Alpha-emitting radionuclides for use in the treatment of peritoneal cancer.

Abstract

The present invention relates to a pharmaceutical composition comprising a therapeutically relevant amount of an alpha-emitting radionuclide for use in cancer treatment, particularly where an individual has already undergone surgery to debulk one or more peritoneal tumors prior to administration of the pharmaceutical composition.

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition comprising a therapeutically relevant amount of an alpha-emitting radionuclide for use in cancer treatment, particularly where an individual has already undergone surgery to debulk one or more peritoneal tumors prior to administration of the pharmaceutical composition. [Background technology]

[0002] Peritoneal metastasis can be a serious problem depending on the type of cancer.

[0003] Primary and metastatic cancers within the peritoneal cavity are usually treated with chemotherapy, surgery, or radiation therapy, or some combination of these. Although these treatments can significantly improve disease-free and overall survival, there is a substantial unmet need for novel therapies to improve outcomes.

[0004] Peritoneal cancers can be primary tumors of the peritoneum (peritoneal mesothelioma and primary peritoneal carcinoma) or disseminated as peritoneal metastases from tumors in other organs, either intraperitoneally (gastric cancer, pancreatic cancer, colorectal cancer, small intestine cancer, ovarian cancer, endometrial cancer, appendix cancer, and sarcoma) or extraperitoneally (lung tumors, breast tumors, and kidney tumors). All of these are candidates for debulking surgery (CRS), with or without hyperthermic intraperitoneal chemotherapy (HIPEC) or alpha-emitter compositions such as Radspherin.

[0005] To this end, two phase I trials have been conducted using alpha-emitting radioimmunoconjugates to treat patients with peritoneal cancer, but neither involved surgery or HIPEC. These trials were completed several years ago, but no further follow-up studies appear to have been conducted, suggesting that this approach was not sufficiently compelling to warrant further clinical development.

[0006] Primary colorectal cancer, ovarian cancer, gastric cancer, appendix cancer, and other cancers that appear in adjacent tissues of the peritoneal cavity can all be treated relatively effectively with debulking surgery (CRS), but the disease may later reappear in the form of intraperitoneal and / or distant metastases. Distant metastases can often be effectively treated, for example, with surgery, external beam radiation therapy (XBR), or chemotherapy. Local intraperitoneal (ip) cancer metastases are often difficult to treat effectively. Some centers use a two-stage procedure to treat certain abdominal cancers, adding postoperative hyperthermic intraperitoneal chemotherapy (HIPEC). Following surgical removal of cancerous tumors, attempts have been made to remove residual cancer cells by applying heated chemotherapy directly into the peritoneal cavity. Unfortunately, the addition of HIPEC to surgical procedures has only provided relatively limited improvement. Therefore, there is a significant need for additional therapies that can reduce the risk of recurrence due to local intraperitoneal metastases.

[0007] During debulking surgery for tumors adjacent to the peritoneal cavity, small amounts of cells (e.g., microseeds) detached from the tumor may "leak" and recur as local metastases months to years later. Minimal residual disease after surgery is also a problem. To address this, the use of regional chemotherapy (e.g., HIPEC) or radiation therapy has been explored, but with limited success. A limitation of XBR for the peritoneal cavity is the high radiosensitivity of some adjacent tissues, particularly the bowel, which limits the radiation dose that can be delivered. This radiosensitivity is also a limiting factor when using longer-range radiation, such as that emitted by radionuclides such as beta-emitters.

[0008] Radiation to the healing surgical wound area can also be problematic, as radiation may adversely affect the wound repair process (Gu et al., 1998; Diaz et al., 2021; Haubner et al., 2012). Postoperative radiotherapy is associated with serious adverse events (Komori et al., 2011). Locally injected beta-emitting radioactive materials for intraperitoneal irradiation are available. 32The use of colloidal particles of P Phosphocol has also been recognized to be associated with significant complications ( Vergote et al., 1993 ), and its inadequate efficacy versus safety profile ( Fields et al., 2017 ) led to its withdrawal in most countries after decades of use.

[0009] Therefore, there is a need for new types of radiation therapy for the local treatment of intraperitoneal cancer cells and micrometastases that can deliver therapeutically effective doses (equivalent doses) without causing harmful side effects such as adverse effects on postoperative wound healing. Summary of the Invention

[0010] In its broadest aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically relevant amount of an alpha-emitting radionuclide, which can be used in the treatment of cancer, where the individual has already undergone surgery to debulk one or more peritoneal tumors prior to administration of the pharmaceutical composition.

[0011] In one or more embodiments of the present invention, the alpha-emitting radionuclide is administered at a radiation dose ranging from 6 Gy (30 Sv) to 2000 Gy (10,000 Sv), more specifically, from 10 to 200 Gy (50 to 1,000 Sv). In one or more embodiments of the present invention, the alpha-emitting radionuclide is administered at a radiation dose ranging from 10 Gy (50 Sv) to 200 Gy (1,000 Sv). In one or more embodiments of the present invention, the alpha-emitting radionuclide is administered at a radiation dose ranging from 10 Gy (50 Sv) to 1,000 Gy (5,000 Sv). In one or more embodiments of the present invention, the alpha-emitting radionuclide is administered at a radiation dose ranging from 20 Gy (100 Sv) to 500 Gy (2,500 Sv). In one or more embodiments of the present invention, the alpha-emitting radionuclide is administered at a radiation dose ranging from 10 Gy (50 Sv) to 2000 Gy (10,000 Sv). In one or more embodiments of the present invention, the alpha-emitting radionuclide is administered at a radiation dose ranging from 20 Gy (100 Sv) to 200 Gy (1,000 Sv). In one or more embodiments of the present invention, the alpha-emitting radionuclide is administered at a radiation dose ranging from 10 Gy (50 Sv) to 500 Gy (2,500 Sv). In one or more embodiments of the present invention, the alpha-emitting radionuclide is administered at a radiation dose ranging from 10 Gy (50 Sv) to 300 Gy (1,500 Sv).

[0012] In one or more embodiments of the present invention, the radionuclide is 224 Ra, 225 Ac, 211 At, 213 Bi, 212 Bi, 225 Ra, 223 Ra, 149 Tb, 213 Pb, 230 U, 255 Fm and 227 The alpha-emitting radionuclides are selected from the group consisting of therapeutically suitable alpha-emitting radionuclides consisting of Th.

[0013] In one or more embodiments of the present invention, the radionuclide is a progeny radionuclide 220 Rn, 216 Po, 212 Pb, 212 Bi,212 Po and 208 Alpha-radioactivity with Tl 224 Ra is selected from the group consisting of

[0014] In one or more embodiments of the invention, the radionuclide is a beta emitter with a therapeutically suitable alpha emitting progeny nuclide, which 212 Pb, and the progeny radionuclides are 212 Bi, 212 Po and 208 It is Tl.

[0015] In one or more embodiments of the present invention, the alpha-emitting radionuclide is contained in particles that may be biodegradable.

[0016] In one or more embodiments of the invention, the particles comprise a degradable compound and an alpha-emitting radionuclide.

[0017] In one or more embodiments of the present invention, the particles further comprise a phosphorus-containing additive.

[0018] In one or more embodiments of the invention, the degradable compound is selected from the group consisting of CaCO3, MgCO3, SrCO3, BaCO3, calcium phosphates such as hydroxyapatite Ca5(PO4)3(OH) and fluoroapatite, and complexes containing any of these as a major component.

[0019] In one or more embodiments of the invention, the degradable compound is CaCO3, for example, PEG-modified CaCO3, protein-modified CaCO3 including mAb and Fab, carbohydrate-modified CaCO3, lipid-modified CaCO3, vitamin-modified CaCO3, organic compound-modified CaCO3, polymer-modified CaCO3, and / or inorganic crystal-modified CaCO3. In one or more embodiments of the invention, the degradable compound is CaCO3.

[0020] In one or more embodiments of the present invention, the phosphorus-containing additive is a phosphate selected from the group consisting of orthophosphates, linear oligophosphates, polyphosphates, and cyclic polyphosphates.

[0021] In one or more embodiments of the present invention, the phosphorus-containing additive is a polyphosphate selected from the group consisting of pyrophosphates, tripolyphosphates, and triphosphonophosphates.

[0022] In one or more embodiments of the present invention, the phosphorus-containing additive is a cyclic polyphosphate that is sodium hexametaphosphate (SHMP).

[0023] In one or more embodiments of the present invention, the phosphorus-containing additive is a phosphonate.

[0024] In one or more embodiments of the invention, the phosphonate is a bisphosphonate.

[0025] In one or more embodiments of the invention, the bisphosphonate is selected from the group consisting of etidronate, clodronate, tiludronate, pamidronate, neridronate, olpadronate, alendronate, ibandronate, risedronate, and zoledronate.

[0026] In one or more embodiments of the invention, the phosphonate is a polyphosphonate.

[0027] In one or more embodiments of the present invention, the polyphosphonate is selected from the group consisting of EDTMP = ethylenediaminetetra(methylenephosphonic acid), DOTMP = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl-tetrakis(methylphosphonic acid), and DTPMP = diethylenetriaminepenta(methylenephosphonic acid). In one or more embodiments of the present invention, the polyphosphonate is EDTMP = ethylenediaminetetra(methylenephosphonic acid).

[0028] In one or more embodiments of the invention, the particles comprise one or more compounds selected from the group consisting of polymers, alginates and crystalline salts (including sulfates), silica, phosphates, carbonates, gelatin, polystyrene, lactates and barium sulfate.

[0029] In one or more embodiments of the present invention, the size of the particles is from 1 nm to 500 μm.

[0030] In one or more embodiments of the invention, the pharmaceutical composition comprises one or more particles according to the invention and a diluent, carrier, surfactant and / or excipient.

[0031] In one or more embodiments of the present invention, the pharmaceutical composition is prepared using a quantity of radionuclide that provides 1 kBq to 10 GBq per dose, or 50 MBq to 100 GBq, suitable for industrial-scale production of multiple doses.

[0032] In one or more embodiments of the invention, the composition is a particle suspension comprising monodisperse or polydisperse particles as defined herein.

[0033] In one or more embodiments of the present invention, the cancer is selected from the group consisting of intraperitoneal cancer, intracranial cancer, pleural cancer, bladder cancer, cardia cancer, and intrathecal cancer.

[0034] In one or more embodiments of the present invention, the debulking surgery of the one or more peritoneal tumors is performed prior to administration, for example on the same day, 1 day before, such as at least 2 days before, for example at least 3 days before, such as at least 4 days before, for example at least 5 days before, such as at least 6 days before, such as at least 7 days before, for example at least 8 days before, such as at least 9 days before, such as at least 10 days before, for example at least 11 days before, such as at least 12 days, for example at least 13 days before, such as at least 14 days before.

[0035] In one or more embodiments of the present invention, the pharmaceutical compositions are used in combination with other cancer therapies, such as chemotherapy such as taxanes (e.g., paclitaxel, docetaxel), platinum-based drugs (e.g., carboplatin, cisplatin), doxorubicin, mitomycin, etc., DNA repair inhibitors, such as PARP inhibitors (e.g., olaparib, rucaparib, niraparib, talazoparib, veliparib, pamiparib, CEP9722, E7016, and 3-aminobenzamide), and radioimmunotherapy.

[0036] In one or more embodiments of the invention, the pharmaceutical composition is or is included in a medical device.

[0037] In one or more embodiments of the invention, the concentration of the phosphonate and / or phosphate compound is from 1 μg to 1000 mg / ml, for example, from 0.1 mg to 10 mg per ml of final solution or from 1 μg to 1000 mg per g of particles in the final solution.

[0038] In one or more embodiments of the invention, the individual has already undergone hyperthermic intraperitoneal chemotherapy (HIPEC).

[0039] In one or more embodiments of the present invention, the pharmaceutical composition is administered to an individual in need thereof. DETAILED DESCRIPTION OF THE INVENTION

[0040] In this study, the inventors have shown that alpha-emitting radionuclides have the unique property of being able to treat cancer in individuals who have undergone debulking surgery for one or more peritoneal tumors prior to administration of the alpha-emitting radionuclides.

[0041] Alpha-emitting radionuclides can be incorporated into particles. The main objective of this modality is to minimize the risk of systemic toxicity by placing the alpha source in particles with high local retention, and to use short-range alpha particles, which can limit the depth of radiation penetration into adjacent peritoneal tissues and potentially reduce the risk of intestinal toxicity. 224Preclinical studies of various modified versions of Ra-labeled microparticles have recently been published (Li et al., 2021). However, several factors, such as the clinically relevant particle dose and number of radionuclides per particle, related to disease progression, toxicity, and human dosimetry, require more precise determination based on clinical data. One key unknown factor not tested in preclinical models was the use of radiation in patients with fresh surgical wounds resulting from the removal of cancerous tissue. It is known in the art that irradiating wounds can be problematic due to potential disruption of healing. Irradiating the surface of the peritoneal region immediately after surgery with highly focused, short-range α-particles is expected to be particularly problematic due to the potential adverse effects of α-particle irradiation on wound healing (Xueting et al., 2019). Therefore, the present inventors performed a dosimetric evaluation and surprisingly found that it was possible to deliver very high dose equivalents of radiation in this setting without increasing the incidence of serious adverse events.

[0042] Surprisingly, dose calculations performed for radioactivity levels found to be safe in clinical trials showed that very high doses, in terms of dose equivalents of alpha particle radiation (Sieverts; Sv), could be administered intraperitoneally without significant toxicity to patients. Clinical data herein also show that administration of alpha emitters after surgical removal of tumors originating from cancers of adjacent peritoneal tissues may strongly limit the recurrence of local intraperitoneal metastases, as shown by data from colorectal and ovarian cancer patients.

[0043] Thus, the present invention relates to a pharmaceutical composition comprising a therapeutically relevant amount of an alpha-emitting radionuclide. The pharmaceutical composition can be used to treat cancer, and can be used when the individual has already undergone debulking surgery for one or more peritoneal tumors prior to administration of the pharmaceutical composition. In one or more embodiments of the present invention, the individual has already undergone hyperthermic intraperitoneal chemotherapy (HIPEC).

[0044] It is very common for some of the particulate suspensions to form macroscopic "granules" of particles due to settling, aggregation, etc., which can cause radiation "hot spots." The inventors herein describe a therapeutically relevant composition of an alpha emitter, e.g., Radspherin, at 1000 W / g of calcium carbonate, e.g., 1000 W / g of calcium carbonate per 1000 W / g of calcium carbonate. 224 For example, if Ra is 10 MBq (i.e., per 3 μm particle) 224 It has been shown that when a 126 Ra atom is used (approximately 126 Ra atoms, see examples), very little alpha leakage is observed, thus contributing to the favorable safety profile of the product.

[0045] If the number of radioactive atoms per particle is too high, e.g., 20,000 or 100,000 atoms per 3 μm particle, the risk of complications from "hot spot" toxicity increases significantly. If the number of atoms per particle is too low, e.g., 1 atom per particle or less, the amount of particles required to cover the peritoneal area becomes so large that the volume of fluid with sufficient radioactivity becomes so large that the degree of self-absorbed radiation becomes excessive. Therefore, it is advantageous and clinically relevant to optimize the constituents of the particles to ensure that there is an average of more than 1 atom per 3 μm particle, such as an average of more than 5 atoms per 3 μm particle, for example an average of more than 10 atoms per 3 μm particle, for example an average of more than 25 atoms per 3 μm particle, for example an average of more than 50 atoms per 3 μm particle, and an average of less than 100,000 atoms per 3 μm particle, for example an average of 20,000 atoms per 3 μm particle, for example an average of 10,000 atoms per 3 μm particle, for example an average of 10,000 atoms per 3 μm particle, for example an average of 50 atoms per 3 μm particle. Aspects of the invention relate to particles described herein, in which there is an average of more than 1 atom per 3 μm particle. In one or more embodiments of the invention, there is an average of more than 5 atoms per 3 μm particle. In one or more embodiments of the invention, there is an average of more than 10 atoms per 3 μm particle. In one or more embodiments of the invention, there is an average of more than 25 atoms per 3 μm particle. In one or more embodiments of the invention, there are an average of more than 50 atoms per 3 μm particle and an average of less than 100,000 atoms per 3 μm particle. In one or more embodiments of the invention, there are an average of 20,000 atoms per 3 μm particle. In one or more embodiments of the invention, there are an average of 10,000 atoms per 3 μm particle. In one or more embodiments of the invention, there are an average of 10,000 atoms per 3 μm particle. In one or more embodiments of the invention, there are an average of 50 atoms per 3 μm particle. The particles may be clinically suitable in pharmaceutical compositions and for the uses described herein.

[0046] In one or more embodiments of the present invention, the pharmaceutical composition is administered to an individual in need thereof.

[0047] The present invention relates to alpha emitters contained in particles, such as particles used in suspensions. The particles may be microparticles. The particles may be of an appropriate size, with a number of radioactive atoms per particle and total amount relative to the surface area to be treated. The alpha-emitting compounds, for example in microparticle suspensions, are suitable for use in human therapy and exhibit an acceptable toxicity profile, even for post-operative patients with surgical wounds in the early stages of healing.

[0048] In the examples, 224 The results show that Ra-labeled microparticles were observed to be able to deliver an unprecedented high equivalent radiation dose while suppressing cancer recurrence in the peritoneal cavity without causing harmful side effects. The parameters required for clinical utility, such as particle size, the number of radioactive atoms required per microparticle, and the amount of particles in grams required to cover the surface area of ​​the peritoneum to adequately distribute the dose, are described. By fine-tuning these parameters for clinical use, it is possible to develop a suspension containing Ra-labeled microparticles that exhibits adequate antitumor activity and acceptable toxicity in patients. 224 Pharmaceutical compositions containing alpha emitters such as Ra-labeled microparticles have been discovered.

[0049] Alpha-emitting radionuclides of the present invention, such as those contained in microparticles, can be administered using a catheter to ensure intracavitary administration. The size of the particles results in substantial local retention, reducing systemic exposure. The radionuclide retention may be, for example, 10-100%, such as 50-100%, such as 60-80%.

[0050] The particles of the present invention can be autoclavable. The particles can be used to prepare a suspension for clinical use in radiotherapy of peritoneal cancer patients after debulking surgery to remove macroscopic tumors. The present inventors have found that the particles in the suspension can be used to treat peritoneal micrometastases and tumor debris and cells leaked during surgery. 224It has been found that alpha emitters such as Ra-labeled particles can be used.

[0051] The pharmaceutical composition of the present invention, such as Radspherin, can be administered intracatheterically. Administration can be intraperitoneal. Local administration as described above may be more advantageous than intravenous administration.

[0052] In an embodiment, the numerical size is about 3 μm in diameter, and the radioactive atom 224 Current research has found that intraperitoneal administration of 0.7 g of microparticles containing approximately 126 Ra per particle to patients undergoing CRS (radio-reducing surgery) is highly optimal in terms of therapeutic activity and toxicity to normal tissues. This treatment can also be combined with HIPEC after CRS without increasing observable adverse events, suggesting that alpha-emitting radionuclides, such as Radspherin, are highly suitable for combined therapy to inactivate micrometastases and extravasated cells in body cavities after standard treatment of gross tumor removal. In one or more embodiments of the present invention, the microparticles are present in an amount of 0.1 g to 10 g per therapeutically appropriate pharmaceutical dose. In one or more embodiments of the present invention, the microparticles are present in an amount of 0.5 g to 5 g per therapeutically appropriate pharmaceutical dose. In one or more embodiments of the present invention, the microparticles are present in an amount of 0.5 g to 10 g per therapeutically appropriate pharmaceutical dose. In one or more embodiments of the present invention, the microparticles are present in an amount of 0.1 g to 5 g per therapeutically appropriate pharmaceutical dose.

[0053] Thus, the radionuclide in the particles of the present invention can be tailored depending on the intended use.

[0054] The main medical advantage of using alpha particle-emitting compounds for localized therapy, e.g., intraperitoneally, is that the range of alpha particles is short, typically less than 0.1 mm, compared to the range of beta particles from medical beta emitters, which are measured in mm to cm.

[0055] The use of alpha emitters in the intracavitary environment reduces the risk of toxicity from irradiation of deeper internal organs, such as radiosensitive intestinal crypt cells, when administered intraperitoneally (IP). The high linear energy transfer of the emitted alpha particles is also advantageous, as only a very small number of alpha particle hits are required to kill a cell. Resistance mechanisms, such as the cellular ability to repair DNA strand breaks, are less of an issue due to the high probability of irreparable double-strand breaks.

[0056] Higher efficacy per decay means that less radioactivity is required, reducing the need for shielding of medical staff and relatives, although most alpha and beta emitters also emit some x-rays and gamma rays that require shielding.

[0057] In situations where cancer is characterized by bulky mass lesions, the longer range of beta particles may be advantageous over alpha particles. The longer path length of beta particles can result in the so-called crossfire effect, whereby a large number of adjacent and distant cells are irradiated, resulting in damage to cells far from the radiolabeled particle.

[0058] Progeny in this context is understood to be a radionuclide that is produced as a result of the decay of a parent radionuclide. Thus, if the parent radionuclide is e.g. 224 If Ra is 220 Rn (daughter radionuclide), 216 Po (grandchild radionuclide) and 212 Pb (great-grandchild radionuclide). 220 Rn, 216 Po and 212 All Pb 224 It is considered a progeny radionuclide of Ra.

[0059] Thus, in one embodiment, an alpha-emitting radionuclide 224 Ra is the daughter radionuclide 220 Rn, grandchild radionuclides 216 Po and great-grandchild radionuclides 212Pb. For the particles of the present invention, the radionuclide 224 If Ra, all of these will be included in the particle.

[0060] In one or more embodiments of the present invention, the radionuclide is 224 Ra, 225 Ac, 211 At, 213 Bi, 212 Bi, 225 Ra, 223 Ra, 149 Tb, 213 Pb, 230 U, 255 Fm and 227 In one or more embodiments of the present invention, the radionuclide is selected from the group consisting of therapeutically suitable alpha-emitting radionuclides consisting of Th or 224 In one or more embodiments of the present invention, the radionuclide is 225 It is Ac.

[0061] In one or more embodiments of the present invention, the radionuclide is 211 In one or more embodiments of the present invention, the radionuclide is 213 In one or more embodiments of the present invention, the radionuclide is 212 In one or more embodiments of the present invention, the radionuclide is 225 In one or more embodiments of the present invention, the radionuclide is 223 In one or more embodiments of the present invention, the radionuclide is 149 In one or more embodiments of the present invention, the radionuclide is 213 In one or more embodiments of the present invention, the radionuclide is 213 In one or more embodiments of the present invention, the radionuclide is 225 In one or more embodiments of the present invention, the radionuclide is 230 In one or more embodiments of the present invention, the radionuclide is 255 In one or more embodiments of the present invention, the radionuclide is 227Th.

[0062] In one or more embodiments of the present invention, the radionuclide is a progeny radionuclide 220 Rn, 216 Po, 212 Pb, 212 Bi, 212 Po and 208 Alpha-radioactive with Tl 224 Ra is selected from the group consisting of

[0063] In one or more embodiments of the invention, the radionuclide is a beta emitter with a therapeutically suitable alpha emitting progeny nuclide, which 212 Pb, and the progeny radionuclides are 212 Bi, 212 Po and 208 It is Tl.

[0064] In one or more embodiments of the invention, the alpha-emitting radionuclide is contained in a particle, which may be biodegradable. In one or more embodiments of the invention, the particle contains a degradable compound and an alpha-emitting radionuclide. In one or more embodiments of the invention, the particle further comprises a phosphorus-containing additive.

[0065] Thus, the present invention relates to particles comprising a degradable compound, a radionuclide, and a phosphorus-containing additive. The phosphorus-containing additive can be incorporated into the particle, associated with the particle surface, or present around the particle, i.e., in the composition or suspension of which the particle is a part. Thus, one aspect of the present invention relates to a composition or suspension containing particles, wherein the particles comprise a degradable compound, a radionuclide, and a phosphorus-containing additive, and the phosphorus-containing additive is associated with the particle by being present in the composition or suspension. It may be present as part of the particle. It may be present on the particle surface. It may be present in a dispersion of the particle. It may be present as part of the particle composition or suspension and / or dispersion. It may be present both as part of the particle and as part of the particle composition or suspension. These individual components can be combined to form different types of particles with different characteristics depending on the intended use of the particle.

[0066] This means that typically, at least trace amounts of phosphorus-containing additives, such as EDTMP and / or pamidronate, are present on or associated with individual particles. Therefore, when particles contained in a composition, such as a solution, are tested for their phosphorus-containing additive content, typically, at least a portion of the phosphorus-containing additives, such as EDTMP and / or pamidronate, will be found on or within the particles. The total amount of phosphorus-containing additives, such as EDTMP and / or pamidronate, in a composition (e.g., a solution) will vary depending on the particle design, but typically, at least 0.01 to 80% of the total amount of phosphorus-containing additives in the composition will be present within or on the particles, with the remainder being present in the composition. The at least 0.01 to 80% of the total amount of phosphorus-containing additives in the composition present within or on the particles may be 0.1 to 50%, for example, 10 to 50%, for example, 20 to 80%, for example, 10 to 80%.

[0067] The degradable compound of the present invention can be any compound that can be degraded. Degradation can be achieved by any pathway selected from the group consisting of high pH, ​​low pH, temperature, proteases, enzymes, nucleases, and / or by intracellular processes such as endocytosis, including phagocytosis. Thus, the degradable compound can be a non-toxic salt or a crystal of a non-toxic salt.

[0068] In one or more embodiments of the present invention, the particles comprise one or more compounds selected from the group consisting of polymers, alginates and crystalline salts (including sulfates), silica, phosphates, carbonates, gelatin, proteins such as albumin and gelatin, polystyrene, lactate, and barium sulfate. In one or more embodiments of the present invention, the particles comprise polymers. In one or more embodiments of the present invention, the particles comprise alginates. In one or more embodiments of the present invention, the particles comprise crystalline salts (including sulfates). In one or more embodiments of the present invention, the particles comprise silica. In one or more embodiments of the present invention, the particles comprise gelatin. In one or more embodiments of the present invention, the particles comprise polystyrene. In one or more embodiments of the present invention, the particles comprise lactate.

[0069] In one or more embodiments of the invention, the degradable compound is selected from the group consisting of CaCO3, MgCO3, SrCO3, BaCO3, calcium phosphates such as hydroxyapatite Ca5(PO4)3(OH) and fluoroapatite, and complexes containing any of these as a major component.

[0070] The major component is defined as at least 20% of the molecular weight of the whole particle, for example at least 30% of the molecular weight of the whole particle, for example at least 40% of the molecular weight of the whole particle, for example at least 50% of the molecular weight of the whole particle, for example at least 60% of the molecular weight of the whole particle, for example at least 70% of the molecular weight of the whole particle, for example at least 80% of the molecular weight of the whole particle, for example at least 90% of the molecular weight of the whole particle, for example at least 95% of the molecular weight of the whole particle, for example at least 98% of the molecular weight of the whole particle, for example at least 99% of the molecular weight of the whole particle.

[0071] In one or more embodiments of the invention, the degradable compound is CaCO3, for example, PEG-modified CaCO3, protein-modified CaCO3 including mAb and Fab, carbohydrate-modified CaCO3, lipid-modified CaCO3, vitamin-modified CaCO3, organic compound-modified CaCO3, polymer-modified CaCO3, and / or inorganic crystal-modified CaCO3.

[0072] The degradable compound can be MgCO3 selected from the group consisting of PEG-modified MgCO3, protein-modified MgCO3 including mAb and Fab, carbohydrate-modified MgCO3, lipid-modified MgCO3, vitamin-modified MgCO3, organic compound-modified MgCO3, polymer-modified MgCO3 and / or inorganic crystal-modified MgCO3.

[0073] The degradable compound can be SrCO3 selected from the group consisting of PEG-modified SrCO3, protein-modified SrCO3 including mAb and Fab, carbohydrate-modified SrCO3, lipid-modified SrCO3, vitamin-modified SrCO3, organic compound-modified SrCO3, polymer-modified SrCO3, and / or inorganic crystal-modified SrCO3.

[0074] The degradable compound can be BaCO3 selected from the group consisting of PEG-modified BaCO3, protein-modified BaCO3 including mAb and Fab, carbohydrate-modified BaCO3, lipid-modified BaCO3, vitamin-modified BaCO3, organic compound-modified BaCO3, polymer-modified BaCO3, and / or inorganic crystal-modified BaCO3.

[0075] The degradable compound can be Ca5(PO4)3(OH) selected from the group consisting of PEG-modified Ca5(PO4)3(OH), protein-modified Ca5(PO4)3(OH), including mAb and Fab, carbohydrate-modified Ca5(PO4)3(OH), lipid-modified Ca5(PO4)3(OH), vitamin-modified Ca5(PO4)3(OH), organic compound-modified Ca5(PO4)3(OH), polymer-modified Ca5(PO4)3(OH), and / or inorganic crystal-modified Ca5(PO4)3(OH).

[0076] The degradable compound can be a fluoroapatite selected from the group consisting of PEG-modified fluoroapatite, protein-modified fluoroapatite including mAb and Fab, carbohydrate-modified fluoroapatite, lipid-modified fluoroapatite, vitamin-modified fluoroapatite, organic compound-modified fluoroapatite, polymer-modified fluoroapatite, and / or inorganic crystal-modified fluoroapatite.

[0077] The composite particles may contain two or more of these degradable compounds, in which the major components defined above are combined.

[0078] The degradable compounds can also be used as other salts or complexes with proteins or peptides, or can be surface modified with oleates or other similar surfactants.

[0079] In particular embodiments, the degradable compound is used in conjunction with a compound selected from the group consisting of particles of degradable compounds modified with polyethylene glycol (PEG) or degradable compounds modified with inorganic crystals.

[0080] In particular embodiments, the degradable compounds are modified with functional receptor- and / or antigen-binding groups, such as monoclonal antibodies and derivatives and vitamins and derivatives, thereby enabling the particles to bind to target cells and diseased tissues in an individual via receptor or antibody binding. That is, the modification of the particles involves attaching other compounds to the degradable compounds. This can be done in various ways, such as through interactions such as dipole-dipole interactions, ion-dipole interactions, ion-induced dipole interactions, hydrogen bonding, van der Waals forces, and the relative strength of the forces.

[0081] The chelating agents can be used preferentially by binding to target affinity molecules, such as monoclonal or polyclonal antibodies or antibody derivatives, vitamins or vitamin derivatives.

[0082] Monoclonal antibodies (mAb), polyclonal antibodies (pAb), antigen-binding fragments (Fab), and other types of polypeptides and proteins can be used to specifically target particles, i.e., the addition of specific targeting molecules can increase the affinity of the particles for specific target cells in the body.

[0083] The phosphorus-containing additive can be a phosphate, thus resulting in a phosphate-containing additive. The phosphorus-containing additive can also be a phosphonate, thus resulting in a phosphonate-containing additive. In one or more embodiments of the present invention, the phosphorus-containing additive is a phosphate selected from the group consisting of orthophosphates, linear oligophosphates and polyphosphates, and cyclic polyphosphates.

[0084] In one or more embodiments of the present invention, the phosphorus-containing additive is a polyphosphate selected from the group consisting of pyrophosphates, tripolyphosphates, and triphosphonophosphates.

[0085] Phosphonates and phosphonic acids are organophosphorus compounds containing the C-PO(OH) or C-PO(OR) group (R = alkyl, aryl). Phosphonic acids, usually treated as salts, are generally non-volatile solids that are poorly soluble in organic solvents, but are soluble in water and common alcohols. Therefore, various salts and acids of phosphonic acid are also considered part of the definition of phosphonate.

[0086] Phosphoric acid in the general sense is a phosphorus oxoacid, where each phosphorus atom has an oxidation state of +5 and is bonded to four oxygen atoms, one of which is bonded via a double bond, and the four oxygen atoms are arranged at the vertices of a tetrahedron. + If some of the hydrogen atoms are removed, phosphoric acid is converted to a phosphate anion. If some of the hydrogen atoms are removed, a hydrogen phosphate anion is obtained.

[0087] The phosphorus-containing additive can be a phosphonate. The phosphonate can be a bisphosphonate. The bisphosphonate can be selected from the group consisting of etidronate, clodronate, tiludronate, pamidronate, neridronate, olpadronate, alendronate, ibandronate, risedronate, and zoledronate. In one or more embodiments of the present invention, the bisphosphonate is etidronate. In one or more embodiments of the present invention, the bisphosphonate is clodronate. In one or more embodiments of the present invention, the bisphosphonate is tiludronate. In one or more embodiments of the present invention, the bisphosphonate is pamidronate. In one or more embodiments of the present invention, the bisphosphonate is neridronate. In one or more embodiments of the present invention, the bisphosphonate is olpadronate. In one or more embodiments of the present invention, the bisphosphonate is alendronate. In one or more embodiments of the present invention, the bisphosphonate is ibandronate. In one or more embodiments of the present invention, the bisphosphonate is risedronate. In one or more embodiments of the invention, the bisphosphonate is zoledronate.

[0088] The phosphonate may be a polyphosphonate. The polyphosphonate may be selected from the group consisting of EDTMP = ethylenediaminetetra(methylenephosphonic acid), DOTMP = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl-tetrakis(methylphosphonic acid), and DTPMP = diethylenetriaminepenta(methylenephosphonic acid). In one or more embodiments of the present invention, the phosphonate is EDTMP = ethylenediaminetetra(methylenephosphonic acid). In one or more embodiments of the present invention, the phosphonate is DOTMP = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl-tetrakis(methylphosphonic acid). In one or more embodiments of the present invention, the phosphonate is DTPMP = diethylenetriaminepenta(methylenephosphonic acid). Thus, the phosphonate may be EDTMP = ethylenediaminetetra(methylenephosphonic acid).

[0089] In one embodiment, the particles of the present invention comprise CaCO3 as the degradable compound, EDTMP = ethylenediaminetetra(methylenephosphonic acid) as the phosphorus-containing additive, and PEG-100 as the radionuclide. 224 Includes Ra.

[0090] In one embodiment, the particles of the present invention comprise CaCO3 as the degradable compound, pamidronate as the phosphorus-containing additive, and PEG-4 as the radionuclide. 212 Contains Pb.

[0091] The phosphate-containing additive can be selected from the group consisting of orthophosphates, linear oligophosphates and polyphosphates, and cyclic polyphosphates. The polyphosphate can be selected from the group consisting of pyrophosphates, tripolyphosphates, and triphosphonophosphates. The phosphorus-containing additive can be a cyclic polyphosphate, which can be, for example, sodium hexametaphosphate (SHMP).

[0092] In one or more embodiments of the present invention, the phosphorus-containing additive is a cyclic polyphosphate, which is sodium hexametaphosphate (SHMP). In one or more embodiments of the present invention, the phosphorus-containing additive is a phosphonate. In one or more embodiments of the present invention, the phosphonate is a bisphosphonate. In one or more embodiments of the present invention, the bisphosphonate is selected from the group consisting of etidronate, clodronate, tiludronate, pamidronate, neridronate, olpadronate, alendronate, ibandronate, risedronate, and zoledronate. In one or more embodiments of the present invention, the phosphonate is a polyphosphonate.

[0093] In one or more embodiments of the invention, the polyphosphonate is selected from the group consisting of EDTMP = ethylenediaminetetra(methylenephosphonic acid), DOTMP = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl-tetrakis(methylphosphonic acid) and DTPMP = diethylenetriaminepenta(methylene-phosphonic acid).

[0094] The concentration of the phosphonate and / or phosphate compound is from 1 μg to 1000 mg / ml, for example, from 0.1 mg to 10 mg per ml of final solution or from 1 μg to 1000 mg per g of particles in the final solution.

[0095] Thus, for phosphate-containing additives such as EDTMP, the patient dose can range from 1 μg to 1 g / mL or 1 μg to 1 g / g particles. For example, the patient dose can be 2.5 mg / mL or 25 mg per gram of degradable compound such as CaCO3. Phosphate-containing additives such as EDTMP can be added at 0.1 to 10%. This amount can also be 0.5 to 5% or 0.5 to 2%. This amount can also be at least 1%.

[0096] The phosphate-containing additive such as EDTMP can be used at a concentration of 24.4 mg of phosphate-containing additive such as EDTMP per 10 ml of product, for example in the range of 20-30 mg per 10 mL of product.

[0097] Phosphate-containing additives such as EDTMP can also be used as excipients in the range of 4.6-6.6 mM for a final concentration of 5.6 mM (2.44 mg / mL).

[0098] Phosphate-containing additives such as EDTMP can be used at 24.4 mg per gram of calcium carbonate, or in the range of 10 mg to 50 mg per gram of calcium carbonate.

[0099] Phosphate-containing additives such as EDTMP can be used in the range of 1-20% w / w, with 2.4% w / w.

[0100] The amount of phosphate-containing additive such as EDTMP can be 24.4 mg per 10 ml of product.

[0101] Phosphate-containing additives such as EDTMP or EDTMPA (acid) can be used as excipients at a concentration of 5.6 mM (2.44 mg / mL).

[0102] The concentration of phosphate-containing additives such as EDTMP or EDTMPA (acid) can be 5.6 mM ± 15%.

[0103] For phosphonate-containing additives such as pamidronate, patient dosages can range from 1 μg to 1 g / mL or 1 μg to 1 g / g particles. For example, patient dosages can be 2.5 mg / mL or 25 mg per gram of degradable compound such as CaCO3. Phosphate-containing additives such as pamidronate can be added at 0.1 to 10%. This addition can also be 0.5 to 5% or 0.5 to 2%. This addition can also be at least 1%.

[0104] The phosphate-containing additive such as pamidronate can be used at a concentration of 10 mg of phosphate-containing additive such as pamidronate per 10 ml of product, for example, in the range of 5 to 50 mg per 10 mL of product.

[0105] Phosphate-containing additives such as pamidronate can be used as excipients in the range of 0.1 to 10 mM to achieve a final concentration of 4 mM (1 mg / mL).

[0106] Phosphate-containing additives such as pamidronate can be used at 0.01 g per gram of calcium carbonate or in the range of 1 mg to 50 mg per gram of calcium carbonate.

[0107] Phosphate-containing additives such as pamidronate can be used at 1% w / w, with ranges of 0.1-5% w / w.

[0108] The amount of a phosphate-containing excipient such as pamidronate may be 10 mg in 10 ml of product.

[0109] Phosphate-containing additives such as pamidronate or pamidronic acid can be used as excipients at a concentration of 4 mM (1 mg / mL).

[0110] The concentration of phosphate-containing additives such as pamidronate or pamidronic acid can be 4 mM ± 25%.

[0111] The above radionuclides may be combined in the particles of the present invention so that one or more of the above-mentioned radionuclides are contained in the particle. This may also occur by natural processes, such as the decay of a radionuclide to its natural progeny. Such situations include, for example: 224 Ra is the parent radionuclide, 220 Rn (daughter radionuclide), 216 Po (grandchild radionuclide) and 212 This can occur when Pb (great-grandchild radionuclide) is produced. 220 Rn,216 Po and 212 All Pb 224 It is considered a progeny radionuclide of Ra, 224 Due to the natural decay of Ra, a certain amount of it automatically becomes present in the particle.

[0112] Depending on the intended use of the particles, more than one radionuclide may be included in the particles, as amounts beyond those available through natural decay may be advantageous. 224 Ra and 212 This can occur when Pb is mixed into the particles. 212 The concentration of Pb was 224 This will be higher than the concentration obtained when particles are prepared using Ra.

[0113] The amount of radionuclide used per patient dose can range from 1 kBq to 10 GBq, more preferably from 100 kBq to 100 MBq, and even more preferably from 0.5 MBq to 25 MBq. The dose range can be from 10 MBq to 10 GBq per patient dose. The dose range can be from 10 MBq to 5 GBq per patient dose. This range can be for beta-emitters, alpha-emitters, or a combination thereof. This range can be for therapeutic or imaging use. The dose will vary depending on the type of cancer, disease activity, etc. In one embodiment, the dose is 10 to 100 kBq / kg, e.g., 20 to 50 kBq / kg. In another embodiment, the dose is 10 to 1000 kBq / kg, e.g., 25 to 300 kBq / kg. In a further embodiment, the dose is 100 to 500 kBq / kg, e.g., 150 to 300 kBq / kg. In one embodiment, the dosage is 1-100 MBq / kg, for example, 5-20 MBq / kg. In another embodiment, the dosage is 1-1000 MBq / kg, for example, 10-50 MBq / kg. In a further embodiment, the dosage is 100-500 MBq / kg, for example, 150-300 MBq / kg.

[0114] In one embodiment of the present invention, the pharmaceutical composition is prepared using an amount of radionuclide that will provide 1 kBq to 10 GBq per single dose. For example, if one batch is produced per day for 100 patients, a total of 1 to 10 GBq can be divided into 100 single-dose vials or pre-filled syringes (ready-to-use syringes).

[0115] In another embodiment of the invention, the pharmaceutical composition is prepared using an amount of radionuclide suitable for industrial scale production of multiple doses, for example 50 MBq to 100 GBq.

[0116] Thus, the compositions of the invention can be prepared using amounts of radionuclide ranging from 1 kBq to 10 GBq per dose, or can be prepared using amounts of radionuclide ranging from 50 MBq to 100 GBq suitable for industrial scale production of multiple doses.

[0117] The pharmaceutical composition of the present invention is injected as a suspension to ensure appropriate distribution, either after flushing with a pharmaceutically acceptable solution or without flushing. When injected intraperitoneally, the suspension of microparticles labeled with an α-emitter in the pharmaceutical composition can contain 50 to 3,000 mg, for example, 500 to 1,500 mg, and the radioactivity is 1 MBq to 500 MBq, for example, 4 to 12 MBq, dispersed in 1 to 2,000 ml, for example, 10 to 500 ml, for example, 100 to 300 ml.

[0118] The present invention relates to the use of a pharmaceutical composition of the present invention for intraperitoneal injection into the peritoneal cavity of a patient who has recently been treated with debulking surgery, with or without HIPEC. Following peritoneal tumor debulking surgery, alpha particle-emitting radionuclides are used and administered, e.g., in particles, to deliver radiation to the peritoneal surface at an equivalent radiation dose ranging from 30 Sv to 10,000 Sv, e.g., 50 to 1,000 Sv, e.g., 100 to 500 Sv. In one or more embodiments of the present invention, the alpha-emitting radionuclide is administered at a radiation dose ranging from 10 Gy (50 Sv) to 200 Gy (1,000 Sv). In one or more embodiments of the present invention, the alpha-emitting radionuclide is administered at a radiation dose ranging from 10 Gy (50 Sv) to 1,000 Gy (5,000 Sv). In one or more embodiments of the present invention, the alpha-emitting radionuclide is administered at a radiation dose ranging from 20 Gy (100 Sv) to 500 Gy (2500 Sv). In ten or more embodiments of the present invention, the alpha-emitting radionuclide is administered at a radiation dose ranging from 10 Gy (50 Sv) to 2000 Gy (1000 Sv). In one or more embodiments of the present invention, the alpha-emitting radionuclide is administered at a radiation dose ranging from 20 Gy (100 Sv) to 200 Gy (1000 Sv). In one or more embodiments of the present invention, the alpha-emitting radionuclide is administered at a radiation dose ranging from 10 Gy (50 Sv) to 500 Gy (2500 Sv). In one or more embodiments of the present invention, the alpha-emitting radionuclide is administered at a radiation dose ranging from 10 Gy (50 Sv) to 300 Gy (1500 Sv). The particles have a numerical size of 0.1 to 30 μm, e.g., 1 to 10 μm, in mean diameter, and are radiolabeled with 1 to 2000 atoms of α-emitter per particle, e.g., 50 to 1000 atoms per particle. In one or more embodiments of the present invention, the particles may have a mean diameter of 1 to 30 μm. In one or more embodiments of the present invention, the particles may have a mean diameter of 1 to 10 μm. In one or more embodiments of the present invention, the particles may have a mean diameter of 0.1 to 20 μm. In one or more embodiments of the present invention, the particles may have a mean diameter of 5 to 30 μm. To ensure adequate antitumor efficacy and acceptable results in terms of toxicity, the level of radioactivity used may be adjusted to 100 μm per gram of microparticles. 224For example, 10 MBq per 1 g of microparticles can be used so that Ra is in the range of 2 MBq to 50 MBq. To obtain an appropriate distribution relative to the surface area and volume of the peritoneal cavity, 0.3 to 5 g of particles, for example, 0.7 g of particles per administration, can be used as the radiolabeled carrier. In one or more embodiments of the present invention, 0.3 to 5 g of particles are used per administration. In one or more embodiments of the present invention, 0.7 to 1 g of particles are used per administration. In one or more embodiments of the present invention, 0.1 to 10 g of particles are used per administration. In one or more embodiments of the present invention, 0.5 to 5 g of particles are used per administration. In one or more embodiments of the present invention, the number of radioactive atoms can be in the range of 10 to 2000 atoms per particle, for example, 50 to 1000 atoms per particle, for example, 100 to 500 atoms per particle, for example, 100 to 150 atoms per particle. In one or more embodiments of the present invention, the number of radioactive atoms may be in the range of 50 to 1,000 atoms per particle. In one or more embodiments of the present invention, the number of radioactive atoms may be in the range of 100 to 150 atoms per particle. In one or more embodiments of the present invention, the number of radioactive atoms may be in the range of 50 to 500 atoms per particle. In one or more embodiments of the present invention, the number of radioactive atoms may be in the range of 50 to 200 atoms per particle. In one or more embodiments of the present invention, the number of radioactive atoms may be in the range of 50 to 1,000 atoms per particle. The particles may be surface-labeled, internally labeled, or may be surface-labeled first followed by an outer layer of material to better retain the radionuclides.

[0119] Thus, an embodiment of the present invention relates to particles as defined herein having a numerical size of 0.1 to 30 μm in diameter, for example 1 to 10 μm, and radiolabeled with 1 to 2000 atoms of α-emitter per particle, for example 50 to 500 atoms per particle. 224The radioactive dose per patient can be set to 1 to 50 MBq, for example, 4 to 20 MBq, for example, 5 to 10 MBq, and can be administered as a suspension. This suspension can be a pharmaceutical composition as defined herein.

[0120] A further aspect of the present invention relates to a pharmaceutical composition, such as a suspension, containing α-emitter-labeled particles, which may be crystalline, for intraperitoneal injection, containing 50 to 3,000 mg, for example, 500 to 1,500 mg, with a radioactivity of 1 MBq to 500 MBq, for example, 4 to 12 MBq, dispersed in 1 to 2,000 ml, for example, 10 to 500 ml, for example, 100 to 300 ml. These particles, suspensions, and pharmaceutical compositions can be used in cancer treatment. The cancer may be a tumor, specifically an intraperitoneal tumor. Administration can be by topical administration or injection.

[0121] In one or more embodiments of the present invention, the α-emitting radionuclide is dosed and can be administered at a radiation dose ranging from 30 Sv to 10,000 Sv, more specifically, from 50 to 1,000 Sv. The α-emitting radionuclide can be administered at a radiation dose ranging from 200 Sv to 1,000 Sv. The α-emitting radionuclide can be administered at a radiation dose ranging from 200 Sv to 5,000 Sv. The α-emitting radionuclide can be administered at a radiation dose ranging from 100 Sv to 1,000 Sv. The α-emitting radionuclide can be administered at a radiation dose ranging from 300 Sv to 2,000 Sv. The α-emitting radionuclide can be administered at a radiation dose ranging from 100 Sv to 5,000 Sv. The α-emitting radionuclide can be administered at a radiation dose ranging from 50 Sv to 3,000 Sv. Alpha emitting radionuclides can be administered at a radiation dose ranging from 50 Sv to 5000 Sv. Alpha emitting radionuclides can be administered at a radiation dose ranging from 30 Sv to 1000 Sv. Alpha emitting radionuclides can be administered at a radiation dose ranging from 30 Sv to 5000 Sv. Alpha emitting radionuclides can be administered at a radiation dose ranging from 50 Sv to 8000 Sv.

[0122] In one or more embodiments of the invention, the concentration of the phosphonate and / or phosphate compound is from 1 mg to 1000 mg / ml, for example, from 0.1 mg to 10 mg per ml of final solution or from 1 μg to 1000 mg per g of particles in the final solution.

[0123] The particles can have a variety of characteristics and particle size can vary depending on the intended use and application.

[0124] The type of crystals can be any known form of degradable compound, and the size can vary between 1 nm and 500 μm. The size can be in the range of 100 nm to 50 μm, more preferably in the range of 1 to 10 μm. In a preferred embodiment, the size is 1 to 10 μm. In another preferred embodiment, the size is 100 nm to 5 μm, and in another embodiment, 10 to 100 nm. In another preferred embodiment, the size is 1 to 20 μm, and in another embodiment, 2 to 10 μm. The particle size can be in the range of 0.5 to 30 μm, for example, 1 to 10 μm, for example, 1 to 4 μm. A median particle size in the range of 0.5 to 30 μm will be suitable for local retention.

[0125] One aspect relates to a composition comprising one or more particles according to the present invention, which can be a particle suspension comprising monodisperse or polydisperse particles containing a degradable compound, a radionuclide, and a phosphorus additive.

[0126] One or more embodiments of the present invention relate to the use of particles of the present invention, in which the radionuclide is either surface-labeled with the radionuclide, is internally labeled as part of the particle volume, or the surface-radiolabeled particles are covered with a layer of material to protect the radiolabeled surface and prevent release of the radionuclide. Radionuclide-labeled particles can then be obtained by adding a layer of material to the original surface of the particles of the present invention to encapsulate the radionuclide.

[0127] Surface labeling may be performed by adsorption of the radionuclide to the crystalline particles, facilitated by elemental affinity, or labeling may be performed as co-precipitation, where the precipitation process is aided by an additional inorganic compound, in which a chelating agent may be used, which may be incorporated into the particle or on its surface.

[0128] One aspect of the present invention relates to a composition comprising particles containing a degradable compound and a radionuclide, wherein the composition contains a phosphorus-containing additive. The composition can be a suspension of particles. The phosphorus-containing additive can be incorporated into the particles. The phosphorus-containing additive can be associated with the particle surface or can be present in a composition or suspension of which the particles are a part. Thus, one aspect of the present invention relates to a composition or suspension comprising particles, wherein the particles comprise a degradable compound, a radionuclide, and a phosphorus-containing additive, and the phosphorus-containing additive is associated with the particles by being present in the composition or suspension. The phosphorus-containing additive can be part of the particles. It can be present on the surface of the particles. It can be present as part of the composition or suspension of the particles. It can be present both as part of the particles and as part of the composition or suspension of the particles.

[0129] One or more embodiments of the present invention relate to particle suspensions that are a mixture of a solid phase and a liquid phase. The phosphorus-containing additive may be in the liquid phase. The phosphorus-containing additive may be in the solid phase. The phosphorus-containing additive may be in both the solid and liquid phases. If in the solid phase, the phosphorus-containing additive may be on the particle surface, embedded in the particle, or both on the particle surface and embedded in the solid phase. The solid phase may be comprised of nanoparticles, microparticles, or a combination of the two. The radionuclide may be associated with the particle surface, embedded within the volume or bulk of the particle, or both. Thus, the solid phase may include particles containing a degradable compound and a radionuclide, with or without a phosphorus-containing additive; if the phosphorus-containing additive is not part of the solid phase, the phosphorus-containing additive will necessarily be present in the liquid phase. The degradable compound, radionuclide, and phosphorus-containing additive may be any of those disclosed herein.

[0130] The phosphorus-containing compound may or may not be complexed with a radionuclide.

[0131] The composition of the present invention is preferably an aqueous composition. Thus, in this embodiment, the liquid phase is an aqueous phase. The composition can be a saline composition. The composition can be an alcoholic composition. The composition can be a gel matrix composition. The composition of the present invention can be a suspension of the particles of the present invention.

[0132] Thus, a further aspect of the invention relates to a composition or pharmaceutical composition comprising one or more particles according to the invention and a diluent, carrier, surfactant, deflocculating agent and / or excipient. In one or more embodiments of the invention, the pharmaceutical composition comprises one or more particles according to the invention and a diluent, carrier, surfactant and / or excipient.

[0133] Acceptable carriers and pharmaceutical carriers include, but are not limited to, non-toxic buffers, bulking agents, isotonic solutions, solvents and cosolvents, antimicrobial preservatives, antioxidants, humectants, antifoaming agents, and thickening agents. More specifically, pharmaceutical carriers can be, but are not limited to, saline (0.9%), half-normal saline, lactated Ringer's solution, dissolved sucrose, dextrose, e.g., 3.3% dextrose / 0.3% saline. Physiologically acceptable carriers can include stabilizers against radiolysis, e.g., ascorbic acid and human serum albumin, which protect the integrity of the radiopharmaceutical during storage and transport.

[0134] The particles can be dispersed in a variety of buffer solutions compatible with medical injections, for example with dissolved salts and / or proteins and / or lipids and / or sugars.

[0135] The pharmaceutical composition may include multiple particles, which may be the same or different.

[0136] Therefore, in one or more embodiments of the present invention, the size of the particles is between 1 nm and 500 μm.

[0137] The particles and compositions or the present invention can be used as radiotherapeutic compounds and / or radiotherapeutic mixtures (compositions and solutions).

[0138] Aspects of the invention relate to a particle, composition or pharmaceutical composition of the invention for use as a medicament.Aspects of the invention relate to a particle, composition or pharmaceutical composition of the invention for use in treating cancer.

[0139] Intracavitary therapy can include, for example, the treatment of intraperitoneal cancer, intracranial cancer, pleural cancer, bladder cancer, cardia cancer, and intrathecal cancer. Cavities in which the particles can be used include, for example, the cranial cavity, thoracic cavity, pulmonary cavity, spinal cavity, pelvic cavity, pericardial cavity, pleural cavity, bladder cavity, or a combination thereof, including cancer that has spread to the peritoneum or meninges and organs within any of these cavities.

[0140] In one or more embodiments of the present invention, the cancer is selected from the group consisting of intraperitoneal cancer, intracranial cancer, pleural cancer, bladder cancer, cardiac cancer, intrathecal cancer, and non-intracavitary targets such as melanoma, non-small cell lung cancer, and metastases.

[0141] In one embodiment of the present invention, the cancer is selected from the group consisting of metastatic cancer, lung cancer, ovarian cancer, colorectal cancer, gastric cancer, pancreatic cancer, breast cancer, neoplastic meningitis, peritoneal cancer, pleural effusion, malignant mesothelioma, breast cancer, sarcoma, brain cancer such as glioblastoma and astrocytoma, prostate cancer, bladder cancer, and liver cancer. One or more embodiments of the present invention relate to the use according to the present invention, wherein the cancer is metastatic cancer. One or more embodiments of the present invention relate to the use according to the present invention, wherein the cancer is lung cancer. One or more embodiments of the present invention relate to the use according to the present invention, wherein the cancer is ovarian cancer. One or more embodiments of the present invention relate to the use according to the present invention, wherein the cancer is colorectal cancer. One or more embodiments of the present invention relate to the use according to the present invention, wherein the cancer is gastric cancer. One or more embodiments of the present invention relate to the use according to the present invention, wherein the cancer is pancreatic cancer. One or more embodiments of the present invention relate to the use according to the present invention, wherein the cancer is breast cancer. One or more embodiments of the present invention relate to the use according to the present invention, wherein the cancer is neoplastic meningitis. One or more embodiments of the present invention relate to the use according to the present invention, wherein the cancer is peritoneal cancer. One or more embodiments of the present invention relate to the use according to the present invention, wherein the cancer is pleural effusion. One or more embodiments of the present invention relate to the use according to the present invention, wherein the cancer is malignant mesothelioma. One or more embodiments of the present invention relate to the use according to the present invention, wherein the cancer is breast cancer. One or more embodiments of the present invention relate to the use according to the present invention, wherein the cancer is prostate cancer. One or more embodiments of the present invention relate to the use according to the present invention, wherein the cancer is pericardial cancer. One or more embodiments of the present invention relate to the use according to the present invention, wherein the cancer is sarcoma. One or more embodiments of the present invention relate to the use according to the present invention, wherein the cancer is brain cancer, such as glioblastoma or astrocytoma. One or more embodiments of the present invention relate to the use according to the present invention, wherein the cancer is bladder cancer. One or more embodiments of the present invention relate to the use according to the present invention, wherein the cancer is liver cancer. One or more embodiments of the present invention relate to the use according to the present invention, wherein the cancer is micrometastasis, which may be intraperitoneal.

[0142] The pharmaceutical compositions of the present invention, such as Radspherin, can be used after surgery for cancers in which the spread of cancer cells into the abdominal cavity can be a problem, such as adrenal cancer, appendix cancer, colon and rectum cancer, stomach cancer, liver cancer, mesothelioma, ovarian cancer, pancreatic cancer, and peritoneal cancer. The cancer may be adrenal cancer. The cancer may be appendix cancer. The cancer may be colon and rectum cancer. The cancer may be stomach cancer. The cancer may be mesothelioma. The cancer may be pancreatic cancer. The cancer may be peritoneal cancer.

[0143] In particular embodiments for using the present particles, diseases that are infections or inflammations rather than cancer, or diseases that are infections or inflammations in addition to cancer, are treated or ameliorated. The inflammation can be, for example, arthritis.

[0144] In one embodiment of the invention, the infection is selected from the group consisting of a bacterial infection and a viral infection.

[0145] Radioembolization therapy can include the treatment of primary or metastatic cancers of an organ, such as the liver, by administering particles of the invention to blood vessels leading to tumors in the liver or other solid organs infiltrated by tumor tissue.

[0146] Radiation synovectomy for joint disorders involving chronic inflammation is a targeted radiation therapy using radioactive materials for painful joint disease, including the treatment of hemophilic arthritis.

[0147] The particles are preferably administered locally, for example by intracavitary injection. In a particular embodiment, the particles are injected directly into the tumor.

[0148] Another aspect of the present invention relates to a method of treatment, inhibition or amelioration comprising administering to an individual in need thereof a particle or pharmaceutical composition of the present invention, as described herein.

[0149] In one or more embodiments of the present invention, debulking surgery for one or more peritoneal tumors is performed preoperatively, e.g., on the same day, one day before, for example at least two days, for example at least three days, for example at least four days, for example at least five days, for example at least six days, for example at least seven days, for example at least eight days, for example at least nine days, for example at least ten days, for example at least 11 days, for example at least 12 days, for example at least 13 days, for example at least 14 days before administration of a pharmaceutical composition comprising a therapeutically relevant amount of an α-emitting radionuclide. In one or more embodiments of the present invention, debulking surgery for one or more peritoneal tumors is performed preoperatively, e.g., on the same day as administration of a pharmaceutical composition comprising a therapeutically relevant amount of an α-emitting radionuclide as described herein. In one or more embodiments of the present invention, debulking surgery for one or more peritoneal tumors is performed the day before administration of a pharmaceutical composition comprising a therapeutically relevant amount of an α-emitting radionuclide as described herein. In one or more embodiments of the present invention, debulking surgery for one or more peritoneal tumors is performed the day before administration of a pharmaceutical composition comprising a therapeutically relevant amount of an α-emitting radionuclide as described herein. In one or more embodiments of the present invention, debulking surgery for one or more peritoneal tumors is performed two days before administration of a pharmaceutical composition comprising a therapeutically relevant amount of an α-emitting radionuclide as described herein. In one or more embodiments of the present invention, debulking surgery for one or more peritoneal tumors is performed three days before administration of a pharmaceutical composition comprising a therapeutically relevant amount of an α-emitting radionuclide as described herein. In one or more embodiments of the present invention, debulking surgery for one or more peritoneal tumors is performed four days before administration of a pharmaceutical composition comprising a therapeutically relevant amount of an α-emitting radionuclide as described herein. In one or more embodiments of the present invention, debulking surgery for one or more peritoneal tumors is performed five days before administration of a pharmaceutical composition comprising a therapeutically relevant amount of an α-emitting radionuclide as described herein. In one or more embodiments of the invention, debulking surgery for one or more peritoneal tumors is performed 6 days prior to administration of a pharmaceutical composition comprising a therapeutically relevant amount of an alpha-emitting radionuclide as described herein. In one or more embodiments of the invention, debulking surgery for one or more peritoneal tumors is performed 7 days prior to administration of a pharmaceutical composition comprising a therapeutically relevant amount of an alpha-emitting radionuclide as described herein.In one or more embodiments of the present invention, debulking surgery for one or more peritoneal tumors is performed 8 days prior to administration of a pharmaceutical composition comprising a therapeutically relevant amount of an α-emitting radionuclide as described herein. In one or more embodiments of the present invention, debulking surgery for one or more peritoneal tumors is performed 9 days prior to administration of a pharmaceutical composition comprising a therapeutically relevant amount of an α-emitting radionuclide as described herein. In one or more embodiments of the present invention, debulking surgery for one or more peritoneal tumors is performed 10 days prior to administration of a pharmaceutical composition comprising a therapeutically relevant amount of an α-emitting radionuclide as described herein. In one or more embodiments of the present invention, debulking surgery for one or more peritoneal tumors is performed 11 days prior to administration of a pharmaceutical composition comprising a therapeutically relevant amount of an α-emitting radionuclide as described herein. In one or more embodiments of the present invention, debulking surgery for one or more peritoneal tumors is performed 12 days prior to administration of a pharmaceutical composition comprising a therapeutically relevant amount of an α-emitting radionuclide as described herein. In one or more embodiments of the invention, debulking surgery for one or more peritoneal tumors is performed 13 days prior to administration of a pharmaceutical composition comprising a therapeutically relevant amount of an alpha-emitting radionuclide as described herein. In one or more embodiments of the invention, debulking surgery for one or more peritoneal tumors is performed 14 days prior to administration of a pharmaceutical composition comprising a therapeutically relevant amount of an alpha-emitting radionuclide as described herein.

[0150] In one or more embodiments of the invention, the pharmaceutical composition is used as or contained in a medical device.

[0151] A medical device is any instrument, apparatus, appliance, software, material or other article, used alone or in combination (including any software intended by its manufacturer to be used specifically for diagnostic and / or therapeutic purposes and essential to its proper use), that is intended by its manufacturer to be used in humans for the following purposes: diagnosing, preventing, monitoring, treating or mitigating disease; diagnosing, monitoring, treating, mitigating or compensating for injury or disability; examining, replacing or modifying an anatomical or physiological process; or controlling conception, and whose primary intended action in or on the human body is not achieved by pharmacological, immunological or metabolic means, although such means may support its function.

[0152] Medical devices vary according to their intended use and indications, with examples ranging from simple tools such as tongue depressors, medical thermometers, and disposable gloves to sophisticated instruments such as computers, implants, and prosthetics that assist in the performance of medical tests.

[0153] According to the FDA, a medical device is "any instrument, apparatus, implement, machine, contrivance, implant, extracorporeal reagent, or other similar or related article, including any component parts or accessories, listed in the official National Formulary or the United States Pharmacopeia, or any of their appendices, intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease or other conditions in humans or other animals, or intended to affect the structure or function of the body of humans or other animals, and which accomplishes its primary intended purpose not through chemical action in or on the body of humans or other animals, and which does not depend on metabolism for the accomplishment of any of its primary intended purposes."

[0154] The particles are not metabolized or have any significant chemical effects in the body. The particles are carriers of radioactivity that are designed not to be metabolized or chemically affected in the body, allowing radiation therapy to be delivered with significantly limited unwanted side effects such as toxicity.

[0155] Thus, in one embodiment, the term "medical device" is understood as defined by the FDA above.

[0156] The degradable particles can include many different additional compounds, which can provide a variety of effects including targeting, stability, solubility, and degradation rate.

[0157] In one embodiment of the present invention, the particles comprise one or more compounds selected from the group consisting of monoclonal antibodies, polyclonal antibodies, radioimmunoconjugates, immunoconjugates, chelating antibody conjugates, vitamins including folic acid and folic acid derivatives, peptides, minibodies, and affibodies.

[0158] In one embodiment, the particles comprise an antibody, an antibody fragment, or a protein or peptide or vitamin derivative (targeting conjugate) that has affinity for a receptor such as an antigen on a tumor cell.

[0159] In other embodiments, the particles comprise radiolabeled antibodies, antibody fragments, or proteins or peptides or vitamin derivatives (targeting conjugates) that have affinity for receptors such as antigens on tumor cells, resulting in the formation of a particle radiation field across the entire surface of the labeled particle, which delivers an alpha particle dose specifically to tumor cells by binding of the labeled antibody or analog to the receptor or antigen.

[0160] The radionuclides of the present invention can be conjugated to targeting molecules through the use of bifunctional chelators.

[0161] This can be a cyclic, linear or branched chelating agent, and in particular a polyaminopolyacid chelating agent comprising a linear, cyclic or branched polyazaalkane backbone with acidic (e.g., carboxyalkyi) groups attached to nitrogens of the backbone.

[0162] Suitable chelating agents include DOTA derivatives, such as p-isothiocyanatobenzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bz-DOTA) and a variant of this DOTA compound having four primary amides, known as TCMC, and DTPA derivatives, such as p-isothiocyanatobenzyl-diethylenetriaminepentaacetic acid (p-SCN-Bz-DTPA), the former being a cyclic chelating agent and the latter being a linear chelating agent.

[0163] The complexing moiety may be metallated either before or after attachment of the complexing moiety to the targeting moiety.

[0164] Generally, if a chelating agent is bound to an antibody before radiolabeling, the radiolabeling process becomes simpler in terms of the time required, etc.

[0165] Aspects of the invention relate to the particles, compositions or pharmaceutical compositions of the invention for use according to the invention, in combination with other cancer therapies.

[0166] Examples of therapies include chemotherapy such as taxanes (e.g., paclitaxel, docetaxel), platinum-based drugs (e.g., carboplatin, cisplatin), doxorubicin, and mitomycin. Other examples include DNA repair inhibitors, such as PARP inhibitors (e.g., olaparib, rucaparib, niraparib, talazoparib, veliparib, pamiparib, CEP9722, E7016, and 3-aminobenzamide). Further examples include radioimmunotherapy.

[0167] The DNA repair inhibitor may be selected from the group consisting of poly(ADP-ribose) polymerase inhibitors (PARPi), MGMT inhibitors, DNA-dependent protein kinase inhibitors (DNA-PK inhibitors), ataxia telangiectasia and Rad3-related (ATR) kinase inhibitors, ataxia telangiectasia mutated (ATM) kinase inhibitors, Wee1 kinase inhibitors, and checkpoint kinase 1 and 2 (CHK1 / 2) inhibitors.

[0168] In one or more embodiments of the invention, the PARPi is selected from the group consisting of olaparib, rucaparib, niraparib, talazoparib, veliparib, pamiparib, CEP9722, E7016, and 3-aminobenzamide.

[0169] The PARPi can be olaparib. The PARPi can be rucaparib. The PARPi can be niraparib. The PARPi can be talazoparib. The PARPi can be veliparib. The PARPi can be pamiparib. The PARPi can be CEP9722. The PARPi can be E7016. The PARPi can be 3-aminobenzamide.

[0170] Methods for preparing particles An embodiment of the present invention relates to a method for preparing particles according to the present invention, comprising contacting a degradable compound, a radionuclide, and a phosphorus-containing additive with or without a carrier for the radionuclide. The degradable compound and the radionuclide can form first particles in an initial step, followed by an additional step of adding a degradable compound to the already radiolabeled particles to obtain layered particles. A phosphorus-containing additive is then added to stabilize the particles. In this process, the phosphorus-containing additive can become part of the particles or remain in the composition in which the particles are present. The phosphorus-containing additive can also both become part of the particles and remain in the composition containing the particles.

[0171] Phosphorus-containing compounds, such as phosphonates and phosphates, can be applied to stabilize crystalline particles; i.e., these are phosphorus-containing additives described herein. They can be added to particles, such as crystalline particles, for size control purposes during particle formation, after particle formation, after labeling, or in the final formulation. The product can be sterilized by autoclaving, and the additive can be included before or after this process. The size control additive can also be used as a component of a kit used to prepare the final product.

[0172] Thus, in some embodiments, an additional size control agent is added in the preparation of the particles. In some embodiments, the additional size control agent is an alcohol, such as, but not limited to, a diol or triol. In some embodiments, the additional size control agent is ethylene glycol (EG), PEG, glycerol, dextran, or ethanol. In some embodiments, the additional size control agent is glycerol.

[0173] Phosphorus-containing compounds can stabilize crystalline particles of monodisperse and polydisperse particles. Because the particles are made in solution, they are typically polydisperse, but they may share common characteristics, such as having a size within a certain similar range.

[0174] Thus, one aspect of the present invention relates to the use of a phosphorus-containing additive to control the size of particles comprising a degradable compound. Another aspect of the present invention relates to the use of a phosphorus-containing additive to stabilize particles comprising a degradable compound. These particles may be particles of the present invention before or after the addition of a radionuclide. Thus, the particles may themselves be the degradable compound. In one embodiment of the present invention, the degradable compound is a crystalline particle.

[0175] Solutions or compositions containing radionuclides, e.g., progeny 212 Pb mixed in 224The solution or composition of Ra may be added to the particles prior to labeling. 212 Pretreatment with chelate-antibody conjugates to complex Pb allows for antigen-specific therapeutics. 212 Pb radioimmunoconjugates and α-emitters for common intracavitary treatments, e.g. 224 A two-component therapeutic system can be obtained, which includes particles labeled with Ra. Biological compounds such as antibodies can also be part of these particles. These can then be mixed with a phosphorus-containing additive to obtain size-controlled particles. The particles of the composition can be 212 in antigen-specific therapeutic compositions with Pb 212 Pb-labeled particles may also be used.

[0176] One embodiment relates to a three-component system or kit comprising a radionuclide, such as an antigen-specific therapeutic radioimmunoconjugate, a degradable compound, and a phosphorus-containing additive.

[0177] A preferred method of using this is to mix vial A, which contains the chelate-conjugated antibody, with a radionuclide, e.g., a daughter nuclide, in equilibrium with the radionuclide. 224 The kit comprises a vial B containing Ra and a vial C containing microparticles, whereby the contents of A are added to vial B, or vice versa, and after incubation for a few minutes to a few hours, the mixture is transferred to vial C, incubated for a further few minutes to a few hours, mixed with a phosphorus-containing additive, and then transferred to a syringe and injected into a patient.

[0178] In such a system 224 Since Ra-particles are expected to strongly contribute to antitumor activity, this approach could be useful for therapies requiring, e.g. 212 The amount of Pb radioactive immunocomplexes can be significantly reduced.

[0179] Another aspect of the invention relates to a kit comprising the nano- or microparticles of the invention and, optionally, instructions for use with the kit.

[0180] In one embodiment of the invention, the kit comprises a chelator-binding molecule, such as a monoclonal antibody.

[0181] The method and product allow for centralized production and transportation to end users, as the half-life of the radionuclides is only a few days. Another aspect of the invention is the use of biodegradable particles that slowly dissolve to calcium and carbonate, thereby generating small amounts of products already abundant in the body. The following features are also noteworthy: the radionuclides, e.g. 224 When Ra is absorbed into decomposable compounds such as calcium carbonate, it becomes 220 Rn(t 1 / 2 =56s) is released in large quantities, which is an extremely short-lived 216 Po(t 1 / 2 =0.16s) and produces two alpha particles, which decay into longer-lived beta emitters. 212 Pb(t 1 / 2 = 10.6h). Lead has a very strong tendency to form precipitates, for example with calcium carbonate, and therefore 212 Pb has a higher tendency to recombine with particles and leak into the systemic circulation 212 Pb decreases.

[0182] therefore, 224 Ra decays to a gas that can diffuse outside the particle, and then decays further to 212 The formation of Pb and the formation of a precipitate with calcium carbonate is a very specific technical feature.

[0183] Pre-preparing particles and then precipitating the radionuclide onto the particle surface or co-precipitating the radionuclide for deeper incorporation are two methods useful for preparing therapeutic products. After forming the first particles with the radionuclide and degradable compound, the first particles can then be sized using a phosphorus-containing additive to form the particles of the present invention.

[0184] Particles can be produced in sizes ranging from nanometers to tens of micrometers, labeled with high labeling yields, and stored for several days. This is important to enable centralized production and delivery of ready-to-use particle suspensions to hospitals. This can be done without jeopardizing particle integrity, thus ensuring that the particles remain intact and have the size required for their intended use.

[0185] Aspects of the invention relate to particles made by any of the methods described herein. The particles may be microparticles.

[0186] Here are some definitions: CRC: colorectal cancer. EDTMP: ethylenediaminetetra(methylenephosphonic acid) or its salts. Debulking surgery (CRS): The gross surgical removal of cancerous tumors from the abdominal cavity. This procedure may be used with or without HIPEC therapy. Equivalent dose: Equivalent dose is a measure of radiation dose to tissue, corrected for RBE to account for differences in the relative biological effectiveness of different types of ionizing radiation. Quantitatively, equivalent dose is less fundamental than absorbed dose, but is biologically more important. Equivalent dose is measured in sieverts (Sv). HIPEC: Hyperthermic intraperitoneal chemotherapy (HIPEC) is a procedure that washes the peritoneal cavity with warmed chemotherapy drugs in an attempt to inactivate any remaining cancer cells after CRS. Ip: intraperitoneal LET: Linear Energy Transfer. Linear energy transfer (LET) is the average energy deposited per unit length of the path and describes the energy deposition pattern within the path of a photon or particle. Traditional therapeutic radiation is considered low-LET radiation because it is less ionizing. High-LET radiation includes particles with substantial mass and charge, such as alpha particles. Low-energy neutrons, which have no charge, are also high-LET radiation. Even for the same radiation dose, the distribution of energy within cells greatly affects the degree of biological damage. Particle diameter: The median number-based diameter of the particles in suspension is approximately equal to one-third of the volume-based mean diameter of the particles in suspension. Monodisperse: Having roughly the same particle size. OC: ovarian cancer Polydisperse: Having a wide range of particle sizes. Radspherin: 224 It is a microparticle composed of calcium carbonate radioactively labeled with Ra and is used as a suspension. In the text, micrometers are sometimes written as um or μm. RBE: Relative biological effectiveness (RBE) is a relative measure of the damage a given type of radiation causes to biological tissue per unit of energy deposited. High-LET alpha particles have a higher RBE compared to low-LET beta particles, x-rays, and external beam radiation therapy. At therapeutic levels of radiation, the RBE for alpha particles relative to low-LET radiation is often assumed to be 5 (for purposes of radiation protection in the context of low-dose population exposures, an RBE of 20 for alpha particles is commonly assumed). XBR: External beam radiation therapy.

[0187] general It should be understood that any features and / or embodiments discussed above with respect to the compounds according to the invention apply equally to the methods described herein.

[0188] The following figures and examples are given to illustrate the invention and are intended for illustrative purposes and should not be construed as limiting in any way. [Brief explanation of the drawings]

[0189] [Figure 1] These are gamma camera scan images of the abdominal cavity taken 3 hours (left), 26 hours (center), and 50 hours (right) after local intraperitoneal administration of Radspherin to a patient. [Example]

[0190] Example 1: Surgery + HIPEC + Radspherin treatment for colorectal cancer patients Methods: Patients underwent debulking surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), and Radspherin was administered intraperitoneally via a catheter on postoperative days 2-4. Patients were usually discharged within one week after surgery.

[0191] The Phase 1 dose-escalation portion of the study included Radspherin at doses of 1 MBq, 2 MBq, 4 MBq, and 7 MBq, with at least three patients per dose level to assess dose-limiting toxicity. Gamma camera imaging was performed on some patients. Patients were followed for recurrence using standard radiological methods.

[0192] Example 2: Adverse event frequency in colorectal cancer patients treated with HIPEC and Radspherin after debulking surgery Methods: Data from patients treated with CRS+HIPEC+Radspherin were compared with historical control data from similar patients who underwent CRS+HIPEC at the same institution (Froysnes et al, 2016), and the results are shown in Table 1.

[0193] Results: The data in Table 1 show that the addition of Radspherin to combination therapy did not increase the incidence of grade III or higher serious adverse events, regardless of the low or maximum Radspherin dose. The incidence rates were 15%, 9%, and 8% in the CRS + HIPEC historical control group, CRS + HIPEC + 1-4 MBq Radspherin group, and CRS + HIPEC + 7 MBq Radspherin group, respectively.

[0194] In conclusion, administration of 7MBq of Radsperin after CRS+HIPEC did not result in increased local toxicity in terms of serious adverse events.

[0195] [Table 1]

[0196] Example 3: Surgery and Radspherin treatment for ovarian cancer patients Methods: Patients underwent CRS (without HIPEC) and received intraperitoneal injection of Radspherin via a catheter on postoperative days 2-4. Patients were usually discharged within one week after surgery.

[0197] The Phase 1 dose-escalation portion of the study included Radspherin at doses of 1 MBq, 2 MBq, 4 MBq, and 7 MBq, with at least three patients per dose level to assess dose-limiting toxicity. Gamma camera imaging was performed on some patients. Patients were followed for recurrence using standard radiological methods.

[0198] Example 4: Simple peritoneal dosimetry for α-particle therapy with Radspherin Background: Intraperitoneal in patients after weight loss surgery 224 The Ra-labeled microparticles (Radsperin) were administered by injection, and the radioactivity level was measured by scanning with a gamma camera at various times after injection. Table 3 shows the radioactive source of Radsperin. 224The various alpha particles produced in the Ra series are shown. Each radium atom will produce a total of four alpha particles as it decays through its progeny nuclides.

[0199] Based on the signals measured in gamma camera scans of patients administered Radspherin (e.g., Figure 1), it was estimated that, on average, approximately 75% of the administered radioactivity decayed within the abdominal cavity.

[0200] [Table 2]

[0201] Dose calculation In the following work, an alpha particle quality factor of 5 for XBR has been assumed. Therefore, at the therapeutic level of alpha particle radiation, 1 Gy is 5 Sv. This calculation is performed for the maximum dose tested for Radpsherin, i.e., a dose of 7 MBq per patient.

[0202] Part 1: Assumptions: The radiolabeled product is distributed primarily as a uniform layer over the surface, and its specific activity is equal in the liquid and on the surface. The tissue surface is covered by a 35 μm liquid film. It is assumed that the dose in the 35 μm "radiation area" on both sides of the "particle layer" is uniform on both sides of the "particle layer." Assumptions: Surface area of ​​the peritoneum = 17500 cm 2 Intraperitoneal retention of injected radionuclides: 75% The average thickness of the radiation area on the surface is 35 μm × 2 = 70 μm, i.e., the volume of the irradiated surface area is 122.5 ml (half of which is the liquid film on the surface and half is the tissue) (this is the "surface area"). 1.6×10 -13 J / MeV 224Alpha particles from the Ra series: 27.3 MeV Using this model, the radiation dose is: Dose = (7 x 10^6 x 3600 x 24 x 3.6 x 0.75 x 1.6 x 10^-13 x 27.5) / (ln2 x 0.1225) = 84.6 Gy → 423 Sv (5 Sv / Gy)

[0203] Part 2: Assuming that the amount of radioactivity is uniformly distributed in the liquid Intraperitoneal fluid volume: 75-500 ml * If the average intraperitoneal fluid volume is 75 ml (for a typical person), the total irradiated volume (including surface tissue) is 122.5 / 2 + 75 (including fluid film) = 136.25 ml ** If the average intraperitoneal fluid volume is 500 ml, the total irradiated volume is 122.5 / 2 + 500 (including the fluid membrane) = 561.25 ml Calculations were performed using 7MBq of Radspherin. 224 About Ra * Volume 75ml: Dose = (7 x 10^6 x 3600 x 24 x 3.6 x 0.75 x 1.6 x 10^-13 x 27.5) / (ln2 x 0.13625) = 75.5 Gy → 378 Sv (5 Sv / Gy) ** Volume 500ml: Dose = (7 x 10^6 x 3600 x 24 x 3.6 x 0.75 x 1.6 x 10^-13 x 27.3) / (ln2 x 0.56125) = 18.4 Gy → 92 Sv (5 Sv / Gy) From these results, assuming an average liquid volume of 200 ml, the equivalent dose of the liquid according to this calculation model is 198 Sv.

[0204] Example 5: Comparison of recurrence-free survival rates after standard treatment (as previously reported) versus standard treatment plus Radspherin α particle therapy in second-line treatment after debulking surgery + HIPEC for colorectal cancer Methods: The control group consisted of colorectal cancer (CRC) patients with resectable lesions who underwent HIPEC after complete debulking surgery (CRS). In this control group, progression at 12 months was interpolated from published survival curves (Froysnesetal., 2016). The control (C) and Radspherin (R) groups were similar: 65% (C) and 70% (R) women; median age 58 (C) and 64 (R); type of HIPEC in both groups was primarily mitomycin C (except for a few patients who received oxaliplatin, i.e., 4 / 23 in the Radspherin group). Patients were followed for recurrence using standard radiological methods.

[0205] [Table 3]

[0206] Results: Table 4 shows that the patient group treated with CRS plus HIPEC + Radspherin had a higher proportion of recurrence-free patients at 12 months compared with historical controls treated with CRS + HIPEC without Radspherin. That is, the recurrence rate at 12 months in the CRS + HIPEC + 7MBq Radspherin group was less than half that of the historical control group that underwent CRS + HIPEC.

[0207] Currently, data from the 7MBq group in the ongoing study with 15 and 18 months of follow-up indicate that 0 / 8 and 0 / 6 patients, respectively, had local intraperitoneal recurrence within the peritoneum at these time points.

[0208] In conclusion, data to date indicate that Radspherin treatment has substantial antitumor effects.

[0209] Example 6: Comparison of recurrence-free survival rates after standard therapy (as previously reported) versus standard therapy plus Radspherin α particle therapy in second-line treatment after debulking surgery for ovarian cancer Methods: Radspherin was administered intraperitoneally via catheter 2-4 days after surgery as second-line treatment to patients with ovarian cancer who had undergone gross tumor removal by debulking surgery. Patients were followed for recurrence using standard radiological methods.

[0210] [Table 4]

[0211] Results: The current status is shown in Table 5. In the ovarian cancer group that received Radspherin after CRS (without HIPEC), no intraperitoneal metastasis was observed at 12 months (only two cases of distant metastasis), which is a promising trend.

[0212] Example 7: Metastatic patterns in patients receiving Radspherin after debulking surgery for colorectal and ovarian cancer Methods: Metastatic patterns in patients treated with CTR (with or without HIPEC) plus Radspherin for peritoneal tumors are shown. Results of a 12-month follow-up are shown.

[0213] [Table 5]

[0214] result: Colorectal cancer: Table 6 shows that after 12 months of follow-up, intraperitoneal metastasis was observed in 3 out of 7 colorectal cancer patients who received Radspherin at a low dose of 1-2 MBq per patient, whereas no intraperitoneal metastasis occurred in those receiving 7 MBq (0 / 12) (Table 6). This suggests that the protective effect of Radspherin is dose-dependent and is fully effective at a dose of 7 MBq.

[0215] Ovarian cancer: The data presented here are limited but encouraging, with no intraperitoneal metastases observed at 12 months follow-up.

[0216] Example 8: Radiation therapy and wound healing Preclinical studies have already demonstrated that Radspherin has a suitable safety profile. Healthy mice without wounds were injected with Radspherin either without (safety study) or after (treatment study) tumor cell injection, and safety and antitumor activity were investigated.

[0217] However, the preclinical model used differs from the clinical situation in an important respect: there is no wound, whereas patients have fresh surgical wounds from debulking surgery prior to Radspherin administration.

[0218] In the field of radiotherapy, it is known that particularly high radiation doses can have a negative impact on wound healing (Diaz et al., Surgeries 2021, 2(1), 35-57).

[0219] Radiation therapy is used to kill cancerous cells, but it also damages healthy cells, resulting in numerous acute and long-term side effects. One of the most serious complications is wound healing problems. Long-term effects of radiation therapy include skin atrophy, soft tissue fibrosis, and microvascular damage, increasing the risk of developing problematic, non-healing wounds that cannot be surgically repaired (Dormand et al., Int Wound J. 2005 Jun; 2(2):1 12-127).

[0220] Complications after radiation therapy occur in up to 60% of surgical patients (Haubner et al., Radiat Oncol. 2012; 7:162).

[0221] Radiation therapy is an invaluable tool in cancer treatment. However, both the immediate and long-term adverse effects of radiation can have significant impacts on local tissues. Wound healing in radiation-damaged tissues is a major challenge. Poor wound healing can lead to chronic ulcers, pain, secondary infections, and psychological distress, potentially compromising the outcomes of general or reconstructive surgery.

[0222] Alpha particle irradiation has also been reported to adversely affect wound healing. For example, in an experimental model (Xueting et al., Poster viewing Q & A session volume 105, issue 1, supplement, E661, September 1, 2019, International Journal of Radiation Oncology), even a relatively low dose of 0.56 Gy (equivalent to 2.8 Sv assuming 5 Sv / Gy) adversely affected wound healing.

[0223] Surprisingly, we found no signs of complications from Radsperin treatment, as evidenced by the fact that the frequency of adverse events did not change significantly, even when equivalent doses well above 100 Sv (assuming 5 Sv / Gy) were administered within the abdominal cavity in the newly created surgical wound following debulking surgery.

[0224] In one case in which an estimated 1 MBq (out of a 7 MBq dose) of Radspherin was accidentally administered subcutaneously at the catheter incision site due to extravasation caused by catheter displacement, the catheter incision healed after 2 months without ulceration or necrosis. This was unexpected, as it is known from the literature that radiopharmaceutical extravasation can cause severe soft tissue damage (Van der Pol et al, 2017). This indicates that even clinical levels of Radspherin can have a suitable toxicity profile upon extravasation.

[0225] Example 9: Comparative dose assessment Methods: Dose estimates for Radspherin were compared with literature data for fractionated external beam radiation therapy and radionuclide therapy. External radiation and beta-emitters with a radiobiological effectiveness (RBE) of 1 were used. 32 Low linear energy transfer (LET) radiation from P with an estimated RBE=5 211 At(+descendant), 212 Pb(+offspring) and 224Comparison was made with high-LET α radiation from Ra(+ offspring).

[0226] [Table 6]

[0227] Results: Table 7 shows that Radspherin administered intraperitoneally provided a significantly higher equivalent dose compared to other types of radiation therapy. It should be noted that the external beam radiation therapy group and the Radspherin group consisted of patients who received concomitant treatment after debulking surgery.

[0228] Example 10: Safety aspects, avoiding toxicity from radiation "hot spots" Background: When using radiolabeled microparticles for therapy, it is important to avoid the adverse effects of particle settling, which can lead to so-called "hot spots" where the particulate matter delivers a high localized dose over a small area. To reduce this risk, it is necessary to optimize the specific activity of the microparticles, expressed in Bq per gram.

[0229] Methods and calculation results: Typically, Radspherin therapy involves 7MBq of Radspherin bound to 0.7g of particles. 224 Using a suspension of Ra, consider a scenario in which 10% of the particles produce a sediment that deposits locally on the peritoneal surface. Consider how much alpha particle radiation would reach the peritoneum from that sediment. The particle density is 2 g / cm 3 In this case, the total volume of injected particles is 0.7 / 2 = 0.35 cm 3 This becomes: Assuming that 10% of the injected particles become spherical, their weight is 0.035 cm 3 =35mm 3 is. Following formula: Volume V=4 / 3πr 3(where V = volume and r = radius), we find that the median radius of the granules is 2.03 mm. The surface area of ​​such a sphere is A = 4πr 2 =51.8mm 2 This becomes: Assuming that the maximum range R of alpha rays within this particle sphere is an average of 40 μm = 0.04 mm, the total volume of the precipitated material that generates alpha rays and reaches the surface of the sphere is Vr = AR = 2.072 mm 3 Assuming that half of the alpha particles generated in Vr are directed toward the outside, which is the surface, and half are directed toward the interior of the sediment, only 2.072 mm of the total activity reaches the surface. 3 / 2) / 35mm 3 = 0.03, or 3%. Assuming that less than 50% of the sphere surface is in contact with the peritoneal surface, the fraction of alpha particles from the interior of the sediment sphere that reaches the peritoneal tissue is less than 1.5%.

[0230] In conclusion, the hot spot problem can be largely prevented by using sufficient materials as carriers of alpha-emitting radioactivity.

[0231] Example 11: Particle characteristics The median numerical diameter of the particles is estimated to be approximately 3 μm. The density is 2 g / cm 3 Assuming that the spheres are round with a radius of 1.5 μm, the volume of each sphere is calculated using the formula V=4 / 3πr 3 According to 14.1μm 3 Therefore, the number of particles contained in the administered 0.7 g of Radspherin is 0.35 cm 3 / 14.1μm 3 =3.5×10 11 μm 3 / 14.1μm 3 =2.48×10 10 Becomes an individual.

[0232] contained in 0.7g of particles 224 The average number of Ra atoms is N=At 1 / 2 / ln2=7×10 6 ×3.6×24×3600 / ln2=3.14×10 12(N is the number of atoms; A is the amount of radioactivity; t 1 / 2 is the physical half-life of the radionuclide).

[0233] Therefore, per particle 224 The average number of Ra atoms is 3.14×10 12 / (2.48×10 10 ) = 126 particles / particle.

[0234] If we assume that the surface area of ​​the radiation area irradiated by one particle is a circle with a radius of 25 μm centered on the particle, the surface area of ​​the radiation area is A = πr 2 =1963μm 2 The surface area of ​​the peritoneum is estimated to be 17,500 cm 2 =17500×1×10 8 μm 2 =1.75×10 12 μm 2 It is assumed that:

[0235] The total area of ​​radiation that can be covered by the radiation emitted from the particle is: 2.48 x 10 10 ×1963μm 2 =4.86×10 13 μm 2 This becomes:

[0236] In this case, assuming a perfectly uniform distribution of the irradiated area over the peritoneal surface, there would be approximately 28 times as many particles as needed to cover the surface. However, as shown by the gamma camera images, the particle distribution is expected to be significantly non-uniform, so the number of particles administered is considered reasonable.

[0237] Example 12: Comparison of parameters related to the dose, number of atoms per particle, and anti-metastatic effect of microparticles labeled with α-emitters Methods: Patients were given various doses of 224 Equal doses of Ra-labeled particles were administered. The number of atoms per particle, therapeutic efficacy, and product-related serious adverse events are shown for each treatment group.

[0238] [Table 7]

[0239] Results: The data presented in Table 8 suggest a dose response in terms of the frequency of intraperitoneal metastases, and also show that no regional metastases were found at 12 months with a dose of 7 MBq.

[0240] Conclusion: This data 224 Even when Ra-Radspherin was administered at very high equivalent doses, there was no sign of an increase in the incidence of adverse events of grade III or higher, indicating promising suppression of the occurrence of local metastases. Therefore, considering the high equivalent dose, Radspherin's α-particles were unexpectedly well tolerated. This data also indicates that a high equivalent dose is necessary to achieve maximum therapeutic efficacy.

[0241] The inventors speculate that the limited depth dose of short-range alpha particles (less than 0.1 mm in tissue) and the poor chemical penetration of microparticles into the wound site in this therapeutic setting potentially allow the described radionuclide-microparticle combination to be used at unexpectedly high equivalent doses (in Sv). 220 Other aspects may also contribute to this clinical finding, such as the possibility that Rn may provide a "dose smoothing" effect that may be advantageous from a therapeutic and toxicity standpoint.

[0242] Example 13: Interim safety results after the dose-limiting toxicity (DLT) period in a dose-escalation study of Radspherin after debulking surgery in ovarian cancer patients Method: The outline of the study is as described in Example 3. The radioactive dose of Radspherin was gradually increased from 1 to 2 to 4 to 7 MBq.

[0243] Results: Fourteen patients were enrolled in the dose-escalation cohort. All dose levels were well tolerated, with no dose-limiting toxicities, deaths, or discontinuations due to adverse events reported. In the initial safety analysis of patients with recurrent ovarian cancer treated with Radspherin after secondary debulking surgery, all dose levels were well tolerated, with no DLTs, no deaths, and only one serious adverse event (SAE) related to Radspherin administration. This grade 2 event was a procedural complication (leakage during administration) and was medically significant, so it was reported as an SAE. No complications were identified during follow-up.

[0244] CONCLUSIONS: In this dose-escalation study, intraperitoneal Radspherin treatment in patients with ovarian cancer after debulking surgery was well tolerated at all dose levels, with no DLTs.

[0245] Example 14: Safety and efficacy at 18 months of intraperitoneal Radspherin treatment after debulking surgery and intraperitoneal hyperthermic chemotherapy for colorectal cancer peritoneal metastasis Methods: The study outline is as described in Example 1. Safety and efficacy signals of Radspherin administered intraperitoneally 2 days after CRS-HIPEC. After dose escalation (1-2-4-7MBq), a dose of 7MBq was selected. Safety and efficacy evaluations were performed every 3 months.

[0246] Results: Twenty-three patients were enrolled; one was excluded from the efficacy analysis, leaving 12 patients receiving 7 MBq. Fourteen serious adverse events (SAEs) unrelated to Radspherin were reported in eight patients. At 18 months, none of the 12 patients receiving 7 MBq had peritoneal recurrence, while four had non-peritoneal recurrence (33%). Across all doses, nine of 22 patients (41%) had recurrence, including three with peritoneal recurrence.

[0247] Conclusions: Radspherin was well tolerated, and no related SAEs were reported. In this study of peritoneal treatment after CRS-HIPEC for colorectal cancer, no patients receiving 7MBq, the highest dose tested, experienced peritoneal recurrence by 18 months.

[0248] References: Gu Q, Wang D, Cui C, Gao Y, Xia G, Cui X. Effects of radiation on wound healing. J Environ Pathol Toxicol Oncol. 1998;17(2):117-23. Koji Komori, Kenya Kimura, Takashi Kinoshita, Tsuyoshi Sano, Seiji Ito, Tetsuya Abe, Yoshiki Senda, Kazunari Misawa, Yuichi Ito, Norihisa Uemura, Ryosuke Kawai, and Yasuhiro Shimizu. Complications Associated With Postoperative Adjuvant Radiation Therapy for Advanced Rectal Cancer. Int Surg. 2014 Mar-Apr; 99(2): 100-105. Li RG, Lindland K, Tonstad SK, Bonsdorff TB, Juzeniene A, Westrom S, Larsen RH. Improved Formulation of 224Ra-Labeled Calcium Carbonate Microparticles by Surface Layer Encapsulation and Addition of EDTMP. Pharmaceutics. 2021 Apr 29;13(5):634. Diaz C, Hayward CJ et al., Ionizing Radiation Mediates Dose Dependent Effects Affecting the Healing Kinetics of Wounds Created on Acute and Late Irradiated Skin. Surgeries 2021 , 2(1), 35- 57. https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC7951225 / Haubner F, Ohmann E, Pohl F, Strutz J, and Gassner HG. Wound healing after radiation therapy: Review of the literature. Radiat Oncol. 2012; 7: 162. Published online 2012 Sep 24. doi: 10.1186 / 1748-717X-7- 162 Xueting Z, Yang H, LiYuan Z. The Detrimental Effect of Alpha Particle Radiation on Wound Healing and the Underlying Mechanism. Radiat Oncol Biol Phys. Poster Viewing Q&A Session| Volume 105, ISSUE 1 , SUPPLEMENT , E661 , September 01 , 2019 Vergote IB , Winderen M, De Vos LN, Trope CG. Intraperitoneal radioactive phosphorus therapy in ovarian carcinoma. Analysis of 313 patients treated primarily or at second-look laparotomy. Cancer 1993 Apr 1 ;71(7):2250-60. Fields EC, McGuire WP, Lin L, Temkin SM. Radiation Treatment in Women with Ovarian Cancer: Past, Present, and Future. Front. Oncol., 21 August 2017 Sec. Radiation Oncology, https: / / doi.org / 10.3389 / fonc.2017.00177 Froysnes IS, Larsen SG, Spasojevic M, Dueland S, Flatmark K. Complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastasis in Norway: Prognostic factors and oncologic outcome in a national patient cohort. J Surg Oncol. 2016 Aug;114(2):222-7. Arians N, Kieser M, Benner L, Rochet N et al. Arians N, Kieser M, Benner L, Rochet N, Schroder L, Katayama S, Herfarth K, Schubert K, Schneeweiss A, Sohn C, Lindel K, Debus J. Adjuvant intensity modulated whole-abdominal radiation therapy for high-risk patients with ovarian cancer FIGO stage III: final results of a prospective phase 2 study Radiat Oncol. 2019 Oct 21 ; 14(1 ):179. Watson EE, Stabin MG, Davis JL, Eckerman KF. A model of the peritoneal cavity for use in internal dosimetry. J Nucl Med. 30:2002-2011 ,1989. Meredith R, Torgue J, Shen S, Fisher DR, Banaga E, Bunch P, Morgan D, Fan J, Straughn JM Jr. Dose escalation and dosimetry of first-in-human a radioimmunotherapy with 212Pb-TCMC- trastuzumab.J Nucl Med. 2014 Oct;55(10):1636-42. Meredith RF, Torgue JJ, Rozgaja TA, Banaga EP, Bunch PW, Alvarez RD, Straughn JM Jr, Dobelbower MC, Lowy AM. Safety and Outcome Measures of First-in-Human Intraperitoneal a Radioimmunotherapy With 212Pb-TCMC-Trastuzumab. Am J Clin Oncol. 2018 Jul;41 (7):716-721. Hallqvist A, Bergmark K, Back T, Andersson H, Dahm-Kahler P, Johansson M, Lindegren S, Jensen H, Jacobsson L, Hultborn R, Palm S, Albertsson P. Intraperitoneal a-Emitting Radioimmunotherapy with 21 1At in Relapsed Ovarian Cancer: Long-Term Follow-up with Individual Absorbed Dose Estimations. J Nucl Med. 2019 Aug;60(8):1073-1079. doi: 10.2967 / jnumed.118.220384. Epub 2019 Jan 25. PMID: 30683761 Andersson H, Cederkrantz E, Back T, Divgi C, Elgqvist J, Himmelman J, Horvath G, Jacobsson L, Jensen H, Lindegren S, Palm S, Hultborn R. Intraperitoneal alpha-particle radioimmunotherapy of ovarian cancer patients: pharmacokinetics and dosimetry of (211 )At-MX35 F(ab')2--a phase I study. J Nucl Med. 2009 Jul;50(7): 1153-60. Van der Pol J, Vbb S, Bucerius J, Mottaghy FM. Consequences of radiopharmaceutical extravasation and therapeutic interventions: a systematic review. Eur J Nucl Med Mol Imaging. 2017; 44(7): 1234-1243. Dormand EL, Banwell PE, Good a ere TEE. Radiotherapy and wound healing. Int Wound J. 2005 Jun; 2(2): 112-127.

[0249] [item] 1. A pharmaceutical composition comprising a therapeutically relevant amount of an alpha-emitting radionuclide. 2. The pharmaceutical composition according to item 1, wherein the α-emitting radionuclide is dose-set and can be administered at a radiation dose in the range of 6 Gy (30 Sv) to 2000 Gy (10000 Sv), more specifically 10 to 200 Gy (50 to 1000 Sv). 3. The radionuclide is 224 Ra, 225 Ac, 211 At, 213Bi, 212 Bi, 223 Ra, 149 Tb, 225 Ra, 230 U, 255 Fm and 227 3. The pharmaceutical composition according to item 1 or 2, wherein the therapeutically suitable alpha-emitting radionuclide is selected from the group consisting of Th. 4. The radionuclide is a progeny radionuclide 220 Rn, 216 Po, 212 Pb, 212 Bi, 212 Po and 208 Alpha-radioactivity with Tl 224 4. The pharmaceutical composition according to any one of items 1 to 3, wherein the composition is selected from the group consisting of Ra. 5. The radionuclide is a beta emitter with an alpha-emitting progeny suitable for therapy, which is 212 Pb, and the progeny radionuclides are 212 Bi, 212 Po and 208 5. The pharmaceutical composition according to any one of items 1 to 4, wherein the compound is Tl. 6. The pharmaceutical composition according to any one of items 1 to 5, wherein the α-emitting radionuclide is contained in particles which may be biodegradable. 7. The pharmaceutical composition according to item 6, wherein the particles comprise a degradable compound and the alpha-emitting radionuclide. 8. The pharmaceutical composition according to item 6 or 7, wherein the particles further comprise a phosphorus-containing additive. 9. The pharmaceutical composition according to any one of items 6 to 8, wherein the degradable compound is selected from the group consisting of CaCO3, MgCO3, SrCO3, BaCO3, calcium phosphates such as hydroxyapatite Ca5(PO4)3(OH) and fluoroapatite, and complexes containing any of these as a major component. 10. The pharmaceutical composition according to any one of items 6 to 9, wherein the degradable compound is CaCO3, for example, PEG-modified CaCO3, protein-modified CaCO3 including mAb and Fab, carbohydrate-modified CaCO3, lipid-modified CaCO3, vitamin-modified CaCO3, organic compound-modified CaCO3, polymer-modified CaCO3 and / or inorganic crystal-modified CaCO3. 11. The pharmaceutical composition according to any one of items 8 to 10, wherein the phosphorus-containing additive is a phosphate selected from the group consisting of orthophosphates, linear oligophosphates and polyphosphates, and cyclic polyphosphates. 12. The pharmaceutical composition according to any one of items 8 to 11, wherein the phosphorus-containing excipient is a polyphosphate selected from the group consisting of pyrophosphate, tripolyphosphate, and triphosphonophosphate. 13. The pharmaceutical composition according to any one of items 8 to 12, wherein the phosphorus-containing additive is a cyclic polyphosphate that is sodium hexametaphosphate (SHMP). 14. The pharmaceutical composition according to any one of items 8 to 13, wherein the phosphorus-containing additive is a phosphonate. 15. The pharmaceutical composition according to any one of items 8 to 14, wherein the phosphonate is a bisphosphonate. 16. The pharmaceutical composition according to any one of items 8 to 15, wherein the bisphosphonate is selected from the group consisting of etidronate, clodronate, tiludronate, pamidronate, neridronate, olpadronate, alendronate, ibandronate, risedronate and zoledronate. 17. The pharmaceutical composition according to any one of items 8 to 16, wherein the phosphonate is a polyphosphonate. 18. The pharmaceutical composition according to item 17, wherein the polyphosphonate is selected from the group consisting of EDTMP = ethylenediaminetetra(methylenephosphonic acid), DOTMP = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl-tetrakis(methylphosphonic acid) and DTPMP = diethylenetriaminepenta(methylenephosphonic acid). 19. The pharmaceutical composition according to item 17, wherein the polyphosphonate is EDTMP = ethylenediaminetetra(methylenephosphonic acid). 20. The pharmaceutical composition according to item 6, wherein the particles comprise one or more compounds selected from the group consisting of polymers, alginates and crystalline salts (including sulfates), silica, phosphates, carbonates, gelatin, polystyrene, lactates and barium sulfate. 21. The pharmaceutical composition according to any one of items 1 to 20, wherein the size of the particles is between 1 nm and 500 μm. 22. The pharmaceutical composition according to any one of items 1 to 21, wherein the pharmaceutical composition comprises one or more particles according to any one of claims 6 to 20 and a diluent, carrier, surfactant and / or excipient. 23. The pharmaceutical composition according to any one of items 1 to 22, prepared using a quantity of radionuclide that provides 1 kBq to 10 GBq per dose, or 50 MBq to 100 GBq per dose suitable for industrial-scale production of multiple doses. 24. The pharmaceutical composition according to any one of items 1 to 23, wherein the composition is a particle suspension comprising monodisperse or polydisperse particles according to items 6 to 22. 25. The pharmaceutical composition according to any one of items 1 to 24 for use in the treatment of cancer. 26. The pharmaceutical composition according to any one of items 1 to 25, wherein the cancer is selected from the group consisting of intraperitoneal cancer, intracranial cancer, pleural cancer, bladder cancer, cardia cancer, cancer in the subarachnoid space, and non-intracavitary targets such as melanoma, non-small cell lung cancer and metastasis. 27. The pharmaceutical composition according to any one of items 1 to 26, wherein the individual has undergone debulking surgery for one or more peritoneal tumors prior to administration of the pharmaceutical composition. 28. The pharmaceutical composition according to any one of items 1 to 27, wherein said debulking surgery of the one or more peritoneal tumors is performed prior to the surgery, such as on the same day, 1 day before, such as at least 2 days before, for example at least 3 days before, such as at least 4 days before, for example at least 5 days before, such as at least 6 days before, such as at least 7 days before, for example at least 8 days before, such as at least 9 days before, such as at least 10 days before, for example at least 11 days before, such as at least 12 days, for example at least 13 days before, such as at least 14 days before the day of administering the pharmaceutical composition comprising a therapeutically relevant amount of an alpha-emitting radionuclide. 29. The pharmaceutical composition according to any one of items 1 to 28, wherein the pharmaceutical composition is used in combination with other cancer therapies, for example, chemotherapy such as taxanes (e.g., paclitaxel, docetaxel), platinum agents (e.g., carboplatin, cisplatin), doxorubicin, mitomycin, etc., DNA repair inhibitors, for example PARP inhibitors (e.g., olaparib, rucaparib, niraparib, talazoparib, veliparib, pamiparib, CEP9722, E7016, and 3-aminobenzamide), and radioimmunotherapy. 30. The pharmaceutical composition according to any one of items 1 to 29, wherein the pharmaceutical composition is a medical device or is contained in a medical device. 31. The pharmaceutical composition according to any one of items 1 to 30, wherein the concentration of the phosphonate and / or phosphate compound is between 1 μg and 1000 mg / ml, such as between 0.1 mg and 10 mg per ml of final solution or between 1 μg and 1000 mg per g of particles in said final solution. 32. The pharmaceutical composition according to any one of items 1 to 31, wherein the particles are used in an amount of 0.1 to 10 g per dose, for example, 0.5 to 5 g of particles per dose. 33. 2MBq to 50MBq per gram of particles 224 33. The pharmaceutical composition according to any one of items 1 to 32, wherein Ra is present. 34. The pharmaceutical composition according to any one of items 1 to 33, wherein the average particle size is 0.1 to 30 μm, for example 1 to 10 μm, and the composition is radiolabeled with 1 to 2000 atoms of an α-emitter per particle, for example 50 to 500 atoms per microparticle. 35. The pharmaceutical composition for use according to any one of items 1 to 34, wherein the individual has already received hyperthermic intraperitoneal chemotherapy (HIPEC). 36. The pharmaceutical composition for use according to any one of items 1 to 35, wherein the pharmaceutical composition is administered to an individual in need thereof. 37. The pharmaceutical composition for use according to any one of items 1 to 36, wherein the pharmaceutical composition is injected into the abdominal cavity of a patient who has recently been treated with debulking surgery with or without HIPEC. 38. The pharmaceutical composition for use according to any one of items 1 to 37, wherein the tumor is one or more peritoneal tumors. 39. Particles having a numerical size of 0.1-30 μm in diameter, e.g., 1-10 μm, and radiolabeled with 1-2000 atoms of an alpha emitter per particle, e.g., 50-500 atoms per microparticle. 40. Alpha emitters, e.g. 224 39. The particles according to item 38, which are radiolabeled with Ra and are administered as a suspension so as to provide a radioactive dose of 1 to 50 MBq, for example 4 to 20 MBq, for example 5 to 10 MBq per patient. 41. A suspension of particles, e.g., crystalline particles, labeled with an α-emitter according to any one of items 1 to 40, for intraperitoneal injection, the suspension containing 50 to 3000 mg, e.g., 500 to 1500 mg, having a radioactivity of 1 MBq to 500 MBq, e.g., 4 to 12 MBq, dispersed in 1 to 2000 ml, e.g., 10 to 500 ml, e.g., 100 to 300 ml.

Claims

1. 1. A pharmaceutical composition comprising a therapeutically relevant amount of an alpha-emitting radionuclide, wherein said alpha-emitting radionuclide or progeny is dosed and can be administered to provide a radiation dose in the range of 6 Gy (30 Sv) to 2000 Gy (10,000 Sv), more particularly 10 to 200 Gy (50 to 1,000 Sv).

2. The radionuclide is ２２４ Ra, ２２５ Ac, ２１１ At, ２１３ Bi, ２１２ Bi, ２２３ Ra, １４９ Tb, ２２５ Ra, ２３０ U. ２５５ Fm and ２２７ 2. The pharmaceutical composition of claim 1, wherein the therapeutically suitable alpha-emitting radionuclide is selected from the group consisting of Th.

3. The radionuclide is a progeny radionuclide ２２０ Rn, ２１６ Po, ２１２ Pb, ２１２ Bi, ２１２ Po and ２０８ Alpha-ray radioactivity with Tl ２２４ The pharmaceutical composition according to claim 1 or 2, wherein the compound is selected from the group consisting of Ra.

4. The radionuclide is a beta emitter with a therapeutically suitable alpha emitting progeny nuclide, which ２１２ Pb, and the progeny radionuclides are ２１２ Bi, ２１２ Po and ２０８ The pharmaceutical composition according to any one of claims 1 to 3, wherein the compound is Tl.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the alpha-emitting radionuclide is contained in particles which may be biodegradable.

6. 8. The pharmaceutical composition of claim 6 or 7, wherein the particles further comprise a phosphorus-containing additive.

7. The decomposable compound is CaCO ３ , MgCO ３ , SrCO ３ , BaCO ３ , hydroxyapatite Ca ５ (P.O. ４ ) ３ The pharmaceutical composition according to any one of claims 6 to 8, wherein the calcium phosphate is selected from the group consisting of calcium phosphates such as (OH) and fluoroapatite, and complexes containing any of these as a main component.

8. The pharmaceutical composition according to claims 8 to 10, wherein the phosphorus-containing additive is a phosphate selected from the group consisting of orthophosphates, linear oligophosphates and polyphosphates, and cyclic polyphosphates.

9. 9. The pharmaceutical composition of claim 8, wherein the phosphonate is a polyphosphonate.

10. 10. The pharmaceutical composition of claim 9, wherein the polyphosphonate is selected from the group consisting of EDTMP = ethylenediaminetetra(methylenephosphonic acid), DOTMP = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl-tetrakis(methylphosphonic acid), and DTPMP = diethylenetriaminepenta(methylenephosphonic acid).

11. 11. The pharmaceutical composition of claim 10, wherein the polyphosphonate is EDTMP = ethylenediaminetetra(methylenephosphonic acid).

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the size of the particles is between 1 nm and 500 μm.

13. 13. A pharmaceutical composition according to any one of claims 1 to 12, having an average particle size of 0.1 to 30 μm, for example 1 to 10 μm, and radiolabelled with 1 to 2000 atoms of an alpha emitter per particle, for example 50 to 1000 atoms per microparticle.

14. 14. A pharmaceutical composition according to any one of claims 1 to 13, prepared with an amount of radionuclide to provide 1 kBq to 10 GBq per dose, or 50 MBq to 100 GBq suitable for industrial scale production of multiple doses.

15. A pharmaceutical composition according to any one of claims 1 to 14, wherein 0.1 to 10 g of particles are used per dose, such as 0.5 to 5 g of particles per dose.

16. 2MBq to 50MBq per 1g of particles ２２４ The pharmaceutical composition according to any one of claims 1 to 15, wherein Ra is present.

17. A pharmaceutical composition according to any one of claims 1 to 16 for use in the treatment of cancer.

18. The pharmaceutical composition according to any one of claims 1 to 17, wherein the cancer is selected from the group consisting of intraperitoneal cancer, intracranial cancer, pleural cancer, bladder cancer, cardia cancer, and subarachnoid cancer.

19. The pharmaceutical composition of any one of claims 1 to 18, wherein the individual has undergone debulking surgery for one or more peritoneal tumors prior to the administration of the pharmaceutical composition.

20. 20. The pharmaceutical composition for use according to any one of items 1 to 19, wherein the pharmaceutical composition is administered to an individual in need thereof.

21. Particles having a numerical size of 0.1 to 30 μm in diameter, for example 1 to 10 μm, and radiolabeled with 1 to 2000 atoms of an alpha emitter per particle, for example 50 to 1000 atoms per microparticle.

22. Alpha emitters, e.g. ２２４ 22. The particles of claim 21, which are radiolabelled with Ra and are administered as a suspension to provide a radioactive dose of 1 to 50 MBq, such as 4 to 20 MBq, for example 5 to 10 MBq per patient.

23. 23. A suspension of alpha emitter labeled particles, e.g. crystalline particles, according to any one of claims 1 to 22, for intraperitoneal injection containing 50 to 3000 mg, e.g. 500 to 1500 mg, with a radioactivity of 1 MBq to 500 MBq, e.g. 4 to 12 MBq, dispersed in 1 to 2000 ml, e.g. 10 to 500 ml, e.g. 100 to 300 ml.

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