WO2017174437A1 - Nanoparticules d'oxyde de cérium destinées à être utilisées dans le traitement du carcinome hépatocellulaire - Google Patents

Nanoparticules d'oxyde de cérium destinées à être utilisées dans le traitement du carcinome hépatocellulaire Download PDF

Info

Publication number
WO2017174437A1
WO2017174437A1 PCT/EP2017/057570 EP2017057570W WO2017174437A1 WO 2017174437 A1 WO2017174437 A1 WO 2017174437A1 EP 2017057570 W EP2017057570 W EP 2017057570W WO 2017174437 A1 WO2017174437 A1 WO 2017174437A1
Authority
WO
WIPO (PCT)
Prior art keywords
cerium oxide
crystal
oxide nanoparticle
albumin
diameter
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/EP2017/057570
Other languages
English (en)
Inventor
Wladimiro JIMÉNEZ POVEDANO
Víctor FRANCO PUNTES
Guillermo FERNÁNDEZ VARO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Universitat de Barcelona UB
Institucio Catalana de Recerca i Estudis Avancats ICREA
Hospital Clinic de Barcelona
Institut Catala de Nanociencia i Nanotecnologia ICN2
Centro de Investigacion Biomedica en Red CIBER
Original Assignee
Universitat de Barcelona UB
Institucio Catalana de Recerca i Estudis Avancats ICREA
Hospital Clinic de Barcelona
Institut Catala de Nanociencia i Nanotecnologia ICN2
Centro de Investigacion Biomedica en Red CIBER
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 Universitat de Barcelona UB, Institucio Catalana de Recerca i Estudis Avancats ICREA, Hospital Clinic de Barcelona, Institut Catala de Nanociencia i Nanotecnologia ICN2, Centro de Investigacion Biomedica en Red CIBER filed Critical Universitat de Barcelona UB
Publication of WO2017174437A1 publication Critical patent/WO2017174437A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/244—Lanthanides; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0038—Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
    • A61K47/6931—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer
    • A61K47/6933—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being obtained by reactions only involving carbon to carbon, e.g. poly(meth)acrylate, polystyrene, polyvinylpyrrolidone or polyvinylalcohol
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5169—Proteins, e.g. albumin, gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01F—COMPOUNDS OF THE METALS BERYLLIUM, MAGNESIUM, ALUMINIUM, CALCIUM, STRONTIUM, BARIUM, RADIUM, THORIUM, OR OF THE RARE-EARTH METALS
    • C01F17/00—Compounds of rare earth metals
    • C01F17/20—Compounds containing only rare earth metals as the metal element
    • C01F17/206—Compounds containing only rare earth metals as the metal element oxide or hydroxide being the only anion
    • C01F17/224—Oxides or hydroxides of lanthanides
    • C01F17/235—Cerium oxides or hydroxides
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2002/00—Crystal-structural characteristics
    • C01P2002/60—Compounds characterised by their crystallite size

Definitions

  • the present invention relates to the field of medicine, in particular to cancer treatment. It also relates to nanoparticles and conjugates comprising them, as well as to pharmaceutically or veterinary compositions for the treatment of cancer.
  • HCC Hepatocellular carcinoma
  • Sorafenib a receptor tyrosine kinase inhibitor
  • Sorafenib is a small molecule that inhibits tumor-cell proliferation and tumor angiogenesis.
  • nanoparticles have been administered to an A375 xenograft model of nude mice in order to test them in a melanoma model.
  • the data are summarized in ANN et al., "Downregulation of Tumor Growth and Invasion by Redox-Active
  • CNPs redox-active cerium oxide nanoparticles
  • Cerium oxide nanoparticles have emerged thus in biomedical applications due to their superoxide dismutase (SOD) and catalase mimetic activity. CNPs act as catalysts with mixed valence that can exist in a reduced (+3) or oxidized (+4) state.
  • SOD superoxide dismutase
  • cerium oxide nanopartides are toxic. As an example, Cheng et al., in "Cerium oxide nanopartides induce cytotoxicity in human hepatoma SMMC-7721 cells via oxidative stress and the activation of MAPK signalling pathways",
  • CNPs or any other nanopartides with low diameters (fewer than 7 nm) have low residence time in the body, and poor solubility (See Hak Soo et al., "Renal clearance of quantum dots", Nature biotechnology - 2007, vol. no. 25(10), pp.: 1 165-1 170).
  • toxic reagents such as hexamethylenetetramine; HMT, making them hazardous for biomedical applications if they are not separated from the nanopartides before, which sometimes is difficult or imply expensive procedures.
  • Inventors propose using particular cerium oxide nanopartides in the treatment of HCC, which surprisingly allowed increasing the survival of treated animals in a remarkably way. Moreover, proliferation of cancer cells was highly reduced when the nanopartides were administered to mammals with induced HCC. Thus, the treatment avoided tumour growth.
  • a first aspect the invention relates to single-crystal cerium oxide nanopartides of formula (I) for use in the treatment of hepatocellular carcinoma, formula (I) defined by:
  • NP is a cerium oxide nanoparticle with a crystal diameter measured by transmission electron microscopy (TEM) from 3 to 24 nm;
  • TEM transmission electron microscopy
  • A is a molecule selected from the group consisting of albumin, polyvinylpyrrolidone (PVP), and combinations thereof; and
  • n is an integer from 0 to 40
  • n is an integer from 1 to 12.
  • nanoparticles are conjugated with A, so that they are also called in the present invention as conjugates.
  • the invention provides the unexpected effect of conjugates with CNPs or of CNPs that can be safely applied to HCC treatment.
  • the conjugates or CNPs are effective due to a proper non- agglomeration (or non-aggregation) of the nanoparticles, and due to a size that, though relative small, can be retained in liver.
  • the invention relates to particular single-crystal cerium oxide nanoparticles of formula (I),
  • NP is a cerium oxide nanoparticle with a crystal diameter from 3 to 7 nm;
  • A is a molecule selected from the group consisting of albumin, polyvinylpyrrolidone, and combinations thereof;
  • n is an integer from 1 to 12.
  • Yet another aspect of the invention is a conjugated single-crystal cerium oxide nanoparticle of formula (I):
  • NP is a cerium oxide nanoparticle with a crystal diameter from 8 to 24 nm;
  • A is a molecule of albumin
  • N is an integer from 5 to 40.
  • CNPs of Bushan et al. were synthesized by the hydrothermal method. By TEM images it was seen that the average size of CNPs was of 4.35 ⁇ 1 .07 nm. CNPs were then encapsulated inside albumin nanoparticles via a desolvation technique using ethanol as the desolvating agent and glutaraldehyde as a cross linking agent to obtain least aggregated spherical BCNPs with uniform distribution.
  • the single-crystal cerium oxide nanoparticles of the invention can be administered to mammals in several forms appropriated for administration.
  • another aspect of the invention is a pharmaceutical or veterinary composition comprising these nanoparticles of formula (I) as defined above, together with one or more pharmaceutically or veterinary acceptable excipients or carriers.
  • These pharmaceutical or veterinary compositions comprising the new single-crystal cerium oxide nanoparticles of the invention are also for use in the treatment of hepatocellular carcinoma.
  • FIG. 1 shows in (A) optical microscope images (200X) of Ki-67-tincted hepatic cells from Wistar rats treated with cerium oxide nanoparticles (CeO2NPs) or with vehicle, which was a suspension of TMAOH 0.8 mM in phosphate saline buffer (PBS).
  • FIG. 1 shows in (A) optical microscope images (200X) of Ki-67-tincted hepatic cells from Wistar rats treated with cerium oxide nanoparticles (CeO2NPs) or with vehicle, which was a suspension of TMAOH 0.8 mM in phosphate saline buffer (PBS).
  • PBS phosphate saline buffer
  • Example 2 is a graphic with the survival (percentage of survival; %S) of the rats versus the time (T, weeks (W)) after reception of last dose of single-crystal cerium oxide nanoparticles of formula (I) in which A is albumin (CeO2NPs) or of vehicle as disclosed for FIG. 1 .
  • FIG. 3 related with Example 1 depicts the monitoring of the synthesis kinetics of CeO2NPs (single-crystal cerium oxide nanoparticles of formula (I) in which A is either albumin or PVP).
  • A the pH evolution of the synthesis solution.
  • B UV-visible spectrum of initial cerium (III) precursor (black line); as-synthesized NPs at 1 h of reaction, diluted 1 /20 (soft grey line); as-synthesized NPs at 48h of reaction, diluted 1 /20 (dark grey line).
  • FIG. 4 shows the characterization of PVP- conjugated CeO2NPs (single-crystal cerium oxide nanoparticles of formula (I) in which A is PVP) by transmission electron microscopy (TEM).
  • TEM transmission electron microscopy
  • FIG. 4 a high resolution TEM micrograph (HR-TEM) at high (400.000X) magnification, revealing the atomic planes of single-crystal nanoparticles
  • FIG. 4 b High Angle Annular Dark Field-Scanning Transmission Electron Microscopy (STEM-HAADF) image
  • STEM-HAADF High Angle Annular Dark Field-Scanning Transmission Electron Microscopy
  • FIG. 4 c HR-TEM image at low magnification (7.000 check); in FIG.
  • FIG. 4 d atomic resolution HR-TEM image of one single (single-crystal) CeO2NP, showing spherical morphology and the correspondent atomic planes; in FIG. 4 e) Fast Fourier Transformation (FFT) digital diffractogram calculated from the particle shown in FIG. 4 d); in FIG. 4 f) Electron energy-loss spectroscopy (EELS, X-axis Energy in kiloelectrovolts (keV); Y-axis counts (C) in arbitrary units (a.u.)) map of the chemical composition of as synthesized CeO2NP. Panels d), e) and F appear in Cont.FIG. 4 as a magnified image of squared single-crystal nanoparticle of panel c) in FIG. 4.
  • FFT Fast Fourier Transformation
  • FIG. 5, related with Example 1 is an X-ray diffraction (XRD) pattern of a single-crystal CeO2 nanoparticle of formula (I) with 5 nm of crystal size diameter.
  • XRD X-ray diffraction
  • FIG. 6 depicts the Dynamic Light Scattering (DLS) of BSA-coated CeO2NPs of the invention (single-crystal cerium oxide nanoparticles of formula (I) in which A is albumin).
  • DLS Dynamic Light Scattering
  • FIG. 6 a DLS of the as- synthesized BSA-coated (1 mM) CeO 2 NPs, by Intensity.
  • FIG. 6 b DLS of the as-synthesized BSA-coated (1 mM) CeO 2 NPs, by Number.
  • FIG. 6 c DLS of the supernatant only, containing free BSA, by Intensity.
  • FIG. 6 is an image of X ray contrast imaging of samples at different CeO2NPs concentrations ranging from 0 to 100 mg/ml .
  • FIG. 8 is a graphic showing the CeO2NPs antioxidant effect on fluorescently- labeled hydrogen peroxidase (EuTc-H2O2 complex),
  • (F) is fluorescence and (t) time in minutes(min).
  • nanoconjugate refers to a single-crystal cerium oxide nanoparticle which is attached to another compound selected from polyvinylpyrrolidone and proteins, in particular globular proteins, such as albumin.
  • conjugate also referred to as NP-A, refers to a single-crystal cerium oxide nanoparticle (NP) which is adsorbed by coordinate bonding to a molecule (A), that can be PVP and/or albumin.
  • single-crystal cerium oxide nanoparticle it is to be understood that said nanoparticle is not aggregated (by weak physical interaction) with other nanoparticles, in such a way that the nanoconjugate comprises only one nanoparticle as a core of the conjugate and of a particular crystal size diameter (or simply crystal diameter). All these structures can be seen by X-Ray diffraction and TEM. Thus, single-crystal or monocrystal means that there is only one crystal of cerium oxide configuring the nanopartide, with a particular crystal diameter.
  • nanopartide refers to a particle with at least two dimensions at the nanoscale, particularly with all three dimensions at the nanoscale, where the nanoscale is the range about 1 nm to about 100 nm, more particularly from 1 to 50 nm, and even more particularly from 5 to 20 nm.
  • Preferred crystal diameters of the nanopartides of the invention are from 5 to 10 nm (including, 5, 6, 7, 8, 9, and 10 nm), more preferably 5 nm.
  • shape of the nanopartides described herein there are included spheres and polyhedral.
  • the nanopartide is spherical.
  • the “nanopartide” refers to a particle with at least two dimensions at the
  • nanoscale this two dimensions being the cross-section of the nanopartide.
  • the term "size" refers to a characteristic physical dimension.
  • the size of the nanopartide corresponds to the diameter of the nanopartide.
  • the set of nanopartides can have a distribution of sizes around the specified size.
  • nanopartides can refer to a mode of a distribution of sizes, such as a peak size of the distribution of sizes.
  • the diameter is the equivalent diameter of the spherical body including the object.
  • cerium oxide refers to cerium (III) oxide (Ce 3+ ) and cerium (IV) oxide (Ce 4+ ) species that are both present when constituting the nanopartides. Although many of the cerium oxide nanopartides are usually in the (Ce 4+ ) oxidation state, small cerium oxide nanopartides are also in the (Ce 3+ ) oxidation state. Cerium oxide nanopartides (abbreviated also as Ceria- NP, CeO2-NP or simply CNP) are used in a variety of applications mainly due to its high surface area and the ability of cerium oxide to cycle between (III and IV) oxidation states. In a particular embodiment, cerium oxide
  • nanopartides are in the (Ce 4+ ) oxidation state
  • the diameter of the nanoparticle relates to the crystal size diameter (single-crystal).
  • Crystal size is usually measured from X-ray diffraction patterns while particle size is measured by TEM. In the case of single-crystal nanoparticles, XRD and TEM sizes coincide.
  • Typical crystal size diameters of the nanoparticles used in the present invention range from 3 to 24 nm (including 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23 and 24 nm), when measured by TEM, more particularly the crystal size diameter of the nanoparticles is about 5 nm.
  • hydrodynamic diameter determined by dynamic light scattering (DLS) techniques based on the Stoke-Einstein equation is used herewith to refer to the single-crystal nanoparticle conjugated (also termed herein
  • the coated/encapsulated with the compound defined by A. It can be measured by illuminating the particles with a laser and analysing the intensity fluctuations in the scattered light. Dynamic light scattering measures Brownian motion and relates it to the size of the particles for which light intensity is proportional to the square of the volume of the particle. The resulting diameter corresponds not only to the single-crystal particle diameter, but also to the molecules strongly adsorbed onto its surface. Therefore, the hydrodynamic size is always larger than the size observed by transmission electron microscopy, this later the one of the single-crystal nanoparticles.
  • Typical hydrodynamic diameters of the single-crystal cerium oxide nanoparticles of formula (I) with n higher than 0 and used in the present invention range from 5 to 60 nm, more particularly from 5 to 30 nm. In this particular case, the hydrodynamic diameter is a function of n in formula (I).
  • the combinations encompass one molecule of each type, or several molecules of each type depending of the surface of the nanoparticle directly correlated with its hydrodynamic diameter.
  • the conjugates in particularly those comprising albumin or other proteins adsorbed on the nanoparticle surface, have the property of being captured on the cell surface, mainly due to this so-called "protein corona”. They can so penetrate into the cells, in this case into hepatocytes, and the release of the metal ions performs therein its effects, mainly by scavenging reactive oxygen species (ROS).
  • ROS reactive oxygen species
  • single-crystal cerium oxide nanoparticles of formula (I) for use in the treatment of HCC have a NP with a crystal diameter from 3 to 15 nm.
  • the crystal size diameter of the NP are from 3 to 12 nm, more particularly from 3 to 7 nm, and even more particularly from 4 to 7 nm, more in particular 5 nm. As above indicated when the crystal size diameter of NP is from 3 to 7 nm, then n is from 1 to 12.
  • the single-crystal cerium oxide nanoparticles of formula (I) are in form of a conjugate of formula (I) for being used in the treatment of HCC:
  • NP is a cerium oxide nanoparticle with a crystal diameter from 3 to 7 nm;
  • A is a molecule selected from the group consisting of albumin, polyvinylpyrrolidone, and combinations thereof;
  • n is an integer from 1 to 12.
  • NP is a cerium oxide nanoparticle with a crystal diameter from 3 to 24 nm
  • A is a molecule selected from the group consisting of albumin, polyvinylpyrrolidone, and combinations thereof; and n is an integer from 1 to 40.
  • the single-crystal cerium oxide nanoparticles for use in the treatment of HCC are conjugates.
  • the single-crystal cerium oxide nanoparticle is one in which NP is a cerium oxide nanoparticle with a crystal diameter from 3 to 12 nm.
  • the single-crystal cerium oxide nanoparticle for use in HCC is one in which NP is a cerium oxide nanoparticle with a crystal diameter from 3 to 7 nm, more particularly from 4 to 5 nm, A is a molecule selected from the group consisting of albumin, polyvinylpyrrolidone, and combinations thereof; and n is an integer from 1 to 12.
  • the single-crystal cerium oxide nanoparticles are those of formula (I) in the form of conjugates, wherein A is a molecule of albumin, n is and integer from 1 to 40, and NP is a cerium oxide nanoparticle with a crystal size diameter from 3 to 24 nm.
  • NP is a cerium oxide nanoparticle with a crystal size diameter from 3 to 7 nm
  • A is a molecule of albumin
  • n is an integer from 1 to 12.
  • NP is a single-crystal cerium oxide nanoparticle with a crystal size diameter from 4 to 5 nm, an n is from 1 to 4, more particularly, n is 1 .
  • Another particular embodiment of the first aspect of the invention relates to a single-crystal cerium oxide nanoparticle for use in the treatment of HCC, in which NP is a cerium oxide nanoparticle with a crystal diameter from 3 to 24 nm, A is a molecule of polyvinylpyrrolidone, and n is and integer from 1 to 40.
  • NP in the single-crystal cerium oxide nanoparticle, is a cerium oxide nanoparticle with a crystal diameter from 3 to 7 nm, and n is an integer from 1 to 12.
  • A is a molecule of polyvinylpyrrolidone; NP is a single-crystal cerium oxide nanoparticle with a crystal size diameter from 4 to 5 nm, and n is from 1 to 4, more particularly, n is 1 .
  • Another particular embodiment of the first aspect of the invention relates to single-crystal cerium oxide nanoparticles of formula (I) for use in the treatment of HCC, in which NP is a cerium oxide nanoparticle with a crystal size diameter from 3 to 7 nm, A is a combination of molecules of albumin and polyvinylpyrrolidone; and n is an integer from 2 to 12, most particularly 2 to 4.
  • the particular conjugates, in which a combination of molecules of albumin and polyvinylpyrrolidone are adsorbed to the NP can be represented as a subgroup of conjugates of formula (I) as follows:
  • A' is polyvinylpyrrolidone;
  • A is albumin; and
  • n and n' are integers from 1 to 2, and particularly n and n' are both 1 .
  • cerium oxide nanoparticles of formula (I) are in particular for use as inhibitors of cell proliferation in hepatocellular carcinoma.
  • the single-crystal cerium oxide nanoparticles of formula (I) are adapted for use as a co-treatment of an hepatocellular carcinoma therapy selected from the group consisting of radiotherapy, microwave ablation (MWA), radiofrequency ablation (RFA), transarterial radioembolization (TARE), chemotherapy, surgical resection, liver transplantation, targeted therapy, hyperthermia and combinations thereof.
  • an hepatocellular carcinoma therapy selected from the group consisting of radiotherapy, microwave ablation (MWA), radiofrequency ablation (RFA), transarterial radioembolization (TARE), chemotherapy, surgical resection, liver transplantation, targeted therapy, hyperthermia and combinations thereof.
  • the single-crystal cerium oxide nanoparticles of formula (I) are adapted for use as a co-treatment of an hepatocellular carcinoma therapy selected from the group consisting of radiotherapy, transarterial
  • TARE radioembolization
  • the single-crystal cerium oxide nanoparticles of formula (I) are for use in the treatment of hepatocellular carcinoma in combination with an hepatocellular carcinoma therapy agent and/or drug, in particular, the agent and/or drug selected from the group consisting of a radiotherapy agent, a chemotherapeutic drug, a targeted therapy drug, and combinations thereof.
  • the single-crystal cerium oxide nanopartides of formula (I) for use in the treatment of HCC are for use in combination with an hepatocellular carcinoma therapy agent and/or drug selected from the group consisting of a radiotherapy agent, a chemotherapeutic drug, a targeted therapy drug, and combinations thereof.
  • an hepatocellular carcinoma therapy agent and/or drug is to be understood as any drug used in this kind of cancer, as well as any compound commonly used in hepatocellular carcinoma therapies, such as the
  • radioenhancement in combination with the radiation itself. It also
  • cerium oxide nanopartides of formula (I) absorb radiation, such as ionizing radiation (including X radiation, gamma rays and higher part of ultraviolet radiation) in a highly efficient manner. The efficiency of this process (for both energy transfer and
  • the single-crystal cerium oxide nanoparticle of formula (I) are for use in the treatment of hepatocellular carcinoma in combination with radiotherapy.
  • the single-crystal cerium oxide nanoparticle of formula (I) are for use in the treatment of hepatocellular carcinoma in combination with radiotherapy.
  • the single-crystal cerium oxide nanoparticle of formula (I) are for use in combination with a targeted therapy agent (also named targeted therapy compound), which can be formulated as that they are for use as co-treatment of a targeted therapy for HCC.
  • a targeted therapy agent also named targeted therapy compound
  • Targeted therapy is defined as the specially targeted delivery vehicles to increase effective levels of chemotherapy for tumor cells while reducing effective levels for other cells. This result in an increased tumor kill and/or reduced toxicity.
  • Particular targeted therapies of HCC include administration of sorafenib. Therefore, the nanoparticles for use according to the invention are, in a particular embodiment for use in
  • CeO2 NPs for use in the treatment of HCC can also be adapted to be used in combination (as co-treatment) with other chemotherapeutic approaches commonly used in this type of cancer and selected from the group consisting of transcatheter arterial chemoembolization (TACE), transcatheter arterial chemotherapy (TAC), intra-arterial infusion chemotherapy (HAC), systemic chemotherapy (SCT), portal vein chemotherapy (PVC), portal vein embolization (PVE), percutaneous acetic acid injection (PAI), percutaneous ethanol injection (PEI), and combinations thereof.
  • TACE transcatheter arterial chemoembolization
  • TAC transcatheter arterial chemotherapy
  • HAC intra-arterial infusion chemotherapy
  • SCT systemic chemotherapy
  • PVC portal vein chemotherapy
  • PVE portal vein embolization
  • PAI percutaneous acetic acid injection
  • PEI percutaneous ethanol injection
  • the single-crystal nanoparticles for use according to the invention are used in combination with one or more of the above therapies, and/or agents for use in these therapies, depending on the stage of the disease (i.e of the HCC).
  • TACE is used in initial stages of HCC and HAC in advanced stages, this later in combination with surgery resection of the tumour and/or liver transplantation.
  • Targeted therapies including the sorafenib are used also in advanced stages of HCC and in combination with surgery resection of the tumour and/or liver transplantation.
  • the invention relates as a second aspect to particular single-crystal cerium oxide nanoparticles of formula (I),
  • NP is a cerium oxide nanoparticle with a crystal diameter from 3 to 7 nm;
  • A is a molecule selected from the group consisting of albumin, polyvinylpyrrolidone, and combinations thereof;
  • n is an integer from 1 to 12.
  • Particular embodiments of the second aspect of the invention, thus of the conjugated single-crystal cerium oxide nanoparticles are those in which NP is a cerium oxide nanoparticle with a crystal diameter from 4 to 5 nm.
  • A is a molecule of albumin; and n is an integer from 1 to 4, more particularly n is 1 .
  • A is albumin; NP is a cerium oxide nanoparticle with a crystal diameter from 4 to 5 nm; and n is an integer from 1 to 4, more particularly n is 1 .
  • the single- crystal cerium oxide nanoparticle is the one of formula (I), wherein A is a molecule of polyvinylpyrrolidone; and n is an integer from 1 to 4, more particularly 1 .
  • A is polyvinylpyrrolidone; NP is a cerium oxide nanoparticle with a crystal diameter from 4 to 5 nm; and n is an integer from 1 to 4, more particularly n is 1 .
  • the invention relates also to single-crystal cerium oxide nanoparticles as conjugates of formula (I):
  • A' polyvinylpyrrolidone
  • A is albumin
  • n and n' are integers from 1 to 2, and particularly n and n' are both 1 .
  • PVP has a molecular weight from 10 kDa to 30 kDa, more in particular from 10 kDa to 20 kDa, being preferred PVP of 10 kDa.
  • albumin is mammal albumin, in particular selected from human serum albumin and bovine serum albumin.
  • Human serum albumin is the one defined in in UniProtKB database by accession number P02768, version 255 of the entry and version 2 of the sequence of January 20, 2016.
  • Bovine serum albumin is the one defined in in UniProtKB database by accession number P02769, version 150 of the entry and version 4 of the sequence of December 9, 2015.
  • Single-crystal cerium oxide nanoparticles of formula (I), in which n is zero and NP has a diameter higher than 7, particularly from 8 to 24 nm, are obtainable by a method comprising (a) dissolving a cerium (III) salt, particularly cerium (III) nitrate, in water or in an organic solvent, particularly ethanol; (b) adding an oxidizing and stabilizer compound, in particular selected from
  • TMAOH tetramethylammonium hydroxide and hexamethylenetetramine
  • HMT hexamethylenetetramine
  • the single-crystal cerium oxide nanoparticles of formula (I), in which n is higher than zero, thus the conjugated nanoparticles with n from 1 to 40, are obtainable by a method comprising the steps of:
  • A is albumin, and optionally PVP, then an oxidizing and stabilizer compound is added in this solution 2, in particularly selected from TMAOH and HTM, and preferably TMAOH, and
  • an oxidizing and stabilizer compound is added in this step (iii), in particularly selected from TMAOH and HTM, and preferably TMAOH;
  • CNPs single- crystal CeO2NPs
  • TEM single- crystal CeO2NPs
  • said CNPs being conjugated with albumin, PVP or mixtures thereof, thus being single-crystal cerium oxide nanopartides of formula (I) with n from 1 to 40, and having a hydrodynamic diameter from 10 to 32 nm, in particular from 1 1 to 23 nm, the hydrodynamic diameter measured by DLS.
  • TMAOH is preferred in any of the steps wherein it is used, since it is non-toxic to cells.
  • the cerium (III) salt is cerium (III) nitrate. TMAOH acts as oxidizing agent, as surfactant and also as stabilizer because it avoids nanoparticle aggregation.
  • the buffered solvent in (i) is phosphate- buffered saline (PBS) with a pH from 6.0 to 8.5 that comprises water and salts selected from sodium hydrogenphosphate, sodium chloride and mixtures thereof, and optionally potassium chloride and potassium
  • PBS phosphate- buffered saline
  • solution 2 has a pH below 9, preferably from 6.0 to 8.5, more preferably from 7.0 to 8.0.
  • the stabilizer for colloidal stability and to avoid CeO2NPs aggregation has to be administrated before aggregation takes place, which is immediately after nucleation, this is, at the beginning of the synthesis process.
  • other stabilizers like TMAOH can be added during synthesis.
  • the cerium (III) salt is particularly cerium (III) nitrate, and in yet another more particular embodiment it is in a concentration at solution 2 to give an initial cerium (III) concentration from 9.0 mM to 10.0 mM.
  • the final concentration of albumin in solution 1 is from 0.70 to 0.80 mM, more particularly 0.75 mM.
  • nanopartides of formula (I) of the invention wherein NP is a cerium oxide nanoparticle with a crystal diameter from 3 to 7 nm; A is a molecule selected from the group consisting of albumin, polyvinylpyrrolidone, and combinations thereof; and n is an integer from 1 to 12, are obtainable by a method comprising the steps of:
  • A is albumin, and optionally PVP, then an oxidizing and stabilizer compound is added in this solution 2, in particularly selected from TMAOH and HTM, and preferably TMAOH, and
  • an oxidizing and stabilizer compound is added in this step (iii), in particularly selected from TMAOH and HTM, and preferably TMAOH;
  • CNPs single- crystal CeO 2 NPs
  • TEM crystal size diameter measured by TEM from 3 to 7 nm
  • said CNPs being conjugated with albumin, PVP or mixtures thereof, thus being single-crystal cerium oxide nanopartides of formula (I) with n from 1 to 12, and having a hydrodynamic diameter from 1 1 to 23 nm, the hydrodynamic diameter measured by DLS.
  • the nanoconjugates are constituted by single-crystal nanopartides, duly conjugated with albumin, PVP or both.
  • these single-crystal cerium oxide nanopartides of formula (I), in which n is higher than zero, thus the conjugated nanopartides with n from 1 to 40, and obtainable as indicated in any of the above embodiments, are catalytically active single- crystal cerium oxide nanopartides.
  • the nanopartides being catalytically active means that they retain its superoxide dismutase (SOD) and catalase mimetic activity.
  • This catalytically active feature can be measured by many technologies, such as for example, by means of the CeO2NPs antioxidant effect on fluorescently-labeled hydrogen peroxidase (EuTc-H2O2 complex), Amplex Red or 2', 7' -dichlorofluorescin diacetate (DCFDA).
  • Particular pharmaceutical or veterinary compositions comprising the nanopartides as defined above, are those further comprising physiologic saline buffer, such as Phosphate-buffered saline (PBS).
  • PBS Phosphate-buffered saline
  • physiologic saline buffer is to be understood a water-based salt solution with osmolarity, pH (6- 7.5) and ion concentrations of mammal bodies, in particular of humans.
  • compositions comprise the serum of the individual mammal to which the composition is to be administered.
  • HR-TEM Transmission Electron Microscopy
  • FEI Tecnai G2 F20 200 kV The ultrafin 200-mesh copped TEM grids (Ted-Pella, Inc.) were placed on a filter paper. Afterwards, fifty microliters of the NPs colloidal suspension were deposited drop by drop over the grid and left to dry in air. The obtained HR- TEM images were analyzed by Image J program: for each sample, at least 150 NPs were measured and the average size and size-distribution were obtained.
  • UV-Vis Spectroscopy UV-visible spectra was acqired with Schimadzu UV-2400 spectrofotometer. Regarding the detection limits of the apparatus and a high concentration of the synthesis, an aliquot of the synthesis solution was diluted in water (1/15) and than measured in a wavelength range between 260 and 800 nm.
  • DLS A 1 ml aliquot of the synthesis solution was placed in a sizing couvette and analyzed by a Zetasizer Nano-ZS (Malvern Instruments). Thus, the surface charge (Zeta Potential, ZP), the Dynamic Light Scattering (DLS) and the Isoelectric Point (pi) of the nanoparticles were measured.
  • X-rav diffraction A 10 ml aliquot of the synthesis solution was centrifuged twice (45 min at 12.000g), in order to ensure a maximal precipitation of the nanoparticles. A supernatant was discarded and the precipitates were dried at room
  • Example 1 Synthesis of cerium oxide nanoparticles.
  • LPS lipopolysaccharide
  • FIG. 3 (A) shows pH evolution of the synthesis solution
  • Nanoceria characterization by Electron Microscopy To minutely examine the quality of produced CeO 2 NPs, in terms of
  • FIG. 4 shows as-synthesized PVP- coated samples
  • FIG. 4 (b) shows the dark-field STEM-HAADF image of the NPs
  • FIG. 4 (c) inspects the homogeneity
  • FIG. 4 (d) shows a typical single-crystalline CeO 2 NP and its correspondent Fourier Transformation, FFT (FIG. 4 (e)).
  • FFT Fourier Transformation
  • the structural and compositional characterization, phase identification and size of CeO 2 NPs were analyzed by X-ray Diffraction (XRD).
  • XRD X-ray Diffraction
  • the XRD pattern of as-synthesized CeO 2 NPs of 4 nm is displayed in FIG. 5.
  • the XRD pattern was scanned from 20 to 80 degrees and the XRD profile confirmed the monocrystalline nature of CeO 2 NPs (single-crystal cerium oxide
  • Crystal size diameter estimation Three techniques were used to estimate the average crystal size diameter of as-synthesized in 1 .1 or 1 .2 CeO 2 NPs: Image J analysis software for HR- TEM; size estimation using the Scherrer equation of XRD pattern and the Dynamic Light Scattering (DLS) of colloidal suspension of the NPs (measuring hydrodynamic diameter). Table 1 shows a comparison between three sizing techniques for as-synthesized CeO2NPs: (a) Dynamic Light Scattering (DLS) and the polydispersity index (PDI) of this DLS, (b) Image J analysis of HR- TEM images, and (c) Scherrer equation calculations from XRD profile.
  • DLS Dynamic Light Scattering
  • PDI polydispersity index
  • PDI is a parameter in DLS related with size distribution of molecules or particles in suspension. For a perfectly uniform sample, the PDI would be 0.0. PDI from 0.0 to 0.1 reflects a narrow non-uniform distribution type sample. From 0.1 to 0.4 the PDI indicates a moderate non-uniform distribution type sample. PDI higher than 0.4 is usually understood as a broad distribution type sample.
  • the size (diameter in nm) and aggregation state of the CeO 2 NPs conjugated with albumin disclosed in 1 .2 were again corroborated by DLS technique. In both measurements, by intensity and by number, it was observed one single peak at around 12 nm (hydrodynamic diameter). The absence of peaks at larger size axis corroborates the absence of aggregates in the designed synthesis method. Moreover, as an internal control, the BSA-coated NPs were purified by centrifugation and measured by DLS the supernatant only (FIG. 6 (c) and (d)), that contains free BSA in excess. The size distribution coincides with previously obtained data in FIG.
  • DEN diethylnitrosamine
  • liver sections of non-treated with CeO2 NPs rats had a more dysmorphic appearance also with more superficial deformities than liver of CeO2 NPs treated rats.
  • the liver weight percentage in relation to total body weight was slightly lower in animals receiving CeO2 NPs in comparison with non-treated animals. Non meaningful differences were observed in serologic standard hepatic functional parameters and in renal parameters between bot animal groups.
  • Data are depicted in FIG. 1 (A and B), wherein the microscope image (FIG. 1 (A)) of the liver of non- treated cells (VEHICLE) shows a higher percentage of Ki-67 stained
  • Example 3 CeO2 NPs for use in combination with radiotherapy.
  • FIG. 7 is an image of X ray contrast imaging of samples at different CeO2NPs concentrations ranging from 0 to 100 mg/ml .
  • the samples where imaged at 90 kV and 160 microA.
  • the bright white signal, indicative of X-ray absorption increases with CeO2 concentration as expected. This X-ray absorption is at the basis of X-ray imaging and X-ray therapy.
  • CeO2 NPs absorbed X radiation, in a highly efficient manner. Transfer of energy was also high with these nanoparticles. Therefore, they are good contrast agents (in particular as X-ray contrast agents), as well as good to be used in combination with radiotherapy, providing to the subject the intrinsically effect of the ceria nanoparticles (due to their superoxide dismutase (SOD) and catalase mimetic activity), and enhancing the effect of the administered radiotherapy.
  • SOD superoxide dismutase
  • catalase mimetic activity enhancing the effect of the administered radiotherapy.
  • Example 4 Catalytic activity of PVP-conjugated CeO 2 NPs (single-crystal cerium oxide nanoparticles of formula (I) in which A is PVP)
  • Results are depicted in FIG. 8, a graphic displaying for each assayed nanoparticle type the decay of fluorescence (F) versus time (t, in min).
  • PVP-coating slightly decreases CeO 2 NPs reactivity, but as deducible from FIG. 8, PVP-coated 5nm-sized CeO 2 NPs of the invention maintained the catalytic activity, and not so did commercial.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Nanotechnology (AREA)
  • Inorganic Chemistry (AREA)
  • Optics & Photonics (AREA)
  • Biomedical Technology (AREA)
  • Immunology (AREA)
  • Dermatology (AREA)
  • Physics & Mathematics (AREA)
  • Geology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des nanoparticules d'oxyde de cérium utiles dans le traitement du carcinome hépatocellulaire (HCC), lesdites nanoparticules étant des nanoparticules monocristallines d'oxyde de cérium de formule (I) NP-(A)n (I), NP étant une nanoparticule d'oxyde de cérium monocristalline présentant un diamètre de cristal de 3 à 24 nm ; A étant une molécule choisie parmi le groupe constitué de l'albumine, de la polyvinylpyrrolidone et de leurs combinaisons ; et n étant un entier de 0 à 40. Si le diamètre de cristal de la nanoparticule est de 3 à 7 nm, alors n est un entier de 1 à 12. L'invention concerne également des nanoparticules particulières de formule (I) en tant que conjugués, ainsi que des compositions pharmaceutiques les comprenant.
PCT/EP2017/057570 2016-04-05 2017-03-30 Nanoparticules d'oxyde de cérium destinées à être utilisées dans le traitement du carcinome hépatocellulaire Ceased WO2017174437A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP16163838 2016-04-05
EP16163838.2 2016-04-05

Publications (1)

Publication Number Publication Date
WO2017174437A1 true WO2017174437A1 (fr) 2017-10-12

Family

ID=55802181

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2017/057570 Ceased WO2017174437A1 (fr) 2016-04-05 2017-03-30 Nanoparticules d'oxyde de cérium destinées à être utilisées dans le traitement du carcinome hépatocellulaire

Country Status (1)

Country Link
WO (1) WO2017174437A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2021132659A1 (fr) * 2019-12-26 2021-07-01
CN113842469A (zh) * 2021-08-25 2021-12-28 中国科学院过程工程研究所 一种囊泡表面原位结晶高催化活性铈纳米晶的递药系统及其制备方法和应用
CN114105128A (zh) * 2020-08-28 2022-03-01 中国科学院上海硅酸盐研究所 具有多种生物酶模拟活性的氧化铈还原氧化石墨烯纳米复合材料及其制备方法与应用
EP3901096A4 (fr) * 2018-12-18 2022-08-31 Toray Industries, Inc. Nanoparticules d'oxyde de cérium, procédé d'analyse d'acide nucléique, procédé d'analyse de polypeptide, procédé de fabrication de nanoparticules d'oxyde de cérium, agent oxydant, antioxydant, agent antifongique et agent antiviral
EP4074319A1 (fr) * 2021-04-15 2022-10-19 Fundació Hospital Universitari Vall d'Hebron - Institut de Recerca Composition topique ophtalmique avec des nanoparticules à cérium pour le traitement des maladies du segment postérieur de l' il
CN116899551A (zh) * 2023-06-20 2023-10-20 齐鲁理工学院 一种铈基纳米酶、其制备方法及应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016011328A1 (fr) * 2014-07-17 2016-01-21 Baker Cheryl Traitement du cancer associant un rayonnement, des nanoparticules d'oxyde de cérium et un agent chimiothérapeutique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016011328A1 (fr) * 2014-07-17 2016-01-21 Baker Cheryl Traitement du cancer associant un rayonnement, des nanoparticules d'oxyde de cérium et un agent chimiothérapeutique

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
"Ultraviolet Spectrophotometric Determination of Cerium(III", ANAL CHEM, vol. 29, 1957, pages 1531
ALILI ET AL.: "Downregulation of Tumor Growth and Invasion by Redox-Active Nanoparticles", ANTIOXIDANT & REDOX SIGNALING (ORIGINAL RESEARCH COMMUNICATION, vol. 00, 2013, pages 1 - 14
BHARAT BHUSHAN ET AL: "Antioxidant nanozyme: a facile synthesis and evaluation of the reactive oxygen species scavenging potential of nanoceria encapsulated albumin nanoparticles", JOURNAL OF MATERIALS CHEMISTRY B, vol. 3, no. 24, 1 January 2015 (2015-01-01), GB, pages 4843 - 4852, XP055302510, ISSN: 2050-750X, DOI: 10.1039/C5TB00572H *
BUSHAN ET AL.: "Antioxidant nanozyme: a facile synthesis and evaluation of the reactive oxygen species scavenging potential of nanoceria encapsulated albumin nanoparticles", JOURNAL OF MATERIALS CHEMISTRY B, vol. 3, 2015, pages 4843 - 4852
CHEN ET AL.: "Cerium oxide nanoparticles induce cytotoxicity in human hepatoma SMMC-7721 cells via oxidative stress and the activation of MAPK signalling pathways", TOXICOLOGY IN VITRO, vol. 27, 2013, pages 1082 - 1088
CHENG ET AL.: "Cerium oxide nanoparticles induce cytotoxicity in human hepatoma SMMC-7721 cells via oxidative stress and the activation of MAPK signalling pathways", TOXICOLOGY IN VITRO, vol. 27, 2013, pages 1082 - 1088
H.L.GREENHAUS ET AL.: "Ultraviolet Spectrophotometric Determination of Cerium(III", ANAL CHEM, vol. 29, 1957, pages 1531
HAK SOO ET AL.: "Renal clearance of quantum dots", NATURE BIOTECHNOLOGY, vol. 25, no. 10, 2007, pages 1165 - 1170
LONG WANG ET AL: "Nano-cerium-element-doped titanium dioxide induces apoptosis of Bel 7402 human hepatoma cells in the presence of visible light", WORLD JOURNAL OF GASTROENTEROLOGY, vol. 13, no. 29, 1 January 2007 (2007-01-01), CN, pages 4011 - 4014, XP055302404, ISSN: 1007-9327 *
MARSALEK ET AL.: "Adsoprtion of Bovine Serum Albumin on Ce02", INTERNATIONAL JOURNAL OF CHEMICAL. NUCLEAR. MATERIALS AND METALLURGICAL ENGINEERING, vol. 8, no. 12, 2014, pages 1269 - 1272
PATIL ET AL: "Protein adsorption and cellular uptake of cerium oxide nanoparticles as a function of zeta potential", BIOMATERIALS, ELSEVIER SCIENCE PUBLISHERS BV., BARKING, GB, vol. 28, no. 31, 18 August 2007 (2007-08-18), pages 4600 - 4607, XP022207000, ISSN: 0142-9612, DOI: 10.1016/J.BIOMATERIALS.2007.07.029 *
RUTH C. MERRIFIELD ET AL: "Synthesis and Characterization of Polyvinylpyrrolidone Coated Cerium Oxide Nanoparticles", ENVIRONMENTAL SCIENCE & TECHNOLOGY, vol. 47, no. 21, 5 November 2013 (2013-11-05), US, pages 12426 - 12433, XP055302490, ISSN: 0013-936X, DOI: 10.1021/es402541z *
ZHANG LI ET AL: "Selective cytotoxicity effect of cerium oxide nanoparticles under UV irradiation.", JOURNAL OF BIOMEDICAL NANOTECHNOLOGY FEB 2014, vol. 10, no. 2, February 2014 (2014-02-01), pages 278 - 286, XP009191656, ISSN: 1550-7033 *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3901096A4 (fr) * 2018-12-18 2022-08-31 Toray Industries, Inc. Nanoparticules d'oxyde de cérium, procédé d'analyse d'acide nucléique, procédé d'analyse de polypeptide, procédé de fabrication de nanoparticules d'oxyde de cérium, agent oxydant, antioxydant, agent antifongique et agent antiviral
US11937598B2 (en) 2018-12-18 2024-03-26 Toray Industries, Inc. Cerium oxide nanoparticle, decomposition method of nucleic acid, decomposition method of polypeptide, method of producing cerium oxide nanoparticle, oxidizing agent, antioxidant, antifungal agent, and anti-virus agent
US20230000906A1 (en) * 2019-12-26 2023-01-05 Toray Industries, Inc. Dispersion solution of complex of cerium oxide nanoparticle with protein, method of scavenging reactive species, and method of producing dispersion solution of complex of cerium oxide nanoparticle with protein
WO2021132659A1 (fr) * 2019-12-26 2021-07-01 東レ株式会社 Dispersion liquide de complexe de nanoparticules d'oxyde de cérium et de protéine ainsi que procédé de fabrication de celle-ci, et procédé d'élimination de substance active
US12616719B2 (en) * 2019-12-26 2026-05-05 Toray Industries, Inc. Dispersion solution of complex of cerium oxide nanoparticle with protein, method of scavenging reactive species, and method of producing dispersion solution of complex of cerium oxide nanoparticle with protein
JP7803131B2 (ja) 2019-12-26 2026-01-21 東レ株式会社 酸化セリウムのナノ粒子とタンパク質との複合体の分散液、活性種の消去方法、および酸化セリウムのナノ粒子とタンパク質との複合体の分散液の製造方法
JPWO2021132659A1 (fr) * 2019-12-26 2021-07-01
CN114105128B (zh) * 2020-08-28 2023-05-09 中国科学院上海硅酸盐研究所 具有多种生物酶模拟活性的氧化铈还原氧化石墨烯纳米复合材料及其制备方法与应用
CN114105128A (zh) * 2020-08-28 2022-03-01 中国科学院上海硅酸盐研究所 具有多种生物酶模拟活性的氧化铈还原氧化石墨烯纳米复合材料及其制备方法与应用
WO2022219050A1 (fr) 2021-04-15 2022-10-20 Fundació Hospital Universitari Vall D'hebron - Institut De Recerca Composition ophtalmique topique avec des nanoparticules d'oxyde de cérium pour le traitement de maladies du segment postérieur de l'œil
EP4074319A1 (fr) * 2021-04-15 2022-10-19 Fundació Hospital Universitari Vall d'Hebron - Institut de Recerca Composition topique ophtalmique avec des nanoparticules à cérium pour le traitement des maladies du segment postérieur de l' il
IL307730B1 (en) * 2021-04-15 2025-04-01 Fundacio Hospital Univ Vall Dhebron Institut De Recerca Preparations containing cerium oxide nanoparticles for topical ophthalmic administration and their use for the treatment of diseases in the posterior segment of the eye
IL307730B2 (en) * 2021-04-15 2025-08-01 Fundacio Hospital Univ Vall Dhebron Institut De Recerca Ophthalmic topical composition with ceria nanoparticles for treating diseases of posterior segment of the eye
CN113842469B (zh) * 2021-08-25 2024-04-02 中国科学院过程工程研究所 一种囊泡表面原位结晶高催化活性铈纳米晶的递药系统及其制备方法和应用
CN113842469A (zh) * 2021-08-25 2021-12-28 中国科学院过程工程研究所 一种囊泡表面原位结晶高催化活性铈纳米晶的递药系统及其制备方法和应用
CN116899551A (zh) * 2023-06-20 2023-10-20 齐鲁理工学院 一种铈基纳米酶、其制备方法及应用

Similar Documents

Publication Publication Date Title
Liu et al. S-nitrosothiols loaded mini-sized Au@ silica nanorod elicits collagen depletion and mitochondrial damage in solid tumor treatment
Talelli et al. Superparamagnetic iron oxide nanoparticles encapsulated in biodegradable thermosensitive polymeric micelles: toward a targeted nanomedicine suitable for image-guided drug delivery
Huang et al. A NIR‐II Photoactivatable “ROS Bomb” with High‐Density Cu2O‐Supported MoS2 Nanoflowers for Anticancer Therapy
Salehizadeh et al. Synthesis and characterization of core-shell Fe3O4-gold-chitosan nanostructure
Fang et al. Dendrimer-stabilized bismuth sulfide nanoparticles: synthesis, characterization, and potential computed tomography imaging applications
Brown et al. pH-dependent synthesis and stability of aqueous, elemental bismuth glyconanoparticle colloids: potentially biocompatible X-ray contrast agents
Che et al. Paclitaxel/gelatin coated magnetic mesoporous silica nanoparticles: Preparation and antitumor efficacy in vivo
Wang et al. Albumin-mediated platinum nanocrystals for in vivo enhanced computed tomography imaging
US20110300222A1 (en) Luminescent porous silicon nanoparticles, methods of making and using same
Singh et al. Biosynthesis of folic acid appended PHBV modified copper oxide nanorods for pH sensitive drug release in targeted breast cancer therapy
Mahdavinia et al. (Magnetic laponite/κ-carrageenan)@ chitosan core–shell carrier for pH-sensitive release of doxorubicin
Barbosa-Barros et al. Formation and characterization of biobased magnetic nanoparticles double coated with dextran and chitosan by layer-by-layer deposition
Xiao et al. Facile synthesis of acetylated dendrimer-entrapped gold nanoparticles with enhanced gold loading for CT imaging applications
Zhang et al. Chitosan and dextran stabilized GO-iron oxide nanosheets with high dispersibility for chemotherapy and photothermal ablation
US11684572B2 (en) Methods for producing carboxylate ligand modified ferric iron hydroxide colloids and related compositions and uses
Gomez et al. Stability and biocompatibility of photothermal gold nanorods after lyophilization and sterilization
Du et al. Van-mediated self-aggregating photothermal agents combined with multifunctional magnetic nickel oxide nanoparticles for precise elimination of bacterial infections
ES2505890T3 (es) Conjugados que comprenden nanopartículas recubiertas con compuestos que contienen platino
Gervits et al. A facile method of preparation of polymer-stabilized perfluorocarbon nanoparticles with enhanced contrast for molecular magnetic resonance imaging
D'Onofrio et al. Inhalable drug-loaded silk fibroin carriers for pulmonary drug delivery
He et al. Chitosan/nanocellulose-coated MOF nanocarriers for camptothecin delivery
DE202012012795U1 (de) Agglomerierende Magnetische alkoxysilan-beschichtete Nanopartikel
Weitz et al. In vitro evaluation of copper release from MRI-visible, PLGA-based nanospheres
Lakshmi Narayanan et al. Preparation and characterization of gold nanoparticles in chitosan suspension by one-pot chemical reduction method
Wang et al. A novel high doxorubicin-loaded Fe3O4@ void@ ZnO nanocomposite: pH-controlled drug release and targeted antitumor activity

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17715099

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 17715099

Country of ref document: EP

Kind code of ref document: A1