Alpha-emitter radionuclide-loaded gel

Abstract

A mixture for treating a tumor, comprising: an agent that becomes a hydrogel upon addition of calcium ions; a vehicle that carries the agent so as to allow injection of the mixture into the tumor; and a radium radionuclide bound to the agent in a concentration sufficient to treat the tumor by radiation therapy.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 480,016, filed January 16, 2023, and U.S. Provisional Application No. 63 / 450,971, filed March 9, 2023, both of which are incorporated by reference in their entireties. The present invention relates generally to tumor treatment, and more particularly to intratumoral alpha emitter radiotherapy. [Background technology]

[0002] Ionizing radiation is commonly used to treat certain tumors, including malignant cancerous tumors, by destroying their cells. Alpha radiation is one of the most powerful forms of radiation for cell destruction, but its range is extremely short, making its delivery to tumors a difficult challenge. Diffusing alpha-emitter radiation therapy (DaRT), described in U.S. Patent No. 8,834,837 to Kelson, for example, loads a source (also called a seed) with alpha-emitting radium radionuclides such that, upon radium decay, the radium radionuclides generally do not leave the source, but a significant proportion of their daughter radionuclides (radon-220 in the case of radium-224 and radon-219 in the case of radium-223) leave the source and enter the tumor. These radionuclides, and their own radioactive daughter atoms, spread around the source by diffusion for radial distances of several millimeters before decaying by alpha emission. Thus, the extent of tumor destruction is increased compared to radionuclides that remain on the source along with their daughters. For tumor treatment to be effective, the DaRT seeds used for treatment should be implanted throughout the tumor at small intervals, e.g., less than 5 millimeters apart. Some tumors are easily accessible to physicians from the outside for seed implantation, while others are located in internal organs. Furthermore, seed implantation in some organs can cause discomfort and pain, such as in the eye. Even for tumors that are easily accessible, tumor destruction may require the implantation of more than 100 seeds. Furthermore, seed production is a laborious and expensive undertaking. Another method used to deliver alpha-emitting radioactive atoms to malignant cells is targeted radionuclide therapy, using methods such as radioimmunoconjugates. In targeted therapy, targeting carriers such as antibodies and / or liposomes are bound to radioactive atoms and injected into the patient's bloodstream. During circulation, the targeting carriers bind to or remain adjacent to malignant cells, and when alpha particles are emitted by the radioactive atoms, at least some of the emitted alpha particles destroy the malignant cells.

[0003] Larsen, International Publication No. 01 / 60417, entitled "Radioactive Therapeutic Liposomes," Larsen, International Publication No. 02 / 05859, entitled "Method of Radiotherapy," and Larsen, U.S. Patent Application Publication No. 2004 / 0208821, entitled "Method of Radiotherapy," the disclosures of which are incorporated herein by reference in their entireties, describe liposomes encapsulating heavy alpha particle-emitting radionuclides. Radionuclides can include radium-223, radium-224, and thorium-227, among others. The daughter radionuclide generally remains trapped during the transmutation of the radionuclide.

[0004] WO 2006 / 110889, entitled "Multi-Layer Structure Having a Predetermined Layer Pattern Including an Agent," describes a polymeric multi-layer structure that can be used to deliver radioisotopes for radiation therapy.

[0005] Alpha-emitting radioactive atoms can also be delivered to tumors in microparticles or nanoparticles that limit the transport of the radioactive atoms into and out of the bloodstream. U.S. Patent Application Publication No. 2017 / 0000911, entitled "Radiotherapeutic Particles and Suspensions," states that microparticles and nanoparticles can be stable or slowly degrade. WO 2010 / 028048, entitled "Brachytherapy Seed with Fast Dissolving Matrix for Optimal Delivery of Radionuclides to Cancer Tissue," describes polymer seeds embedded with microspheres containing beta-emitting or alpha-emitting radionuclides. After the seeds are implanted in a tumor, they are dissolved so that the radionuclides within the microspheres can destroy the tumor cells.

[0006] US Patent No. 8,470,294 describes flexible brachytherapy seeds. U.S. Patent No. 9,539,346 to Larsen et al. and the article Westrom S, Malenge M, Jorstad IS, Napoli E, Bruland OS, Bonsdorff TB, Larsen RH., "Ra-224 labeling of calcium carbonate microparticles for internal α-therapy: Preparation, stability, and biodistribution in mice", J Labelled Comp Radiopharm. 2018 May 30;61(6):472-486. doi: 10.1002 / jlcr.3610. Epub 2018 Mar 12. PMID: 29380410; PMCID: PMC6001669 propose the use of calcium carbonate microparticles as a carrier of radium-224, designed for the localized treatment of disseminated cancer in cavitary areas.

[0007] U.S. Patent Application Publication No. 2022 / 0152228 to Thorek et al. describes the administration of alpha particle radiotherapeutic agents in an injectable gel or hydrogel, where the radiotherapeutic agent is chelated with a macrocycle or combined with an ion modifier. U.S. Patent No. 7,776,310 to Kaplan, entitled "Flexible and / or Elastic Brachytherapy Seed or Strand," describes a resilient and / or flexible, preferably biodegradable, brachytherapy strand carrying a radionuclide capable of emitting gamma, beta, or alpha radiation. In one embodiment, the strand is a hydrogel strand prepared by dripping a polymer solution, such as alginate, from a container through a microdroplet generator into a stirred ion bath.

[0008] An article by Holte et al. entitled "Preparation of a radionuclide / gel formulation for localized radiotherapy to a wide range of organs and tissues" in Pharmazie 61 (2006) describes the encapsulation of radiolabeled particles into gel formulations, including alginate gels. Yu Chao et al., in their paper "Combined local immunostimulatory radioisotope therapy and systemic immune checkpoint blockade imparts potent antitumor responses," Nature Biomedical Engineering, Vol. 2, August 2018, reported that radioisotope-labeled natural enzymes ( 131 I-Cat), the natural polysaccharide alginate, and the synthetic oligodeoxynucleotide CpG for the treatment of cancer. The book "In-Situ gelling polymers: for Biomedical applications" describes a variety of hydrogels that can be used for sustained drug release. Summary of the Invention

[0009] Thus, in accordance with an embodiment of the present invention, there is provided a mixture for treating a tumor, the mixture comprising: an agent that becomes a hydrogel upon addition of calcium ions; a vehicle that carries the agent so as to allow injection of the mixture into the tumor; and a radium radionuclide bound to the agent in a concentration sufficient to treat the tumor by radiation therapy. The mixture may have a viscosity of less than 20,000 cP. The medium may include an aqueous solution, and the agent may be uniformly dispersed in the aqueous solution. The mixture may further include an agent that modulates an immune checkpoint and / or an imaging agent dispersed in the mixture. In some embodiments, the mixture has a viscosity suitable for injection into a tumor through a needle. The mixture may be thermosensitive, such that the viscosity of the mixture increases by at least two-fold when its temperature is increased from room temperature to body temperature. The mixture may be adapted to solidify in less than two hours after injection into a tumor. In some embodiments, the agent comprises alginate and / or pluronic. In some embodiments, the radium radionuclide is radium-224 radionuclide. The mixture may further include calcium. The mixture may include calcium at a concentration of about 5-10 millimolar. In some embodiments, the mixture does not bind radon and lead. The agent that becomes a hydrogel upon the addition of calcium ions may comprise 2-4% of the mixture.

[0010] There is further provided in accordance with embodiments of the present invention a method of treating a tumor, the method comprising injecting into the tumor a mixture containing an agent that becomes a hydrogel upon contact with calcium ions; and injecting into the tumor a radium radionuclide having a radioactivity suitable for treating the tumor. In some embodiments, the method comprises injecting calcium into the tumor. Injecting calcium into the tumor may occur before injecting the mixture. Alternatively, or additionally, injecting calcium into the tumor occurs after injecting the mixture into the tumor. In some embodiments, injecting calcium into the tumor comprises including calcium in a mixture and injecting the mixture into the tumor. Injecting calcium into the tumor may comprise injecting the mixture and calcium simultaneously. In some embodiments, injecting a radium radionuclide into the tumor comprises including radium in a mixture and injecting the mixture into the tumor. There is further provided, in accordance with an embodiment of the present invention, a method of producing a mixture for treating a tumor, comprising providing an inert excipient, adding to the inert excipient an agent that forms a hydrogel upon contact with calcium ions; and adding to the inert excipient a radium radionuclide in a concentration sufficient to treat the tumor by radiation therapy. Adding the active agent and radium to the inert excipient may include combining the active agent and radium before they are added to the inert excipient and adding the active agent and radium combination together to the inert excipient. Alternatively, or in addition, adding the active agent and radium to the inert excipient includes adding the radium to the inert excipient only after the active agent has been added to the inert excipient. [Brief explanation of the drawings]

[0011] [Figure 1] 1 is a flowchart of the actions taken in creating a mixture for tumor delivery of radium according to one embodiment of the present invention. [Figure 2] 1 is a flowchart of actions taken during the treatment of tumors according to one embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0012] An aspect of some embodiments of the present invention relates to the delivery of alpha-emitter radium radionuclides to a tumor, tumor bed, or other site in need of treatment in a mixture (e.g., solution) containing an agent that becomes a hydrogel upon the addition of calcium ions. In some embodiments, the mixture includes calcium ions and / or other ions with properties similar to calcium, which can transform the liquid mixture into a hydrogel. The calcium and / or other ions may crosslink the polymer chains of the agent to form a polymeric network. This can occur, for example, in a manner similar to the "egg-crate" model described in "A Study of Sodium Alginate and Calcium Chloride Interaction Through Films for Intervertebral Disc Regeneration Uses," Congresso Brasileiro de Engenharia e Ciencia dos Materiais 09 a 13 de Novembro de 2014, the disclosure of which is incorporated herein by reference.

[0013] The use of such a mixture has the advantage that the agent chemically binds to radium, which is similar to calcium in some chemical properties, essentially preventing the radium from leaving the mixture, while the mixture remains in the tumor for a sufficient time required for treatment due to gelation. On the other hand, the agent does not substantially bind to radioactive progeny nuclides of radium, such as radon and lead. These progeny are allowed to diffuse or otherwise disperse throughout the tumor into which the mixture is implanted, despite the presence of the mixture within the tumor. The mixture may be injectable.

[0014] composition The mixture may include, in a vehicle, an agent that becomes a hydrogel when contacted with calcium ions, and a radium radionuclide that binds to the agent. In some embodiments, the vehicle includes an inert excipient such as water, saline, and / or phosphate buffered saline (PBS). In some embodiments, the mixture includes one or more additional agents that are delivered with the radionuclide. In some embodiments, the mixture includes one or more other materials, such as a contrast agent or an isotope for imaging. The mixture may comprise a biocompatible aqueous solution having a viscosity suitable for direct injection into a tumor. The aqueous solution may have a viscosity of at least 10, 20, 50, or even 200 centipoise (cP) at 20 degrees Celsius, but less than 1,000 cP. Alternatively, the aqueous solution may have a high viscosity of at least 2,000 cP, at least 5,000 cP, or even at least 10,000 cP. The required viscosity may be achieved by adding a sufficient amount of calcium to the mixture. Generally, the more calcium added to the mixture, the higher the viscosity of the mixture. Alternatively, other materials may be added to the mixture to control its viscosity.

[0015] In some embodiments, the mixture is designed to spread within the tumor to which it is delivered but be sufficiently viscous to remain within the tumor and retain the radium within the tumor until at least 80%, at least 90%, at least 95%, or even at least 97% of the radium radionuclide undergoes radioactive decay. After injection, the mixture may be sufficiently viscous so that 24 hours after delivery to the tumor, no more than 50%, no more than 30%, no more than 10%, no more than 5%, or even no more than 3% of the agent has left the tumor. In some embodiments, the component of the mixture that retains radium within the tumor is not biodegradable, or is biodegradable but is only slowly degradable or begins to degrade only after a predetermined period of time after injection, such that no more than 50%, no more than 40%, no more than 25%, no more than 15%, no more than 5%, no more than 3%, or even no more than 1% of the radium that does not undergo radioactive decay can escape the tumor.

[0016] Alternatively or additionally, some of the components of the mixture not required to retain the radium within the tumor are biodegradable to allow closer, more direct contact of the radium with the tumor cells.

[0017] preparation FIG. 1 is a flowchart of actions taken in preparing a mixture for delivering radium to tumors according to one embodiment of the present invention. The method (100) includes providing a medium (102) and adding to the medium (104) an agent that hydrogels upon contact with calcium ions. In some embodiments, the medium acts as a diluter for the agent. Alternatively, or in addition, small particles containing the agent are dispersed in the medium. A radium radionuclide is added to the agent (106) before or after the agent is added to the medium. In some embodiments, calcium is added to the mixture (108). Alternatively, or in addition, other components, such as one or more therapeutic agents, in-situ gelling polymers, and / or contrast agents, are added to the mixture (110). In some embodiments, some or all of the components of the mixture are each provided in separate solutions, and the solutions are combined to form the mixture. In some embodiments, a first solution of 10% sodium alginate (also referred to as alginate) and a second solution of radium-224 radionuclide are prepared separately. The first and second solutions may have the same volume (e.g., 100 microliters each). The first and second solutions are then mixed together such that the alginate concentration is reduced to 5%.

[0018] It should be noted that the method of FIG. 1 is merely one example of a method that can be used to create the mixture. In particular, the components of the mixture can be combined in any suitable order. For example, in other embodiments, radium is added to the medium before the agent is added to the medium. In some embodiments, calcium is added to the medium before the radium and / or the agent. In other embodiments, the agent and calcium are mixed, or the agent solution and calcium solution are mixed together, and the radium is added only thereafter. In still other embodiments, calcium and radium, or their solutions, are mixed together, and the combined radium and calcium are mixed with the agent. After adding the radium to the mixture, the mixture may be left for an incubation period of at least 45 seconds, at least 90 seconds, at least 210 seconds, at least 360 seconds, or even at least 10 minutes, during which time the radium can spread and / or bind to the agent. In some embodiments, the mixture is stirred or otherwise mixed to achieve a more uniform distribution of its components. In some embodiments, the mixture is sterilized, for example, using autoclave sterilization, before delivery to the tumor. Sterilization may occur after the components are mixed. Alternatively, the components are sterilized separately. Mixing may occur at room temperature. In some embodiments, the mixture is prepared by adding a radium radionuclide to a commercially available alginate-based product such as GUARDIX® SG.

[0019] agent With respect to adding an active substance (104), in more detail, the active substance may include sodium alginate, as described in Abasalizadeh, F., Moghaddam, SV, Alizadeh, E. et al. Alginate-based hydrogels as drug delivery vehicles in cancer treatment and their applications in wound dressing and 3D bioprinting. J Biol Eng 14, 8 (2020), doi.org / 10.1186 / s13036-020-0227-7, which is incorporated herein by reference. Alternatively or additionally, the active substance may include a poloxamer, also known as a pluronic.

[0020] The agent may not be biodegradable, or may be slowly biodegradable such that substantial degradation begins only after at least one, at least two, or even at least five half-lives of the radium radionuclide. In the case of radium-224, substantial degradation of the agent may begin only after at least 10 days, at least 20 days, or even at least one month after implantation. Degradation to levels of less than 10% may continue over a period of at least 10 days, at least 20 days, or even at least 30 days. Thus, the agent locks the radium in place as long as it remains substantially radioactive.

[0021] In some embodiments, the agent is at least 0.1%, at least 0.4%, at least 0.5%, at least 1%, at least 2%, at least 3.5%, or even at least 4.5% w / w of the mixture, hi some embodiments, the agent is less than 12%, less than 10%, less than 8%, less than 6.5%, less than 5%, or even less than 4% w / w of the mixture. In embodiments in which the mixture contains low levels of calcium (e.g., less than 3 or even less than 2 millimolar), or even no calcium at all so that gelation is primarily due to endogenous calcium and / or other ions, the agent may be included in the mixture at a concentration of at least 3 mg / ml, or even at least 5 mg / ml, or at a concentration of less than 7 mg / ml or even less than 6 mg / ml, such that the mixture forms a gel with weak mechanical strength that disperses semi-uniformly throughout the tumor, allowing the radium in the mixture to distribute throughout the tumor without significant leakage outside the tumor.

[0022] In some embodiments, the agent is included at a concentration of at least 5 mg / ml, 7 mg / ml, at least 9 mg / ml, or even at least 12 mg / ml, such that the mixture forms a gel that is a more viscous solid and has greater mechanical strength. For mixtures with higher levels of calcium, for example, greater than 4 or even greater than 5 millimolar, the agent concentration may be less than 6 mg / ml, less than 5 mg / ml, less than 4 mg / ml, or even less than 2 mg / ml. In some embodiments, the agent is uniformly dispersed throughout the medium. Thus, the radium that binds to the agent is uniformly dispersed throughout the mixture. In other embodiments, the mixture is heterogeneous and includes small particles (e.g., microparticles, nanoparticles, and / or beads) formed from the agent, carrying the agent, or carrying at least a significant percentage of the agent. The heterogeneous structure increases the surface area of ​​the agent, from which radon can escape. As the non-agent portion of the mixture dissolves, the uniformity of the spread of the agent to which the radium binds increases. In still other embodiments, a portion of the agent in the mixture (e.g., at least 20%, at least 40%, or even at least 60%) is dispersed throughout the medium, while another portion of the agent (e.g., at least 25%, at least 35%, or at least 45%) is contained in the small particles.

[0023] In this application, the term "microparticle" refers to a particle having a diameter of 0.1 to 100 micrometers. The term "nanoparticle" refers to a particle having a diameter of 0.1 to 100 nanometers. It should be noted that in some embodiments, small particles are larger than microparticles, e.g., having a diameter of at least 150 micrometers, at least 250 micrometers, or even at least 400 micrometers. In these embodiments, small particles may have a diameter of less than 500 micrometers. In some embodiments, small particles are spheres and / or beads. Alternatively, small particles are any other suitable shape.

[0024] In some embodiments, small particles are formed by dripping a solution of the agent into a concentrated calcium solution. In other embodiments, small particles are generated by adding air to a solution of the agent and calcium. Alternatively or additionally, small particles are formed by mixing the agent with an aqueous solution. In some embodiments, small particles are created by changing the relationship of the agent and calcium such that the resulting mixture contains small particles in aqueous solution. The small particles may be produced using any suitable method known in the art, such as any of the methods described in Andrea Dodero et al., "An Up-To-Date Review on Alginate Nanoparticles and Nanofibers for Biomedical and Pharmaceutical Applications", Advanced Materials Interfaces, Vol. 8, Issue 22, November 23, 2021; Patricia Severino, "Alginate Nanoparticles for Drug Delivery and Targeting", Current Pharmaceutical Design, Volume 25, Issue 11, 2019; Anna Letocha, "Preparation and Characteristics of Alginate Microparticles for Food, Pharmaceutical and Cosmetic Application", Polymers 2022, and / or Jerome P. Paques, "Formation of Alginate nanospheres", Thesis, Wageningen University, 2014.

[0025] The small particles may be of any suitable type known in the art, such as, for example, microfluidic devices provided by CD Bioparticles (www.cd-bioparticles.net / alginates), Elve Flow (https: / / www.elveflow.com / microfluidics-application-packs / nanoparticles-packs / easy-microfluidic-alginate-beads-generation-pack), and / or Thomas Scientific (www.thomassci.com / nav / cat1 / alginatechitinbeads / 0). Methods for producing small particles that can be used in the present invention are described, for example, in Alginate particle production by Elve Flow, www.techusci.com / UploadFiles / 2021-03 / 369 / 2021032014063196895.pdf, and / or Alginate Microbeads Production by Fluigent (www.fluigent.com / wp-content / uploads / 2022 / 01 / alginate-beads-production-application-note.pdf). In some embodiments, the small particles are formed from a solution already containing a radium radionuclide, while in other embodiments, the small particles are formed from an inert solution that does not contain the radium radionuclide, and the radium radionuclide is added to the small particles after their formation, for example, by incubating the small particles in a radium solution.

[0026] The small particles may be formed so that the agent and bound radium are on or in close proximity to the outer surface of the small particles such that there is a high probability, e.g., at least 25%, at least 35%, or even at least 40%, that the daughter radionuclides resulting from radioactive decay will leave the small particles. For example, when radium is added after the small particles are formed, the addition may be performed so that the radium collects on the outer surface of the small particles rather than in their interior. Alternatively, or in addition, the small particles may be formed so that the interior is formed of a material that does not attract radium, while the outer surface includes a material that attracts radium. Alternatively, the agent and radium are located inside some or all of the small particles, particularly nanoparticles that are small enough to allow radon to diffuse out of the nanoparticles even from their interiors. The small particles may have a viscosity of at least 100 cP, at least 200 cP, at least 300 cP, or even at least 500 cP. The viscosity of the particles may be less than 2,000 cP, less than 1,500 cP, or even less than 1,000 cP.

[0027] radium In some embodiments, the radium ions are not bound to large particles made of materials other than the agent. In particular, the radium radionuclide may not be bound to particles with diameters greater than 100 nanometers, other than the agent, nor may it be bound to targeting elements (e.g., antibodies) that bind to cells, proteins and / or enzymes (e.g., catalase), and / or vectors (e.g., liposomes, radionucleotides) that are taken up by cancer cells. The mixture may not contain large microparticles, enzymes, liposomes, radionucleotides, and / or targeting elements that may bind to the radium. In this way, the movement of the radium is restricted by the agent, which prevents it from leaving the tumor in which it is located, but allows for small movement within the tumor, thereby achieving better tumor coverage by radiation from the radium. However, in other embodiments, the radium is bound to large particles, and distribution of the radium throughout the tumor is achieved by initial injection of the mixture into the tumor.

[0028] The radium may include radium-224 or radium-223. In some embodiments, the mixture comprises 1×10 10 At least 2 radium molecules per molecule of agent, 1 × 10 10 At least 5 radium molecules per molecule of agent, 1 × 10 10 at least 10 radium molecules per agent molecule, or even 1 x 10 10 However, the mixture contains at least 20 radium molecules per 1 × 10 agent molecule. 10 Less than 100 radium molecules per molecule of agent, 1 × 10 10 Less than 50 radium molecules per molecule of agent, 1 × 10 10 less than 30 radium molecules per molecule of agent, or even less than 1 x 10 10 The radium may contain fewer than 20 molecules of radium per molecule of agent.

[0029] The activity per volume of the radium may be at least 25 kilobecquerels per milliliter of mixture, at least 75 kilobecquerels per milliliter of mixture, at least 150 kilobecquerels per milliliter of mixture, at least 300 kilobecquerels per milliliter of mixture, or even at least 500 kilobecquerels per milliliter of mixture. On the other hand, in some embodiments, the radium concentration is less than 1 megabecquerel per milliliter of mixture, less than 700 kilobecquerels per milliliter of mixture, less than 500 kilobecquerels per milliliter of mixture, or even less than 400 kilobecquerels per milliliter of mixture. The activity of the radium used may depend on the specific tumor type according to the required biologically effective dose (BED) of the tumor type and other characteristics of the tumor. Higher levels of activity may be used when a relatively large proportion of the mixture is expected to escape the tumor. The radium may be bound to the agent. In some embodiments, after gelation, the radium is essentially trapped within the mixture, and the rate of radium atom release is less than 3% per day, less than 2% per day, or even less than 1% per day for a period of at least 5 days, or even at least 10 days after gelation. In some embodiments, the low leakage of radium from the mixture persists for a period of at least one half-life of radium, at least two half-lives of radium, or even at least three half-lives of radium.

[0030] The diffusion of radium, e.g., radium-224, in the mixture of this embodiment may be extremely low so that radium does not escape the tumor in significant amounts. -12 cm 2 / sec less than or even 2 * 10 -13 cm 2 1 / sec. On the other hand, during the radioactive decay of radium, its daughter radionuclides (including radon and its progeny) have a significant probability of leaving the mixture, e.g., at least 15%, at least 30%, or even at least 40% probability of release. The radon daughter radionuclides of radium radionuclide atoms are present in the mixture at 10 -7 cm 2 1 / sec. In some embodiments, adding radium to the mixture (106) is performed by first combining the radium with the agent and then adding the combined radium and agent to the medium. In other embodiments, the agent is added first to the medium and then the radium is added to the mixture of the agent and medium. In still further embodiments, the radium and agent are first each in separate solutions and the solutions are combined to form the mixture. In yet other embodiments, the radium is first added to the calcium mixture or solution and then the combined radium and calcium are added to the mixture of the agent and medium.

[0031] Adding radium (106) may be accomplished by adding a radium-containing solution to the other components of the mixture. The radium-containing solution can be generated using any suitable method known in the art, such as any of the methods described in International Publication No. WO 2021 / 070029, "Wet preparation of Radiotherapy Sources," the disclosures of which are incorporated herein by reference in their entireties. Alternatively, or in addition, any of the methods described in Russian Patent No. 2734429, U.S. Patent No. 6,126,909 to Rotmensch et al., and / or U.S. Patent No. 5,038,046 to Norman et al., the disclosures of which are incorporated herein by reference, can be used to generate the radium-containing solution.

[0032] Alternatively, radium can be added to the mixture by disposing other components of the mixture in a flux of radium radionuclides (106). The flux can be generated by a flux-generating surface source. For example, when the radionuclide is Ra-224, the flux can be generated by a thorium-228 (Th-228) surface source. A Th-228 surface source can be prepared, for example, by collecting Th-228 atoms emitted from a parent surface source of U-232. Such a parent surface source can be prepared, for example, by spreading a thin layer of acid containing U-232 over the metal. Alternatively or additionally, the flux can be generated using any of the methods described in U.S. Patent Application Publication No. 2015 / 0104560 to Kelson et al., entitled "Method and Device for Radiotherapy," the entire disclosure of which is incorporated herein by reference. Alternatively, dissolvable seeds carrying the alpha-emitting radionuclide are first produced, and the seeds are dissolved in the other components of the mixture.

[0033] calcium In some embodiments, the mixture includes calcium ions such that gelation of the mixture within the tumor is not solely dependent on calcium in the tumor. Calcium may be added as free calcium ions. In some embodiments, a chloride compound is dissolved in a solution to create chloride ions, and a solution containing chloride ions is included in the mixture. The chloride compound may include calcium chloride. Other chloride compounds, such as calcium nitrate, calcium acetate, and / or calcium gluconate, may also be used.

[0034] In some embodiments, calcium is added to the mixture well before injection of the mixture into the tumor (108). According to these embodiments, the calcium in the mixture may be at a low concentration that does not cause the mixture to gel immediately, but rather causes faster gelation upon injection and / or a higher viscosity of the mixture after gelation than would be possible if the mixture were solely dependent on intratumoral calcium. Following this option, calcium may be provided as free-standing calcium ions. In other embodiments, calcium is contained in calcium-loaded nanoparticles, such as liposomes. In some of these embodiments, the calcium-loaded nanoparticles are thermosensitive and configured to release calcium at or near body temperature (e.g., above 32°C, above 33°C, above 34°C), resulting in the agent becoming a gel after insertion into the tumor. Alternatively, or in addition, the calcium-loaded nanoparticles are designed to release calcium for other reasons, such as pH differences, upon injection. In yet other embodiments, calcium is added to the mixture sufficiently prior to injection into the patient (108), and the added calcium causes gelation to occur prior to injection, resulting in the mixture being injected in gel form. In other embodiments, calcium is added to the mixture shortly before injection of the mixture into the tumor (108), causing complete gelation or solidification only after a few seconds or minutes, so that gelation and / or solidification of the mixture occurs only after injection.

[0035] Calcium may be added to the mixture (108) only after the radium has been added (106) and bound to the agent, so that the calcium does not prevent the radium from binding to the agent. Alternatively, calcium may be added to the mixture (108) before the radium is added (106). According to this alternative, the calcium in the mixture may never cover the entire agent to allow the radium to bind to it.

[0036] The concentration of calcium in the mixture before injection governs the proportion of radium that remains in the tumor over time. Low concentrations of calcium result in a mixture with a low viscosity, thus allowing higher levels of radium to leave the tumor before radioactive decay. High concentrations of calcium may result in a mixture with too high a viscosity upon injection into the tumor, such that the mixture is not injectable or does not disperse properly within the tumor. Calcium may be at least 0.1%, at least 0.3%, at least 0.5%, at least 0.8%, at least 1.5%, or even at least 2.5% of the mixture by weight / weight (w / w). In some embodiments, calcium is less than 10%, less than 8%, less than 6%, less than 5%, or even less than 4% of the mixture w / w. In some embodiments, for example, in embodiments where the calcium in the mixture is not intended to convert the mixture into a gel as is, calcium is added at a concentration of at least 1 millimolar (mM), at least 2 mM, at least 4 mM, at least 6 mM, or even at least 8 mM, but less than 30 mM, less than 20 mM, less than 15 mM, or even less than 12 mM (108). In other embodiments, for example, in embodiments where the mixture is intended to be delivered to a treatment site as a gel, calcium in the mixture is at a concentration of at least 50 millimolar, at least 75 millimolar, or even at least 100 millimolar.

[0037] Alternatively, the mixture does not contain calcium, and the agent becomes a hydrogel within the tumor by collecting endogenous calcium present in the tumor after administration of the mixture, or by collecting calcium separately injected into the tumor before, during, or after injection of the mixture. Calcium may be injected into the tumor before, during, and / or after injection of the mixture using a separate needle different from the needle used to inject the mixture. In some embodiments, calcium is injected simultaneously with the mixture, for example, using a split needle. In some embodiments, the mixture is designed to have a low pH to extract calcium from surrounding tissue.

[0038] In yet other embodiments, instead of using calcium to induce gelation of the agent, any other suitable component that stiffens the agent is used, such as any of the biocompatible components described in Hu et al., "Ions-induced gelation of alginate: Mechanisms and Applications," International Journal of Biological Macromolecules, the disclosure of which is incorporated herein by reference. For example, instead of using calcium to induce gelation, magnesium is used to induce gelation.

[0039] Further ingredients In some embodiments where the radium is contained within a small particle, the small particle is targeted by attaching an antibody to it. Additional materials may be added to help the particle connect to the antibody to target the tumor. The mixture may include a contrast agent that appears bright in diagnostic imaging, such as gold, titanium, titanium oxide, zirconium oxide, silicon oxide, and / or any other suitable metal. In some embodiments, the contrast agent includes a radionuclide other than radium that emits alpha, beta, and / or gamma radiation, which are primarily used for imaging. After injecting the mixture into the tumor, the tumor may be imaged to determine the layout of the mixture within the tumor and whether further injections of the mixture are required.

[0040] In some embodiments, the active agent is contained within the small particles, and the contrast agent is contained within the small particles. In some embodiments, the contrast agent is mixed with the active agent, and the small particles are formed from a mixture of the contrast agent and the active agent. Alternatively or additionally, the small particles comprise a metal base, such as a gold base, coated with the active agent, or with the active agent including an inert excipient. To prevent the patient's sodium ions from breaking the bonds formed with the calcium that form the gel, the mixture may contain an aldehyde that prevents the sodium from breaking the bonds of the hydrogel. The one or more additional materials may include, for example, any of the materials listed in Andrea Dodero et al., "An Up-to-Date Review on Alginate Nanoparticles and Nanofibers for Biomedical and Pharmaceutical applications", 2021, available at doi.org / 10.1002 / admi.202100809, the disclosure of which is incorporated herein by reference.

[0041] In some embodiments, the one or more additional materials do not substantially inhibit the diffusion of radium daughters (including daughters of daughters further down the decay chain), i.e., the one or more additional materials may be selected as materials that do not bind to and / or interfere with the diffusion of radon progeny, such as lead.

[0042] Further alternatively or additionally, the vehicle may comprise an in-situ gelling polymer that is provided in sol form at room temperature and that converts to a gel state in response to changes in temperature, pH, and / or ionic composition upon injection into a patient, such as any suitable in-situ gelling polymer described in Kouchak M. In situ gelling systems for drug delivery, Jundishapur J Nat Pharm Prod. 2014 Jun 1;9(3):e20126. doi: 10.17795 / jjnpp-20126. PMID: 25237648; PMCID: PMC4165193 and / or Xian Jun Loh, "In-Situ Gelling Polymers, for Biomedical Applications", 2014, the disclosures of which are incorporated herein by reference.

[0043] Combination with other drugs In some embodiments, in addition to the alpha-emitter radium radionuclide, the mixture includes one or more agents. The one or more agents can be any agent suitable for treating the patient, for example, an agent known to have a positive synergistic effect with alpha-emitter radiation therapy. In some embodiments, the one or more agents include a substance that activates cytoplasmic sensors for intracellular pathogens in tumors, for example, as described in WO 2020 / 089819, entitled "Intratumoral Alpha-Emitter Radiation and Activation of Cytoplasmic Sensors For Intracellular Pathogens," the disclosure of which is incorporated herein by reference in its entirety. Alternatively or additionally, the one or more agents include an immune checkpoint modulator, such as those described in International Application No. PCT / IB2022 / 055680, entitled "Intratumoral Alpha-Emitter Radiation in Combination with Checkpoint Regulators," the disclosure of which is incorporated herein by reference in its entirety. Further, alternatively, or in addition, the one or more agents include a vasculature inhibitor, such as those described in International Application No. PCT / IB2022 / 055679, entitled "Intratumoral Alpha-Emitter Radiation in Combination with Vasculature Inhibitors," the disclosure of which is incorporated herein by reference in its entirety. In some embodiments, the one or more agents included in the mixture include a TLR agonist and / or an immune adjuvant, such as PolyIC. Alternatively, or additionally, the one or more agents included in the mixture include an antibody, such as an angiogenesis inhibitor and / or an immune blocker. Alternatively or additionally, the one or more agents may include any other agent suitable for chemotherapy, immunotherapy (e.g., aPD-1), gene therapy, targeted therapy, and / or anti-angiogenic therapy. The one or more agents may be dispersed throughout the mixture and / or may be contained within small particles.

[0044] Combination treatment The mixture may be infused into a patient in combination with one or more other anti-cancer treatments, such as radiation, immunotherapy, targeted therapy, chemotherapy, and surgery. These treatments may be synergistic with the alpha emitters (see the aforementioned patents). The other anti-cancer treatments may be administered before, simultaneously with, or after the injection of the mixture.

[0045] experiment Applicant conducted an experiment in which an aqueous radium solution was mixed with a sodium alginate solution to a final concentration of 4% w / w sodium alginate in the solution. The resulting solution was mixed with an aqueous calcium chloride solution at a concentration of 1% w / w. The resulting hydrogel was then placed in fetal bovine serum. The serum was replaced with fresh serum solution four times every three days, and the replaced serum was subjected to radioactivity measurements to characterize the percentage probability of Pb-212 release from the gel to the serum at each time point and the daily percentage rate of radium leakage from the gel.

[0046] The results for each time point are shown in the following table. [Table 1] Experiments have shown that while Ra-224 molecules are relatively highly immobilized in alginate-based hydrogels, radium daughter atoms are released from the gel into the external liquid environment in significant quantities. Other gels may allow a greater proportion of radium to leak out or may have a much lower release rate of the daughter radionuclide.

[0047] use Typical tumors that can be treated with the combination are tumors of the digestive tract (colon cancer, rectal cancer, colorectal cancer, large intestine cancer, colorectal adenoma, hereditary nonpolyposis type 1, hereditary nonpolyposis type 2, hereditary nonpolyposis type 3, hereditary nonpolyposis type 6; large intestine cancer, hereditary nonpolyposis type 7, small intestine and / or large intestine cancer, esophageal cancer, callus-esophageal cancer (tylosis with esophageal cancer), gastric cancer, pancreatic cancer, pancreatic endocrine tumors), endometrial cancer, dermatofibrosarcoma protuberans, gallbladder cancer, biliary tract tumors, prostate cancer, prostate adenocarcinoma, kidney cancer (e.g., Wilms' tumor type 2 or type 1), liver cancer (e.g., hepatoblastoma, hepatocellular carcinoma, hepatocellular carcinoma), bladder cancer, embryonal rhabdomyosarcoma, germ cell sarcoma, trophoblastic tumor, testicular germ cell tumor, ovary, uterus, immature teratoma of the epithelial ovary, sacrococcygeal tumor, choriocarcinoma, placental trophoblastic tumor, epithelial adult tumor, ovarian cancer, serous ovarian cancer, ovarian sex cord tumor, cervical cancer, cervical cancer, small cell and non-small cell lung cancer, nasopharyngeal, breast cancer (e.g., ductal carcinoma, invasive intraductal carcinoma; breast cancer, susceptibility to breast cancer, type 4 breast cancer, breast cancer-1, breast cancer-3;breast-ovarian carcinoma), squamous cell carcinoma (e.g., of the head and neck), neurogenic tumor, astrocytoma, ganglioneuroblastoma, neuroblastoma, glioma, adenocarcinoma, adrenal tumor, hereditary adrenocortical cell carcinoma, malignant brain tumor (tumor), various other carcinomas (e.g., bronchial large cell, tubular, Ehrlich-Lettre ascites, epidermoid, large cell, Lewis lung, medullary, mucoepidermoid, oat cell, small cell, spindle cell, squamous cell, transitional cell, undifferentiated, carcinosarcoma, choriocarcinoma, cystadenocarcinoma), ependymoblastoma (ep endimoblastoma), epithelioma, erythroleukemia (e.g., Friend, lymphoblastic), fibrosarcoma, giant cell tumor, glioma, glioblastoma (e.g., pleomorphic, astrocytoma), glioma, hepatoma, heterohybridoma, heteromyeloma, histiocytoma, hybridoma (e.g., B cell), adrenal gland tumor, insulinoma, pancreatic islet tumor, keratosis, leiomyoblastoma, leiomyosarcoma, lymphosarcoma, melanoma, breast tumor, mast cell tumor, medulloblastoma, mesothelioma, metastatic tumor, monocytic tumor, multiple tumor Myeloma, myelodysplastic syndrome, myeloma, nephroblastoma, neural glioma, neural tissue-derived tumor, neurofibromatosis, neuroblastoma, oligodendroglioma, osteochondroma, osteomyeloma, osteosarcoma (e.g., Ewing's), papilloma, transitional cell, pheochromocytoma, pituitary tumor (invasive), plasmacytoma, retinoblastoma, rhabdomyosarcoma, sarcoma (e.g., Ewing's, histiocytic, Jensen, osteogenic, reticular cell), schwannoma, subcutaneous tumor, teratocarcinoma ( For example, pluripotent stem cells (e.g., teratoma, testicular tumor, thymoma and trichoepithelioma, gastric cancer, fibrosarcoma, glioblastoma multiforme; multiple glomus tumors, Li-Fraumeni syndrome, liposarcoma, Lynch familial cancer syndrome II, male germ cell sarcoma, medullary thyroid, multiple meningiomas, endocrine tumor myxosarcoma, paraganglioma, familial nonchromaffin, calcifying epithelioma, papillary, familial and sporadic, rhabdoid predisposition syndrome, familial, rhabdoid tumor, soft tissue sarcoma, and Turcot syndrome with glioblastoma. In some embodiments, the mixture is used to treat eye cancer, such as uveal melanoma.

[0048] Administration 2 is a flowchart of actions taken in treating a tumor according to one embodiment of the present invention. The method (200) may include identifying a tumor or other tissue requiring treatment (202) and estimating the required amount of mixture to be injected (204) and / or selecting the exact composition of the mixture to be injected into the identified tumor (206). The mixture is then injected into the tumor (208). In some embodiments, calcium is injected into the tumor before, during, and / or after injection of the mixture (210). Medical images of the tumor may be taken and analyzed (212) to determine whether the entire volume of the tumor has been covered by the mixture. If necessary, further injections of the mixture into uncovered areas of the tumor (208) are performed.

[0049] With regard to estimating the amount of mixture to be injected (204), the amount may be selected proportional to the size of the tumor. In some embodiments, the amount of mixture injected into the tumor is at least 3%, at least 5%, or even at least 10% of the tumor's volume. The mixture injected may be in a volume less than 50%, less than 25%, less than 20%, or even less than 15% of the tumor's volume.

[0050] In some embodiments, the mixture is injectable and / or non-solid. In some of these embodiments, the mixture is injected as a liquid. When injected, the mixture may have a viscosity of less than 25 millipascal-seconds, less than 20 millipascal-seconds, less than 15 millipascal-seconds, or even less than 10 millipascal-seconds. Alternatively, the mixture has a gel structure when injected. When injected, the mixture may have a viscosity of less than 10,000 centipoise (cP), less than 5,000 cP, or even less than 3,000 cP to allow for easy injection into the tumor.

[0051] After injection, the mixture may increase in viscosity within the tumor and, in some cases, further solidify. The viscosity of the mixture may be adjusted by changing its pH. In some embodiments, the mixture is thermosensitive. At room temperature (e.g., 21°C) or below, the mixture may have a viscosity of less than 10,000 centipoise (cP), less than 5,000 cP, or even less than 3,000 cP, while at body temperature the mixture has a higher viscosity of at least 75,000 cP, at least 85,000 cP, at least 90,000 cP, or even at least 95,000 cP. Additionally, or alternatively, the viscosity of the mixture increases within the tumor due to its exposure to endogenous calcium ions. However, in other embodiments, upon injection, the mixture has a higher viscosity of at least 20,000 cP, at least 40,000 cP, or even at least 70,000 cP, resulting in the mixture remaining substantially close to the point where it was injected.

[0052] In other embodiments, the mixture is allowed to solidify before injection and is introduced into the tumor in the form of flexible seeds of any suitable shape. In yet other embodiments, the mixture is included as the outer layer of a seed, catheter, or needle that is inserted into the tumor. In these embodiments, the seed may be covered with a protective layer that prevents the mixture from being removed from the seed before it is inserted into the tumor.

[0053] In some embodiments, the mixture is injected into the center of the tumor (208). Alternatively, or in addition, the mixture is injected into the tumor margins and / or adjacent to the tumor outside the tumor, for example, when treating tumor remnants after surgical removal. In some embodiments, the mixture is injected into the entire tumor. In some embodiments, the tip of the needle through which the mixture is injected is moved, e.g., retracted, during injection to increase the surface area of ​​the mixture within the tumor and therefore the volume of the tumor affected by the radium. The mixture may be injected into the tumor with a single needle insertion. Alternatively, the mixture is injected into the tumor with multiple needle insertions in different regions of the tumor and / or at different times to increase the volume of the tumor covered by the injected mixture and / or to treat tumor cells not sufficiently exposed to radiation in previous injections. Alternatively, the mixture is smeared or spread on the surface of the tumor and / or the surface of the cavity after surgical removal of the tumor. Alternatively, instead of injection into the tumor, the mixture may be injected into the patient's blood circulation, for example when the mixture contains small targeted particles.

[0054] In some embodiments, the mixture is injected into the vasculature adjacent to the tumor in a manner that clogs and / or closes small blood vessels in or near the tumor. In embodiments using targeted nanoparticles, the mixture may also or alternatively be administered intravenously. As noted above, not all embodiments include injecting calcium (210). In some embodiments in which calcium is injected (210), the calcium is injected into the tumor through a needle separate from the needle used to inject the mixture (208) before, during, and / or after injection of the mixture. In some embodiments, the calcium is injected (210) simultaneously with the mixture, for example, using a split needle. Alternatively, the mixture and calcium are loaded into the same needle and injected alternately into the tumor. The calcium may be loaded into a more distal needle and injected into the tumor first. Alternatively, the mixture is loaded into a more distal needle and injected before the calcium. Injecting calcium before the mixture increases the proportion of the mixture that turns into a gel before leaving the tumor, since the calcium needed to induce gelation is already in the tumor when the mixture is injected. Simultaneous injection of the mixture and radium induces immediate mixing of the active agents in the mixture with the calcium, while allowing for easier manipulation by the physician administering the injection.

[0055] In the above description, the agent and radium are mixed together in a solution to be injected prior to injection. In other embodiments, a solution containing the agent is injected into the tumor separately from the administration of the radium radionuclide. In some of these embodiments, the radium radionuclide is administered by injecting a radium solution into the tumor. Alternatively, the radium radionuclide is administered by inserting one or more sources carrying free radium into the tumor. The one or more sources may be designed to allow free radium to detach from the source after implantation of the one or more sources into the tumor. The source may be biodegradable after implantation so that free radium is released into the tumor. Alternatively, the radium on the source is loosely bound so that radium is released from the source upon contact with tumor tissue and / or due to the temperature of the tumor. Radium released from the seeds is captured by the solution containing the agent, thus preventing it from escaping the tumor.

[0056] Separate injections allow for the preparation of the agent solution longer in advance of treatment and for the storage of the agent solution for longer periods. In some embodiments, the agent solution is injected before the radium is administered, for example, at least 5 seconds, at least 15 seconds, at least 45 seconds, or even at least 90 seconds before administration of radium to the tumor. Early injection of the agent allows time for the agent to settle in the tumor before the radium is administered. However, the radium may be administered within less than 1 hour, less than 20 minutes, or even less than 10 minutes after injection of the agent solution. Alternatively, the agent solution is injected after administration of radium to the tumor. In this alternative, the agent solution may be injected within less than 30 seconds, less than 15 seconds, or even less than 5 seconds after administration of radium, so that the radium does not escape before the agent solution is injected, providing long-term fixation of the radium in the tumor. In some embodiments where radium is administered by injecting a radium solution, the radium solution and the agent solution are injected using the same needle. Alternatively, the radium solution and the agent solution are injected through different needles. In another embodiment, the separate injections of the radium solution and the agent solution are performed simultaneously through two different needles.

[0057] In the method of FIG. 2, further injections (208) of the mixture are performed in response to analysis (212) of medical images of the tumor. The images may be acquired immediately and / or later, for example, several days later (e.g., every two or three days). Alternatively, or additionally, repeated injections may be performed periodically based on a pre-established schedule. For example, repeated injections may be performed every two days, every week, or every two weeks. In some embodiments, when treating a patient with multiple tumors, the mixture is injected into multiple separate tumors of the patient in a single treatment session. Alternatively, the mixture is injected into each tumor at separate times so that high levels of radioactivity are not introduced simultaneously.

[0058] In other embodiments, the agent solution is not injected but rather smeared onto the surface needing treatment, such as a cancerous tumor on the outer skin or the tissue of a cavity following tumor removal. In some of these embodiments, a protective sheet may be placed over the smeared mixture to prevent damage to healthy tissue.

[0059] conclusion It should be noted that although the above description relates to a mixture of an agent and an alpha-emitting radium isotope that is converted into a hydrogel by the addition of calcium ions, the agent could also be used with beta-emitters of radium, such as radium-225, with appropriate compatibility. The agent could also be used to form a radiotherapeutic mixture with radionuclides of other isotopes of biocompatible elements that convert the agent into a gel or otherwise bind to the agent and have a half-life suitable for use in medical radiotherapy. The element that converts the agent into a gel could be any of those described in the above-mentioned article: Hu et al., "Ions-induced gelation of alginate: Mechanisms and Applications," International Journal of Biological Macromolecules, for example, Ba 2+ , Cu 2+ , Sr 2+ , Fe 2+ , Zn 2+ , Mn 2+ , Al 3+、 and Fe 3+ and elements with similar properties, such as elements in the groups of these elements in the periodic table. These other isotopes may be beta emitters, positron emitters, and / or electron capturers. These other isotopes include, for example, isotopes of strontium ( 90 Sr and 89 Sr, 85 Sr), isotopes of calcium, copper-64, and / or gold-198.

[0060] It should be understood that the methods and apparatus described above can be interpreted to include apparatus for practicing the methods and methods of using the apparatus. It should be understood that features and / or steps described with respect to one embodiment can sometimes be used with other embodiments, and that not all embodiments of the invention will have all of the features and / or steps shown in a particular figure or described with respect to one of the particular embodiments. Tasks are not necessarily performed in the exact order described.

[0061] It should be noted that some of the above embodiments may include structure, acts, or details of structure and acts that are not essential to the present invention and are described as examples. As is known in the art, structure and acts described herein may be replaced with equivalents that perform the same function, even if the structure or acts are different. The above-described embodiments are cited as examples, and the present invention is not limited to those specifically shown and described above. Rather, the scope of the present invention includes both combinations and subcombinations of the various features described above, as well as variations and modifications that would be obvious to one skilled in the art upon reading the above description and that are not disclosed in the prior art. Therefore, the scope of the present invention is limited only by the elements and limitations used in the claims. It should be noted that in the claims, the terms "comprise," "include," "have," and their conjugates all mean "including, but not necessarily limited to," when used in the claims.

Claims

1. 1. A composition for treating a tumor, comprising: an agent that becomes a hydrogel upon addition of calcium ions; a vehicle that carries the agent so as to allow injection of the mixture into a patient; and a radium radionuclide bound to an agent in a concentration sufficient to treat the tumor by radiation therapy; A mixture comprising:

2. 10. The mixture of claim 1, wherein the medium comprises an aqueous solution and the agent is uniformly dispersed in the aqueous solution.

3. 10. The mixture of claim 1, further comprising a substance that modulates an immune checkpoint dispersed in the mixture.

4. The mixture of claim 1 further comprising a contrast agent.

5. 10. The mixture of claim 1, wherein the mixture is thermosensitive such that the viscosity of the mixture increases by at least two times when its temperature is increased from room temperature to body temperature.

6. The mixture of claim 1 , wherein the agent comprises an alginate.

7. 10. The mixture of claim 1, wherein the agent comprises a pluronic.

8. 2. The mixture of claim 1, wherein the radium radionuclide is radium-224 radionuclide.

9. The mixture of any one of claims 1 to 8, wherein the mixture further comprises calcium.

10. 10. The mixture of claim 9, wherein the mixture comprises calcium at a concentration of 1 to 10 millimolar.

11. The mixture of any one of claims 1 to 8, wherein the mixture does not bind radon and lead.

12. 9. The mixture according to claim 1, wherein the agent that becomes a hydrogel upon addition of calcium ions constitutes 0.5 to 4% of the mixture.

13. 9. The mixture according to claim 1, wherein the active substance is contained in small particles carried by the vehicle.

14. 9. The mixture of any one of claims 1 to 8, wherein the small particles comprise a metal core surrounded by the active substance.

15. 1. A method of treating a tumor, comprising: injecting into the patient a mixture containing an agent that becomes a hydrogel upon contact with calcium ions; and Injecting patients with radium radionuclides of radioactivity suitable for treating tumors A method comprising:

16. 16. The method of claim 15, further comprising injecting calcium into the tumor.

17. 17. The method of claim 16, wherein injecting calcium into the tumor occurs before injecting the mixture.

18. 17. The method of claim 16, wherein injecting calcium into the tumor occurs after injecting the mixture into the tumor.

19. 17. The method of claim 16, wherein injecting calcium into the tumor comprises including the calcium in a mixture and injecting the mixture into the tumor.

20. 17. The method of claim 16, wherein injecting calcium into the tumor comprises injecting the mixture and calcium simultaneously.

21. 21. The method of any one of claims 15 to 20, wherein injecting the radium radionuclide into the tumor comprises including the radium in a mixture and injecting the mixture into the tumor.

22. 21. The method of any one of claims 15 to 20, wherein injecting the mixture into the patient comprises injecting the mixture into a tumor.

23. 1. A method of producing a mixture for treating a tumor, comprising: Providing inert excipients; adding to the inert excipient an agent that forms a hydrogel upon contact with calcium ions; Adding radium radionuclides to an inert vehicle in concentrations sufficient to treat tumors by radiation therapy. A method comprising:

24. 24. The method of claim 23, wherein adding the active ingredient and radium to the inert excipient comprises combining the active ingredient and radium before adding them to the inert excipient, and adding the combination of the active ingredient and radium together to the inert excipient.

25. 24. The method of claim 23, wherein adding the agent and radium to the inert vehicle comprises adding the radium to the inert vehicle only after the agent has been added to the inert vehicle.

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