WO2020092815A1 - Ciblage de tumeur intra-artériel amélioré pour un diagnostic et/ou un traitement - Google Patents

Ciblage de tumeur intra-artériel amélioré pour un diagnostic et/ou un traitement Download PDF

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Publication number
WO2020092815A1
WO2020092815A1 PCT/US2019/059226 US2019059226W WO2020092815A1 WO 2020092815 A1 WO2020092815 A1 WO 2020092815A1 US 2019059226 W US2019059226 W US 2019059226W WO 2020092815 A1 WO2020092815 A1 WO 2020092815A1
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Prior art keywords
combination
tumor
fluid
optionally
emulsion
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PCT/US2019/059226
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English (en)
Inventor
Franz Edward BOAS
Joseph ERINJERI
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Memorial Sloan Kettering Cancer Center
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Publication of WO2020092815A1 publication Critical patent/WO2020092815A1/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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/02—Halogenated hydrocarbons
    • 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
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55577—Saponins; Quil A; QS21; ISCOMS
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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

Definitions

  • the present technology relates generally to methods for diagnosing and/or treating a tumor in a subject.
  • the methods of the present technology relate to localized intra-arterial delivery to a tumor using an omniphobic oil to improve tumor uptake, specificity, and retention, as well as relate to localized intra-arterial delivery of a vaccine adjuvant into a tumor, using a carrier to improve tumor uptake, specificity, and retention.
  • a variety of methods are known in the art for delivering a pharmaceutical composition to a subject in need thereof to treat a medical condition. Such methods include, but are not limited to, topical, oral, intraperitoneal, intradermal, intranasal, and intramuscular delivery. However, it has become common to treat a variety of conditions by introducing a composition directly into a tissue, by means of a catheter, to maximize the therapeutic effect of the composition. Among the various types of localized delivery methods is intra-arterial drug delivery, which is typically used to deliver chemotherapy into liver tumors.
  • the present disclosure provides a method for diagnosing and/or treating a tumor in a subject, the method comprising administering an omniphobic fluid (also referred to in this disclosure as an“omniphobic oil”) to the tumor via an intra-arterial catheter.
  • an omniphobic fluid also referred to in this disclosure as an“omniphobic oil”
  • the present disclosure provides a method for treating a tumor in a subject, the method comprising administering an emulsion to the tumor, wherein the emulsion comprises an omniphobic fluid and water, and wherein the emulsion comprises a volume ratio of the omniphobic fluid to water of about 1 : 1 to about 2: 1.
  • the present disclosure provides a method for intra-arterial therapy, the method comprising injecting a variable-viscosity fluid into an intra-arterial catheter, wherein the variable-viscosity fluid comprises a high-viscosity fluid and a low- viscosity fluid.
  • the present disclosure provides a method for diagnosing and/or treating a tumor in a subject, the method comprising administering an omniphobic fluid (also referred to in this disclosure as an“omniphobic oil”) to the tumor via an intra-arterial catheter.
  • an omniphobic fluid also referred to in this disclosure as an“omniphobic oil”
  • the present disclosure provides a method for treating a tumor in a subject, the method comprising administering an emulsion to the tumor, wherein the emulsion comprises an omniphobic fluid and water, and wherein the emulsion comprises a volume ratio of the omniphobic fluid to water of about 1 : 1 to about 2: 1.
  • the present disclosure provides a method for treating a tumor in a subject in need thereof, the method comprising administering a mixture into the tumor via an intra-arterial catheter, wherein the mixture includes a carrier and a vaccine adjuvant.
  • the present disclosure provides a method for intra-arterial therapy, the method comprising injecting a variable-viscosity fluid into an intra-arterial catheter, wherein the variable-viscosity fluid includes a high-viscosity fluid not miscible with water and a low-viscosity fluid, wherein an emulsion includes the variable-viscosity fluid and a vaccine adjuvant.
  • FIGs. 1 A-1F illustrates a pig model of pancreatic adenocarcinoma, according to the working examples.
  • the Oncopig is a transgenic pig with Cre-inducible p53 and Kras mutations.
  • CT-guided core biopsy of the Oncopig pancreas was performed (FIGs. 1 A and 1B).
  • the core biopsy was incubated with an adenoviral vector carrying the Cre recombinase gene in order to induce p53 and Kras mutations.
  • the transformed core biopsy was injected back into the pancreas, which resulted in a pancreatic tumor, as confirmed by CT (FIG. 1C), and gross pathology (FIG. 1D).
  • FIG. 1F immunohistochemistry shows pig pancreatic adenocarcinoma.
  • FIG. 2 provides an angiogram of a hypervascular Oncopig liver tumor, according to the working examples.
  • FIG. 3 illustrates the systemic results achieved in an Oncopig after local delivery of a mixture of the present technology, according to the working examples.
  • there was reduction in size of both intrahepatic tumors and extrahepatic tumors where (on histology) tumor-infiltrating lymphocytes were seen in the necrotic liver tumors and no viable tumor cells were seen either in the liver or extrahepatic (pancreatic) tumors.
  • FIGs. 4A-4B illustrates the results of bland embolization (negative control) of a liver tumor, according to the working examples. After transarterial embolization of the liver tumor using commercially available 40-120 pm Embospheres, a non-contrast CT
  • FIG. 4A A follow-up contrast-enhanced scan shows decreased size and enhancement of the liver tumor (FIG. 4B).
  • Necropsy demonstrated complete necrosis of the embolized tumor, but viable tumor cells in unembolized tumors. For comparison, after embolization using lipiodol / saponin, complete necrosis of both embolized and unembolized tumors was observed (see FIG. 5).
  • FIG. 5 demonstrates tumor viability before and after treatment of a mixture according to the present technology, where liver tumors were completely necrotic after liver embolization using either Embospheres (transarterial embolization (TAE)) or lipiodol / saponin - however, pancreatic tumors remained viable after liver embolization using Embospheres (transarterial embolization (TAE)) or lipiodol / saponin - however, pancreatic tumors remained viable after liver embolization using Embospheres (transarterial embolization (TAE)) or lipiodol / saponin - however, pancreatic tumors remained viable after liver embolization using TEE.
  • TEE transarterial embolization
  • the term“about” will mean up to plus or minus 5% of the particular term (except where such number would be less than 0% or exceed 100% of a possible value). For example,“about 10 vol.%” would mean“9.5 vol.% to 10.5 vol.%” as well as“10 vol.%.”
  • the“administration” of an agent or drug to a subject includes any route of introducing or delivering to a subject a compound to perform its intended function. Administration can be carried out by any suitable route, including intra-arterially, orally, intranasally, parenterally (intravenously, intramuscularly, intraperitoneally, or subcutaneously), or topically. Administration includes self-administration and the
  • Cm-Cn such as C1-C12, C1-C 6 , or C1-C3 when used before a group refers to that group containing m to n carbon atoms.
  • Alkyl groups include straight chain and branched chain alkyl groups having from 1 to 12 carbon atoms, and typically from 1 to 10 carbons or, in some embodiments, from 1 to 8, 1 to 6, or 1 to 3 carbon atoms.
  • straight chain alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups.
  • branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.
  • Alkyl groups may be substituted or unsubstituted. Representative substituted alkyl groups may be substituted one or more times with substituents such as those listed above, and include without limitation haloalkyl (e.g ., trifluoromethyl), hydroxyalkyl, thioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, carboxyalkyl, and the like.
  • the term“effective amount” refers to a quantity sufficient to achieve a desired therapeutic, e.g., an amount which results in the decrease in a disease or condition described herein or one or more signs or symptoms associated with a disease or condition described herein.
  • the amount of a composition administered to the subject will vary depending on the composition, the degree, type, and severity of the disease and on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors.
  • the compositions can also be administered in combination with one or more additional therapeutic compounds.
  • a“therapeutically effective amount” of a composition refers to composition levels in which the physiological effects of a disease or condition are ameliorated or eliminated. A therapeutically effective amount can be given in one or more administrations.
  • the terms“omniphobic fluid” and“omniphobic oil” are used interchangeably and refer to a liquid that is not miscible with 50% (v/v) water or 50% (v/v) poppyseed oil at 37 °C.
  • the terms“subject,”“individual,” or“patient” are used interchangeably and refer to an individual organism, a vertebrate, a mammal, or a human. In certain embodiments, the individual, patient or subject is a human.
  • Treating”,“treat”, or“treatment” covers the treatment of a disease or disorder described herein, in a subject, such as a human, and includes: (i) inhibiting a disease or disorder, z.e., arresting its development; (ii) relieving a disease or disorder, z.e., causing regression of the disorder; (iii) slowing progression of the disorder; and/or (iv) inhibiting, relieving, or slowing progression of one or more symptoms of the disease or disorder.
  • treatment means that the symptoms associated with the disease are, e.g., alleviated, reduced, cured, or placed in a state of remission.
  • a volume ratio of different liquid components in a liquid composition is determined at 37 °C at a pressure of 1 atmosphere based on the initial volume of each individual component, not the final volume of combined components.
  • the various modes of treatment or prevention of medical diseases and conditions as described are intended to mean“substantial,” which includes total but also less than total treatment or prevention, and wherein some biologically or medically relevant result is achieved.
  • the treatment may be a continuous prolonged treatment for a chronic disease or a single to a few administrations for the treatment of an acute condition.
  • the present disclosure provides a method for diagnosing a tumor in a subject and/or treating a tumor in a subject, the method comprising administering an omniphobic fluid to the tumor via an intra-arterial catheter.
  • the present disclosure also provides a method for treating a tumor in a subject in need thereof, the method comprising administering an emulsion to the tumor via intra-arterial catheter, wherein the emulsion includes an omniphobic fluid and water, and wherein the emulsion includes a volume ratio of the omniphobic fluid to water of about 1 : 1 to about 2: 1.
  • the volume ratio of omniphobic fluid to water may be about 1 : 1, about 1.1 : 1, about 1.2: 1, about 1.3 : 1, about 1.4: 1, about 1.5: 1, about 1.6: 1, about 1.7: 1, about 1.8: 1, about 1.9: 1, about 2: 1, or any range including and/or in between any two of these values.
  • the volume ratio of omniphobic fluid to water may be about 1 : 1, about 1.1 : 1, about 1.2: 1, about 1.3 : 1, about 1.4: 1, about 1.5: 1, about 1.6: 1, about 1.7: 1, about 1.8: 1, about 1.9: 1, about 2: 1, or any range including and/or in between any two of these values.
  • the tumor may be a hypovascular liver tumor, a hypervascular liver tumor, a hepatocellular carcinoma, a cholangiocarcinoma, a lung tumor, pleural tumor, a mediastinal tumor, a liver metastasis (e.g ., from a neuroendocrine tumor, a colorectal cancer, a sarcoma, a pancreatic cancer, a breast cancer, or a melanoma), or a lung metastasis.
  • the tumor may be in the liver, kidney, pancreas, or lung of the subject.
  • the tumor may be a primary tumor or metastatic tumor located in the subject in the liver, kidney, pancreas, lung, pleura, mediastinum, or a combination of any two or more thereof.
  • treating a lung cancer or lung metastases may include administering via bronchial artery, non-bronchial systemic artery, or pulmonary artery.
  • the omniphobic fluid may include one or more of a fluorocarbon oil, a silicone oil, a superhydrophobic fluid, an ionic liquid, a radiopaque omniphobic fluid, a I 13 ⁇ labeled oil (e.g., I 131 -iodosilicone), or a combination of any two or more thereof.
  • the fluorocarbon oil may include one or more of a perfluorotri(C2-C8 alkyl)amine, perfluorooctane, perfluorodecalin, perflubron, iodofluorocarbon, bromofluorocarbon, or a combination of any two or more thereof.
  • the silicone oil may include one or more of
  • the omniphobic fluid may incldue one or more of a perfluorotri(C2-C8 alkyl)amine, perflurooctane, perfluorodecalin, perflubron, a silicone oil, or a combination of any two or more thereof.
  • the omniphobic fluid may include a viscosity of about 10 centipoise (cP) to about 100 centipoise at 37°C.
  • the omniphobic fluid may comprise a viscosity of about 10 cP, about 11 cP, about 12 cP, about 13 cP, about 14 cP, about 15 cP, about 16 cP, about 17 cP, about 18 cP, about 19 cP, about 20 cP, about 22 cP, about 24 cP, about 26 cP, about 28 cP, about 30 cP, about 32 cP, about 34 cP, about 36 cP, about 38 cP, about 40 cP, about 42 cP, about 44 cP, about 46 cP, about 48 cP, about 50 cP, about 52 cP, about 54 cP, about 56 cP, about 58 cP, about 60 cP
  • a chemotherapeutic drug such as tirapazamine and/or staurosporine
  • an anti-glycolytic drug such as bumetanide
  • an immunomodulatory agent such as a vaccine adjuvant, hydroxychloroquine, a corticosteroid, and/or granulocyte-colony stimulating factor (G-CSF)
  • an anti-inflammatory drug such as aspirin and/or ginsenoside
  • an anti -angiogenic medication such as sorafenib
  • an immune checkpoint inhibitor such as an anti -PD- 1 antibody
  • the vaccine adjuvant may include one or more of a saponin, hydroxychloroquine, granulocyte-macrophage colony-stimulating factor (GM- CSF), a bacterial protein, a viral protein, a lipopolysaccharide, a bacterium ( e.g ., inactivated, attenuated, or live), a virus (e.g., inactivated, attenuated, or live), a cytosine-guanine (CpG) oligonucleotide, an alum-based adjuvant, an antibody, a tumor antigen, or a combination of any two or more thereof.
  • GM- CSF granulocyte-macrophage colony-stimulating factor
  • the saponin may include one or more of ginsenoside, OPT-821, QS-21, Qui-A, or a combination of any two or more thereof.
  • the bacterial protein may include one or more of Neisseria meningitidis outer protein P64k, Mycobacterium sp. protein, toll-like receptor ligands, flagellin, or a combination of any two or more thereof.
  • the viral protein may include a protein originating from one or more of Cowpea mosaic virus (CPMV), hepatitis B virus (HBV), papillomavirus, vaccinia virus (VACV), or a combination of any two or more thereof.
  • CPMV Cowpea mosaic virus
  • HBV hepatitis B virus
  • VACV vaccinia virus
  • the lipopolysaccharide may include a lipopolysaccharide originating from one or more of Escherichia coli, Salmonella sp., Pseudomonas sp., or a combination of any two or more thereof.
  • the alum-based adjuvant may include one or more of aluminum sulfate, aluminum phosphate, aluminum hydroxide, or a combination of any two or more thereof.
  • the tumor antigen may include one or more of alpha-fetoprotein (AFP), carbohydrate antigen 19-9 (CA19-9), cancer antigen 125 (CA-125), carcinoembryonic antigen (CEA), b-human chorionic gonadotropin (b-HCG), or a combination of any two or more thereof.
  • AFP alpha-fetoprotein
  • CA19-9 carbohydrate antigen 19-9
  • CA-125 cancer antigen 125
  • CEA carcinoembryonic antigen
  • b-HCG b-human chorionic gonadotropin
  • a ratio of the vaccine adjuvant to the omniphobic oil may be about 1*10 6 to about 1*10 3 by weight.
  • a ratio of the vaccine adjuvant to the emulsion may be about 1*10 6 to about 1*10 3 by weight.
  • chemotherapeutic drugs include, but are not limited to, doxorubicin, cisplatin, epirubicin, mitomycin, irinotecan, gemcitabine, bis-chloroethylnitrosourea
  • BCNU BCNU
  • Exemplary immune checkpoint inhibitors include, but are not limited to, an anti-PD- 1 antibody, an anti-PD-Ll antibody, an anti-CTLA-4 antibody, ipilimumab, nivolumab, pidilizumab, lambrolizumab, pembrolizumab, atezolizumab, avelumab, durvalumab, MPDL3280A, BMS-936559, MEDI-4736, MSB 00107180, LAG-3, TIM3, B7-H3, B7-H4, TIGIT, AMP-224, MDX-1105, arelumab, tremelimumab, IMP321, MGA271, BMS-986016, lirilumab, urelumab, PF-05082566, IPH2101, MEDI-6469, CP-870,893, Mogamulizumab, Varlilumab, Galiximab, AMP-514,
  • the emulsion may include a detergent, a surfactant, an emulsifier, an oil, or a combination of any two or more thereof.
  • exemplary detergents include, but are not limited to, sodium tetradecyl sulfate, sodium dodecyl sulfate, distearyldimonium chloride, egg phospholipid, polysorbate 20, polysorbate 80, Cremophor EL Span 80, or a combination of any two or more thereof.
  • the method may include, prior to the administering step, generating the emulsion by one or more of sonicating, heating, shaking, stirring, or agitating a combination of the omniphobic fluid and water (and optionally a chemotherapeutic drug, a cytotoxic drug, an anti-glycolytic drug, an immunomodulatory agent, an anti-inflammatory drug, an anti -angiogenic medication, an immune checkpoint inhibitor, or a combination of any two or more thereof).
  • the omniphobic fluid and/or the emulsion may include particles.
  • the embodiment disclosed herein may be covalently bound to the particles, non-covalently associated with the particles, or both. In such embodiments, it may be that the vaccine adjuvant is covalently bound and/or non-covalently associated with an exterior surface of the particles and/or the vaccine adjuvant is released from the particle over time.
  • the particles may have a weight average diameter of about 20 pm to about 900 pm.
  • the particles may have a weight average diameter of about 20 pm, about 22 pm, about 24 pm, about 26 pm, about 28 pm, about 30 pm, about 32 pm, about 34 pm, about 36 pm, about 38 pm, about 40 pm, about 42 pm, about 44 pm, about 46 pm, about 48 pm, about 50 pm, about 52 pm, about 54 pm, about 56 pm, about 58 pm, about 60 pm, about 62 pm, about 64 pm, about 66 pm, about 68 pm, about 70 pm, about 72 pm, about 74 pm, about 76 pm, about 78 pm, about 80 pm, about 82 pm, about 84 pm, about 86 pm, about 88 pm, about 90 pm, about 92 pm, about 94 pm, about 96 pm, about 98 pm, about 100 pm, about 110 pm, about 120 pm, about 130 pm, about 140 pm, about 150 pm, about 160 pm, about 170 pm, about 180 pm, about 190 pm, about 200 pm, about 220 pm, about 240 pm, about 260 pm, about 280 pm, about 300
  • the particles may include glass, metal, plastic, gel, or a combination of any two or more thereof.
  • the metal particles may be composed of tantalum.
  • the emulsion of any embodiment disclosed herein may include one or more of a protic solvent, an aprotic polar solvent, or a hydrocarbon.
  • the protic solvents may include, but are not limited to, ammonia, t- butanol (7-BuOH), n-propanol, ethanol, methanol, acetic acid, water, or a combination of any two or more thereof.
  • the aprotic polar solvents may include, but are not limited to, N-m ethyl pyrrol i done, chloroform,
  • THF tetrahydrofuran
  • EtOAc ethyl acetate
  • acetone dimethylformamide
  • MeCN acetonitrile
  • DMSO dimethyl sulfoxide
  • PC propylene carbonate
  • An omniphobic fluid e.g ., an emulsion including an omniphobic fluid
  • an omniphobic fluid may be administered to the subject in effective amounts (i.e., amounts that have desired therapeutic effect).
  • effective amounts i.e., amounts that have desired therapeutic effect.
  • the dose and dosage regimen will depend upon the degree of the tumor in the subject, the characteristics of the particular omniphobic fluid (e.g ., emulsion) used, etc., e.g ., its therapeutic index, the subject, and the subject’s history.
  • An effective amount may be determined during pre-clinical trials and clinical trials by methods familiar to physicians and clinicians
  • Dosage, toxicity and therapeutic efficacy of the omniphobic fluid (e.g, emulsion) of the present technology can be determined by standard pharmaceutical procedures in experimental animals. While dosages and/or amounts of an omniphobic fluid and/or emulsion of the present technology that exhibit toxic side effects may be used, care should be taken to ensure delivery targets the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.
  • a therapeutically effective amount of an emulsion of the present technology may be defined as a concentration at the target tissue of 10 12 to 1 molar, e.g, approximately 10 3 molar.
  • treatment of a subject can include a single treatment or a series of treatments.
  • the mammal treated in accordance present methods can be any mammal, including, for example, farm animals, such as sheep, pigs, cows, and horses; pet animals, such as dogs and cats; laboratory animals, such as rats, mice and rabbits.
  • the mammal may be a human.
  • the present disclosure also provides a method for treating a tumor in a subject in need thereof, the method including administering a mixture into the tumor via an intra-arterial catheter, wherein the mixture includes a carrier and a vaccine adjuvant.
  • the tumor may be a hypovascular liver tumor, a hypervascular liver tumor, a hepatocellular carcinoma, a cholangiocarcinoma, a lung tumor, pleural tumor, a mediastinal tumor, a liver metastasis (e.g, from a neuroendocrine tumor, a colorectal cancer, a sarcoma, a pancreatic cancer, a breast cancer, or a melanoma), or a lung metastasis.
  • the tumor may be in the liver, kidney, pancreas, or lung of the subject.
  • the tumor may be a primary tumor or metastatic tumor located in the subject in the liver, kidney, pancreas, lung, pleura, mediastinum, or a combination of any two or more thereof.
  • treating a lung cancer or lung metastases may include administering via bronchial artery, non-bronchial systemic artery, or pulmonary artery.
  • the carrier may include one or more of a hydrocarbon oil, lipiodol, an omniphobic fluid, a variable viscosity oil, reactive monomers, a polymer, particles (discussed further herein), or a combination of any two or more thereof.
  • the hydrocarbon oil may include one or more of mineral oil, bromohydrocarbon, iodohydrocarbon, or a combination of any two or more thereof.
  • the omniphobic fluid may include one or more of a fluorocarbon oil, a silicone oil, a superhydrophobic fluid, an ionic liquid, a radiopaque omniphobic fluid, a 13 ⁇ -labeled oil, or a combination of any two or more thereof.
  • the reactive monomers may include one or more of methyl 2- cyanoacrylate (MCA), ethyl 2-cyanoacrylate (ECA), «-butyl cyanoacrylate (//-BCA), octyl cyanoacrylate, 2-octyl cyanoacrylate, or a combination of any two or more thereof.
  • Such reactive monomers may be dissolved in a solvent, such as one or more of a protic solvent, an aprotic polar solvent (e.g ., DMSO), or a hydrocarbon, discussed in more detail herein.
  • the polymer may include one or more of poly(vinyl alcohol) (PVA), ethylene vinyl alcohol (EVOH), melamine, polyethersulfone, nitrocellulose, or a combination of any two or more thereof.
  • the polymer may be dissolved in a solvent, such as one or more of a protic solvent, an aprotic polar solvent (e.g., DMSO), or a hydrocarbon.
  • the vaccine adjuvant may be covalently bound to the hydrocarbon oil, lipiodol, the omniphobic fluid, the variable viscosity oil, the polymer, or the particles.
  • the fluorocarbon oil may include one or more of a perfluorotri(C2-C8 alkyl)amine, perfluorooctane, perfluorodecalin, perflubron, iodofluorocarbon, bromofluorocarbon, or a combination of any two or more thereof.
  • the silicone oil may include one or more of polydimethylsiloxane, iodosilicone, bromosilicone, or a combination of any two or more thereof.
  • the omniphobic fluid may include a viscosity of about 10 centipoise (cP) to about 100 centipoise at 37°C.
  • the omniphobic fluid may comprise a viscosity of about 10 cP, about 11 cP, about 12 cP, about 13 cP, about 14 cP, about 15 cP, about 16 cP, about 17 cP, about 18 cP, about 19 cP, about 20 cP, about 22 cP, about 24 cP, about 26 cP, about 28 cP, about 30 cP, about 32 cP, about 34 cP, about 36 cP, about 38 cP, about 40 cP, about 42 cP, about 44 cP, about 46 cP, about 48 cP, about 50 cP, about 52 cP, about 54 cP, about 56 cP, about 58 cP, about 60 cP
  • the vaccine adjuvant may include one or more of a saponin, hydroxychloroquine, granulocyte-macrophage colony-stimulating factor (GM- CSF), a bacterial protein, a viral protein, a lipopolysaccharide, a bacterium ( e.g ., inactivated, attenuated, or live), a virus (e.g., inactivated, attenuated, or live), a cytosine-guanine (CpG) oligonucleotide, an alum-based adjuvant, an antibody, a tumor antigen, or a combination of any two or more thereof.
  • GM- CSF granulocyte-macrophage colony-stimulating factor
  • the saponin may include one or more of ginsenoside, OPT-821, QS-21, Qui-A, or a combination of any two or more thereof.
  • the bacterial protein may include one or more of Neisseria meningitidis outer protein P64k, Mycobacterium sp. protein, toll-like receptor ligands, flagellin, or a combination of any two or more thereof.
  • the viral protein may include a protein originating from one or more of Cowpea mosaic virus (CPMV), hepatitis B virus (HBV), papillomavirus, vaccinia virus (VACV), or a combination of any two or more thereof.
  • CPMV Cowpea mosaic virus
  • HBV hepatitis B virus
  • VACV vaccinia virus
  • the lipopolysaccharide may include a lipopolysaccharide originating from one or more of Escherichia coli, Salmonella sp., Pseudomonas sp., or a combination of any two or more thereof.
  • the alum-based adjuvant may include one or more of aluminum sulfate, aluminum phosphate, aluminum hydroxide, or a combination of any two or more thereof.
  • the tumor antigen may include one or more of alpha-fetoprotein (AFP), carbohydrate antigen 19-9 (CA19-9), cancer antigen 125 (CA-125), carcinoembryonic antigen (CEA), b-human chorionic gonadotropin (b-HCG), or a combination of any two or more thereof.
  • a ratio of the vaccine adjuvant to the carrier may be about 1 * 10 6 to about 1 * 10 3 by weight.
  • a chemotherapeutic drug such as tirapazamine and/or staurosporine
  • an anti-glycolytic drug such as bumetanide
  • an additional immunomodulatory agent such as hydroxychloroquine, a corticosteroid, and/or granulocyte-colony stimulating factor (G-CSF)
  • an anti-inflammatory drug such as aspirin and/or ginsenoside
  • an anti -angiogenic medication such as sorafenib
  • an immune checkpoint inhibitor such as an anti -PD- 1 antibody
  • chemotherapeutic drugs include, but are not limited to, doxorubicin, cisplatin, epirubicin, mitomycin, irinotecan, gemcitabine, bis- chloroethylnitrosourea (BCMJ), or a combination of any two or more thereof.
  • chemotherapeutic drugs include, but are not limited to, doxorubicin, cisplatin, epirubicin, mitomycin, irinotecan, gemcitabine, bis- chloroethylnitrosourea (BCMJ), or a combination of any two or more thereof.
  • exemplary immune checkpoint inhibitors include, but are not limited to, an anti -PD- 1 antibody, an anti- PD-L1 antibody, an anti-CTLA-4 antibody, ipilimumab, nivolumab, pidilizumab,
  • the mixture of any embodiment herein may be administered in an effective amount to
  • Specific dosages may be adjusted depending on conditions of the subject, the age, body weight, general health conditions, sex, and diet of the subject, dose intervals, excretion rate, and combinations of drugs.
  • the mixture may include a detergent, a surfactant, an emulsifier, an oil, or a combination of any two or more thereof.
  • exemplary detergents include, but are not limited to, sodium tetradecyl sulfate, sodium dodecyl sulfate, distearyldimonium chloride, egg phospholipid, polysorbate 20, polysorbate 80, Cremophor EL Span 80, or a combination of any two or more thereof.
  • the mixture may be an emulsion.
  • the method may include, prior to the administering step, generating the mixture by one or more of sonicating, heating, shaking, stirring, or agitating a combination of the carrier and the vaccine adjuvant (and optionally water, and/or a chemotherapeutic drug, and/or optionally a cytotoxic drug, and/or optionally an anti-glycolytic drug, and/or optionally an additional immunomodulatory agent, and/or optionally an anti-inflammatory drug, and/or optionally an anti-angiogenic medication, and/or optionally an immune checkpoint inhibitor).
  • the mixture may include particles (e.g ., the carrier includes particles).
  • the vaccine adjuvant may be covalently bound to the particles, non-covalently associated with the particles, or both. In such embodiments, it may be that the vaccine adjuvant is covalently bound and/or non- covalently associated with an exterior surface of the particles and/or the vaccine adjuvant is released from the particle over time.
  • the particles may have a weight average diameter of about 20 pm to about 900 pm.
  • the particles may have a weight average diameter of about 20 pm, about 22 pm, about 24 pm, about 26 pm, about 28 pm, about 30 pm, about 32 pm, about 34 pm, about 36 pm, about 38 pm, about 40 pm, about 42 pm, about 44 pm, about 46 pm, about 48 pm, about 50 pm, about 52 pm, about 54 pm, about 56 pm, about 58 pm, about 60 pm, about 62 pm, about 64 pm, about 66 pm, about 68 pm, about 70 pm, about 72 pm, about 74 pm, about 76 pm, about 78 pm, about 80 pm, about 82 pm, about 84 pm, about 86 pm, about 88 pm, about 90 pm, about 92 pm, about 94 pm, about 96 pm, about 98 pm, about 100 pm, about 110 pm, about 120 pm, about 130 pm, about 140 pm, about 150 pm, about 160 pm, about 170 pm, about 180 pm, about 190 pm, about 200 pm, about 220 pm, about 240 pm, about 260 pm, about 280 pm, about 300
  • the particles may include glass, metal, plastic, gel, or a combination of any two or more thereof.
  • the metal particles may be composed of tantalum.
  • the mixture of any embodiment disclosed herein may include one or more of a protic solvent, an aprotic polar solvent, or a hydrocarbon.
  • the protic solvents may include, but are not limited to, ammonia, t- butanol (7-BuOH), n-propanol, ethanol, methanol, acetic acid, water, or a combination of any two or more thereof.
  • the aprotic polar solvents may include, but are not limited to, N-m ethyl pyrrol i done, chloroform,
  • THF tetrahydrofuran
  • EtOAc ethyl acetate
  • acetone dimethylformamide
  • MeCN acetonitrile
  • DMSO dimethyl sulfoxide
  • PC propylene carbonate
  • the present disclosure also provides a method for intra-arterial therapy, comprising injecting a variable-viscosity fluid into an intra-arterial catheter, wherein the variable-viscosity fluid includes a high-viscosity fluid as well as a low-viscosity fluid, wherein an emulsion includes the high-viscosity fluid and a vaccine adjuvant. Additionally or alternatively, in some embodiments, the low-viscosity fluid washes out over time, thus increasing the viscosity of the remaining fluid.
  • the high-viscosity fluid is not miscible with water (i.e., a solubility of less than 0.1 g high-viscosity fluid per 100 g water at 25 °C).
  • the low- viscosity fluid may include one or more of dimethylsulfoxide or a low molecular weight hydrocarbon oil. Additionally or alternatively, in some embodiments, the low-viscosity fluid may include another fluid that may be miscible with both water and the high viscosity fluid. Additionally or alternatively, in some embodiments, the variable-viscosity fluid may be carrier for a vaccine adjuvant.
  • a mixture including a carrier and a vaccine adjuvant may be administered to the subject in effective amounts (i.e ., amounts that have desired therapeutic effect).
  • effective amounts i.e ., amounts that have desired therapeutic effect.
  • the dose and dosage regimen will depend upon the degree of the tumor in the subject, the characteristics of the particular carrier (e.g ., lipiodol or omniphobic fluid) and/or vaccine adjuvant (e.g., saponin) used, etc., e.g. , its therapeutic index, the subject, and the subject’s history.
  • An effective amount may be determined during pre-clinical trials and clinical trials by methods familiar to physicians and clinicians.
  • Dosage, toxicity and therapeutic efficacy of the mixture (e.g, emulsion) of the present technology can be determined by standard pharmaceutical procedures in experimental animals. While dosages and/or amounts of a mixture and/or emulsion of the present technology that exhibit toxic side effects may be used, care should be taken to ensure delivery targets the site of affected tissue in order to minimize potential damage to normal cells and, thereby, reduce side effects.
  • a therapeutically effective amount of a mixture and/or emulsion of the present technology may be defined as a concentration at the target tissue of 10 12 to 1 molar, e.g ., approximately 10 3 molar.
  • treatment of a subject can include a single treatment or a series of treatments.
  • the mammal treated in accordance present methods can be any mammal, including, for example, farm animals, such as sheep, pigs, cows, and horses; pet animals, such as dogs and cats; laboratory animals, such as rats, mice and rabbits.
  • the mammal may be a human.
  • a pig model of liver cancer was used.
  • the right femoral artery was accessed, and a 6 French sheath was placed using the Seldinger technique.
  • a 4 French Cobra catheter was advanced through the sheath under fluoroscopic guidance into the celiac artery, where an angiogram was performed.
  • the 4 French catheter was advanced into a branch of the hepatic artery supplying a liver tumor.
  • a 2.4 French microcatheter was advanced through the 4 French catheter, into the artery supplying the tumor.
  • the perfluorotripentylamine or the lipiodol control was delivered through the catheter into the artery supplying the tumor.
  • the oil was injected until there was slow flow into the artery.
  • homeostasis was achieved via manual compression. Three days post injection, the amount of
  • perfluorotripentylamine and the lipiodol control retained in the tumor and the background liver was quantified (v/v %, Table 1) using non-contrast helical CT, based on Hounsfield units.
  • v/v % Table 1
  • Example 2 Effects of a Mixture of the Present Technolosv on Treatins Tumors in a
  • transgenic pig model of pancreatic and liver cancers was used. Briefly, the transgenic pig model of pancreatic and liver cancer used in this study has Cre-inducible p53 and Kras mutations.
  • a CT-guided core biopsy of the pancreas was performed with an 18 gauge needle (FIG. 1 A and 1B). The core biopsy was subsequently placed into a phosphate- buffered saline (PBS) solution (1 mL) containing an adenoviral vector carrying the Cre recombinase gene (AdCre, 10 9 pfu), in order to induce p53 and Kras mutations.
  • PBS phosphate- buffered saline
  • FIG. 1E cytokeratin immunohistochemistry
  • FIG. 1F cytokeratin immunohistochemistry
  • Treatment using the methods of the present technology e.g ., intra-arterial injection of a carrier and a vaccine adjuvant was performed under general anesthesia.
  • the right groin was sterilized using with chlorhexidine, followed by subsequent draping.
  • Under ultrasound guidance the right femoral artery was accessed using a micropuncture needle, and a 6 French sheath was placed using the Seldinger technique.
  • a 4 French Cobra catheter was advanced through the sheath under fluoroscopic guidance into the celiac artery, where an angiogram was performed (FIG. 2).
  • the 4 French catheter and a guidewire were advanced into a branch of the hepatic artery supplying a liver tumor, under fluoroscopic guidance, where an angiogram was performed to confirm catheter positioning.
  • An emulsion of 2.4 mL lipiodol, 40 microgram (pg) saponin, and 1.6 mL saline was generated by pumping the combined components back and forth 20 times between 2 syringes, through a 3 -way stopcock. Under fluoroscopic guidance, the emulsion was then delivered through the intra-arterial catheter into the liver tumor.
  • mixtures disclosed herein which include a carrier and a vaccine adjuvant administered via an intra-arterial catheter are useful in methods for treating a tumor in a subject in need thereof.
  • a group having 1-3 atoms refers to groups having 1, 2, or 3 atoms.
  • a group having 1-5 atoms refers to groups having 1, 2, 3, 4, or 5 atoms, and so forth.
  • a method for diagnosing and/or treating a tumor in a subject comprising: administering an omniphobic fluid into the tumor via an intra-arterial catheter.
  • the omniphobic fluid comprises one or more of a fluorocarbon oil, a silicone oil, a superhydrophobic fluid, an ionic liquid, a radiopaque omniphobic fluid, a I m -labeled oil, or a combination of any two or more thereof.
  • the emulsion further comprises a chemotherapeutic drug, a cytotoxic drug, an anti-glycolytic drug, an immunomodulatory agent, an anti inflammatory drug, an anti-angiogenic medication, an immune checkpoint inhibitor, or a combination of any two or more thereof.
  • the emulsion further comprises doxorubicin, cisplatin, epirubicin, mitomycin, irinotecan, gemcitabine, bis- chloroethylnitrosourea (BCNU), or a combination of any two or more thereof.
  • chemotherapeutic drug optionally a chemotherapeutic drug
  • cytotoxic drug optionally a cytotoxic drug
  • an immunomodulatory agent optionally an immunomodulatory agent
  • an immune checkpoint inhibitor optionally an immune checkpoint inhibitor.
  • N The method of any one of Paragraphs A-M, wherein the tumor is a primary tumor or metastatic tumor located in the subject in the liver, kidney, pancreas, lung, pleura, mediastinum, or a combination of any two or more thereof.
  • a method for intra-arterial therapy comprising
  • variable-viscosity fluid comprises a high-viscosity fluid not miscible with water and a low-viscosity fluid.
  • a method for treating a tumor in a subject comprising:
  • the emulsion comprises an omniphobic fluid and water
  • the emulsion comprises a volume ratio of the omniphobic fluid to water of about 1 : 1 to about 2: 1.
  • the omniphobic fluid comprises one or more of a perfluorotri(C2-C8 alkyljamine, perflurooctane, perfluorodecalin, perflubron, a silicone oil, a I 131 -labeled oil, or a combination of any two or more thereof.
  • immunomodulatory agent an anti-inflammatory drug, an anti-angiogenic medication, or a combination of any two or more thereof.
  • doxorubicin doxorubicin, cisplatin, epirubicin, mitomycin, irinotecan, gemcitabine, bis- chloroethylnitrosourea (BCNU), or a combination of any two or more thereof.
  • chemotherapeutic drug optionally a chemotherapeutic drug
  • cytotoxic drug optionally a cytotoxic drug
  • an immunomodulatory agent optionally an immunomodulatory agent
  • an immune checkpoint inhibitor optionally an immune checkpoint inhibitor.
  • cholangiocarcinoma a lung tumor, pleural tumor, a mediastinal tumor, a liver metastases, or a lung metastases.
  • AD A method for treating a tumor in a subject in need thereof, the method comprising: administering a mixture into the tumor via an intra-arterial catheter, wherein the mixture comprises a carrier and a vaccine adjuvant.
  • the carrier comprises one or more of a hydrocarbon oil, lipiodol, an omniphobic fluid, a variable viscosity oil, reactive monomers, a polymer, particles, or a combination of any two or more thereof.
  • the omniphobic fluid comprises one or more of a fluorocarbon oil, a silicone oil, a superhydrophobic fluid, an ionic liquid, a radiopaque omniphobic fluid, a 13 ⁇ -labeled oil, or a combination of any two or more thereof.
  • AH The method of any one of Paragraphs AE-AG, wherein the reactive monomers comprise one or more of methyl 2-cyanoacrylate (MCA), ethyl 2-cyanoacrylate (ECA), «-butyl cyanoacrylate (//-BCA), octyl cyanoacrylate, 2-octyl cyanoacrylate, or a combination of any two or more thereof.
  • MCA methyl 2-cyanoacrylate
  • ECA ethyl 2-cyanoacrylate
  • BCA butyl cyanoacrylate
  • octyl cyanoacrylate 2-octyl cyanoacrylate
  • 2-octyl cyanoacrylate 2-octyl cyanoacrylate
  • AI The method of any one of Paragraphs AE-AH, wherein the mixture comprises the
  • poly(vinyl alcohol) PVA
  • EVOH ethylene vinyl alcohol
  • melamine PVA
  • PVA poly(vinyl alcohol)
  • EVOH ethylene vinyl alcohol
  • melamine melamine
  • polyethersulfone polyethersulfone, nitrocellulose, or a combination of any two or more thereof.
  • AJ The method of any one of Paragraphs AE-AI, wherein the fluorocarbon oil comprises one or more of a perfluorotri(C2-C8 alkyl)amine, perfluorooctane, perfluorodecalin, perflubron, iodofluorocarbon, bromofluorocarbon, or a combination of any two or more thereof.
  • the fluorocarbon oil comprises one or more of a perfluorotri(C2-C8 alkyl)amine, perfluorooctane, perfluorodecalin, perflubron, iodofluorocarbon, bromofluorocarbon, or a combination of any two or more thereof.
  • AK The method of any one of Paragraphs AE-AJ, wherein the silicone oil comprises one or more of poly dimethyl siloxane, iodosilicone, bromosilicone, or a combination of any two or more thereof.
  • the vaccine adjuvant comprises one or more of a saponin, a bacterial protein, a viral protein, a lipopolysaccharide, a bacterium ( e.g ., inactivated, attenuated, or live), a virus (e.g, inactivated, attenuated, or live), a cytosine-guanine (CpG) oligonucleotide, an alum-based adjuvant, an antibody, a tumor antigen, or a combination of any two or more thereof.
  • the vaccine adjuvant comprises one or more of a saponin, a bacterial protein, a viral protein, a lipopolysaccharide, a bacterium (e.g ., inactivated, attenuated, or live), a virus (e.g, inactivated, attenuated, or live), a cytosine-guanine (CpG) oligonucleotide, an alum-based adjuvant
  • ginsenoside OPT-821, QS-21, Quil-A, or a combination of any two or more thereof.
  • bacterial protein comprises one or more of Neisseria meningitidis outer protein P64k, Mycobacterium sp. protein, toll-like receptor ligands, flagellin, or a combination of any two or more thereof.
  • AO AO.
  • the viral protein comprises a protein originating from one or more of Cowpea mosaic virus (CPMV), hepatitis B virus (HB V), papillomavirus, vaccinia virus (VACV), or a combination of any two or more thereof.
  • CPMV Cowpea mosaic virus
  • HB V hepatitis B virus
  • VACV vaccinia virus
  • the lipopolysaccharide comprises a lipopolysaccharide originating from one or more of Escherichia coli , Salmonella sp ., Pseudomonas sp ., or a combination of any two or more thereof.
  • the tumor antigen comprises one or more of alpha-fetoprotein (AFP), carbohydrate antigen 19-9 (CA19-9), cancer antigen 125 (CA-125), carcinoembryonic antigen (CEA), b-human chorionic gonadotropin (b-HCG), or a combination of any two or more thereof.
  • AFP alpha-fetoprotein
  • CA19-9 carbohydrate antigen 19-9
  • CA-125 cancer antigen 125
  • CEA carcinoembryonic antigen
  • b-HCG b-human chorionic gonadotropin
  • any one of Paragraphs AD-AR wherein the mixture further comprises a chemotherapeutic drug, a cytotoxic drug, an anti-glycolytic drug, an additional immunomodulatory agent, an anti-inflammatory drug, an anti-angiogenic medication, an immune checkpoint inhibitor, or a combination of any two or more thereof.
  • the immune checkpoint inhibitor comprises an anti -PD- 1 antibody, an anti-PD-Ll antibody, an anti-CTLA-4 antibody, ipilimumab, nivolumab, pidilizumab, lambrolizumab, pembrolizumab, atezolizumab, avelumab, durvalumab, MPDL3280A, BMS-936559, MEDI-4736, MSB 00107180, LAG-3, TIM3, B7-H3, B7-H4, TIGIT, AMP-224, MDX-1105, arelumab, tremelimumab, IMP321, MGA271, BMS-986016, lirilumab, urelumab, PF-05082566, IPH2101, MEDI-6469, CP-870,893, Mogamulizumab, Varlilumab, Galiximab, AMP-514, AU
  • AX The method of any one of Paragraphs AD-AW, wherein the method further comprises, prior to the administering step, generating the mixture by one or more of sonicating, heating, shaking, stirring, or agitating a combination of
  • chemotherapeutic drug optionally a chemotherapeutic drug
  • cytotoxic drug optionally a cytotoxic drug
  • an immune checkpoint inhibitor optionally an immune checkpoint inhibitor.
  • BD The method of any one of Paragraphs AD-BC, wherein the tumor is a primary tumor or metastatic tumor located in the subject in the liver, kidney, pancreas, lung, pleura, mediastinum, or a combination of any two or more thereof.
  • a method for intra-arterial therapy comprising:
  • variable-viscosity fluid comprises a high-viscosity fluid not miscible with water and a low-viscosity fluid
  • an emulsion comprises the variable-viscosity fluid and a vaccine adjuvant.

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Abstract

La présente invention concerne des méthodes pour diagnostiquer et/ou traiter une tumeur chez un sujet. Les méthodes de la présente invention concernent l'administration intra-artérielle localisée à une tumeur à l'aide d'un support comprenant un liquide omniphobe pour améliorer l'absorption, la spécificité et la rétention de tumeur. Le support peut également comprendre une huile à faible viscosité pour améliorer l'extravasation à travers le système vasculaire tumoral. Les méthodes de la présente invention concernent également l'administration intra-artérielle localisée d'un adjuvant de vaccin dans une tumeur, à l'aide d'un support pour améliorer l'absorption, la spécificité et la rétention de tumeur. Le support peut comprendre, par exemple, du lipiodol, une huile omniphobe et/ou des particules, et peut également comprendre une huile à faible viscosité pour améliorer l'extravasation à travers le système vasculaire tumoral.
PCT/US2019/059226 2018-11-01 2019-10-31 Ciblage de tumeur intra-artériel amélioré pour un diagnostic et/ou un traitement WO2020092815A1 (fr)

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WO2022047544A1 (fr) * 2020-09-04 2022-03-10 IP Cornerstone Pty Ltd Traitement à effraction minimale de l'arthrose et d'autres affections
CN116920005A (zh) * 2023-07-18 2023-10-24 常州大学 一种三七人参皂苷提取物及其制备方法

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US20170071976A1 (en) * 2014-05-26 2017-03-16 Songyuan Chen Pharmaceutical solution having anti-tumor effect-enhancing and toxicity-reducing effect, and pharmaceutical composition comprising same
WO2017196524A1 (fr) * 2016-05-10 2017-11-16 Dow Corning Corporation Copolymère séquencé de silicone ayant un groupe de blocage d'extrémité aminofonctionnel et son procédé de préparation et d'utilisation

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US20160346202A1 (en) * 2014-02-07 2016-12-01 Guerbet Composition for Vectorizing an Anti-Cancer Agent
US20170071976A1 (en) * 2014-05-26 2017-03-16 Songyuan Chen Pharmaceutical solution having anti-tumor effect-enhancing and toxicity-reducing effect, and pharmaceutical composition comprising same
WO2017196524A1 (fr) * 2016-05-10 2017-11-16 Dow Corning Corporation Copolymère séquencé de silicone ayant un groupe de blocage d'extrémité aminofonctionnel et son procédé de préparation et d'utilisation

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022047544A1 (fr) * 2020-09-04 2022-03-10 IP Cornerstone Pty Ltd Traitement à effraction minimale de l'arthrose et d'autres affections
CN116920005A (zh) * 2023-07-18 2023-10-24 常州大学 一种三七人参皂苷提取物及其制备方法

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