS.

[0059] The introduction of CAR-T into the embolic bead 1 can create radioembolization in the following ways: In one embodiment, the embolic bead 1 can: 1) embolize blood vessels to stop blood flow to tumor cells; 2) expose tumor cells to ionizing radiation, release radiation to kill tumor cells and upregulate tumor-associated antigen presentation; 3) enhance radiation-induced cell death in tumors; and 4) provide CAR-T to target tumor cells for an extended period of time after the radiation release and hypoxic cell radiosensitizer have worn off.

[0060] Several embodiments of the invention disclosed herein can be used to deliver cell therapy, including CAR-T. For example, in one embodiment, the hollow particle method described in FIG. 1C can be used, where hollow spheres are soaked in CAR-T therapy, then filtered and injected into the patient, or injected simultaneously with the particles. In some embodiments, the method described in FIG. 3A can also be used, where radioembolic beads 1 can be constructed in layers, with each layer constituting one specific means (radiation release, drug elution, CAR-T delivery). Alternatively, the method described with respect to FIG. 6 can be used, where CAR-T therapy can be delivered first to an arterial branch that feeds the tumor, followed immediately or later by delivery of radioembolic beads to the same arterial branch. Thus, CAR-T therapy is delivered to the tumor, and the radioembolic beads proximally occlude the arterial lumen, trapping the CAR-T therapy in a location and preventing systemic migration of the engineered cells. Radioembolic beads 1 can deliver therapeutic radiation. In a further embodiment, the method described in Figures 7A and 7B may be used, where a third particle comprising a cell therapy may be mixed with the radiation-emitting particles and the drug-eluting particles.

[0061] In some embodiments, the embolic beads of the present invention disclosed herein can be used to treat other indications or cancers with various therapeutic agents. For example, in some cases, the lung, like the liver, is supplied with blood from two different sources, the pulmonary artery and the bronchial artery. As liver tumors are supplied by the hepatic artery, lung tumors are typically supplied by the bronchial artery. Thus, much like the liver, the branches of the bronchial artery can be embolized without damaging the remaining healthy tissue of the lung. Furthermore, in some embodiments, the present disclosure includes applicability in the treatment of brain or spinal gliomas and prostate tumors, etc. The terms "tumor" and "tumor cell" are used herein, but such terms can mean "solid tumors".

[0062] The terms "including" and "including" as used herein are intended to be interpreted as inclusive rather than exclusive. The terms "exemplary," "example," and "illustrative" as used herein are intended to mean "serving as an example, instance, or illustration" and should not be interpreted as indicating or not indicating a preferred or advantageous configuration compared to other configurations. The terms "about," "generally," and "approximately" as used herein are intended to encompass variations that may exist at the upper and lower limits of a range of subjective or objective values, such as variations in properties, parameters, sizes, and dimensions. In one non-limiting example, the terms "about," "generally," and "approximately" mean plus or minus 10 percent or less. In one non-limiting example, the terms "about," "generally," and "approximately" mean close enough to be considered included by one of ordinary skill in the relevant art. The term "substantially" as used herein refers to the complete or nearly complete range or degree of an action, feature, characteristic, state, structure, item, or result, as would be understood by one of ordinary skill in the art. For example, an object that is "substantially" circular means that the object is either perfectly circular to a mathematically determinable limit, or approximately circular as recognized or understood by one of ordinary skill in the art. The exact acceptable degree of deviation from absolute perfection may depend on the particular context, as the case may be. Generally, however, the closeness of completion is such that it has the same overall result as if absolute and total completion had been achieved or obtained. The use of "substantially" is equally applicable when used in a negative sense to refer to a complete or nearly complete lack of an action, feature, characteristic, state, structure, item, or result, as would be understood by one of ordinary skill in the art.

[0063] Numerous modifications and alternative embodiments of the present disclosure will be apparent to those skilled in the art in view of the above description. This description should therefore be construed as illustrative only, and is intended to teach those skilled in the art the best mode for carrying out the present disclosure. Details of construction may be substantially changed without departing from the spirit of the present disclosure, and the exclusive use of all modifications that come within the scope of the appended claims is reserved. Although embodiments have been described herein so as to enable a clear and concise specification to be written, it is intended and understood that the embodiments may be variously combined or separated without departing from the invention. It is intended that the present disclosure shall be limited only to the extent required by the appended claims and the applicable rules of law.

Claims

1. Embolistic particles for use in the treatment of tumor cells, wherein the embolic particles are An internal core having a volume within which radioactive isotopes can be contained, and including a surface on which layers can be placed; The outer layer includes an outer layer having a thickness that allows it to contain a therapeutic agent, and which is placed on the surface of the inner core. The inner core and outer layer have a sufficient composite density to allow the embolic particles to move along the pathway with the fluid flow, and the embolic particles have dimensions large enough to engage the pathway and restrict the flow of fluid to tumor cells.

2. The embolic particle according to claim 1, wherein the dimensions of the embolic particle are sufficient to substantially block the flow of fluid through the pathway to tumor cells.

3. The embolic particle according to claim 2, wherein the embolic particle treats at least one primary or metastatic tumor of the liver, lungs, brain or spinal cord, prostate, breast, esophagus, upper respiratory tract, gastrointestinal tract, including the nasopharynx, nasal cavity, oral cavity, oropharynx, hypopharynx, larynx, neck, thyroid gland, lungs, mediastinum, stomach, small intestine, large intestine, pancreas, spine, kidneys, ureters, bladder, urethra, vagina, uterus, cervix, ovaries, lymph nodes, muscles and bones.

4. The embolic particle according to claim 1, wherein a therapeutic agent is injected into the outer layer.

5. The embolic particle according to claim 4, wherein the outer layer releases a therapeutic agent to tumor cells, and the embolic particle restricts the flow of fluid to the tumor cells.

6. The embolic particle according to claim 5, wherein the embolic particle treats at least one primary or metastatic tumor of the liver, lungs, brain or spinal cord, prostate, breast, esophagus, upper respiratory tract, gastrointestinal tract, including the nasopharynx, nasal cavity, oral cavity, oropharynx, hypopharynx, larynx, neck, thyroid gland, lungs, mediastinum, stomach, small intestine, large intestine, pancreas, spine, kidneys, ureters, bladder, urethra, vagina, uterus, cervix, ovaries, lymph nodes, muscles and bones.

7. The embolic particle according to claim 1, wherein a radioactive isotope is embedded in the internal core.

8. The embolic particle according to claim 7, wherein the internal core emits radiation and the embolic particle restricts fluid flow to irradiate tumor cells.

9. The embolic particle according to claim 8, wherein the embolic particle treats at least one primary or metastatic tumor of the liver, lungs, brain or spinal cord, prostate, breast, esophagus, upper respiratory tract, gastrointestinal tract, including the nasopharynx, nasal cavity, oral cavity, oropharynx, hypopharynx, larynx, neck, thyroid gland, lungs, mediastinum, stomach, small intestine, large intestine, pancreas, spine, kidneys, ureters, bladder, urethra, vagina, uterus, cervix, ovaries, lymph nodes, muscles and bones.

10. The embolic particle according to claim 1, wherein a radioactive isotope is embedded in the inner core and a therapeutic agent is impregnated in the outer layer.

11. The embolic particles restrict the flow of fluid to the tumor cells. The internal core emits radiation to kill tumor cells, and The embolic particle according to claim 10, wherein the outer layer releases a therapeutic agent to treat the remaining tumor cells.

12. The embolic particle according to claim 11, wherein the radioactive isotope comprises yttrium-90 (Y-90) or holmium-166.

13. The embolic particle according to claim 11, wherein the embolic particle treats at least one primary or metastatic tumor of the liver, lungs, brain or spinal cord, prostate, breast, esophagus, upper respiratory tract, gastrointestinal tract, including the nasopharynx, nasal cavity, oral cavity, oropharynx, hypopharynx, larynx, neck, thyroid gland, lungs, mediastinum, stomach, small intestine, large intestine, pancreas, spine, kidneys, ureters, bladder, urethra, vagina, uterus, cervix, ovaries, lymph nodes, muscles and bones.

14. The embolic particle according to claim 1, wherein the internal core is formed from at least one of a polymer, ceramic, glass, or glass-ceramic composite.

15. The embolic particle according to claim 14, wherein the internal core is sintered to a porosity of approximately 10% to approximately 75%.

16. The embolic particle according to claim 1, wherein the outer layer forms a uniform shape around the inner core.

17. The embolic particle according to claim 1, wherein the outer layer is formed from a polymer.

18. The embolic particle according to claim 17, wherein a radiopaque material is embedded in the outer layer.

19. The embolic particle according to claim 1, wherein the embolic particle has a substantially spherical shape.

20. The embolic particle according to claim 1, wherein the size of the embolic particle is approximately 15 μm to approximately 1000 μm.

21. The embolic particle according to claim 1, further comprising at least one further layer, wherein at least one further layer is different from the inner core and the outer layer.

22. A kit for the treatment of tumor cells, the kit is Multiple embolic particles, where each embolic particle is An internal core having a volume within which radioactive isotopes can be contained, and including a surface on which layers can be placed; The outer layer includes an outer layer having a thickness that allows it to contain a therapeutic agent, and which is positioned on the surface of an inner core; Here, the inner core and outer layer have a sufficient composite density to allow the embolic particles to move along the pathway with the fluid flow, and the embolic particles consist of multiple embolic particles, each having dimensions large enough to engage the pathway and restrict the flow of fluid to tumor cells; A liquid containing a therapeutic agent, wherein multiple embolic particles can be immersed in the liquid to inject the therapeutic agent into the outer layer; vial for containing liquid A kit that includes this.

23. The kit according to claim 22, wherein the liquid is placed inside a vial.

24. The kit according to claim 22, wherein when multiple embolic particles are placed in a liquid, a therapeutic agent is injected into the outer layer of the multiple embolic particles.

25. The kit according to claim 22, wherein the liquid comprises physiological saline.

26. The kit according to claim 22, wherein when multiple embolic particles are placed in a liquid, the size of the multiple embolic particles increases.

27. The kit according to claim 22, wherein when multiple embolic particles are placed in a liquid, the multiple embolic particles remain of the same size.

28. A method for producing embolic particles, wherein the method is A step of providing an internal core having a volume within which radioactive isotopes can be contained and including a surface on which layers can be placed; A step of providing a composition into which a therapeutic agent can be injected; and A process of creating an outer layer by placing a composition on the surface of the inner core. Methods that include...

29. The method according to claim 28, wherein the internal core includes a hollow internal chamber capable of containing a radioactive isotope or therapeutic agent.

30. The method according to claim 28, further comprising the step of injecting a radioactive isotope into the internal core.

31. The method according to claim 30, further comprising the step of activating a radioactive isotope so that the embolic particle emits radiation.

32. The method according to claim 30, further comprising the step of injecting a therapeutic agent into the outer layer.

33. The method according to claim 28, wherein the therapeutic agent is pre-mixed with the outer layer before the placement step.

34. An agent for treating tumor cells comprising embolic particles, wherein the method is: To provide a plurality of embolic particles, each having an inner core with a volume capable of containing a radioactive isotope and an outer layer with a thickness capable of containing a therapeutic agent; Identifying the target site containing tumor cells to be treated; and The goal is to deliver embolic particles into the lumen, allow multiple embolic particles to move along the pathway towards the target site with the fluid flow, and for the embolic particles to engage with the pathway to restrict fluid flow to tumor cells. A drug containing [something].

35. The agent according to claim 34, wherein the method further comprises activating a radioactive isotope within an internal core.

36. The agent according to claim 35, wherein the method further comprises irradiating tumor cells at a target site.

37. The agent according to claim 34, further comprising impregnating the outer layer of each of a plurality of embolic particles with a therapeutic agent.

38. The agent according to claim 37, wherein the impregnation step further comprises arranging a plurality of embolic particles in a fluid containing the therapeutic agent and injecting the therapeutic agent into at least the outer layer.

39. The agent according to claim 34, wherein the dimensions of each embolic particle restrict the movement of each embolic particle through the lumen of the target site, thereby preventing multiple embolic particles from moving away from the target site.

40. The agent according to claim 34, wherein the delivery step comprises delivering a plurality of embolic particles through arterial branches that supply nutrients to tumor cells.

41. The agent according to claim 35, further comprising a method of treating at least one primary or metastatic tumor of the liver, lungs, brain or spinal cord, prostate, breast, esophagus, upper respiratory tract, gastrointestinal tract, including the nasopharynx, nasal cavity, oral cavity, oropharynx, hypopharynx, larynx, neck, thyroid gland, lungs, mediastinum, stomach, small intestine, large intestine, pancreas, spine, kidneys, ureters, bladder, urethra, vagina, uterus, cervix, ovaries, lymph nodes, muscles and bones.

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