WO2018064963A1 - Utilisation d'une structure à base de fullerène dans la préparation d'un médicament pour le traitement d'une tumeur - Google Patents

Utilisation d'une structure à base de fullerène dans la préparation d'un médicament pour le traitement d'une tumeur Download PDF

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WO2018064963A1
WO2018064963A1 PCT/CN2017/104665 CN2017104665W WO2018064963A1 WO 2018064963 A1 WO2018064963 A1 WO 2018064963A1 CN 2017104665 W CN2017104665 W CN 2017104665W WO 2018064963 A1 WO2018064963 A1 WO 2018064963A1
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fullerene
soluble
water
metal
hollow
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PCT/CN2017/104665
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English (en)
Chinese (zh)
Inventor
王春儒
甄明明
周悦
白春礼
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北京福纳康生物技术有限公司
中国科学院化学研究所
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Priority claimed from CN201610878746.1A external-priority patent/CN107137423A/zh
Priority claimed from CN201610878750.8A external-priority patent/CN106620727A/zh
Priority claimed from CN201610878766.9A external-priority patent/CN106619715A/zh
Priority claimed from CN201710322487.9A external-priority patent/CN108853141A/zh
Priority claimed from CN201710879059.6A external-priority patent/CN107913289A/zh
Application filed by 北京福纳康生物技术有限公司, 中国科学院化学研究所 filed Critical 北京福纳康生物技术有限公司
Publication of WO2018064963A1 publication Critical patent/WO2018064963A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/01—Hydrocarbons
    • A61K31/015—Hydrocarbons carbocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/244—Lanthanides; Compounds thereof
    • 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
    • A61K41/0028—Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
    • A61K41/0033—Sonodynamic cancer therapy with sonochemically active agents or sonosensitizers, having their cytotoxic effects enhanced through application of ultrasounds
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid

Definitions

  • the invention belongs to the field of biomedicine, and particularly relates to the application of a fullerene structure in preparing a medicament for treating tumor.
  • Cancer also known as malignant tumor, is the body's abnormal proliferation and metastasis caused by the loss of normal gene regulation caused by the body's cells under the stimulation of various carcinogenic factors. At present, cancer has become the second biggest killer of human health after cardiovascular disease. According to the World Cancer Report 2014 published by the World Health Organization's (WHO) International Agency for Research on Cancer, cancer has become the leading cause of global morbidity and mortality; in 2012, the number of new cancer patients worldwide increased by approximately 14 million. The number of deaths of cancer patients also reached 8.2 million in the same period; the report also pointed out that in the next 20 years, the number of new cancer patients may increase from 14 million in 2012 to 22 million. The current effective diagnosis and treatment of cancer has become one of the major problems that need to be solved in contemporary medicine.
  • Chemotherapy is one of the most commonly used methods in the current treatment of cancer, but the lack of targeting of chemotherapeutic drugs can also cause the death of normal cells while killing tumor cells, and thus often cause serious side effects.
  • the rapid development of nanotechnology has brought new hopes and possibilities for opening up new ways of cancer treatment.
  • Fullerenes are caged carbon clusters composed of different numbers of carbon atoms, which are another allotrope of carbon other than graphite, diamond and amorphous carbon.
  • the most abundant fullerene molecule is C 60 , then C 70 , C 84 , followed by C 76 , C 78 , C 82 , etc. with relatively low content.
  • the inside of the carbon cage of fullerenes is a cavity structure, the internal cavity can embed different atoms, ions or clusters of atoms, which is called inlaid fullerene, such as Gd@C 82 , indicating Gd inlay.
  • Gd@C 82 In the cage structure of C 82 , @ represents at, and the image expresses the meaning of inline.
  • One of the objects of the present invention is to provide a fullerene structure for use in the preparation of a medicament for treating tumors
  • a second object of the present invention is to provide a method, a pharmaceutical composition and a kit for treating a tumor
  • the third object of the present invention It is to provide a health care product or health food for improving tumors.
  • a fourth object of the present invention is to provide a water-soluble hollow fullerene nano material and a water-soluble metal fullerene nano material which can be used for the above-mentioned treatment of tumors.
  • the present invention provides the following technical solutions:
  • a use of a fullerene structure for preparing a medicament for treating a tumor comprising at least one active ingredient selected from the group consisting of oil-soluble hollow fullerenes, oil-soluble metal fullerenes, a combination of the oil-soluble hollow fullerene and the oil-soluble metal fullerene, a water-soluble hollow fullerene, a water-soluble metal fullerene, the water-soluble hollow fullerene, and A composition of a water-soluble metal fullerene, a pharmaceutically acceptable ester of the above six or a pharmaceutically acceptable salt of the above six.
  • the invention also provides a method of treating a tumor comprising administering to a subject having a tumor an effective amount of a fullerene structure comprising at least one active ingredient selected from the group consisting of: oil soluble Hollow fullerenes, oil-soluble metal fullerenes, compositions of the oil-soluble hollow fullerenes and the oil-soluble metal fullerenes, water-soluble hollow fullerenes, water-soluble metal rich a composition of a olefin, a water-soluble hollow fullerene and the water-soluble metal fullerene, a pharmaceutically acceptable ester of the above six or a pharmaceutically acceptable salt of the above six.
  • a fullerene structure comprising at least one active ingredient selected from the group consisting of: oil soluble Hollow fullerenes, oil-soluble metal fullerenes, compositions of the oil-soluble hollow fullerenes and the oil-soluble metal fullerenes, water-soluble hollow fullerenes, water-soluble metal rich a composition of
  • the method further comprises the step of: using a source of radiant energy matched to the fullerene structure The tumor site of the subject is irradiated.
  • the present invention also provides a pharmaceutical composition for treating a tumor comprising at least one fullerene structure selected from the group consisting of oil-soluble hollow fullerenes, oil-soluble metal fullerenes, and said oil a composition of a soluble hollow fullerene and the oil-soluble metal fullerene, a water-soluble hollow fullerene, a water-soluble metal fullerene, the water-soluble hollow fullerene, and the water-soluble a composition of a metal fullerene, a pharmaceutically acceptable ester of the above six or a pharmaceutically acceptable salt of the above six; the pharmaceutical composition further comprising a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent and At least one of the pharmaceutically acceptable excipients.
  • the present invention also provides a kit for treating a tumor comprising the above pharmaceutical composition and a device for generating a source of radiant energy.
  • the present invention also provides a health care product or health food for improving tumors, comprising at least one fullerene structure selected from the group consisting of oil-soluble hollow fullerenes, oil-soluble metal fullerenes, and a composition of an oil-soluble hollow fullerene and the oil-soluble metal fullerene, a water-soluble hollow fullerene, a water-soluble metal fullerene, the water-soluble hollow fullerene, and the a composition of a water-soluble metal fullerene, a pharmaceutically acceptable ester of the above six or a pharmaceutically acceptable salt of the above six; the health care product or health food further comprises an acceptable carrier in a health care product or a health food product At least one of a diluent, and an excipient.
  • the water-soluble hollow fullerene is selected from one or more of the group consisting of: (1) in hollow fullerenes The outer surface of the carbon cage of the body is modified with a hydrophilic group of modified fullerenes; (2) the modified fullerenes of the outer surface of the carbon cage of the hollow fullerene body are encapsulated by hydrophilic biological small molecules; (3) a modified fullerene formed by loading a hollow fullerene body with a biocompatible carrier material; (4) a fullerene of a water-soluble supramolecular system formed by self-assembly.
  • the water-soluble metal fullerene is selected from one or more of the group consisting of: (1) in metal fuller The outer surface of the carbon cage of the olefin body is modified with a hydrophilic group of modified fullerenes; (2) the modified fullereene of the outer surface of the carbon cage of the metal fullerene body is surrounded by a hydrophilic biological small molecule; a modified fullerene formed by loading a metal fullerene body with a biocompatible carrier material; (4) a metal fullerene of a water-soluble supramolecular system formed by self-assembly.
  • the hollow fullerene body comprises one or more cage structures composed of carbon atoms of the formula C 2m , 20 ⁇ m ⁇ 60, optional 30 ⁇ m ⁇ 60 , for example; C 60 , C 70 , C 84 and the like.
  • the metal fullerene body comprises: M@C 2n , M 2 @C 2n , MA@C 2n , M 3 N At least one of @C 2n , M 2 C 2 @C 2n , M 2 S@C 2n , M 2 O@C 2n , and M m A 3-m N@C 2n ; wherein M and A are both metals
  • the element, the M and A are each selected from at least one of Sc, Y and a lanthanide metal element, and the optional rare earth metal is Gd, La, etc.; 20 ⁇ n ⁇ 60, optionally 30 ⁇ n ⁇ 60,
  • n is 41 or 30 or 35, 0 ⁇ m ⁇ 3, and n and m are integers.
  • the hydrophilic group includes one or more of a hydroxyl group, a carboxyl group, a thiol group, an amino group, and an amino acid residue.
  • the amino acid residue refers to a part of an amino acid that loses an amino acid molecule when modifying a hollow fullerene body or a metal fullerene body.
  • the remaining incomplete amino acids, ie, the amino acid residues are part of the amino acid molecule, which are incomplete amino acids.
  • Any part of the missing amino acid molecule is considered to be an amino acid residue, such as: amino acid loses hydrogen on the amino group to bond with the hollow fullerene bulk or metal fullerene body, amino acid loses hydrogen or hydroxyl group on the carboxyl group, and hollow fullerene Bonding of the olefinic body or the metal fullerene body occurs.
  • the amino acid residue is a water-soluble amino acid residue, such as an alanine residue, a glycine residue, a serine residue, an arginine residue, a lysine residue, and a glutamic acid residue. At least one of them.
  • the water-soluble hollow fullerene has the formula C 2a (OH) b (Amino Acid) c and Amino Acid represents the above application, method, pharmaceutical composition, health care product or health food.
  • the water-soluble metal fullerene has the formula of metallofullerene-(OH) x (Amino Acid) y , and the metallofullerene represents a metal.
  • the water-soluble metal fullerene has the formula M@C 2d (OH) x (Amino Acid) y ,
  • Amino Acid represents a water-soluble amino acid residue;
  • the hydrophilic biological small molecule comprises at least one of an amino acid and a peptide chain.
  • the biocompatible carrier material comprises at least one of a liposome and a cell membrane carrier.
  • the water-soluble hollow fullerene or the water-soluble metal fullerene has an average hydrated particle diameter of from 1 to 1000 nm, optionally selected from the above-mentioned applications, methods, pharmaceutical compositions, health care products or health foods. It is 1-200 nm, 100-200 nm, 120-160 nm.
  • the fullerene structure in the present application can be In the case of nanomaterials, the size of the water-soluble fullerene structure can be controlled by controlling the size of the agglomerated nanoparticles formed by the intermolecular interaction by changing the solvent species in a solvent environment.
  • the water-soluble hollow fullerene is obtained by water-soluble modification of a hollow fullerene body, the water-soluble solution.
  • the metal fullerenes are obtained by water-soluble modification of the metal fullerene body.
  • method, pharmaceutical composition, health care product or health food product is any one of the following methods:
  • a method of modifying only a hydroxyl group on the outer surface of the carbon cage of the hollow fullerene body and/or the metal fullerene body includes at least one of the following two methods:
  • the first method is a solid-liquid reaction: mixing a hollow fullerene body and/or a metal fullerene body, a hydrogen peroxide solution and an alkali solution (alkaline solution: sodium hydroxide solution or potassium hydroxide solution), and reacting the reaction solution. Washing, then collecting the precipitate and then dialysis;
  • the solid-liquid reaction is: (a) a hydrogen peroxide solution having a mass percentage of 1-40% (optionally 1-30%) and a sodium hydroxide solution having a mass percentage of 10-80% or
  • the potassium hydroxide solution is mixed in a volume ratio of 1-10:1 to obtain a mixed solution, and 20-500 mg of hollow fullerene body and/or metal fullerene body (for example, C 60 solid or C 70 solid or Gd@C 82 solid), stirred (optional stirring at 50-80 ° C, further optional stirring time is 4-24 h, stirring speed 1000 r / min) until the solids are all dissolved, filtered , retaining the filtrate; (b) adding the filtrate to an excess concentration of 85%-100% ethanol for washing, and centrifuging (optional centrifugal speed of 10000r / min, centrifugation time of 1-10min), collecting the precipitate, The precipitate is dissolved in water to obtain a solution; (c) the solution obtained in the step (b) is subject
  • the second method is liquid-liquid reaction: the hollow fullerene body and / or metal fullerene body, phase transfer
  • the catalyst was mixed with tetramethylammonium hydroxide, mixed with a sodium hydroxide solution and/or a potassium hydroxide solution, and the reaction solution was washed, and then the precipitate was collected and dialyzed.
  • the preparation method is selected from at least one of the following two methods:
  • Method 1 comprising the steps of: (a) formulating a water-soluble amino acid alkali solution using an amino acid with NaOH and/or KOH (optionally, the molar ratio of amino acid to NaOH and/or KOH is 1:1-10, and optionally It is 1:2 or 1:1-8; alternatively, the mass fraction of NaOH and/or KOH in the amino acid alkali solution may be 10-50%, and optionally 14% or 10-30%); According to the molar ratio of amino acid to hollow fullerene body and / or metal fullerene body is 1-1000:1, optionally 50-1000:1, 100-1000:1,200-1000:1,1 -100:1, mixing an amino acid base solution with a hollow fullerene body and/or a metal fullerene body; (c) reacting the above mixture at 40-80 ° C (optionally, the reaction is a stirring reaction 1 - 7 hours), unreacted small amount of solid powder is removed by filtration; (d) filtrate is dialyzed to remove small molecular impur
  • Method 2 Mixing the sodium hydroxide solution and/or the potassium hydroxide solution containing the amino acid with ethanol, and adding to the hollow fullerene body and/or the metal fullerene body (for example, C 60 solid or C 70 solid or Gd In the toluene solution of @C 82 solid), the upper layer of toluene was removed by stirring, and the lower layer was dialyzed.
  • the hollow fullerene body and/or the metal fullerene body for example, C 60 solid or C 70 solid or Gd In the toluene solution of @C 82 solid
  • the number of amino acids and hydroxyl groups modified on the surface of the carbon cage may also be different, but those skilled in the art can obtain the passage according to the content disclosed in the present application.
  • Carbon cages modified with different amino acids and hydroxyl groups The number of amino acids and hydroxyl groups modified on the surface of the carbon cage was detected.
  • the physical coating method is: mixing the hollow fullerene body and/or the metal fullerene body with at least one of polyethylene glycol, polyvinylpyrrolidone and cyclodextrin and performing ball milling or ultrasonicing, etc.
  • Coated water-soluble hollow fullerenes and/or water-soluble metal fullerenes such as polyethylene glycol-coated hollow fullerenes and/or polyethylene glycol-coated metal fullerenes, can be obtained.
  • the amino acid used in the water-soluble modification is alanine, glycine, serine, arginine, lysine, and aspartic acid. At least one of them.
  • the oil-soluble hollow fullerene is coated with edible oil on the outer surface of the hollow cage of the hollow fullerene body.
  • Hollow fullerenes for example, the outer surface of the carbon cage of the hollow fullerene body is coated with modified hollow fullerenes of olive oil, and the outer surface of the hollow cage of the hollow fullerene body is coated with sunflower oil.
  • Hollow fullerenes the outer surface of the carbon cage of the hollow fullerene body is coated with modified hollow fullerenes of linseed oil, and the outer surface of the carbon cage of the hollow fullerene body is coated with modified hollow squalane The outer surface of the carbon cage of the hollow fullerene body is coated with a modified hollow fullerene of a mixed oil of various oils.
  • the oil-soluble metal fullerene is modified by an edible oil for the outer surface of the carbon cage of the metal fullerene body.
  • Metal fullerenes for example, the outer surface of the carbon cage of the metal fullerene body is coated with modified metal fullerenes of olive oil, and the outer surface of the carbon cage of the metal fullerene body is coated with modified metal of sunflower oil Fullerene, the outer surface of the carbon cage of the metal fullerene body is coated with a modified metal fullerene of linseed oil, and the outer surface of the carbon cage of the metal fullerene body is coated with a modified metal fullerene of squalane The outer surface of the carbon cage of the alkene, metal fullerene body is coated with a modified metal fullerene of a mixed oil of various oils.
  • the oil-soluble hollow fullerene comprises an edible oil-coated C 60 , an edible oil-coated C 70 or an edible oil.
  • the above-mentioned application, method, pharmaceutical composition, health care product or health food product At least one of the coated C 84 ; the oil-soluble metal fullerene comprises edible oil coated Gd@C 82 .
  • the oil-soluble hollow fullerene and/or oil-soluble metal fullerene, the fullerene body and the above-mentioned application, method, pharmaceutical composition, health care product or health food may range from 50 to 50000 ppm (mg/kg), alternatively from 50 to 10000 ppm, from 100 to 5000 ppm, from 5000 to 10000 ppm, from 1000 to 2000 ppm or from 1500 ppm.
  • the oil-soluble hollow fullerenes are obtained by oil-soluble modification of a hollow fullerene body;
  • the oil-soluble metal is the above-mentioned application, method, pharmaceutical composition, health care product or health food.
  • Fullerenes are obtained by oil-soluble modification of the metal fullerene body.
  • the oil-soluble modification method is achieved by covalent or non-covalent action.
  • the oil-soluble modification (modification may also be referred to as modification) is: coating the fullerene body and/or the metal fullerene body with edible oil to obtain the oil-soluble hollow fullerene and / or oil-soluble metal fullerene, further optional, the method of coating may be carried out by dispersing a hollow fullerene body and/or a metal fullerene body in the edible oil to obtain a mixed liquid, and mixing the obtained The liquid is sequentially removed by centrifugation, and then the resulting supernatant liquid is filtered to obtain an oil-soluble modified liquid; optionally, the mixture is subjected to ball milling or ultrasonic treatment before centrifugation.
  • the hollow fullerene body comprises one or more cage structures composed of carbon atoms of the formula C 2m , 20 ⁇ m ⁇ 60, optional 30 ⁇ m ⁇ 60 , for example; C 60 , C 70 , C 84 and the like.
  • the metal fullerene body comprises: M@C 2n , M 2 @C 2n , MA@C 2n , M 3 N At least one of @C 2n , M 2 C 2 @C 2n , M 2 S@C 2n , M 2 O@C 2n , and M m A 3-m N@C 2n ; wherein M and A are both metals
  • the element, the M and A are each selected from at least one of Sc, Y and a lanthanide metal element, and the optional rare earth metal is Gd, La, etc.; 20 ⁇ n ⁇ 60, optionally 30 ⁇ n ⁇ 60,
  • n is 41 or 30 or 35, 0 ⁇ m ⁇ 3, and n and m are integers.
  • 0.05 to 500 mg of the hollow fullerene body and/or the metal fullerene body is dispersed in each 1 ml of the edible oil to obtain a mixed liquid.
  • the disclosure of this range should be considered as a disclosure of all values in the range, optionally with fullerene bulk material and/or metal fullerene body of 0.05-1 mg, 5-10 mg, 0.05-10 mg, 0.05-100 mg, etc.
  • the material was dispersed in 1 ml of cooking oil.
  • the mixture is subjected to ball milling or ultrasonication for 30 min to 15 h, optionally for 30 min to 1 h, 30 min to 2 h, and 2 h to 5 h.
  • the centrifugation is performed after the mixture is subjected to ball milling or ultrasonication, and the mixture is stored in a cool, dry, dark place. Allow to stand for a certain period of time and then centrifuge.
  • a certain time refers to 2h-24h.
  • the edible oil may be a single component oil or a mixed oil formed of different oils.
  • the edible oil is at least one of vegetable oil, such as olive oil, linseed oil, sunflower oil, corn germ oil, corn oil, palm oil, castor oil and soybean oil, and optionally animal fat.
  • vegetable oil such as olive oil, linseed oil, sunflower oil, corn germ oil, corn oil, palm oil, castor oil and soybean oil, and optionally animal fat.
  • vegetable oil such as olive oil, linseed oil, sunflower oil, corn germ oil, corn oil, palm oil, castor oil and soybean oil
  • animal fat such as squalane and so on.
  • the tumor, the liver cancer, the lung cancer, the colorectal cancer, the kidney cancer, the pancreatic cancer, the bone cancer, the breast cancer, the ovarian cancer, the prostate At least one of cancer, esophageal cancer, gastric cancer, oral cancer, nasal cancer, laryngeal cancer, cholangiocarcinoma, cervical cancer, uterine cancer, testicular cancer, meningioma, skin cancer, melanoma, and sarcoma.
  • the treating a tumor comprises: destroying at least one of a tumor structure and inhibiting tumor growth.
  • the treating the tumor comprises: reducing the tumor volume, reducing the tumor mass, destroying the tumor vascular structure, blocking the tumor blood vessel, At least one of destroying endothelial junction of tumor blood vessels, reducing the content of VE-cadherin at the tumor site, inhibiting tumor volume increase, inhibiting tumor mass increase, slowing down tumor volume increase, and slowing tumor mass increase .
  • the drug or the pharmaceutical composition of the above application is a tumor vascular blocker.
  • the medicament or the pharmaceutical composition is a pharmaceutically acceptable dosage form, and may be a tablet, a pill, a powder, a lozenge, a sachet, or a sachet. Preparations of tinctures, suspensions, emulsions, solutions, syrups, aerosols, ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions or aseptically packaged powders.
  • the active ingredient is prepared into a pharmaceutical or pharmaceutical composition such that the active ingredient is released, sustained release or delayed release after administration to a subject, for example, the active ingredient may be mixed with a carrier, diluted with a carrier or encapsulated in a carrier. In the carrier.
  • some examples suitable as carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starch, resins, Acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methylcellulose, methylparaben And propyl ester, talc, magnesium stearate and liquid paraffin.
  • a solvent or carrier suitable as a drug include water, physiological saline, PBS buffer, and Tris- At least one of HCl solutions; optionally, the concentration of the physiological saline is 0.85-0.90%; alternatively, the concentration of the PBS buffer is 0.01-0.1 mol/L, and the composition of the component is specifically Na 2 HPO 4. KH 2 PO 4 , NaCl and KCl; optionally, the concentration of the Tris-HCl solution is 0.05 mol/L.
  • the medicament or the above pharmaceutical composition in the above application may additionally comprise a lubricant, a wetting agent, an emulsifying and suspending agent, a preservative, a sweetener or a flavoring agent. And other additives.
  • the drug in the above application or the above pharmaceutical composition is in another embodiment, when the drug When the substance or the pharmaceutical composition is present in a liquid form, the concentration of the fullerene structure in the drug or the pharmaceutical composition is 0.01-1000 mg/mL, optionally 0.01-10 mg/mL, 0.01-20 mg.
  • the concentration of the fullerene structure in the drug or the pharmaceutical composition is from 0.1 to 1000 mg/g, alternatively from 0.1 to 100 mg/g, from 0.01 to 50 mg/g, from 0.01 to 10 mg/g. 0.01-20 mg/g, 0.01-30 mg/g, 0.01-40 mg/g, 20-30 mg/g, 30-40 mg/g.
  • the subject may also be referred to as a tumor-bearing organism, which may be a human or an animal, and the animal may be a mammal, such as a mouse, a guinea pig, a rat, a dog, a rabbit, a pig, Monkeys, etc.
  • a tumor-bearing organism which may be a human or an animal
  • the animal may be a mammal, such as a mouse, a guinea pig, a rat, a dog, a rabbit, a pig, Monkeys, etc.
  • the fullerene structure is administered at a time selected from the group consisting of an initial stage of tumor growth, when tumor blood vessels have not yet formed, a middle stage of tumor growth, and/or a late stage of tumor growth;
  • the method is at least one of gavage, intravenous injection, intraperitoneal injection, oral administration and topical administration; the fullerene structure is administered at a dose of 1 mg/kg/d to 1000 mg/kg/d, optionally 1 -100 mg/kg/d, 1-20 mg/kg/d, 1-10 mg/kg/d, 10-100 mg/kg/d, and the total dose of the specific subject is converted according to its body weight;
  • the course of enema structure administration depends on the growth cycle of the tumor, and the growth rate of different tumors is different, and can be applied for several days to several tens of days, such as 5-30 days for one course of treatment.
  • the radiant energy source may be a radio frequency.
  • the radiant energy source used may have a frequency of 1-1000 MHz, optionally 200 MHz, 1-200 MHz, 200-1000 MHz, 50-500 MHz or 150-500 MHz;
  • the transmission power is 1mW-10kW, optional 20W;
  • the absorption power of the organism is 1mW-10kW, optionally 1-1000mW, optionally 5mW, 1mW-5mW, 5mW-10kW or 1mW- 100mW;
  • radiation energy source for irradiation time is 10min-2h, optional 10min-30min, 30min, 10min-1h, 20min-1h, 1h, 30min-2h, 1h-2h or 10min-1.5h;
  • RF radiation The source is pulse mode.
  • the method of injecting the drug is performed after 0-2 hours. Photo; optional 10min, 10min-50h or 10min-2h.
  • the invention also provides a water-soluble fullerene nano material having the structural formula: C 2n (OH) x (Amino Acid) y ;
  • Amino Acid is a water soluble amino acid.
  • n may specifically be 30 or 35.
  • the number of amino acids and hydroxyl groups modified on the surface of the carbon cage is also different due to the difference in affinity of the different amino acids to the fullerene carbon cage in the reaction.
  • the water-soluble amino acid is at least one of alanine, glycine, serine, arginine, lysine, and aspartic acid.
  • the nanomaterial has a hydrated particle diameter of from 1 to 1000 nm.
  • the water-soluble fullerene nano material has a structural formula of C 2n (OH) x (Amino Acid) y , which can change the number of x and y by adjusting the reaction conditions, thereby adjusting the intermolecular interaction force, thereby The hydrated particle size of the water-soluble fullerene nanomaterial agglomerated in a solvent is changed.
  • the water-soluble fullerene nanomaterial of the present invention can be prepared by the following method:
  • a method of modifying a hydroxyl group on the outer surface of a carbon cage of a hollow fullerene body C 2n includes at least one of the following two methods:
  • the first method is a solid-liquid reaction: mixing a hollow fullerene body C 2n , hydrogen peroxide and an alkali solution (alkaline solution: sodium hydroxide solution or potassium hydroxide solution) and reacting, washing the reaction liquid, then collecting the precipitate and then collecting the precipitate Dialysis
  • the solid-liquid reaction is: (a) a hydrogen peroxide solution having a mass percentage of 1-40% and a sodium hydroxide solution or a potassium hydroxide solution having a mass percentage of 10-80% by volume ratio of 1- Mixing 10:1 to obtain a mixture, adding 20-500 mg of hollow fullerene bulk C 2n per 10-200 ml of the mixture, stirring (optionally stirring at 50-80 ° C, further optional stirring time is 4-24h, stirring speed is 1000r/min) until the solid is completely dissolved, filtered, and the filtrate is retained; (b) the filtrate is added to an excess concentration of 85%-100% ethanol for washing, and centrifugation (optional centrifugation) The rotation rate is 10000 r/min, the centrifugation time is 1-10 min), the precipitate is collected, the precipitate is dissolved in water to obtain a solution; (c) the solution obtained in the step (b) is subjected to dialysis treatment (optional dialysis to the The conductivity of the solution at
  • the second method is a liquid-liquid reaction: mixing a hollow fullerene body C 2n , a phase transfer catalyst tetramethylammonium hydroxide, and a sodium hydroxide solution or a potassium hydroxide solution, and reacting the reaction liquid, and then collecting the precipitate. Then dialysis.
  • the preparation method comprises the steps of: mixing a sodium hydroxide solution or a potassium hydroxide solution containing an amino acid with ethanol, and adding to the hollow rich The toluene solution of the enantiomer C 2n was stirred to remove the upper toluene layer, and the lower layer was dialyzed.
  • the present invention provides an amino acid-modified metal fullerene water-soluble nanoparticle having a structural formula of metallofullerene-(OH) x (Amino Acid) y ;
  • metallofullerene is a metal fullerene
  • Amino Acid is a water soluble amino acid.
  • the metal fullerenes include; M@C 2n , M2@C 2n , MA@C 2n , M 3 N@C 2n , M 2 C 2 @C 2n , M 2 S@C 2n At least one of M 2 O@C 2n and M m A 3-m N@C 2n ; wherein M and A are both metal elements, and both M and A are selected from the group consisting of Sc, Y and lanthanide metal elements At least one of 30 ⁇ n ⁇ 60, 0 ⁇ m ⁇ 3, and n and m are integers;
  • the water-soluble amino acid is at least one of alanine, glycine, serine, arginine, lysine, and aspartic acid.
  • the lanthanide metal elements are lanthanum (La), cerium (Ce), praseodymium (Pr), cerium (Nd), cerium (Pm), cerium (Sm), cerium (Eu), cerium (Gd), cerium. (Tb), Dy, Ho, Er, Tm, Yb, Lu;
  • the rare earth metal may specifically be Gd, and the metal fullerene may specifically be Gd@C 82 or Gd 3 N@C 80 .
  • the nanoparticles may have a hydrated particle diameter of from 1 to 1000 nm, specifically from 10 to 300 nm. Specifically, it may be 100-150 nm.
  • the present invention also provides a method for preparing the above-mentioned nanoparticles, comprising the steps of: mixing an alkali solution of the water-soluble amino acid with the metal fullerene to carry out a nucleophilic addition reaction, thereby obtaining the metal modified by the amino acid Fullerene water soluble nanoparticles.
  • the metal fullerene is purified by high performance liquid chromatography coupled with fullerene/inlaid metal fullerene-specific chromatography column Buckyprep/Buckyprep-M.
  • the preparation method of the present invention is equally applicable to hollow fullerenes, that is, the metal fullerenes are replaced by hollow fullerenes; the hollow fullerenes include C 60 or C 70 .
  • the alkali solution of the water-soluble amino acid may have a mass fraction of 10-50%, specifically 14% or 10-30%, 10-14%, 14-50% or 11-25. %; the molar ratio of the water-soluble amino acid to the base may be 1:1-10, specifically 1:2 or 1:1-8; the alkali solution used in the alkali solution of the water-soluble amino acid may specifically be hydrogen a sodium oxide solution and/or a potassium hydroxide solution;
  • the molar ratio of the water-soluble amino acid to the metal fullerene may be from 1 to 1000:1, specifically from 1000:1, from 50 to 1000:1 or from 1 to 100:1.
  • the temperature of the nucleophilic addition reaction may be 50-100 ° C, specifically 50 ° C; the time of the nucleophilic addition reaction may be 1-48 h, specifically 1 to 1.5 h. , 1 to 5h, 1-30h, 1.5h, 1.5 to 7h, 1.5-24h, 2h, 4h or 24h.
  • a small molecular impurity specifically, a water-soluble amino acid and a base
  • the water-soluble fullerene nanoparticles prepared by the invention, the surface modified carboxyl residue facilitates further coupling with the biological ligand, and provide more possibilities for subsequent biological applications.
  • an effective amount means an amount sufficient to effectively deliver an active ingredient for treating a tumor when administered by the method of the present invention, or an active ingredient may be administered to a patient a single or multiple times.
  • the effective amount can be determined by the participating diagnostician as a result of known techniques by those skilled in the art and in similar circumstances.
  • the participating diagnostician should consider a variety of factors including, but not limited to, the mammalian species; volume, age, and general health; the particular disease involved Degree or severity of involvement of the disease; response of the individual patient; specific compound administered; mode of administration; bioavailability properties of the administered formulation; selected dosing regimen; use with drug therapy; Related situation.
  • hollow fullerene body means a hollow fullerene which is neither water-soluble nor oil-soluble modified, that is, a hollow fullerene raw material.
  • metal fullerene body as used in the present invention means a metal fullerene which is neither water-soluble nor oil-soluble modified, that is, a metal fullerene material.
  • the concentration of the fullerene structure in the drug or pharmaceutical composition is 0.01-50 mg/mL.
  • concentration of the carbon cage of the hollow fullerene body and/or the metal fullerene body detected in the drug or pharmaceutical composition is 0.01-50 mg/mL.
  • fullerene and metal fullerene can be quantitatively determined by inductively coupled plasma optical emission spectrometry (ICP) or liquid chromatography HPLC.
  • the present invention has the following beneficial effects:
  • the invention discloses a use of a fullerene structure in the preparation of a medicament for treating tumors, wherein the fullerene structure has high inhibition efficiency on tumors, and can inhibit tumor growth, for example, inhibiting tumor volume increase and inhibiting tumors.
  • Increased mass, slower tumor volume increase, and slower tumor mass increase can also destroy existing tumor structures, such as reducing the volume and quality of existing tumors, destroying existing tumor vascular structures, and destroying There is endothelial junction of tumor blood vessels, reducing the content of VE-cadherin in the tumor site;
  • the fullerene structure of the present invention can be used together with radio frequency, or can be used alone, and is flexible in use, and can be applied to tumor patients in different situations.
  • the fullerene structure When used with radio frequency, the fullerene structure can achieve high tumor inhibition rate in a single use. After the drug enters the organism, it reaches the tumor site through blood circulation, and then RF stimulation is applied to make the nanoparticles in the tumor site play a role in the blood vessel. Because tumor blood vessels are very different from normal tissue blood vessels, the endothelial cells of tumor blood vessels have large gaps and incomplete structure, which leads to tumor blood vessels usually containing a large number of nanometer-scale pores, due to the high permeability of tumors.
  • EPR effect Retention effect
  • fullerene nanoparticles can be embedded in these small holes to destroy tumor blood vessels, thereby introducing a large amount of bleeding inside the tumor, cutting off the nutrient supply of the tumor tissue, thereby inhibiting the growth of the tumor.
  • the treatment is not limited by the distribution of the tumor in the living body, and can treat tumors near the surface of the living body as well as tumors of deep organs or tissues of the living body.
  • the treatment When not used with radiofrequency, the treatment can be achieved by taking the fullerene structure multiple times.
  • the purpose of the tumor this method of use greatly facilitates cancer patients who are not suitable for radiofrequency.
  • the present invention is directed to the difference between tumor blood vessels and normal blood vessels, and has a broad spectrum by treating tumors by specifically blocking tumor blood vessels.
  • the present invention makes the fullerene structure easier to enter cells by water-soluble modification or oil-soluble modification, and has a good affinity with the organism. It is more biosafer and has no toxic side effects on normal biological tissues. When used, the dosage is small.
  • the present invention also provides a water-soluble hollow fullerene nano material modified with a hydroxyl group and an amino acid, a preparation method thereof, and a water-soluble metal fullerene nano material modified by a hydroxyl group and an amino acid, and a preparation method thereof, the two nanometers
  • the materials belong to the fullerene structure of the invention and can be applied to the preparation of a medicament for treating tumors.
  • the preparation of the two nanomaterials does not require the intervention of an organic solvent, does not require separation of intermediate products, does not require anhydrous and oxygen-free conditions, and has a simple preparation method. Economic, green and other advantages.
  • the nanomaterial prepared by the method has the characteristics of small particle size distribution and narrowness.
  • thermogravimetric analysis and a micro-commercial thermogravimetric analysis curve of C 70 (OH) 29 ⁇ 10H 2 O of the present invention.
  • thermogravimetric analysis and a micro-commercial thermogravimetric analysis curve of C 70 (OH) 13 (CH 2 OHCHNHCOOH) 4 ⁇ 15H 2 O of the present invention.
  • thermogravimetric analysis and a micro-commercial thermogravimetric analysis curve of C 70 (OH) 24 ⁇ 5H 2 O according to the present invention.
  • Figure 4 is a graph showing the hydrated particle size of C 70 (OH) 29 and C 70 (OH) 13 (CH 2 OHCHNHCOOH) 4 in pure water of the present invention.
  • Figure 5 is a graph showing the hydrated particle size distribution curve of C 70 (OH) 24 in pure water of the present invention.
  • Figure 6 is a Zeta potential of C 70 (OH) 29 in pure water of the present invention.
  • Figure 7 is a high resolution atomic force microscope image of C 70 (OH) 29 and C 70 (OH) 13 (CH 2 OHCHNHCOOH) 4 in pure water of the present invention.
  • Fig. 8 is a graph showing the therapeutic effects of C 70 (OH) 29 and C 70 (OH) 13 (CH 2 OHCHNHCOOH) 4 on mouse liver cancer tumors of the present invention.
  • Figure 9 is a photograph of liver cancer tumors of saline control mice before and after treatment.
  • Figure 10 is a graph showing the effects of different reagents on H22 tumors; wherein a) is a photograph of a large amount of congestion at the tumor at 24 hours after treatment of H22 tumors with C 70 (OH) 29 ; Figure b) is a saline control group H22 tumor HE staining picture; Figure c) is a HE staining picture of the tumor treated with C 70 (OH) 29 for 24 h after treatment of H22 tumor; Figure d) is C 70 (OH) 13 (CH 2 OHCHNHCOOH) 4 treatment of H22 tumor 24 h after tumor HE stained picture.
  • Figure 11 is a HE staining picture of each organ of the saline group, C 70 (OH) 29 , C 70 (OH) 13 (CH 2 OHCHNHCOOH) 4 24 h after treatment;
  • a1-a5 is a saline group HE staining pictures of heart, liver, spleen, lung and kidney were treated, and b1-b5 were HE staining pictures of heart, liver, spleen, lung and kidney for C 70 (OH) 29 , respectively
  • c1-c5 were C 70 (OH 13 (CH 2 OHCHNHCOOH) 4 treatment of heart, liver, spleen, lung, kidney HE staining pictures
  • Figure 12 is a comparison of the effects of physiological saline group, C 70 (OH) 29 , C 70 (OH) 13 (CH 2 OHCHNHCOOH) 4 on the treatment of mouse sarcoma S180, wherein a1, a2, and a3 are saline groups, respectively.
  • C 70 (OH) 29 , C 70 (OH) 13 (CH 2 OHCHNHCOOH) 4 before treatment of mouse sarcoma S180; b1, b2, b3 are saline group, C 70 (OH) 29 , C A picture of 70 (OH) 13 (CH 2 OHCHNHCOOH) 4 after treatment with mouse sarcoma S180.
  • FIG 13 of the present invention C 70 (OH) 29 drug group and control group tumor fluorescence imaging at different time points.
  • Figure 14 is a graph showing the tumor growth curves of the C 70 (OH) 29 drug group and the saline control group in the present invention.
  • FIG 16 of the present invention C 70 (OH) 29 after treatment changes in tumor vascular endothelial CD31 staining connected through 2h and 6h.
  • Figure 17 is a result of immunoblotting of VE-cadherin in tumors at different time points after treatment of C70 (OH) 29 in the present invention.
  • Figure 18 is a graph showing changes in body weight of a C 70 (OH) 29 drug group and a saline control group in the present invention.
  • Figure 19 is a flow chart showing the experiment of inhibiting the growth of mouse liver cancer tumors by C 70 -OH in the present invention.
  • Figure 20 is a picture showing the growth of mouse liver cancer tumors of different groups at different time points in the present invention, wherein Saline (ip) is a control group for intraperitoneal injection of physiological saline; C 70 -OH (ip) is intraperitoneal injection of C 70 -OH The drug group; C 70 -OH (iv) is a drug group for intravenous injection of C 70 -OH.
  • Figure 21 is a comparative photograph of liver cancer tumors of 4 parallel mice of each group of the drug group and the control group at the end of the experiment in the present invention.
  • Figure 22 is a graph showing tumor volume and quality data of a drug group and a control group in the present invention.
  • Figure 23 is a graph showing the weight gain of mice in the drug group and the control group during the experiment in the present invention.
  • Figure 24 is a graph showing conventional blood index data of a drug group and a control group in the present invention.
  • ALT is alanine aminotransferase
  • AST is aspartate aminotransferase
  • ALP is alkaline phosphatase
  • BUN is urea nitrogen.
  • Figure 26 is a graph showing the tumor growth curves of the drug group and the control group in the present invention.
  • Figure 27 is a graph showing the weight gain of mice in the drug group and the control group during the experiment in the present invention.
  • ALT is alanine aminotransferase
  • AST is aspartate aminotransferase
  • ALP is alkaline phosphatase
  • BUN is urea nitrogen.
  • Figure 29 is a thermogravimetric analysis and micro-commercial thermogravimetric analysis curve of Gd@C 82 (OH) 13 (NHCH 2 CH 2 COOH) 6 (abbreviated as GF-Ala) prepared in the present invention.
  • Figure 31 is an infrared spectrum of Gd@C 82 (OH) 13 (NHCH 2 CH 2 COOH) 6 of the present invention.
  • Figure 32 is a graph showing the ultraviolet-visible absorption spectrum of Gd@C 82 (OH) 13 (NHCH 2 CH 2 COOH) 6 of the present invention.
  • Figure 35 is a graph plotting the reciprocal 1/T1 of the longitudinal relaxation time measured by the reverse-recovery sequence of the metal fullerene Gd@C 82 nanoparticles prepared in accordance with the present invention for different Gd concentrations.
  • Figure 37 is a graph showing the thermogravimetric and micro-commerce thermogravimetric curves of the water-soluble hollow fullerene C 70 structure C 70 (OH) 13 (NHCH 2 CH 2 COOH) 6 prepared according to the present invention.
  • Figure 40 is a thermogravimetric analysis and a micro-commercial thermogravimetric analysis curve of the water-soluble hydroxyl-modified Gd@C 82 nanoparticles (abbreviated as GF-OH) of the present invention.
  • Figure 41 Magnetization curve and magnetization-temperature curve of two drugs, GF-Ala and GF-OH.
  • Figure 42 High-resolution atomic force microscopy images of GF-Ala and GF-OH.
  • Figure 43 Fluorescence quenching curve of GF-Ala and GF-OH drugs, from which the protein binding rate of the two drugs can be calculated, where F0 is the fluorescence of the protein without fullerene, and F is rich. The fluorescence of the post-leene protein, Q is the fullerene concentration.
  • Figure 44 is a magnetic resonance imaging picture of the GF-Ala drug of the present invention before, after, and 24 hours after treatment.
  • Figure 45 Comparison of tumor inhibition rates of the two drugs in the present invention, tumor state changes of mouse tumors at different time points during long-term observation for 12 days, and tumor volume and weight comparison of mice after 12 days.
  • Figure 46 is an environmental scanning photograph of tumor blood vessels of the two drugs in the present invention 24 hours after treatment (where a is GF-Ala plus radiofrequency, b is a partial enlarged view of a, c is GF-OH plus radiofrequency, d is GF-Ala Without radiofrequency, e is physiological saline plus radiofrequency, f is only injected with normal saline).
  • Figure 47 is a graph showing tumor volume growth curves of different groups of mice in the present invention.
  • Figure 48 is a graph showing changes in body weight of different groups of mice in the present invention.
  • the raw material C 60 solid powder used in the following examples was purchased from Xiamen Funa New Material Technology Co., Ltd., with a molecular weight of 720 and a purity of 99%.
  • the raw material C 70 solid powder used in the following examples was purchased from Xiamen Funa New Material Technology Co., Ltd., with a molecular weight of 840 and a purity of 99%.
  • the raw material Gd@C 82 solid powder used in the following examples was purchased from Xiamen Funa New Material Technology Co., Ltd., with a molecular weight of 1141 and a purity of 99.1%.
  • Other materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
  • step (b) The solution obtained in the step (a) was added to a 50 ml centrifuge tube, and an excess of 95% ethanol was added. After centrifugation (rotation speed: 10000 r/min, time: 4 min), the upper colorless solution was removed, and the collected precipitate was dissolved in ultrapure water to obtain a yellow clear solution.
  • step (c) The solution obtained in the step (b) was placed in a dialysis bag (cutoff molecular weight: 3,500) and dialyzed in ultrapure water, and the conductivity of the ultrapure water at room temperature was less than 1 ⁇ s/cm to obtain a yellow solution.
  • step (d) The solution after the dialysis in step (c) is placed in a 50 mL plastic centrifuge tube, frozen in liquid nitrogen, and placed in a freeze dryer to freeze-dry (temperature: -29 ° C, vacuum: 55 Pa, time: 48 h). The resulting yellow solid was placed in a brown vial for later use.
  • Example 2 Modifying the number of hydroxyl groups and the number of amino acids of the water-soluble hollow fullerene structure
  • the number of hydroxyl groups can be calculated as 13, so the average molecular formula of the product is C 70 (OH) 13 (CH 2 OHCHNHCOOH) 4 15H 2 O, referred to herein as C 70 -Ser or C 70 (OH) 13 (CH 2 OHCHNHCOOH) 4 .
  • C 70 (OH) 29 , C 70 (OH) 13 (CH 2 OHCHNHCOOH) 4 and C 70 (OH) 24 powders prepared in Example 1 of the present invention are dissolved in water to form a dilute solution due to intermolecular interaction.
  • C 70 (OH) 29 and C 70 (OH) 13 (CH 2 OHCHNHCOOH) 4 and C 70 (OH) 24 are agglomerated into nanoparticles in water to form particles having a hydrated particle size of from 1 to 200 nm.
  • the average particle size of (OH) 24 is 136.4 ⁇ 0.5 nm, 134.7 ⁇ 0.4 nm, and 135.9 nm, respectively, and the distribution range of C 70 (OH) 13 (CH 2 OHCHNHCOOH) 4 and C 70 (OH) 24 is narrower. 4 and Figure 5.
  • the Zeta potential of C 70 (OH) 29 is -55.6 mV, see Figure 6.
  • Example 4 therapeutic effect of C 70 (OH) 29 and C 70 (OH) 13 (CH 2 OHCHNHCOOH) 4 on mouse liver cancer tumors
  • Animal strain Balb/c female, 5 weeks, weighing between 16-20 g.
  • Tumor model mouse liver cancer H22 tumor strain
  • mice were subcutaneously inoculated with 100 ⁇ L of H22 hepatoma cells at a concentration of 5 ⁇ 10 7 /ml. After about 5-7 days of growth, the tumor size reached 50-100 mm 3 for the experiment.
  • 150 ⁇ L of C 70 (OH) 29 and C 70 -Ser were injected into the tumor-bearing mice through the tail vein. After 10 minutes of injection, radiofrequency (200 MHz, 5 mW) was applied for 1 h. The control group was injected with the same dose of normal saline. The changes of tumor sites before and after treatment were observed. After the experiment, the mouse organs and tumors were taken and fixed with 4% paraformaldehyde fixative.
  • the interstitial cell space of tumor blood vessels is large and the structure is incomplete.
  • the tumor blood vessels usually contain a large number of nanometer-scale pores.
  • the fullerene particles can be embedded in these small pores to destroy the tumor blood vessels, thereby introducing a large amount of hemorrhage inside the tumor and cutting off the tumor tissue.
  • the nutritional supply which in turn inhibits tumor growth. From HE staining sections (Fig. 10), it was found that after treatment with C 70 (OH) 29 and C 70 -Ser, a large number of tumor cells were necrotic and withered, while the control cells showed a strong growth trend.
  • Animal strain Balb/c female, 5 weeks, weighing between 16-20 g.
  • Tumor model mouse sarcoma S180 tumor strain.
  • Mode of administration intravenous injection.
  • Dosage 5 mg/ml, 0.15 ml injection.
  • mice 100 ⁇ L of S180 sarcoma cells at a concentration of 5 ⁇ 10 7 /ml were inoculated subcutaneously. After about 5-7 days of growth, the tumor size reached 50-100 mm 3 for the experiment.
  • 150 ⁇ L (5 mg/ml) of C 70 (OH) 29 and C 70 -Ser were injected into the tumor-bearing mice through the tail vein, and the drug was injected for 10 minutes, followed by RF (200 MHz). , 5mW) treatment for 1h.
  • the control group was injected with the same dose of normal saline. The changes in tumor sites before and after treatment were observed.
  • the mouse organs and tumors were taken and fixed with 4% paraformaldehyde fixative.
  • Animal strain Balb/c nude mice, female, 5 weeks, weighing between 16-20 g.
  • Tumor model green fluorescent protein-labeled mouse breast cancer cell line (4T1-GFP).
  • Mode of administration intravenous injection.
  • Dosage 4 mg/ml, 150 ⁇ L in a single injection, a total of 2 injections.
  • mice were subcutaneously inoculated with 100 ⁇ L of 4 ⁇ 1-GFP breast cancer tumor cells at a concentration of 5 ⁇ 10 7 /ml. After about 5-7 days of growth, the tumor size reached 50-100 mm 3 for the experiment.
  • C 70 (OH) 29 150 ⁇ L 4 mg/ml was injected into the tumor-bearing mice through the tail vein.
  • the control group was injected with the same dose of normal saline.
  • the changes of tumor sites before and after treatment were observed and fluorescence imaging was performed.
  • the second administration was performed after 7 days, and the experiment was terminated on the 11th day.
  • the organs and tumors of the mice were taken and fixed with 4% paraformaldehyde fixative.
  • Tumor growth and metastasis depend on the presence of vascular networks, which are the nutrient channels and metastatic pathways of cancer cells. By selectively destroying the formed tumor vascular network, the blood supply of the tumor is rapidly cut off, and the ischemic necrosis of the tumor cells is induced, which is an effective method for inhibiting tumor growth and preventing metastasis.
  • vascular networks which are the nutrient channels and metastatic pathways of cancer cells.
  • VE-cadherin The tumors at different times after treatment were subjected to Western Blot. From Fig. 17, it can be seen that the content of VE-cadherin in the tumor site was significantly decreased 4 h after C 70 (OH) 29 treatment, indicating that C 70 (OH) 29 It can target VE-cadherin, which reduces tumor blood vessels, thereby destroying the vascular endothelium junction, causing the rupture of tumor blood vessels, and cutting off the nutrient supply of tumor cells to inhibit tumor growth. With the prolongation of time, the content of VE-cadherin in the tumor site gradually recovered, indicating that the 4T1-GFP tumor strain had a tendency to relapse, so the second treatment was performed in the experimental design to prevent recurrence.
  • VE-cadherin vascular endothelial cadherin, also known as vascular endothelial cadherin belongs to type II cadherin, which is a surface-specific transmembrane adhesion protein on vascular endothelial cells. It mediates adhesion between adjacent endothelial cells and maintains vascular integrity, regulates permeability between endothelial cells, regulates signaling in endothelial cells, angiogenesis, and stabilization of the intravascular environment. has played an important role.
  • Example 7 an injection solution containing C 70 -OH (ie C 70 (OH) 24 )
  • Example 1 100 mg of the C 70 -OH solid obtained in Example 1 was dissolved in 100 mL of physiological saline, sonicated at room temperature for 5 minutes, and packaged in a glass bottle to prepare an injection solution.
  • Example 8 growth inhibition of mouse liver cancer tumors by C 70 -OH (ie C 70 (OH) 24 )
  • Animal strain Balb/c female, 5 weeks, weighing between 16-20 g.
  • Tumor model mouse liver cancer H22 tumor strain.
  • mice were subcutaneously inoculated with 100 ⁇ L of H22 hepatoma cells at a concentration of 5 ⁇ 10 7 /ml, and the administration was started 24 hours after the inoculation, and the drug group and the control group were administered according to FIG. 19, respectively.
  • the drug A group and the drug group B were administered with the solution for injection obtained in Example 7, and administered once every other day for 6 days, for a total of 10 times.
  • the body weight of the mice was weighed every other day during the experiment and the growth of the tumor was observed, and it was observed that the experiment was terminated 15 days after the inoculation (Fig. 20).
  • the tumors of the mice were weighed and measured, and the organs were fixed with 4% paraformaldehyde fixative. Dosage: 1 mg/ml, a single injection of 0.15 ml, a total of 10 injections.
  • Animal strain Balb/c female nude mice, 5 weeks, weighing between 16-20 g.
  • Tumor model human breast cancer MDA-MB-231.
  • Mode of administration intraperitoneal injection.
  • mice 1, saline control group; 2, positive drug (paclitaxel, paclitaxel) control group; 3, test group (C 70- OH, the solution for injection obtained in Example 7).
  • mice were weighed every other day during the experiment and observed for tumor growth. The experiment was terminated until 21 days after inoculation.
  • the tumors of the mice were weighed and measured, and the organs were fixed with 4% paraformaldehyde fixative.
  • metal fullerene (M@C 2n ) was purified by high performance liquid chromatography coupled with fullerene/embedded metal fullerene-specific chromatography column Buckyprep/Buckyprep-M.
  • water-soluble hydroxyl-modified Gd@C 82 nanoparticles having a structural formula of Gd@C 82 (OH) 26 (abbreviated as GF-OH) are prepared by reference to Carbon, 2013, 65, 175.
  • the brown-black solution obtained by filtration using a 220 nm microporous membrane was the amino acid-modified water-soluble metal fullerene structure of the present invention.
  • Gd@C 82 (OH) 13 (NHCH 2 CH 2 COOH) 6 also known as ⁇ -alanine modified metal fullerene nanoparticles, the structure is simply Gd@C 82 (OH) 13 (NHCH 2 CH 2 COOH) 6 , abbreviated as GF-Ala).
  • the elemental ratio of carbon, nitrogen and hydrogen obtained by elemental analysis of the ⁇ -alanine-modified water-soluble metal fullerene structure of the present invention is shown in Table 2. It can be seen from Table 2 that according to the thermogravimetric analysis, 11.5% of the water in the original solid powder can be obtained, and about 13 H 2 O molecules are calculated, and then combined with elemental analysis, it is further estimated that the average molecular formula of the substance is Gd@ C 82 (OH) 13 (NHCH 2 CH 2 COOH) 6 .
  • Figure 29 shows the thermogravimetric analysis and the micro-commercial thermogravimetric analysis curve of Gd@C 82 (OH) 13 (NHCH 2 CH 2 COOH) 6 (abbreviated as GF-Ala), which is calculated to contain 11.5% moisture in the solid. According to the C, H, and N contents in the elemental analysis, the average molecular formula is Gd@C 82 (OH) 13 (NHCH 2 CH 2 COOH) 6 .
  • Fig. 31 is a stretching vibration in which the strong absorption peak of the infrared spectrum is about 3300 cm -1 is assigned to OH.
  • the ⁇ -alanine-modified water-soluble metal fullerene structure of the present invention contains the above-mentioned hydrophilic group, that is, the present invention is water-soluble.
  • Gd@C 82 (OH) 13 (NHCH 2 CH 2 COOH) 6 has strong absorption within a wavelength of 400 nm.
  • the Gd@C 82 (OH) 13 (NHCH 2 CH 2 COOH) 6 of the present invention has a longitudinal relaxation rate r 1 of 65.53 mM -1 s -1 at a magnetic field of 0.5 T, which is clinically used for Gd-DTPA. 10 times or more.
  • the purified 10 mg Gd@C 82 solid was mixed with 6 mL of a 14% by mass L-lysine base solution (L-lysine to NaOH molar ratio of 1:2), and vigorously stirred at 50 ° C for 2 h.
  • the black solid gradually dissolved to form a brownish black solution, and the remaining conditions were the same as in Example 10 of the present invention.
  • the purified 10 mg Gd@C 82 solid was mixed with 6 mL of a 14% L-serine base solution (L-serine to NaOH molar ratio of 1:2), vigorously stirred at 50 ° C for 4 h, and the black solid gradually The solution formed a brown-red solution, and the remaining conditions were the same as in Example 10 of the present invention.
  • the average particle size of the lysine reaction product is the smallest and the distribution is the widest; the average particle size of the serine reaction product is the largest and the distribution is the narrowest.
  • Example 15 Tumor treatment and effect comparison of ⁇ -alanine modified water-soluble metal fullerene structure under the action of radiofrequency
  • mice with a body weight of 16.0 to 20.0 g at 5 weeks of age were selected, and 100 ⁇ L of H22 liver cancer cells at a concentration of 5 ⁇ 10 7 /ml were inoculated subcutaneously. After about 5-7 days of growth, the tumor size reached 50-100 mm 3 for the experiment.
  • Comparative drug water-soluble hydroxyl modified Gd@C 82 nanoparticle, whose surface is modified with a large number of hydroxyl groups, as shown in Figure 40 for its thermogravimetric analysis of TGA and DTG curves, combined with elemental analysis of C, H, N content ( C 36.95%, H 2.36%, N ⁇ 0.3%) is presumed to have an average molecular formula of Gd@C 82 (OH) 26 .
  • the ⁇ -alanine-derivatized GF-Ala and hydroxylated GF-OH obtained in Example 10 were injected into the tumor-bearing mice by tail vein injection, followed by application of radiofrequency (Fig. 1 (mmol) at a concentration of 1 mmol/L, 2 mg/kg). 200MHz, 5mW) treatment for 30min. T2 magnetic resonance imaging was performed before treatment, after treatment and 24 hours after treatment, and the antitumor effect of the two drugs was observed for a long time. Three control groups were set up, only saline (Saline), normal saline, and radiofrequency (Saline+RF), and only ⁇ -alanine-modified metal fullerene (GF-Ala) was injected.
  • the effective magnetic moment of the metal fullerene amino acid nanoparticles of the present invention is 8.9 ⁇ , which is higher than that of the similar metal fullerene 8.5 ⁇ ; as shown in Fig. 42, the functional group or molecule modified on the surface of the carbon cage is simultaneously changed. It improves the dispersibility and uniformity of the nanoparticles and is beneficial to the stability of the drug.
  • the binding constant of the metal fullerene amino acid nanoparticle of the present invention and the protein is 0.98 ⁇ 10 5 L. ⁇ mol -1
  • the same type of metal fullerol is only 0.13 ⁇ 10 5 L ⁇ mol -1 .
  • the metal fullerene structure GF-Ala modified using the amino acid of the present invention is more excellent in tumor treatment than the similar metal fullerenol GF-OH.
  • the metal fullerene nanoparticle GF-(Ala) modified by alanine amino acid is 1/5 to 1/10 of the dose of the hydroxyl-modified metal fullerene nanoparticle GF-(OH).
  • the possible reason is to change
  • the metal fullerene water-soluble preparation method has milder reaction conditions, less modified functional groups or small molecules on the surface of the carbon cage, and stronger carbon cage integrity, which makes the metal fullerene nanoparticles more magnetic.
  • Figure 44 is a graph showing the T2 magnetic resonance imaging of the tumor site of the GF-Ala drug of the present invention before, after, and 24 hours after treatment. It can be seen from Fig. 44 that after treatment, a large area of necrosis occurred in the central region of the tumor, and the imaging showed blackening, and the proportion of necrosis was greatly improved 24 h after the treatment.
  • Figure 45 is a comparison of the long-term tumor inhibition rate of the GF-Ala drug and the GF-OH drug at the same dose according to the present invention.
  • the tumor tissue showed obvious necrosis and blackening phenomenon.
  • the tumor site almost collapsed; while the GF-OH drug showed a certain therapeutic effect compared with the control group,
  • the tumor volume and weight at 12 days after treatment were approximately twice that of the GF-Ala drug of the present invention.
  • Figure 46 is a photograph showing the environment of tumor blood vessels at 24 h after treatment of the GF-Ala drug, GF-OH drug and the control group of the present invention. It can be observed from the figure that the GF-Ala drug of the present invention has a large-scale shedding of tumor vascular endothelial cells after radiofrequency-assisted treatment, and the vascular basement membrane is exposed, indicating that the GF-Ala drug of the present invention can rapidly target the tumor blood vessel and cut off the tumor site. Nutritional supply. However, GF-OH drug endothelial cells shed less, and the attacking power of tumor blood vessels at the same dose was not as good as the GF-Ala drug of the present invention.
  • the water-soluble hydroxyl modified C70 is more effective than the corresponding C60 in treating tumors.
  • hollow fullerene C 60 solid powder 100 mg were mixed and ball milled for 10 hours. After the reaction, the centrifuge was used, and the uncoated C 60 solid powder was repeatedly centrifuged at 10,000 rpm until no solid powder was centrifuged. The hollow fullerene was coated with hollow fullerenes at a concentration of 1500 ppm (mg/kg).
  • Example 17 Growth inhibition of human breast cancer MDA-MB-231 by Oil-C 60
  • Animal strain Balb/c female nude mice, 5 weeks, weighing between 16-20 g.
  • Tumor model human breast cancer MDA-MB-231 cells.
  • mice 1, saline control group (Saline); 2, soybean oil control group (Oil); 3, positive drug (paclitaxel, paclitaxel) control group; 4, experimental group (Oil-C 60 , 1500ppm). 6 in each group are parallel.
  • mice were subcutaneously inoculated with 100 ⁇ L of human breast cancer MDA-MB-231 cells at a concentration of 5 ⁇ 10 7 /ml.
  • the administration was started 24 hours after the inoculation, and the doses of the respective groups were as follows: 200 ⁇ L of physiological saline per day in the saline control group; 200 ⁇ L of soybean oil per day in the soybean oil control group; the drug control group was administered once every 3 days.
  • the dose administered was 10 mg/kg; the experimental group was given Oil-C 60 prepared in Example 1 every day, and the daily dose was 1500 ppm of Oil-C 60 200 ⁇ L (about 15 mg/kg/d) until the 21st day. End the test.
  • the mice were weighed every other day during the experiment and observed for tumor growth. The experiment was terminated until 21 days after inoculation.
  • the tumors of the mice were weighed and measured, and the organs were fixed with 4% paraformaldehyde fixative.
  • the invention discloses a use of a fullerene structure in preparing a medicament for treating tumor, the fullerene structure comprising at least one active ingredient selected from the group consisting of oil-soluble hollow fullerenes and oil-soluble metals.
  • a fullerene, a combination of the oil-soluble hollow fullerene and the oil-soluble metal fullerene, a water-soluble hollow fullerene, a water-soluble metal fullerene, the water-soluble hollow rich A composition of a lenone and the water-soluble metal fullerene, a pharmaceutically acceptable ester of the above six or a pharmaceutically acceptable salt of the above six.
  • the fullerene structure has high inhibition efficiency on tumors, and can inhibit tumor growth, such as inhibiting tumor volume increase, inhibiting tumor mass increase, slowing down tumor volume increase, and slowing tumor mass increase. It can also destroy existing tumor structures, such as: reducing the volume and quality of existing tumors, destroying the existing tumor vascular structure, destroying the endothelial junction of existing tumor blood vessels, and reducing the content of VE-cadherin in the tumor site.

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Abstract

L'invention concerne l'utilisation d'une structure à base de fullerène comprenant au moins un ingrédient actif choisi dans un groupe constitué d'un fullerène creux soluble dans l'huile, un métallofullerène soluble dans l'huile, une composition du fullerène creux soluble dans l'huile et du métallofullerène soluble dans l'huile, un fullerène creux soluble dans l'eau, un métallofullerène soluble dans l'eau, une combinaison du fullerène creux soluble dans l'eau et du métallofullerène soluble dans l'eau, un ester pharmaceutiquement acceptable des six mentionnées précédemment, ou un sel pharmaceutiquement acceptable des six mentionnées précédemment, dans la préparation d'un médicament pour le traitement d'une tumeur. L'invention concerne également une composition pharmaceutique, un produit de soins de santé ou un aliment santé comprenant la structure de fullerène. L'invention concerne en outre un procédé de préparation de la structure à base de fullerène.
PCT/CN2017/104665 2016-10-08 2017-09-29 Utilisation d'une structure à base de fullerène dans la préparation d'un médicament pour le traitement d'une tumeur WO2018064963A1 (fr)

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CN201610878746.1A CN107137423A (zh) 2016-10-08 2016-10-08 一种水溶性富勒烯纳米材料及其制备方法与应用
CN201610878750.8A CN106620727A (zh) 2016-10-08 2016-10-08 一种氨基酸修饰的金属富勒烯水溶性纳米颗粒及其制备方法与应用
CN201610878746.1 2016-10-08
CN201610878766.9 2016-10-08
CN201610878766.9A CN106619715A (zh) 2016-10-08 2016-10-08 氨基酸修饰的金属富勒烯水溶性纳米颗粒在制备肿瘤血管阻断剂中的应用
CN201610878750.8 2016-10-08
CN201710322042 2017-05-09
CN201710322487.9A CN108853141A (zh) 2017-05-09 2017-05-09 油溶性富勒烯结构在制备抑制肿瘤生长药物中的应用
CN201710322042.0 2017-05-09
CN201710322487.9 2017-05-09
CN201710879059.6 2017-09-26
CN201710879059.6A CN107913289A (zh) 2016-10-08 2017-09-26 水溶性富勒烯结构在制备治疗肿瘤的药物中的应用

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