WO2014054884A1 - Composition pour l'hyperthermie comprenant un matériau de sensibilisation - Google Patents

Composition pour l'hyperthermie comprenant un matériau de sensibilisation Download PDF

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WO2014054884A1
WO2014054884A1 PCT/KR2013/008820 KR2013008820W WO2014054884A1 WO 2014054884 A1 WO2014054884 A1 WO 2014054884A1 KR 2013008820 W KR2013008820 W KR 2013008820W WO 2014054884 A1 WO2014054884 A1 WO 2014054884A1
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composition
heat
present
oxygen species
group
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PCT/KR2013/008820
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English (en)
Korean (ko)
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천진우
유동원
노승현
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연세대학교 산학협력단
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Priority to KR1020157015087A priority Critical patent/KR101868675B1/ko
Publication of WO2014054884A1 publication Critical patent/WO2014054884A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Silver heat treatment composition comprising a sensitizer
  • 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.
  • Nanomaterials exhibit new physical and chemical properties different from bulk materials due to their reduced size.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present invention provides a composition for in vivo heat release comprising:
  • 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.
  • 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.
  • composition for heat release refers to itself or to external stimuli. Means a material that radiates heat to the outside.
  • 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.
  • 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”.
  • 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.
  • 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.
  • 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
  • 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).
  • R0S reactive oxygen species
  • 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
  • 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).
  • 4,4'-azobis may be conjugated to the magnetic nanoparticles and used as a single composition.
  • 4,4'-azobis 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.
  • the active oxygen species generating material including 4,4 ' ⁇ 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.
  • 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.
  • 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 ⁇ -phenylethylisothiocyinate, can be used by intracellular metabolism Any substance that can promote the production of free radicals can be used.
  • 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.
  • heat shock protein refers to a protein that is commonly synthesized by all living organisms as a protein induced by the thermal stratification.
  • Hsp heat shock protein
  • thermal stratified proteins have molecular weights of 90,000, 70,000 and
  • Hsp90 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.
  • 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.
  • the thermal shock protein inhibitor of the present invention is geldanamycin ( ⁇ (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 (-(2-3 ⁇ 46 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
  • the thermal stratified protein inhibitor of the present invention is conjugated to the magnetic nanoparticles with a heat sensitive linker.
  • the heat sensitive linker is 4, 4'-azobis (4-cyanovaleric acid) (4,4'-Azob i s (-cy anova 1 er i c acid)).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the magnetic nanoparticles of the present invention are represented by the following general formula (1).
  • 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.
  • a nanomaterial precursor containing a magnetic metal precursor is added to an organic solvent to prepare a mixed solution.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • -SH can be a cross-linking region by forming a disulfide bond with other -SH around.
  • 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.
  • 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.
  • 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 -N3 ⁇ 4 functional groups at both ends, the peptides are naturally attached and active ingredients. The coupling area is provided.
  • peptides including one or more amino acids having at least one of -SH, -C0OH, -N3 ⁇ 4, or -0H as a chain may be used as a specific water-soluble multifunctional ligand.
  • 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, -N3 ⁇ 4, -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.
  • 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.
  • albumin albumin, antibody, antigen, avidin (avidin),
  • Nucleic acid is a ligolimer consisting of a large number of nucleotides, and since it has P0 4 — and -0 ⁇ 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 ⁇ 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.
  • a ligand composed of a hydrophobic long carbon chain exists on the surface thereof.
  • 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.
  • the intermolecular attraction includes hydrophobic bonds, hydrogen bonds, van der Waals bonds, and the like.
  • 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.
  • 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.
  • 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,
  • 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.
  • a polymer or a block copolymer may be used as the hydrophilic group, and the unit elements used are ⁇ 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.
  • specific water soluble polyfunctional ligands in the present invention include carbohydrates. More specific examples include glucose, mannose, fucose,
  • 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.
  • 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.
  • 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.
  • 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.
  • therapeutically effective amount means a subdivided amount capable of treating a disease for treatment, generally 0.0001-100 mg / kg.
  • 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.
  • 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.
  • 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.
  • the disease treated with the composition for treating heat of the present invention is cancer.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a single stimulus of high frequency magnetic field which is useful for an effective therapeutic composition.
  • FIG. 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.
  • FIG. 5 is a 2 ', 7' - dichloro fluorescein diacetate (DCFA, Molecular Probes) is 2 ', ⁇ ' - 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 (3 ⁇ 40 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).
  • FIG. 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.
  • 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.
  • the magnetic nanoparticles 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.
  • the cancer cell survival rate 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 3 ⁇ 4 » and the cells were treated only with substances that produced or induced free radical species.
  • cancer cell death rates of 5-15% were observed due to oxidative stress by the species.
  • 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.
  • thermotherapy and sensitization strategies were classified as follows:
  • FIG. 10 is a diagram showing that apoptosis by the heat treatment using the sensitization strategy is effective even in /.
  • 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
  • Example 7 Effective Silver Control Using Nanoparticle-Thermal Shock Protein Complex
  • 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 °C 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.
  • 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.
  • 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.
  • 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.
  • cancer cells killed up to 17% due to the effect of heat treatment alone (black graph).
  • the cell death rate rapidly increased to 100% as cells were more susceptible to heat treatment.
  • FIG. 15 is a diagram showing that apoptosis by heat treatment using a sensitization strategy also occurs effectively in wVo.
  • 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).

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Abstract

La présente invention concerne une composition de dissipation de chaleur in vivo comprenant un matériau de sensibilisation choisi dans le groupe comprenant (i) des nanoparticules magnétiques et (ii) des médicaments chimiques, des médicaments biologiques et des radio-isotopes, et une composition pour l'hyperthermie, comprenant la composition de dissipation de chaleur in vivo en tant que composant actif. Les compositions de la présente invention peuvent avoir des effets de dissipation de chaleur causés par des stimuli externes et des nanoparticules magnétiques et, par conséquent, peuvent présenter des effets synergiques supérieurs dans l'apoptose de cellules cibles, en particulier des cellules cancéreuses. En particulier, si les compositions de la présente invention sont formées en un composite de « nanoparticules magnétiques-matériau de sensibilisation », un effet thermique par un stimulus unique qui est un champ magnétique à haute fréquence et un effet de sensibilisation par un matériau de sensibilisation sont obtenus simultanément. Par conséquent, les compositions de la présente invention peuvent être utilisées sous forme de compositions efficaces pour traitement.
PCT/KR2013/008820 2012-10-05 2013-10-02 Composition pour l'hyperthermie comprenant un matériau de sensibilisation WO2014054884A1 (fr)

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WO2018231938A1 (fr) 2017-06-13 2018-12-20 Houn Simon Hsia Compositions et méthodes pour l'amélioration d'un traitement par hyperthermie
US10905725B2 (en) 2017-06-13 2021-02-02 Houn Simon Hsia Compositions and methods for enhancing cancer chemotherapy
US10905723B2 (en) 2017-06-13 2021-02-02 Houn Simon Hsia Compositions and methods for enhancing cancer radiotherapy
US11206861B2 (en) 2016-10-03 2021-12-28 Houn Simon Hsia Compositions and methods for enhancing cancer radiotherapy

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KR102175448B1 (ko) * 2020-04-13 2020-11-06 주식회사 지티아이바이오사이언스 중원자-할로겐 화합물이 도핑된 산화철 자성 나노입자
KR102175449B1 (ko) * 2020-04-13 2020-11-06 주식회사 지티아이바이오사이언스 산화철/중원자-할로겐 화합물의 코어/쉘 구조 자성 나노입자
EP3895734B1 (fr) 2020-04-13 2023-01-25 ZTI Biosciences Co., Ltd. Particules magnétiques d'oxyde de fer comprennant des halogénures de cuivre(i)
US20230127444A1 (en) * 2021-10-21 2023-04-27 Zti Biosciences Co, Ltd. Composition comprising iron oxide magnetic particles for a treatment of liver cancer
WO2023068828A1 (fr) * 2021-10-21 2023-04-27 주식회사 지티아이바이오사이언스 Méthode de préparation d'une composition pour le traitement du cancer du foie, comprenant des particules magnétiques d'oxyde de fer, et composition pour le traitement du cancer du foie, comprenant des particules magnétiques d'oxyde de fer

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WO2018231938A1 (fr) 2017-06-13 2018-12-20 Houn Simon Hsia Compositions et méthodes pour l'amélioration d'un traitement par hyperthermie
US10905725B2 (en) 2017-06-13 2021-02-02 Houn Simon Hsia Compositions and methods for enhancing cancer chemotherapy
US10905723B2 (en) 2017-06-13 2021-02-02 Houn Simon Hsia Compositions and methods for enhancing cancer radiotherapy
US10905724B2 (en) 2017-06-13 2021-02-02 Houn Simon Hsia Compositions and methods for enhancing hyperthermia therapy
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