WO2023068423A1 - Composition de médicament anticancéreux complexe utilisant la photoréactivité et son procédé de préparation - Google Patents

Composition de médicament anticancéreux complexe utilisant la photoréactivité et son procédé de préparation Download PDF

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WO2023068423A1
WO2023068423A1 PCT/KR2021/015653 KR2021015653W WO2023068423A1 WO 2023068423 A1 WO2023068423 A1 WO 2023068423A1 KR 2021015653 W KR2021015653 W KR 2021015653W WO 2023068423 A1 WO2023068423 A1 WO 2023068423A1
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formula
core
photosensitizer
group
agent composition
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Korean (ko)
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송영규
심영기
이태헌
김성우
김혜정
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닥터아이앤비(주)
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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
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • 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
    • 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
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
    • 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
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0076—PDT with expanded (metallo)porphyrins, i.e. having more than 20 ring atoms, e.g. texaphyrins, sapphyrins, hexaphyrins, pentaphyrins, porphocyanines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0485—Porphyrins, texaphyrins wherein the nitrogen atoms forming the central ring system complex the radioactive metal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1217—Dispersions, suspensions, colloids, emulsions, e.g. perfluorinated emulsion, sols
    • A61K51/1227—Micelles, e.g. phospholipidic or polymeric micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to an anticancer composition comprising a photosensitizer and a method for preparing the same.
  • Photodynamic therapy refers to a technique for treating incurable diseases such as cancer without surgery using a photosensitizer, and has been attempted since around 1400 BC and actively researched in the early 20th century.
  • PDT used for cancer treatment irradiates light to a photosensitive agent, thereby changing oxygen molecules (O 2 ) into singlet oxygen, creating new radicals, or creating new chemical species to cancer cells. It is to selectively kill only.
  • the photosensitizers used at this time include porphyrin derivatives, which are first-generation photosensitizers, and chlorin, bacteriochlorin, and phthalocyanine, which are second-generation photosensitizers.
  • Photosensitizers are classified according to their chemical structure and physicochemical properties. From the 1st generation to the 2nd generation, the absorption wavelength band is longer and the time to be excreted outside the body is faster. Chlorin derivatives have several advantages, such as a low phototoxicity rate due to rapid excretion in vitro and a large number of substituents capable of chemical change.
  • chlorin compounds such as bonnelin, tolyporphin, and chlorophyllone A have been synthesized, but since the synthesis and extraction of these compounds are very difficult, the synthesis of new photosensitizers has started. It is difficult to use it as a material or to use it as a photosensitizer itself.
  • each radioactive isotope has its own half-life.
  • radioactive iodine iodine-131
  • Cu-67 Copper-67
  • each of these side effects are not severe, mild side effects may persist for more than 6 months.
  • a synthetic material of a radioactive isotope with a relatively long half-life and a photosensitizer with a half-life as short as 1 to 2 days is expected to be a combination that can improve anticancer efficacy and minimize side effects by combining radiotherapy and photodynamic therapy. .
  • Radioactive iodine (iodine-131) was attempted before and after World War II.
  • Thyroid hormone is produced by thyroid tissue in the human body, and iodine is an essential element for making thyroid hormone.
  • radioactive iodine When radioactive iodine is injected into the human body, it accumulates in the thyroid tissue and is detected with a Geiger Counter or gamma camera to analyze the presence, location and size of thyroid cancer. Since radioactive iodine emits beta rays that can kill cancer cells as well as gamma rays detected by gamma camera images, it can be applied to treat thyroid cancer. Therefore, because of the characteristics of radiation emitted from radioactive iodine, imaging diagnosis and treatment of thyroid cancer is possible.
  • the radioactive isotope Cu-67 is an emitter of beta rays and gamma rays, and the average energy of beta rays and gamma rays is 141keV and 157keV, respectively, and has nuclear characteristics suitable for in vivo diagnosis and treatment of malignant tumors of 2 mm in size.
  • the synthetic material of a radioactive isotope for radiotherapy and a photosensitizer for photodynamic therapy has a half-life while simultaneously diagnosing and treating cancer. It is thought that it will be able to meet the needs of the times to minimize side effects by appropriately adjusting.
  • cancer patients receive radiation therapy to remove cancer cells that are difficult to operate or remain after surgery.
  • the energy from the radiation generates 'active oxygen' around the cancer cells, destroying the DNA of the cancer cells.
  • cancer cells that are relatively distant from the blood vessels because they cannot supply enough oxygen and nutrients to the entire cell survive at a high rate. They have resistance to radiation irradiation that is 100 times greater than normal cells, as well as 'strong toughness' that makes it difficult for anti-cancer drugs to penetrate cells.
  • photodynamic therapy is attracting attention as a treatment to kill cancer cells in hypoxic conditions, but due to its low selectivity, it causes damage to surrounding normal tissues.
  • PSs photosensitizers
  • ROS_iA reactive oxygen species inducing amplifier synthetic material
  • Patent Document 1 Korea Patent Registration No. 10-0912446
  • An object of the present invention is to provide an anticancer drug composition showing high anticancer and anti-inflammatory activity and a method for preparing the same.
  • the anticancer drug composition according to one embodiment of the present invention is in the form of micelles including a core and a shell, the core includes a photosensitizer represented by Formula 1 below, and the shell is bovine serum albumin ( Bovine serum albumin (BSA) or human serum albumin (HSA) may be included.
  • BSA bovine serum albumin
  • HSA human serum albumin
  • R 1 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an alkylene group having 1 to 3 carbon atoms, an aldehyde group, an alkylhydroxyl group having 1 to 3 carbon atoms, or ego,
  • R 4 is a radioactive iodine isotope or an iodinated phenyl group containing a radioactive iodine isotope
  • M is a radioactive isotope containing copper-67 (Cu-67),
  • x is 0 or 1
  • L is cystamine or hydrazine
  • n 0 or 1
  • R 2 is a hydroxyl group; hydrazide group; an alkoxy group including at least one selected from the group consisting of a methoxy group, an ethoxy group, and combinations thereof; an anticancer component or a derivative thereof comprising at least one selected from the group consisting of paclitaxel, docetaxel, doxorubicin, and combinations thereof; or Apigenin, Metformin, LY294002, Paraquat, Antimycin-A, Salicylhydroxamic acid, Alloxan, Rotenone , Pyocyanin, Patulin, Piperlongumine, DMNQ, Artesunate, N -[6-(4-Chlorophenoxy)hexyl]- N' - cyano- N'' -4-pyridinylguanidine (CHS-828), 2-(Di-2-pyridinylmethylene)-N,N-dimethyl-hydrazinecarbothioamide (Dp44mT), 2-All
  • the transition metal includes at least one selected from the group consisting of Cu, Fe, Cd, Co, and combinations thereof,
  • the R 3 is a hydrogen atom or -COOCH 3 .
  • the core may include a photosensitizer represented by Chemical Formula 2 below.
  • the core may include a photosensitizer represented by Chemical Formula 3 below.
  • the core may include a photosensitizer represented by Chemical Formula 4 below.
  • the core may include a photosensitizer represented by Chemical Formula 5 below.
  • the core may include a photosensitizer represented by Chemical Formula 6 below.
  • the core may include a photosensitizer represented by Chemical Formula 7 below.
  • the core may include a photosensitizer represented by Chemical Formula 8 below.
  • the core may include a photosensitizer represented by Formula 8b below.
  • the core may include a photosensitizer represented by Chemical Formula 8c.
  • the core may include a photosensitizer represented by Chemical Formula 9 below.
  • the core may include a photosensitizer represented by Chemical Formula 10 below.
  • the core may include a photosensitizer represented by Chemical Formula 11 below.
  • the core may include a photosensitizer represented by Chemical Formula 12 below.
  • the core may include a photosensitizer represented by Chemical Formula 13 below.
  • the shell may be attached to the surface of the core through a hydrophobic bond.
  • the average particle size of the micelles may be 50 nm to 300 nm.
  • the micelle may have a polydispersity index (PDI) of 0.1 to 0.3.
  • PDI polydispersity index
  • the method for preparing an anticancer drug composition according to the present invention includes preparing an aqueous solution containing bovine serum albumin or human serum albumin; Obtaining a mixture by adding dropwise a photosensitizer solution to the aqueous solution and mixing; and concentrating the mixture under reduced pressure to prepare micelles, wherein the micelles include a core containing the photosensitizer; And it may include a shell containing the bovine serum albumin or human serum albumin.
  • the photosensitizer solution includes a photosensitizer and a solvent
  • the solvent may include at least one selected from the group consisting of methanol, ethanol, acetone, hexane, ethyl acetate, dichloromethane, tetrahydrofuran, and combinations thereof can
  • the preparation method may further include freeze-drying the micelles.
  • the micelles may contain additional drugs.
  • the anticancer drug composition in the form of micelles according to the present invention exhibits high anticancer and anti-inflammatory activities.
  • the anticancer drug composition in the form of micelles according to the present invention is obtained by attaching a shell made of an amino acid-based compound with high water solubility to a core containing a photosensitizer, and is easy to develop as a drug due to its high solubility in water.
  • FIG 1 shows the form of an anticancer agent composition according to the present invention.
  • 2a is a result of analyzing the compound according to Formula 8b obtained in Preparation Example 1 by nuclear magnetic resonance (NMR).
  • 2b is a result of analyzing the compound according to Formula 8b obtained in Preparation Example 1 by fast atomic impact mass spectrometry (Fertility Awareness Based Methods, FABMs).
  • Figure 2c is the result of analyzing the compound according to formula 8b obtained in Preparation Example 1 by ultraviolet visible spectrophotometer (UV-Visible Spectrophotometer, UV-Vis).
  • FIG. 3a is a result of analyzing the compound according to Formula 8c obtained in Preparation Example 2 by fast atom impact mass spectrometry (FABMs).
  • Figure 3b is the result of analyzing the compound according to formula 8c obtained in Preparation Example 2 by ultraviolet visible spectroscopy (UV-Vis).
  • FIG. 4a is a result of analyzing the compound according to Formula 11 obtained in Preparation Example 3 by nuclear magnetic resonance spectroscopy (NMR).
  • Figure 4b is a result of analyzing the compound according to Formula 11 obtained in Preparation Example 3 by a matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS).
  • Figure 4c is the result of analyzing the compound according to Formula 11 obtained in Preparation Example 3 by ultraviolet visible spectrophotometer (UV-Visible Spectrophotometer, UV-Vis).
  • FIG. 5a is a result of analyzing the compound according to Formula 12 obtained in Preparation Example 4 by nuclear magnetic resonance spectroscopy (NMR).
  • Figure 5b is a result of analyzing the compound according to Formula 12 obtained in Preparation Example 4 by ultraviolet visible spectrophotometer (UV-Visible Spectrophotometer, UV-Vis).
  • 6a is a result of analyzing the compound according to Formula 13 obtained in Preparation Example 5 by nuclear magnetic resonance spectroscopy (NMR).
  • 6b is a result of analyzing the compound according to Formula 13 obtained in Preparation Example 5 by a matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS).
  • Figure 6c is the result of analyzing the compound according to Formula 13 obtained in Preparation Example 5 by ultraviolet visible spectrophotometer (UV-Visible Spectrophotometer, UV-Vis).
  • 7a is a result of analyzing micelles containing the anticancer drug composition Formula 3 according to Preparation Example 6 with a scanning electron microscope (SEM).
  • 7B is a result of analyzing the particle size of micelles containing the anticancer drug composition Formula 3 according to Preparation Example 6.
  • 8a is a result of analyzing micelles containing the anticancer drug composition Formula 11 according to Preparation Example 6 with a scanning electron microscope (SEM).
  • 8B is a result of analyzing the particle size of micelles containing the anticancer drug composition Formula 11 according to Preparation Example 6.
  • 9a is a result of analyzing micelles containing the anticancer drug composition Formula 13 according to Preparation Example 6 with a scanning electron microscope (SEM).
  • 9B is a result of analyzing the particle size of micelles containing the anticancer drug composition Formula 13 according to Preparation Example 6.
  • 10a is a result of analyzing micelles including anticancer drug composition formula 13 and metformin according to Preparation Examples 6 and 7 with a scanning electron microscope (SEM).
  • 10B is a result of analyzing the particle size of micelles containing the anticancer drug composition Chemical Formula 13 and Metformin according to Preparation Examples 6 and 7.
  • the anticancer agent composition may be in a micelle form including a core 10 and a shell 20.
  • the core 10 may include a photosensitizer represented by Chemical Formula 1 below.
  • the photosensitizer is a chlorine derivative, and the present invention is characterized by maximizing anticancer and anti-inflammatory activity by introducing various substituents thereto.
  • R 1 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an alkylene group having 1 to 3 carbon atoms, an aldehyde group, an alkylhydroxyl group having 1 to 3 carbon atoms, or can be
  • R 4 is an iodine atom or can be
  • the M may be a radioactive isotope including copper-67 (Cu-67).
  • the x may be 0 or 1.
  • the L may be cystamine or hydrazine.
  • the n may be 0 or 1.
  • R 2 is a hydroxyl group; hydrazide group; an alkoxy group including at least one selected from the group consisting of a methoxy group, an ethoxy group, and combinations thereof; an anticancer component or a derivative thereof comprising at least one selected from the group consisting of paclitaxel, docetaxel, doxorubicin, and combinations thereof; or Apigenin, Metformin, LY294002, Paraquat, Antimycin-A, Salicylhydroxamic acid, Alloxan, Rotenone , Pyocyanin, Patulin, Piperlongumine, DMNQ, Artesunate, N -[6-(4-Chlorophenoxy)hexyl]- N' - cyano- N'' -4-pyridinylguanidine (CHS-828), 2-(Di-2-pyridinylmethylene)-N,N-dimethyl-hydrazinecarbothioamide (Dp44mT), 2-All
  • the R 3 may be a hydrogen atom or -COOCH 3 .
  • the photosensitizer may include an anticancer component or a derivative thereof including at least one selected from the group consisting of paclitaxel, docetaxel, doxorubicin, and combinations thereof at the R 2 position.
  • the anti-cancer component or a derivative thereof is a compound targeting cancer tissue, and is intended to enhance the anti-cancer and anti-inflammatory effects of the anti-cancer composition.
  • the photosensitizer is apigenin, metformin, LY294002, paraquat, antimycin-A, salicylhydroxamic acid, alloxan at the R 2 position ( Alloxan), Rotenone, Pyocyanin, Patulin, Piperlongumine, DMNQ, Artesunate, N- [6-(4- Chlorophenoxy)hexyl]- N' -cyano- N'' -4-pyridinylguanidine (CHS-828), 2-(Di-2-pyridinylmethylene)-N,N-dimethyl-hydrazinecarbothioamide (Dp44mT), 2-Allyl-1- It may include a reactive oxygen species inducing amplifier including at least one selected from the group consisting of hydroxy-9,10-anthraquinone (R162), transition metals, and combinations thereof.
  • the transition metal may include Cu, Fe, Cd, Co, and the like.
  • the reactive oxygen species-induced amplifying agent is used alone, it is inevitable to treat at a high dose.
  • the reactive oxygen species induction enhancer when introduced as a substituent of the chlorine derivative, the photosensitizer can generate more active oxygen and reduce its processing capacity.
  • the treatment time can be significantly reduced compared to the case of using the chlorine derivative alone.
  • the L means a linker.
  • the linker may include cystamine or hydrazine.
  • the linker includes one that can be cleaved under weakly acidic conditions or UV-Vis light. Since the weakly acidic condition is similar to the environment in cancer cells, the anticancer component and the active oxygen species enhancer can be specifically accumulated in cancer cells.
  • the photosensitizer may be labeled with a radioactive iodine isotope.
  • the radioactive iodine isotope itself or in the form of an iodinated phenyl group may be substituted at the R 4 position.
  • the radioactive iodine isotope may include at least one selected from the group consisting of 123 I, 124 I, 125 I, 131 I, and combinations thereof.
  • Cancer diagnosis and photodynamic therapy can be performed more easily by labeling the photosensitizer with the radioactive iodine isotope.
  • the photosensitizer may be a radioactive isotope including copper-67 (Cu-67) coordinated. Since copper-67 is a radioactive isotope that emits both gamma rays for diagnosis and beta rays for treatment, cancer diagnosis and photodynamic therapy can be more easily performed by using the photosensitizer according to the present invention.
  • cancer diagnosis efficiency can be increased with a smaller amount.
  • the photosensitizer may include a compound represented by Chemical Formula 2 below.
  • the photosensitizer may include a compound represented by Chemical Formula 3 below.
  • the photosensitizer may include a compound represented by Chemical Formula 4 below.
  • the photosensitizer may include a compound represented by Chemical Formula 5 below.
  • the photosensitizer may include a compound represented by Chemical Formula 6 below.
  • the photosensitizer may include a compound represented by Chemical Formula 7 below.
  • the photosensitizer may include a compound represented by Chemical Formula 8a below.
  • the photosensitizer may include a compound represented by Chemical Formula 8b below.
  • 2a is a result of analyzing the compound according to Formula 8b obtained in Preparation Example 1 by nuclear magnetic resonance (NMR).
  • 2b is a result of analyzing the compound according to Formula 8b obtained in Preparation Example 1 by fast atomic impact mass spectrometry (Fertility Awareness Based Methods, FABMs).
  • Figure 2c is the result of analyzing the compound according to formula 8b obtained in Preparation Example 1 by ultraviolet visible spectrophotometer (UV-Visible Spectrophotometer, UV-Vis).
  • the photosensitizer may include a compound represented by Chemical Formula 8c below.
  • the compound according to Compound 8a and copper acetate (Cu(II)(OAc) 2 ) were dissolved in a mixed solution of methanol and dichloromethane, and then stirred for 6 hours under nitrogen and dark conditions. Dichloromethane and water are added to the reactants to obtain an organic layer. The obtained product is dried and purified by silica column chromatography to obtain a compound according to Formula 8c.
  • FIG. 3a is a result of analyzing the compound according to Formula 8c obtained in Preparation Example 2 by fast atom impact mass spectrometry (FABMs).
  • Figure 3b is the result of analyzing the compound according to formula 8c obtained in Preparation Example 2 by ultraviolet visible spectroscopy (UV-Vis).
  • the photosensitizer may include a compound represented by Chemical Formula 9 below.
  • the photosensitizer may include a compound represented by Chemical Formula 10 below.
  • the photosensitizer may include a compound represented by Formula 11 below.
  • paclitaxel paclitaxel
  • dicyclohexylcarbodiimide N, N'-Dicyclohexylcarbodiimide, DCC
  • 4-dimethylaminopyridine 4-Dimethylaminopyridine, DMAP
  • FIG. 4a is a result of analyzing the compound according to Formula 11 obtained in Preparation Example 3 by nuclear magnetic resonance spectroscopy (NMR).
  • Figure 4b is a result of analyzing the compound according to Formula 11 obtained in Preparation Example 3 by a matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS).
  • Figure 4c is the result of analyzing the compound according to Formula 11 obtained in Preparation Example 3 by ultraviolet visible spectrophotometer (UV-Visible Spectrophotometer, UV-Vis).
  • the photosensitizer may include a compound represented by Chemical Formula 12 below.
  • FIG. 5a is a result of analyzing the compound according to Formula 12 obtained in Preparation Example 4 by nuclear magnetic resonance spectroscopy (NMR).
  • Figure 5b is a result of analyzing the compound according to Formula 12 obtained in Preparation Example 4 by ultraviolet visible spectrophotometer (UV-Visible Spectrophotometer, UV-Vis).
  • the photosensitizer may include a compound represented by Chemical Formula 13 below.
  • 6a is a result of analyzing the compound according to Formula 13 obtained in Preparation Example 5 by nuclear magnetic resonance spectroscopy (NMR).
  • 6b is a result of analyzing the compound according to Formula 13 obtained in Preparation Example 5 by a matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS).
  • Figure 6c is the result of analyzing the compound according to Formula 13 obtained in Preparation Example 5 by ultraviolet visible spectrophotometer (UV-Visible Spectrophotometer, UV-Vis).
  • the shell may contain bovine serum albumin (BSA) or human serum albumin (HAS).
  • BSA bovine serum albumin
  • HAS human serum albumin
  • the shell is a configuration for increasing the water solubility of the anticancer composition.
  • the photosensitizer has low water solubility and high anticancer activity.
  • the bovine serum albumin or human serum albumin has low anticancer activity and high water solubility. Therefore, in the present invention, the photosensitizer is coated with bovine serum albumin or human serum albumin to take advantage of only the advantages of the two materials.
  • the anticancer composition is easy to develop into a drug because its solubility in water is increased by the shell containing bovine serum albumin or human serum albumin.
  • the shell may be attached to the surface of the core including the photosensitizer through a hydrophobic bond.
  • the micelles including the core and the shell may have an average particle size of 50 nm to 300 nm.
  • the average particle size may mean the diameter of the micelle particle.
  • the micelle may have a polydispersity index (PDI) of 0.1 to 0.3.
  • the method for preparing an anticancer drug composition according to the present invention includes preparing an aqueous solution containing bovine serum albumin or human serum albumin, adding a photosensitizer solution to the aqueous solution and mixing to obtain a mixture, and concentrating the mixture under reduced pressure to obtain micelles. It may include a step of preparing, and a step of preparing metformin-added bovine serum nanoparticles (Met-BSA NPs) by stirring metformin with micelles.
  • Method-BSA NPs metformin-added bovine serum nanoparticles
  • the photosensitizer solution may be one in which the aforementioned photosensitizer is dissolved in a solvent.
  • the solvent is not particularly limited, but examples thereof include polar solvents such as methanol, ethanol, acetone, and tetrahydrofuran; or a non-polar solvent such as hexane, ethyl acetate, or dichloromethane.
  • the solvent may preferably include tetrahydrofuran.
  • the photosensitizer solution may be added in a dropwise manner, but is not limited thereto.
  • an anticancer drug composition in the form of a micelle containing the aforementioned core and shell can be obtained.
  • unreacted substances, impurities, and the like may be removed through sonication, centrifugation, and the like for the anticancer drug composition.
  • the manufacturing method may further include freeze-drying the purified anticancer drug composition.
  • the anticancer agent composition can be freeze-dried to make it into a form suitable for distribution and storage.
  • a bovine serum albumin micelle containing an anticancer drug composition can be prepared as follows.
  • aqueous solution of bovine serum albumin dissolved in an aqueous solvent was prepared, and a photosensitizer solution was prepared by dissolving the compounds represented by Chemical Formulas 1 to 13 in tetrahydrofuran, respectively.
  • the photosensitizer solution was added in a dropwise manner.
  • Tetrahydrofuran was gradually removed using a vacuum concentrator to obtain an anticancer agent composition composed of a core containing each compound and a shell containing the bovine serum albumin.
  • the anticancer drug composition was treated with ultrasonic waves, and the remaining material was removed using a centrifugal separator. The product was freeze-dried.
  • 7a is a result of analyzing micelles containing the anticancer drug composition Formula 3 according to Preparation Example 6 with a scanning electron microscope (SEM).
  • 7B is a result of analyzing the particle size of micelles containing the anticancer drug composition Formula 3 according to Preparation Example 6.
  • the average particle size of the anticancer composition is about 140.8 nm, and the polydispersity index (PDI) is 0.168.
  • 8a is a result of analyzing micelles containing the anticancer drug composition Formula 11 according to Preparation Example 6 with a scanning electron microscope (SEM).
  • 8B is a result of analyzing the particle size of micelles containing the anticancer drug composition Formula 11 according to Preparation Example 6. Referring to this, it can be seen that the average particle size of the anticancer composition is about 191.3 nm, and the polydispersity index (PDI) is 0.261.
  • SEM scanning electron microscope
  • 9a is a result of analyzing micelles containing the anticancer drug composition Formula 13 according to Preparation Example 6 with a scanning electron microscope (SEM).
  • 9B is a result of analyzing the particle size of micelles containing the anticancer drug composition Formula 13 according to Preparation Example 6. Referring to this, it can be seen that the average particle size of the anticancer agent composition is about 182.8 nm, and the polydispersity index (PDI) is 0.180.
  • Metformin-added bovine serum nanoparticles (Met-BSA NPs) can be prepared as follows.
  • Metformin was stirred for 24 hours in a micelle and aqueous solution state, and then organic solvent ethanol (EtOH) was added dropwise to obtain metformin-added bovine serum nanoparticles (Met-BSA NPs).
  • the anticancer drug composition was treated with ultrasonic waves, and the remaining material was removed using a centrifugal separator. The product was freeze-dried.
  • 10a is a result of analyzing micelles including anticancer drug composition formula 13 and metformin according to Preparation Examples 6 and 7 with a scanning electron microscope (SEM).
  • 10B is a result of analyzing the particle size of micelles containing the anticancer drug composition Chemical Formula 13 and Metformin according to Preparation Examples 6 and 7.
  • the average particle size of the anticancer composition is about 187.1 nm, and the polydispersity index (PDI) is 0.217.
  • Lung cancer cell line A549 was cultured in RPMI-1640 medium containing 10% FBS and 1% penicillin-streptomycin in an incubator at 37°C and 5% CO 2 environment.
  • the A549 cell line was cultured in a 24-well plate at a density of 5x10 4 cells per well for 24 hours. Thereafter, the anticancer agent compositions were dispensed so that the concentration of the photosensitizer was 1uM and incubated for 24 hours. To evaluate PDT efficacy, a 660 nm laser was irradiated at 2 joules per unit area (J/cm2) x 15 minutes, and after 24 hours, cell viability was calculated using CCK-8 (Cell Counting Kit-8).
  • Preparation Example 7 (Formula 13) is a result of the PDT effect of micelles containing Metformin, one of the active oxygen species induction enhancers, different from Chemical Formula 13 according to Preparation Example 7 on cancer cells.

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Abstract

La présente invention concerne : une composition anticancéreuse de type noyau/enveloppe renfermant un noyau comprenant un photosensibilisateur représenté par la formule chimique 1 et une enveloppe comprenant de l'albumine sérique bovine ou de l'albumine sérique humaine ; et son procédé de préparation.
PCT/KR2021/015653 2021-10-21 2021-11-02 Composition de médicament anticancéreux complexe utilisant la photoréactivité et son procédé de préparation WO2023068423A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20090027470A (ko) * 2007-09-12 2009-03-17 인제대학교 산학협력단 항암활성을 가지는 클로린 유도체
WO2014141289A1 (fr) * 2013-03-12 2014-09-18 Amrita Vishwa Vidyapeetham University Composition pour photochimiothérapie à base de microcapsules à structure cœur-écorce

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20090027470A (ko) * 2007-09-12 2009-03-17 인제대학교 산학협력단 항암활성을 가지는 클로린 유도체
WO2014141289A1 (fr) * 2013-03-12 2014-09-18 Amrita Vishwa Vidyapeetham University Composition pour photochimiothérapie à base de microcapsules à structure cœur-écorce

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
GALINDEV OYUNBILEG, BADRAA NARANGEREL, SHIM YOUNG KEY: "Synthesis of methyl pyropheophorbide-a pyrazole derivatives and their in vitro cell viabilities on A549 cells", JOURNAL OF PORPHYRINS AND PHTHALOCYANINES, BOGNOR REGIS, GB, vol. 11, no. 12, 1 December 2007 (2007-12-01), GB , pages 829 - 835, XP009545392, ISSN: 1088-4246, DOI: 10.1142/S1088424607000953 *
HUANG YAN, HE NA, WANG YUNQING, SHEN DAZHONG, KANG QI, ZHAO RONGFANG, CHEN LINGXIN: "Self-assembly of nanoparticles by human serum albumin and photosensitizer for targeted near-infrared emission fluorescence imaging and effective phototherapy of cancer", JOURNAL OF MATERIALS CHEMISTRY. B, ROYAL SOCIETY OF CHEMISTRY, GB, vol. 7, no. 7, 13 February 2019 (2019-02-13), GB , pages 1149 - 1159, XP093057791, ISSN: 2050-750X, DOI: 10.1039/C8TB03054E *
YOON IL, LI JIA ZHU, SHIM YOUNG KEY: "Advance in Photosensitizers and Light Delivery for Photodynamic Therapy", CLINICAL ENDOSCOPY, vol. 46, no. 1, 1 January 2013 (2013-01-01), pages 7, XP093057794, ISSN: 2234-2400, DOI: 10.5946/ce.2013.46.1.7 *

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