WO2012125486A1 - Polychimiothérapie pour le traitement du cancer - Google Patents

Polychimiothérapie pour le traitement du cancer Download PDF

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Publication number
WO2012125486A1
WO2012125486A1 PCT/US2012/028567 US2012028567W WO2012125486A1 WO 2012125486 A1 WO2012125486 A1 WO 2012125486A1 US 2012028567 W US2012028567 W US 2012028567W WO 2012125486 A1 WO2012125486 A1 WO 2012125486A1
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WIPO (PCT)
Prior art keywords
autophagy
ceramide
cancer
agent
vinblastine
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Ceased
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PCT/US2012/028567
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English (en)
Inventor
Stephan T. STERN
Scott Mcneil
Pavan ADISESHAIAH
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US Department of Health and Human Services
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US Department of Health and Human Services
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Publication of WO2012125486A1 publication Critical patent/WO2012125486A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/164—Amides, e.g. hydroxamic acids of a carboxylic acid with an aminoalcohol, e.g. ceramides
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

  • FIG. 10A and 10B are graphs showing treatment effect on animal body weight.
  • the graphs display mean body weight over the study period for all the treatment groups (A) and high dose vinblastine groups (B). Data represents mean + SD body weight for the treatment groups at each tumor measurement day.
  • FIG. 13A and 13B are graphs showing the results of a C 6 -ceramide/paclitaxel combination index in Hep G2 cells. Based on the 24 and 48 h data generated for FIG. 12, combination index graphs were produced as described in the methods. As evident from the calculated CI values >1, the combination of paclitaxel and ceramide treatment resulted in a less than additive response.
  • administering is inclusive of administration by another person to the subject or self-administration by the subject.
  • a “therapeutically effective amount” refers to a quantity of a specified agent sufficient to achieve a desired effect in a subject being treated with that agent.
  • a therapeutically effective amount may be an amount of an autophagy inducing agent that is sufficient to induce autophagy in at least one cell.
  • a therapeutically effective amount may be an amount of an autophagy inhibiting agent that is sufficient to inhibit autophagy in at least one cell.
  • a therapeutically effective amount of an agent is an amount sufficient to inhibit or treat the disease or condition without causing a substantial cytotoxic effect in the subject. The therapeutically effective amount of an agent will be dependent on the subject being treated, the severity of the affliction, and the manner of administration of the therapeutic composition.
  • Treatment refers to a therapeutic intervention that ameliorates a sign or symptom of a disease or pathological condition after it has begun to develop.
  • the term “ameliorating,” with reference to a disease or pathological condition refers to any observable beneficial effect of the treatment.
  • the beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art that are specific to the particular disease.
  • the synergistic effect of the combination therapy may also enable lower dosage levels of the agents at more frequent, periodic doses ("metronomic dosing").
  • an autophagy inhibiting agent e.g., a vinca alkaloid such as vinblastine
  • administering produces the common side effects of cancer chemotherapy, since these drugs are dosed to the limit of tolerability
  • a higher level of anti-tumor effects can be achieved by using standard autophagy inhibiting agent MTD dosing levels. All of the advantageous dosing scenarios are the product of the larger therapeutic window enabled by combination therapy described herein and will benefit cancer patients through improvements in survival and quality of life.
  • the autophagy inducing agent may be any agent that induces autophagy in cancer cells. Inducing autophagy is inclusive of initiating an autophagic process in cancer cells and inducing cancer cells to commit to an autophagic process. There are several methods for identifying autophagy inducing agents (Tasdemir E, Galluzzi L, Maiuri MC, Criollo A, Vitale I, Hangen E, Modjtahedi N, Kroemer G. Methods Mol Biol. 2008; 445:29-76.). The most laborious is identifying an increase in autophagic vacuoles by electron microscopy in vitro or ex vivo.
  • resorbable nanoparticles having a calcium phosphor- silicate (CPS) shell are provided, in which the ceramide is loaded into the resorbable nanoparticles.
  • the resorbable nanoparticles can deliver the ceramide systemically to living cells, which normally are not transportable through the circulation.
  • a key feature of the synthesis of the resorbable nanoparticles is the proper dispersion (non- aggregation) of the nanoparticles in an aqueous liquid medium.
  • One way to achieve dispersion is the use of size exclusion high performance liquid chromatography (SEC) modified specifically for the silicate-containing shell nanoparticles.
  • SEC size exclusion high performance liquid chromatography
  • Another way to achieve dispersion of the nanoparticles is to attach organic, inorganic or metal-organic dispersants to the outer CPS shell.
  • a carbodiimide- mediated polyethylene glycol (PEG) coupling agent can be attached to the alkylamine silane or alkylcarboxylic acid coupling agent to further ensure the "dispersed" non-aggregating state of the nanoparticles in vivo and to provide a conjugation point for targeting moieties onto the PEG coupling agent, thus enabling the nanoparticles to target specific sites for intracellular drug delivery.
  • PEG polyethylene glycol
  • THF tetrahydrofuran
  • diethyl ether diethyl ether, diglyme
  • alkanes decalin, isooctane, mineral oil
  • aromatics benzene, toluene, chlorobenzene, pyridine
  • amides n-methyl pyrrolidone (NMP), ⁇ , ⁇ -dimethylformamide (DMF)
  • esters ethyl acetate, methyl acetate
  • chlorocarbons CH.sub.2 Cl.sub.2, CHCl.sub.3, CCl.sub.4, 1,2- dichloroethane
  • saturated and/or unsaturated fatty acids and mixtures thereof e.g., a vegetable oil such as soybean oil
  • others such as nitromethane, acetone, ethylene diamine, acetonitrile, and trimethyl phosphate; and mixtures thereof.
  • Illustrative cancers include lymphoma, head and neck cancer, lung cancer, breast cancer, testicular cancer, liver cancer, colon cancer, brain cancer and leukemia.
  • cancers susceptible to treatment with an autophagy mediating agent include liver cancer, colon cancer, and glioma.
  • the tumor volume, in mm was calculated according to the formula: (width x length)/2, where width is always the smaller of the two measurements.
  • Mean tumor volumes for all the groups were calculated by averaging together all the individual animal tumor volumes per measurement date.
  • the neoplasia-related endpoint criteria were ulcerated tumor or tumor diameter >2 cm, at which point animals were euthanized.
  • the morbidity criteria for euthaniztion included loss of greater than 20% of initial body weight and immobility. All remaining animals were euthanized at study termination on day 29.
  • the study objective was to evaluate activation of caspase 3/7 enzymes by C 6 - ceramide/vinblastine combination treatment in comparison to vinblastine alone.
  • Post-fixation of cells were performed in osmium tetroxide (1% osmium tetroxide in 0.1 M cacodylate buffer) and uranyl acetate (0.5% uranyl acetate in 0.1 M cacodylate buffer). Following the post-fixation step, cells were dehydrated stepwise in ethanol and embedded in embed- 182 epoxy resin. Thin sections of 70-90 nm were trimmed using an ultramicrotome and were transferred onto formvar-copper mesh grids. Sections were stained with 3% uranyl acetate and lead citrate. Stained sections were carbon coated, and placed into a Hitachi H7600 microscope running at 80 kV voltage to acquire TEM images.
  • Incorporation of hydrophobic ion paired vinblastine oleate Due to its hydrophilicity, the commercially available salt form of vinblastine (vinblastine sulfate) is not suitable for loading into the oil droplets of the nanoemulsion formulation. Therefore, a stabilizer, sodium oleate, has been utilized to make a hydrophobic ion paired vinblastine oleate to facilitate its incorporation into oil droplets.
  • Incorporation of C Ceramide C 6 Ceramide hydrophobicity requires formulation in a drug delivery vehicle. C 6 ceramide is incorporated into the lipophilic oil droplets of the nanoemulsion formulation for the coadministration with vinblastine.
  • step 4 Homogenize the coarse emulsion mixture from step 4 using a polytron inside the water bath at 63 °C at 8000 rpm for 2 minutes.
  • the standard curve of VB base was made in acetonitrile: ammonium acetate (20 mM in millipore water) mixture (30:70 v/v).
  • Standards were 0.01, 0.025, 0.05, 0.1, 0.2 and 0.3 mg/mL.
  • a 10 mg/mL stock of VB sulfate (500 ⁇ ) was prepared in acetonitrile and further diluted to 1 mg/mL (1 mL) with acetonitrile. This 1 mg/mL stock was used to prepare standards (0.01, 0.025, 0.05, 0.1, 0.2 and 0.3 mg/mL) by diluting with acetonitrile and ammonium acetate (30:70).
  • composition of paragraph 14, wherein the vinca alkaloid is vinblastine.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Dispersion Chemistry (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une méthode de traitement du cancer chez un sujet, le cancer étant sensible au traitement par un agent de médiation de l'autophagie, la méthode comprenant la co-administration au sujet d'un agent induisant l'autophagie et d'un agent inhibant l'autophagie dans des quantités qui, ensemble, sont efficaces dans le traitement du cancer.
PCT/US2012/028567 2011-03-11 2012-03-09 Polychimiothérapie pour le traitement du cancer Ceased WO2012125486A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161451925P 2011-03-11 2011-03-11
US61/451,925 2011-03-11

Publications (1)

Publication Number Publication Date
WO2012125486A1 true WO2012125486A1 (fr) 2012-09-20

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PCT/US2012/028567 Ceased WO2012125486A1 (fr) 2011-03-11 2012-03-09 Polychimiothérapie pour le traitement du cancer

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013182519A1 (fr) * 2012-06-04 2013-12-12 Universitaet Basel Combinaison d'agents lysosomotropiques ou de modulation de l'autophagie et d'un inhibiteur de gsk-3 pour le traitement du cancer
WO2014078522A1 (fr) * 2012-11-14 2014-05-22 Ohio State Innovation Foundation Matières et procédés utiles pour le traitement du glioblastome
WO2014144421A1 (fr) * 2013-03-15 2014-09-18 Memorial Sloan-Kettering Cancer Center Inversion de céramide de la résistance à plusieurs médicaments
CN106526167A (zh) * 2016-10-31 2017-03-22 中国农业大学 一种青霉震颤素结合抗原及其抗体的制备与应用
CN109091490A (zh) * 2018-08-01 2018-12-28 复旦大学附属华山医院 腺苷和自噬抑制剂联用在制备结肠癌治疗药物中的应用
WO2020223609A1 (fr) * 2019-05-01 2020-11-05 New York University Méthodes et compositions pour sensibiliser les cellules cancéreuses à une apoptose induite par un médicament

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WO2000059517A1 (fr) * 1999-04-07 2000-10-12 Roger Williams Hospital Ceramide et agents chimiotherapeutiques induisant l'apoptose
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013182519A1 (fr) * 2012-06-04 2013-12-12 Universitaet Basel Combinaison d'agents lysosomotropiques ou de modulation de l'autophagie et d'un inhibiteur de gsk-3 pour le traitement du cancer
WO2014078522A1 (fr) * 2012-11-14 2014-05-22 Ohio State Innovation Foundation Matières et procédés utiles pour le traitement du glioblastome
US9757432B2 (en) 2012-11-14 2017-09-12 Ohio State Innovation Foundation Materials and methods useful for treating glioblastorna
US11660329B2 (en) 2012-11-14 2023-05-30 University Of Cincinnati Materials and methods useful for treating glioblastoma
WO2014144421A1 (fr) * 2013-03-15 2014-09-18 Memorial Sloan-Kettering Cancer Center Inversion de céramide de la résistance à plusieurs médicaments
US10052387B2 (en) 2013-03-15 2018-08-21 Memorial Sloan-Kettering Cancer Center Ceramide reversal of multi-drug resistance
CN106526167A (zh) * 2016-10-31 2017-03-22 中国农业大学 一种青霉震颤素结合抗原及其抗体的制备与应用
CN106526167B (zh) * 2016-10-31 2019-03-08 中国农业大学 一种青霉震颤素结合抗原及其抗体的制备与应用
CN109091490A (zh) * 2018-08-01 2018-12-28 复旦大学附属华山医院 腺苷和自噬抑制剂联用在制备结肠癌治疗药物中的应用
WO2020223609A1 (fr) * 2019-05-01 2020-11-05 New York University Méthodes et compositions pour sensibiliser les cellules cancéreuses à une apoptose induite par un médicament

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