WO2002024273A1 - Traitement de tumeur - Google Patents

Traitement de tumeur Download PDF

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Publication number
WO2002024273A1
WO2002024273A1 PCT/US2001/029081 US0129081W WO0224273A1 WO 2002024273 A1 WO2002024273 A1 WO 2002024273A1 US 0129081 W US0129081 W US 0129081W WO 0224273 A1 WO0224273 A1 WO 0224273A1
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WO
WIPO (PCT)
Prior art keywords
tumor
substituted
ionic groups
fullerene
fullerene core
Prior art date
Application number
PCT/US2001/029081
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English (en)
Inventor
Long Y. Chiang
Chi Yu
Original Assignee
Chiang Long Y
Chi Yu
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chiang Long Y, Chi Yu filed Critical Chiang Long Y
Priority to AU2001289127A priority Critical patent/AU2001289127A1/en
Priority to EP01968923A priority patent/EP1328314A1/fr
Publication of WO2002024273A1 publication Critical patent/WO2002024273A1/fr

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Classifications

    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/795—Polymers containing sulfur
    • 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
    • A61K41/0038—Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy

Definitions

  • Free radicals have been shown to inhibit tumor growth by causing oxidative damage to lipids, proteins, and nucleic acids of the tumor cells.
  • a photo-sensitizer is first delivered to a tumor site and then activated by irradiation to generate free radicals, thus inhibiting tumor growth.
  • Photofrin II has recently been approved by the U.S. Food and Drug Administration. Preparation of Photofrin II is tedious.
  • Fullerenes are conjugated olefins of a closed cage structure. When photo-excited, they are capable of transforming molecular oxygen into singlet oxygen and then the related free radicals, such as superoxide free radicals, i.e., O 2 " . However, fullerenes have low bioavailability and must be chemically modified before they can be tested for their efficacy, if any, as photo-sensitizers in treating tumor.
  • This invention relates to a method of inhibiting the growth, including causing the death, of tumor cells.
  • the method includes administering to a tumor site of a subject in need thereof a photo-sensitive free radical-generating fullerene compound and, subsequently, exposing the rumor site to irradiation.
  • the compound is a fullerene core which is substituted with 1-30 ionic groups, either directly or via a d. 50 linker. It is administered to the subject in an amount sufficient to inhibit the growth of the tumor cells at the tumor site.
  • the term "fullerene core” refers to C 6 o, Cei, C 6 2, C 63 , C 64 , C ⁇ s, C o, C 76 , C 8 , C ⁇ , C 84 ,
  • C 92 La@C 60 , a@C 74 , La@C 82 , Ho@C 6 o, Ho@C 74 , Ho@C 82 , Gd@C 60 , Gd@C 74 , Gd@C 8 , Er@C 6 o 3 Er@C 7 , Er@C 82 , and the like.
  • C 60 is preferred.
  • the ionic groups mentioned above refer to those groups which are ionized in an aqueous solution at physiological pH. Examples of these ionic groups are sulfonate, sulfate, carbonate, phosphonate, phosphorate, and ammonium groups.
  • a fullerene core for example, can be substituted with 2-16 or 4-10 sulfonate groups to form a fullerene compound to be used in the method of this invention.
  • fullerene compound e.g., CeoCNHs *
  • they can be linked to the fullerene core via a Ci-50 linker (e.g., a C2 6 or C 3 . 8 linker).
  • linkers are alkyl (e.g., -C2H4-), aryl (e.g., -C ⁇ FLr), ester (e.g., -CsHLsCO-O-), ether (e.g., -CsHeOCsHe-), thioether (e.g., -C 7 H ⁇ 4 SC 5 H 10 -), urethane (e.g., -C + HsNH-CO-O-), urea (e.g., -NH-CO-NH-), amide (e.g., -CO-NH-), anhydride (e.g., -CO-O-CO-), amine (e.g., -NrK ⁇ Hr), and ketoether (e.g., -CO-C 3 H6-O-C 5 H ⁇ o-).
  • the fullerene core for example, can be substituted with 6 sulfonate groups, each via a -G ⁇ H 8 - linker
  • the fullerene compounds described above include their pharmaceutically acceptable salts.
  • Such salts can be formed between a negatively charged ionic group (e.g., sulfonate or carbonate) and a positively charged counterion. Suitable counterions include, but are not limited to, sodium, potassium, calcium, or magnesium.
  • a positively charged ionic group e.g., ammonium
  • an anion e.g., chloride, bromide, or iodide.
  • One example of the salts that can be used to practice the method of this invention is hexa(sulfobutyl)fullerene sodium.
  • a fullerene compound to be used to practice the method of this invention is formulated into a pharmaceutical composition prior to its use in tumor treatment.
  • the composition which contains such a fullerene compound and a pharmaceutically acceptable carrier for use in treating the tumor.
  • the carriers include water, colloidal silica oxide, magnesium sterate, lipid, lipoprotein, blood protein, or cellulose.
  • the invention also relates to use of the just-described fullerene compound for the manufacture of a medicament for the treatment of a tumor.
  • fullerene compounds as an active ingredient in a pharmaceutical composition, is first administered to a tumor site of a subject before the tumor site is exposed to radiation. Upon irradiation, the fullerene compound converts surrounding molecular oxygen to highly reactive oxygen radicals, including superoxide radicals, which in turn attack the tumor cells and inhibit their growth.
  • This invention relates to use of a fullerene compound as a photo-sensitizer to inhibit the growth of benign or malignant tumor cells.
  • the fullerene compound is a fullerene core substituted, optionally via a C1.50 linker, with 1-30 ionic groups.
  • the fullerene compound converts oxygen molecules into singlet oxygen and then the related free radicals, such as superoxide free radicals.
  • the free radicals subsequently cause damage to surrounding tumor cells and thereby inhibit the growth of the tumor cells (i.e., reducing the number and size of the tumor cells).
  • the irradiation source can be laser or other lights, e.g., fluorescence or X-rays.
  • the irradiation can be of a wavelength of 400-1000 nm and an energy intensity of 10-300 J/cm 2 , and the irradiation time can be 10-200 minutes.
  • a sulfonate-alkyl-fullerene compound can be prepared by reacting a fullerene with a strong Lewis base (e.g., naphthalide) to produce an anionic fullerene intermediate. The intermediate then reacts with a cyclic sultone to produce sulfoalkylfullerene. See Chiang, et al., Chem. Lett. 1998, 465.
  • An amino-fullerene can be prepared directly by reacting a fullerene with an amine at ambient temperature for 2 days. See Hirsch, et al., Angew. Chem. Int. Ed Engl. 1991, 30, 1309: A carbonate-ended fullerene compound can be prepared by reacting an anionic fullerene intermediate, via naphthalide, with succinic anhydride or reacting a carbonate- ended alkylamine or arylamine with C 6 o(NO2)6 in the presence of a base, such as triethylamine, at 40°C for 5-16 hours. See Chiang, et al., J. Chem. Soc, Perkin Trans. J, 1999, 31.
  • a phosphorate-ended fullerene compound can be prepared by reacting a phosphorate- ended alkylamine or arylamine with C6o(NO2) 6 in the presence of a base, such as triethylamine, at 40°C for 5-16 hours. See Chiang, et al., J. Chem. Soc, Perkin Trans. J, 1999, 31.
  • a sulfate-ended fullerene compound can be prepared by reacting a sulfate-ended alkylamine or arylamine with C6o(NO 2 ) 6 in the presence of a base, such as triethylamine, at 40°C for 5-16 hours. See Chiang, et al., J. Chem. Soc, Perkin Trans. 1, 1999, 31.
  • a suitable fullerene compound or its salt in a sufficient amount is formulated with a pharmaceutically acceptable carrier to form a pharmaceutical composition before being administered to a subject in need of treatment of a tumor.
  • a sufficient amount refers to the amount of the compound which is required to confer therapeutic effect on the treated subject.
  • the pharmaceutical composition may be administered via a parenteral route, e.g., topically, intraperitoneally, and intravenously.
  • parenteral dosage forms include an active compound dissolved in phosphate buffer solution (PBS), or admixed with any other pharmaceutically acceptable carrier.
  • Solubilizing agents such as cyclodextrins, or other solubilizing agents well known to those familiar with the art, can also be included in the pharmaceutical composition.
  • An in vitro inhibition assay can be used to preliminarily evaluate a fullerene compound's ability to inhibit the growth of tumor cells.
  • a fullerene compound solution can be added to a pre-incubated cell suspension. Subsequently, the cell suspension is irradiated with fluorescence light, followed by further incubation.
  • a solution of 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide is added to the cell suspension to react with mitochrondrial dehydrogenase to form formazon, which is extracted with dimethyl sulfoxide (DMSO).
  • DMSO dimethyl sulfoxide
  • the DMSO extract solution is immediately used for optical measurement to determine the quantity of the formazon, which correlates with the quantity of dehydrogenase or the relative number of the living cells.
  • the fullerene compounds that have been preliminarily evaluated can be further tested to confirm their efficacy by an in vivo inhibition assay. See Chiang, et al., Proc. Electrochem. Soc, 1999, 99-12, 238-249.
  • a tumor-bearing mouse can be first administered a suitable fullerene compound in PBS close to the tumor site. The mouse is then kept in the dark while the fullerene compound is circulated to the tumor site. After the hair on and around the tumor site is removed, the tumor site is irradiated with a laser beam or other light source. After the irradiation, the growth of the tumor in the mouse is examined at different intervals. The inhibitory effect is evaluated by measuring the mouse's average body weight and tumor volume.
  • the mouse is euthanatized by carbon dioxide asphyxiation.
  • the final body weight and organ weight of the treated mouse are measured.
  • Blood samples are withdrawn for biochemistry and hematology analyses. All such data can be used to evaluate the efficacy of the fullerene compound to treat tumor.
  • a dimethoxyethane (D E) solution of sodium naphthalide was first titrated with succinic acid. C 6 o was then treated with the sodium naphthalide DME solution (10.0 equiv.) at 25°C to produce a hexaanionic fullerene intermediate. The fullerene intermediate subsequently reacted with an excess of 1,4-butane sultone (15.0 equiv.) to produce FC S. It was obtained in a yield of 80-85% after purification by filtration and repeated precipitation in methanol from an aqueous solution. FC 4 S gave a simple peak in its HPLC chromatogram using a reverse-phase C-18 column and H2O as the eluent.
  • FC 4 S aqueous solutions (1.0 ml each) at various concentrations (0-100 ⁇ M) were respectively added to ferricytochrome c-containing PBS (1.0 ml, 100 ⁇ M). Each of the mixtures was then added into a well of a 24-well plate and then exposed to fluorescence light (27 W) for 0-90 min. The distance between the plate cover and the light source was 5-6 cm. The extent of reduction of ferricytochrome c to ferrocytochrome c was evaluated by optical measurement. The increase of the absorbance at 550 nm corresponded to the increase of the quantity of ferrocytochrome c.
  • FC 4 S upon irradiation, converted molecular oxygen to superoxide free radicals, and electron transfer from the superoxide free radicals to ferricytochrome c reduced the ferricytochrome c to ferrocytochrome c. It was observed that more superoxide free radicals were generated when the FC 4 S dosage and the irradiation time were increased.
  • Tumor cells were prepared as follows: Fibrosarcoma cells (CCRC 60037) and sarcoma 180 cells (obtained form Biochemical Institute of Chung Shan Medical and Dental College, Taiwan) were maintained and cultured in ⁇ -modified eagle medium (MEM) containing E-glutamine and phenol red, 10% fetal bovine serum, and antibiotics (100 units/ml of penicillin G and 100 ⁇ g/ml streptomycin sulfate). The cells were incubated in the dark in 95% humidified air plus 5% CO2. After harvest by treatment with trypsin-EDTA, the cells were suspended in ⁇ -MEM medium at the concentration of 1*10 4 cells/ml.
  • MEM eagle medium
  • Cell suspensions (500 ⁇ l each) thus obtained was placed into the wells of a 24-well plate and pre-incubated at 37°C for 24 hours.
  • FC 4 S solutions (500 ⁇ l each) at various concentrations (0-20 ⁇ M) were added to the wells.
  • Each of the cell suspensions was irradiated with fluorescence light (27 watts) for 0-60 minutes. The distance between the plate cover and the light source was 5-6 cm. After the irradiation, the cells were further incubated for 48 hours.
  • a solution of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT, 0.5% in PBS, 100 ⁇ l each) was then added to each of the cell suspensions to react with mitochrondrial dehydrogenase enzyme in the living cells to produce formazon.
  • the cell suspensions were again incubated for 3 hours at 37°C before the suspension medium was discarded.
  • Formazon was then extracted using dimethyl sulfoxide (DMSO, 1.0 ml each). The DMSO extract solutions were immediately used for optical measurement.
  • DMSO dimethyl sulfoxide
  • the absorbance at 540 nm directly correlated with the quantity of formazon, and thus with the quantity of dehydrogenase enzyme or the relative number of the living cells (i.e., viability).
  • the results showed a decrease in cell viability with the increase in FC 4 S dosage and irradiation time.
  • Fibrosarcoma cell (CCRC 60037) suspensions (4.0 ml) on glass coverslips were incubated in a 6-well plate.
  • the suspensions were irradiation with fluorescence (27 watts) for 40 minutes in the presence of FC 4 S at various concentrations (i.e., 2.5 - 5.0 ⁇ M).
  • FC 4 S concentrations (i.e., 2.5 - 5.0 ⁇ M).
  • the coverslips were washed three times with PBS.
  • the cells were then permeabilized by using methanol for 7 minutes.
  • ICR mice Charles River Japan origin Crl: CD-1 ® (ICR)BR
  • ICR Charles River Japan origin Crl: CD-1 ®
  • the mice were housed in polycarbonated shoe-box cages on hardwood bedding (5 mice/cage) under controlled pathogen-free conditions (temperature 22 ⁇ 1 °C, relative humidity 55 ⁇ 15%, and light/dark cycle 12/12 hours), and were allowed free access to a laboratory rodent diet (# 5K55, Purina Mills, Inc., St. Louis, MO) and water.
  • Murine sarcoma 180 cells were maintained in the abdominal cavities of other mice.
  • Subcutaneous tumor was induced by intraperitoneal injection of lxlO 7 tumor cells (about 0.1-0.15 ml ascitic fluid) to the subcutaneous region of the abdominal cavity of each mouse.
  • the tumor cells were allowed to proliferate at the inoculation site for 5-7 days.
  • mice After intraperitoneal injection of FC 4 S in PBS (5-15 mg/kg body weight of mouse) 2.0 cm away from the tumor site, the mice were kept in the dark for 24 hours. The hair on and around the tumor sites was removed after the mice were anesthetized with avertine (0.3 ml/head). The tumor sites were each subsequently irradiated with an argon ion laser beam (Spectra Physics, Model 168) at a wavelength of 514.5 nm for 0-60 minutes. The beam was delivered via a quartz fiber with the circular area of illumination output focused to a diameter of 7-8 mm with the total light dose adjusted to a level of 100 J/cm 2 in each experiment.
  • an argon ion laser beam Spectra Physics, Model 168
  • mice were examined every 5 days for 30 days. Efficacy of the irradiation therapy was evaluated by measuring the average body weight and tumor volume of each mouse. After 30 days, the mice were euthanatized with carbon dioxide asphyxiation. The final body weight and weights of organs, including liver, kidney, spleen, heart, and tumor, were measured. Blood samples were withdrawn, and plasma biochemistry and blood hematology analyses were conducted with a Hitachi 7050 Automatic Analyzer and a Serono System 9000, respectively. The irradiation therapy-treated mice (groups 3, 4, and 5) showed a body growth rate close to that of tumor-free control (group 6).
  • the untreated tumor-bearing mice in the control had a lower body growth rate than that of mice in groups 2, 3, 4, 5, and 6.
  • the average weight of the tumor isolated from the irradiation therapy-treated mice decreased with the increase in the FC S dosage.
  • the tumor weight was 20% of that of the control (group 1) at day 30.
  • the average tumor weight was 10% of that of the control (group 1).
  • mice in groups 3, 4, and 5 exhibited higher activities of asparate aminotransferase, alanine aminotransferase, and alkaline phosphatase than those in group 1. Lactate dehydrogenase activity was also higher in the mice in group 3, 4, and 5 than those in group 1 at day 30. These observations suggest damage to the tumor cell membrane and leakage of enzyme proteins. The levels of cholesterol and glucose were significantly higher in the mice in groups 3, 4, and 5 than those in group 1, indicating continued proliferation of tumor cells in the mice of group 1 enhanced consumption of these substrates.
  • Untreated tumor cells proliferated continuously at a high rate as expected.
  • the growth rates of the tumor cells in the mice in groups 3, 4, and 5 were much lower than group 1 in all testing periods.
  • the average tumor size of the mice in groups 3, 4, and 5 was 17% of that of those in group 1.
  • mice were divided into 5 groups: (1) tumor control (without treatment); (2) intraperitoneal administration of FC 4 S (15 mg/kg) with laser irradiation at 514.5 nm; (3) intraperitoneal administration of FC 4 S (15 mg/kg) with laser irradiation at 633 nm; (4) intravenous administration (tail) of FC 4 S (15 mg/kg) with laser irradiation at 514.5 nm; and (5) intravenous administration (tail) of FC 4 S (15 mg/kg) with laser irradiation at 633 nm.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une technique d'inhibition de la croissance de cellules tumorales. Cette technique consiste à administrer dans un site tumoral d'un sujet un composé en quantité suffisante pour inhiber la croissance des cellules tumorales sur le site de la tumeur et, ensuite, à exposer ce site tumoral à des rayons. Ce composé est un noyau de fullerène substitué, éventuellement via un lieur en C1-50, avec 1 à 30 groupes ioniques
PCT/US2001/029081 2000-09-21 2001-09-18 Traitement de tumeur WO2002024273A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2001289127A AU2001289127A1 (en) 2000-09-21 2001-09-18 Tumor treatment
EP01968923A EP1328314A1 (fr) 2000-09-21 2001-09-18 Traitement de tumeur

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US66698900A 2000-09-21 2000-09-21
US09/666,989 2000-09-21

Publications (1)

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WO2002024273A1 true WO2002024273A1 (fr) 2002-03-28

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EP (1) EP1328314A1 (fr)
CN (1) CN1462197A (fr)
AU (1) AU2001289127A1 (fr)
WO (1) WO2002024273A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1834637A1 (fr) * 2004-12-07 2007-09-19 Vitamin C60 Bioresearch Corporation Preparation prophylactique/therapeutique contre une maladie due aux radicaux libres
EP1941887A1 (fr) * 2005-09-19 2008-07-09 Inst. of High Energy Phys., Chinese Acad. of Sc. Metallo-fullerenols et leur application dans la preparation de medicaments visant a inhiber la croissance tumorale
WO2008140576A2 (fr) * 2006-12-05 2008-11-20 University Of Florida Research Foundation, Inc. Systèmes et procédés basés sur le chauffage ou l'inflammation, induit par rayonnement, de fullerènes fonctionnalisés

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5294732A (en) * 1991-10-28 1994-03-15 Exxon Research & Engineering Co. Polysubstituted fullerenes and their preparation
US5635581A (en) * 1994-11-28 1997-06-03 National Science Counsel Fullerene polymers
US5648523A (en) * 1995-10-26 1997-07-15 Chiang Long Y Fullerene derivatives as free-radical scavengers
US6162926A (en) * 1995-07-31 2000-12-19 Sphere Biosystems, Inc. Multi-substituted fullerenes and methods for their preparation and characterization

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5294732A (en) * 1991-10-28 1994-03-15 Exxon Research & Engineering Co. Polysubstituted fullerenes and their preparation
US5416188A (en) * 1991-10-28 1995-05-16 Exxon Research & Engineering Co. Polysubstituted fullerenes and their preparation (C-2608)
US5635581A (en) * 1994-11-28 1997-06-03 National Science Counsel Fullerene polymers
US6162926A (en) * 1995-07-31 2000-12-19 Sphere Biosystems, Inc. Multi-substituted fullerenes and methods for their preparation and characterization
US5648523A (en) * 1995-10-26 1997-07-15 Chiang Long Y Fullerene derivatives as free-radical scavengers
US5994410A (en) * 1995-10-26 1999-11-30 National Science Council Therapeutic use of water-soluble fullerene derivatives

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1834637A1 (fr) * 2004-12-07 2007-09-19 Vitamin C60 Bioresearch Corporation Preparation prophylactique/therapeutique contre une maladie due aux radicaux libres
EP1834637A4 (fr) * 2004-12-07 2008-09-10 Vitamin C60 Biores Corp Preparation prophylactique/therapeutique contre une maladie due aux radicaux libres
EP1941887A1 (fr) * 2005-09-19 2008-07-09 Inst. of High Energy Phys., Chinese Acad. of Sc. Metallo-fullerenols et leur application dans la preparation de medicaments visant a inhiber la croissance tumorale
JP2009511432A (ja) * 2005-09-19 2009-03-19 インスティテュート オブ ハイ エナジー フィジックス チャイニーズ アカデミー オブ サイエンシズ 金属フレロール及び腫瘍（癌）生長抑制薬物を製造するための金属フレロールの使用
EP1941887A4 (fr) * 2005-09-19 2010-07-28 Inst Of High Energy Phys Chine Metallo-fullerenols et leur application dans la preparation de medicaments visant a inhiber la croissance tumorale
WO2008140576A2 (fr) * 2006-12-05 2008-11-20 University Of Florida Research Foundation, Inc. Systèmes et procédés basés sur le chauffage ou l'inflammation, induit par rayonnement, de fullerènes fonctionnalisés
WO2008140576A3 (fr) * 2006-12-05 2009-07-16 Univ Florida Systèmes et procédés basés sur le chauffage ou l'inflammation, induit par rayonnement, de fullerènes fonctionnalisés
US9475028B2 (en) 2006-12-05 2016-10-25 University Of Florida Research Foundation, Inc. Systems and methods based on radiation induced heating or ignition of functionalized fullerenes

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Publication number Publication date
AU2001289127A1 (en) 2002-04-02
EP1328314A1 (fr) 2003-07-23
CN1462197A (zh) 2003-12-17

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