WO2015056960A1 - Composition de sensibilisation utilisant des ondes électromagnétiques pour la thérapie thermique de cancers, et cancérothérapie l'utilisant - Google Patents

Composition de sensibilisation utilisant des ondes électromagnétiques pour la thérapie thermique de cancers, et cancérothérapie l'utilisant Download PDF

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WO2015056960A1
WO2015056960A1 PCT/KR2014/009641 KR2014009641W WO2015056960A1 WO 2015056960 A1 WO2015056960 A1 WO 2015056960A1 KR 2014009641 W KR2014009641 W KR 2014009641W WO 2015056960 A1 WO2015056960 A1 WO 2015056960A1
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cancer
ions
electromagnetic waves
iron
thermal therapy
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PCT/KR2014/009641
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English (en)
Korean (ko)
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김현진
홍성출
정혜종
이희관
조해국
유재각
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주식회사 지니스
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Priority claimed from KR1020140109008A external-priority patent/KR101536325B1/ko
Application filed by 주식회사 지니스 filed Critical 주식회사 지니스
Priority to CN201480057376.4A priority Critical patent/CN105682677B/zh
Priority to JP2016524018A priority patent/JP6404920B2/ja
Priority to CA2927528A priority patent/CA2927528C/fr
Priority to RU2016118565A priority patent/RU2016118565A/ru
Priority to EP14853591.7A priority patent/EP3058949B1/fr
Priority to US15/029,726 priority patent/US20160310594A1/en
Publication of WO2015056960A1 publication Critical patent/WO2015056960A1/fr
Priority to US17/219,479 priority patent/US20210236637A1/en
Priority to US17/981,080 priority patent/US11752210B2/en

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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/40—Transferrins, e.g. lactoferrins, ovotransferrins

Definitions

  • the present invention relates to a sensitizer composition for cancer thermal therapy using electromagnetic waves and a method for treating cancer using the same, and more particularly, to a sensitizer composition for cancer thermal therapy increasing cancer sensitivity when treating cancer using electromagnetic waves and cancer treatment using the same. It is about a method.
  • cancer therapies that have been developed to date are merely extending the survival of cancer patients rather than treating them fundamentally. Therefore, there is an urgent need to develop effective cancer treatments with fewer side effects.
  • Surgical therapy is the best treatment for early cancer, but it is difficult to expect a good therapeutic effect if the cancer has spread to other tissues.
  • Radiation therapy and anticancer drug therapy are known to not only lower cancer treatment effects but also affect normal tissues, causing various side effects such as gastrointestinal disorders, decreased immune function, loss of appetite, systemic weakness and hair loss.
  • heat treatment chemotherapy (Wust et al., The Lancet Oncology, 2002, 3: 487-497) .
  • Heat therapy chemotherapy is a chemotherapy that treats cancer by raising the temperature of the cancer tissue and surroundings to 42 ° C. or more using the characteristics of cancer cells lacking heat adaptation ability.
  • the surrounding normal cells can survive the heat shock, but the cancer cells are unable to adapt to high fever and die because of poor heat adaptation ability.
  • various methods such as the use of ultrasonic waves, heat transfer by contact, and electromagnetic waves have been developed.
  • Electromagnetic waves are waves that occur as the electric and magnetic fields change over time;
  • Gamma rays, X-rays, ultraviolet rays, visible light, infrared rays, microwaves, and radio waves are all electromagnetic waves.
  • the electromagnetic waves pass through a polar material, the electromagnetic waves generate heat by stimulating the molecular movement of the polar material.
  • all electromagnetic waves can be used for heat therapy chemotherapy.
  • 13.56 MHz radio The high frequency of frequency is the most commonly used.
  • Electromagnetic waves used in "cancer heat treatment using electromagnetic waves” generate heat through a process called dielectric heating.
  • Water molecules which make up most of the human body, have a dipole moment due to an asymmetric bond between oxygen and hydrogen atoms. Due to the dipole moment of water molecules, water molecules exposed to electromagnetic waves during the "thermal cancer therapy using electromagnetic waves” rotate their molecules by the frequency of electromagnetic waves, and they push, pull or collide with each other. Heat is generated in the tissue. If electromagnetic waves can be exposed only to cancer cells, cancer cells can be efficiently killed because of the characteristics of cancer cells that lack heat adaptation ability. However, exposing electromagnetic waves only to cancer cells without exposing them to normal cells is almost impossible due to the structural and physical limitations of the body.
  • cancer heat treatment using electromagnetic waves is not as effective as cancer treatment drugs or radiation therapy.
  • carcinoma therapy is used only as an adjuvant to chemotherapy or radiation therapy, rather than to treat cancer alone.
  • the best way to enhance the therapeutic efficacy of cancer thermal therapy using electromagnetic waves is to administer cancer thermal therapy using electromagnetic waves after administering a sensitizer for thermal therapy.
  • the thermal sensitizers attempted to date are nanoparticles based on metal components such as gold and iron oxide (International Patent Application No. 2009-091597, International Patent Application No. 2012-036978, International Patent Application No. 2012-177875, United States Patent No. 6561039, Korea Patent No. 0802139).
  • Metals react very well with electromagnetic waves and generate high heat. Therefore, after the metal component is accumulated in cancer cells instead of accumulating in normal cells, radiation of electromagnetic waves may maximize cancer treatment efficacy.
  • a technology for selectively delivering metal components to cancer tissues has not been developed, and the concept of "sensitizer for cancer thermal therapy using electromagnetic waves" has not been realized.
  • Metal nanoparticles such as gold or iron oxides do not have a selectivity for cancer tissues and accumulate in cancer tissues as well as normal tissues. When electromagnetic waves are processed, damage to normal tissues is generated by heat generation in all regions where nanoparticles are located. do. In addition, metal nanoparticles do not decompose or release in vivo, so there is a problem of low safety. Therefore, nanoparticles based on these metal components failed to be commercialized as sensitizers for thermotherapy, and there are no cases of sensitizers for thermotherapy commercialized worldwide.
  • the transferrin protein In human serum, about 70% of the transferrin protein is present as apotransferrin, which is not yet bound to iron ions, and about 30% of the transferrin is known to be iron-transferred apottransferrin, ie monoferric transferrin or diferric transferrin. Huebers et al., 1981, Proc. Natl. Acad. Sci. 78: 2572-2576. Therefore, the blood has a large amount of aporttransferin that can bind to the metal ions from the outside at any time.
  • Transferrin with non-covalently bound metal ions is carried along the blood and binds to the transferrin receptor to enter the cell through endocytosis to deliver metal ions, and the metal ions are separated. Transferrin, or apotransferrin, exits the cell through exocytosis and binds to metal ions, thereby circulating metabolic processes. Transferrin receptors, which play the most important role in the transfer of metal ions bound to transferrin into cells, are known to be overexpressed in cancer cells than in normal cells.
  • Cancer cells strongly absorb metal ions present in the blood because they absolutely require enzymes that use metal ions as coenzymes during cell metabolism. As described above, since metal ions do not exist independently in the blood but in the form of binding to transferrin, the metal ions that cancer cells absorb from the blood are substantially metal ions bound to transferrin. Iron, which is carried by transferrin, is used as an essential carrier and regulator of various enzymes that perform various functions of dividing cells such as DNA synthesis, cell division cycle, and metabolic regulation. Because these enzymes play a key role in metabolism, cancer cells have a strong ability to receive transferrin because they need large amounts of iron to maintain fast metabolism. In other words, cancer cells require more iron than normal cells, and the receptor for transferrin, a protein that delivers iron, is overexpressed.
  • transferrin as a target for cancer targeting, but there have been no reports of using "non-covalently bonded aprotransferrin" (transferrin) as a thermal sensitizer.
  • the present inventors recognized the characteristics of cancer cells that strongly absorb metal ions in the blood and the metals that react sensitively to electromagnetic waves.
  • the present inventors can administer metal ions instead of metals or metal compounds to cancer patients as sensitizers for cancer thermal therapy using electromagnetic waves.
  • the inventors of the present invention show that the treatment of cancer by improving the cancer treatment as described above is possible even by administering "non-covalently bound apattransferrin with a metal ion" to a cancer patient as a sensitizing agent for thermotherapy and performing "cancer thermotherapy using electromagnetic waves". The facts were confirmed and the present invention was completed.
  • the present invention provides a sensitizer composition for cancer thermal therapy using electromagnetic waves.
  • the sensitizer is characterized in that it is selected from the group consisting of a metal ion, a metal ion bond, a non-covalently bonded aprotransferrin and a metal ion-non-covalently bonded aprotransferrin derivative.
  • the metal ion is iron (iron), manganese (manganese), zinc (zinc), copper (copper), magnesium (magnesium), bismuth (bismuth), ruthenium (ruthenium) Selected from the group consisting of titanium ions, gallium ions, indium ions, vanadyl ions, chromium ions, aluminum ions, and plutonium ions It is characterized by.
  • the metal ion combination is dextran, sucrose, gluconate, sorbitol, polysaccharide, citrate, citrate to metal ions.
  • Carboxymaltose, perumoxytol, isomaltoside, maltose, starch, cellulose, chloride, sulfate, fumarate (fumurate) and albumin (albumin) is characterized in that the binder selected from the group comprising a non-covalent bond.
  • the atransferrin or the atransferrin derivative is characterized in that the human or mammalian-derived serum protein or recombinant protein.
  • the sensitizer is characterized in that the concentration of 0.01 ⁇ 100mg / ml.
  • the sensitizer composition for cancer thermal therapy is characterized in that it further comprises a pharmaceutically acceptable carrier.
  • the present invention also provides a kit for cancer thermal therapy, comprising a sensitizer composition for cancer thermal therapy using electromagnetic waves and a device for irradiating electromagnetic waves.
  • the present invention also provides a method for treating cancer, comprising the steps of: (a) administering the sensitizer composition for cancer thermal therapy to animals other than humans, thereby increasing susceptibility to cancer treatment; and (b) treating electromagnetic waves. do.
  • the sensitizer composition for cancer thermal therapy is characterized in that the administration of 1 ⁇ 250mg / kg dose.
  • the electromagnetic wave is selected from the group consisting of gamma rays, X-rays, ultraviolet rays, visible rays, infrared rays, microwaves and radio waves.
  • the cancer treatment method is one selected from the group consisting of chemotherapy, radiation therapy, biological therapy, immunotherapy and photodynamic therapy It is characterized by a combination of the above treatment methods.
  • the sensitizer composition for cancer thermal therapy according to the present invention has a cancer target orientation, thereby selectively transferring metal ions to cancer tissues, and thus, heat generation is increased in cancer tissues in which metal ions are accumulated during cancer thermal therapy using electromagnetic waves. Can maximize cancer treatment efficacy of cancer thermal therapy using.
  • Example 1 is a photograph measured by the thermal imaging camera the temperature of the aqueous solution of aforetransferrin before and after electromagnetic wave treatment according to Experimental Example 3 of the present invention.
  • the graph shows the difference between and temperature change.
  • Figure 2 is a graph showing the difference in the temperature change of the aqueous solution of aquatransferrin before and after electromagnetic wave treatment according to Experimental Example 3 of the present invention.
  • FIG. 3 is a photograph of a transferrin aqueous solution temperature before and after electromagnetic wave treatment according to Experimental Example 3 of the present invention measured by a thermal imaging camera.
  • Figure 5 is a photograph of the measurement of the transfer cell culture normal cell temperature before and after the electromagnetic wave treatment in accordance with Experimental Example 3 of the present invention.
  • FIG. 6 is a graph showing the difference in transfer cell culture normal cell temperature before and after electromagnetic wave treatment according to Experimental Example 3 of the present invention.
  • FIG. 7 is a photograph of a transferrin cultured cancer cell temperature before and after electromagnetic wave treatment according to Experimental Example 3 of the present invention measured by a thermal imaging camera.
  • Figure 8 is a graph showing the difference in transferin culture cancer cell temperature change before and after electromagnetic wave treatment according to Experimental Example 3 of the present invention.
  • FIG. 9 shows normal tissues and cancer tissue regions (arrows) during thermal treatment in which physiological saline (control) is respectively administered to a tumor-induced mouse (Tumor xenograft mouse) and electromagnetic waves are treated according to Example 1 of the present invention. It is a graph showing the difference between the temperature measured by the image camera and the temperature change (White bar: normal tissue, Black bar: cancer tissue).
  • FIG. 10 shows normal tissues and cancer tissue regions during thermal treatments in which thermal susceptibility agents (iron sucrose) are respectively administered to a tumor-induced mouse (Tumor xenograft mouse) and electromagnetic waves are treated according to Example 1 of the present invention.
  • Arrow is a graph showing the difference between the temperature measured with a thermal imaging camera (white bar: normal tissue, black bar: cancer tissue).
  • FIG. 11 shows normal tissues and cancer tissue regions (arrows) during thermal treatments in which a therapeutic agent for thermotherapy according to Example 1 of the present invention is administered to a cancer-induced mouse (Tumor xenograft mouse) and treated with electromagnetic waves.
  • a therapeutic agent for thermotherapy according to Example 1 of the present invention is administered to a cancer-induced mouse (Tumor xenograft mouse) and treated with electromagnetic waves.
  • Example 12 is a result of analyzing the size of the cancer tissue of the mouse treated with electromagnetic waves after administration of saline or metal ion conjugate to the tumor-induced mouse (Tumor xenograft mouse) according to Example 1 of the present invention (biofluorescence)
  • A untreated
  • B physiological saline
  • C iron gluconate
  • D iron sucrose
  • E iron carboxymaltose
  • F iron dextran
  • G iron starch
  • H transferrin
  • Example 13 is a biofluorescence analysis of cancer tissue size of mice treated with electromagnetic waves after administration of saline, iron sucrose, iron dextran and transferrin to a tumor-induced mouse (Tumor xenograft mouse) according to Example 1 of the present invention The result is.
  • the cancer tissue selectivity and cancer treatment of "cancer thermotherapy using electromagnetic waves” when using as a sensitizer capable of delivering metal ions only to cancer cells by using a target-oriented material for cancer tissue without toxicity and side effects It was expected to increase the efficacy.
  • the metal ions are transferred to cancer cells instead of the normal cells to increase the metal ion concentration of the cancer cells, followed by "cancer heat treatment using electromagnetic waves.”
  • cancer heat treatment using electromagnetic waves When the trial was performed, it was confirmed that the cancer treatment effect can be maximized.
  • transferrin is selectively delivered to cancer cells rather than normal cells by transferrin receptors overexpressed in cancer cells; (2) separation of metal ions bound to transferrin results in higher metal ion concentrations in cancer cells than normal cells; (3) increased metal ions in the cancer tissue during electromagnetic wave treatment further increase heat generation; (4) The death of cancer cells was increased by the generated heat, and as a result, it was confirmed that the cancer therapeutic efficacy of cancer thermal therapy using electromagnetic waves was maximized.
  • the metal ion introduced into the blood is excessively present in the blood. Since it is transferred to transferrin in combination with transferrin, it is confirmed that even if the metal ion is administered to cancer patients as a sensitizer for thermal therapy and cancer thermal therapy using electromagnetic waves, the same or better anticancer effect as described above can be obtained. It was.
  • the present invention relates to a sensitizer composition for cancer thermal therapy using electromagnetic waves.
  • the sensitizer is used to enhance cancer treatment efficacy during heat treatment, and has a characteristic of amplifying heat generation in cancer tissues while having a target orientation for cancer tissues when administered to the body.
  • the sensitizer may be selected from the group consisting of a metal ion, a metal ion bond, an apotransferrin non-covalently bonded to a metal ion, and an apotransferrin derivative non-covalently bound to a metal ion.
  • the metal ion is iron (iron), manganese (manganese), zinc (zinc), copper (copper), magnesium (magnesium), bismuth (bismuth), ruthenium (ruthenium) , Titanium ions, gallium ions, indium ions, vanadyl ions, chromium ions, aluminum ions, plutonium ions, etc. It is not limited to this.
  • the metal ion combination is dextran, sucrose, gluconate, sorbitol, polysaccharide, polysaccharide, citrate, carboxymaltose in metal ions. ), Perumoxytol, isomaltoside, maltose, starch, cellulose, chloride, sulfate, fumurate and albumin
  • the combination selected from the group containing (albumin) is non-covalently bound, and any combination that can be used as a medicament can be used without limitation, and may include iron dextran, iron sucrose, iron gluconate, iron carboxymaltose, iron isomaltoside, iron ferumoxytol , iron sorbitol, iron polysaccharide, ferric citrate, ferrous gluconate, ferrous sulfate, ferrous fumurate, magnesium chloride, gallium citrate, aluminum citrate, and the like.
  • the metal ions have a charge, they have polarity, that is, a dipole moment, and thus generate heat by amplifying molecular motion during electromagnetic wave treatment, and thus have a sensitizer characteristic that reacts more sensitively to electromagnetic waves than the metal itself.
  • non-covalently bonded aforttransferrin is a blood cell to cancer cells
  • selective delivery of cancer cells to the cancer cells by the overexpressed transferrin receptors will increase the concentration of metal ions delivered by the transferrin in the cancer cells
  • heat treatment using electromagnetic waves heat generation occurs intensively in cancer cells accumulated with metal ions, which minimizes damage to normal cells while intensively killing only cancer cells.
  • the transferrin is a protein widely distributed in blood, and refers to a metalloprotein that binds to metal ions such as iron and spins blood to transfer metal ions to cells having transferrin receptors.
  • the aforetransferin or aforetransferin derivative may be human or mammalian-derived serum protein or recombinant protein without particular limitation, as long as it has cancer targeting ability and is capable of binding with metal ions such as iron, manganese, and zinc.
  • the transferrin is preferably a transferrin in a form in which a metal ion is non-covalently bonded to an aprotransferrin, and as a iron-bound transferrin, iron-bound transferrin, monoferric transferrin, and diferric transferrin. , Holo-transferrin, ferric acetyl transferrin, and the like.
  • the transferrin binds to the transferrin receptor, which is overexpressed in cancer tissue, is delivered into cancer cells, and releases the bound metal ions into the cancer cells, thereby finally delivering metal ions selectively to the cancer tissue.
  • metal ions such as iron, manganese, and zinc are highly charged ions, they have a much stronger polarity than the dipole moment of water molecules. When metal ions with strong polarities are exposed to electromagnetic waves, molecular motion is amplified to maximize heat generation.
  • transferrin When the transferrin is administered to a cancer patient, 1) transferrin is selectively delivered to cancer cells rather than normal cells by a transferrin receptor overexpressed in cancer cells; 2) the concentration of metal ions in cancer cells is higher than that of normal cells due to the separation of metal ions bound to transferrin; 3) increased metal ions of the cancer tissue during electromagnetic wave treatment further increases heat generation; 4) The death of cancer cells is increased by the generated heat, which has the characteristics of cancer treatment efficacy.
  • the sensitizer composition for cancer thermal therapy is not particularly limited, but the concentration of the sensitizer is preferably 0.01-100 mg / ml. If the concentration is less than 0.01mg / ml there is an inconvenience to be administered in an excess volume, there is a problem that difficult to manufacture if it exceeds 100mg / ml.
  • the sensitizer composition for cancer thermal therapy may further include a pharmaceutically acceptable carrier or lubricant, wetting agent, emulsifier, suspending agent, preservative and the like.
  • the present invention relates to a cancer thermal therapy kit including the device for irradiating electromagnetic waves and the sensitizer composition for cancer thermal therapy in another aspect.
  • the sensitizer composition for cancer thermal therapy of the present invention treats various diseases related to cancer, such as gastric cancer, lung cancer, breast cancer, ovarian cancer, liver cancer, bronchial cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, colon cancer, cervical cancer, etc. It can be used to, it can be included in the kit for cancer thermal therapy, including a device for irradiating electromagnetic waves.
  • the electromagnetic waves are waves generated as the electric and magnetic fields change with time, and may include gamma rays, X-rays, ultraviolet rays, visible rays, infrared rays, microwaves, radio waves, and the like. Phosphorus electromagnetic wave irradiation apparatus can be used.
  • the present invention provides a method for treating cancer, comprising the steps of: (a) administering the sensitizer composition for cancer thermal therapy to animals other than humans to increase susceptibility to cancer treatment; and (b) treating electromagnetic waves. It is about.
  • the sensitizer composition for cancer thermal therapy is a metal ion, a metal ion conjugate, a covalently bonded aforttransferrin, or a metal covalently bonded aforttransferrin derivative in a solution such as water, physiological saline suitable for injection 0.01 It is preferable to dissolve it at a concentration of ⁇ 100 mg / ml.
  • the dosage of the sensitizer composition for cancer thermal therapy is preferably in the range of 0.1 to 50 mg / kg in the case of metal ions and metal ion conjugates, and the atransferrin and non-covalently bonded metal ions In the case of derivatives, the dosage range of 0.1 to 200 mg / kg is preferred.
  • cancer thermal therapy using the electromagnetic wave it is preferable to perform cancer thermal therapy using electromagnetic waves within 1 to 48 hours after administering the sensitizer composition for cancer thermal therapy.
  • thermotherapy therapy using the electromagnetic wave can be easily determined and used by known thermotherapy therapy.
  • a treatment that is irradiated for 30 to 60 minutes with a thermal therapy device that outputs 13.56 MHz high frequency can be performed twice or more for four weeks or more per week.
  • Cancer treatment method can improve the therapeutic effect of cancer by using in conjunction with or in combination with existing chemotherapy.
  • Existing chemotherapy may be exemplified by chemotherapy, radiation therapy, biological therapy, immunotherapy and photodynamic therapy.
  • Oral or injectable metal ions for human consumption are in the form of conjugates combined with salts or conjugated polymers such as carbohydrates or proteins.
  • salts bound with metal ions include citrate, chloride, sulfate, fumurate, and the like.
  • Ferrous sulfate, ferrous fumarate, and the like are combined. (ferrous fumurate), ferrous gluconate and the like can be exemplified.
  • Carbohydrates bound to metal ions include gluconate (monosaccharide), sucrose (disaccharide), maltose (maltose), isomaltoside (polymal), carboxymaltose, and dextran (dextran) ), Starch, cellulose (saccharides) such as cellulose (saccharides) and the like, as the protein bound to the metal ions (transferrin, albumin, etc.) can be exemplified.
  • the ferrous sulfate solution which is a metal ion and salt combination
  • the exothermic ability of the metal ion binder was confirmed by measuring the temperature after treating the electromagnetic wave.
  • iron gluconate, magnesium sucrose, iron sucrose, iron isomaltoside, iron carboxymaltose, iron dextran, and iron starch complex solutions which are metal ions and carbohydrate combinations, are prepared as follows to treat the electromagnetic wave and then measure the temperature to generate the exothermic ability of the metal ion binders. It was confirmed.
  • Ferrous sulfate solution was prepared by dissolving 1 g of FeSO 4 7H 2 O in 10 ml of distilled water, stirring for 30 minutes or more, passing through a 0.22 ⁇ m filter, and diluting with sterile distilled water.
  • Iron gluconate solution sodium ferric gluconate complex
  • Sanofi Ferrlecit product was used by diluting Sanofi Ferrlecit product with sterile distilled water.
  • Magnesium sucrose solution was prepared by passing 83.6mg of MgCl 2 H 2 O and 150mg of sucrose in 10ml of distilled water, stirring for 30 minutes or more, passing through a 0.22 ⁇ m filter, and diluting with distilled water.
  • iron sucrose solution (ferric hydroxide sucrose complex) is first prepared the sucrose aqueous solution into the sugar 100mg in 50ml distilled water and continue stirring the addition of 5M NaOH was dissolved in 1ml 90 °C then put FeCl 3 0.9g in 50ml distilled water for 20 min or more Stir-dissolved 0.01M FeCl 3 aqueous solution was added to an aqueous solution of sucrose at 90 ° C., and then adjusted to pH 12 by dropping 5M NaOH solution. Next, after reacting for 2 hours at 80 °C centrifuged for 5 minutes at 5,000 rpm to obtain a ferric hydroxide sucrose complex, washed with distilled water and dried.
  • Iron isomaltoside complexes, iron carboxymaltose complexes, and iron starch complexes were also prepared by changing only carbohydrates from the method of preparing iron sucrose.
  • the metal ion conjugate was prepared in 10 mg / ml concentration of metal ions, and 0.1 ml was dispensed into 3 wells in a 96-well plate. At this time, 0.1ml of distilled water was used as a control. After exposing the 96-well plate at high frequency thermal cancer treatment device (EHY-2000, Oncothermia) for 5 minutes at 100W energy dose, the temperature was measured by thermal imaging camera (E60, Korea Rental, Korea) after 5 minutes. The difference in temperature after the change is shown in Table 1.
  • Table 1 delta Temp. (°C) control 0.5 ferrous sulfates 3.3 magnesium sucrose 5.2 iron sucrose 4.7 iron gluconate 5.7 iron isomaltoside 3.2 iron carboxymaltose 5.8 iron dextran 6.4 iron starch 4.5
  • transferrin binding capacity (Unsaturated Iron-Binding Capacity, UIBC) was measured according to the concentration of ferric iron (FeIII +) as follows.
  • FeCl 3 (Sigma Aldrich, USA) was added to 400 ml of distilled water to melt an aqueous solution of iron and stirred for at least 20 minutes. Then, 5 M NaOH solution was dropped dropwise to pH 9. When reddish brown precipitate was observed, the mixture was stirred at 90 ° C. for 2 hours, centrifuged at 5,000 rpm for 5 minutes to obtain precipitated ferric hydroxide, washed with distilled water, and dried. Ferric hydroxide in powder form was dissolved in distilled water to prepare ferric hydroxide solution of 1, 10, 50, 200, 500g / dL concentration.
  • Apotransferrin (Sigma Aldrich, USA) was added to the aqueous solution of iron ions at each concentration to 200 mg / dL, mixed with vortex for 1 minute, and apotransferrin reacted with iron ions at 37 ° C. for 30 minutes.
  • Ferrozine colorimetric method was used to measure the unsaturated iron-binding capacity of apoptransferin.
  • Ferrous chloride was prepared at 500 g / dL concentration in Hydroxylamine hydrochloride as an iron standard, and a reaction solution of apotransferrin and iron ions was prepared in the experimental group.
  • 2 ml of 0.5 M Tris buffer (pH 8) was dispensed into all test tubes.
  • 1 ml of distilled water, 0.5 ml of distilled water and 0.5 ml of iron standard, and 0.5 ml of apotransferrin and iron ion reaction solution and 0.5 ml of iron standard in test tube were mixed with vortex for 1 minute.
  • Absorbance A1 was measured after the spectrophotometer value was zero at 560 nm. Next, 50 ml of Ferrozine Hydroxylamine hydrochloride solution at a concentration of 16.6 mM was added, and then mixed with vortex for 1 minute. All test tubes were incubated at 37 ° C. for 10 minutes, and then absorbance A2 was measured at 560 nm. Absorbance A 560 at 560 nm was calculated by subtracting absorbance A1 from absorbance A2, and is shown in Table 2.
  • Unsaturated Iron-binding capacity was calculated by the following equation.
  • the temperature was measured after treating electromagnetic apattransferrin and iron-bonded apattransferrin solution with iron.
  • the iron ion aqueous solution was reacted with the aprotransferrin as follows. 3.6 g of FeCl 3 (Sigma Aldrich, USA) was added to 400 ml of distilled water and stirred for more than 20 minutes to dissolve. Then, 5 M NaOH solution was dropped dropwise to pH 9. When the reddish brown precipitate was observed, the mixture was incubated with stirring at 90 ° C. for 2 hours, followed by centrifugation at 5,000 rpm for 5 minutes to obtain precipitated ferric hydroxide, washed with distilled water, and dried.
  • FeCl 3 Sigma Aldrich, USA
  • Ferric hydroxide in powder form was dissolved in distilled water to prepare a ferric hydroxide solution at a concentration of 100 ⁇ g / dL.
  • Apottransferrin was added to 500 mg / dL in an aqueous solution of iron ions, mixed with vortex for 1 minute, and the aforetransferrin and iron ions were reacted at 37 ° C. for 30 minutes.
  • the iron ion-coupled aprotransferrin solution was diluted to 0, 0.04, 0.2, 1, and 5 mg / ml concentrations, and 0.1 ml of each concentration was prepared by dispensing in a 96-well plate.
  • thermotransfer camera (E60, Korea) exposed the temperature before and after exposing the APOTHERPIN aqueous solution plate and iron ion-coupled APOTHERPIN (transferrin) aqueous solution plate at 100W energy dose for 3 minutes in high frequency thermal cancer treatment device (EHY-2000, Oncothermia). Rental, Korea) and the difference in temperature change is shown in FIGS. 1 to 4.
  • the temperature change before and after the electromagnetic wave treatment of the aqueous solution of aprotransferrin was maintained at less than 3 °C at all treatment concentrations, while before and after the electromagnetic wave treatment of the aqueous solution of aprotransferrin (transferrin) with iron ions
  • the temperature change was found to increase 4.4 °C at 1mg / ml and 10.9 °C was increased at 5mg / ml.
  • Iron ion-coupled apattransferrin (transferrin) aqueous solution was added to 0, 0.04, 0.2, 1 or 5mg / ml in each of the prepared normal cell line and cancer cell line plates, and then cultured in a 37 ° C. CO 2 incubator for 4 hours.
  • the plate that completed transferrin and cell culture was washed with DMEM medium to remove transferrin that did not enter the cells.
  • each plate was exposed to an energy dose of 100 W for 3 minutes in a high-frequency thermal cancer treatment device (EHY-2000, Oncothermia), and then the temperature change was measured by a thermal imaging camera (E60, Korea Rental, Korea), and the results are shown in FIG. 5. It is shown to -8.
  • the temperature change before and after the electromagnetic wave treatment in the normal cell line was maintained at about 7 °C at all treatment concentrations, while in the cancer cell line the temperature change before and after the electromagnetic wave treatment was increased by 11.9 °C at 1mg / ml , 5mg / ml was confirmed to increase by 12.6 °C.
  • a tumor xenograft animal model was prepared as follows. After culturing the lung cancer cell line NCI-H460-luc2 (Califer Life Sciences), 5 ⁇ 10 6 cells were injected subcutaneously in 6-8 week old female BALB / c athymic nude mice (multiple science). Next, a cancer x-graft animal model was prepared by growing cancer tissues over 100 mm 3 for 10 days.
  • Established tumor xenograft BALB / c athymic nude mice were diluted with 0.2 mg / ml of magnesium sucrose, iron sucrose, and iron dextran aqueous metal ions prepared in Experiment 1, and then injected 0.1 ml intravenously to a dose of 1 mg / kg. .
  • 1 g of each tissue was removed for ICP-MS measurement, ground in an ice bath to a tissue grinder, and 1 ml of the pulverized liquid was dried at -60 ° C. and 7 ⁇ m Hg for 24 hours. 2 ml of 6N HCl was added to the dried powder, which was placed in a closed glass reactor and incubated in a 55 ° C. incubator.
  • each sample was vortexed, centrifuged at 1,000 rpm for 15 minutes, the supernatant was dried with nitrogen gas, and again, 1 ml of 0.01 N HCl was added and vortexed, followed by centrifugation at 1,000 rpm for 15 minutes. After the supernatant was recovered, the concentration of metal ions in normal and cancerous tissues was measured by inductively coupled plasma mass spectrometry (ICP-MS; Varian 800-MS, Palo Alto, US).
  • ICP-MS inductively coupled plasma mass spectrometry
  • Table 3 shows the results of measuring the concentration of metal ions accumulated in normal tissues and cancer tissues by ICP-MS after magnesium sucrose was administered to cancer-induced mice (Tumor xenograft mice).
  • magnesium sucrose administration increased the magnesium ion concentration of cancer tissue by more than 2.4 times.
  • Table 4 shows the results of measuring the concentration of metal ions accumulated in normal tissue and cancer tissue by ICP-MS after iron sucrose was administered to tumor xenograft mice.
  • the iron ion concentration of cancer tissue increased more than 3.3 times when iron sucrose was administered, which was higher than the major organs such as liver, kidney, heart, stomach and brain.
  • Table 5 shows the results of measuring the concentration of metal ions accumulated in normal tissues and cancer tissues by ICP-MS after iron dextran was administered to cancer-induced mice (Tumor xenograft mice).
  • the iron ion concentration of cancer tissues increased more than 3.4 times compared to the control group when iron dextran was administered, which was significantly higher than that of major organs such as liver, kidney, heart, stomach and brain.
  • the iron-bound transferrin aqueous solution was administered to rats, and the concentration of metal ions in normal tissues and cancer tissues was measured.
  • An aqueous solution of apottransferrin (transferrin) in which iron ions were bound was prepared at 4 mg / ml, followed by 0.1 ml intravenous injection at a 16 mg / kg dose. After 24 hours, each tissue was collected in the same manner as in Experimental Example 5, and the concentration of metal ions was measured by Inductively coupled plasma mass spectrometry (ICP-MS; Varian 800-MS, Palo Alto, US).
  • ICP-MS Inductively coupled plasma mass spectrometry
  • Table 6 shows the concentration of iron ions accumulated in normal tissues and cancer tissues by ICP-MS after administration of "iron ion-bound atransferrin" (transferrin) to cancer-induced mice (Tumor xenograft mice). One result.
  • the iron ion concentration of iron ion-coupled atransferrin increased more than 3.2 times the concentration of iron ions in cancer tissues compared to the control group, which was found in major organs such as liver, kidney, heart, stomach and brain. It was significantly higher than the increase rate.
  • Example 1 Administration of sensitizer for thermal therapy and cancer thermal therapy using electromagnetic waves
  • Cancer cells have poor metabolic control instead of rapidly receiving the nutrients needed for rapid cell division in order to continue abnormal division.
  • cancer cells overexpress the transferrin receptor and receive a lot of iron required for cell division, but are poor in heat regulation and are relatively sensitive to high fever compared to normal cells. Therefore, if heat is concentrated only on cancer cells, selective killing of cancer cells is possible.
  • Transferrin which has a target orientation to cancer cells, delivers iron to cancer cells intensively through transferrin receptors overexpressed in cancer cells.
  • Example 1 the use of a metal ion conjugate with excellent temperature rise in the experimental example was used as a sensitizer for heat treatment, thereby confirming the possibility of anticancer efficacy in the heat treatment of a tumor xenograft animal model.
  • the lung cancer cell line NCI-H460-luc2 (Califer Life Sciences) was cultured, and then 5 ⁇ 10 6 cells were subcutaneously injected into 6-8 week old female BALB / c athymic nude mice (multiple science). After injection, the tumor tissue was grown for 10 days to grow 100 mm 3 or more to produce a tumor xenograft animal model to study the therapeutic efficacy of the cancer.
  • iron sucrose which is a sensitizer composition for thermal therapy
  • 0.1 ml intravenous was injected with a 0.2 mg / ml iron sucrose aqueous solution to a dose of 1 mg / kg in the established tumor xenograft mice.
  • the transferrin aqueous solution of 5 mg / ml concentration to 20 mg / kg dose to the established tumor xenograft mice 0.1 ml intravenous injection.
  • Physiological saline was administered to the control group. After 4 hours of administration, high-frequency thermal cancer treatment device (EHY-2000, Oncothermia) was irradiated with an energy dose of 100W for 3 minutes, and then the temperature of normal tissue and cancer tissue was taken with a thermal imaging camera (E60, Korea Rental, Korea). The results are shown in FIGS. 9 to 11.
  • EHY-2000, Oncothermia high-frequency thermal cancer treatment device
  • the temperature in the normal tissue and the cancer tissue before and after the electromagnetic wave treatment both increased by about 1 °C level was no difference.
  • the temperature change before and after electromagnetic wave treatment was 1 °C for normal tissues and 1.9 °C for cancer tissues.
  • the temperature change before and after electromagnetic wave treatment was also different.
  • the use of the metal ion combination as a sensitizer for heat treatment confirmed the possibility of cancer treatment during heat treatment.
  • NCI-H460-luc2 Califer Life Sciences
  • 5 ⁇ 10 6 cells were injected subcutaneously in 6-8 week old female BALB / c athymic nude mice (multiple science).
  • a tumor xenograft animal model was prepared to study the therapeutic efficacy of cancer by growing cancer tissues over 100 mm 3 while growing for 10 days.
  • the metal ion monosaccharide conjugate iron gluconate
  • the metal ion disaccharide conjugate iron sucrose
  • metal ion in the tumor xenograft mouse Oligosaccharide conjugates (iron isomaltoside), metal ion polysaccharide conjugates (iron carboxymaltose, iron dextran, iron starch) were injected 0.1 ml intravenously to a 1 mg / kg dose.
  • the iron ion-coupled aprotransferrin (transferrin), a sensitizer composition for thermotherapy was injected 0.1 ml intravenously to a dose of 20 mg / kg in the established tumor xenograft mice.
  • the high-frequency heat cancer treatment device (EHY-2000, Oncothermia) underwent heat treatment for 10 minutes with 100W energy dose three times a week for 4 weeks. At this time, the untreated group and the saline treated group proceeded to the control group. In the last week, bioluminescence imaging was performed to analyze cancer tissue size.
  • D-luciferin (Xenogen, USA) was intraperitoneally injected into mice at a concentration of 150 mg luciferin / kg / d to luminesce luciferase-expressing cancer cell line NCI-H460-luc2, and with isoflurane gas After inhalation anesthesia mixed with oxygen, the cancer cells luminesced with Xenogen imager (IVIS 200) were superimposed and analyzed using Igor Pro imaging analysis software, and the results are shown in FIG. 12.
  • Example 12 is untreated (A), saline (B), iron gluconate (C), iron sucrose (D), iron carboxymaltose in cancer-induced mouse (Tumor xenograft mouse model animal) according to Example 1 of the present invention (E), iron dextran (F), iron starch (G), and transferrin (H) were administered and biofluorescence was analyzed for the size of the cancerous tissue in the mouse model after radiofrequency thermal treatment.
  • iron dextran and iron sucrose groups 0.1 ml intravenous injection of 0.2 mg / ml iron dextran or iron sucrose, respectively, and in the transferrin group, 0.1 ml intravenous injection of 5 mg / ml transferrin aqueous solutions.
  • the untreated group and physiological saline administration group was progressed to the control group.
  • the experimental group administered iron dextran as a sensitizer and the experimental group administered iron sucrose as a sensitizer it was confirmed that the growth rate of cancer was clearly decreased during the heat treatment using electromagnetic waves.
  • the transferrin-administered group it was found that the anticancer efficacy was markedly suppressed and reduced in size, and disappeared completely after 4 weeks at the end of the test.
  • the sensitizer composition for cancer thermal therapy according to the present invention, only cancer cells can selectively accumulate metal components, and thus can be the most ideal anti-cancer therapy with significantly improved cancer treatment efficacy without pain and side effects. It is expected to be widely used, and can be used in combination with other cancer treatment methods such as chemotherapy and radiation therapy, thereby increasing the cure potential of cancer.

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Abstract

La présente invention concerne une composition de sensibilisation utilisant des ondes électromagnétiques pour la thérapie thermique de cancers, et une cancérothérapie l'utilisant. Plus particulièrement, la présente invention concerne une composition de sensibilisation utilisant des ondes électromagnétiques pour accroître la sensibilité d'un traitement de cancer, et une cancérothérapie l'utilisant. La composition de sensibilisation utilisant des ondes électromagnétiques pour la thérapie thermique de cancers selon la présente invention comprend des ions métalliques, une matière de liaison d'ions métalliques, « l'apotransferrine à laquelle des ions métalliques sont liés de façon non-covalente » (transferrine), ou un inducteur d'apotransferrine auquel des ions métalliques sont liés de façon non-covalente. Étant donné que la composition de sensibilisation pour la thérapie thermique de cancers selon la présente invention a une sélectivité cible de cancers lorsqu'elle est administrée au corps humain, des ions métalliques sont sélectivement administrés à un tissu cancéreux. Par conséquent, la génération de chaleur dans un tissu cancéreux, dans lequel sont accumulés les ions métalliques, est accrue lorsque la thérapie thermique de cancers utilisant des ondes électromagnétiques est réalisée. Ainsi, il est possible de maximiser l'efficacité de traitement de cancer de la thérapie thermique de cancers utilisant des ondes électromagnétiques. En outre, étant donné qu'il est possible d'accroître considérablement l'efficacité de traitement de cancer sans douleur ni effets secondaires, la présente invention peut être largement utilisée pour un traitement anti-cancéreux. De plus, étant donné qu'il est possible de combiner d'autres cancérothérapies telles qu'une chimiothérapie et radiothérapie, la probabilité de guérison complète d'un cancer peut être accrue.
PCT/KR2014/009641 2013-10-16 2014-10-14 Composition de sensibilisation utilisant des ondes électromagnétiques pour la thérapie thermique de cancers, et cancérothérapie l'utilisant WO2015056960A1 (fr)

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JP2016524018A JP6404920B2 (ja) 2013-10-16 2014-10-14 電磁波を利用した癌温熱治療用感作剤組成物及びこれを用いた癌治療方法
CA2927528A CA2927528C (fr) 2013-10-16 2014-10-14 Composition de sensibilisation utilisant des ondes electromagnetiques pour la therapie thermique de cancers, et cancerotherapie l'utilisant
RU2016118565A RU2016118565A (ru) 2013-10-16 2014-10-14 Сенсибилизирующая композиция для термотерапии рака с применением электромагнитных волн и терапия рака с ее применением
EP14853591.7A EP3058949B1 (fr) 2013-10-16 2014-10-14 Composition de sensibilisation utilisant des ondes électromagnétiques pour la thérapie thermique de cancers, et cancérothérapie l'utilisant
US15/029,726 US20160310594A1 (en) 2013-10-16 2014-10-14 Sensitizing composition using electromagnetic waves for thermal therapy of cancers, and cancer therapy using same
US17/219,479 US20210236637A1 (en) 2013-10-16 2021-03-31 Sensitizing composition using electromagnetic waves for thermal therapy of cancers, and cancer therapy using same
US17/981,080 US11752210B2 (en) 2013-10-16 2022-11-04 Sensitizing composition using electromagnetic waves for thermal therapy of cancers, and cancer therapy using same

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