WO2014054884A1 - Composition for hyperthermia comprising sensitization material - Google Patents

Abstract

The present invention relates to an in vivo heat-dissipating composition comprising a sensitization material selected from the group consisting of (i) magnetic nanoparticles and (ii) chemodrugs, biodrugs and radioisotope; and to a composition for hyperthermia, comprising the vivo heat-dissipating composition as an active ingredient. The compositions of the present invention may have heat-dissipating effects caused by both external stimuli and magnetic nanoparticles, and therefore, may exhibit superior synergistic effects in the apoptosis of target cells, in particular cancer cells. In particular, if the compositions of the present invention are made into a composite of 'magnetic nanoparticle-sensitization material', both a thermal effect by a single stimulus which is a high frequency magnetic field and a sensitization effect by a sensitization material are achieved at the same time. Thus, the compositions of the present invention can be used as effective compositions for treatment.

Description

 【Specification】

 [Name of invention]

 Silver heat treatment composition comprising a sensitizer

[Technical field]

 The present invention relates to a composition for thermotherapy having improved sensitivity to silver heat of a target cell by including magnetic nanoparticles and a sensitizing material.

[Background technology]

 Nanomaterials exhibit new physical and chemical properties different from bulk materials due to their reduced size. In addition, many researches on nanomaterials have made it possible to control not only the size but also the composition and shape of the material, allowing the physical and chemical properties of the nanoscale to be controlled as in the bulk domain. Taking advantage of these new properties, nanomaterials are now expanding their applicability to catalysts for chemical reactions, the creation of next-generation nanodevices, new energy developments, and cancer diagnostics and treatments due to the combination of medical and life sciences (Nano Madison). In addition, it is widely used in various fields.

Among them, magnetic nanomaterials generate heat due to the following three phenomena when high frequency magnetic field is applied to them due to their unique magnetic properties. First, Brownian relaxation due to the electrolysis of the nanomaterial itself dispersed in the liquid. Second, Neil relaxation due to the energy barrier of the spin inside the nanomaterial. Third, toward the external high frequency magnetic field. In the process of magnetization, heat is generated due to the hysteresis phenomenon caused by the movement of the spin domains in the material (/. Mater. Che. 2004, 14, 2161-2175.). By using the generated heat, magnetic nanomaterials can be used in various heat generating devices or technologies. In particular, in the medical field, heat generated by applying high frequency to magnetic nanomaterials is used for treating hyperthermia including cancer. Hyperthermia is the use of heat in the treatment of diseases, including cancer, by taking advantage of the phenomenon that cancer cells begin to die above 42 ° C. Since high frequency magnetic field is not affected by skin tissue and there is no limit of penetration depth, nanoparticles can be selectively heated when they accumulate in cancer tissues in the body. Have been received. In principle, cancer cells may be selectively killed at a temperature of about 43 ^° C. Therefore, the use of these self-thermotherapy techniques has been limited due to their low therapeutic efficiency. Accordingly, the present inventors attempted to use a sensitization strategy to dramatically increase the cancer treatment effect by the self-heat treatment technology. The sensitization strategy is to apply additional external stimuli to cancer cells and cancer tissues, making them more susceptible to thermal therapy with magnetic particles. External stimulants can use a variety of cytotoxic agents, including chemodrugs, biodrugs, and radioisotopes. Through this sensitization strategy, the sensitivity of cancer cells to heat is greatly increased, and thus the death of cancer cells is dramatically increased even by a small number of nanoparticles and a short time of high frequency magnetic field loading. Patent documents are referenced and their citations are indicated. The disclosures of cited papers and patent documents are incorporated herein by reference in their entirety, and the level of the technical field to which the present invention belongs and the contents of the present invention are more clearly explained.

[Detailed Description of the Invention]

 [Technical problem]

The present inventors earnestly researched to improve the sensitivity of the heat treatment of the cells forming the lesion tissue to increase the efficiency of the heat treatment technology using magnetic nanomaterials under high frequency magnetic field. As a result, the use of additional external stimuli to sensitizers, ie lesion cells and lesion tissue, The present invention has been completed by discovering that stress or restraining the mechanism of resistance to heat makes it more susceptible to thermal therapy using magnetic particles, thereby achieving synergistic apoptosis.

 It is therefore an object of the present invention to provide a composition for heat release in vivo.

 Another object of the present invention to provide a composition for hyperthermia therapy.

 Another object of the present invention is to provide a method of hyperthermia therapy. Other objects and advantages of the present invention will become apparent from the following detailed description, claims and drawings.

Technical Solution

 According to one aspect of the present invention, the present invention provides a composition for in vivo heat release comprising:

 (a) magnetic nanoparticles;

(b) at least one sensitization substance selected from the group consisting of chemodrugs, biodrugs and radioisotopes. The present inventors earnestly researched to improve the sensitivity of the heat treatment of the cells forming the lesion tissue to increase the efficiency of the thermotherapy technology using magnetic nanomaterials under high frequency magnetic field. As a result, sensitizers, ie, lesion cells and tissues, are subjected to additional external stimuli or to suppress heat resistance mechanisms, making them more susceptible to thermal therapy using magnetic particles, resulting in synergistic apoptosis effects. It was found that it can be harvested. As used herein, the term "composition for heat release" refers to itself or to external stimuli. Means a material that radiates heat to the outside. Thus, "composition for heat release in vivo" means a substance that increases the temperature in vivo by releasing heat in vivo. The heat dissipating composition of the present invention can be used to artificially raise the natural temperature in vivo for various purposes. For example, the composition for heat release of the present invention may be used for the purpose of inducing death of target cells, in which case the composition of the present invention may be defined as "composition for inducing cell death". As used herein, the term "sensitization material" means a material that allows lesion cells and lesion tissues to react more sensitively to thermal stress caused by magnetic nanoparticles, thereby leading to more efficient cell death. In other words, the sensitizer is a substance that causes a stress caused by an additional external stimulus or suppresses a mechanism of resistance to heat, and thus exhibits a synergistic effect with magnetic nanoparticles in apoptosis. As used herein, the term “chemodrugs” refers to compounds administered to treat disease such as cancer by ultimately killing lesion cells such as cancer cells or inhibiting the mechanism of resistance to heat exerted for the death of the cells. it means. Chemotherapeutic agents that can be used in the present invention are cisplatin, carboplatin, procarbazine, mechlorethamine, cyclophosphamide, and phosphamide (ifosfamide), melphalan, chlorambucil, bisulfan, nitrosourea

(nitrosourea), diactinomycin, daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, mitomycin, etoposide, table wood Tamoxifen, taxol, transplatinum, 5-fluorouracil, vincristin, vinblastin, methotrexate, active oxygen Reactive oxygen species (R0S), reactive oxygen species (R0S generator), reactive oxygen species inducing substances and HSP inhibitors. Including but not limited to. According to a specific embodiment of the present invention, the chemotherapeutic agent of the present invention is selected from the group consisting of reactive oxygen species, reactive oxygen species generating substance, reactive oxygen species generating substance and heat shock protein inhibitor (Hsp inhibitor).

As used herein, the term "reactive oxygen species" (R0S) refers to molecules that contain oxygen and have chemically high activity with unpaired valence shell electrons. Active oxygen species are produced as a by-product of the normal metabolism of oxygen, but due to environmental stress such as ultraviolet rays or thermal stratification, active oxygen species can be greatly increased in vivo, thereby causing significant damage to cell structure. . According to a specific embodiment of the present invention, the active oxygen species used in the present invention is hydrogen peroxide (), superoxide anion (0 ² —), hydroxyl radical (OH ·), lipid peroxide (lipid peroxide) ), Peroxitrite (N0 ₃ ^{2 "} ), thiol peroxy radical (R-S0 ^2_ ), the term" ROS generator "(ROS generator) ) "Refers to a compound that generates free radicals in vivo by a radical initiation reaction using free radicals. The free radical species generating material which can be used in the present invention may be various halogen molecules, azo ( azo) compounds and organic peroxides, including but not limited to all compounds capable of chemically generating free radicals in vivo using free radicals According to a specific embodiment of the present invention, the active oxygen species generating material azo compound used in the present invention, and more specifically 4,4 '-azobis (4-cyano valeric acid) (4, 4'- Azobis (4-cyanovaleric acid), hereinafter referred to as 4,4'-azobis).

Most specifically, 4,4'-azobis may be conjugated to the magnetic nanoparticles and used as a single composition. When 4,4'-azobis is used conjugated to magnetic nanoparticles, solving the technical problem of "induction of heat generation in vivo" and "killing the target cells" through it Magnetic nanoparticles and sensitizers are not administered in parallel, but rather are administered as a complex of magnetic nanoparticles-sensitizers. In addition, the active oxygen species generating material, including 4,4 'ᅳ azobis, is initiated free radical generation when a high frequency magnetic field is applied, resulting in an increase in the generation efficiency of active oxygen species in vivo. Therefore, the composite of the nanoparticle-sensitizing material of the present invention can exert a dual apoptosis effect of increasing heat release and reactive oxygen species generation by nanoparticles by applying a high frequency magnetic field with a single stimulus. As used herein, the term "active oxygen species generation inducer" means a substance that induces active oxygen species generation using intracellular metabolism. The reactive oxygen species generating inducer, unlike the active oxygen species generating material, which directly initiates the generation of reactive oxygen species by using free radicals of its own, acts on enzymes involved in the redox metabolism of cells to generate reactive oxygen species. Promote indirectly. The reactive oxygen species generating inducers that can be used in the present invention include 3,7-diaminophenothiazinium redox dye, 2- (phenyltelluryl) -3-methyl- [1,4] naphthoquinone, tria Various redox chemodrugs, including but not limited to Triapine, Varacin, Reinamycin, and β-phenylethylisothiocyinate, can be used by intracellular metabolism Any substance that can promote the production of free radicals can be used. According to a specific embodiment of the present invention, the reactive oxygen species generation inducing substance used in the present invention is anthamycin A (Antimycin A). Antamicin A promotes the production of free radical superoxide by binding to the Qi site of cytochrome C reductase and inhibiting the oxidation of ubiquinol in the oxidative phosphorylation of the electron transfer chain process.

As used herein, the term "heat shock protein (Hsp)" refers to a protein that is commonly synthesized by all living organisms as a protein induced by the thermal stratification. The present inventors have shown that the cells treated with heat treatment show resistance to this, and thus the treatment efficiency is greatly reduced. In light of this, in order to eliminate this resistance, the production and activity of heat-stratum protein, which is one of its resistance mechanisms, was inhibited. As a result, it was confirmed that lesion cells and lesion tissues could be more easily affected by thermal treatment using magnetic particles.

 Representative thermal stratified proteins have molecular weights of 90,000, 70,000 and

There are 60,000 Hsp90, Hsp70 and Hsp60. Heat shock proteins act as protective cells and bind to heat-damaged proteins to promote their regeneration. Therefore, cells overproducing heat shock protein by heat treatment are resistant to high temperatures.

 As used herein, the term "Hsp inhibitor" refers to a compound that inhibits the production and activity of Hsp. Hsps capable of inhibiting production and activity with the compositions of the present invention include all of Hsp90, Hsp70 and Hsp60. According to a specific embodiment of the present invention, the thermal shock protein inhibitor of the present invention is geldanamycin (쒜 (3113 ^ (: ^), 17AAGC17-N-A1 lylamino-17- demethoxyge 1 danamyc in) 17-DMAG (17-di me t hy 1 am i no-ge 1 danamyc in), Pitithrin (-(2-¾6 16 ^^ 1 1131 6) 1 (-437 (3-[(£;)-1,3- Benzod i oxo 1 -5-y 1 me t hy 1 ene] -2-oxopyrrol idine-l-carbaldehyde), schisandrin (schandrin) -B, quercetin (2- (3, 4-di hydr oxypheny 1)-3, 5, 7-tri hydroxy-4H-chr omen-4-one and ETB (Epolactaene Tertiary Butyl Ester) Most specifically, the heat stratified protein inhibitor of the present invention is geldanamycin to be.

 According to a specific embodiment of the present invention, the thermal stratified protein inhibitor of the present invention is conjugated to the magnetic nanoparticles with a heat sensitive linker. More specifically, the heat sensitive linker is 4, 4'-azobis (4-cyanovaleric acid) (4,4'-Azob i s (-cy anova 1 er i c acid)).

When a thermal stratified protein inhibitor is used conjugated to a nanoparticle, magnetic nanoparticles and a thermal shock protein inhibitor are combined in order to solve the technical problem of the present invention, "induction of heat generation in vivo," and "killing target cells." It is not administered, but in a form administered as a complex of magnetic nanoparticle-thermal shock protein. In addition, the heat-sensitive linker It decomposes only when a high frequency magnetic field is applied so that its action can be initiated at a desired time. Therefore, the nanoparticle-thermal shock protein inhibitor complex of the present invention may be an example of a complex of nanoparticle-sensitive materials, and may exert a dual cell death effect of inhibiting heat release and heat resistance by nanoparticles by applying a high frequency magnetic field. Can be. As shown in the following examples, the composition for heat release in vivo of the present invention consisting of magnetic nanoparticles and thermal shock protein inhibitors is compared to the case where only the thermal stratified protein inhibitor is treated to the cells or only the magnetic nanoparticles are treated to the cells. By showing a dramatically increased cancer cell killing effect, it was confirmed that it can be used as a very effective heat treatment composition.

 As used herein, the term "biodrug" includes cytotoxic proteins, oligonucleotides, hormones and antibodies that inhibit the proliferation or survival of lesion cells, including cancer cells; It is not limited to this. More specifically, the biopharmaceutical of the present invention is an antibody.

 As used herein, the term "antibody" refers to a therapeutic antibody that specifically binds to proteins involved in the proliferation or survival of lesion cells, including cancer cells, thereby inhibiting their activity or leading to death. Antibodies that can be used in the present invention include, but are not limited to, anti-VEGF antibodies, anti-CD20 antibodies, anti-Erb2 antibodies, anti-EGF antibodies, anti-CD52 antibodies, and anti-CD33 antibodies.

As used herein, the term "radioisotope" refers to an element that emits alpha particles, beta particles, or gamma rays in the process of being decomposed into stable elements among other isotopes. More specifically, the radioisotope mentioned in the present specification means a therapeutic radioisotope for killing lesion cells including cancer cells. Rapidly dividing cells are particularly susceptible to radiation damage, and radiation is widely used to treat cancer. Radioisotopes that may be used in the present invention include, but are not limited to, ⁶⁰ Co, ¹³¹ I, ¹⁹² Ir, ⁸⁹ Sr, ¹⁵³ Sm, ¹⁸⁶ Re and ¹⁰ B.

According to a specific embodiment of the present invention, the magnetic nanoparticles of the present invention are represented by the following general formula (1). Formula 1

ΜχΜΊ- _χ Ρθ2θ ₄ (Μ = Ba, Zn, Mn, Fe, Co, and Ni with one or more metals selected from the group consisting of 0 <x <5, M '= Ba, Zn, Mn, Fe, Co, and Ni One or more metals selected from the group consisting of). More specifically, at least one metal selected from the group consisting of M = Zn, Mn and Co of the general formula 1, 0≤x≤3, M '= at least one metal selected from the group consisting of Mn and Fe to be.

 Most specifically, M = Zn of the general formula 1, 0 <χ≤1, Μ '= Fe. Magnetic nanoparticles of the present invention are specifically 1-500 nm, more specifically 10-200 nm, even more specifically 10-100 nm, even more specifically 10-50 nm, most specifically 10- It has a size of 20 nm.

 In the magnetic nanoparticles of the present invention, a nanomaterial precursor containing a magnetic metal precursor is added to an organic solvent to prepare a mixed solution.

(ii) heating the mixed solution to a high temperature (eg, 150-500 ° C.) to pyrolyze the precursor material to form a magnetic metal oxide nanomaterial and

(iii) may be prepared by the step of separating the nanomaterial. The nanomaterial precursors are metal nitrate compounds, metal sulfate-based compounds, metal acetylacetonate-based compounds, metal fluoroacetoacetate-based compounds, metal halide-based compounds, metal perchlorate-based compounds, metal An alkyl oxide-based compound, a metal walpamate-based compound, a metal styreate-based compound, or an organometallic-based compound may be used, but is not limited thereto. In addition, the magnetic nanomaterial synthesized by the above-described manufacturing method may be used in an aqueous solution by phase transition using a water-soluble polyfunctional ligand.

In the present specification, the 'water-soluble polyfunctional ligand' is a ligand that binds to the nanoparticles for the solubilization and stabilization of the nanoparticles, and enables binding with biological / chemically active substances, especially the active oxygen species generating material of the present invention. to be. A water soluble polyfunctional ligand comprises (a) an attachment region (1, adhesive region), (b) an active ingredient binding region (L _n , reactive region), (c) a cross linking region (L _m , cross linking region), Or an active ingredient binding region-cross linking region (L _n -L _m ) that includes the active ingredient binding region (L _n ) and the crosslinking region (L _m ) at the same time. The water-soluble multifunctional ligand is described in more detail below.

The “attachment region ()” is a part of a multifunctional ligand including a functional group capable of attaching to the nanomaterial, and specifically means a terminal of the multifunctional ligand. Therefore, the attachment region preferably includes a functional group having high affinity with the material forming the nanomaterial. In this case, the bond between the nanomaterial and the attachment region may be attached by an ionic bond, a covalent bond, a hydrogen bond, a hydrophobic bond, or a metal-ligand coordination bond. Accordingly, the attachment region of the multifunctional ligand may be variously selected depending on the material of the nanomaterial. For example, the attachment region using a silver bond, a covalent bond, a hydrogen bond, or a metal-ligand coordination bond is -COOH, -NH ₂₎ -SH, -C0NH _2> -P0 ₃ H, -0P0 ₄ H ₂ , -S0 ₃ H, -0S0 ₃ H, -N ₃ , -NR3OH (R = C _n H _{2n +} i, 0 <n <16), -OH, -SS-, -N0 _2> -CH0, -COX (X = F, It may include CI, Br, I), -C00C0-, -C0NH-, or -CN, the attachment region using a hydrophobic bond may include a hydrocarbon chain consisting of two or more carbon atoms, but is not limited thereto.

The “active ingredient binding region (L ′)” is a part of a multifunctional ligand including a functional group capable of binding to a chemical or biofunctional material, and specifically means a terminal opposite to the attachment region. The functional group of the active ingredient binding region may vary depending on the type of active ingredient and its chemical formula (see Table 1). In the present invention, the active ingredient binding region is -SH, -CH0, -COOH, -NH ₂ , -OH, -PO3H, -0P0 ₄ H ₂₎ -S0 ₃ H, -OSO3H, -NR ₃ ⁺ X ^" (R = C _n H _m , 0 <n <16, 0 <m <34, X = OH, CI, Br), -N ₃ , -SCOCH3, -SCN, -NCS, -NC0, -CN, -F, -CI , -1, -Br, epoxy group, sulfonate group, nitrate group, phosphonate group, aldehyde group, hydrazone group, -OC-, or -C≡C-may be included, but is not limited thereto.

Said "cross-linking region (L _m )" is a portion of a multifunctional ligand comprising a functional group capable of crosslinking with an adjacent multifunctional ligand, specifically It means the attachment attached to the center. By "crosslinking" is meant that one polyfunctional ligand is bound by an intermolecular interacting ion with another polyfunctional ligand located in close proximity. The intermolecular attraction includes, but is not particularly limited to, hydrophobic attraction, hydrogen bonds, covalent bonds (eg, disulfide bonds), van der Waals bond ionic bonds, and the like. Therefore, crosslinkable functional groups can be selected in various ways depending on the kind of intermolecular attraction. Cross-linking regions are for example -SH, -CHO, -C00H, -NH ₂₎ -OH, -PO3H, -0P0 ₄ H ₂ , -S0 ₃ H, -OSO ₃ H, -N¾ ⁺ X ^_ (R = C _n H _m 0 <n <16, 0 <m <34, X = OH, CI, Br), N ⁺ X— (R = CJ 0 <n <16, 0 <m <34 X = OH, CI, Br), -N ₃ , -SCOCH ₃ , -SCN, -NCS, -NCO, -CN, -F, -CI, -I, -Br, epoxy group, -0N0 ₂ , -P0 (0H) ₂ , -C = NNH ₂₎ —CO, or —C≡C— may be included as a functional group, but is not limited thereto.

[Table 1]

Examples of functional groups of active ingredient binding regions that can be included in multifunctional ligands

(I: functional group of active component binding region of polyfunctional ligand, II: active component, III: binding by reaction of I and II) In the present invention, a compound originally possessing the functional group as described above can be used as a water-soluble polyfunctional ligand. Although it is also possible, a compound modified or prepared to have a functional group as described above through chemical reactions known in the art may be used as a polyfunctional ligand.

 Specific multifunctional ligands of the invention include monomolecules, polymers, carbohydrates, proteins, peptides, nucleic acids, lipids, or amphiphilic ligands.

Examples of specific multifunctional ligands in the water-soluble nanomaterial according to the present invention are monomolecules containing the aforementioned functional groups as single molecules, and specifically, dimercaptosuccinic acid. This is because dimercapto succinic acid originally contains an attachment region, a cross-linking region and an active ingredient binding region. That is, one -C00H of the dimercapto succinic acid is bound to the magnetic signaling core, and -C00H and -SH at the distal end function to bind the active ingredient. In addition, in the case of -SH can be a cross-linking region by forming a disulfide bond with other -SH around. In addition to the dimercapto succinic acid, compounds including -C00H as the functional group of the attachment region, -C00H, -NH _{2 (} or -SH as the functional group of the binding region, can all be used as specific multifunctional ligands, but are not limited thereto. no.

 Other examples of specific water-soluble polyfunctional ligands of the present invention include polyphosphazenes, polylactides, polylactide-co-glycolides, polycaprolactones, polyanhydrides, polymalic acid, derivatives of polymalic acid, polyalkyls 1 type from the group consisting of cyanoacrylate, polyhydrooxybutylate, polycarbonate polyorthoester, polyethylene glycol, poly-L-lysine, polyglycolide, pullimethyl methacrylate and polyvinylpyridone The above polymer is not limited thereto.

Another example of a specific multifunctional ligand in the magnetic nanoparticles according to the present invention is a peptide. Peptides are oligomers / polymers consisting of amino acids. Because amino acids have -C00H or -N¾ functional groups at both ends, the peptides are naturally attached and active ingredients. The coupling area is provided. In addition, in particular, peptides including one or more amino acids having at least one of -SH, -C0OH, -N¾, or -0H as a chain may be used as a specific water-soluble multifunctional ligand.

Another example of a specific multifunctional ligand in the magnetic nanoparticles according to the present invention is a protein. Proteins are polymers consisting of more amino acids than peptides, that is, hundreds to hundreds of thousands of amino acids. They contain -C00H and-^ ₂ functional groups at both ends, as well as dozens of -COOH, -N¾, -SH, -OH,- C0NH ₂ and the like. Therefore, the protein may naturally have an attachment region, a cross linking region, and an active ingredient binding region according to its structure, as in the above-described peptide, and thus may be usefully used as the phase change ligand of the present invention. Representative examples of specific proteins as phase transfer ligands include structural proteins, storage proteins, transport proteins, hormone proteins, receptor proteins, contraction proteins, defense proteins, and enzyme proteins. More specifically, albumin, antibody, antigen, avidin (avidin), cytochrome, casein, myosin glycinin, keratin, collagen, globular protein, light protein, streptavidin, protein A, protein G, protein S, immunity Globulin, lectin, selectin, angiopoietin, anticancer protein, antibiotic protein, hormonal antagonist protein, inter leukin, interferon, growth factor protein, tumor Necrosis factor protein, endotoxin protein, lymphotoxin protein, tissue plasminogen activator, urokinase, streptokinase, protease inhibitor , Alkyl phosphochol ine, surfactants, cardiovascular pharmaceuticals, nervous system drugs (neuro phar maceuticals), gastrointestinal pharmaceuticals, and the like.

Another aspect of the specific water soluble multifunctional ligand in the present invention is a nucleic acid. Nucleic acid is a ligolimer consisting of a large number of nucleotides, and since it has P0 ₄ — and -0Η functional groups at both ends, it naturally has an attachment region and an active component binding region (LrLm), or an attachment region and a cross-linking region ( L 厂 L _n ) may be usefully used as the phase change ligand of the present invention. The nucleic acid is optionally modified to have a functional group of -SH, -NH ₂₎ -C00H, -OH at the 3 'end or 5' end.

Another example of a specific multifunctional ligand in the water-soluble nanomaterial according to the present invention is an amphiphilic ligand having both a hydrophobic functional group and a hydrophilic functional group. In the case of nanomaterials synthesized in an organic solvent, a ligand composed of a hydrophobic long carbon chain exists on the surface thereof. At this time, the hydrophobic functional group present in the amphiphilic ligand added and the hydrophobic ligand on the surface of the nanomaterial are bonded by intermolecular attraction to stabilize the nanomaterial, and the hydrophilic functional group is exposed at the outermost side of the nanomaterial, resulting in producing a water-soluble nanomaterial. Can be. The intermolecular attraction includes hydrophobic bonds, hydrogen bonds, van der Waals bonds, and the like. At this time, the portion bonded by the nanomaterial and the hydrophobic attraction is an attachment region, and together with the organic component, the active component binding region (L ′) or the cross-linking region (L _m ) may be introduced. In addition, in order to increase stability in aqueous solution, a polymer multi-amphiphilic ligand having a plurality of hydrophobic functional groups and a hydrophilic functional group may be used, or the amphiphilic ligand may be cross-linked with each other using a linking molecule. As an example of a specific amphiphilic ligand as such a phase-transfer ligand, first, the hydrophobic functional group is a hydrophobic molecule composed of a chain having 2 or more carbons and has a linear or branched structure, and more specifically, ethyl, n-propyl, Alkyl functional groups such as isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, tetradecyl, nucleodecyl, aicosyl, tetracosyl, dodecyl, or cyclopentyl, cyclonuclear, and ethynyl, propenyl, Carbon-carbon double bonds such as isopropenyl, butenyl, isobutenyl, octenyl, decenyl, oleyl, or propynyl, isopropynyl, butynyl, isobutynyl, octaynyl, desinyl, etc. And a functional group having an unsaturated carbon chain having a carbon-carbon triple bond. Also included in hydrophilic functional groups are neutral at certain _P Hs, such as -SH, -C00H, -NH ₂₎ -OH, -P0 ₃ H, -OPO4H2, -S0 ₃ H, -0S0 ₃ HN ⁺ X—, etc. At high or low pH it refers to positive or negatively charged functional groups. In addition, a polymer or a block copolymer may be used as the hydrophilic group, and the unit elements used are ᅤ ethyl glycol, acrylic acid, alkyl acrylic acid, Ataconic acid, maleic acid, fumaric acid, acrylamidomethylpropanesulfonic acid, vinylsulfonic acid, vinyl phosphate, vinyllactic acid, styrenesulfonic acid, allyl ammonium, acryronitrile, N-vinylpyridone, N-vinyl Formamide, and the like, but is not limited thereto.

 Other examples of specific water soluble polyfunctional ligands in the present invention include carbohydrates. More specific examples include glucose, mannose, fucose,

N-acetylglumine, N-acetylgalactosamine, N-acetylneuraminic acid, fructose, xylose sorbitan, sucrose, maltose, glycoaldehyde, dihydroxyacetone ᅳ erythrose, erythrorose, arabinose , Gyroulows, lactose, trehalose, melaboose, cellobiose, raffinose, melizetose, maltose, starchose, strawdogs, zairan, araban, nucleic acid, frock Tan, galactan, met, agalopectin, alginic acid, tarazane, hemicellose, hypromellose, amylose, deoxy acetone, glycerinaldehyde, chitin, agarose, dextrin, ribose, riburoose , Galactose, carboxymethylcellose or glycogen dextran, carbodextran, polysaccharide, cyclodextran, pullulan, cellulose, starch, glycogen, and the like It is not. According to another aspect of the present invention, the present invention provides a composition for hyperthermia therapy comprising the composition for heat release in vivo of the present invention as an active ingredient.

As used herein, the term “thermotherapy” means exposing body tissues to a temperature slightly above normal temperature to kill lesion cells, including cancer cells, or to make them more susceptible to radiation therapy or anticancer agents. . According to the present invention, the composition of the present invention is synergistic by the effect of the thermal effect of the magnetic nanoparticles and the external stimulus using active oxygen species at the same time, even by a small number of nanoparticles and a high frequency magnetic field load for a short time has an excellent cancer cell killing effect, such effect was confirmed that all the Dex Perry commercially available nanomaterials ^"remarkably excellent.

The composition for thermal treatment of the present invention is usually a pharmaceutical composition Is provided. Therefore, the thermotherapy composition of the present invention comprises a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are conventionally used in the preparation of lactose, dextrose, sucrose, sorbet, manny, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cells. Loose, polyvinylpyridone, cellulose, water, syrup, methyl cellulose, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate, or mineral oil, and the like, but not limited thereto. . Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).

 The composition for treating heat of the present invention is preferably administered parenterally. In the case of parenteral administration, it can be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, or intralesional injection, etc. Suitable dosages of the composition of the present invention may be formulated, mode of administration, patient It may be prescribed by factors such as age, body weight, sex, morbidity, food, time of administration, route of administration, rate of excretion and reaction. The thermotherapy composition of the present invention comprises a therapeutically effective amount of the composition for heat release. The term "therapeutically effective amount" means a subdivided amount capable of treating a disease for treatment, generally 0.0001-100 mg / kg.

 The pharmaceutical compositions of the present invention may be prepared in unit dose form by formulating with a pharmaceutically acceptable carrier and / or excipient according to methods which can be easily carried out by those skilled in the art. Or may be prepared by incorporation into a multi-dose container. In this case, the formulation may be in the form of a solution, suspension, or emulsion in an oil or an aqueous medium, or may be in the form of axes, powders, granules, tablets, or capsules, and may further include a dispersing agent or a stabilizing agent.

 The composition for thermotherapy of the present invention is administered to a patient by a suitable route of administration, and then a high frequency magnetic field is added, thereby generating heat, and at the same time promoting the production of free radicals in the target cell. The high frequency magnetic field may be a high frequency magnetic field having a frequency of 100 kHz to 10 MHz.

According to a specific embodiment of the present invention, the disease treated with the composition for treating heat of the present invention is cancer. In particular, the composition for treating heat of the present invention, It is useful for treating cancers such as stomach cancer, lung cancer, breast cancer, ovarian cancer, liver cancer, bronchial cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, colon cancer, cervical cancer, brain cancer, prostate cancer, bone cancer, skin cancer, thyroid cancer, parathyroid cancer. And death of cancer cells in various cancer diseases such as ureter cancer. According to another aspect of the present invention, the present invention provides a hyperthermia therapy method and cancer treatment method comprising administering the composition for heat release in vivo of the present invention.

 In vivo heat-release compositions used in the present invention, cancers that can be treated with the compositions of the present invention and the like have been described above, so that description thereof is omitted to avoid excessive duplication.

Advantageous Effects

 The features and advantages of the present invention are summarized as follows:

 (a) The present invention provides a heat release in vivo comprising (i) magnetic nanoparticles and (ii) sensitizers selected from the group consisting of chemotherapeutic agents, biodrugs and radioisotopes. Composition; And it provides a heat treatment composition comprising the in vivo heat release composition as an active ingredient.

 (b) The composition of the present invention shows an excellent synergistic effect on the killing of target cells, in particular cancer cells, due to the simultaneous application of heat release by external stimulation and magnetic nanoparticles.

 (c) In particular, when the composition of the present invention is composed of a composite of 'magnetic nanoparticle-sensitive material', the thermal effect and the sensitizing effect of the sensitizing material are simultaneously achieved by a single stimulus of high frequency magnetic field, which is useful for an effective therapeutic composition. Can be.

[Brief Description of Drawings]

1 is an exemplary magnetic nanoparticle used in the present invention. (ZnO.4Fe2.604) is a diagram showing the results of observation using a transmission electron microscope. 2 and 3 are graphs showing the results of measuring the increase in temperature under an alternating high frequency magnetic field after preparing the magnetic nanoparticles of the present invention and ferridex, which are conventionally commercialized nanoparticles, at the same concentration, respectively (FIG. 2) and This is a graph showing the heat release coefficient value calculated through the rate of change of the initial temperature of the analyte (Fig. 3). FIG. 4 is a graph showing that the silver content of the cell culture was maintained at 43 ± 1 ° C. while controlling the silver change while the external magnetic field was applied to the nanoparticles while observing the optical fiber thermometer. 5 is a 2 ', 7' - dichloro fluorescein diacetate (DCFA, Molecular Probes) is 2 ^{', Ί'} - dichloro-fluorescein (DCF) fluorescence microscope (FV1000 confocal microscope, Olympus) to oxidize observed Shows the result of confirming the generation of reactive oxygen species. Figure 6 is a graph showing the cell death rate by the external magnetic field when treated only nanoparticles of the present invention. FIG. 7 shows the case where no treatment (left bar), active oxygen species (¾0 ₂ ) and nanoparticles were treated and no magnetic field was applied (middle bar), and reactive oxygen species and nanoparticles were treated and magnetic fields were applied ( Graph showing each cell death rate in the right bar). Figure 8 shows no oxygen treatment (left bar), active oxygen species product (4, 4'-azobis) and nanoparticles treated without magnetic field (middle bar) and active oxygen species product and nano This is a graph showing the cell death rate of each of the particles treated with the magnetic field (right bar). 9 shows the treatment of reactive oxygen species generating inducer (antamycin A) and the treatment of nanoparticles without any magnetic field (center bar) and the treatment of active oxygen species generating inducer and nanoparticles It is a graph showing the rate of cell death for each of the treated and magnetic field (right bar). 10 is data showing that apoptosis of sensitization strategy via reactive oxygen species is effectively applied to phosphorus ^^. FIG. 11 is a graph showing that the heat sensitive linker is decomposed when the exemplary magnetic nanoparticle-thermolayer protein inhibitor complex used in the present invention is subjected to a magnetic field, and the thermal layer protein inhibitor is effectively discharged. 12 is a graph showing that the temperature of the cell culture was maintained ^at 43 ^° C. 1 ^° C. by controlling the temperature change while observing the temperature change with an optical fiber thermometer while applying an external magnetic field to the nanoparticles. FIG. 13 is a graph showing the cell death rate by an external magnetic field when treated with only the nanoparticles of the present invention (black) and a graph when the nanoparticle-thermolayer protein inhibitor complex was treated and applied with a magnetic field (red). 14 is a diagram showing the results of Western blotting showing the effective inhibition of the production of Hsp90, a type of thermal stratified protein. 15 is a diagram showing that the apoptosis of the sensitization strategy through thermal stratified protein inhibition is effectively applied in.

[Form for implementation of invention]

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention in more detail, It will be apparent to those skilled in the art that the scope of the invention is not limited by these examples in accordance with the spirit of the invention. EXAMPLES Example 1 Synthesis of Spherical Ferrite Nanoparticles Containing Zinc Consisting of Composition of Zn _x Mi- _x Fe ₂ 04 (M = Fe, x = 0.4)

As an example of the heat-emitting nanoparticles described herein, the spherical ferrite nanoparticle heat-releasing agent containing zinc having a composition of the formula Zn ^ Fes i (M = Fe, x = 0.4) was synthesized by the following method. In a benzyl ether solution containing oleic acid (Sigma, 1.068 g), Zn (acac) ₃ (Sigma, 0.276 g) and Fe (acac) ₃ (Sigma, 0.247 g) were reacted at room temperature for 1 hour, followed by argon (Ar ) ZrixM ^ Fes i (M = Fe, x = 0.4) nanoparticles with 15 nm core size were synthesized by pyrolysis ^at 290 ^° C. for 30 minutes. The spherical ferrite nanoparticles containing zinc were precipitated with excess ethane and separated, and then the nanoparticles were redispersed again with leuene to form a colloidal solution. Thereafter, the nanoparticles dispersed in toluene at 20 mg / ml were precipitated with excess ethane, and the reaction mixture was reacted for 2 hours with a butanol solution containing an excess of tetramethylammonium hydroxide, followed by centrifugation of the nanoparticles. It was separated and dispersed in water. The nanoparticles synthesized in this way have a uniform sized sphere shape and were analyzed by transmission electron microscope (FIG. 1). Example 2 Comparison of the Heat Dissipation Coefficients of Ferriteex and Materials Consisting of Zno.4Fe2.eO4

15 nm sized spherical ferrite nanoparticles containing zinc were synthesized and prepared in the same concentration with ferdex, a spherical iron oxide nanomaterial that has been commercially available, and then used in an alternating electromagnetic field generator (HF 10K, Taeyang System Co., Korea) was used to measure the amount of heat emitted from magnetic nanoparticles under high frequency magnetic field. All other experimental conditions were equally matched to observe the difference in heat release between the two materials. The specific experimental method is as follows. Prepare an analytical sample dispersed in water at 2 mg / ml concentration The glass vials were placed in the center of a 500 kHz coil and an alternating current was flowed into the coil to generate an induction magnetic field of 30.0 kA / m intensity. At this time, nanoparticles were quantified by ICP-AES analysis for accurate concentration calculation of analytical samples, and the space between vials and coils containing analytical samples was insulated with styrofoam for accurate temperature measurement. The change in temperature of the sample with the time of applying the high frequency magnetic field was observed in real time using an optical fiber calibrator (M602, Lumasense technologies, Inc. USA). As shown in FIG. 2, it was confirmed that the temperature of the analytical sample increased with increasing time of applying the high frequency magnetic field. Zn ₀ . ₄ Fe ₂ . _In the case of ₆ 0 ₄ , the rapid temperature change immediately after applying the magnetic field was also confirmed. By calculating the rate of change of the initial temperature of the analytical sample from the temperature change graph and substituting it into the equation, the heat release coefficient can be calculated. The measured values are shown in FIG. 3. In fact, it was confirmed that the spherical ferrite nanoparticles of 15 nm size containing zinc increased about 400% of the heat release effect than ferdex, which is a commercially available spherical iron oxide nanoparticle (FIG. 3). Example 3: Confirmation of reactive oxygen species generation

To confirm the development of reactive oxygen species, 2 ', 7'-dichlorofluorescein diacetate (DCFA, Molecular Probes) was oxidized to 2 ^' , Τ-dichlorofluorescein (DCF) in the presence of intracellular reactive oxygen species. Was observed. The specific experimental method is as follows. The MDA-MB-231 breast cancer cell group was treated with 4,10'-azobis (cyanovaleric acid) (Sigma, 10 mM) to 4 × 10 ⁵ cells per well using a 35 mm ³ dish and incubated for 24 hours. Phosphate buffered saline (PBS) was washed 4,4'-azobis (cyanovaler ic acid) in the cells several times and 4 μΜ DCFA was incubated in the dark at 37 ⁰ C for 15 minutes. After washing the cells with PBS again, the generation of reactive oxygen species was confirmed by observing green fluorescence by DCF in the cells through a fluorescence microscope (FV1000 confocal microscope, Olympus) (FIG. 5). Example 4: Experiment for confirming the effect of heat treatment through sensitization strategy using a substance generating or inducing reactive oxygen species

By applying an external high frequency magnetic field, the magnetic nanoparticles The experiment was conducted to investigate the effect of heat treatment through the sensitization strategy using reactive oxygen species in killing cancer cells with heat by inducing heat release. As a control, none of the conjugated magnetic nanoparticles was used as a control to compare the difference in thermotherapy effect according to the presence or absence of reactive oxygen species. The cancer cell used in the experiment was MDA-MB-231, a breast cancer cell group. To examine the effect of simultaneous cancer cell killing with each of the heat treatments using three different substances that generate or induce reactive oxygen species, only nanoparticles were applied to the cells. When treated, cells treated with only the substance that generates or induced the generation of reactive oxygen species, the cancer cell survival rate at a temperature of about 43 ^° C when the nanoparticles and reactive oxygen species were treated at the same time using the CCK-8 method Quantitative analysis through. 4 is a graph showing that the temperature of the cell culture was maintained ^at 43 ^° C. 1 ^° C. by adjusting the temperature change when the external magnetic field was applied to the nanoparticles for a given time while observing the optical fiber thermometer. If the nanoparticles were only treated in the cells and no external alternating magnetic field was applied, the cancer cell death rate was 0 ¾ », and the cells were treated only with substances that produced or induced free radical species. Cell death rates of 5-15% were observed due to oxidative stress by the species. On the other hand, when a magnetic field is applied when a substance generating or inducing reactive oxygen species and nanoparticles are present together, cancer cell death rate is about 50-% due to oxidative stress caused by reactive oxygen species as well as heat generated during the loss of magnetic history. It was confirmed that the increase to 60% level. The specific experimental method is as follows. The MDA-MB-231 breast cancer cell group was incubated for 24 hours with IX 10 ⁴ cells per well using a 96-well plate, and one group contained magnetic nanoparticles containing 200 yg / ml zinc and reactive oxygen species. The material produced or induced was treated together and the other group treated only with magnetic nanoparticles. A 500 kHz high frequency magnetic field of 30 kA / m intensity was added thereto while maintaining the temperature of the cell culture at 43 ^° C. for 30 minutes. After culturing for 24 hours, the living cells were quantified using the CCK-8 assay. Figure 6-9 is an experimental result confirming the cell death rate when added to the external alternating magnetic field 30 minutes. In the case of cells treated only with nanoparticles as a whole, cancer cells were killed by up to 17% by the effect of heat treatment alone (FIG. 6). When treated with nanoparticles, it was confirmed that the cell death rate rapidly increased to 50-60 ¾> as cells were more susceptible to thermotherapy due to the sensitization strategy by reactive oxygen species. Depending on the combination of thermotherapy and sensitization strategies with nanoparticles, they were classified as follows:

 (1) reactive oxygen species themselves, (FIG. 7);

 (2) a substance that generates free radical species using radicals, 4,4′-azobis (cyanovaleric acid) (FIG. 8); and

 (3) substances that induce reactive oxygen species production using intracellular metabolism, Antamycin A (Antimycin A) (FIG. 9). Simultaneous treatment of reactive oxygen species and magnetic nanoparticles under the experimental conditions showed that cancer cell death was increased by about three times or more than when treated with active oxygen only cells or when treated with magnetic nanoman cells. Example 5: Confirm the effect of heat treatment through sensitization strategy In vivo experiment

10 is a diagram showing that apoptosis by the heat treatment using the sensitization strategy is effective even in /. After transplanting MDA-MB-231 breast cancer cells to mice, the composition was injected when the size of the cancerous tissue became 100 mm ³ , and an alternating magnetic field was applied for 30 minutes to maintain a temperature of 43 ^° C. 14 days later, the size of the cancer was checked. You can see the cancer is completely removed with just one heat treatment. This shows that apoptosis is effectively occurred even in actual w w by the heat treatment which is enhanced by the sensitization strategy (FIG. 10). Example 6 Synthesis of Magnetic Nanoparticle-Thermal Shock Protein Inhibitor Complex and Effective Release of Thermal Shock Protein Inhibitor Using Magnetic Field

As an example of the heat-emitting nanoparticles described herein, a spherical ferrite nanoparticle heat-releasing agent containing zinc having a composition of the formula ZnxMi-xFes ^ (M = Fe, x = 0.4) was synthesized as follows. Zn (acac) ₃ (Sigma, 0.276 g) and Fe (acac) ₃ (Sigma, 0.247 g) were reacted at room temperature for 1 hour in a benzyl ether solution containing Eleic acid (Sigma, 1.068 g), followed by argon ( Ar) under atmosphere Pyrolysis was performed ^at 290 ^° C. for 30 minutes to synthesize Zn ^ _h Fea t (M = Fe, x = 0.4) nanoparticles having a 15 nm core size. The spherical ferrite nanoparticles containing zinc were precipitated with excess ethanol and separated, and then the nanoparticles were redispersed again with leuene to form a colloidal solution. After surface treatment, the azobis compound, a heat-sensitive linker, was conjugated and finally a geldanamycin derivative, a thermal shock protein inhibitor, was introduced. The magnetic field was added to the synthesized composite so that the temperature of the media in which the composite was dissolved was maintained at 43 rc rc, and the release of the thermal stratified protein inhibitor was confirmed using a UV-Vis spectrometer (FIG. 11). It was confirmed that all of the inhibitors were effectively released within 60 minutes of applying the magnetic field. Example 7: Effective Silver Control Using Nanoparticle-Thermal Shock Protein Complex

 After synthesizing the composite, it was tested using an alternating electromagnetic field generator (HF 10R, Taeyang System Co., Korea) to effectively control the silver using heat generated from magnetic nanoparticles under high frequency magnetic fields. An analytical sample dispersed in water at a concentration of 0.1 mg / ml was prepared, placed in a glass vial, placed in the center of a 500 kHz coil, and an alternating current was flowed into the coil to generate an induction magnetic field of 37.4 kA / m intensity. At this time, nanoparticles were quantified by ICP-AES analysis for accurate concentration calculation of analytical samples, and the space between vials and coils containing analytical samples was insulated with styrofoam for accurate temperature measurement. The high frequency magnetic field was adjusted according to the temperature to maintain the desired temperature. This change in temperature was observed in real time using a fiber optic thermometer (M602, Lumasense technologies, Inc. USA). As shown in Figure 12 by adjusting the high frequency magnetic field to effectively maintain the temperature of the media 43 ℃ 1 ° C range. It was confirmed that the temperature of the sample increased with increasing time. Example 8: Experiment to confirm the effect of heat treatment through sensitization strategy using heat shock protein inhibitor

The application of an external high frequency magnetic field causes the magnetic nanoparticles to induce heat release through a loss of magnetic history, thereby killing cancer cells with heat. Experiments were conducted to determine the effect of heat therapy through the sensitization strategy using heat stratified protein inhibitors. As a control, none of the non-conjugated magnetic nanoparticles was used as a control to compare the effect of heat treatment according to the presence or absence of a thermal stratified protein. The cancer cells used in the experiment are MDA-MB-231, a breast cancer cell population. If one to determine the cancer killing effects of heat treatment only nanoparticles processing in cells, nanoparticles - the tumor rejection at a temperature of about 43 ^° C when treated with heat cheunggyeok protein inhibitor complex to cells via CCK-8 method Quantitative analysis (FIG. 13). If the nanoparticles were only treated with cells and no external alternating magnetic field, there was no toxicity and cancer cell death rate remained at 0% (black graph), and the nanoparticle-thermolayer protein complex had little toxicity. Was observed (red graph). On the other hand, when the magnetic field is applied to the complex, cancer cell death rate is weak due to the inhibition of the formation and action of thermal stratified protein as well as the heat induced during the loss of magnetic history.

It was confirmed that the increase significantly to the 100% level. The specific experimental method is as follows. The MDA-MB-231 breast cancer cell group was incubated for 24 hours with 1 × 10 ⁴ cells per well using a 96-well plate, and one group was treated with 100 g / ml nanoparticle-thermal stratified protein complex material and the other. The group treated only magnetic nanoparticles. A 500 kHz high frequency magnetic field of 37.4 kA / m intensity was added thereto while maintaining the temperature of the cell culture at 43 ^° C. for 80 minutes. After culturing for 24 hours, the living cells were quantified using a CC-8 assay. 13 is an experimental result showing the cell death rate with time when an external alternating magnetic field was applied up to 80 minutes. In case of cells treated with nanoparticles alone, cancer cells killed up to 17% due to the effect of heat treatment alone (black graph). As a result of the sensitization strategy, the cell death rate rapidly increased to 100% as cells were more susceptible to heat treatment.

In the experimental conditions, it was confirmed that the heat treatment through the sensitization strategy showed cancer cell killing effects increased by about five times or more than when only the magnetic nanoparticles were treated with the cells. Example 9 Experiment for Confirming Inhibition of Thermal Lamellar Protein Production

14 is a Western blotting experiment showing that the nanoparticle-thermal stratified protein complex effectively inhibits the production of Hs _P 90 when subjected to a magnetic field. The treatment of magnetic nanoparticles (MNP) only increased the production of Hsp90, but the complex (RAIN) showed that the level of Hsp90 retained by the cells was maintained when no heat was applied. This was quantified using GAPDH (g 1 y cer a 1 dehyde 3 phosphate dehydrogenase). In the case of thermotherapy using nanoparticles, Hsp90 is produced three times more than cells without heat treatment. In the case of the inhibitor complex, it was confirmed that the amount of Hsp90 produced was maintained at an unheated level without increasing after heat treatment. Example 10: Confirmation of the effect of heat treatment through sensitization strategy In vivo experiment

15 is a diagram showing that apoptosis by heat treatment using a sensitization strategy also occurs effectively in wVo. After transplanting MDA-MB-231 breast cancer cells to mice, the composition was injected when the size of the cancerous tissue became 100 mm ³ , and an alternating magnetic field was applied for 30 minutes to maintain a temperature of 43 ^° C. 14 days later, the size of the cancer was checked. You can see the cancer is completely removed with just one heat treatment. This shows that apoptosis effectively occurs even in actual by the heat treatment that the effect is enhanced through the sensitization strategy (FIG. 15). Having described the specific part of the present invention in detail, it is apparent to those skilled in the art that the specific technology is merely a preferred embodiment, and the scope of the present invention is not limited thereto. Accordingly, the substantial scope of the invention will be defined by the appended claims and equivalents thereof.

Claims

[Patent Claims]

 [Claim 1]

 In vivo heat release composition comprising:

 (a) magnetic nanoparticles;

 (b) at least one sensitization substance selected from the group consisting of chemodrugs, biodrugs and radioisotopes.

[Claim 2]

 The composition of claim 1, wherein the magnetic nanoparticles are represented by the following general formula (1):

 Formula 1

MxM ^, i- _x Fe ₂ 0 ₄ (M = Ba, Zn, Mn, Fe, Co, and at least one metal selected from the group consisting of Ni, 0 <χ <5, Μ '= Ba, Zn, Mn, Fe , At least one metal selected from the group consisting of Co and Ni).

[Claim 33]

 According to claim 2, wherein at least one member selected from the group consisting of M = Zn, Mn and Co of the general formula 1, 0≤x≤3, M '= at least one selected from the group consisting of Mn and Fe Composition comprising a metal.

[Claim 4]

 The composition according to claim 3, wherein M = Ζη, 0 <χ <1, and M '= Fe in the general formula (1).

[Claim 5]

 The composition of claim 1, wherein the chemotherapeutic agent is selected from the group consisting of reactive oxygen species, reactive oxygen species generating materials, reactive oxygen species generating inducing substances, and heat shock protein inhibitors (Hsp inhibitors).

[Claim 6] According to claim 5, The reactive oxygen species is hydrogen peroxide (¾0 ₂ ), superoxide anion (superoxide anion, 0 ^{2 "} ), hydroxyl radical (ΟΗ '), lipid peroxide, peroxynit Light (peroxinitrite, N0 ₃ ^{2 "} ), thi is selected from the group consisting of peroxy radicals (R-S0 ^2_ ).

[Claim 7]

 6. The composition according to claim 5, wherein the reactive oxygen species generating material is 4,4'-Azobis (4-cyanovaleric acid) (4,4'-Azobis (4-cyanovaleric acid)).

[Claim 8]

 6. The composition of claim 5, wherein the reactive oxygen species generating inducing substance is anthamycin A.

[Claim 9]

 8. The composition of claim 7, wherein the 4,4'-azobis (4-cyanovaleric acid) (4,4'-Azobis (4-cyanovaleric acid)) is conjugated to the magnetic nanoparticles. .

[Claim 10]

 The method of claim 5, wherein the Hsp inhibitor is gel danamyc (1 danamyc in), 17AAG (17-NA 1 laminoamino-17- demethoxyge 1 danamyc in) 17-DMAG (17-di methyl ami no-gel danamyc in), Pifithrin-y ^ -Phenylethynesulfonamid KNK ^ s S-KE ^ -l ^-Benzodioxol-S-ylmethylene] -oxopyrrol idine-l-carbaldehyde), schi sandr in From the group consisting of -B, Quercet in (2- (3, 4-dihydroxyphenyl) -3, 5,7-tri hydr oxy-4H-chr omen-4-one) and ETB (Epolactaene Tertiary Butyl Ester) Selected composition.

[Claim claim Π] The composition of claim 10, wherein the heat shock protein inhibitor (Hsp inhibitor) is geldanamycin.

[Claim 12]

 The composition of claim 10, wherein the thermal striatum protein inhibitor is conjugated to the magnetic nanoparticles with a heat sensitive linker.

[Claim 13]

 13. The composition of claim 12, wherein the heat sensitive linker is 4,4'-azobis (4-cyanovaleric acid) (4,4'-Azobis (4-cyanovaleric acid)).

[Claim 14]

 The composition of claim 1, wherein the biopharmaceutical is an antibody.

[Claim 15]

 15. A composition for hyperthermia therapy comprising the composition for in vivo heat release of any one of claims 1 to 14 as an active ingredient.

[Claim 16]

 The composition of claim 15, wherein the composition for treating heat is a composition for treating cancer.

[Claim 17]

 15. A method of hyperthermia therapy comprising administering the composition of any one of claims 1-14.

[Claim 18]

 A method of treating cancer, comprising administering the composition of any one of claims 1-14.