Radioembolic beads and methods for treating tumor cells

Abstract

Disclosed herein are methods, devices, and systems including embolic particles for treating tumor cells. An embolic particle may include an inner core and an outer layer. The inner core may have a volume in which a radioisotope may be received, the inner core may include a surface on which a layer may be disposed. An outer layer may have a thickness that may accommodate a therapeutic agent therein, the outer layer may be disposed on a surface of the inner core. The inner core and outer layer may have a combined density sufficient to cause the embolic particles to move along a path with fluid flow, while the embolic particles include dimensions sufficiently large to engage the path to limit fluid flow to tumor cells.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This patent application claims the benefit of U.S. Provisional Application No. 63 / 330,389, filed on April 13, 2022, entitled “RADIO-EMBOLIC BEADS FOR TREATING CANCER,” and U.S. Provisional Application No. 63 / 337,773, filed on May 03, 2022, entitled “RADIO-EMBOLIC BEADS FOR TREATING CANCER,” each of which is incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure relates to injectable particles for intravascular embolization of tumor cells with or without local delivery of radiation or therapeutic agents. Background Art

[0004] Malignant tumors of the liver include primary tumors, such as hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma, wherein HCC is the most common primary liver tumor. In addition, metastatic tumors from positions (such as intestine, breast, lung and esophagus) may involve the liver. For some patients, curative treatment can be provided by surgical resection of liver tumors. However, many patients suffering from primary or metastatic liver cancer will have potential medical complications or impaired liver function, which hinders radical liver surgery. In addition, the anatomical location or extent of liver tumors may make it technically impossible to resect. Summary of the invention

[0005] An alternative treatment modality for patients with inoperable liver tumors includes selective intra-arterial embolization of the tumor with microsphere particles. Liver tumors have an alternative blood supply from the normal liver parenchyma. Most primary and metastatic liver tumors will obtain most of their blood supply from the systemic arterial circulation through the branches of the celiac trunk. However, normal hepatocytes obtain their blood supply through the portal circulation. By utilizing this difference in blood supply, intra-arterial embolization selectively targets the tumor vasculature while retaining most of the blood supply of normal hepatocytes. In addition, similar to the liver, the lungs are supplied with blood by two different supplies from the pulmonary artery and the bronchial artery. Most lung tumors obtain their blood supply from the bronchial artery, while most lung parenchyma obtains its blood supply from the pulmonary artery. Therefore, essentially the same as the liver, the branches of the bronchial artery can be embolized with a low risk of damage to the surrounding normal lung parenchyma. In addition, the present disclosure also includes applicability in the treatment of tumors such as gliomas in the brain or spinal cord and prostate.

[0006] Microspheres for liver tumor embolization may include drug eluting substances for delivering chemotherapeutic agents. Alternatively, microspheres may contain radioactivity for a procedure commonly referred to as radioembolization. The most commonly used radioisotope is yttrium-90 (yttrium-90, Y-90), which is a pure beta-emitting isotope. The half-life of Y-90 is 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 a nuclear reactor), and Y-90 decays into zirconium-90. There are currently only two types of Y-90 microspheres available. Currently available glass spheres are microspheres composed of glass measuring 20 to 30 microns. Currently available resin spheres are resin spheres measuring 20 to 60 microns.

[0007] Low linear energy transfer forms of radiation (including 2.28 MeV beta particles produced by Y-90 decay) kill cancer cells through what is known as indirect action. Indirect action causes strand breaks in the phosphate-ribose backbone of DNA in chromosomes. Single-strand breaks are easily repaired, but double-strand DNA breaks will generally cause cells to die during mitosis. Indirect action is mediated by the formation of hydroxyl and peroxide free radicals produced when ionizing radiation passes through the body. The formation of these free radicals requires the presence of oxygen, and therefore indirect action is enhanced in well-oxygenated tissues. This can be mathematically expressed as the oxygen enhancement ratio (OER), and tissues with a robust vascular supply of well-oxygenated blood have a higher OER. By embolizing the arterioles that supply the tumor, cancer cells are in a more hypoxic environment, resulting in a lower OER, and therefore a lower level of tumor cell killing.

[0008] Radiosensitizers are chemicals that enhance radiation-related cell killing. Hypoxic cell radiosensitizers selectively enhance the killing of hypoxic cells, and have little effect on cells with normal oxygenation (oxygenation). Nitroimidazoles are a class of antibiotic drugs (metronidazole (metronidazole), which is most widely used as an antimicrobial agent), and also provide hypoxic cell radiosensitization. Misonidazole (misonidazole) is a second-generation 2-nitroimidazole, which, when combined with radiotherapy for the treatment of head and neck cancer patients in a randomized study (DAHANCA 2) in the Netherlands, shows improved outcomes. Recently, DAHANCA5 to 85 show that, in the case of adding nimorazole (nimorazole) to radiotherapy for the treatment of head and neck cancer, both local control and total survival are improved. Unfortunately, the systemic use of drugs (such as misonidazole and nimorazole) is subject to the limitations of its side effects and the delivery system (logistics) of accurately arranging drug dosage time in the case of radiotherapy, and the side effects include central nervous system toxicity.

[0009] Local delivery of hypoxic cell radiosensitizers may improve the therapeutic ratio of radioembolization by enhancing tumor cell killing while also mitigating the systemic side effects of radiosensitizing drugs. In 1992, Wang et al. published the results of an animal study involving intrahepatic arterial infusion of misonidazole in rabbits with VX2 hepatoma cells. The hepatic arterial infusion of misonidazole was then followed by 15 Gy external beam radiation therapy. When compared to rabbits that did not receive misonidazole, those that underwent hepatic arterial infusion exhibited the greatest tumor response, showing extensive fibrosis and necrosis.

[0010] In addition to the radiosensitization of hypoxic cells, many other chemicals and drugs have been shown to have radiosensitization properties. Chemotherapeutic drugs are usually delivered simultaneously with external beam radiotherapy, taking advantage of the synergistic cell killing effect caused by radiosensitization. Alkylating agents and anti-metabolic chemotherapeutic drugs inhibit the DNA repair pathways used by cells to repair sublethal damage due to ionizing radiation. The accumulation of sublethal damage that is not properly repaired leads to increased cell death. Taxane chemotherapeutic agents and other microtubule inhibitors block the cell cycle at the G2-M phase interface, when cells are most sensitive to radiotherapy. In addition, through the upregulation of radiation-induced antigen presenting cells (dendritic cells, etc.) and other proinflammatory effects, there is a well-documented synergy between ionizing radiation and immunotherapy for upregulating immune targeting of cancer cells. These drugs include anti-CTLA4 drugs, anti-PD-1 and PDL-1 drugs / checkpoint inhibitors, chimeric antigen receptor T cells (chimeric antigenreceptor T-cell, CAR-T) treatment and other immunomodulatory drugs.

[0011] Disclosed herein are novel embolic beads that combine radiation emitting embolic beads with moieties capable of containing and delivering drugs, including radiosensitizers. The disclosure described herein utilizes the enhanced radiation cell killing of radiosensitizers while minimizing the systemic effects of the drugs. By combining the two on a single embolic bead, they can be delivered together in a single injection and their colocation is ensured, thereby maximizing the effectiveness of the combination.

[0012] The present disclosure relates to embolic particles for treating tumor cells. The embolic particles include: an inner core having a volume that can accommodate a radioactive isotope therein, the inner core including a surface on which a layer can be arranged; an outer layer having a thickness that can accommodate a therapeutic agent therein, the outer layer being disposed on the surface of the inner core; and the inner core and the outer layer having a density sufficient to allow the embolic particles to move along a path with fluid flow, while the embolic particles include a size large enough to engage the path to restrict fluid flow to the tumor cells.

[0013] In some embodiments, the size of the embolic particles may be sufficient to substantially block fluid flow through the pathway to the tumor cells.The embolic particles may treat at least one of: a tumor of the liver, lung, prostate, or a glioma in the brain or spinal cord.

[0014] In some embodiments, the therapeutic agent may be injected into the outer layer. The outer layer may release the therapeutic agent to the tumor cells while the embolic particles restrict fluid flow to the tumor cells. The embolic particles may treat at least one of the following primary or metastatic tumors: 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 inner core may be embedded with a radioactive isotope. The inner core may emit radiation, and the embolic particles restrict fluid flow to irradiate tumor cells. The embolic particles may treat at least one of the following primary or metastatic tumors: 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 embedded with a radioactive isotope, and the therapeutic agent may be impregnated in the outer layer. The embolic particles may restrict fluid flow to tumor cells, the inner core may emit radiation to kill tumor cells, and the outer layer may release the therapeutic agent to treat residual tumor cells. The radioactive isotope may be yttrium-90 (Y-90). The embolic particles may treat at least one of the following primary or metastatic tumors: 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.

[0017] In some embodiments, the inner core may be formed of at least one of a polymer, a ceramic, a glass, a glass-ceramic composite. The inner core may be sintered with a porosity of about 10% to about 75%. The outer layer may be formed into a uniform shape around the inner core. The outer layer may be formed of a polymer. The outer layer may be embedded with a radiopaque substance. The embolic particle may have a substantially spherical shape. The size of the embolic particle may be about 15 microns to about 1000 microns. The embolic particle may include at least one additional layer, which may be different from the inner core and the outer layer.

[0018] In one embodiment, a kit for treating tumor cells is provided herein. The kit comprises: a plurality of embolic particles; a liquid containing a therapeutic agent and in which the plurality of embolic particles can be soaked to allow the therapeutic agent to be injected into the outer layer; a vial to contain the liquid; each embolic particle comprises: an inner core having a volume in which a radioactive isotope can be contained, the inner core comprising a surface on which a layer can be arranged; an outer layer having a thickness in which a therapeutic agent can be contained, the outer layer being disposed on the surface of the inner core; and the inner core and the outer layer having a density sufficient to allow the embolic particles to move along a path with fluid flow, while the embolic particles comprise a size large enough to engage the path to restrict fluid flow to the tumor cells.

[0019] In some embodiments, the liquid may be placed in a vial. When the plurality of embolic particles are placed in the liquid, the therapeutic agent may be injected into the outer layer of the plurality of embolic particles. The liquid may include saline. When the plurality of embolic particles are placed in the liquid, the size of the plurality of embolic particles may expand. When the plurality of embolic particles are placed in the liquid, the plurality of embolic particles may remain the same size.

[0020] Disclosed herein is a method for preparing embolic particles. The method includes providing an inner core having a volume in which a radioactive isotope can be contained, the inner core including a surface on which a layer can be disposed; providing a composition in which a therapeutic agent can be injected, and disposing the composition on the surface of the inner core to produce an outer layer.

[0021] In some embodiments, the inner core may include a hollow inner chamber that may contain a radioisotope or a therapeutic agent. The method may additionally include injecting a radioisotope into the inner core. The method may also include activating the radioisotope so that the embolic particles emit radiation. The method may also include injecting the therapeutic agent into the outer layer. The therapeutic agent may be premixed with the outer layer prior to the step of disposing.

[0022] Disclosed herein is a method for treating tumor cells using embolic particles. The method includes providing a plurality of embolic particles, each embolic particle having an inner core and an outer layer, the inner core having a volume that can accommodate a radioisotope therein, the outer layer having a thickness that can accommodate a therapeutic agent therein; identifying a target site including tumor cells to be treated; and delivering the embolic particles to a lumen and allowing the plurality of embolic particles to move along a path to the target site with fluid flow, so that the embolic particles engage with the path, thereby restricting fluid flow to the tumor cells.

[0023] In some embodiments, the method may further include activating the radioisotope within the kernel. The method may further include irradiating tumor cells at the target site. In some embodiments, the method may further include impregnating a therapeutic agent into the corresponding outer layers of a plurality of embolic particles. The impregnation step may further include placing a plurality of embolic particles in a fluid containing a therapeutic agent to inject the therapeutic agent into at least the outer layer. The size of each embolic particle may limit the movement of each embolic particle through the lumen at the target site to prevent the migration of a plurality of embolic particles from the target site. The delivery step may include delivering a plurality of embolic particles through arterial branches that supply tumor cells. The method may further include treating at least one of the following with a plurality of embolic particles: tumors of the liver, lungs, prostate, or gliomas in the brain or spinal cord. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1A is a partially cut-away perspective view of an embolic bead according to one embodiment of the present disclosure.

[0025] Figure 1B is a partially cut-away perspective view of an embolic bead having an inner core of radioisotope particles surrounded by an outer layer having a radiosensitizing drug.

[0026] Figure 1C is a cross-sectional view of an embolic bead according to one embodiment of the present disclosure.

[0027] Figure 2A is a partially cut-away perspective view of an embolic bead comprised of a single uniform sphere according to one embodiment of the present disclosure.

[0028] Figure 2B is a partially cut-away perspective view of an embolic bead having a single uniform sphere containing both a radioisotope and a radiosensitizing drug.

[0029] Figures 3A to 3C is a cross-sectional view of an embolic bead according to some embodiments of the present disclosure.

[0030] Figure 4A and 4B is a schematic diagram of an injection method according to some embodiments of the present disclosure.

[0031] Figure 5 is a cross-sectional view of an embolic bead according to one embodiment of the present disclosure.

[0032] Figure 6 An injection method according to one embodiment of the present disclosure is shown.

[0033] Fig. 7A and 7B is a schematic diagram of an injection method according to some embodiments of the present disclosure. DETAILED DESCRIPTION

[0034] In one embodiment, the present disclosure overcomes the shortcomings of the above-mentioned existing devices by providing such embolic beads or particles, which have co-administration of radioembolic and therapeutic agents (e.g., radiosensitizers). The present embolic beads initially increase tumor cell death caused by tumor irradiation. In some embodiments, the present embolic beads combine a radiation source with a drug eluting component containing a therapeutic agent (e.g., radiosensitizer) so that the administration of radiotherapy is carried out simultaneously with the administration of the radiosensitizer, or the administration of radiotherapy is followed by the administration of the radiosensitizer. In some embodiments, the present embolic beads allow the simultaneous administration of two therapeutic agents in the same position of the tumor microvasculature. The delivery of drugs from the outer layer may depend on the formulation of the outer layer so that the drug is released immediately upon delivery (by dissolving the outer layer) or delayed / timed release of the drug (slower dissolution of the outer layer). Advantageously, the present embolic beads allow for combined forms of treatment for interventional oncology while minimizing the radiation resistance of tumor cells due to hypoxia or other cellular and molecular processes, providing optimized activity, and having good flow characteristics. Such a device allows for curative treatment of a variety of tumors (eg, liver tumors) in an outpatient setting.

[0035] In other words, in various embodiments, the present embolic beads can advantageously provide at least dual treatments for certain tumor cells. By providing a single particle type having a radiation source for radiation therapy (e.g., radiation therapy for liver cancer) and a drug eluting component containing a therapeutic agent, the present embolic beads provide a more effective treatment than either treatment alone. The present embolic beads provide important benefits not found in prior art treatments. That is, prior art treatments use only one of radiation or a radiosensitizer, whereas the present disclosure provides a more comprehensive treatment than previously provided.

[0036] In general, liver cancer can be treated with embolization. Embolization can be used for tumors that cannot be removed by traditional surgery. For example, embolization can be used in cases where the tumor is too large to be treated with ablation (e.g., the tumor diameter is greater than 5 cm), and there is still enough liver function. Embolization can reduce blood supply to normal liver tissue, so for some patients whose liver is damaged by diseases (e.g., hepatitis or cirrhosis), this embolization may not be a good choice. However, since the liver has two blood supplies, the hepatic artery that usually provides blood supply to cancer in the liver can be blocked or otherwise restricted, while allowing the portal vein to supply blood to healthy liver cells. In addition, similar to the liver, the lungs are supplied with blood by two different supplies from the pulmonary artery and the bronchial artery. Just as liver tumors are attached to the hepatic artery, almost all lung tumors are attached to the bronchial arteries. Therefore, basically the same as the liver, the branches of the bronchial arteries can be embolized without damaging the remaining healthy tissue in the lungs. Other organs and anatomical parts in the human body are easy to implant radioactive sources directly into the interstitial tissue or in the body cavity, and this process is called interstitial or intracavitary brachytherapy. The present embolic beads may additionally be used for interstitial or intracavitary brachytherapy, providing a method for anatomically localized simultaneous delivery of therapeutic radiation and therapeutic agents (e.g., radiosensitizers) by routes other than transarterial embolization. Thus, the present disclosure includes applicability in the treatment of primary or metastatic tumors in the 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, spine, kidney, ureter, bladder, urethra, vagina, uterus, cervix, ovary, lymph node, muscle and bone, etc.

[0037] According to one embodiment of the present disclosure, the embolic beads include a radioembolic or radiotherapeutic portion and a drug eluting portion or a radiosensitizer eluting portion. In one embodiment, the radioembolic portion can be the internal portion of the embolism and can be composed of a substantially hard material, such as a polymer, glass, ceramic, or glass-ceramic composite material. In one embodiment, in order to provide an internal portion with radiotherapy capabilities, the internal portion can be injected or embedded with Y-90 or a resin containing Y-90. Alternatively, any similar radioactive isotope can be used as a radiotherapy source. Therefore, substantially hard particulate materials similar to glass or resin can also be used as substrates for radioactive isotopes. In some embodiments, the radiation emitting portion can be a uniform mixture of glass, polymer or hydrogel, ceramic, glass-ceramic composite, or any other material with a radiation emitting radioisotope. Alternatively, the radiation emitting portion can be a non-uniform mixture of glass, polymer or hydrogel, ceramic, glass-ceramic composite, or any other material with a radiation emitting radioisotope.

[0038] In some embodiments, radioembolic beads may be coated, encapsulated or otherwise combined with a drug eluting compound or drug that can carry a therapeutic agent for slow release after or during the irradiation period. For example, in one embodiment, the therapeutic agent may be released after the irradiation period to ensure that any tumor cells that are not killed by irradiation are eliminated. Drug eluting embolic agents may include polyvinyl alcohol (PVA) polymers doped with sulfonyl groups, which allow electrostatic charges to bind to polarized molecules. Some examples include DC / LC beads and QuadraSphere beads. Additional embolic beads for chemical embolization may include iodized oil, gelatin sponges, polymethyl methacrylate (Oncozene) and degradable starch (Spherex). However, it should be understood that these embolic beads do not share the same drug elution properties as PVA polymers.

[0039] In one embodiment, the radioembolic beads may include a glass, ceramic, or Y-90 resin-containing radioembolic core coated with a drug eluting shell (e.g., PVA polymer or other polymers. Other drug eluting coatings, known or unknown, or other ways of incorporating drugs into or on the surface of the microparticles are within the scope and spirit of the present disclosure. For example, the PVA polymer can carry a hypoxic cell radiosensitizer for slow elution into the irradiated area.

[0040] In some embodiments, the diameter of the embolic beads 1 of the present disclosure may be greater than about 15 microns to prevent embolism through arteriovenous shunts and non-target organ embolism, biliary ischemia, hepatobiliary infarction, or other adverse effects. In one embodiment, the upper size threshold that the embolic beads may include is 1,000 microns, because larger sizes can lead to blockage of commonly used microcatheters. In addition, large particles can cause more proximal arterial blockage, promote hypoxia, and can sub-select more resistant cancer cell populations. However, in practice, the embolic particles can be any size that meets the clinical requirements for achieving the desired anatomical distribution.

[0041] The present disclosure will now be described in detail below with reference to the accompanying drawings. The present disclosure is not intended to be limited to the described embodiments; rather, the detailed description is provided to enable any person skilled in the art to make and practice the present disclosure.

[0042] Go to Figure 1A and 1BIn one embodiment, the embolic bead 1 may be composed of an inner core 2 and an outer layer 3. The overall size of the embolic bead 1 may be any value from about 5 microns to about 1000 microns. The terms size or dimensions used herein may refer to external dimensions, including width, length, diameter, etc. The embolic bead 1 may be any regular or irregular 3D shape, including but not limited to spheres, hemispheres, cubes, cones, cylinders, octahedrons, etc. The drawings presented in the present disclosure are shown as spherical or circular. These are for illustrative purposes only and do not reflect the only embodiments in which the particles can be. In some embodiments, at least a portion of the embolic bead 1 may have a radiopaque substance embedded therein. The radiopaque substance may advantageously allow visualization of the delivery of one or more embolic beads 1 in a patient to a target site (e.g., the location of a tumor).

[0043] According to one embodiment, the inner core 2 may be made of a polymer, glass, ceramic, glass-ceramic composite, resin, or a combination thereof. A core composed of any other biocompatible material capable of accommodating a radioactive isotope is also within the scope of the present disclosure. In one embodiment, the inner core 2 of the embolic bead 1 may provide a volume within which a radioactive isotope 7 may be placed, which may deliver localized radiation therapy to the surrounding tumor when the embolic bead 1 is deployed to the tumor site. Exemplary radioactive isotopes used in such a procedure may be yttrium-90 (Y-90) or holmium-166, but utilizing any known or unknown beta or gamma emitting radioactive isotope is also within the scope of the present disclosure. In some embodiments, such as Figure 1A and 1B As shown, the core 2 may be solid, such as a solid sphere. Figure 1C As shown, the inner core 2 can be porous, having a plurality of irregularly or regularly positioned pores 11; and includes a hollow internal section 10, which is used to contain additional drugs or radiosensitizing compounds, including those described above. In some cases, the inner core 2 can be a solid or hollow core sintered to a porosity of about 10% to 75%. The deposition of the fluid in the hollow internal section 10 can be achieved by immersing the embolic bead 1 in a specific fluid bath and allowing the fluid to be deposited inside the particles (e.g., through the pores 11). The particles can then be filtered out to separate them from the fluid bath. Filtering the embolic beads 1 from the fluid bath can be performed 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, such as an outer layer 3.

[0044] In one embodiment, the outer layer 3 may include glass, ceramic, ceramic / glass, resin, polymer, metal or other biocompatible material for drug elution or release, which can be deposited, adhered, coated or otherwise attached to the inner core 2, and can be delivered and eluted when deployed in vivo. In one embodiment, the outer layer 3 can be deposited or coated on the inner core 2 so that the resulting embolic bead 1 does not have any rough or jagged edges to prevent the embolic bead 1 from damaging any healthy tissue in contact with it during administration. In some embodiments, the outer layer 3 of the embolic bead 1 may have a thickness that can accommodate therapeutic agents (e.g., radiosensitizing compounds, hypoxic cytotoxins, immunotherapy, CAR-T therapy, etc.), and thus have a resulting volume, which can be spread or emitted from the embolic bead to the surrounding tumors and body tissues at the same time or at different times when the radioisotope compound treats the tumor. In one embodiment, the compound can be a hypoxic cell radiosensitizer, such as nitroimidazole. However, the use of any known or unknown therapeutic compound is within the scope of the present disclosure. In some embodiments, the outer core 3 may remain intact after delivery to the intended site in the patient's body, or alternatively, the outer core 3 may be absorbed into the body after delivery. In addition, although the figure shows the core 2 having the radioactive isotope and the outer layer 3 having the drug eluting portion, the positions of the two layers can be reversed to have the drug eluting portion in the core and the radioactive isotope in the outer layer. In this configuration, the materials constituting the core and outer layer may also need to be reversed. Alternatively, as Figure 2A and 2B As shown, in some embodiments, the embolic bead 4 can be a uniform material 5 forming the entire bead, such as resin, glass, polymer or ceramic-glass composite material. Radioisotope 9 and radiosensitizer 8 can be mixed in the embolic bead 4.

[0045] In some embodiments, the therapeutic agent can be a radiosensitizer, which can be a nitroimidazole hypoxic cell radiosensitizer. Alternatively, the drug eluting portion can contain any other therapeutic compound, including but not limited to non-nitroimidazole hypoxic cell radiosensitizers, radiosensitizing chemotherapeutic agents such as taxanes (e.g., paclitaxel) or platinum-containing compounds (e.g., cisplatin), or other radiosensitizing compounds yet to be identified.

[0046] In some embodiments, the present embolic beads 1 may include an inner core 2 and an outer layer 3, wherein the inner core 2 does not contain a radioactive substance and the outer layer does not contain a therapeutic agent. In such a case, the embolic beads 1 may perform TAE or bland embolization on the tumor to deprive the tumor of an energy source. Alternatively, in some cases, the present embolic beads 1 may be used for trans-arterial chemoembolization (TACE). TACE is typically used as an initial embolization type for large liver cancers that cannot be treated with surgery or ablation, and embolization is combined with chemotherapy (chemo). For example, the drug eluting portion may include doxorubicin, cisplatin, epirubicin, miriplatin, carboplatin, mitomycin C, gemcitabine, or 5FU. In the case of treating metastatic tumors derived from hepatocellular carcinoma (HCC), the drug-eluting portion may include certain systemic agents, including Atezolizumab, Bevacizumab, Tremelimumab-actl, Darvalumab, Soreafenib, Lenvatinib, Pembrolizumab, Nivolumab, Ipilimumab, Regorafenib, Cabozantinib, Ramucirumab, Dostarlimab, or Selpercatinib.In some embodiments, in the case of treating metastatic tumors derived from colorectal cancer, the drug eluting portion may include 5FU, Oxaliplatin, Leukovorin, Capecitabine, Irinotecan, Bevacizumab, Panitumumab, Nivolumab, Ipilimumab, Pembrolizumab, Trastuzumab, Pertuzumab, mab), Lapatinib, Tucatinib, Ramuciumab, Ziv-aflibercept, Cetuximab, Panitumumab, Encorafenib, Dotalimumab-GXLY, Lapatinib, Fam-Trastuzumab, Deruxtecan, Regorafenib, Trifluridine, or Tipiracil.

[0047] In some embodiments, when treating metastatic tumors derived from cholanigiocarcinoma, the drug eluting portion may include those drugs commonly treated with TACE, including doxorubicin, cisplatin, epirubicin, miplatin, carboplatin, mitomycin C, gemcitabine, or 5FU. Alternatively, the drug eluting portion may include any of the following: 5FU, Capecitabine, Oxaliplatin, Leucovorin, Gemcitabine, Cisplatin, Durvalumab, Paclitaxel & NAB-Paclitaxel, Regorafenib, Irinotecan, Lenvatinib, Pembrolizumab, Entrectinib, Larotrectinib, Nivolumab, Ipilimumab, Pralsetinib, Selpercatinib, Dotalimumab-gxly, Dabrafenib, Trametinib, Futibatinib, Pemigatinib, Ivosidenib, Trastuzumab, or Pertuzumab.

[0048] In some embodiments, when treating metastatic tumors derived from breast cancer, the drug eluting portion may include Adriamycin, Cyclophosphamide, Paclitaxel, Docetaxel, Olaparib, Pebrolizumab, 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 may include carboplatin, paclitaxel, cisplatin, pemetrexed, gemcitabine, docetaxel, vinorelbine, etoposide, nivolumab, osimertinib, atezolizumab, pembrolizumab, or darvalumab. In some embodiments, when treating metastatic tumors derived from prostate cancer, the drug eluting portion may include Nilutamide, Flutamide, Bicalutamide, Abiraterone, Enzalutamide, Apalutamide, Darolutamide, Docetaxel, Ketoconazole, Cabazitaxel, Carboplatin, Mitoxantrone, and Pembrolizumab. In some embodiments, when treating metastatic tumors derived from pancreatic cancer, the drug eluting portion may include 5FU, Oxaliplatin, Irinotecan, Leucovorin, Gemcitabine, Paclitaxel, Nab-Paclitaxel, Cisplatin, Erlotinib, Dabrafenib, Trametinib, Pembrolizumab, Larotrectinib, Entrectinib, Dabrafenib, Olaparib, Rucaparib.

[0049] By combining a radioisotope and a drug eluting layer infused with a therapeutic agent on the same embolic bead or microparticle, tumor cell killing can be enhanced while maintaining a simplified procedure that only requires a single hepatic artery cannulation and a single therapeutic substance injection. In addition, the range of the beta particles emitted by Y-90 is only about 1 mm in the tissue. Therefore, it is crucial to ensure that the common location of the radiation source and the radiosensitizer elution is crucial. This can be achieved by co-administering on the same embolic bead, because combining radioactive embolic beads with separate drug eluting particles cannot guarantee that two therapeutic agents will be delivered to the same anatomical location. In some embodiments, in addition to biological radioembolization involving simultaneous delivery of therapeutic agents, the present embolic beads can be used for TAE (or mild embolization), TACE (or chemoembolization) and TARE (or radioembolization). In the case of TARE, if the physician chooses to do so, the present embolic beads may have the ability to deliver drugs. In some embodiments, in the case of TARE, without embedding the therapeutic agent in the outer layer 3, the present embolic bead 1 can activate the radioactive material embedded in the inner core 2. In such an embodiment, the embolic beads 1 can be injected into the patient so that the embolic beads 1 treat the tumor at the target site by emitting only radiation. In some embodiments, the therapeutic substance can be injected into the outer layer 3 after the time of delivery to the hospital or health care facility but before injection into the patient. In some embodiments, the present embolic beads can provide a specific combination of specific drugs and radiation emitting beads. In some cases, the present embolic beads may not have activated radioactive isotopes, which will produce particles with polymer coatings on the core and the exterior, and will also be used in the TAE and TACE markets. Therefore, the present embolic beads allow embolic beads that can have radiation emission, drug delivery and embolic capabilities, while some embolic beads can only have drug delivery and embolism (no radiation).

[0050] In some embodiments, the radiosensitizer can be used to treat a variety of metastatic tumors affecting the liver. For example, the radiosensitizer can be a nitroimidazole hypoxic cell radiosensitizer. Alternatively, the drug eluting portion can contain any other radiosensitizing compound, including but not limited to non-nitroimidazole hypoxic cell radiosensitizers, radiosensitizing chemotherapeutic agents such as taxanes (e.g., paclitaxel) or platinum-containing compounds (e.g., cisplatin), or other radiosensitizing compounds yet to be identified. For example, in some embodiments, in the case of treating metastatic tumors in the liver derived from colorectal cancer, the drug eluting portion or outer layer 3 can be injected with: 5FU, oxaliplatin, leucovorin, capecitabine, irinotecan, bevacizumab, panitumumab, nivolumab, ipilimumab, pembrolizumab, trastuzumab, pertuzumab, lapatinib, tucatinib, ramucirumab, Ziv-aflibercept, cetuximab, panitumumab, connefenib, dotalimumab-gxly, lapatinib, Fam-trastuzumab, delutec, regorafenib, trifluridine or tipiracil.

[0051] 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 greater than the density of the second material density. However, advantageously, the embolic bead 1 made 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 have buoyancy or neutral buoyancy in the fluid, and thus the embolic bead 1 may have favorable flow characteristics in the fluid (e.g., human blood). Favorable flow characteristics may be understood to mean that the embolic bead 1 may flow in the fluid without sinking and getting stuck in a lumen (e.g., 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 a hole or a hollow cavity may be more buoyant than a solid inner core of the same size.

[0052] In some embodiments, the embolic bead 1 can be constructed of any combination of layers, such as an inner core 2 of a radiation emitting substance 7 and an outer layer 3 of a drug eluting substance 6, such as Figure 1A and 1B Alternatively, the embolic bead 1 may be formed of any number of layers, such as Figure 3A As shown, some of the combinations are: one of the layers is a radiation emitting layer 2, and one of the layers is a drug eluting layer 3. In some embodiments, as Figure 3B As shown, the embolic bead 1 may incorporate a binding layer 20 that binds the drug eluting layer 3 to other layers (e.g., the radiation emitting layer 2). The binding layer 20 may be incorporated at the interface of any of the multiple layers. The binding layer may be a binding agent, which may be polymeric in nature or utilize some form of ionic bonding. The embolic bead 1 may incorporate a sacrificial encapsulation layer 30 that contains the eluting drug relative to the rest of the particle, such as Figure 3C When the particles are administered to a patient, the sacrificial layer may dissolve and disappear, thereby exposing the drug eluting layer 3 at the desired destination location.

[0053] In the method of use, it may be necessary to activate drug elution. For example, in order to initiate drug delivery at a target site, it may include removing the sacrificial layer 30 to expose the drug eluting layer 3, such as Figure 3CAs shown, or activate the already exposed drug layer. Activation can be accomplished in a variety of ways, including: exposing the embolic bead 1 to body fluids; exposing the embolic bead 1 to body temperature; exposing the embolic bead to an external energy source, such as radiation, heat, MRI, or ultrasound; exposing the embolic bead 1 to a fluid, such as saline, outside the patient's body before administering the particles; exposing the embolic bead 1 to light; exposing the embolic bead 1 to magnetic force; injecting CO2 that can react with the drug; and / or radiation emission from isotope fission within the nucleus 2 to transform the drug. In some embodiments, the method may include delivering an energy delivery device (such as ablation / heat) percutaneously to the target site after delivering the embolic bead 1, and delivering energy with the energy delivery device (such as ablation / heat) at the target site. In one embodiment, the method of activating the drug may include using an internal gas source implanted in the particle, which expands and ruptures the particle or forms holes when exposed to body temperature or some other energy source.

[0054] In some embodiments, methods are 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, such as Figure 4A As shown. In some embodiments, fluid 40 can be a chemotherapeutic drug, a hypoxic radiosensitizing drug, or any other agent used to treat tumor cells. The term radiosensitizer used herein refers to a hypoxic cell radiosensitizer, a bioreductive drug, a radiosensitizing chemotherapeutic agent, an immunotherapeutic agent, or any other radiosensitizing chemical, protein, drug, or compound known today or in the future. The embolic beads 1 and the fluid 40 can be contained in a single vial 100 and delivered to a clinician for use. For example, the embolic beads 1 can be transported without the drug eluting layer 3 including any therapeutic agent. In such a case, the hospital can mix the embolic beads 1 with the therapeutic agent through the fluid 40 before administering the embolic beads 1 to the patient.

[0055] 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 approximately 100% NaCl 0.9% aqueous solution, a non-ionic contrast medium, or an approximately 50 / 50 mixture of NaCl 0.9% aqueous solution and a contrast agent. Alternatively, the fluid 40 may be any therapeutic agent disclosed herein. When the polymer layer (e.g., the drug eluting layer 3) is exposed to the fluid 40, the embolic beads 1 may swell, causing their diameter to expand. Alternatively, exposure of the fluid 40 to the embolic beads may activate the drug eluting layer 3 without causing the embolic beads 1 to swell. In some embodiments, the introduction of the embolic beads 1 into the fluid 40 may occur before or after the embolic beads 1 are transported to the hospital. In an alternative embodiment, the radiation-emitting micron-sized embolic beads 1 are delivered in a vial 100 different from the fluid 40, where the two are mixed and injected via a delivery mechanism, such as Figure 4B shown.

[0056] In some embodiments, the embolic beads may be radiation emitting drug eluting embolic beads. Figure 1A and 1B Compared to the embolic beads 1, the particles 50 may be a single mixture of a base material 52, a radiation emitting isotope 54 and a drug 56, such as Figure 5 As shown. When the base substance is absorbed in the body, the drug can be sustained-release to advantageously allow the drug 56 and the radiation-emitting isotope 54 to be provided to the patient in larger quantities without causing harmful side effects. The overall size of the particle 50 can be from about 5 microns to about 1000 microns. The particle 50 can be made of any bioabsorbable material (e.g., polymers, hydrogels, etc.). The particle 50 can be any regular or irregular 3D shape, including spheres, hemispheres, cubes, cones, cylinders, octahedrons, etc. Although the drawings presented in the present disclosure show the particles 50 as spherical or circular, these drawings are for illustrative purposes only and do not reflect the only embodiments that the particles can be.

[0057] According to one embodiment, in the present embolic bead delivery method, the method may encompass non-simultaneous delivery of radiation emitting embolic particles 1 and fluid 40 (e.g., chemotherapeutic drugs, hypoxia radiosensitizer drugs, or any other agent for treating tumor cells), such as Figure 6As shown. In some embodiments, the fluid 40 may first be delivered to the arterial branch 200 supplying the tumor 300 via a microcatheter 400. Whether immediately or afterwards, the method may include delivering the radioembolic beads 1 into the same arterial branch 200. The idea is to deliver the fluid 40 or drug to the tumor 300, and the radioembolic beads 1 may block the lumen to trap the drug in place and prevent systemic migration of the drug. Additionally and advantageously, the radioembolic beads 1 may additionally deliver the necessary radiation to treat the tumor 300. Alternatively, the method may include delivering the drug directly into the tumor using an ultrasound-guided percutaneous approach, followed by delivery of the radioembolism using standard techniques of a microcatheter placed in an appropriate vessel.

[0058] Some embodiments may include combining two separate particles. One particle 70 may be a radiation emitting micron-sized embolic bead and the second particle 80 may be micron-sized and drug eluting. Elution of the drug may be accomplished in any of the ways described in the above embodiments. In some embodiments, the drug may be a chemotherapeutic drug, a hypoxic radiosensitizer drug, or any other agent used to treat tumor cells, such as those disclosed herein. The particles 70, 80 may be of any shape or substance as described in the other embodiments described above. The two particles 70, 80 may be the same substance or different substances and may have the same or different densities. In some embodiments, the two particles 70, 80 may have the same size and shape, or alternatively, they may have two different sizes and shapes. The two particles 70, 80 may be already mixed together, such as Fig. 7A As shown, or can be mixed when injected into the patient via a delivery device, such as Figure 7B Alternatively, in some embodiments, the delivery method may involve first injecting the drug eluting particles 80 alone into the patient and then subsequently injecting the radiation emitting particles 70 thereafter, or vice versa. The ratio of one particle to the other can be over a fairly wide range.

[0059] In some embodiments, in addition to the drug added to the embolic beads 1, CAR-T therapy or other cell therapy may be added as an additional element. Cell therapy (including CAR-T) generally requires the extraction of the patient's natural cells, genetic modification of these 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) can be collected from the patient. Then, the T cells are genetically modified by gene editing technology (such as CRISPR / Cas9) to identify and target tumor-specific antigens. Then, the modified T cells can be reintroduced into the patient by injection to stimulate the immune response targeting cancer cells. CAR-T can not only include targeting specific antigens and proteins, but can also be tailored to target hypoxic cancer cells. This is different from hypoxic cell radiosensitization, because CAR-T may be more like a bioreduction drug that is directly toxic to hypoxic cells. Therefore, CAR-T therapy can be introduced in addition to hypoxic cell radiosensitizer drugs, but not necessarily instead of it. Systemic administration of CAR-T therapy often leads to cytokine release syndrome (CRS), a potentially life-threatening inflammatory response to treatment. Local delivery of CAR-T cells directly to tumors (e.g., with the present embolic beads) can reduce the severity of CRS.

[0060] Introducing CAR-T into embolic beads 1 can produce radioembolism in the following modes. In one embodiment, embolic beads 1 can provide 1) vascular embolism to block blood flow to tumor cells; 2) radiation emission to expose tumor cells to ionizing radiation, kill tumor cells and upregulate tumor-associated antigen presentation; 3) radiosensitization to enhance radiation-induced cell death in tumors; and 4) CAR-T to target tumor cells for an extended period of time after radiation emission and hypoxic cell radiosensitizers have subsided.

[0061] Various embodiments of the invention disclosed herein can be used to deliver cell therapy (including CAR-T). For example, in one embodiment, the invention can be used as Figure 1C The hollow particle method described in , wherein the hollow spheres are immersed in the CAR-T therapy and then filtered out and injected into the patient, or injected simultaneously with the particles. In some embodiments, it is also possible to use Figure 3A The method described in, wherein the radioembolic beads 1 can be constructed in layers, wherein each layer constitutes a specific form (radiation emission, drug elution, CAR-T delivery). Alternatively, the method can be used with respect to Figure 6The method described herein, wherein the CAR-T therapy may first be delivered to a branch of an artery supplying a tumor, and immediately or subsequently, followed by delivery of radioembolic beads into the same branch of an artery. Thus, the CAR-T therapy is delivered to the tumor, and the radioembolic beads occlude the lumen of the artery proximally, trapping the CAR-T therapy in place and preventing systemic migration of the modified cells. The radioembolic beads 1 may also deliver therapeutic radiation. In an additional embodiment, the radioembolic beads 1 may be used Fig. 7A and 7B The method wherein the third particle containing the cell therapy can be mixed with the radiation emitting particles and the drug eluting particles.

[0062] In some embodiments, the present embolic beads disclosed herein can be used to treat other indications or cancers together with a variety of therapeutic agents. For example, in some cases, similar to the liver, the lungs are supplied with blood from two different supplies, the pulmonary artery and the bronchial artery. Just as liver tumors are supplied by the hepatic artery, lung tumors are typically supplied by the bronchial arteries. Therefore, essentially the same as the liver, the branches of the bronchial arteries can be embolized without damaging the remaining healthy tissue in the lungs. In addition, in some embodiments, the present disclosure also includes applicability in the treatment of gliomas in the brain or spinal cord and tumors of the prostate, etc. Although the terms "tumor" and "tumor cells" are used herein, such terms may also refer to "solid tumors."

[0063] The term "include / comprises" and its variations used herein are intended to be interpreted as inclusive, not exclusive. The terms "exemplary", "example" and "illustrative" used herein are intended to mean "used as an example, instance or illustration", and should not be interpreted as indicating or not indicating a preferred or advantageous configuration relative to other configurations. The terms "about", "usually" and "approximately" used herein are intended to cover changes that may exist in the upper and lower limits of subjective or objective value ranges, such as changes in characteristics, parameters, sizes and dimensions. In a non-limiting example, the terms "about", "usually" and "approximately" mean to be or plus 10% or less, or minus 10% or less. In a non-limiting example, the terms "about", "usually" and "approximately" mean close enough to be considered included by a person skilled in the relevant art. As understood by those skilled in the art, the term "substantially" used herein refers to the complete or almost complete range or degree of an action, feature, characteristic, state, structure, article or result. For example, as recognized or understood by those skilled in the art, an object "substantially" circular means that the object is completely circular, or close to a circular shape, for a mathematically determinable limit. In some cases, the exact degree of deviation from absolute completeness that is permitted may depend on the specific context. However, in general, nearly complete will have all the results as if absolute and complete completion were achieved or obtained. As will be understood by those skilled in the art, the use of "substantially" is equally applicable when "substantially" is used in a negative sense to refer to the complete or nearly complete lack of an action, feature, characteristic, state, structure, item, or result.

[0064] In view of the foregoing description, multiple modifications and alternative embodiments of the present disclosure will be obvious to those skilled in the art. Therefore, this description should be interpreted as illustrative only, and is for the purpose of teaching those skilled in the art to implement the best mode of the present disclosure. Without departing from the spirit of the present disclosure, the details of the structure can be significantly changed, and the exclusive use of all modifications within the scope of the attached claims is retained. In this specification, embodiments have been described in a manner that enables a clear and concise description to be written, but the purpose is and should be understood that, without departing from the present invention, embodiments can be variously combined or separated. It is intended that the present disclosure is limited to the scope required by the attached claims and applicable laws and regulations.

Claims

1. An embolic particle for treating tumor cells, the embolic particle comprising: an inner core having a volume in which the radioisotope may be contained, the inner core including a surface on which the layer may be disposed; an outer layer having a thickness capable of accommodating a therapeutic agent therein, the outer layer being disposed on a surface of the inner core; and The inner core and outer layer have a combined density sufficient to allow the embolic particles to move along a pathway with fluid flow, while the embolic particles comprise a size large enough to engage the pathway to restrict fluid flow to the tumor cells.

2. The embolic particle of claim 1, wherein the embolic particle is of a size sufficient to substantially block the flow of the fluid through the pathway to the tumor cell.

3. The embolic particle of claim 2, wherein the embolic particle treats at least one of the following primary or metastatic tumors: 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.

4. The embolic particle of claim 1, wherein the therapeutic agent is infused into the outer layer.

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

6. The embolic particle of claim 5, wherein the embolic particle treats at least one of the following primary or metastatic tumors: 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. The embolic particle of claim 1 , wherein the inner core is embedded with a radioactive isotope.

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

9. The embolic particle of claim 8, wherein the embolic particle treats at least one of the following primary or metastatic tumors: 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.

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

11. The embolic particle of claim 10, wherein the embolic particle restricts the flow of the fluid to the tumor cell, The core emits radiation to kill the tumor cells, and The outer layer releases the therapeutic agent to treat residual tumor cells.

12. The embolic particle of claim 11, wherein the radioisotope comprises yttrium-90 (Y-90) or holmium-166.

13. The embolic particle of claim 11, wherein the embolic particle treats at least one of the following primary or metastatic tumors: 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.

14. The embolic particle of claim 1, wherein the inner core is formed of at least one of a polymer, a ceramic, a glass, and a glass-ceramic composite.

15. The embolic particle of claim 14, wherein the inner core is sintered to have a porosity of about 10% to about 75%.

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

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

18. The embolic particle of claim 17, wherein the outer layer is embedded with a radiopaque material.

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

20. The embolic particle of claim 1, wherein the embolic particle has a size of about 15 microns to about 1000 microns.

21. The embolic particle of claim 1, further comprising at least one additional layer, the at least one additional layer being different from the inner core and outer layer.

22. A kit for treating tumor cells, the kit comprising: A plurality of embolic particles, each embolic particle comprising, an inner core having a volume in which the radioisotope may be contained, the inner core including a surface on which the layer may be disposed; an outer layer having a thickness capable of accommodating a therapeutic agent therein, the outer layer being disposed on a surface of the inner core; and The inner core and outer layer have a combined density sufficient to allow the embolic particles to move along a pathway with fluid flow, while the embolic particles include a size large enough to engage the pathway to restrict fluid flow to the tumor cells; a liquid comprising the therapeutic agent and into which the plurality of embolic particles can be soaked to allow the therapeutic agent to infuse into the outer layer; A vial to contain the liquid.

23. The kit of claim 22, wherein the liquid is disposed in the vial.

24. The kit of claim 22, wherein the therapeutic agent is infused into an outer layer of the plurality of embolic particles when the plurality of embolic particles are placed in the liquid.

25. The kit of claim 22, wherein the liquid comprises saline.

26. The kit of claim 22, wherein the plurality of embolic particles expand in size when placed in the liquid.

27. The kit of claim 22, wherein the plurality of embolic particles remain the same size when placed in the liquid.

28. A method for preparing embolic particles, the method comprising, providing an inner core having a volume in which the radioisotope can be accommodated, the inner core including a surface on which the layer can be disposed; Providing a composition into which a therapeutic agent can be injected, and The composition is disposed on the surface of the inner core to produce an outer layer.

29. The method of claim 28, wherein the inner core comprises a hollow interior chamber that can contain the radioisotope or the therapeutic agent.

30. The method of claim 28, further comprising, The radioactive isotope is implanted into the inner core.

31. The method of claim 30, further comprising, The radioisotope is activated so that the embolic particles emit radiation.

32. The method of claim 30, further comprising, The therapeutic agent is infused into the outer layer.

33. The method of claim 28, wherein the therapeutic agent is premixed with the outer layer prior to the disposing step.

34. A method for treating tumor cells using embolic particles, the method comprising, providing a plurality of embolic particles, each embolic particle having an inner core having a volume capable of receiving a radioactive isotope therein and an outer layer having a thickness capable of receiving a therapeutic agent therein; identifying a site of interest comprising tumor cells to be treated; and The embolic particles are delivered to the lumen and the plurality of embolic particles are moved along a path to the target site along with the flow of fluid, so that the embolic particles are engaged with the path, thereby restricting the flow of fluid to the tumor cells.

35. The method of claim 34, further comprising, The radioactive isotope within the core is activated.

36. The method of claim 35, further comprising, Tumor cells at the site of interest are irradiated.

37. The method of claim 34, further comprising impregnating the therapeutic agent into respective outer layers of the plurality of embolic particles.

38. The method of claim 37, wherein the impregnating step further comprises, A plurality of embolic particles are placed in a fluid containing the therapeutic agent to infuse the therapeutic agent into at least the outer layer.

39. The method of claim 34, wherein the size of each embolic particle limits movement of the individual embolic particles through the lumen at the site of interest to prevent migration of the plurality of embolic particles away from the site of interest.

40. The method of claim 34, wherein the delivering step comprises delivering the plurality of embolic particles through a branch of an artery supplying the tumor cells.

41. The method of claim 35, further comprising: Treatment of at least one of the following primary or metastatic tumors: 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.

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