Convection-enhanced diffuse alpha emitter radiation therapy

Abstract

The device for treating the tumor comprises a needle for insertion into the tumor and a volume of at least 1*10 6 and a pump for continuously pumping the generated solution to the needle.

Description

[Technical field]

[0001] The present invention relates generally to radiation therapy, and more particularly to devices and methods for delivering radiation therapy to tumors. [Background technology]

[0002] Many therapeutic approaches have been proposed to treat cancer, some of which involve the delivery of drugs or other agents to the tumor.

[0003] US Pat. No. 5,720,720 to Laske et al. describes a method for convection-enhanced drug delivery, the disclosure of which is incorporated herein by reference.

[0004] Ionizing radiation is commonly used in the treatment of certain tumors, including malignant cancers, to destroy their cells. Alpha particles are a powerful means of radiation therapy because they induce clustered double-strand breaks in DNA that the cell cannot repair. Unlike conventional radiation, the destructive effect of alpha particles is largely unaffected by low cellular oxygen levels and is equally effective against hypoxic cells present in tumors, the presence of which is the main cause of failure of conventional radiation therapy based on photon or electron beams. In addition, the short distance of alpha particles (less than 100 micrometers) in tissues ensures that surrounding healthy tissue is spared when alpha particle-emitting atoms are confined to the tumor volume.

[0005] For example, Diffusing alpha-emitters radiation therapy (DaRT), described in U.S. Patent No. 8,834,837 to Kelson, extends the therapeutic range of alpha radiation by using radium-223 or radium-224 atoms that undergo several radioactive decay chains, with dominant half-lives of 3.6 days for radium-224 and 11.4 days for radium-223. In DaRT, the radium atoms are bound to a source (also called a "seed") implanted in the tumor with sufficient strength that they do not leave the source to be wasted (by being removed from the tumor through the blood), but a significant proportion of daughter radionuclides (radon-220 in the case of radium-224 and radium-219 in the case of radium-223) leave the source and enter the tumor upon radium decay. These radionuclides, as well as their own radioactive daughter atoms, spread around the source by diffusion up to a radial distance of several millimeters before decaying by alpha emission. Thus, the extent of destruction within the tumor increases proportionately to the radionuclide that remains in the source along with its daughter.

[0006] Given the measured diffusion lengths across a wide range of tumor types, seeds are typically placed in a closely spaced geometric configuration with seed spacing of 3.5-5 mm to improve efficacy. Depending on the size of the tumor, tens to hundreds of seeds with multiple penetration points may be used in a given treatment.

[0007] Stein et al., U.S. Publication No. 2022 / 0273832, "Radiolabeled Liposomes and Methods of Use Thereof," describes convection-enhanced delivery of radiolabeled liposomes.

[0008] US Publication No. 2011 / 0135569, "Method for Therapeutic Administration of Radionucleosides," describes the direct injection under pressure of Auger electron-emitting radionucleosides. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] U.S. Patent No. 5,720,720 [Patent Document 2] U.S. Patent No. 8,834,837 [Patent Document 3] US Publication No. 2022 / 0273832 [Patent Document 4] US Publication No. 2011 / 0135569 Summary of the Invention [Means for solving the problem]

[0010] Thus, according to some embodiments of the present invention, there is provided a method of treating a tumor comprising identifying a tumor and injecting a liquid containing a free radionuclide into the tumor for a period of at least six hours.

[0011] Optionally, the step of identifying the tumor includes identifying a tumor having a maximum diameter of at least 2 cm, and the step of injecting the liquid includes injecting through a single needle. Optionally, the step of injecting the liquid includes injecting during a period of at least 72 hours, alternatively at least 110 hours. In some embodiments, the step of injecting the liquid includes injecting a liquid comprising a beta-emitting radionuclide. Alternatively or additionally, the step of injecting the liquid includes injecting a liquid comprising an alpha-emitting therapeutic radionuclide. Optionally, the step of injecting the liquid includes: 212 Optionally, the step of injecting the liquid includes injecting a liquid containing a Pb radionuclide at a concentration of at least 2*10 per microliter. 7 Optionally, the step of injecting the liquid includes injecting a liquid containing a radionuclide of an alpha-emitting therapeutic isotope in a greater than negligible amount. 224 Ra, 220 Rn, and 216infusing the liquid without Po. Optionally, the step of infusing the liquid includes infusing at a rate of at least 2.5 microliters per minute and / or at a rate of less than 10 microliters per minute.

[0012] Optionally, the step of injecting the liquid includes pumping the liquid through a vial holding one or more seeds therein having a parent radionuclide attached thereto in a manner such that the parent radionuclide does not leave the seed, but a significant proportion of the daughter nuclides escape from the seed into the liquid upon decay. Optionally, the one or more seeds have a concentration of at least 10 microcuries. 224 Ra radionuclide, at least 100 microcuries 224 Ra radionuclide, or at least 250 microcuries 224 It carries the Ra radionuclide.

[0013] Optionally, the method further comprises acquiring an image of the distribution of the radionuclide in the tumor, determining whether regions of the tumor have not received a sufficient number of the radionuclide in response to the acquired image, and adjusting injection parameters in response to determining that regions of the tumor have not received a sufficient number of the radionuclide. Optionally, at least a portion of the radionuclide is injected bound to nanoparticles that function as contrast agents that appear in the acquired image. Optionally, adjusting the injection parameters comprises altering a flow rate at which the liquid is injected. Optionally, adjusting the parameters comprises altering a concentration of the radionuclide in the liquid.

[0014] In some embodiments of the present invention, a device for treating a tumor is provided, the device comprising a needle for insertion into the tumor and a volume of at least 1*10 per microliter. 6 and a pump for continuously pumping the generated solution through the needle.

[0015] Optionally, the device further comprises a controller programmed to control the pump to pump the liquid solution through the vial and into the needle continuously for at least 24 hours. Optionally, the controller is programmed to control the pump to pump the liquid solution through the vial at a rate of at least 2.5 microliters per minute. Optionally, the controller is programmed to control the pump to pump the liquid solution through the vial at a rate of at least 10 microliters per minute. Optionally, the solution generator is programmed to pump at least 2*10 microliters per minute. 9 of atoms 212 Optionally, the solution generator comprises a vial containing one or more seeds therein having radium radionuclides attached thereto in such a manner that the radium radionuclides do not leave the seeds but a significant proportion of daughter radionuclides leave the seeds upon decay, and a tube connecting the vial to the needle, the pump configured to pump liquid through the vial and into the tube to produce the solution. Optionally, the one or more seeds have a concentration of at least 10 microcuries. 224 Ra radionuclide, at least 100 microcuries 224 Ra radionuclide, or at least 250 microcuries 224 Optionally, the solution generator carries at least 1*10 Ra radionuclide per microliter. 8 With a concentration of atoms of 212 The device is configured to generate a liquid solution containing Pb atoms.

[0016] In some embodiments of the present invention, a solution for treating tumors is provided, comprising 1*10 6 and 1*10 11 At a concentration of free atoms between 212 Further provided is a solution comprising a biocompatible liquid solution containing Pb atoms. Optionally, the solution has a concentration of at least 1*10 per microliter. 7 With a concentration of atoms of 212 Optionally, the solution contains at least 1*10 Pb atoms per microliter.8 With a concentration of atoms of 212 Pb atoms. Optionally, the solution contains 2*10 9 At a concentration of less than 212 Optionally, the solution contains at least 1*10 Pb atoms per microliter. 9 With a concentration of atoms of 212 Optionally, the solution comprises: 212 It is suitable for convection-enhanced delivery of Pb atoms. [Brief description of the drawings]

[0017] [Figure 1] 1 is a schematic diagram of a radiation therapy solution injection system according to one embodiment of the present invention; [Diagram 2] FIG. 2 is a flow diagram of a convection-enhanced radiation therapy method according to an embodiment of the present invention. [Diagram 3] 1 shows the effect of varying flow rates from 0 to 10 μL / min for a constant source activity of 300 μCi224Ra and a 5 day treatment period, according to one embodiment of the present invention. [Figure 4] 1 shows the effect of varying source radioactivity from 10 to 1000 μCi 224Ra for a constant flow rate of 5 μL / min and a treatment period of 5 days, according to one embodiment of the present invention. [Diagram 5] 1 shows the effect of varying source activity from 30 to 3000 μCi 224Ra for a constant flow rate of 5 μL / min and 12 hours of treatment according to one embodiment of the present invention. [Figure 6] 1 shows processing times for a source activity of 300 μCi224Ra and a constant flow rate of 5 μL / min according to one embodiment of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] An aspect of some embodiments of the present invention relates to the delivery of radionuclides in solution to tumors by enhanced convection delivery. The solution is continuously infused over a relatively long period of time, at least several hours. The alpha-emitting radionuclides in the solution are free so that the radionuclides and / or their daughter radionuclides can flow by convection in the tumor. The term "free" means that the radionuclides are not bound to large particles (e.g., particles with a diameter of more than 100 nanometers) that prevent flow between cells, are not bound to targeting elements (e.g., antibodies) that bind to cells, and are not bound to vectors (e.g., liposomes, radionucleosides) that are internalized in cancer cells.

[0019] 1 is a schematic diagram of a radiotherapy solution injection system 10 according to one embodiment of the present invention. System 10 includes one or more injection tubes 12, a delivery tube 14, a pump 16, and a source 18 of radionuclide solution.

[0020] Injection tube 12 is optionally a hollow needle designed to remain within the tumor for a period of at least several hours or days. Alternatively or additionally, injection tube 12 comprises a catheter. Delivery tube 14 is designed to direct the radionuclide solution from a source 18, through injection tube 12, and into the tumor.

[0021] In some embodiments of the invention, the number of injection tubes 12 used depends on the size of the tumor. Optionally, a minimum number of injection tubes 12 are used to cover the entire tumor, in order to minimize the number of inlets to the patient with the tumor being treated. The layout of the injection tube 12 outlets is optionally selected such that no point in the tumor is further than a predetermined maximum distance from at least one of the outlets. In some embodiments, the predetermined maximum distance is at least 5 mm, at least 7 mm, at least 9 mm, at least 11 mm, or at least 13 mm. It is noted that in the use of DaRT seeds, the maximum distance used is about 1.5-2.5 mm. Thus, the method significantly reduces the number of patient penetrations compared to other radiation therapy methods. However, optionally, the maximum distance in some embodiments is less than 15 mm, less than 13 mm, less than 11 mm, or even less than 10 mm to ensure sufficient radiation to the entire tumor. Thus, even a large tumor can be covered with less than 10 injection tubes 12, less than 6 injection tubes 12, or even less than 4 injection tubes 12. In many cases, only a single injection tube 12 is used. In other embodiments, at least two or at least three are used as a minimum to provide robustness in case one of the injection tubes 12 becomes clogged or falls out of place. In some embodiments, the same flow rate of solution and the same radionuclide concentration are provided through all of the one or more injection tubes 12. Alternatively, the flow rate and / or radionuclide concentration of one or more injection tubes 12 can be adjusted separately from the flow rate and / or radionuclide concentration of the other injection tubes 12.

[0022] FIG. 2 is a flow diagram of a method of treating a patient using the system 10, according to an embodiment of the invention. The method includes inserting one or more injection tubes 12 into a tumor (50) and operating the system 10 to continuously inject (52) a radionuclide solution into the tumor. During the injection step (52), the pump 16 causes the solution to flow at a specified rate, so that the solution flows radially outward from the outlet of the injection tube 12 and disperses into the tumor. In some embodiments, after an initial period, one or more images are acquired (54) of the treated tumor to confirm the distribution of the radionuclide within the tumor. If necessary, the treatment is adjusted (56) based on the acquired images. The injection of the radionuclide solution then continues with the adjusted process if adjustments were made, or with the original parameters if no adjustments were made. Optionally, the acquisition of images (54) and adjustment of the treatment (56) are repeated periodically.

[0023] In some embodiments, the system 10 and / or the method of FIG. 2 are used to treat malignant tumors in locations that are difficult to access, such as deep organs. For example, the system 10 and / or the method of FIG. 2 are used to treat tumors of the brain (e.g., glioblastoma tumors, brain metastases of other tumor types), lung, pancreas, and / or kidney. In further embodiments, the system 10 and / or the method of FIG. 2 are used to treat large tumors, such as sarcomas. However, it should be noted that the system 10 and / or the method of FIG. 2 can be used for any other type of tumor.

[0024] The system 10 optionally delivers the radionuclide solution into the tumor at a constant or near constant rate, for example, within 20%, 10%, or 5% of a reference rate. The constant or reference rate is optionally at least 0.1 microliters per minute, at least 0.5 microliters per minute, at least 1 microliter per minute, at least 2.5 microliters per minute, or at least 4 microliters per minute. Typically, the constant or reference rate is less than 50 microliters per minute, less than 20 microliters per minute, less than 10 microliters per minute, or less than 8 microliters per minute. In an exemplary embodiment, the constant or reference rate is on the order of 5 microliters (μL) per minute. Instead of a constant or near constant rate, the radionuclide solution can be delivered at a predetermined profile that varies over time, such as a profile having an increasing rate, a decreasing rate, a sinusoidal variation, or some other modulation. In some embodiments, the time-dependent predetermined profile is designed to compensate for fluctuations in the concentration of the radionuclide in solution by increasing the flow rate when the radioactivity concentration decreases and / or decreasing the flow rate when the concentration increases.

[0025] Optionally, pump 16 is controlled by controller 26 to deliver the radionuclide solution according to a predetermined profile.

[0026] It should be noted that instead of being injected continuously, the radionuclide solution can be injected intermittently, for example allowing for interruptions every few hours.

[0027] In some embodiments, the injected solution contains one or more radionuclides that are alpha-emitting radionuclides or that are parents of a decay chain that includes at least one alpha-emitting radionuclide. As used herein, the term "alpha-emitting therapeutic radionuclide" is used to refer to both alpha-emitting radionuclides and radionuclides whose decay chain includes an alpha-emitting decay (even if the first decay in the decay chain is not an alpha-emitting decay). In other embodiments, the injected solution contains one or more radionuclides that emit only beta radiation.

[0028] In some embodiments, the one or more radionuclides are those that are rapidly cleared by the blood circulation at a high rate, thereby providing built-in protection against damage to normal tissue surrounding the tumor, since when the radionuclides reach the tumor periphery, they are rapidly captured by red blood cells and cleared by the blood circulation. Optionally, the one or more radionuclides are lead atoms, (e.g., 213 Pb, 212 Pb, 211 Pb, 209 Pb) atoms may become trapped in red blood cells and / or become trapped in blood vessels for other reasons.

[0029] Alternatively or additionally, the one or more radionuclides in the injected solution have a decay chain with the longest half-life to dominant release (i.e., the release that provides the primary therapy), which is not too short so that it loses too much of its radioactivity before reaching the tumor, and not too long so that a high proportion of the radionuclide leaves the tumor before its dominant release. The longest half-life to dominant release of a radionuclide is the longest half-life of the radionuclide and its daughter radionuclides until the desired release at the end of the decay chain. For example, 213 The radioactive Pb nuclide has the following decay chain: 213 Pb(10.2 min)-> 213 Bi(45.59 min)-> 213 Po(3 microseconds) or 209 Ti(2 min)-> 209 Pb(3.253 hours)-> 209Bi (basically stable) The longest half-life for dominant release in this sequence is 45.59 min.

[0030] Accordingly, applicants have determined that it is preferable to use isotopes that have a maximum half-life before release of less than 48 hours, less than 24 hours, less than 16 hours, less than 12 hours, or less than 10 hours, whereas to maximize the effective range of treatment from the outlet of the infusion tube 12, the maximum half-life before release is at least 10 minutes, at least 30 minutes, at least 60 minutes, at least 3 hours, or at least 5 hours.

[0031] In some embodiments, the one or more radionuclides in the infusion solution are 212 Alternatively or additionally, the one or more radionuclides in the injection solution include 211 Pb atoms. Further alternatively, the one or more radionuclides in the injection solution include: 213 Pb or 213 In yet another embodiment, the one or more radionuclides in the infusion solution include: 224 Ra, 223 Ra and / or 225 Contains Ac.

[0032] The base of the injection solution optionally comprises distilled water, saline, or any other suitable liquid that is biocompatible and suitable for injection into a tumor, such as liquids known to be used in convection-enhanced delivery of drugs.

[0033] The radionuclide in solution optionally flows freely within the tumor by convection. In some embodiments, when injected, the radionuclide is not bound to other particles. However, it is noted that within the tumor, the radionuclide may bind to proteins, which generally does not prevent it from distributing throughout the tumor. Alternatively, some or all of the radionuclide is bound to small nanoparticles that are not targeted to cells and have a diameter of less than 40 nanometers, less than 30 nanometers, less than 20 nanometers, less than 10 nanometers, or even less than 5 nanometers. This option can be used to slow the removal of the radionuclide from the tumor and increase the proportion of the radionuclide that decays within the tumor. This option is particularly desirable for isotopes with the longest half-lives of the decay chain, greater than 12 hours, or greater than 24 hours. Alternatively or additionally, the nanoparticles or a portion thereof (e.g., at least 10%, at least 20%, at least 50%, at least 80%) include a material that is easily identified in medical images, such as gold.

[0034] Referring specifically to acquiring the image 54, in some embodiments the image is acquired by gamma imaging. Alternatively, any other suitable modality, such as computed tomography (CT), is used to acquire the image 54. Optionally, as described above, nanoparticles containing a contrast agent, such as gold, are attached to the radionuclides to aid in identifying the layout of the radionuclides in the image.

[0035] Adjusting the treatment (56) may include, for example, increasing the flow rate and / or increasing the concentration of the radionuclide in solution if a large area of ​​the tumor is determined to have low levels of the radionuclide. If high levels of the radionuclide in the tumor are identified, the flow rate and / or the radionuclide concentration can be decreased. Additionally, if one or more specific areas of the tumor are identified to have low radionuclide content, additional injection tubes 12 can be inserted into the specific areas of the tumor and / or solid radiotherapy seeds can be implanted in the specific areas.

[0036] Radionuclide solution source In some embodiments, the radionuclide solution source 18 is a reservoir that carries a solution containing the radionuclide to be injected. The solution in the radionuclide solution source 18 optionally contains the radionuclide at the concentration to be injected. Alternatively, the radionuclide solution source 18 contains a high concentration of the radionuclide, and the solution removed from the reservoir is diluted by the pump 16 with a base liquid source (not shown). Optionally, in these embodiments, the solution containing the radionuclide is generated separately from the system 10 using any method known in the art.

[0037] In some embodiments, the solution containing the radionuclide is produced using any of the wet preparation methods described in WO 2021 / 070029, "Wet preparation of Radiotherapy Sources," the entire disclosures of which are incorporated herein by reference. Alternatively or additionally, 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, are used to produce the solution.

[0038] In another embodiment, the radionuclide solution source 18 comprises a vial containing one or more physical elements 22 carrying one or more parent radionuclides of one or more radionuclides contained in the injection solution. The liquid present in the vial or passing through the vial collects daughter radionuclides of these one or more parent radionuclides. The parent radionuclides are optionally attached to the physical element 22 with a bond strong enough so that the parent radionuclides do not leave the physical element 22 with the liquid. Alternatively, the parent radionuclides are optionally bound to the physical element 22 such that a significant proportion (e.g., at least 20%, at least 30%, at least 40%, or at least 50%) of the daughter radionuclides produced upon nuclear decay leave the physical element 22 and enter the liquid. The parent radionuclide is attached to the physical element 22 using any suitable method known in the art, such as any of the methods described in Kelson, U.S. Pat. No. 8,834,837, WO 2007 / 0130260, “A radioactive Surface Source and a Method for Producing the Same,” and WO 2018 / 207105, “Polymer Coatings for Brachytherapy Devices,” the entire disclosures of which are incorporated herein by reference.

[0039] The physical elements 22 include surface sheets, bars, balls, seeds, wires, or any other suitable structure. Optionally, the physical elements 22 are disposed within the radionuclide solution source 18 in a replaceable manner during treatment of a patient. In some embodiments, the radionuclide solution source 18 includes multiple physical elements 22. One of the physical elements is replaced periodically, for example every few hours, with a new element to increase the radioactivity introduced into the solution and to prevent too great a decrease in the radioactivity of the radionuclide solution provided to the patient.

[0040] In some embodiments, the parent radionuclide on the physical element 22 is 224 Ra, 223 Ra and / or 225Ac. The parent radionuclide optionally has a radioactivity of at least 10 microcuries (μCi), at least 50 μCi, at least 150 μCi, at least 250 μCi, at least 500 μCi, at least 800 μCi, at least 1500 μCi, at least 2000 μCi, or at least 3000 μCi. The casing of the radionuclide solution source 18 is optionally designed to shield radiation within the radionuclide solution source 18 depending on the level of radiation therein.

[0041] radioactivity Various tumors require different amounts of radiation according to the particular type of tumor. As described in WO 2022 / 259166, "Activity Levels for Diffusing Alpha-Emitter Radiation Therapy," which is incorporated herein by reference, the applicant has determined the following biologically effective doses (BEDs) in gray equivalent (GyE) for various types of cancer tumors. These dose values ​​are for photon-based radiation (X-rays, gamma rays). Because alpha radiation is believed to be more lethal to cells, the gray equivalent dose of alpha radiation is multiplied by a correction factor known as the relative biological effectiveness (RBE), which is currently estimated at 5, to convert it to a BED in gray equivalent (GyE). The BED for an alpha emitter is the sum of the alpha and beta doses multiplied by the RBE.

[0042] (Table 1) JPEG2025507661000002.jpg57133

[0043] When planning treatment sessions, it is important to take into account that radionuclides are washed out of the tumor before they decay. The proportion of radionuclides that leaves the tumor before decaying is determined by the ratio of the average time the radionuclide is present in the tumor to the half-life of the radionuclide.

[0044] When using convection to enhance delivery of radionuclides to tumors, it is believed that the dispersion of the radionuclide throughout the tumor is primarily due to convection, and the diffusion length does not have a direct significant effect on treatment. To destroy the tumor, it is necessary to deliver the radionuclide within 1 cm of the tumor, assuming that the radionuclide is evenly distributed throughout the tumor. 3 Approximately 10 per 10 Alpha-emitting decay of the radionuclide is required. To compensate for the radionuclide leaving the tumor before decaying and for the uneven distribution of the radionuclide within the tumor, more radionuclide is delivered to the tumor during treatment.

[0045] For alpha-emitter radionuclides that have a 50% chance of leaving the tumor before decaying, each cm 3 At least 1*10 11 , at least 2.5*10 11 , at least 5*10 11 , at least 1*10 12 , at least 5*10 12 , or at least 1*10 13 A total dose of radionuclides of 10 is used, whereas the number of radionuclides expected to leave the tumor before decaying is arbitrarily set to 1*10 to avoid systemic damage to the patient. 13 Less than 5*10 12 Less than 2*10 12 Less than or 1*10 12 In particular, when the alpha-emitter radionuclide is Pb-212, the number of radionuclides expected to leave the tumor before decaying is less than 2*10 13 Less than or 2*10 12 is less than.

[0046] For beta-emitting radionuclides that have a 50% chance of leaving the tumor before decay, 3 At least 1*10 12 of radionuclides, at least 2*10 12 of radionuclides, at least 1*10 13 of radionuclides, or at least 1*10 14A total dose of radionuclides of 10 ... 14 Less than 5*10 13 Less than 1*10 13 Less than 5*10 12 Less than or 2*10 12 is less than.

[0047] Duration and Concentration The total number of radionuclides can be provided at higher concentrations for shorter durations or at lower concentrations for longer durations. Longer durations are preferred for logistical reasons to avoid handling of the high activity source in the system 10 and waste of the parent radionuclides used to generate the radionuclides delivered to the patient. On the other hand, shorter durations may be desired for patient convenience. Treatment is optionally performed for several hours to allow accumulation of the radionuclides in the tumor. Treatment is optionally provided for at least 6 hours, at least 12 hours, at least 24 hours, at least 48 hours, at least 96 hours, or at least 120 hours.

[0048] The injected solution typically flows at a rate of at least 2*10 per second. 5 of radionuclides, at least 5*10 per second 5 of radionuclides, at least 2*10 per second 6 of radionuclides, at least 5*10 per second 6 of radionuclides, or at least 2*10 per second 8 On the other hand, to avoid using too high a concentration, the injection solution is optionally delivered at a rate of 2*10 per second. 9 Less than 1*10 radionuclides per second 9 Less than 5*10 radionuclides per second 8 Less than 2*10 radionuclides per second 8 Less than 1*10 radionuclides per second 8 Radionuclides of less than 5*10 per second, and in some embodiments even less than 5*10 per second 7Contains less than 1000 radionuclides.

[0049] The injected solution optionally has a concentration of at least 1*10 per microliter. 6 of radionuclides, at least 4*10 per microliter 6 of radionuclide, at least 1*10 per microliter 7 of radionuclide, at least 1*10 per microliter 8 of radionuclide, at least 1*10 per microliter 9 of radionuclide, or at least 1*10 per microliter 10 In some embodiments, the injected solution has a radionuclide concentration of 1*10 per microliter. 11 Less than 1*10 radionuclides per microliter 10 Less than 1*10 radionuclides per microliter 9 Less than 4*10 per microliter of radionuclide 8 has a radionuclide concentration of less than

[0050] Localized or systemic damage In some embodiments, the injected solution does not contain significant amounts of radionuclides that are not rapidly trapped in the bloodstream, where they may reach and damage healthy tissue surrounding the tumor. Alternatively or additionally, the injected solution may be 224 Radionuclides with a long half-life of 3 days or more, such as Ra, 223 It does not contain significant amounts of radionuclides with long half-lives of 8 days or longer, such as Ra, because these radionuclides can cause systemic damage if administered in large amounts.

[0051] Optionally, in these embodiments, the solution contains at least 1*10 per second of a radionuclide with a long half-life. 5 No more atoms than 1*10 4 No more atoms, or 1*10 3contains no more atoms than the parent radionuclide. 224 When Ra is included, optionally, 224 Ra, 220 Rn and / or 216 The amount of Po can be negligible, or larger amounts of these radionuclides can be tolerated in the injection solution, as long as the numbers of these radionuclides do not reach safety limits. 224 In embodiments where Ra is used, 212 Pb and its daughter atoms ( 212 Bi, 212 Po and 208 Tl) enters the tumor, 224R a and its short-lived daughter atoms 220 Rn and 216 Po generally remains outside the tumor or is expressed in very small or negligible amounts of daughter atoms. 220 Rn and 216 Po enters the tumor. The radiation dose in the tumor is 212 Bi and 212 Alpha decay of Po dominates, and 212 Pb, 212 Bi, 208 Beta electrons from Tl also contribute.

[0052] In another embodiment, the radionuclide in the injected solution is 224 Ra, 223 Ra, or 225 These include radionuclides that initiate multiple alpha-emitting chains despite their relatively long half-lives, such as Ac, of greater than 3 days or greater than 8 days. Although greater than 90% of the radionuclides may leave the tumor before decaying, the additional decay of the chains allows for extra destruction of tumor cells, thereby allowing the use of fewer radionuclides that are below the safety limit for systemic damage.

[0053] analysis The spatial fall-off of the dose field is dominated by solution convection, with negligible contributions from diffusion, and diffusion to healthy tissue outside the tumor is similar to DaRT from seeds implanted within the tumor. By exploiting convection, a larger area can be covered through a single penetration point, reducing the total activity required to cover the tumor volume.

[0054] Figures 3 and 4 show the results of dose calculations in CE-DaRT under the simplifying assumption that the system has spherical symmetry (the presence of the needle is not taken into account). The diameter of the exit opening of the injection tube 12 is 1 mm. The treatment is assumed to last for 5 days.

[0055] Figure 3 shows that the injected solution 212 The source activity of the radionuclide solution source 18 is 300 μCi, containing Pb. 224 The effect of varying the flow rate from 0 to 10 μL / min at a constant Ra is shown.

[0056] Figure 4 shows the source activity from 10 to 1000 μCi for a constant flow rate of 5 μL / min. 224 The effect of varying the dose from 0.01 to 0.15 mm is shown in Fig. 1. In both figures, a line of 10 Gy is shown as the reference therapeutic alpha particle dose. As can be seen, with a reasonable choice of source activity and flow rate, a spherical area of ​​radius 10-15 mm can be covered from one entry point.

[0057] Figure 5 shows the effect of varying source activity from 30 to 3000 μCi at a constant flow rate of 5 μL / min over a 12-hour treatment. 224 The effect of changing the temperature is shown in Fig. 1.

[0058] Figure 6 shows a source activity of 300 μCi 224 The treatment time is shown for Ra and a constant flow rate of 5 μL / min.

[0059] In some embodiments, in preparation for a treatment session, the size and type of the tumor is determined. Depending on the size of the tumor, the required treatment radius is determined, possibly after insertion of the injection tube 12. Depending on the type of tumor, the required radiation level in Gray is optionally determined. Thus, using the graphs of Figures 4 and / or 5, the radiation level is determined based on the required treatment radius from the exit of the injection tube 12. Alternatively or additionally, using the graph of Figure 6, the duration of the treatment is selected. Still alternatively or additionally, using the graph of Figure 3, the flow rate is selected.

[0060] conclusion It will be understood that the methods and apparatus described above should also be construed as including apparatus for performing the methods, and methods of using the apparatus. It will be understood that features and / or steps described with respect to one embodiment may be used with other embodiments, and that not all embodiments of the invention will have all the features and / or steps shown in a particular figure or described with respect to one of the particular embodiments. Tasks will not necessarily be performed in the exact order described.

[0061] While the above description is primarily concerned with free radionuclides that are not bound to larger particles, to targeting elements, or to vectors that are internalized by cancer cells, some embodiments of the invention involve the use of radionuclides that are not completely free. In some of these embodiments, a small percentage (less than 30%, less than 20%, less than 10%) of the radionuclides are not free. Alternatively or additionally, the radionuclides are not free in that they slightly exceed the definition of free.

[0062] Some of the above-described embodiments include structure, acts, or details of structure and acts described by way of example, which are not essential to the present invention. Structures and acts described herein may be replaced with equivalents performing the same function, as known in the art, even if these structures or acts are different. The above-described embodiments are given by way of example, and the present invention is not limited to what has been specifically shown and described above. Rather, the scope of the present invention includes both combinations and subcombinations of the various features described hereinabove, as well as variations and modifications thereof that may occur to those skilled in the art upon reading the above description and that are not disclosed in the prior art. Thus, the scope of the present invention is limited only by the elements and limitations used in the claims, and the terms "comprise, include, have" and variations thereof, when used in the claims, shall mean "comprise but not necessarily limited to." [Explanation of symbols]

[0063] 50 Insert the infusion tube(s) into the tumor 52 Injecting radionuclide solution 54 Obtaining images of radionuclide dispersion 56 Adjust treatment if necessary

Claims

1. 1. A method of treating a tumor, comprising: identifying a tumor; injecting the tumor with a liquid containing a free radionuclide for a period of at least 6 hours; The method includes:

2. 10. The method of claim 1, wherein the step of identifying the tumor comprises identifying a tumor having a maximum diameter of at least 2 cm, and the step of injecting the liquid comprises injecting through a single needle.

3. The method of claim 1 , wherein the step of infusing the liquid comprises infusing for a period of at least 72 hours.

4. The method of claim 3 , wherein the step of injecting the liquid comprises injecting for a period of at least 110 hours.

5. The method of claim 1 , wherein the step of injecting a liquid comprises injecting a liquid containing a beta-emitting radionuclide.

6. The method of claim 1 , wherein the step of injecting a liquid comprises injecting a liquid containing an alpha-emitting therapeutic radionuclide.

7. The step of injecting the liquid includes: 212 The method of claim 6 comprising injecting a liquid containing a Pb radionuclide.

8. The step of injecting the liquid may include injecting at least 2*10 7 13. The method of claim 1, comprising injecting a liquid containing a radionuclide of an alpha-emitting therapeutic isotope.

9. The step of injecting liquid comprises injecting more than a negligible amount of liquid. 224 Ra, 220 Rn and 216 The method of claim 1 comprising injecting a Po-free liquid.

10. The method of claim 1 , wherein the step of injecting the liquid comprises injecting at a rate of at least 2.5 microliters per minute.

11. The method of claim 1 , wherein the step of injecting the liquid comprises injecting at a rate of less than 10 microliters per minute.

12. 2. The method of claim 1, wherein the step of injecting the liquid comprises pumping the liquid through a vial holding therein one or more seeds having the parent radionuclide attached to the seeds in a manner such that the parent radionuclide does not leave the seeds, but a significant proportion of daughter nuclides escape from the seeds into the liquid upon decay.

13. The one or more seeds have a density of at least 10 microcuries. 224 The method of claim 12, carrying a Ra radionuclide.

14. The one or more seeds have a density of at least 100 microcuries. 224 The method of claim 13, carrying a Ra radionuclide. In

15. The one or more seeds have a density of at least 250 microcuries. 224 15. The method of claim 14, which carries a Ra radionuclide.

16. obtaining an image of the distribution of the radionuclide in the tumor; determining whether a region of the tumor has not received a sufficient number of radionuclides in response to the acquired images; adjusting injection parameters in response to determining that the region of the tumor is not receiving a sufficient number of radionuclides; The method of any one of claims 1 to 15, further comprising:

17. 17. The method of claim 16, wherein at least a portion of the radionuclides are injected bound to nanoparticles that function as imaging agents that appear in the acquired images.

18. The method of claim 16 , wherein adjusting the injection parameters comprises changing a flow rate at which the liquid is injected.

19. 17. The method of claim 16, wherein adjusting the injection parameters comprises altering a concentration of the radionuclide in the liquid.

20. 1. An apparatus for treating a tumor, comprising: a needle for insertion into the tumor; At least 1*10 per microliter 6 a solution generator configured to generate a liquid solution containing a free alpha-emitting therapeutic radionuclide at an atomic concentration of a pump for continuously pumping the generated solution through the needle; An apparatus comprising:

21. 21. The device of claim 20, further comprising a controller programmed to control the pump to continuously pump the liquid solution through the vial and into the needle for at least 24 hours.

22. 22. The apparatus of claim 21, wherein the controller is programmed to control the pump to pump the liquid solution through the vial at a rate of at least 2.5 microliters per minute.

23. 22. The apparatus of claim 21, wherein the controller is programmed to control the pump to pump the liquid solution through the vial at a rate of at least 10 microliters per minute.

24. The solution generator has a flow rate of at least 2*10 per microliter. 9 of atoms 212 21. The apparatus of claim 20 configured to generate the liquid solution having a Pb radionuclide.

25. The solution generator includes: a vial containing therein one or more seeds having said radium radionuclides attached thereto in a manner such that the radium radionuclides do not leave the seeds, but a significant proportion of daughter radionuclides leave said seeds upon decay; a tube connecting the vial to the needle; Equipped with 25. Apparatus according to any of claims 20 to 24, wherein the pump is configured to pump liquid through the vial and into the tube to produce the solution.

26. The one or more seeds have a density of at least 10 microcuries. 224 26. The device of claim 25, carrying a Ra radionuclide.

27. The one or more seeds have a density of at least 100 microcuries. 224 27. The device of claim 26, carrying a Ra radionuclide.

28. The one or more seeds have a density of at least 250 microcuries. 224 28. The device of claim 27, carrying a Ra radionuclide.

29. The solution generator has a flow rate of at least 1*10 per microliter. 8 With a concentration of atoms of 212 25. An apparatus according to any of claims 20 to 24, configured to generate a liquid solution comprising Pb atoms.

30. A solution for treating a tumor, comprising: 1*10 per microliter 6 and 1*10 11 At a concentration of free atoms between 212 A solution comprising a biocompatible liquid solution containing Pb atoms.

31. The solution has a concentration of at least 1*10 per microliter 7 With a concentration of atoms of 212 31. The solution of claim 30 comprising Pb atoms.

32. The solution has a concentration of at least 1*10 per microliter 8 With a concentration of atoms of 212 31. The solution of claim 30 comprising Pb atoms.

33. The solution contains 2*10 9 At a concentration of less than 212 33. The solution of claim 32 comprising Pb atoms.

34. The solution has a concentration of at least 1*10 per microliter 9 With a concentration of atoms of 212 31. The solution of claim 30 comprising Pb atoms.

35. The solution is 212 35. A solution according to any of claims 30 to 34, suitable for convection-enhanced delivery of Pb atoms.

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