Apparatus and method for manufacturing nanoparticle composition including radioactive isotope

Abstract

The present invention relates to a system for manufacturing a nanoparticle composition which is for targeted therapy and comprises a radioactive isotope, the system comprising a reaction device, wherein the reaction device comprises: a stirring module configured to stir a reactant solution prepared in a reaction vessel; and a heating module configured to heat the stirred reactant solution to obtain a solution including an intermediate product, and the prepared reactant solution comprises at least one of a nanoparticle composition precursor including a hydrophobic or hydrophilic organic compound-metal complex, an inorganic compound and an organic solvent, a first mixture including a radioisotope, and a second mixture including a hydrophilic organic polymer.

Description

Device for producing a nanoparticle composition containing a radioactive isotope and method for producing the same

[0001] The present invention relates to a method and a device for producing a nanoparticle composition containing a radioactive isotope, and more particularly, to a method and a device for producing a nanoparticle composition for treating cancer containing a radioactive isotope.

[0002] Radiation therapy is a treatment method that kills cancer cells or reduces the size of tumors. It is broadly divided into external radiation therapy and internal radiation therapy. Internal radiation therapy involves placing radioactive materials (e.g., radioisotopes) around cancer cells and irradiating them.

[0003] Internal radiation therapy is a treatment method that irradiates the body by inserting a therapeutic agent containing a radioactive isotope that generates radiation. To achieve a high therapeutic effect, a large amount of radiation must be delivered to target cells or target organs in the body, while the radiation dose to normal tissues must be minimized.

[0004] To achieve such high therapeutic efficacy, it is crucial to maintain a stable amount of radioactive material or radioisotope within the cancer treatment until it reaches the target cells or organs. In other words, for a high therapeutic effect, after administration, the cancer treatment must be able to reach the target cells or organs without loss of the drug in the bloodstream.

[0005] Existing radiopharmaceuticals consist of a chelator to which a radioisotope is bound, a linker or carrier, and a ligand attached to the linker or carrier.

[0006] Conventional chelator-based radiopharmaceuticals present various problems. Radiopharmaceuticals have high concentrations of metal-binding proteins such as albumin in the bloodstream, so the radioactive metal is lost through binding to serum proteins. This loss can lead to the accumulation of radioactivity in non-target organs such as the liver, spleen, and kidneys, thereby reducing the amount available for tumor targeting. Furthermore, as the radiopharmaceutical moves through the bloodstream to target cells or target organs, the radioisotope and / or daughter nuclei generated during the nuclear decay of the radioisotope are released. This instability of the radioimmunoconjugate can lead to serious side effects such as bone marrow toxicity and can reduce the therapeutic and imaging efficacy.

[0007] On the other hand, radioactive nanoparticles offer several advantages. They allow the design of radioimmunoconjugates composed of multiple targeting molecules on the nanoparticle surface, enable the internalization of various radioisotopes, and eliminate the need for complex and costly multi-step chelate synthesis procedures. Nanoparticles can reduce radiotoxicity by preventing radioactive metal binding to components such as albumin. Furthermore, because each nanoparticle contains numerous metal atoms, they can serve as carriers for large quantities of low-activity isotopes or isotopes with diverse wavelengths.

[0008] Furthermore, existing radiopharmaceuticals have the problem of causing fatal renal toxicity if the drug is not smoothly excreted from the kidneys after its action. Meanwhile, it is known that the particle size suitable for renal excretion is in the range of 2 nm to 8 nm for solid inorganic particles. If the particle size is smaller than this, the radiopharmaceutical passes through the kidneys too quickly, reducing the drug efficacy. Conversely, if the particle size is larger than this, renal excretion is poor, the radiopharmaceutical can accumulate in the kidneys, and cause renal toxicity.

[0009] Furthermore, existing radiopharmaceuticals using inorganic particles have the problem that, during the manufacturing process, most of the radioisotope attaches to the surface of the inorganic particles, with only a very small amount remaining within the particles themselves. This leads to the majority of radioisotopes separating in unintended locations during drug action in the body, potentially causing fatal organ damage. Furthermore, once the radiopharmaceutical reaches the target organ, it fails to achieve the intended therapeutic effect.

[0010] The present invention provides a method and a manufacturing device for a nanoparticle composition for cancer treatment that prevents a radioactive material placed in the process of reaching a target cell or target organ from being easily released.

[0011] In addition, the present invention provides a method and a manufacturing device for a nanoparticle composition for cancer treatment that can be smoothly excreted through the kidney.

[0012] In addition, an object of the present invention is to provide a method and a manufacturing device for a nanoparticle composition for treating cancer, wherein the ratio of the concentration of a radioisotope disposed in an inorganic core is higher than the concentration of a radioisotope attached to the surface of the nanoparticle during the manufacturing process.

[0013] The present invention relates to a system for manufacturing a nanoparticle composition for targeted therapy containing a radioisotope, wherein the system comprises a reaction device, wherein the reaction device comprises: a stirring module configured to stir a reactant solution prepared in a reaction vessel; and a heating module configured to heat the stirred reactant solution to obtain a solution containing an intermediate product; wherein the prepared reactant solution comprises at least one of a nanoparticle composition precursor containing a hydrophobic or hydrophilic organic compound-metal complex, an inorganic compound, and an organic solvent, a first mixture containing a radioisotope, and a second mixture containing a hydrophobic or hydrophilic organic polymer.

[0014] Additionally, the first mixture is a mixture containing a metal inorganic compound and a radioactive isotope inorganic compound.

[0015] In addition, the system further includes a post-processing device, and the post-processing device includes a column chromatography module configured to separate the intermediate product from a solution containing the intermediate product to obtain a final product; a centrifugation module; and a filtration module; and the filtration module is configured to separate the intermediate product under membrane conditions of 1 nm or more and 500 nm or less to obtain a final product.

[0016] In addition, the post-processing device further includes a binding module configured to bind at least one of an antibody, an antibody fragment, a nucleic acid / peptide aptamer, and a receptor-binding nanomaterial to the separated intermediate product.

[0017] Additionally, the binding module is configured to bind an antibody to the separated intermediate product.

[0018] Additionally, the heating module is configured to heat the stirred reactant solution with electromagnetic waves at a temperature of 40°C or higher.

[0019] The present invention comprises a preparation step of preparing a reactant solution in a reaction vessel; a heating step of heating the prepared reactant solution to obtain a product solution; and a separation step of separating a nanoparticle composition precursor from the obtained product solution; wherein the reactant solution comprises a hydrophobic or hydrophilic organic compound-metal oxide complex, an inorganic compound, and an organic solvent.

[0020] In addition, the hydrophobic or hydrophilic organic compound-metal oxide complex comprises a hydrophobic or hydrophilic organic acid, and the metal is copper (Cu), tin (Sn), lead (Pb), manganese (Mn), iridium (Ir), platinum (Pt), rhodium (Rh), rhenium (Re), silver (Ag), gold (Au), palladium (Pd), osmium (Os), tantalum (Ta), ytterbium (Yb), zirconium (Zr), hafnium (Hf), terbium (Tb), thulium (Tm), cerium (Ce), dysprosium (Dy), erbium (Er), europium (Eu), holmium (Ho), iron (Fe), lanthanum (La), neodymium (Nd), praseodymium (Pr), lutetium (Lu), scandium (Sc), strontium (Sr), yttrium (Y), At least one metallic element selected from the group consisting of samarium (Sm), bismuth (Bi), radium (Ra), actinium (Ac), thorium (Th), cobalt (Co), arsenic (As), gallium (Ga), technetium (Tc), titanium (Ti), vanadium (V), chromium (Cr), nickel (Ni), rubidium (Rb), niobium (Nb), tungsten (W), ruthenium (Ru), molybdenum (Mo), antimony (Sb), and indium (In).

[0021] In addition, the metal is preferably at least one metal element selected from the group consisting of manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), yttrium (Y), lutetium (Lu), zirconium (Zr), hafnium (Hf), tin (Sn), lead (Pb), antimony (Sb), bismuth (Bi), actinium (Ac), and cerium (Ce).

[0022] In addition, the inorganic compounds include copper (Cu), tin (Sn), lead (Pb), manganese (Mn), iridium (Ir), platinum (Pt), rhodium (Rh), rhenium (Re), silver (Ag), gold (Au), palladium (Pd), osmium (Os), tantalum (Ta), ytterbium (Yb), zirconium (Zr), hafnium (Hf), terbium (Tb), thulium (Tm), cerium (Ce), dysprosium (Dy), erbium (Er), europium (Eu), holmium (Ho), iron (Fe), lanthanum (La), neodymium (Nd), praseodymium (Pr), lutetium (Lu), scandium (Sc), strontium (Sr), yttrium (Y), samarium (Sm), bismuth (Bi), radium (Ra), actinium (Ac), A compound comprising at least one metal element selected from the group consisting of thorium (Th), cobalt (Co), arsenic (As), gallium (Ga), technetium (Tc), titanium (Ti), vanadium (V), chromium (Cr), nickel (Ni), rubidium (Rb), niobium (Nb), tungsten (W), ruthenium (Ru), molybdenum (Mo), antimony (Sb), and indium (In), and at least one element selected from the group consisting of fluorine (F), chlorine (Cl), bromine (Br), iodine (I), phosphorus (P), sulfur (S), selenium (Se), nitrogen (N), and oxygen (O).

[0023] In addition, the heating step is configured to heat the reaction vessel with electromagnetic waves,

[0024] The method further includes a depressurizing step of reducing the pressure inside the heated reaction vessel to a vacuum pressure; an injection step of injecting an inert gas into the depressurized reaction vessel; and a cooling step of cooling the reaction vessel.

[0025] In addition, the heating step is configured to heat the reaction vessel with the electromagnetic wave at a temperature of 40°C or higher.

[0026] The present invention comprises a preparation step of preparing a nanoparticle composition precursor comprising a hydrophobic or hydrophilic organic compound-metal oxide complex, a first mixture containing a radioactive isotope, and a second mixture containing a hydrophilic-organic polymer; an obtaining step of mixing the precursor, the first mixture, and the second mixture to obtain a third mixture; a heating step of heating the third mixture to obtain a solution containing an intermediate product; and a first separation step of separating the intermediate product from the solution.

[0027] Additionally, the first mixture is a mixture containing a metal inorganic compound and a radioactive isotope inorganic compound.

[0028] Additionally, the heating step is configured to heat the third mixture at a temperature of 40°C or higher using electromagnetic waves.

[0029] In addition, the first separation step includes at least one centrifugation step and a membrane filtration separation step, and the membrane filtration separation step is configured to filter the intermediate product under membrane conditions of 1 nm or more and 100 nm or less.

[0030] A preparatory step of preparing a nanoparticle composition precursor comprising a hydrophobic or hydrophilic organic compound-metal oxide complex, a first mixture containing a radioisotope, and a second mixture containing a hydrophilic-organic polymer;

[0031] An obtaining step of obtaining a third mixture by mixing the precursor, the first mixture, and the second mixture;

[0032] A heating step of heating the third mixture to obtain a solution containing an intermediate product; and

[0033] The present invention further includes a first separation step of separating the intermediate product from the solution; a binding step of binding one or more substances selected from the group consisting of antibodies, antibody fragments, hexane / peptide aptamers, and receptor-binding nanomaterials to the separated intermediate product; and a second separation step of obtaining a final product by separating a solution containing the intermediate product bound to one or more substances selected from the group consisting of antibodies, antibody fragments, hexane / peptide aptamers, and receptor-binding nanomaterials.

[0034] Additionally, in the above binding step, the substance binding to the separated intermediate product is composed of an antibody.

[0035] Additionally, the above-described combining step is configured to stir the separated intermediate product at a temperature of 0°C or higher and 100°C or lower.

[0036] In addition, the secondary separation step includes a column chromatography separation step and at least one membrane filtration separation step, and the at least one membrane filtration separation step is configured to filter the antibody-bound intermediate product under membrane conditions of 1 nm to 500 nm.

[0037] According to the present invention, there is an advantage in that the therapeutic effect can be increased because the radioactive material placed in the nanoparticle (100) composition for cancer treatment is not easily released during the process of reaching the target cell or target organ.

[0038] In addition, according to the present invention, there is an advantage in that the possibility of occurrence of renal toxicity can be reduced by smoothly excreting the nanoparticle (100) composition for cancer treatment through the kidneys.

[0039] In addition, according to the present invention, there is an advantage in that the therapeutic effect can be increased and the possibility of attacking normal cells can be reduced by increasing the concentration ratio of the radioisotope (140) placed in the inorganic core (120) compared to the concentration of the radioisotope (140) attached to the surface of the nanoparticle (100) during the manufacturing process.

[0040] FIG. 1a is a drawing showing a nanoparticle (100) according to one embodiment of the present invention.

[0041] FIG. 1b is a drawing showing a radioactive isotope included in a lattice structure of a metal oxide according to one embodiment of the present invention.

[0042] Figure 1c is a diagram visually comparing the effects of daughter nuclei produced during the nuclear decay process of a radioactive isotope on a conventional radiopharmaceutical and the effects of the daughter nuclei on a radiopharmaceutical.

[0043] FIG. 2 is a drawing illustrating the degree to which a radioactive isotope is liberated when a radiopharmaceutical utilizing nanoparticles (100) according to some embodiments of the present invention is administered into the body.

[0044] Figure 3 is a schematic diagram illustrating a method for manufacturing a nanoparticle (100) composition.

[0045] Figure 4 is a drawing comparing a one-step coating method and a multi-step coating method.

[0046] FIG. 5a is a drawing showing a reaction of binding a target ligand (180) using Protein A to an inorganic core (120) coated with CM (Carboxymethyl)-dextran according to the present invention.

[0047] FIG. 5b is a drawing showing a reaction of binding a target ligand (180) using Protein A to an inorganic core (120) surrounded by an organic shell (160) containing Lipid-PEG according to the present invention.

[0048] FIG. 6 is a diagram showing a single-step reaction and a multi-step reaction of binding a target ligand (180) to a CM (Carboxymethyl)-dextran-coated inorganic core (120) according to the present invention.

[0049] Figure 7 is a drawing for explaining a manufacturing process of a precursor of a nanoparticle composition for targeted treatment according to the present invention.

[0050] FIG. 8 is a drawing illustrating a manufacturing process of a nanoparticle composition for targeted therapy containing a radioactive isotope according to the present invention.

[0051] FIG. 9 is a drawing illustrating a manufacturing process of a nanoparticle composition for targeted therapy containing a radioactive isotope conjugated to an antibody according to the present invention.

[0052] FIG. 10 is a diagram showing a reaction of binding a targeting ligand (180) to an inorganic core (120) surrounded by an organic shell (160) including Lipid-PEG, according to some embodiments of the present invention.

[0053] FIG. 11a and FIG. 11b are graphs showing the distribution ratio of radioactive isotopes in nanoparticles (100) manufactured by a manufacturing method according to some embodiments of the present invention.

[0054] Figure 12 is a graph showing the results of comparing the Rf patterns of a radioactive labeled nanoparticle (100) drug and a free radioisotope according to one embodiment of the present invention.

[0055] FIGS. 13a to 13c are drawings showing the results of measuring the size of radiopharmaceuticals using nanoparticles (100) manufactured by a manufacturing method according to some embodiments of the present invention based on the number of particles using dynamic light scattering (DLS) analysis.

[0056] FIGS. 14a to 14c are drawings showing the results of measuring the size of radiopharmaceuticals using nanoparticles (100) manufactured by a manufacturing method according to some embodiments of the present invention based on the intensity of light scattering of the nanoparticles (100) using a dynamic light scattering (DLS) analysis method.

[0057] FIGS. 15a to 15c are drawings showing the results of measuring the size of radiopharmaceuticals using nanoparticles (100) manufactured by a manufacturing method according to some embodiments of the present invention based on the volume of the nanoparticles (100) using dynamic light scattering (DLS) analysis.

[0058] Figure 16 is a drawing for explaining a manufacturing system for a nanoparticle composition for targeted treatment according to the present invention.

[0059] Figure 17a is a drawing for explaining a manufacturing process of a precursor of a nanoparticle composition for targeted treatment according to the present invention.

[0060] FIG. 17b is a drawing illustrating a manufacturing process of a nanoparticle composition for targeted therapy containing a radioactive isotope according to the present invention.

[0061] Figure 17c is a drawing for explaining a manufacturing process of a nanoparticle composition for targeted therapy containing a radioactive isotope conjugated to an antibody according to the present invention.

[0062] Figure 18 is a drawing for explaining an example in which Oleyl alcohol according to the present invention participates in a reaction.

[0063] Overall composition

[0064] Hereinafter, with reference to the attached drawings, a composition of nanoparticles (100) containing a radioactive isotope according to embodiments of the present invention and a method for manufacturing the same are described in detail.

[0065] Structure of nanoparticles (100)

[0066] FIG. 1a is a drawing showing a nanoparticle (100) according to one embodiment of the present invention.

[0067] As illustrated, the nanoparticle (100) may include an inorganic core (120), a radioisotope (140), an organic shell (160), and a targeting ligand (180). Specifically, the nanoparticle (100) may stably contain the radioisotope (140) therein, thereby preventing the radioisotope (140) from being randomly released from a target organ in the body.

[0068] According to the present invention, the nanoparticle (100) may include an inorganic core (120) and an organic shell (160). Specifically, the inorganic core (120) may be coated with a flexible organic shell (160) to ensure an appropriate blood circulation time of the radiopharmaceutical and induce smooth renal excretion, thereby maximizing drug efficacy while minimizing renal toxicity.

[0069] Radioactive isotope (140)

[0070] According to the present invention, since the nanoparticle (100) contains a large amount of radioactive isotope (140) inside the nanoparticle (100) rather than on the surface of the nanoparticle (100), side effects in organs other than the target organ can be prevented and the drug effect in the target organ can be maximized.

[0071] According to one embodiment of the present invention, the radioactive isotope (140) is iodine (I)-123, iodine (I)-125, iodine (I)-131, gallium (Ga)-67, gallium (Ga)-68, copper (Cu)-64, copper (Cu)-67, gold (Au)-198, lead (Pb)-210, nickel (Ni)-63, dysprosium (Dy)-165, radium (Ra)-226, lanthanum (La)-140, rhenium (Re)-186, rhenium (Re)-188, ruthenium (Ru)-82, lutetium (Lu)-177, manganese (Mn)-54, molybdenum (Mo)-99, bismuth (Bi)-213, samarium (Sm)-153, Cesium (Ce)-137, sodium (Na)-24, scandium (Sc)-46, strontium (Sr)-82, strontium (Sr)-85, strontium (Sr)-89, strontium (Sr)-90, americium (Am)-241, zinc (Zn)-65, erbium (Er)-169, uranium (U)-234, uranium (U)-235, uranium (U)-238, silver (Ag)-110m, iridium (Ir)-192, iridium (Ir)-169, iridium (Ir)-177, yttrium (Yt)-169, yttrium (Yt)-177, indium (In)-111, germanium (Ge)-68, Iron (Fe)-55, cadmium (Cd)-109, calcium (Ca)-47, californium (Cf)-252, cobalt (Co)-57, cobalt (Co)-60, curium (Cm)-244, chromium (Cr)-51, chromium (Cr)-57, krypton (Kr)-81, krypton (Kr)-85, thallium (Tl)-201, thallium (Tl)-204, technetium (Tc)-99m, thorium (Th)-229, thorium (Th)-230, lead (Pd)-103, potassium (K)-42, polonium (Po)-210, promethium (Pm)-147, plutonium (Pu)-238, actinium (Ac)-225, and radium (Ra)-223 It can be any one of, but is not limited to, these.

[0072] Weapon Core (120)

[0073] According to one embodiment of the present invention, the inorganic core (120) may be physically or chemically bonded or connected to the radioisotope (140). For example, the radioisotope (140) may be placed inside the inorganic core (120). In addition, the inorganic core (120) and the radioisotope (140) may be mutually bonded. In addition, the radioisotope (140) may be formed by introducing a general coating method to the interface of the inorganic core (120), or may be formed by introducing a doping method such as a diffusion process or an ion implantation process. However, the present invention is not limited thereto.

[0074] According to one embodiment of the present invention, the inorganic core (120) may further include a metal oxide. Specifically, the metal oxide may form a lattice structure upon aggregation, and the lattice structure of the metal oxide may semi-permanently contain or capture a radioactive isotope (140) or semi-permanently bind to the radioactive isotope (140) to prevent any release of the radioactive isotope (140).

[0075] According to the present invention, the metal oxide may include an impurity including silicon (Si). The impurity including silicon (Si) may stabilize the surface of the nanoparticle (100).

[0076] According to one embodiment of the present invention, the organic shell (160) surrounding the inorganic core (120) may include at least one of an organic polymer or a peptide. Meanwhile, the organic polymer may be any one of polyaniline, polyisobutylene, polyethylene, polystyrene, paraffin, graphene, polyvinylpyrrolidone, polyethylene glycol, gelatin, propylene glycol, poly(3,4-ethylenedioxythiophene), and poly(methyl methacrylate), but is not limited thereto.

[0077] M inside the weapon core (120) x X y L z

[0078] According to the present invention, the inorganic core (120) has M inside. x X y L z may further include. In some embodiments, M represents a metal element, for example, copper (Cu). In some embodiments, X may be fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). In some embodiments, L may be an organic ligand comprising any one of nitrogen (N), sulfur (S), and phosphorus (P). In some embodiments, x is an integer from 1 to 6, y is an integer from 1 to 6, and z is an integer from 0 to 6. According to one embodiment, specifically, M x X y L z may be, but is not limited to, CuI.

[0079] According to the present invention, M is a weapon core (120) and M x X y L z can be physically or chemically bonded or linked. In some embodiments, X or L is M x X y L z and radioactive isotopes (140) can be physically or chemically combined or linked.

[0080] According to one embodiment of the present invention, when the inorganic core (120) further includes CuI, it is possible to control the ratio of the concentration of the radioisotope (140) included in the inorganic core (120) to the sum of the concentration of the radioisotope (140) included in the inorganic core (120) and the concentration of the radioisotope (140) attached to the surface of the nanoparticle (100) during the manufacturing process.

[0081] According to the present invention, M x X y Lz can be combined or connected with both the weapon core (120) and the radioactive isotope (140). Specifically, M x X y L z can serve to connect the weapon core (120) and the radioactive isotope (140). For example, M x X y L z can be located between the inorganic core (120) and the radioactive isotope (140). During the manufacturing process, the inorganic core (120) is M x X y L z If the inorganic core (120) of the nanoparticle (100) further includes a radioactive isotope (140), the inorganic core (120) of the nanoparticle (100) may further include a radioactive isotope (140). In this way, the drug effect or stability is enhanced. For example, if the inorganic core (120) is M x X y L z When more radioactive isotopes (140) are included, more radioactive isotopes (140) can be bound to the inorganic core (120). In this way, the radiopharmaceutical can emit a large amount of radiation at the target organ, the radiation treatment effect can be maximized, and damage to normal cells can be minimized. According to one embodiment of the present invention, M x X y L z may be, but is not limited to, CuI.

[0082] In some embodiments, the weapon core (120) has M x X y L z It includes a weapon core (120) and M x X y L z Includes physically or chemically bonded or connected. For example, M inside the inorganic core (120) x X y L z can be deployed. For example, the weapon core (120) and M x Xy L z They can be mutually bonded through this hydrogen bond. For example, MxXyLz can be coated on the surface of the inorganic core (120) through a general coating method. For example, MxXyLz can be doped on the surface of the inorganic core (120) through a doping method such as a diffusion process or an ion implantation process. For example, MxXyLz can form a layer and be coated on the surface of the inorganic core (120). However, the present invention is not limited thereto.

[0083] Specifically M x X y L z In this case, CuI, the I of CuI can bind to the inorganic core (120) in one direction and to the radioactive isotope (140) in the other direction. In this case, the radioactive isotope (140) added during the manufacturing process is included in the inorganic core (120). In addition, the radiopharmaceutical can emit a large amount of radiation at the target organ.

[0084] Target ligand (180)

[0085] According to one embodiment of the present invention, the targeting ligand (180) attached to the organic shell (160) may include one or more of a peptide, a small molecule, an antibody, and a therapeutic agent. However, the present invention is not limited thereto.

[0086] According to the present invention, a peptide may refer to a substance composed of a peptide capable of specifically binding to at least one of a specific cell or a substance expressed in a specific cell. Specifically, the peptide may be any one of Somatostatin, Gastrin-releasing-peptide (GRP), Glu-Urea-Lys (GUL), and PSMA-I&T (Glu-Urea-based ligand), but is not limited thereto.

[0087] According to the present invention, a small molecule may refer to a substance composed of a small molecule that can specifically bind to at least one of a specific cell or a substance expressed in a specific cell. Specifically, it may be any one of Fructose, Levan, Glucose, Adenosine, Mannose, Glycine, Tryptophane, Alanine, Arginine, Lysine, Arginine, Riboflavin, Biotin, Thiamine, Vitamin B12, Methotrexate, Anisamide, Anacardic acid, phenylboric acid, Tamoxifen, Methotrexate, Folate, Imatinib, Vemurafenib, and Sorafenib, but is not limited thereto.

[0088] An antibody according to one embodiment of the present invention may refer to a substance composed of an antibody capable of specifically binding to at least one of a specific cell or a substance expressed in a specific cell. Specifically, the antibody may be any one of a chimeric monoclonal antibody, a humanized monoclonal antibody, a human monoclonal antibody, an antibody fragment, an antibody-drug conjugate (ADC), and an immunoconjugate, but is not limited thereto.

[0089] A therapeutic agent according to one embodiment of the present invention may refer to a substance comprising a therapeutic agent capable of specifically binding to at least one of a specific cell or a substance expressed in a specific cell. Specifically, the therapeutic agent may include at least one selected from the group consisting of Trastuzumab, Pertuzumab, Ado-Trastuzumab Emtansine, Trastuzumab Deruxtecan, Rituximab, Cetuximab, Nivolumab, Bevacizumab, Atezolizumab, Blinatumomab, Olaratumab, Daratumumab, Elotuzumab, and Ipilimumab, but is not limited thereto.

[0090] Organic Shell (160)

[0091] According to the present invention, the organic shell (160) may further include a lipid nanoparticle shell. In this case, the overall diameter of the radiopharmaceutical is within the range of 5 nm to 100 nm, and the radiopharmaceutical can pass through a structure having a diameter of 2 nm to 8 nm. In one embodiment of the present invention, the overall diameter may be a hydrodynamic size.

[0092] Meanwhile, a structure can refer to any shape that has an internal, passable void space and an outer wall surrounding that void space. The diameter of the structure can refer to the diameter of the internal void space. Furthermore, the diameter of the internal void space can vary within a single structure. For example, a structure may include, but is not limited to, a human kidney drainage tract.

[0093] Meanwhile, the hydrodynamic diameter, which is an aspect of the total diameter used in this document, refers to the size of a virtual sphere that is assumed to diffuse in the same manner as the particle whose diameter is to be measured. For example, the hydrodynamic diameter, which is an example of the total diameter of a radiopharmaceutical utilizing a nanoparticle (100), may refer to the diameter of the particle that takes into account all of the inorganic core (120) of the nanoparticle (100), the organic shell (160) surrounding the inorganic core (120), and the targeting ligand (180) attached to the organic shell (160).

[0094] According to one embodiment of the present invention, even though the overall diameter of the nanoparticle (100) is 5 nm to 100 nm, which is larger than the diameter of the renal excretory passage (2 nm to 8 nm), the nanoparticle (100) can pass through a structure having a diameter ranging from 2 nm to 8 nm corresponding to the renal excretory passage.

[0095] That is, the radiopharmaceutical utilizing nanoparticles (100) according to one embodiment of the present invention can prevent excessively rapid renal excretion since the overall diameter is larger than the diameter of the renal excretion passage. In addition, the radiopharmaceutical utilizing nanoparticles (100) according to one embodiment of the present invention can pass through the renal excretion passage having a diameter smaller than the overall diameter of the radiopharmaceutical utilizing nanoparticles (100) due to the elasticity or flexibility of the organic shell (160) surrounding the inorganic core (120). Accordingly, the radiopharmaceutical may not accumulate in the body. As a result, the radiopharmaceutical can remain in the blood at an appropriate level to achieve the intended drug effect, and the radiopharmaceutical does not accumulate in the body, thereby preventing renal toxicity.

[0096] FIG. 1b is a drawing showing a radioactive isotope included in a lattice structure of a metal oxide according to one embodiment of the present invention.

[0097] According to the present invention, the lattice structure of the metal oxide can serve to stably contain or capture not only the radioisotope (140) itself present within the nanoparticle (100), but also the daughter nuclei generated during the nuclear decay process of the radioisotope (140). Accordingly, damage to normal organs or the drug itself due to radiation emitted from the daughter nuclei can be prevented.

[0098] Figure 1c is a diagram visually comparing the effects of daughter nuclei produced during the nuclear decay process of a radioactive isotope on a conventional radiopharmaceutical and the effects of the daughter nuclei on a radiopharmaceutical.

[0099] According to one embodiment of the present invention, the inorganic core (120) may further include a metal oxide. Specifically, the metal of the metal oxide may be at least one of scandium (Sc), titanium (Ti), vanadium (V), chromium (Cr), manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu), yttrium (Y), zirconium (Zr), niobium (Nb), molybdenum (Mo), technetium (Tc), ruthenium (Ru), rhodium (Rh), palladium (Pd), silver (Ag), hafnium (Hf), tantalum (Ta), tungsten (W), rhenium (Re), osmium (Os), iridium (Ir), platinum (Pt), and gold (Au), but is not limited thereto.

[0100] According to one embodiment of the present invention, the metal oxide may be iron oxide. The iron oxide according to one embodiment of the present invention is an oxide of iron, for example, Fe 13 O 19 , Fe3O4 (magnetite), γ-Fe2O3 (magemite) and α-Fe2O3 (hematite), β-Fe2O3 (beta phase), ε-Fe2O3 (epsilon phase), FeO (Wustite), FeO2 (Iron Dioxide), Fe4O5, Fe5O6, Fe5O7, Fe 25 O 32, may be at least one of Ferrite type and Delafossite, but is not limited thereto.

[0101] FIG. 2 is a drawing illustrating the degree to which a radioactive isotope is liberated when a radiopharmaceutical utilizing nanoparticles (100) according to some embodiments of the present invention is administered into the body.

[0102] According to the present invention, M in the inorganic core (120) x X y L z It contains radioactive isotope (140) M x X y L z And is included in the inorganic core (120) in a state of being physically or chemically bound or connected, so that the radioactive isotope (140) can be stably placed in the inorganic core (120). For example, if the radioactive isotope (140) is M x X y L z It can be coated on the interface of the weapon core (120) in a state of being combined with. For example, a radioactive isotope (140) is M x X y L z It can be placed inside the weapon core (120) in a state of being combined with. For example, the radioactive isotope (140) forms a layer and M x X y L z It may be coated on the interface of the weapon core (120) in a state of being combined with, but is not limited thereto.

[0103] Figure 3 is a schematic diagram illustrating a method for manufacturing a nanoparticle (100) composition.

[0104] The method for manufacturing a nanoparticle (100) composition according to the present invention comprises the steps of: mixing and heating a metal hydrate and an organic salt to form a hydrophobic organic compound-metal complex; adding the complex to MxXyLz and then heating to react the metal to oxidize the metal and form an inorganic core (120) including a metal oxide and MxXyLz; mixing the inorganic core (120), a radioisotope (140), and an organic shell (160) material to form the radioisotope (140) and M in the inorganic core (120). x X y L z A method for manufacturing a nanoparticle (100) composition is described in detail below.

[0105] Step of preparing a hydrophobic organic compound-metal complex (S100)

[0106] According to the present invention, the method for manufacturing a nanoparticle (100) composition includes a step (S100) of preparing a hydrophobic organic compound-metal complex. Specifically, the step (S100) of preparing a hydrophobic organic compound-metal complex comprises preparing a hydrate of a metal chloride (ACl n -xH2O) may refer to a step of converting a hydrophobic organic compound-metal complex.

[0107] According to one embodiment of the present invention, the step (S100) of preparing a hydrophobic organic compound-metal complex comprises adding a hydrophobic organic compound and a metal chloride hydrate (ACl) to a solvent. n -xH2O), heating the mixture to react, removing unreacted material through washing with deionized water (DI water), heating and applying vacuum to remove the solvent, obtaining a hydrophobic organic compound-metal complex, and dissolving the complex in an oleyl alcohol / 1-octadecene solution and blending.

[0108] According to one embodiment of the present invention, a hydrate of a hydrophobic organic compound and a metal chloride (ACl n The solvent to which -xH2O is added may be, but is not limited to, ethanol / hexane.

[0109] The step of dissolving and blending the complex in an oleyl alcohol / 1-octadecene solution can improve the accuracy and convenience of quantitative measurement of a hydrophobic organic compound-metal complex in an oil form with viscosity and facilitate storage.

[0110] Figure 18 is a drawing for explaining an example in which Oleyl alcohol according to the present invention participates in a reaction.

[0111] As illustrated in FIG. 18, Oleyl alcohol may be used as a solvent, but may also be included in the precursor of a targeted therapeutic nanoparticle composition containing a radioisotope by directly participating in the reaction. In addition, examples in which Oleyl alcohol is included in the precursor of a targeted therapeutic nanoparticle composition containing a radioisotope by directly participating in the reaction are specifically described below when describing the manufacturing process of the precursor of a targeted therapeutic nanoparticle composition.

[0112] hydrophobic organic compounds

[0113] Meanwhile, the hydrophobic organic compound according to the present invention includes at least one compound selected from the group consisting of aliphatic hydrocarbon salts and amine compounds having 4 to 25 carbon atoms, but is not limited thereto.

[0114] According to the present invention, the aliphatic hydrocarbon salt having 4 to 25 carbon atoms may be any one of butyrate, valerate, caproate, enanthate, caprylic acid, pelargonate, caprate, laurate, myristate, pentadecylate, acetate, palmitate, palmitoleate, margarate, stearate, oleate, vaccenate, linoleate, (9,12,15)-linolenate, (6,9,12)-linolenate, eleostearate, tuberculostearate, rachidate, arachidonate, behenate, lignocerate, nervonate, ceroterate, montanate, and melissate and a peptide salt comprising one or more amino acids, but is not limited thereto. In addition, these compounds may be used alone or in the form of a mixed salt of two or more thereof.

[0115] According to the present invention, the metal component of the aliphatic hydrocarbon salt having 4 to 25 carbon atoms may be any one of calcium (Ca), sodium (Na), potassium (K), and magnesium (Mg), but is not limited thereto.

[0116] According to the present invention, the amine compounds are methylamine, ethylamine, propylamine, isopropylamine, butylamine, amylamine, hexylamine, octylamine, 2-ethylhexylamine, nonylamine, decylamine, laurylamine, pentadecylamine, cetylamine, stearylamine and cyclohexylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine, diamylamine, dioctylamine, di(2-ethylhexyl)amine, didecylamine, dilaurylamine, dicetylamine, distearylamine, methylstearylamine, ethylstearylamine and butylstearylamine, triethylamine, triamylamine, trihexylamine and trioctylamine, triallylamine and oleylamine, laurylaniline, stearylaniline, triphenylamine, N,N-dimethylaniline and dimethylbenzylaniline, It may be any one of monoethanolamine, diethanolamine, triethanolamine, dimethylaminoethanol, diethylenetriamine, triethylenetetramine, tetraethylenepentaamine, benzylamine, diethylaminopropylamine, xylylenediamine, ethylenediamine, hexamethylenediamine, dodecamethylenediamine, dimethylethylenediamine, triethylenediamine, guanidine, diphenylguanidine, N,N,N',N'-tetramethyl-1,3-butanediamine, N,N,N',N'-tetramethylethylenediamine, 2,4,6-tris(dimethylaminomethyl)phenol, morpholine, N-methylmorpholine, 2-ethyl-4-methylimidazole and 1,8-diazabicyclo(5,4,0)undecene-7(DBU), but is not limited thereto.

[0117] metal

[0118] According to the present invention, the metal in the hydrophobic organic compound-metal complex may include a magnetic metal that forms a certain lattice structure when aggregated in the form of an oxide. Specifically, the metal may be any one of scandium (Sc), titanium (Ti), vanadium (V), chromium (Cr), manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu), yttrium (Y), zirconium (Zr), niobium (Nb), molybdenum (Mo), technetium (Tc), ruthenium (Ru), rhodium (Rh), palladium (Pd), silver (Ag), hafnium (Hf), tantalum (Ta), tungsten (W), rhenium (Re), osmium (Os), iridium (Ir), platinum (Pt), and gold (Au).

[0119] According to the present invention, the metal oxide can form a lattice structure upon aggregation. The lattice structure can stably contain or capture a radioactive isotope (140) and prevent any release of the radioactive isotope (140).

[0120] metal oxide

[0121] According to one embodiment of the present invention, the metal oxide may be iron oxide in detail. The iron oxide according to the present invention is Fe 13 O 19 , Fe3O4 (magnetite), γ-Fe2O3 (magemite) and α-Fe2O3 (hematite), β-Fe2O3 (beta phase), ε-Fe2O3 (epsilon phase), FeO (Wustite), FeO2 (Iron Dioxide), Fe4O5, Fe5O6, Fe5O7, Fe 25 O 32 , can be either Ferrite type or Delafossite.

[0122] Metal oxides and M x X y L z Step (S200) of preparing a weapon core (120) including

[0123] A method for manufacturing a nanoparticle (100) composition according to one embodiment of the present invention includes a step (S200) of preparing an inorganic core (120) including a metal oxide and MxXyLz.

[0124] According to the present invention, the step (S200) of preparing an inorganic core (120) including a metal oxide and MxXyLz is to prepare a hydrophobic organic compound-metal complex and M x X y L z Step of mixing, heating and reacting metal oxide and M x X y L z The method may include a step of producing an inorganic core (120) including a desired size, a step of performing centrifugation to collect inorganic cores (120) of a desired size, a step of discarding pellets obtained through centrifugation to remove large-sized inorganic cores (120), a step of dispersing the desired inorganic cores (120) through ultrasonic treatment, a step of washing the dispersed inorganic cores (120) with ethanol and hexane and centrifuging to remove impurities, a step of dispersing the inorganic cores (120) in hexane, filtering through a syringe filter, and then removing the hexane through rotary evaporation, a step of measuring the weight of the dried inorganic cores (120) and adding toluene to adjust the concentration of the suspension, and a step of storing the suspension in a glass vial container covered with PTFE.

[0125] According to one embodiment of the present invention, by heating and reacting, a metal oxide and M x X y L z In the step of producing a weapon core (120) including , heating may be performed under nitrogen (N2) gas. In addition, heating may be performed under argon (Ar2) gas. In addition, heating may be performed under a gas mixed with nitrogen (N2) and argon (Ar2).

[0126] According to the present invention, M x Xy L z It can play a role in allowing the radioactive isotope (140) and the inorganic core (120) to be combined in the inorganic core (120) during the manufacturing process. In addition, M x X y L z can play a role in adjusting the size of the weapon core (120).

[0127] According to one embodiment of the present invention, M x X y L z The lattice shape of the lattice structure formed by the metal oxide included in the inorganic core (120) when added can be changed. Accordingly, the size of the inorganic core (120) can be changed. Meanwhile, M added during the manufacturing process x X y L z The size or shape of the weapon core (120) can be changed by adjusting the ratio or changing the type.

[0128] According to one embodiment of the present invention, M x X y L z When M plays a role in enabling the radioactive isotope (140) and the inorganic core (120) to be combined during the manufacturing process, x X y L z may be CuI.

[0129] According to one embodiment of the present invention, M x X y L z When M plays a role in controlling the size of the weapon core (120) during the manufacturing process, x X y L z can be CuF. The above-mentioned M x X y L z The specific materials are merely examples for illustrative purposes and are not limited thereto.

[0130] Metal oxides and M x Xy L z Step (S300) of combining a radioactive isotope (140) with a weapon core including the weapon core and coating the surface of the weapon core (120)

[0131] A method for manufacturing a nanoparticle (100) composition according to one embodiment of the present invention includes a step (S300) of combining a radioactive isotope (140) with an inorganic core (120) including a metal oxide and MxXyLz and coating the surface of the inorganic core (120).

[0132] Single-step coating method

[0133] According to one embodiment of the present invention, the step (S300) of combining a radioisotope (140) with an inorganic core (120) including a metal oxide and MxXyLz and coating the surface of the inorganic core (120) may include the steps of adding a solution containing an organic shell (160) material including at least one organic polymer or peptide, a radioisotope (140), a target ligand (180), chloroform, and ethanol to a solution containing the inorganic core (120), stirring the reaction vessel to react, and then removing the solvent using an evaporator or electromagnetic waves, adding distilled water and then using an ultrasonic generator to disperse the inorganic core (120) to which the radioisotope (140) is combined and coated with the organic shell (160) and the target ligand (180), purifying the reaction solution through centrifugation or ion exchange chromatography, and exchanging and concentrating the buffer of the purified solution. (Hereinafter, single One-step coating method)

[0134] According to one embodiment of the present invention, M represents a metal element, and may be, for example, copper (Cu). In some embodiments, X may be fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). In some embodiments, L may be an organic ligand comprising at least one member selected from the group consisting of nitrogen (N), sulfur (S), and phosphorus (P). In some embodiments, x is an integer from 1 to 6, y is an integer from 0 to 6, and z is an integer from 0 to 6. According to one embodiment, specifically, M x X y L z may be, but is not limited to, CuI.

[0135] According to one embodiment of the present invention, the radioactive isotope (140) is iodine (I)-123, iodine (I)-125, iodine (I)-131, gallium (Ga)-67, gallium (Ga)-68, copper (Cu)-64, copper (Cu)-67, gold (Au)-198, lead (Pb)-210, nickel (Ni)-63, dysprosium (Dy)-165, radium (Ra)-226, lanthanum (La)-140, rhenium (Re)-186, rhenium (Re)-188, ruthenium (Ru)-82, lutetium (Lu)-177, manganese (Mn)-54, molybdenum (Mo)-99, bismuth (Bi)-213, samarium (Sm)-153, Cesium (Ce)-137, sodium (Na)-24, scandium (Sc)-46, strontium (Sr)-82, strontium (Sr)-85, strontium (Sr)-89, strontium (Sr)-90, americium (Am)-241, zinc (Zn)-65, erbium (Er)-169, uranium (U)-234, uranium (U)-235, uranium (U)-238, silver (Ag)-110m, iridium (Ir)-192, iridium (Ir)-169, iridium (Ir)-177, yttrium (Yt)-169, yttrium (Yt)-177, indium (In)-111, germanium (Ge)-68, Iron (Fe)-55, cadmium (Cd)-109, calcium (Ca)-47, californium (Cf)-252, cobalt (Co)-57, cobalt (Co)-60, curium (Cm)-244, chromium (Cr)-51, chromium (Cr)-57, krypton (Kr)-81, krypton (Kr)-85, thallium (Tl)-201, thallium (Tl)-204, technetium (Tc)-99m, thorium (Th)-229, thorium (Th)-230, lead (Pd)-103, potassium (K)-42, polonium (Po)-210, promethium (Pm)-147, plutonium (Pu)-238, actinium (Ac)-225, radium (Ra)-223 It may include, but is not limited to, one or more radioactive isotopes (140) selected from the group consisting of:

[0136] According to one embodiment of the present invention, the organic shell (160) material may include at least one organic polymer or peptide. Meanwhile, the organic polymer may be at least one organic polymer selected from the group consisting of polyaniline, polyisobutylene, polyethylene, polystyrene, paraffin, graphene, polyvinylpyrrolidone, polyethylene glycol, gelatin, propylene glycol, poly(3,4-ethylenedioxythiophene), and poly(methyl methacrylate), but is not limited thereto.

[0137] Multi-stage coating method

[0138] In addition, according to one embodiment of the present invention, the step (S300) of combining a radioisotope (140) with an inorganic core (120) including a metal oxide and MxXyLz and coating the surface of the inorganic core (120) includes the steps of: adding a solution containing an organic shell (160) material, a radioisotope (140), chloroform, and ethanol, to a solution containing the inorganic core (120); stirring the reaction vessel to react, and then removing the solvent using an evaporator or electromagnetic waves; adding distilled water and then using an ultrasonic generator to disperse the inorganic core (120) to which the radioisotope (140) is combined and coated with the organic shell (160); separating the solution through a centrifuge, discarding the precipitate, and taking the supernatant; adding a solution containing a target ligand (180) to the reaction vessel to coat the target ligand (180) with the organic shell. It may include a step of binding to the surface of the inorganic core (120), a second purification step of purifying the reaction solution through centrifugation or ion exchange chromatography, and a step of exchanging and concentrating the buffer of the purified solution. (Hereinafter, a multi-step coating method)

[0139] Binding of organic shell and target ligand

[0140] Meanwhile, according to one embodiment of the present invention, the organic shell material may be combined with a water-soluble functionalized substance. The water-soluble functionalized substance may include a functional group that serves to introduce a target ligand (180) into the organic shell through a series of chemical reactions. Specifically, the water-soluble functionalized substance may include an amine group (-NH 2, amine group) or azide group (-N3 - , azide group) may be included, but is not limited thereto. Specifically, the organic shell (160) material may be combined with a water-soluble functionalized substance, which means that the organic shell (160) material and the water-soluble functionalized substance may be added together to the reaction solution, or the terminal of the compound included in the organic shell (160) material may include an amine group (-NH) derived from the water-soluble functionalized substance. 2, amine group) or azide group (-N3 - , azide group) may be substituted, but is not limited thereto.

[0141] According to the present invention, a solution containing a targeting ligand (180) may include a compound capable of binding the targeting ligand (180) to the surface of the entire nanoparticle (100) containing the organic shell (160) when added to an inorganic core (120) coated with the organic shell (160) by reacting with an organic shell (160) material in which a water-soluble functionalized substance is mixed. Specifically, the compound may be EDC (N-(3-Dimethylaminopropyl)-N'-ethylcarbodimide hydrochloride), Sulfo-NHS (N-Hydroxysuccinimide), targeting ligand (180)-DBCO (Dibenzocyclooctyne), targeting ligand (180)-azide group (-N3 - , azide group) complexes, but are not limited thereto.

[0142] According to one embodiment of the present invention, the water-soluble functionalized material comprises an amine group (-NH 2, In the case of a compound having an amine group, the outer terminal of the organic shell (160) surrounding the inorganic core (120) is an amine group (-NH 2, amine group). Here, when the target ligand (180) and EDC (N-(3-Dimethylaminopropyl)-N'-ethylcarbodimide hydrochloride) and Sulfo-NHS (N-Hydroxysuccinimide) are reacted together, the amine group (-NH) of the organic shell (160) is reacted through an amine-mediated EDC / NHS coupling reaction. 2, amine group) and the target ligand (180).

[0143] In addition, the water-soluble functionalized substance is an azide group (-N3 - , azide group), the outer terminal of the organic shell (160) surrounding the inorganic core (120) is an azide group (-N3 - , azide group). Here, when the target ligand (180)-DBCO (Dibenzocyclooctyne) complex is added and reacted, the azide group (-N3) of the organic shell (160) is formed through the azide-DBCO click chemistry technique. - , azide group) and a target ligand (180) can be combined.

[0144] Meanwhile, according to one embodiment of the present invention, when the water-soluble functionalized material is a compound having DBCO (Dibenzocyclooctyne), the outer terminal of the organic shell (160) surrounding the inorganic core (120) can be substituted with DBCO (Dibenzocyclooctyne). Here, the target ligand (180) - azide group (-N3 -, azide group) complex is added to react, the DBCO (Dibenzocyclooctyne) of the organic shell (160) and the target ligand (180) can be combined through the azide-DBCO click chemistry technique.

[0145] Differences between single-step and multi-step coating methods

[0146] In other words, a one-step coating method and a multi-step coating method can be distinguished depending on whether the step of coating the inorganic core (120) with a hydrophilic organic shell (160) and the step of binding a targeting ligand (180) to the end of the organic shell (160) are performed in one reaction step or are performed separately in multiple reaction steps. In the one-step coating method, a targeting ligand (180) is also added to the reaction vessel in the step of coating the inorganic core (120) with a hydrophilic organic shell (160) so as to bind the targeting ligand (180) to the end of the organic shell (160) surrounding the inorganic core (120). In contrast, the multi-step coating method involves completing the step of coating the inorganic core (120) with a hydrophilic organic shell (160), then performing a first purification step, and then adding the target ligand (180) to the reaction vessel to bind the target ligand (180) to the end of the organic shell (160) surrounding the inorganic core (120).

[0147] Figure 4 is a drawing comparing a one-step coating method and a multi-step coating method.

[0148] Advantages of multi-stage coating methods

[0149] As illustrated, the multi-step coating method can produce nanoparticles (100) having a uniform distribution between the nanoparticles (100) and the targeting ligand (180) compared to the case of using the single-step coating method. In addition, the multi-step coating method can increase the rate at which the targeting ligand (180) is activated after being bound to the surface of the inorganic core (120). In addition, the multi-step coating method can prevent the aggregation of the nanoparticles (100) by preventing the connection or binding between the targeting ligands (180) bound to the surface of the inorganic core (120).

[0150] FIG. 5a is a drawing showing a reaction of binding a target ligand (180) using Protein A to an inorganic core (120) coated with CM (Carboxymethyl)-dextran according to the present invention.

[0151] FIG. 5b is a drawing showing a reaction of binding a target ligand (180) using Protein A to an inorganic core (120) surrounded by an organic shell (160) containing Lipid-PEG according to the present invention.

[0152] According to the present invention, the step (S300) of coating the surface of the inorganic core (120) may include a step of binding a target ligand (180) to the surface of the inorganic core (120) using Protein A. In addition, the step may include coating the inorganic core (120) with CM (Carboxymethyl)-dextran and binding the target ligand (180) to the coated inorganic core (120) in either a single-step or multi-step manner.

[0153] FIG. 6 is a diagram showing a single-step reaction and a multi-step reaction of binding a target ligand (180) to a CM (Carboxymethyl)-dextran-coated inorganic core (120) according to the present invention.

[0154] Meanwhile, the step (S300) of coating the surface of the inorganic core (120) may include a step of combining a radioactive isotope (140) to the inorganic core (120) and a step of coating the surface of the inorganic core (120) including the radioactive isotope (140) with an organic shell (160). According to one embodiment of the present invention, the step of combining a radioactive isotope (140) to the inorganic core (120) and the step of coating the surface of the inorganic core (120) including the radioactive isotope (140) with an organic shell (160) may be performed independently.

[0155] The entire manufacturing process

[0156] According to one embodiment of the present invention, a method for manufacturing a nanoparticle (100) composition comprising: an inorganic core (120) including iron oxide and CuI; an organic shell (160) composed of polyethylene glycol (PEG) surrounding the inorganic core (120); folic acid (FA) attached to the end of the organic shell (160) to function as a targeting ligand (180); and Lu-177, a radioactive isotope (140) that binds to CuI in the inorganic core (120) is described.

[0157] Example of [Step of preparing a hydrophobic organic compound-metal complex (S100)]

[0158] This is the step of converting iron(III) chloride hydrate (FeCl3-xH2O) into a hydrophobic iron oleate complex. The main process is to mix iron(III) chloride hydrate (FeCl3-xH2O) with sodium oleate, ethanol, and hexane and heat to 110℃ to react.

[0159] 1) Initial synthesis: Mix sodium oleate, ethanol, nucleic acid, and iron (III) chloride hydrate (FeCl3-xH2O) and heat at 110℃ for 9 hours to react, and remove any unreacted hydrophilic substances by washing (extracting) with deionized water (DI water).

[0160] 2) Dehydration of solution: Heat at 150℃ for 12 hours to react, and remove the solvent (nucleic acid) remaining after the reaction by applying vacuum.

[0161] 3) Blending: Since the iron-oleate complex is in the form of a viscous oil, it is dissolved in an oleyl alcohol / 1-octadecene solution and blended during the mixing process to improve the accuracy and convenience of quantitative measurement and to facilitate storage.

[0162] [Example of the step (S200) of preparing an inorganic core (120) containing metal oxide and MxXyLz]

[0163] 1) Synthesis: Dopant powder CuF2 is added to the hydrophobic iron oxide-oleate synthesized above and heated under nitrogen (N2) gas to form an iron oxide inorganic core (120). CuF2 functions as a dopant, changing the lattice shape of the inorganic core (120) and controlling the size of the inorganic core.

[0164] 2) Centrifugation is performed to collect the inorganic core (120) of the desired size, the pellet is discarded to remove the inorganic core (120) of a large size, and then the desired particles are dispersed through ultrasonic treatment.

[0165] 3) Cut off: Wash the weapon core with ethanol and nucleic acid to remove impurities.

[0166] 4) Purification: Disperse the inorganic core (120) in the nucleic acid, filter it through a syringe filter, and then remove the nucleic acid through rotary evaporation.

[0167] 5) Measure the weight of the dried inorganic core (120), add toluene to adjust the suspension concentration, and then store the suspension in a glass vial container covered with PTFE.

[0168] [Example of a step (S300) of combining a radioactive isotope (140) with an inorganic core (120) including a metal oxide and MxXyLz and coating the surface of the inorganic core (120)]

[0169] 1) Coating: Add Lu-177, iodine, polyethylene glycol (PEG), folic acid (FA), etc. to the completed inorganic core (120, first mixture). Lu-177 and Cu of CuI are bonded to the inorganic core (120) through the iodine bridge, and the surface is lipid-coated with DSPE-PEG (2000). Afterwards, polyethylene glycol (PEG) is functionalized with folic acid (FA) in a microwave-assisted heating process.

[0170] 2) Cut off and purification: By removing impurities and removing products by centrifugation and syringe filter, a radiopharmaceutical utilizing nanoparticles (100) is obtained, which includes an inorganic core (120) containing iron oxide and CuI; an organic shell (160) composed of polyethylene glycol (PEG) surrounding the inorganic core (120); folic acid (FA) attached to the end of the organic shell (160) and functioning as a targeting ligand (180); and Lu-177, a radioactive isotope (140) that binds to CuI in the inorganic core (120).

[0171] Meanwhile, the specific materials, numbers, and manufacturing methods described above are merely examples described to explain the manufacturing process according to one embodiment of the present invention, and the present invention is not limited thereto.

[0172] Example of a step (S300) of coating the surface of a weapon core (120)

[0173] One embodiment of a one-step coating method

[0174] According to one embodiment of the present invention, a one-step coating method (bonding Lu-177 to an inorganic core (120) including iron oxide and CuI and coating the surface of the inorganic core (120) with polyethylene glycol (PEG) and folic acid (FA)) is described.

[0175] A solution as shown in [Table 1] below is added to a solution containing an inorganic core (120) containing iron oxide and CuI, and the reaction vessel is stirred to react, after which the solvent is removed using an evaporator or electromagnetic waves. After adding 4 ml of distilled water, an ultrasonic generator is used for 1 minute to bind Lu-177 to the CuI of the inorganic core (120) and disperse the inorganic core (120) coated with polyethylene glycol (PEG) and folic acid (FA). Afterwards, the solution is centrifuged (12,000 rpm / 30 min) using a centrifuge, and the precipitate is discarded and the supernatant is collected for primary purification. The purpose of this is to remove large particles. Then, secondary purification is performed once through an IEX column connected to FPLC equipment. The purified solution is washed three times with water for use using a purification centrifuge tube and a centrifuge, and concentrated to the final concentration based on the finished product. For example, the final concentration in the finished product may be 1 mg / ml of iron oxide nanoparticles.

[0176] After buffer exchange and concentration are completed, a radiopharmaceutical product is obtained that is bound to Lu-177 and has its surface coated with polyethylene glycol (PEG) and folic acid (FA).

[0177] [Table 1]

[0178]

[0179] Meanwhile, the specific materials, numbers, and manufacturing methods described above are merely examples described to explain the manufacturing process according to one embodiment of the present invention, and the present invention is not limited thereto.

[0180] One embodiment of a multi-step coating method

[0181] According to one embodiment of the present invention, a multi-step coating method (coating the surface of an inorganic core (120) including iron oxide and CuI with polyethylene glycol (PEG) and a targeting therapeutic agent that selectively attacks HER2 factor) is described.

[0182] First, a method for manufacturing a Lipid-PEG coated iron oxide inorganic core (120) according to one embodiment of the present invention is described. 30 mg of inorganic core dispersed in 1 ml of chloroform per inorganic core surface area (1 nm 2 ) Add DSPE-PEG2000 (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]) in a ratio of 8 and sonicate for 1 hour. After that, remove chloroform using an evaporator, add 3 ml of ethanol, and sonicate for 1 hour. After removing ethanol using an evaporator, disperse in 1 ml of water. The remaining reactant is separated using centrifugation (12,000 rpm, 1 h), and a lipid-PEG coated iron oxide inorganic core (120) is obtained.

[0183] FIG. 10 is a diagram showing a reaction of binding a targeting ligand (180) to an inorganic core (120) surrounded by an organic shell (160) including Lipid-PEG, according to some embodiments of the present invention.

[0184] Next, a method for binding a targeted therapeutic agent that selectively attacks the HER2 factor to a coated inorganic core (120) according to one embodiment of the present invention is described.

[0185] 30 mg of nanoparticles dispersed in 1 ml of chloroform per 1 nm of inorganic core (120) surface area 2) DSPE-PEG2000 (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]) and DSPE-PEG2000-amine (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000]) are added at a ratio of 1:10 and sonicated for 1 hour. After removing chloroform using an evaporator, 3 ml of ethanol is added and sonicated for 1 hour. After removing ethanol using an evaporator, it is dispersed in 1 ml of water. The remaining reactant is separated using centrifugation (12,000 rpm, 1 h), and an inorganic core (120) with an amine group introduced is obtained. Sulfo-SMCC (Thermofisher Scientific) is added to the magnetic particles with an amine group introduced. After adding, stir at room temperature for 1 hour, and add a targeted therapeutic agent that selectively attacks the HER2 factor with a thiol group introduced, and add 4 o The reaction was carried out at C for 12 hours. To purify the inorganic core (120) bound to the antibody, the antibody-inorganic core (120) complex was obtained using Fast Protein Liquid Chromatography (FPLC). The obtained antibody-inorganic core (120) complex was concentrated to the target concentration using a Stirred Cell and a 100K MWCO Amicon Centrifugal Filter, and then filtered using a filter. o Stored in C.

[0186] Another embodiment of a multi-step coating method

[0187] According to one embodiment of the present invention, a multi-step coating method (combining Lu-177 to an inorganic core (120) including iron oxide and CuI and coating the surface of the inorganic core (120) with polyethylene glycol (PEG) and folic acid (FA)) is described.

[0188] A solution such as [Table 2] is added to a solution containing an inorganic core (120) containing iron oxide and CuI, and the reaction vessel is stirred to react, after which the solvent is removed using an evaporator or electromagnetic waves. After adding 4 ml of distilled water, an ultrasonic generator is used for 1 minute to bind Lu-177 to the Cu of CuI contained in the inorganic core (120), and the inorganic core (120) coated with polyethylene glycol (PEG) or PEG-Amine is dispersed. Afterwards, the solution is separated using a centrifuge (12,000 rpm / 30 min), and the first purification is performed by discarding the precipitate and taking the supernatant. The purpose of this is to remove large particles.

[0189] [Table 2]

[0190]

[0191] Next, add the solution as shown in [Table 3] to the reaction vessel and react at room temperature for 16 hours by stirring. After the reaction is completed, the solution is centrifuged using a purification centrifuge tube and centrifuge (4000 rpm / 20 min), washed three times with distilled water, and then purified once through ion exchange chromatography connected to FPLC equipment for secondary purification. After the purification is completed, the solution is washed three times with water for use using a purification centrifuge tube and centrifuge, and concentrated to the final concentration based on the finished product.

[0192] [Table 3]

[0193]

[0194] After buffer exchange and concentration are completed, a radiopharmaceutical product is obtained that is bound to Lu-177 and has its surface coated with polyethylene glycol (PEG) and folic acid (FA).

[0195] Meanwhile, the specific materials, numbers, and manufacturing methods described above are merely examples described to explain the manufacturing process according to one embodiment of the present invention, and the present invention is not limited thereto.

[0196] Another embodiment of a multi-step coating method

[0197] According to one embodiment of the present invention, a multi-step coating method (bonding Lu-177 to an inorganic core (120) including iron oxide and CuI and coating the surface of the inorganic core (120) with polyethylene glycol (PEG) and folic acid (FA)) is described.

[0198] A solution such as [Table 4] is added to a solution containing an inorganic core (120) containing iron oxide and CuI, and the reaction vessel is stirred to react, after which the solvent is removed using an evaporator or electromagnetic waves. After adding 4 ml of distilled water, an ultrasonic generator is used for 1 minute to bind Lu-177 to the Cu of CuI contained in the inorganic core (120), and the inorganic core (120) coated with polyethylene glycol (PEG) or PEG-Amine is dispersed. Afterwards, the solution is separated using a centrifuge (12,000 rpm / 30 min), and the first purification is performed by discarding the precipitate and taking the supernatant. The purpose of this is to remove large particles.

[0199] [Table 4]

[0200]

[0201] Next, add the solution as shown in [Table 5] to the reaction vessel and react at room temperature for 16 hours by stirring. After the reaction is completed, the solution is centrifuged using a purification centrifuge tube and centrifuge (4000 rpm / 20 min), washed three times with distilled water, and then purified once through ion exchange chromatography connected to FPLC equipment for secondary purification. After the purification is completed, the solution is washed three times with water for use using a purification centrifuge tube and centrifuge, and concentrated to the final concentration based on the finished product.

[0202] [Table 5]

[0203]

[0204] After buffer exchange and concentration are completed, a radiopharmaceutical product is obtained that is bound to Lu-177 and has its surface coated with polyethylene glycol (PEG) and folic acid (FA).

[0205] Meanwhile, the specific materials, numbers, and manufacturing methods described above are merely examples described to explain the manufacturing process according to one embodiment of the present invention, and the present invention is not limited thereto.

[0206] One embodiment of a method for coating an inorganic core (120) with CM (Carboxymethyl)-dextran and binding a targeting ligand (180) to the coated inorganic core (120) in either a single-step or multi-step manner.

[0207] According to one embodiment of the present invention, a method for coating an inorganic core (120) with CM (Carboxymethyl)-dextran is described.

[0208] An inorganic core (120) containing iron oxide is dispersed in toluene using an ultrasonic bath, and a tetramethylammonium hydroxide solution (25 wt% in methanol) is mixed with the dispersed magnetic particles. The mixture is reacted in an ultrasonic bath for 1 hour, the particles are collected using a magnet, and the filtrate is discarded. The remaining particles are dispersed in distilled water. Afterwards, CM (Carboxymethyl)-dextran is dissolved in distilled water, the pretreated inorganic core is added, and the mixture is heated at 70°C for 8 hours. After the reaction is complete, the solution is transferred to a centrifuge tube, centrifuged at 12,000 rpm for 10 minutes to separate the aggregated particles, and the supernatant is collected. An excess of ethanol is added to the separated supernatant to cause precipitation, which is then separated using a magnet. This process is repeated several times to obtain coated magnetic particles.

[0209] Hereinafter, a method for binding a targeting ligand (180) to an inorganic core (120) coated with CM (Carboxymethyl)-dextran in a single step manner is described.

[0210] FIG. 6 is a diagram showing a single-step reaction and a multi-step reaction of binding a target ligand (180) to a CM (Carboxymethyl)-dextran-coated inorganic core (120) according to the present invention.

[0211] Add 25 mg of EDC (1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide), 30 mg of S-NHS (N-hydroxysulfosuccinimide), and pH 6 MES buffer to the inorganic core (5 mg / ml) coated with CM (Carboxymethyl)-dextran dispersed in distilled water and stir at room temperature for 60 minutes. In addition, add pH 7.4 PBS buffer and remove unreacted EDC and sulfo-NHS using a PD-10 desalting column. Add a targeted therapeutic agent that selectively attacks cancer cells expressing HER2 as an antigen and make the total volume 150 ml with pH 7.4 PBS buffer and 4 o The reaction was carried out at C for 12 hours. After the reaction was completed, the mixture was concentrated using a 30K stirred cell, and the antibody-inorganic core complex was obtained using Fast Protein Liquid Chromatography (FPLC) to purify the magnetic particles bound to the antibody. The obtained antibody-inorganic core complex was concentrated to the target concentration using a stirred cell and a 100K MWCO Amicon Centrifugal Filter, and then filtered using a filter and 4 o Stored in C.

[0212] Below, a method for binding a target ligand (180) to an inorganic core (120) coated with CM (Carboxymethyl)-dextran in a multi-step manner is described.

[0213] Diamino-PEG (2K, 100 mg) and 1.5 ml of distilled water are added to the inorganic core (5 mg / ml) coated with CM (Carboxymethyl)-dextran dispersed in 1 ml of distilled water and stirred for 30 minutes. 15 mg of EDC (1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide) and 20 mg of S-NHS (N-hydroxysulfosuccinimide) are added and reacted at room temperature for 12 hours. Additionally, pH 7.4 PBS buffer is added and unreacted EDC and sulfo-NHS are removed using a PD-10 desalting column to obtain an inorganic core with an amine group introduced. To prepare an antibody with a thiol group introduced, a targeted therapeutic agent that selectively attacks the HER2 factor, Traut's reagent (2-Iminothiolane, Thermofisher Scientific), is added and treated at room temperature for 1 hour. After adding Sulfo-SMCC (Thermofisher Scientific) to the inorganic core with an amine group, stirring was performed at room temperature for 1 hour, and a targeted therapeutic agent that selectively attacks the HER2 factor with a thiol group was added for 4 o The reaction was carried out for 12 hours at C. Fast Protein Liquid Chromatography (FPLC) was used to purify the inorganic core bound to the antibody, and the antibody-inorganic core complex was obtained.

[0214] The obtained antibody-inorganic core complex was concentrated to the target concentration using a Stirred Cell and a 100K MWCO Amicon Centrifugal Filter, then filtered and 4 o Stored in C.

[0215] Meanwhile, the specific materials, numbers, and manufacturing methods described above are merely examples described to explain the manufacturing process according to one embodiment of the present invention, and the present invention is not limited thereto.

[0216] One example of a step of binding a target ligand (180) to the surface of a weapon core (120) using Protein A.

[0217] FIG. 5a is a drawing showing a reaction of binding a target ligand (180) using Protein A to an inorganic core (120) coated with CM (Carboxymethyl)-dextran according to the present invention.

[0218] According to one embodiment of the present invention, a step of binding a target ligand (180) to the surface of an iron oxide inorganic core (120) coated with CM (Carboxymethyl)-dextran using Protein A is described.

[0219] Protein A (50 mg) and 1.5 ml of distilled water were added to iron oxide inorganic core (120) (5 mg / ml) coated with CM (Carboxymethyl)-dextran dispersed in 1 ml of distilled water, and stirred for 30 minutes. After adding 15 mg of EDC (1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide) and 20 mg of S-NHS (N-hydroxysulfosuccinimide), 4 o React at C for 12 hours. In addition, add pH 7.4 PBS buffer and remove unreacted EDC and sulfo-NHS using PD-10 desalting column to obtain inorganic core with Protein A attached. Add targeted therapeutic agent that selectively attacks HER2 factor, which is an antibody, to the inorganic core with Protein A attached and 4 o The reaction was carried out at C for 12 hours. The inorganic core bound to the antibody was purified using Fast Protein Liquid Chromatography (FPLC), and the antibody-inorganic core complex was obtained. The obtained antibody-inorganic core complex was concentrated to the target concentration using a stirred cell and a 100K MWCO Amicon Centrifugal Filter, and then filtered using a filter. oStored in C.

[0220] Total diameter and target ligand (180) / nanoparticle (100) ratio of nanoparticles measured using a dynamic light scattering (DLS) particle size analyzer.

[0221] The hydrate radius was measured in a single-step and multi-step coating process using a particle size analyzer in an aqueous solution. The target ligand (180) bound to the nanoparticle (100) was quantified using an ELISA kit. The results are shown in [Table 6].

[0222] In [Table 6], the dynamic light scattering particle size analyzer (DLS) size (nm, int) in the first column of the results indicates the hydrate radius of the nanoparticle (100). The target ligand (180) / nanoparticle (100) ratio (ELISA kit quantitative) in the second column of the results indicates the ratio between the coated nanoparticle (100) and the target ligand (180) that is not attached to the nanoparticle (100). A higher target ligand (180) / nanoparticle (100) ratio (ELISA kit quantitative) may mean that the amount of the target ligand added during the process of coating the nanoparticle (100) is greater.

[0223] [Table 6] shows that in the case of one-step coating, as the target ligand (180) / nanoparticle (100) ratio (quantitative ELISA kit) increases, the dynamic light scattering particle size analyzer (DLS) size (nm, int) also increases. This means that as the amount of target ligand (100) added increases, the amount of target ligand (180) attached per unit nanoparticle (100) also increases.

[0224] [Table 6] shows that in the case of multi-step coating, the dynamic light scattering particle size analyzer (DLS) size (nm, int) showed minimal change even when the target ligand (180) / nanoparticle (100) ratio (quantitative ELISA kit) increased. This means that even if the amount of target ligand (100) added increased, the amount of target ligand (180) attached per unit nanoparticle (100) did not change significantly. In other words, it was confirmed that the distribution between nanoparticles (100) and target ligands (180) was uniform.

[0225] [Table 6]

[0226]

[0227] The ratio between radioisotopes (140) in drugs and radioisotopes outside drugs according to the amount of iron oxide inorganic core (120) used during the manufacturing process.

[0228] The results of removing the radioactive isotope on the particle surface according to an appropriate ratio by adjusting the amount of iron oxide inorganic core (120) used and encapsulating the radioactive isotope inside the polyethylene glycol (PEG) coating (inside the nanoparticle (100)) are shown in [Table 7].

[0229] When the amount of radioisotope (140) used was maintained the same and the amount of iron (Fe) oxide inorganic core (120) used was varied during synthesis, it was confirmed that as the amount of iron (Fe) oxide inorganic core (120) used increased, the ratio of radioisotope within the drug increased and the ratio of radioisotope outside the drug decreased. During the manufacturing process, isotopes outside the drug were gradually removed over time.

[0230] [Table 7]

[0231]

[0232] Ratio of radioisotopes in and outside the drug according to the amount of iron oxide (Fe) inorganic core (120) used during the manufacturing process (analysis results for Fe 0.2 mg / ml)

[0233] FIG. 11a and FIG. 11b are graphs showing the distribution ratio of radioactive isotopes in nanoparticles (100) manufactured by a manufacturing method according to some embodiments of the present invention.

[0234] Prep-LC equipment was used to select nanoparticles (100) containing radioisotopes (140) and free radioisotopes, and then ICP-MS equipment was used to measure the amount of radioisotopes in drugs and radioisotopes outside of drugs using nanoparticles (100).

[0235] Specifically, FIG. 11a is a graph showing the distribution ratio of radioisotopes in nanoparticles (100) when the amount of iron oxide (Fe) inorganic core (120) used is 0.2 mg / ml of Fe in a manufacturing process according to one embodiment of the present invention. FIG. 10b is a graph showing the distribution ratio of radioisotopes in nanoparticles (100) when the amount of iron oxide (Fe) inorganic core (120) used is 30 mg / ml of Fe in a manufacturing process according to one embodiment of the present invention.

[0236] When the concentration of iron oxide (Fe) inorganic core (120) used was 0.2 mg / ml of Fe, the ratio of radioisotopes in the drug (140) (56.62%) and the ratio of radioisotopes outside the drug (45.38%) were confirmed. The results are shown in Fig. 11a. [Table 8] shows the usage of iron oxide (Fe) inorganic core (120), the ratio of radioisotopes inside the drug to the total radioisotopes, and the ratio of radioisotopes outside the drug to the total radioisotopes.

[0237] [Table 8]

[0238]

[0239] The ratio of radioisotopes in and outside the drug according to the amount of iron oxide (Fe) inorganic core (120) used during the manufacturing process (analysis results for Fe 30 mg / ml)

[0240] When the concentration of iron oxide (Fe) inorganic core (120) used was 30 mg / ml of Fe, the ratio of radioisotopes in the drug (140) (99.97%) and the ratio of radioisotopes outside the drug (0.03%) were confirmed. The results are shown in Fig. 11b. [Table 9] shows the usage of iron oxide (Fe) inorganic core (120), the ratio of radioisotopes inside the drug to the total radioisotopes, and the ratio of radioisotopes outside the drug to the total radioisotopes.

[0241] [Table 9]

[0242]

[0243] Radiochemical Purity (Radio-TLC): Comparison of the Rf patterns of radiolabeled nanoparticles (100) and free radioisotopes

[0244] Figure 12 is a graph showing the results of comparing the Rf patterns of a radioactive labeled nanoparticle (100) drug and a free radioisotope according to one embodiment of the present invention.

[0245] By comparing the radioisotope (140) bound to the inorganic core (120) containing iron oxide and the free radioisotope, the degree of binding between the inorganic core (120) and the radioisotope was confirmed. Through the graph of Fig. 12, it was confirmed that the radioisotope (140) bound to the inorganic core (120) is not separated from the inorganic core (120) and follows a different pattern (Rf value) from the free radioisotope. This confirms that the radioisotope (140) is not separated from the inorganic core (120) but is bound.

[0246] Results of measuring the overall diameter of radiopharmaceuticals using nanoparticles (100) manufactured by a manufacturing method according to some embodiments of the present invention

[0247] FIGS. 13a to 14c are drawings showing the results of measuring the sizes of radiopharmaceuticals using nanoparticles (100) manufactured by a manufacturing method according to some embodiments of the present invention using dynamic light scattering (DLS) analysis.

[0248] As described above, the method for manufacturing a radiopharmaceutical using nanoparticles (100) according to one embodiment of the present invention includes a method for manufacturing a radiopharmaceutical by controlling the overall diameter of the nanoparticles (100). Specifically, the overall diameter may be, but is not limited to, 5 nm to 100 nm.

[0249] As described above, in one embodiment of the present invention, the total diameter may be a hydrodynamic size. Meanwhile, the hydrodynamic diameter, which is an aspect of the total diameter used in this document, refers to the size of a virtual sphere that is assumed to diffuse in the same manner as the particle whose diameter is to be measured. For example, the hydrodynamic diameter, which is an aspect of the total diameter of a radiopharmaceutical utilizing a nanoparticle (100), may refer to the diameter of the particle that takes into account all of the inorganic core (120) of the nanoparticle (100), the organic shell (160) surrounding the inorganic core (120), and the targeting ligand (180) attached to the organic shell (160).

[0250] FIGS. 13a to 13c are diagrams showing the results of measuring the size of radiopharmaceuticals using nanoparticles (100) manufactured by a manufacturing method according to some embodiments of the present invention based on the number of particles using dynamic light scattering (DLS) analysis. FIG. 13a is a graph showing the distribution of nanoparticles (100) having a total diameter of standard (15 nm to 25 nm), and it was confirmed that the peak size was 15.36 nm and the Z-Average was 23.48 nm. FIG. 13b is a graph showing the distribution of nanoparticles (100) having a total diameter of standard+10 nm (25 nm to 35 nm), and it was confirmed that the peak size was 19.29 nm and the Z-Average was 30.97 nm. Figure 13c is a graph showing the distribution of nanoparticles (100) with a total diameter of standard+15 nm (30 nm to 40 nm), and it was confirmed that the peak size was 23.13 nm and the Z-Average was 35.91 nm.

[0251] FIGS. 14a to 14c are diagrams showing the results of measuring the size of radiopharmaceuticals using nanoparticles (100) manufactured by a manufacturing method according to some embodiments of the present invention based on the intensity of light scattering of the nanoparticles (100) using dynamic light scattering (DLS) analysis. FIG. 14a is a graph showing the distribution of nanoparticles (100) having a total diameter of standard (15 nm to 25 nm), and it was confirmed that the peak size was 26.49 nm and the Z-Average was 23.48 nm. FIG. 14b is a graph showing the distribution of nanoparticles (100) having a total diameter of standard+10 nm (25 nm to 35 nm), and it was confirmed that the peak size was 33.15 nm and the Z-Average was 30.97 nm. Figure 14c is a graph showing the distribution of nanoparticles (100) with a total diameter of standard+15 nm (30 nm to 40 nm), and it was confirmed that the peak size was 37.40 and the Z-Average was 35.91 nm.

[0252] FIGS. 15A to 15C are diagrams showing the results of measuring the size of radiopharmaceuticals using nanoparticles (100) manufactured by a manufacturing method according to some embodiments of the present invention based on the volume of the nanoparticles (100) using dynamic light scattering (DLS) analysis. FIG. 15A is a graph showing the distribution of nanoparticles (100) having a total diameter of standard (15 nm to 25 nm), and it was confirmed that the peak size was 19.01 nm and the Z-Average was 23.48 nm. FIG. 15B is a graph showing the distribution of nanoparticles (100) having a total diameter of standard+10 nm (25 nm to 35 nm), and it was confirmed that the peak size was 23.79 nm and the Z-Average was 30.97 nm. Figure 15c is a graph showing the distribution of nanoparticles (100) with a total diameter of standard+15 nm (30 nm to 40 nm), and it was confirmed that the peak size was 28.09 and the Z-Average was 35.91 nm.

[0253] Figure 16 is a drawing for explaining a manufacturing system for a nanoparticle composition for targeted treatment according to the present invention.

[0254] As illustrated, the manufacturing system (300) for a nanoparticle composition for targeted therapy may include a preprocessing device (310), a reaction device (320), and a postprocessing device (330). Specifically, the preprocessing device (310) may include a remote control module (311) and a dispensing module (312). For example, the dispensing module (312) may be configured to perform a function of preplanning raw materials according to a process instruction and transferring and mixing them into a designated container in an input order and amount. In addition, the dispensing module (312) may be configured to perform a function of dispensing a fluid or raw material into a specific vial using an electric pipette mounted on one end of two robotic transfer modules (not shown) that move horizontally and vertically. In addition, the dispensing module (312) may be equipped with a gripper that automatically moves the vial, may be equipped with an automatic vial capping and decapping device, and may be configured to transmit designated process data to a PC. Additionally, the dispensing module (312) may be a two-channel electric pipette and automatic transfer device, and the pipette tip may use 1 mL, 0.2 mL, the precision may be 0.001 mL, and may be configured to perform Ethernet, USB, or RS-232 communication, but is not limited thereto.

[0255] According to one embodiment of the present invention, the pretreatment device (310) of the manufacturing system (300) of the nanoparticle composition for targeted treatment may include a dispensing module (312) and a remote control module (311). For a specific example, the remote control module (311) may be configured to perform functions such as moving a reaction vessel to a dispensing device, moving raw materials and buffers to a reaction vessel holder of the reaction device (320), or moving a reaction vessel that has been cooled by a cooling module (323) to the outside of the reaction device (320), but is not limited thereto.

[0256] According to the present invention, the reaction device (320) of the manufacturing system (300) of the nanoparticle composition for targeted treatment may include a stirring module (321), a heating module (322), and a cooling module (323). For example, the stirring module (321) may be configured to perform a mixing or mechanical stirring function for the mixed solution. In addition, when the stirring module (321) performs a mechanical stirring function, the stirring module (321) may be configured to record stirring speed data in a PC, and the stirring speed may be 50 RPM or more and 400 RPM or less, and when the stirring module (321) mixes the mixed solution, it may be configured to mix for a time of 1 second or more and 20 seconds or less, but is not limited thereto.

[0257] According to the present invention, the reaction device (320) of the manufacturing system (300) of the nanoparticle composition for targeted treatment may include a stirring module (321), a heating module (322), and a cooling module (323). For example, the heating module (322) may function to heat using microwaves, and may be configured to perform a reaction status image monitoring function, a solvent temperature, pressure, and time data acquisition function inside the microwave reactor, a gas exhaust function such as gas or nitrogen gas generated when the solvent is vaporized, a radioactive material or harmful gas adsorption function, an automatic dispensing function for injecting a dispersion solvent for dispersing a reaction-completed material after the microwave reaction is completed, an ultrasonic dispersion function for automatically dispersing a reaction-completed material, a capping / decapping function for automatically opening and closing the cap of the reaction vial, a function for transferring vials into and out of a microwave chamber (not shown), and a function for controlling each component according to process conditions and sequences by installing dedicated software and recording, storing, and processing process data to transmit information to an integrated management system, but is not limited thereto.

[0258] According to the present invention, the reaction device (320) of the manufacturing system (300) of the nanoparticle composition for targeted treatment may include a stirring module (321), a heating module (322), and a cooling module (323). For a specific example, the cooling module (323) may be configured to have a condenser connected to a cooling chiller connected to a side port of the reaction vessel to cool the reaction vessel after heating is completed in the heating module (322), and the temperature of the cooling chiller may be 10°C or more and 30°C or less, and the cooling attainment temperature may be configured to be 50°C or less, but is not limited thereto.

[0259] As illustrated, the manufacturing system (300) for a nanoparticle composition for targeted therapy includes a pretreatment device (310), a reaction device (320), and a post-treatment device (330). Specifically, the post-treatment device (330) of the manufacturing system (300) for a nanoparticle composition for targeted therapy may include a centrifugation module (331), a chromatography module (332), a filtration module (333), and a binding module (334).

[0260] According to the present invention, the centrifugal separation module (331) may be configured to first purify the reaction-completed material by placing it in a centrifugal separation tube with a filter and then centrifuging it. In addition, the centrifugal separation module (331) may be configured to secondarily purify and concentrate the reaction-completed material by placing it in a centrifugal separation tube with a filter and then centrifuging it. In addition, it may have specifications of 6,000 rpm or 3,500 rcf (relative centrifugal force) or more, and may be configured to have specifications of a swing arm type rotor and arm, and a size that can be installed inside a hot cell, but is not limited thereto.

[0261] According to the present invention, the post-processing device (330) of the manufacturing system (300) of the nanoparticle composition for targeted treatment may further include a dispersion module (335) illustrated in FIG. 17A, and the dispersion module (335) may be configured to disperse for 1 minute at a frequency of 300 Hz with a Bath-type ultrasonic generator at an output of 30% to 100% before and after centrifugation in the centrifugal separation module (331). For a specific example, as illustrated in FIG. 7, a total of three purification steps may be performed in the separation step (S600) of separating the nanoparticle composition precursor from the obtained product solution, and in the first purification step (S610), after adding the reactants to the centrifugal separation bottle, the Bath-type ultrasonic generator may be dispersed for 1 minute at a frequency of 300 Hz with an output of 100%, and then centrifugation may be performed in the centrifugal separation module (331). In addition, in the second purification step (S620), a total of two centrifugations may be performed, and before the first centrifugation of the second purification step (S620), the bath-type ultrasonic generator may be configured to disperse for 2 minutes at a frequency of 300 Hz with 100% output, and after the first centrifugation of the second purification step (S620), the bath-type ultrasonic generator may be configured to disperse for 2 minutes at a frequency of 300 Hz with 100% output, and after the second centrifugation is performed and the supernatant is discarded, the bath-type ultrasonic generator may be configured to disperse for 2 minutes at a frequency of 300 Hz with 100% output, but is not limited thereto.

[0262] According to the present invention, the chromatography module (332) may be configured to inject a compound in a syringe into an FPLC injection port. In addition, a PBS (Phosphate buffer saline) buffer may be injected into the used syringe, and then PBS may be injected again into the injection port. The FPLC may be configured to operate the Method, receive the compound in a fraction, and then record the FPLC chromatogram on a PC. In addition, the chromatography module (332) may utilize a Sephacryl S-300HR 26 / 60 or equivalent column, and may be configured to function at a flow rate of 2.6 mL / min.

[0263] According to the present invention, when manufacturing a targeted therapeutic nanoparticle composition containing a radioactive isotope, the filtration module (333) may be configured to inject a reaction vessel containing a mixture into a tangential flow filtration device when separating an intermediate product using a chromatography module (332), operate the established tangential flow filtration device, and record data of the tangential flow filtration device into a PC. In addition, the filtration module (333) may be configured such that the diafiltration PBS volume is 100 times the fraction volume, and the membrane may be configured to be 10 nm or more and 100 nm or less, but is not limited thereto.

[0264] According to the present invention, when manufacturing a nanoparticle composition for targeted treatment containing a radioactive isotope, the antibody binding module (335) may be configured to operate the antibody binding module (335) by a set method by centrifuging in a centrifugation module (331), and then placing a solution containing a composite and an antibody in a centrifugation tube into a conjugation reaction vessel. For a specific example, the antibody binding module (335) according to the present invention may be configured to operate the antibody binding module (335) for a time of 30 minutes to less than 2 hours with an antibody solution such as PBS (pH 7.2 to pH 7.6) at a temperature of 4°C to 30°C, depending on the antibody, and a shaker speed of 10 rpm to 100 rpm, but is not limited thereto.

[0265] According to the present invention, when manufacturing a nanoparticle composition for targeted treatment containing a radioactive isotope, the binding module (334) may be configured to operate the binding module (334) by a set method by centrifuging in the centrifugation module (331), then placing the solution containing the composite and the antibody in the centrifugation tube into the conjugation reaction vessel. For a specific example, the binding module (334) may be configured to operate the binding module (334) for a time of 30 minutes to less than 2 hours with an antibody solution such as PBS (pH 7.2 to pH 7.6) at a temperature of 4°C to 30°C, depending on the antibody, and a shaker speed of 10 rpm to 500 rpm, but is not limited thereto.

[0266] Figure 17a is a drawing for explaining a manufacturing process of a precursor of a nanoparticle composition for targeted treatment according to the present invention.

[0267] Figure 7 is a drawing for explaining a manufacturing process of a precursor of a nanoparticle composition for targeted treatment according to the present invention.

[0268] As illustrated, a method for preparing a precursor for a nanoparticle composition for targeted therapy may include a step (S100) of preparing a reactant solution in a reaction vessel. Specifically, in the step (S100) of preparing a reactant solution in a reaction vessel, the raw materials illustrated in FIG. 17a may be prepared, and a hydrophobic or hydrophilic organic compound-metal oxide complex (410), an inorganic compound (420), and an organic solvent (430) may be prepared in the reaction vessel.

[0269] According to the present invention, the hydrophobic or hydrophilic organic compound-metal oxide complex (410) may include a hydrophobic or hydrophilic organic acid, and the metal of the hydrophobic or hydrophilic organic compound-metal oxide complex (410) is copper (Cu), tin (Sn), lead (Pb), manganese (Mn), iridium (Ir), platinum (Pt), rhodium (Rh), rhenium (Re), silver (Ag), gold (Au), palladium (Pd), osmium (Os), tantalum (Ta), ytterbium (Yb), zirconium (Zr), hafnium (Hf), terbium (Tb), thulium (Tm), cerium (Ce), dysprosium (Dy), erbium (Er), europium (Eu), holmium (Ho), iron (Fe), lanthanum (La), neodymium (Nd), praseodymium (Pr), It may be at least one metal element selected from the group consisting of lutetium (Lu), scandium (Sc), strontium (Sr), yttrium (Y), samarium (Sm), bismuth (Bi), radium (Ra), actinium (Ac), thorium (Th), cobalt (Co), arsenic (As), gallium (Ga), technetium (Tc), titanium (Ti), vanadium (V), chromium (Cr), nickel (Ni), rubidium (Rb), niobium (Nb), tungsten (W), ruthenium (Ru), molybdenum (Mo), antimony (Sb), and indium (In).

[0270] According to the present invention, the hydrophobic or hydrophilic organic compound-metal oxide complex (410) may include a hydrophobic or hydrophilic organic acid, and the metal of the hydrophobic or hydrophilic organic compound-metal oxide complex (410) may be preferably one or more metal elements selected from the group consisting of manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), yttrium (Y), lutetium (Lu), zirconium (Zr), hafnium (Hf), tin (Sn), lead (Pb), antimony (Sb), bismuth (Bi), actinium (Ac), and cerium (Ce).

[0271] According to the present invention, the hydrophobic or hydrophilic organic compound-metal oxide complex (410) may be, but is not limited to, iron oleate.

[0272] According to the present invention, in the step (S100) of preparing a reactant solution in a reaction vessel, the raw material shown in FIG. 17a can be prepared, and an inorganic compound (420) can be prepared in the reaction vessel. For specific examples, the inorganic compound (420) may be copper (Cu), tin (Sn), lead (Pb), manganese (Mn), iridium (Ir), platinum (Pt), rhodium (Rh), rhenium (Re), silver (Ag), gold (Au), palladium (Pd), osmium (Os), tantalum (Ta), ytterbium (Yb), zirconium (Zr), hafnium (Hf), terbium (Tb), thulium (Tm), cerium (Ce), dysprosium (Dy), erbium (Er), europium (Eu), holmium (Ho), iron (Fe), lanthanum (La), neodymium (Nd), praseodymium (Pr), lutetium (Lu), scandium (Sc), strontium (Sr), yttrium (Y), samarium (Sm), bismuth (Bi), radium (Ra), It may be a compound in which at least one metal element selected from the group consisting of actinium (Ac), thorium (Th), cobalt (Co), arsenic (As), gallium (Ga), technetium (Tc), titanium (Ti), vanadium (V), chromium (Cr), nickel (Ni), rubidium (Rb), niobium (Nb), tungsten (W), ruthenium (Ru), molybdenum (Mo), antimony (Sb), gadolinium (Gd), astatine (At), and indium (In) is combined with at least one element selected from the group consisting of fluorine (F), chlorine (Cl), bromine (Br), iodine (I), phosphorus (P), sulfur (S), selenium (Se), nitrogen (N), and oxygen (O). For a specific example, the inorganic compound (420) may be a dopant powder, and may be, but is not limited to, CuF2.

[0273] Figure 18 is a drawing for explaining an example in which Oleyl alcohol according to the present invention participates in a reaction.

[0274] According to the present invention, in the step (S100) of preparing a reactant solution in a reaction vessel, the raw materials illustrated in FIG. 17a may be prepared, and an organic solvent (430) may be prepared in the reaction vessel. For specific examples, a 1-octadecene solution or an oleyl alcohol solution may be used as the organic solvent (430), but as illustrated in FIG. 18, oleyl alcohol may participate in the reaction and be included in the nanoparticle composition precursor (400).

[0275] As illustrated in FIG. 17A, a method for manufacturing a precursor of a nanoparticle composition for targeted treatment may include a heating step (S200) of heating a prepared reactant solution to obtain a product solution. Specifically, the heating step (S200) of heating a prepared reactant solution to obtain a product solution may be configured to prepare a hydrophobic or hydrophilic organic compound-metal oxide complex (410), an inorganic compound (420), and an organic solvent (430) in a reaction vessel in the step (S100) of preparing a reactant solution in a reaction vessel, and then using a dispensing module (312) to add the inorganic compound (420) to the reaction vessel containing the hydrophobic or hydrophilic organic compound-metal oxide complex (410) and the organic solvent (430), measure the weight using an ultra-precision balance, record the weight in a PC, and then use a remote control module (311) to move the reaction vessel to a reaction device (320). Additionally, the reaction vessel may be configured to mix reactants through a stirring module (321) and record stirring speed data to a PC. Accordingly, the heating module (322) may be configured to heat the reaction vessel with electromagnetic waves.

[0276] According to the present invention, the heating module (322) can heat the reaction vessel using microwaves, but is not limited thereto.

[0277] According to the present invention, a method for manufacturing a precursor of a nanoparticle composition for targeted therapy may include a depressurization step (S300) of reducing the pressure inside a heated reaction vessel to a vacuum pressure. For example, the depressurization step (S300) of reducing the pressure inside the heated reaction vessel to a vacuum pressure may be configured to operate a vacuum pump connected to the reaction vessel 30 minutes after the start of heating to reduce the pressure inside the reaction vessel and record the vacuum pressure on a PC.

[0278] According to the present invention, a method for manufacturing a precursor of a nanoparticle composition for targeted therapy may include an injection step (S400) of injecting an inert gas into a depressurized reaction vessel. For example, the injection step (S400) of injecting an inert gas into the depressurized reaction vessel may be configured to open a gas line valve connected to a reaction device and inject nitrogen gas at a constant flow rate. The injection pressure at this time may be 1.5 Bar or less, but is not limited thereto.

[0279] According to the present invention, a method for manufacturing a precursor of a nanoparticle composition for targeted therapy may include a cooling step (S500) for cooling a reaction vessel. According to a large-scale temperature profile, natural cooling may be configured to occur 140 minutes after the start of heating, and according to a lab-scale temperature profile, natural cooling may be configured to occur 160 minutes after the start of heating, but is not limited thereto. The cooling temperature may be 50°C or lower, but is not limited thereto.

[0280] According to the present invention, a method for manufacturing a nanoparticle composition precursor for targeted treatment may include a separation step (S600) of separating the nanoparticle composition precursor from the obtained product solution, and the separation step (S600) of separating the nanoparticle composition precursor from the obtained product solution may include a first purification step (S610), a second purification step (S620), and a third purification step (S630).

[0281] According to the present invention, the first purification step (S610) may be configured such that a reactant is introduced into one centrifugal separation bottle of the centrifugal separation module (331) illustrated in FIG. 17a, n-Hexane is introduced into the centrifugal separation bottle containing the reactant in a volume ratio of 2:1 with respect to the amount of the reactant, and dispersion is performed in a bath-type ultrasonic generator by a dispersion module (335). Accordingly, the centrifugal separation bottle containing the reactant may be placed in the centrifugal separation module (331) to start centrifugation, and after completion of centrifugation, the supernatant may be transferred to an HDPE bottle, but is not limited thereto.

[0282] According to the present invention, the second purification step (S620) may be configured to include a process in which the reactants contained in the HDPE bottle upon completing the first purification step (S610) are dispensed into a centrifuge bottle, n-Hexane and ethyl alcohol are added to the centrifuge bottle, dispersed by a dispersion module (335), centrifuged again by a centrifuge module (331), and then the supernatant is discarded and n-Hexane is added. In addition, the second purification step may be configured to include a process in which n-Hexane is added, dispersed again by a dispersion module (335), ethyl alcohol is added to the centrifuge bottle, centrifuged again by a centrifuge module (331), then the supernatant is discarded, n-Hexane is added again, and then dispersed by a dispersion module (335).

[0283] According to the present invention, the third step of purification (S630) may be configured to attach a syringe to a syringe, take a reactant in a centrifuge bottle, remove the syringe from the syringe, attach a syringe filter, and filter and put the reactant in the syringe into a flask, but is not limited thereto. In this case, the diameter of the syringe filter may be 25 mm, and the pore size of the syringe filter may be 0.2 μm, but is not limited thereto.

[0284] According to the present invention, a method for manufacturing a nanoparticle composition precursor for targeted therapy may include an obtaining step (S700) of obtaining a nanoparticle composition precursor by evaporating a solvent. Specifically, a flask containing a reactant may be connected to an evaporation module (336), and the evaporation module (336) may be configured to operate to evaporate the solvent of the reactant. For a specific example, the evaporation module (336) may be operated at a chiller temperature of -10°C for 30 minutes, and may be configured to measure the weight of the reactant amount after complete evaporation of the solvent, but is not limited thereto.

[0285] According to the present invention, when complete evaporation of the solvent is performed in the evaporation module (336) by the method for producing a precursor of a nanoparticle composition for targeted treatment, a precursor of a nanoparticle composition for targeted treatment (400) can be produced.

[0286] FIG. 17b is a drawing illustrating a manufacturing process of a nanoparticle composition for targeted therapy containing a radioactive isotope according to the present invention.

[0287] FIG. 8 is a drawing illustrating a manufacturing process of a nanoparticle composition for targeted therapy containing a radioactive isotope according to the present invention.

[0288] As illustrated, the manufacturing process of a nanoparticle composition for targeted therapy may include a preparatory step (S101) of preparing a nanoparticle composition precursor, a first mixture containing a radioisotope, and a second mixture containing a hydrophilic-organic polymer. Specifically, a nanoparticle composition precursor (400) containing a hydrophobic or hydrophilic organic compound-metal oxide complex, a first mixture (500) containing a radioisotope, and a second mixture (600) containing a hydrophobic or hydrophilic-organic polymer may be prepared. For a specific example, the first mixture (500) containing a radioisotope may be a mixture containing a metal inorganic compound and a radioisotope inorganic compound, but is not limited thereto.

[0289] According to the present invention, the second mixture (600) containing a hydrophobic or hydrophilic organic polymer may be any one of PLGA-PEG, PLA-PEG, PCL-PEG, Methoxy Polyethylene Glycol, oly(lactic-co-glycolic acid), Polylactic Acid, Polycaprolactone, Poly(ethylene oxide), Polydioxanone (PDO), Poly(γacid), Polyhydroxybutyrate, Polyhydroxyvalerate, Hyaluronic Acid, Chitosan, Alginate, Dextran, Polyurethanes (PU), Collagen, DSPE-PEG, DSPE-PEG-FA, DSPE-PEG-DBCO, DSPE-PEG-Maleimide, DSPE-PEG-Azaide, DSPE-PEG-Aldehyde, DSPE-PEG-Amine, DSPE-PEG-thiol, DSPE-PEG-hydroxyl, DSPE-PEG-Carboxyl, but is not limited thereto.

[0290] According to the present invention, the manufacturing process of a nanoparticle composition for targeted therapy may include an obtaining step (S201) of mixing a precursor, a first mixture, and a second mixture to obtain a third mixture. Specifically, the third mixture may be obtained by mixing the precursor, the first mixture, and the second mixture by a dispensing module (312), and may be moved to a mixer module (324) by a remote control module (311), so that the reaction vessel may be mixed.

[0291] According to the present invention, the manufacturing process for a nanoparticle composition for targeted therapy may include a heating step (S301) of heating a third mixture to obtain a solution containing an intermediate product. Specifically, the heating module (322) may be configured to heat the third mixture at a temperature of 40°C or higher. Thereafter, deionized water (DIW) may be introduced into the reaction vessel, and the mixture may be dispersed using ultrasonic waves.

[0292] According to the present invention, the manufacturing process of a nanoparticle composition for targeted therapy may include a first separation step (S401) of separating an intermediate product from a solution containing the intermediate product. Specifically, after the mixture is dispersed using ultrasonic waves, it may be moved to a centrifugal separation module (331) using a remote control module (311), and after centrifugation, separation may be performed using a chromatography module (332).

[0293] According to the present invention, the chromatography module (332) may be configured to inject a compound in a syringe into an FPLC injection port. At this time, the compound may be received as a fraction through the FPLC, and the chromatography of the FPLC may be configured to be recorded on a PC.

[0294] According to the present invention, a container containing a mixture may be installed to be injected into a filtration module (333), and data of the filtration module (333) may be recorded on a PC. That is, the first separation step (S401) of separating an intermediate product from a solution containing the intermediate product may include at least one centrifugation step and a membrane filtration separation step, and the membrane filtration separation step may be configured to filter the intermediate product under membrane conditions of 1 nm or more and 100 nm or less.

[0295] According to the present invention, a sterilization module (337) can be configured to sterilize a composite, conduct a sterility test, and record a report. At this time, one of steam, dry heat, filtration, and radiation can be used as the sterilization method, and the sterility test can be comprised of a membrane filtration method or LAL test. Accordingly, a targeted therapeutic nanoparticle composition (700) containing a radioactive isotope can be manufactured.

[0296] Figure 17c is a drawing for explaining a manufacturing process of a nanoparticle composition for targeted therapy containing a radioactive isotope conjugated to an antibody according to the present invention.

[0297] FIG. 9 is a drawing illustrating a manufacturing process of a nanoparticle composition for targeted therapy containing a radioactive isotope conjugated to an antibody according to the present invention.

[0298] According to the present invention, a method for manufacturing a nanoparticle composition for targeted therapy containing a radioisotope may include a preparatory step (S102) of preparing a nanoparticle composition precursor, a first mixture containing a radioisotope, and a second mixture containing a hydrophilic-organic polymer. Specifically, a nanoparticle composition precursor (400) containing a hydrophobic or hydrophilic organic compound-metal oxide complex, a first mixture (500) containing a radioisotope, and a second mixture (600) containing a hydrophilic-organic polymer may be prepared. For a specific example, the first mixture (500) containing a radioisotope may be a mixture containing a metal inorganic compound and a radioisotope inorganic compound, but is not limited thereto.

[0299] According to the present invention, the manufacturing process of a nanoparticle composition for targeted therapy may include a obtaining step (S202) of mixing a precursor, a first mixture, and a second mixture to obtain a third mixture. Specifically, the third mixture may be obtained by mixing the precursor, the first mixture, and the second mixture by a dispensing module (312), and may be moved to a mixer module (324) by a remote control module (311), so that the reaction vessel may be mixed.

[0300] According to the present invention, the manufacturing process for a nanoparticle composition for targeted therapy may include a heating step (S302) of heating a third mixture to obtain a solution containing an intermediate product. Specifically, the heating module (322) may be configured to heat the third mixture at a temperature of 40°C or higher. Thereafter, deionized water (DIW) may be introduced into the reaction vessel, and the mixture may be dispersed using ultrasonic waves.

[0301] According to the present invention, the manufacturing process for a nanoparticle composition for targeted therapy may include a first separation step (S402) of separating an intermediate product from a solution containing the intermediate product. Specifically, after the mixture is dispersed using ultrasonic waves, it may be moved to a centrifugal separation module (331) using a remote control module (311), and after centrifugation, separation may be performed using a chromatography module (332).

[0302] According to the present invention, the chromatography module (332) may be configured to inject a compound contained in a syringe into an FPLC injection port. At this time, the FPLC may be configured to operate the method, receive the compound in a fraction, and then record the FPLC chromatography on a PC.

[0303] According to the present invention, a container containing a mixture may be installed to be injected into a filtration module (333), and data of the filtration module (333) may be recorded on a PC. That is, the first separation step (S402) of separating an intermediate product from a solution containing the intermediate product may include at least one centrifugation step and a membrane filtration separation step, and the membrane filtration separation step may be configured to filter the intermediate product under membrane conditions of 1 nm or more and 100 nm or less.

[0304] According to the present invention, the manufacturing process of a nanoparticle composition for targeted therapy may include a binding step (S502) of binding at least one substance selected from the group consisting of antibodies, antibody fragments, heptane / peptide aptamers, and receptor-binding nanomaterials to a separated intermediate product. Specifically, the binding step (S502) of binding at least one substance selected from the group consisting of antibodies, antibody fragments, heptane / peptide aptamers, and receptor-binding nanomaterials to a separated intermediate product may be configured to stir the separated intermediate product at a temperature of 0°C or higher and 100°C or lower.

[0305] According to the present invention, the manufacturing process of the nanoparticle composition for targeted treatment may include a secondary separation step (S602) of obtaining a final product by separating a solution containing an intermediate product bound in the binding step. Specifically, the secondary separation step (S602) of obtaining a final product by separating a solution containing an intermediate product bound in the binding step includes a column chromatography separation step and at least one membrane filtration separation step, and the at least one membrane filtration separation step may be configured to filter the intermediate product bound to the antibody under membrane conditions of 1 nm to 100 nm, but is not limited thereto.

[0306] According to the present invention, a sterilization module (337) can be configured to sterilize a composite, conduct a sterility test, and record a report. At this time, one of steam, dry heat, filtration, and radiation can be used as the sterilization method, and the sterility test can be comprised of a membrane filtration method or LAL test. Accordingly, a targeted therapeutic nanoparticle composition (800) containing an antibody and a radioisotope can be manufactured.

[0307] The scope of the present invention is not limited to the embodiments described above, but can be implemented in various forms within the scope of the appended claims. Any person skilled in the art, without departing from the spirit of the invention as claimed in the claims, may make various modifications to the invention, which are deemed to fall within the scope of the claims.

[0308] [Explanation of symbols]

[0309] 300: Manufacturing system for nanoparticle composition for targeted therapy

[0310] 310: Preprocessing unit

[0311] 311: Remote Control Module

[0312] 312: Busy Module

[0313] 320: Reaction device

[0314] 321: Stirring module

[0315] 322: Heating module

[0316] 323: Cooling module

[0317] 330: Post-processing device

[0318] 331: Centrifuge module

[0319] 332: Chromatography Module

[0320] 333: Filtration module

[0321] 334: Combination Module

[0322] 400: Nanoparticle composition precursor

[0323] 410: Hydrophobic or hydrophilic organic compound-metal oxide complex

[0324] 420: Inorganic compounds

[0325] 430: Inorganic solvent

[0326] 700: Nanoparticle composition for targeted therapy containing a radioactive isotope

[0327] 800: Nanoparticle composition for targeted therapy comprising an antibody and a radioactive isotope

[0328] S100: Preparatory step of preparing a reactant solution in a reaction vessel

[0329] S101: Preparatory step of preparing a nanoparticle composition precursor, a first mixture containing a radioactive isotope, and a second mixture containing a hydrophilic-organic polymer.

[0330] S102: Preparatory step of preparing a nanoparticle composition precursor, a first mixture containing a radioactive isotope, and a second mixture containing a hydrophilic-organic polymer.

[0331] S200: Heating step for heating the prepared reactant solution to obtain a product solution.

[0332] S201: Obtaining step of obtaining a third mixture by mixing a precursor, a first mixture, and a second mixture.

[0333] S202: Obtaining step of obtaining a third mixture by mixing a precursor, a first mixture, and a second mixture.

[0334] S300: Depressurization step for reducing the pressure inside the heated reaction vessel to vacuum.

[0335] S301: Heating step of heating the third mixture to obtain a solution containing an intermediate product.

[0336] S302: Heating step of heating the third mixture to obtain a solution containing an intermediate product.

[0337] S400: Injection step for injecting inert gas into a depressurized reaction vessel

[0338] S401: A first separation step for separating an intermediate product from a solution containing the intermediate product.

[0339] S402: A first separation step for separating an intermediate product from a solution containing the intermediate product.

[0340] S500: Cooling step for cooling the reaction vessel

[0341] S502: A binding step of binding one or more substances selected from the group consisting of antibodies, antibody fragments, heptan / peptide aptamers, and receptor-binding nanomaterials to the separated intermediate product.

[0342] S600: Separation step for separating the nanoparticle composition precursor from the obtained product solution.

[0343] S602: A secondary separation step for obtaining the final product by separating the solution containing the combined intermediate product in the combination step.

[0344] S610: Refining Stage 1

[0345] S620: Refining Stage 2

[0346] S630: Refining Stage 3

[0347] S700: Obtaining step of obtaining nanoparticle composition precursor by evaporating solvent

Claims

1. In a manufacturing system of a nanoparticle composition for targeted therapy containing a radioactive isotope, The above system comprises a reaction device, The above reaction device, A stirring module configured to stir a reactant solution prepared in a reaction vessel; and A heating module configured to heat the stirred reactant solution to obtain a solution containing an intermediate product; The above prepared reactant solution comprises at least one of a nanoparticle composition precursor comprising a hydrophobic or hydrophilic organic compound-metal complex, an inorganic compound and an organic solvent, a first mixture containing a radioisotope and a second mixture containing a hydrophobic or hydrophilic organic polymer. A system for manufacturing a nanoparticle composition for targeted therapy containing a radioactive isotope.

2. In paragraph 1, The above first mixture is, A mixture containing metal inorganic compounds and radioactive isotope inorganic compounds, A system for manufacturing a nanoparticle composition for targeted therapy containing a radioactive isotope.

3. In paragraph 1, The above system further comprises a post-processing device, The above post-processing device, A column chromatography module configured to separate the intermediate product from a solution containing the intermediate product to obtain a final product; a centrifugation module; and a filtration module; The above filtration module is configured to separate the intermediate product under membrane conditions of 1 nm or more and 500 nm or less to obtain the final product. A system for manufacturing a nanoparticle composition for targeted therapy containing a radioactive isotope.

4. In paragraph 3, The above post-processing device, A binding module configured to bind at least one of an antibody, an antibody fragment, a nucleic acid / peptide aptamer, and a receptor-binding nanomaterial to the separated intermediate product; A system for manufacturing a nanoparticle composition for targeted therapy containing a radioactive isotope.

5. In paragraph 4, The above binding module is configured to bind an antibody to the separated intermediate product, A system for manufacturing a nanoparticle composition for targeted therapy containing a radioactive isotope.

6. In paragraph 1, The above heating module, Configured to heat the above stirred reactant solution with electromagnetic waves at a temperature of 40°C or higher, A system for manufacturing a nanoparticle composition for targeted therapy containing a radioactive isotope.

7. Preparatory step of preparing a reactant solution in a reaction vessel; A heating step of heating the prepared reactant solution to obtain a product solution; and A separation step for separating a nanoparticle composition precursor from the obtained product solution; The above reactant solution comprises a hydrophobic or hydrophilic organic compound-metal oxide complex, an inorganic compound and an organic solvent. A method for preparing a precursor for a nanoparticle composition for targeted therapy containing a radioactive isotope.

8. In paragraph 7, The above hydrophobic or hydrophilic organic compound-metal oxide complex comprises a hydrophobic or hydrophilic organic acid, The above metals are copper (Cu), tin (Sn), lead (Pb), manganese (Mn), iridium (Ir), platinum (Pt), rhodium (Rh), rhenium (Re), silver (Ag), gold (Au), palladium (Pd), osmium (Os), tantalum (Ta), ytterbium (Yb), zirconium (Zr), hafnium (Hf), terbium (Tb), thulium (Tm), cerium (Ce), dysprosium (Dy), erbium (Er), europium (Eu), holmium (Ho), iron (Fe), lanthanum (La), neodymium (Nd), praseodymium (Pr), lutetium (Lu), scandium (Sc), strontium (Sr), yttrium (Y), samarium (Sm), bismuth (Bi), radium (Ra), actinium (Ac), thorium (Th), At least one metallic element selected from the group consisting of cobalt (Co), arsenic (As), gallium (Ga), technetium (Tc), titanium (Ti), vanadium (V), chromium (Cr), nickel (Ni), rubidium (Rb), niobium (Nb), tungsten (W), ruthenium (Ru), molybdenum (Mo), antimony (Sb), and indium (In). A method for preparing a precursor for a nanoparticle composition for targeted therapy containing a radioactive isotope.

9. In paragraph 8, The metal is preferably at least one metal element selected from the group consisting of manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), yttrium (Y), lutetium (Lu), zirconium (Zr), hafnium (Hf), tin (Sn), lead (Pb), antimony (Sb), bismuth (Bi), actinium (Ac), and cerium (Ce). A method for preparing a precursor for a nanoparticle composition for targeted therapy containing a radioactive isotope.

10. In paragraph 7, The above inorganic compounds are copper (Cu), tin (Sn), lead (Pb), manganese (Mn), iridium (Ir), platinum (Pt), rhodium (Rh), rhenium (Re), silver (Ag), gold (Au), palladium (Pd), osmium (Os), tantalum (Ta), ytterbium (Yb), zirconium (Zr), hafnium (Hf), terbium (Tb), thulium (Tm), cerium (Ce), dysprosium (Dy), erbium (Er), europium (Eu), holmium (Ho), iron (Fe), lanthanum (La), neodymium (Nd), praseodymium (Pr), lutetium (Lu), scandium (Sc), strontium (Sr), yttrium (Y), samarium (Sm), bismuth (Bi), radium (Ra), actinium (Ac), thorium (Th), At least one metal element selected from the group consisting of cobalt (Co), arsenic (As), gallium (Ga), technetium (Tc), titanium (Ti), vanadium (V), chromium (Cr), nickel (Ni), rubidium (Rb), niobium (Nb), tungsten (W), ruthenium (Ru), molybdenum (Mo), antimony (Sb), gadolinium (Gd), astatine (At), and indium (In), A compound in which at least one selected from the group consisting of fluorine (F), chlorine (Cl), bromine (Br), iodine (I), phosphorus (P), sulfur (S), selenium (Se), nitrogen (N), and oxygen (O) is combined. A method for preparing a precursor for a nanoparticle composition for targeted therapy containing a radioactive isotope.

11. In paragraph 7, The above heating step is configured to heat the reaction vessel with electromagnetic waves, The above method, A depressurization step of reducing the pressure inside the heated reaction vessel to a vacuum pressure; An injection step of injecting an inert gas into the above-depressurized reaction vessel; and further comprising a cooling step for cooling the reaction vessel; A method for preparing a precursor for a nanoparticle composition for targeted therapy containing a radioactive isotope.

12. In paragraph 11, The above heating step is, The above reaction vessel is configured to be heated with the electromagnetic wave at a temperature of 40°C or higher, A method for preparing a precursor for a nanoparticle composition for targeted therapy containing a radioactive isotope.

13. A preparatory step of preparing a nanoparticle composition precursor comprising a hydrophobic or hydrophilic organic compound-metal oxide complex, a first mixture containing a radioisotope, and a second mixture containing a hydrophilic-organic polymer; An obtaining step of obtaining a third mixture by mixing the precursor, the first mixture, and the second mixture; A heating step of heating the third mixture to obtain a solution containing an intermediate product; and A first separation step for separating the intermediate product from the solution; A method for preparing a nanoparticle composition for targeted therapy containing a radioactive isotope.

14. In paragraph 13, The first mixture is a mixture containing a metal inorganic compound and a radioactive isotope inorganic compound. A method for preparing a nanoparticle composition for targeted therapy containing a radioactive isotope.

15. In paragraph 13, The above heating step is configured to heat the third mixture at a temperature of 40°C or higher using electromagnetic waves. A method for preparing a nanoparticle composition for targeted therapy containing a radioactive isotope.

16. In paragraph 13, The above first separation step includes at least one centrifugation step and a membrane filtration separation step, The above membrane filtration separation step is configured to filter the intermediate product under membrane conditions of 1 nm or more and 100 nm or less. A method for preparing a nanoparticle composition for targeted therapy containing a radioactive isotope.

17. A preparatory step of preparing a nanoparticle composition precursor comprising a hydrophobic or hydrophilic organic compound-metal oxide complex, a first mixture containing a radioisotope, and a second mixture containing a hydrophilic-organic polymer; An obtaining step of obtaining a third mixture by mixing the precursor, the first mixture, and the second mixture; A heating step of heating the third mixture to obtain a solution containing an intermediate product; and A first separation step of separating the intermediate product from the solution; A binding step of binding at least one substance selected from the group consisting of antibodies, antibody fragments, hexane / peptide aptamers, and receptor-binding nanomaterials to the separated intermediate product; and A second separation step of obtaining a final product by separating a solution containing an intermediate product bound to at least one substance selected from the group consisting of the antibody, antibody fragment, hexane / peptide aptamer, and receptor-binding nanomaterial; A method for preparing a nanoparticle composition for targeted therapy containing a radioactive isotope.

18. In paragraph 17, The substance that binds to the separated intermediate product in the above binding step is composed of an antibody. A method for preparing a nanoparticle composition for targeted therapy containing a radioactive isotope.

19. In paragraph 17, The above combining step is configured to stir the separated intermediate product at a temperature of 0℃ or more and 100℃ or less. A method for preparing a nanoparticle composition for targeted therapy containing a radioactive isotope.

20. In paragraph 17, The above secondary separation step comprises a column chromatography separation step and at least one membrane filtration separation step, The at least one membrane filtration separation step is configured to filter the antibody-bound intermediate product under membrane conditions of 1 nm to 500 nm. A method for preparing a nanoparticle composition for targeted therapy containing a radioactive isotope.

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