Iron oxide magnetic particles comprising at least one radioisotope

Abstract

The present invention relates to iron oxide magnetic particles comprising iron oxide and M1M2X, wherein: M1 and M2 are different from each other; M1 and M2 each independently comprise at least one selected from the group consisting of 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), 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), indium (In), and lutetium (Lu); and X comprises at least one selected from the group consisting of fluorine (F), chlorine (Cl), bromine (Br), iodine (I), astatine (At), phosphorus (P), sulfur (S), selenium (Se), nitrogen (N), oxygen (O), and tennessine (Ts).

Description

Iron oxide magnetic particles containing one or more radioactive isotopes

[0001] The present invention relates to iron oxide magnetic particles comprising one or more radioactive isotopes.

[0002] The use of radioisotopes to treat diseases such as cancer began in the early 20th century. Various methods, including whole-body radioisotope therapy using radiopharmaceuticals, sealed-source radiotherapy, and brachytherapy, are being used clinically to localize radiation to the tumor site. Furthermore, recent research is also underway on various drug delivery systems capable of delivering radioisotopes to the tumor site, including EDTA-like ligands.

[0003] Magnetic particles have been widely used in biomedical applications, including cell labeling, magnetic resonance imaging (MRI), drug delivery, and hyperthermia. Among various types of magnetic particles, superparamagnetic iron oxide-based nanoparticles have been extensively studied in biomedicine due to their high magnetic susceptibility and superparamagnetism.

[0004] The short half-lives of existing radioactive diagnostic / therapeutic agents make long-term storage and long-distance distribution difficult. Therefore, most medical institutions produce and use locally available doses of these agents daily. However, when these radiopharmaceuticals are administered, the labeled radionuclide can dissociate, potentially causing adverse effects on normal tissues. Furthermore, existing radioactive diagnostic / therapeutic agents can only contain a single radioisotope.

[0005] [Prior Art Literature]

[0006] Non-patent literature: Wust et al. Lancet Oncology, 2002, 3:487-497.

[0007] The problem to be solved by the present invention is to provide iron oxide magnetic particles containing one or more radioactive isotopes.

[0008] In order to solve the above problem, the present invention is an iron oxide magnetic particle including iron oxide and M1M2X, wherein M1 and M2 are different from each other, and M1 and M2 are each independently selected from the group consisting of 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), An iron oxide comprising at least one selected from the group consisting of 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), gadolinium (Gd), astatine (At), indium (In), and lutetium (Lu), wherein X comprises at least one selected from the group consisting of fluorine (F), chlorine (Cl), bromine (Br), iodine (I), astatine (At), phosphorus (P), sulfur (S), selenium (Se), nitrogen (N), oxygen (O), and tennessine (Ts). Provides magnetic particles.

[0009] The iron oxide magnetic particles according to the present invention can be manufactured into uniform particles having a size of tens of nanometers or less without forming clusters because aggregation does not occur easily between the iron oxide magnetic particles.

[0010] The above iron oxide magnetic particles exhibit stable magnetic properties without structural change and are extremely low in toxicity, making them harmless to the human body. Therefore, they can be used as drug delivery vehicles for delivering radioisotopes. Furthermore, the above iron oxide magnetic particles can be widely used as therapeutic agents in biomedicine fields such as radiation-based therapy.

[0011] Furthermore, since the iron oxide magnetic particles have high structural stability due to the bonding force between iron oxide and M1M2X, there is no concern about side effects that may occur due to each component of the iron oxide magnetic particles, and since they have low toxicity, they can be safely applied to the human body.

[0012] FIG. 1a and FIG. 1b illustrate heating temperature profiles of an iron precursor mixture and a radioactive isotope according to one embodiment of the present invention.

[0013] FIGS. 2A to 2E are XPS analysis results of radioisotope-containing iron oxide magnetic particles coated with hydrophilic ligands according to one embodiment of the present invention.

[0014] FIGS. 3A and 3B are TEM analysis results of radioisotope-containing iron oxide magnetic particles coated with hydrophilic ligands according to one embodiment of the present invention.

[0015] FIG. 4 is a CS-TEM analysis result of a radioisotope-containing iron oxide magnetic particle coated with a hydrophilic ligand according to one embodiment of the present invention.

[0016] FIG. 5 is a Cryo-TEM analysis result of iron oxide magnetic particles containing a radioisotope and an antibody coated with a hydrophilic ligand according to one embodiment of the present invention.

[0017] Hereinafter, various embodiments of the present invention are described. It should be understood that the present invention is not limited to specific embodiments, but rather encompasses various modifications, equivalents, and / or alternatives of the embodiments of the present invention. In connection with the description of the drawings, similar reference numerals may be used for similar components.

[0018] In this document, the expressions “has”, “may have”, “includes”, or “may include” indicate the presence of a feature (e.g., a number, function, operation, or component such as a part), but do not exclude the presence of additional features.

[0019] In this document, the expressions "A or B," "at least one of A and / or B," or "one or more of A and / or B" can include all possible combinations of the listed items. For example, "A or B," "at least one of A and B," or "at least one of A or B" can all refer to cases where (1) at least one A is included, (2) at least one B is included, or (3) at least one A and at least one B are included.

[0020] The expression "configured to" as used herein can be used interchangeably with, for example, "suitable for", "having the capacity to", "designed to", "adapted to", "made to", or "capable of". The term "configured to" does not necessarily mean "specifically designed to".

[0021] The terms used in this document are used only to describe specific embodiments and may not be intended to limit the scope of other embodiments. The singular expression may include the plural expression unless the context clearly indicates otherwise. Terms used herein, including technical or scientific terms, may have the same meaning as commonly understood by those of ordinary skill in the art described in this document. Terms defined in general dictionaries among the terms used in this document may be interpreted as having the same or similar meaning in the context of the relevant technology, and shall not be interpreted in an idealized or overly formal sense unless explicitly defined in this document. In some cases, even if a term is defined in this document, it cannot be interpreted to exclude the embodiments of this document.

[0022] The embodiments disclosed in this document are presented for the purpose of explaining and understanding the disclosed technical content and are not intended to limit the scope of the present invention. Therefore, the scope of this document should be interpreted to include all modifications or various other embodiments based on the technical concept of the present invention.

[0023] Hereinafter, preferred embodiments of the present invention will be described in detail. Prior to this, it should be noted that the terms and words used in this specification and claims should not be construed as limited to their conventional or dictionary meanings. Based on the principle that the inventor can appropriately define the concept of a term to best explain his or her invention, they should be interpreted in a way that aligns with the technical spirit of the present invention.

[0024] Accordingly, the configurations of the embodiments described in this specification are only some of the most preferred embodiments of the present invention and do not represent all of the technical ideas of the present invention, so it should be understood that there may be various equivalents and modified examples that can replace them at the time of filing this application.

[0025] Throughout the specification, whenever a part is said to "include" a component, this does not mean that it excludes other components, but rather that it may include other components, unless otherwise stated.

[0026] Hereinafter, the present invention will be described in detail.

[0027] According to one embodiment of the present invention, the iron oxide magnetic particle is an iron oxide magnetic particle including iron oxide and M1M2X, wherein M1 and M2 are different from each other, and the M1 and M2 are each independently selected from the group consisting of 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), It includes at least one selected from the group consisting of 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), gadolinium (Gd), astatine (At), indium (In), and lutetium (Lu), and the X may include at least one selected from the group consisting of fluorine (F), chlorine (Cl), bromine (Br), iodine (I), astatine (At), phosphorus (P), sulfur (S), selenium (Se), nitrogen (N), oxygen (O), and tennessine (Ts).

[0028] The term "iron oxide" refers to oxides of iron, for example, Fe 13 O19 , 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 and may include, but is not limited to, one or more selected from the group consisting of Delafossite.

[0029] The above M1M2X may include at least one selected from the group consisting of CuLuF, CuLuF2, CuLuF3, CuLuCl, CuLuCl2, CuLuCl3, CuLuBr, CuLuBr2, CuLuBr3, CuLuI, CuLuI2, CuLuI3, CuAcF, CuAcF2, CuAcF3, CuAcCl, CuAcCl2, CuAcCl3CuAcBr, CuAcBr2, CuAcBr3, CuAcI, CuAcI2, CuAcI3, CuLuAcF, CuLuAcF2, CuLuAcF3, CuLuAcCl, CuLuAcCl2, CuLuAcCl3, CuLuAcBr, CuLuAcBr2, CuLuAcBr3, CuLuAcI, CuLuAcI2, CuLuAcI3. Preferably, M1M2X may include at least one selected from the group consisting of CuLuF, CuLuCl, CuLuBr, CuLuI, CuAcF, CuAcCl, CuAcBr, CuAcI, CuLuAcF, CuLuAcCl, CuLuAcBr and CuLuAcI.

[0030] The above M1, M2, and X may each independently comprise a radioactive isotope of M1 and M2 or a mixture of radioactive isotopes of X. The term "radioisotope" refers to all compounds in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

[0031] The above M1, M2, and At least one of X may contain a radioactive isotope. The above M1, M2, and X is each independently 123 I, 125 I, 131 I, 67 Ga, 68 Ga, 64 Cu, 67 Cu, 198 Au, 210 Pb, 63 Ni, 165 Dy, 226 Ra, 140 La, 186 Re, 188 Re, 82 Ru, 177 Lu, 54 Mn, 99 Mo, 213 Bi, 153 Sm, 137 Ce, 24 Na, 46 Sc, 82 Sr, 85 Sr, 89 Sr, 90 Sr, 241 Am, 65 Zn, 169 Er, 234 U, 235 U, 238 U, 110 Ag, 192 Ir, 169 Ir, 177 Ir, 169 Yt, 177 Yt, 111 In, 68 Ge,55 Fe, 109 CD, 47 Ca, 252 Cf, 57 Co, 60 Co, 244 Cm, 51 Cr, 57 Cr, 81 Kr, 85 Kr, 201 Tl, 204 Tl, 99 Tc, 229 Th, 230 Th, 103 Pd, 42 K, 210 Po, 147 Pm, 238 Pu, 225 Ac, 223 Ra and 177 It may include one or more selected from the group consisting of Lu.

[0032] According to one embodiment of the present invention, the radioactive isotope included in the nanoparticles may be included in the nanoparticles in an amount having a radiation dose of 1 to 1000 mCi. Here, the Ci value in radiation means Curie. Curie is a unit of radioactivity, indicating the rate at which a radioactive material decays, and 1 Curie (Ci) is 3.7 × 10^ per second. 10 It refers to the amount of radioactivity at which the decay of a molecule occurs. The value of the radiation dose (Ci) emitted from the nanoparticles of the present invention may increase in proportion to the mole number (mole) of the above-described radioactive isotope contained in the nanoparticles.

[0033] According to the present invention, the meaning that M1M2X is included in the iron oxide particles is that between the iron oxide particles and M1M2X It may be that a physical or chemical bond is formed. Specifically, it may be that M1M2X is arranged between iron oxide particles, or that iron oxide and M1M2X are bonded through hydrogen bonds, or that the M1M2X is formed by introducing a general coating method to the surface of the iron oxide core, or by introducing a doping method such as a diffusion process or an ion implantation process, or that iron oxide crystal nuclei are formed inside the M1M2X so that a shell structure can be formed. In addition, in some cases, one selected from the group consisting of M1, M2, and X with iron oxide as the center is the primary It may be that one selected from the group consisting of M1, M2 and X forms a secondary shell structure, and one selected from the group consisting of M1, M2 and X forms a tertiary shell structure in steps.

[0034] According to the present invention, particles containing M1M2X in iron oxide particles have magnetism and can amplify the contrast effect of iron oxide under conditions of a relatively low alternating magnetic field strength and / or a low frequency magnetic field or various radiation conditions.

[0035] The iron oxide magnetic particles of the present invention have very stable bonds between the iron oxide particles and the heavy atom-halogen compound and between the heavy atom and the halogen, so there is almost no concern about side effects that each of the constituent components, i.e., iron oxide, heavy atom, and halogen element, may cause to the human body.

[0036] The iron oxide magnetic particles may have at least a portion of their surface coated with a hydrophilic or charged ligand or polymer. The hydrophilic ligand may be introduced to increase the water solubility and enhance the stabilization of the iron oxide magnetic particles according to one embodiment, or to enhance targeting or penetration into specific cells such as cancer cells. The iron oxide magnetic particles having at least a portion of their surface coated with a hydrophilic ligand may have a size of 4.0 to 5.5 nm. Referring to FIGS. 3A, 3B, and 4, TEM analysis results of the iron oxide magnetic particles containing radioisotopes coated with hydrophilic ligands show that the iron oxide magnetic particles may have a size of 4.0 to 5.5 nm.

[0037] The hydrophilic ligand may preferably have biocompatibility and may include, but is not limited to, one or more selected from the group consisting of polyethylene glycol, polyethyleneamine, polyethyleneimine, polyacrylic acid, polymaleic anhydride, polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl amine, polyacrylamide, polyethylene glycol, phosphate-polyethylene glycol, polybutylene terephthalate, polylactic acid, polytrimethylene carbonate, polydioxanone, polypropylene oxide, polyhydroxyethyl methacrylate, starch, dextran derivatives, sulfonic acid amino acids, sulfonic acid peptides, silica, and polypeptides. If necessary, when targeting cancer cells, a peptide or protein including folic acid, transferrin or RGD may be used as the hydrophilic ligand, and hyaluronidase or collagenase may be used to enhance penetration into cells, but is not limited thereto.

[0038] The iron oxide included in the iron oxide magnetic particles of the present invention may be derived from a complex of iron and one or more compounds selected from the group consisting of fatty acid salts and alcohol compounds having 4 to 25 carbon atoms.

[0039] Examples of the fatty acid salt having 4 to 25 carbon atoms include at least one selected from the group consisting 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, melissate, and peptide salts containing one or more amino acids. These compounds may be used alone or in the form of a mixed salt of two or more.

[0040] The metal component of the fatty acid salt having 4 to 25 carbon atoms may include at least one selected from the group consisting of calcium, sodium, potassium, and magnesium.

[0041] Examples of the above alcohol compounds include 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 include at least one selected from the group consisting 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).

[0042] The above iron oxide magnetic particles may further comprise at least one selected from the group consisting of antibodies, antibody fragments, aptamers, and receptor-binding nanomolecules. When the iron oxide magnetic particles, wherein at least a portion of the surface of the iron oxide magnetic particles is coated with a hydrophilic ligand, further comprise an antibody or antibody fragment, the antibody or antibody fragment may have a size of 2.5 nm (see FIG. 4).

[0043] The content of M1M2X in the iron oxide magnetic particles can be calculated during the manufacturing process of the iron oxide magnetic particles according to one embodiment of the present invention. After iron forms a complex with at least one compound selected from the group consisting of fatty acid salts and alcohol compounds having 4 to 25 carbon atoms, the complex goes through a series of processes to form iron oxide, and when M1M2X is combined with the formed iron oxide, the content of M1M2X added can be based on 100 mol% of the total complex.

[0044] The weight ratio of iron oxide and AxByXz of the above iron oxide magnetic particles may be 1:0.001 to 0.01 (the above ratio is specified based on the results of ICP (Inductively coupled plasma) Mass Spectroscopy, which is a metal content analysis device).

[0045] Additionally, the weight ratio of M1M2 and X in the above M1M2X may be 1: 0.001 to 0.5.

[0046] The above iron oxide magnetic particles may have an average particle diameter (d50) of 1 nm to 5 nm. When the size of the iron oxide magnetic particles has an average particle diameter (d50) of 1 nm to 5 nm, they can be used as a component of contrast agents, anticancer agents, and radiotherapy agents, and when the size of the iron oxide magnetic particles exceeds 10 nm, they can be applied to various in vitro medical fields.

[0047] In one specific example, the average particle diameter (d50) of the iron oxide magnetic nanoparticles can be adjusted depending on the administration method, administration location, and the organ to be diagnosed. If the average particle diameter (d50) is 15 nm or less, intravenous injection is preferred, and if the average particle diameter (d50) exceeds 15 nm, intralesional or intratumoral injection may be preferred.

[0048] Furthermore, because it has high structural stability due to the bond formed between iron oxide and heavy atom-halogen compounds, there is no concern about side effects that may occur due to each component, and it has low toxicity, so it can be safely applied to the human body.

[0049] The iron oxide magnetic particles according to one embodiment of the present invention can be used for cancer treatment. The cancer may be any one selected from the group consisting of breast cancer, colon cancer, kidney cancer, lung cancer, skin cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, stomach cancer, thyroid cancer, and uterine cancer, but is not limited thereto.

[0050] The iron oxide magnetic particles according to one embodiment of the present invention may be used as a drug delivery vehicle or for use in radiation therapy for killing cancer cells. The cancer cells may be any one selected from the group consisting of breast cancer cells, colon cancer cells, kidney cancer cells, lung cancer cells, skin cancer cells, ovarian cancer cells, pancreatic cancer cells, prostate cancer cells, rectal cancer cells, stomach cancer cells, thyroid cancer cells, and uterine cancer cells, but are not limited thereto.

[0051] According to one embodiment of the present invention, the iron oxide magnetic particles may be included in a composition for bioimaging. The iron oxide magnetic particles according to the present invention have magnetic properties and thus may be usefully used in diagnostic methods utilizing magnetic properties.

[0052] According to another embodiment of the present invention, a method for manufacturing iron oxide magnetic particles is provided.

[0053] According to another embodiment of the present invention, there is provided an iron oxide magnetic particle comprising iron oxide and M1X, wherein M1 and X are different from each other, and M1 is selected from the group consisting of 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), The present invention provides iron oxide magnetic particles, which include at least one selected from the group consisting of 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), gadolinium (Gd), astatine (At), indium (In), and lutetium (Lu), wherein X includes at least one selected from the group consisting of fluorine (F), chlorine (Cl), bromine (Br), iodine (I), astatine (At), phosphorus (P), sulfur (S), selenium (Se), nitrogen (N), oxygen (O), and tennessine (Ts).

[0054]

[0055] Hereinafter, the present invention will be described in detail using examples to aid understanding. However, the examples according to the present invention may be modified in various ways, and the scope of the present invention should not be construed as being limited to the following examples. The examples of the present invention are provided to more fully explain the present invention to those of average skill in the art.

[0056]

[0057] Examples and Comparative Examples

[0058] Example 1

[0059] Synthesis of iron precursor (S1)

[0060] FeCl3·6H2O 0.95 g (3.5 mmol), sodium oleate 3.01 g (9.9 mmol), hexane 12.2 L, ethanol 6.6 L, and deionized water 4.95 L were placed in a 50 L reactor, and a chiller set to 15°C for mixing was connected to the condenser-reactor, and the mixture was stirred and reacted at 150 RPM for 8 hours at 60°C to prepare a reaction solution.

[0061] The transparent lower layer of the reaction solution was removed using a separatory funnel, 10 L of deionized water was added to the brown upper organic layer, and the mixture was stirred at 150 RPM for 10 minutes. The removal of the lower water layer was repeated three times. The remaining brown organic layer was transferred to a beaker and heated at 110°C for 3 hours to evaporate the hexane, thereby synthesizing the iron precursor.

[0062] Preparation of iron precursor mixture (S2)

[0063] 2.93 kg (3.2 mol) of the iron precursor prepared above, 9.6 kg (25.0 mol) of oleyl alcohol, and 5.53 kg (19.7 mol) of 1-octadecene were placed in a 50 L reaction vessel and stirred at 150 RPM. When the temperature of the reactants reached 100°C, a vacuum pump was operated, and when it reached 140°C, it was heated for 3 hours to prepare an iron precursor mixture.

[0064] Synthesis of iron oxide particles containing CuF2 (S3)

[0065] 520 g of the iron precursor mixture prepared above and 0.52 g (5.1 mmol) of CuF2 were placed in a 1 L reaction vessel and heated according to the temperature profile while stirring at 800 RPM (see Figs. 1a and 1b). Upon completion of the reaction, the mixture was washed with hexane and ethanol in a volume ratio of 1:2 and centrifuged to precipitate the particles. The hexane and ethanol were removed, and the obtained precipitate particles were dispersed in toluene. Iron oxide particles containing CuF2 were obtained.

[0066] Iron oxide particles containing CuF2 and radioisotope mixture and coating with hydrophilic ligand (S4)

[0067] 4 mg of iron oxide particles containing CuF2 obtained above were dispersed in 80 uL of toluene and Na 125 I 250mCi and 177 Lu 250 mCi was dispersed in 50 uL of toluene, and 40 mg of hydrophilic ligand (DSPE-PEG2000) was dispersed in 72.4 uL of ethanol, placed in a 20 ml reaction vessel, and heated with electromagnetic waves (Microwave 2.4 GHz 1000 W, 40°C or higher) for 1 minute. 800 uL of distilled water was added to the reactant heated with electromagnetic waves, centrifuged at 10,000 RPM or higher for 1 hour, the supernatant was collected, the reactant was concentrated to 60 mg / mL, filtered through a 0.2 μm filter, and a dispersion of iron oxide magnetic particles containing radioactive isotopes coated with hydrophilic ligands was collected.

[0068] Example 2

[0069] Na in step S4 of the above Example 1 125 Department I 177 In the process of dispersing Lu in 50uL of toluene, 177 On behalf of Lu 255 The same procedure as Example 1 was followed except that Ac was dispersed.

[0070] Example 3

[0071] Na in step S4 of the above Example 1 125 Department I177 In the process of dispersing Lu in 50uL of toluene, 255 The same procedure as Example 1 was followed, except that 250 mCi of Ac was additionally dispersed in 50 uL of toluene.

[0072] Example 4

[0073] 10 mg of antibody dispersed in PBS was mixed per 1 mg of Fe mass of the dispersion of radioactive isotopes of iron oxide magnetic particles coated with hydrophilic ligands of Example 1 above, and the mixture was stirred for 1 hour at 50 RPM or higher to react. The mixture was purified using an SEC column at a flow rate of 2.6 mL / min with PBS buffer, and the mixture was converted into an injection solution using a tangential flow filtration device.

[0074] Example 5

[0075] 10 mg of antibody dispersed in PBS was mixed per 1 mg of Fe mass of the dispersion of radioactive isotopes of iron oxide magnetic particles coated with hydrophilic ligands of Example 2 above, and the mixture was stirred for 1 hour at 50 RPM or higher to react. The mixture was purified using an SEC column at a flow rate of 2.6 mL / min with PBS buffer, and the mixture was converted into an injection solution using a tangential flow filtration device.

[0076] Example 6

[0077] 10 mg of antibody dispersed in PBS was mixed per 1 mg of Fe mass of the dispersion of radioactive isotopes of iron oxide magnetic particles coated with hydrophilic ligands of Example 3 above, and the mixture was stirred for 1 hour at 50 RPM or higher to react. The mixture was purified using an SEC column at a flow rate of 2.6 mL / min with PBS buffer, and the mixture was converted into an injection solution using a tangential flow filtration device.

[0078] Experimental example

[0079] Experimental Example 1: Microwave Stability Analysis of Iron Oxide Magnetic Particles

[0080] The particles of the above examples were irradiated for 15 minutes each at 2,400-2,500 MHz and 1,000 W using a microwave device manufactured by CEM, USA. After microwave irradiation, the content of halogen elements was measured using a prodigy High Dispersion ICP measuring device equipped with a halogen option from Teledyne Leeman Labs, to confirm whether the particles had disintegrated. The results are shown in Table 1.

[0081] Measured halogen elements (ppm) Example 118 Example 214 Example 315 Example 417 Example 516 Example 615.5

[0082] Experimental Example 2: Measurement of radiochemical purity

[0083] After the nanoparticles of the above example were administered to BALC / c mice, the radiochemical purity of urine samples collected over 48 hours was measured using the equipment below.

[0084] Equipment: Radio-HPLC-SEC

[0085] Radio-HPLC Detector: LABLOGIC's FLOW-RAM

[0086] HPLC: AGILENT 1260

[0087] COLUMN: SEPHACRYL S-300

[0088] The results are shown in Table 2. Table 2 shows the purity calculated as % after 7 days based on 100% mCi measured before injection.

[0089] Before injection (%) 7 days later (%) Example 1 10098.3 Example 2 10098.9 Example 3 10099.2 Example 4 10098.6 Example 5 10099.2 Example 6 10099.5

[0090] Experimental Example 3: Thermogravimetric (TGA) analysis of iron oxide magnetic particles

[0091] In order to investigate the thermal stability of the iron oxide magnetic particles of the present invention (purpose: to confirm how stably halogen and metal elements are combined in the iron oxide magnetic particles), thermogravometric analysis (TGA) was performed using Scinco's S-1000. Specifically, the particles of the examples and the control group were compared by measuring TGA up to 200°C at a rate of 20 / min under nitrogen. The results are shown in Table 3. In Examples 1 to 3, the analysis was conducted only on the nanoparticles excluding the hydrophilic ligand.

[0092] Weight loss ratio (%) Example 17.0 Example 26.8 Example 35.7 Control group 1 (iron oxide-KI wt% doping) 14 Control group 2 (iron oxide-MgI 26 wt% doping) 13

Claims

1. Iron oxide and M 1 M 2 As an iron oxide magnetic particle containing X, Above M 1 And M 2 are different from each other, Above M 1 And M 2 are each independently 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), Containing at least one 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), indium (In), and lutetium (Lu), The iron oxide magnetic particle wherein the above X contains at least one selected from the group consisting of fluorine (F), chlorine (Cl), bromine (Br), iodine (I), astatine (At), phosphorus (P), sulfur (S), selenium (Se), nitrogen (N), oxygen (O), and tenesine (Ts).

2. In claim 1, Above M 1 , M 2 , and Iron oxide magnetic particles containing at least one radioactive isotope of X.

3. In claim 1, Above M 1 M 2 X is CuLuF, CuLuF 2 , CuLuF 3 , CuLuCl, CuLuCl 2 , CuLuCl 3 , CuLuBr, CuLuBr 2 , CuLuBr 3 , CuLuI, CuLuI 2 , CuLuI 3 , CuAcF, CuAcF 2 , CuAcF 3 , CuAcCl, CuAcCl 2 , CuAcCl 3 CuAcBr, CuAcBr 2 , CuAcBr 3 , CuAcI, CuAcI 2 , CuAcI 3 , CuLuAcF, CuLuAcF 2 , CuLuAcF 3 , CuLuAcCl, CuLuAcCl 2 , CuLuAcCl 3 , CuLuAcBr, CuLuAcBr 2 , CuLuAcBr 3 , CuLuAcI, CuLuAcI 2 and CuLuAcI 3 Iron oxide magnetic particles comprising at least one selected from the group consisting of:

4. In claim 1, An iron oxide magnetic particle, wherein at least a portion of the surface of the iron oxide magnetic particle is coated with a hydrophilic ligand.

5. In claim 1, The above nanoparticles are iron oxide magnetic particles having a radiation dose of 1 to 1000 mCi emitted by the one or more radioactive isotopes.

6. In claim 1, The above iron oxide is Fe 13 O 19 , Fe 3 O 4 (magnetite), γ-Fe 2 O 3 (maghemite) and α-Fe 2 O 3 (hematite), β-Fe 2 O 3 (beta phase), ε-Fe 2 O 3 (epsilon phase), FeO (Wustite), FeO 2 (Iron Dioxide), Fe 4 O 5 , Fe 5 O 6 , Fe 5 O 7 , and Fe 25 O 32 Iron oxide magnetic particles comprising at least one selected from the group consisting of:

7. In claim 4, An iron oxide magnetic particle wherein the hydrophilic ligand comprises at least one selected from the group consisting of polyethylene glycol, polyethylene amine, polyethylene imine, polyacrylic acid, polymaleic anhydride, polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl amine, polyacrylamide, polyethylene glycol, phosphoric acid-polyethylene glycol, polybutylene terephthalate, polylactic acid, polytrimethylene carbonate, polydioxanone, polypropylene oxide, polyhydroxyethyl methacrylate, starch, dextran derivatives, sulfonic acid amino acids, sulfonic acid peptides, silica, and polypeptides.

8. In claim 4, An iron oxide magnetic particle, wherein the iron oxide magnetic particle further comprises at least one selected from the group consisting of antibodies, antibody fragments, aptamers, and receptor-binding nanomolecules.

9. Iron oxide and M 1 As an iron oxide magnetic particle containing X, Above M 1 and X are different from each other, Above M 1 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), Containing at least one 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), indium (In), and lutetium (Lu), The iron oxide magnetic particle wherein the above X contains at least one selected from the group consisting of fluorine (F), chlorine (Cl), bromine (Br), iodine (I), astatine (At), phosphorus (P), sulfur (S), selenium (Se), nitrogen (N), oxygen (O), and tenesine (Ts).

10. In claim 1, The above iron oxide magnetic particles are iron oxide magnetic particles used for cancer treatment.

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