EP4013511A1 - Nanoparticles for the treatment of cancer by radiofrequency radiation - Google Patents

Nanoparticles for the treatment of cancer by radiofrequency radiation

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Publication number
EP4013511A1
EP4013511A1 EP20772361.0A EP20772361A EP4013511A1 EP 4013511 A1 EP4013511 A1 EP 4013511A1 EP 20772361 A EP20772361 A EP 20772361A EP 4013511 A1 EP4013511 A1 EP 4013511A1
Authority
EP
European Patent Office
Prior art keywords
nanoparticle
tumor
nanoparticles
treatment
radiofrequency
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.)
Pending
Application number
EP20772361.0A
Other languages
German (de)
French (fr)
Inventor
Victor Timoshenko
Alexander KHARIN
Volodymyn LYSENKO
Simon Champagne
François LUX
Paul ROCCHI
Olivier Tillement
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.)
NH Theraguix SA
National Research Nuclear University Mephi Moscow Engineering Physics Institute
Original Assignee
NH Theraguix SA
National Research Nuclear University Mephi Moscow Engineering Physics Institute
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 NH Theraguix SA, National Research Nuclear University Mephi Moscow Engineering Physics Institute filed Critical NH Theraguix SA
Publication of EP4013511A1 publication Critical patent/EP4013511A1/en
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/547—Chelates, e.g. Gd-DOTA or Zinc-amino acid chelates; Chelate-forming compounds, e.g. DOTA or ethylenediamine being covalently linked or complexed to the pharmacologically- or therapeutically-active agent
    • 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
    • A61K47/6935—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 otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Nanoparticles for the treatment of cancer by radiofrequency radiation are nanoparticles for the treatment of cancer by radiofrequency radiation.
  • the present disclosure relates to a method for treating tumors.
  • the invention relates to a novel therapeutic use of nanoparticles as a sensitizing agent for radiofrequency radiation.
  • the invention relates more particularly to the use of nanoparticles in combination with radiofrequency radiation for the treatment of tumors, the radiofrequencies inducing hyperthermia of said tumor comprising the nanoparticles in the patient.
  • the radio waves easily penetrate the various tissues and deep areas can be reached.
  • the waves locally induce ionic agitation which triggers molecular frictional movements responsible for thermal elevation which is transmitted to adjacent tissues leading to an increase in the internal temperature of the tissues leading to cell damage or even death.
  • the radiofrequency can therefore be used either to induce localized hyperthermia in the tumor via a specific probe leading to the ablation of tumor cells, or to make the tumor more sensitive to certain treatments.
  • tumor cells are more sensitive to changes in temperature than healthy cells, treatment with radiofrequency radiation does not make it possible to target a very specific area.
  • agents making it possible to absorb the energy of the waves and to increase the local hyperthermia can be used.
  • These agents, called sensitizing agents are for example silicon or gold nanoparticles or carbon nanotubes (Tamarov KP et al. 2014, Scientific Reports, 4: 7034; Rejinov NJ et al. 2015, Journal of Controlled Release, 204: 84-97).
  • the agents are inserted into the tumors and thus allow, following treatment by radiofrequency radiation, a local increase in temperature specifically in the tumor cells.
  • these agents have many drawbacks. They are large in size and do not specifically target tumor cells. These agents must therefore be injected into the tumor. Moreover, these agents are not very biocompatible and difficult to eliminate. In addition, these agents are not suitable for intravenous administration.
  • nanoparticles comprising a non-conductive and non-magnetic matrix functionalized at the surface by metal cations such as gadolinium can interact favorably with radiofrequencies and cause a local increase in the temperature, in particular cancer cells comprising these nanoparticles and thus block tumor growth.
  • a nanoparticle for use in the treatment of a tumor by radiofrequency radiation in a patient inducing hyperthermia of said tumor characterized in that said nanoparticle comprises a non-conductive and non-matrix. magnetic and metal cations having an atomic number Z greater than 40, said nanoparticle being administered before said treatment with radiofrequency radiation.
  • said matrix is a polysiloxane matrix.
  • said nanoparticle for the use as described above comprises at least one chelating agent, preferably DOTA, DTPA, DOTAGA or one of its derivatives intended for complexing metal cations.
  • the metal cations of said nanoparticle represent more than 10% of the mass of said nanoparticle, preferably less than 50% of the mass of said nanoparticle, even more preferably, the metal cations are placed on the surface of said matrix.
  • Said metal cations are preferably gadolinium or bismuth.
  • the nanoparticle for the use as described above has a size of less than 10 nm, preferably less than 5 nm.
  • the nanoparticle is used for the treatment of a tumor, preferably solid, and advantageously selected from the group consisting of a renal tumor, a lung tumor, a hepatic tumor, a breast tumor, a tumor. bones, said nanoparticle preferably being in a form suitable for intravenous, intratumoral or inhalation administration.
  • the invention also relates to a radiofrequency hyperthermic sensitizing agent comprising said nanoparticle as described above.
  • FIG. 1 represents the transition temperature of deionized water (black square), of a saline medium (triangle), of a saline medium in the presence of albumin (inverted triangle) and of the AGulX solution (diamond) under treatment with radiofrequency radiation at 27 MHz.
  • FIG. 2 represents the transition temperature of deionized water, of a medium comprising yttrium, gadolinium, bismuth, terbium, AGulX under treatment with radio frequency radiation at 27 MHz.
  • FIG. 3 shows MRI images of mice before and after intratumoral injection of AGulX saline solution.
  • FIG. 4 shows thermal images of a mouse during treatment with radiofrequency radiation for 1, 5 and 10 min.
  • FIG. 5 is a graph (A) representing the size of the tumor at different times after the treatment with radiofrequency radiation of the different groups of control mice (black circle), injected intratumorally with a solution comprising AGulX (round ), injected intratumorally with a solution comprising AGulX followed by radiofrequency treatment (square), (B) representing the size of the tumor after radiofrequency treatment of mice injected intratumorally with saline solution followed by radiofrequency treatment (square), and of mice injected intratumorally with a solution comprising AGulX followed by treatment with radiofrequency radiation (round).
  • Fig. 6 is a graph (A) representing the size of the tumor at different times after the treatment with radiofrequency radiation of the different groups of control mice (black circle), injected intratumorally with a solution comprising AGulX (round ), injected intratumorally with a solution comprising AGulX followed by radiofrequency treatment (square), (B) representing the size of the tumor after radiofrequency treatment of mice injected intratumorally with saline solution followed by radio
  • FIG. 6 is a graph showing the survival at different times after the Lewis lung carcinoma transplant of the different groups of mice injected intratumorally with saline solution (black square), injected intratumorally with saline followed by radiofrequency treatment (inverted triangle), injected intratumorally with a solution comprising AGulX (round), injected intratumorally with a solution comprising AGulX followed by radiofrequency treatment (triangle).
  • nanoparticles comprising a matrix of non-magnetic and non-conductive polymer and metal cations having an atomic number greater than 40 leads to a decrease in tumor growth in vivo in mice.
  • the nanoparticles according to the invention are deposited in the tumor and will act as a sensitizing agent for radiofrequency treatment.
  • the nanoparticles present in the tumor will absorb a large amount of energy and cause greater energy dissipation leading to local hyperthermia in the tumor and elimination of tumor cells.
  • hyperthermia is meant temperatures above body temperature, in particular above 37 ° C in humans.
  • hyperthermia is meant a local body temperature of between 37.5 ° C and 45 ° C, preferably 39 and 45 ° C. Hyperthermia will make it possible to eliminate or damage the target cells or to sensitize them for other treatment, in particular radiotherapy or chemotherapy.
  • the present invention thus relates to nanoparticles comprising a non-magnetic and non-conductive matrix and metal cations having an atomic number Z greater than 40 for use in the treatment of a tumor by radiofrequency radiation in a patient , said nanoparticle being administered before said treatment with radiofrequency radiation.
  • Nanoparticles are particles on the order of one nanometer.
  • the nanoparticles are administered to the subject by the intravenous route.
  • the nanoparticles must be small enough to be able to target tumor cells via the vascular system and be eliminated quickly by the kidneys.
  • the nanoparticles have a diameter of less than 20 nm, preferably less than 10 nm.
  • the nanoparticles are particles whose average diameter is between 1 and 20 nm, preferably between 1 and 10 nm and even more preferably between 2 and 5 nm, or alternatively between 1 and 6 nm.
  • nanoparticles of very small diameter for example between 1 and 10 nm, preferably between 2 and 5 nm.
  • the size distribution of the nanoparticles is for example measured using a commercial particle size analyzer, such as a Malvern Zetasizer Nano-S particle size analyzer based on PCS (Photon Correlation spectroscopy). This distribution is characterized by an average hydrodynamic diameter.
  • a commercial particle size analyzer such as a Malvern Zetasizer Nano-S particle size analyzer based on PCS (Photon Correlation spectroscopy). This distribution is characterized by an average hydrodynamic diameter.
  • mean diameter is meant the harmonic mean of the diameters of the particles. A method for measuring this parameter is also described in ISO 13321: 1996.
  • the nanoparticles according to the invention are nanoparticles comprising a non-magnetic and non-conductive organic or hybrid matrix (organic-inorganic).
  • non-conductive matrix is meant an insulating matrix, that is to say a matrix which does not conduct electricity.
  • the matrix does not contain conductive materials such as metals in their metallic form (at zero oxidation).
  • non-magnetic matrix is meant a matrix that is not attracted to the magnetic field.
  • the nanoparticle according to the invention comprises a non-ferromagnetic and / or non-super-paramagnetic matrix, and preferably does not comprise or less than 5% of iron, cobalt or nickel of the mass of the matrix.
  • the nanoparticle comprises a non-magnetic and non-conductive matrix which is a biocompatible polymer such as polyethylene glycol, polyethylene oxide, polyacrylamide, biopolymers, polysaccharides or polysiloxane, preferably polysiloxane.
  • a biocompatible polymer such as polyethylene glycol, polyethylene oxide, polyacrylamide, biopolymers, polysaccharides or polysiloxane, preferably polysiloxane.
  • the nanoparticles as described above further comprise metal cations having an atomic number greater than 40 making it possible to act as sensitizing agents to radiofrequencies.
  • the metal cations are chosen from heavy metals, preferably from the group consisting of: Pt, Pd, Sn, Ta, Zr, Tb, Tm, Ce, Dy, Er, Eu, La, Nd, Pr, Lu , Yb, Bi, Hf, Ho, Sm, In and Gd, or a mixture of these.
  • the metal cations are Bi and / or Gd.
  • the nanoparticle for the use according to the invention has a mass ratio of metal cation, in particular of Bi and / or Gd, of more than 10%, preferably between 10 and 50%.
  • the metal cations can be coupled to the matrix by covalent couplings or trapped by non-covalent bond, for example by encapsulation or hydrophilic / hydrophobic interaction or using a chelating agent.
  • the metal cations are located at the surface of the matrix of the nanoparticle.
  • the nanoparticles which can be used according to the invention comprise chelating agents which are covalently linked to the matrix and make it possible to complex the metal cations.
  • the chelating agents are grafted to the surface of the matrix of the nanoparticle so as to complex the metal cations at the surface of the matrix.
  • the nanoparticle for use according to the invention comprises a polysiloxane matrix, a chelating agent covalently bonded to said matrix and a metal cation complemented by the chelating agent.
  • the chelating agent is chosen from the following products:
  • DOTA 1, 4,7,10-tetraazacyclododecane-N, N ', N ”, N'” - teracetic acid
  • DTPA diethylene triamine penta-acetic acid
  • EDTA 2,2 ', 2 ", 2"' - (ethane-1, 2-diyldinitrilo) tetraacetic acid
  • EGTA ethylene glycol-bis (2-aminoethyl ether) acid) - N, N, N ', N'-tetraacetic
  • BAPTA 1-, 2-bis (o-aminophenoxy) ethane-N, N, N', N'-tetraacetic acid
  • NOTE 1, 4,7- acid triazacyclononan-1, 4,7-triacetic)
  • DOTAGA 2,4,7,10- tris (carboxymethyl) -1
  • cyclam derivatives such as TETA (1, 4,8,11- tetraazacydotetradecane-N, N ', N'', N "' - tetraacetic acid), TETAM (1, 4,8,11- tetraazacyclotetradecane-N, N ', N'',N"' - tetrakis (carbamoylmethyl)), TETP (1, 4,8,11- tetraazacyclotetradecane-N, N ', N'', N "' - tetrakis (methylene phosphonate)), and mixtures thereof,
  • the chelating agent is chosen from DOTA, DTPA, EDTA, EGTA, BAPTA, NOTA, DOTAGA, DTPABA, DOTAM, DOTP, NOTP and their mixtures.
  • the chelating agent is DOTA, DTPA, DOTAGA or one of its derivatives, preferably DTPA, DOTAGA or one of its derivatives such as by example DOTAM or NOTAM.
  • the ratio of metal cations per nanoparticle for example the ratio of rare earth elements, for example gadolinium (optionally chelated with DOTAGA) per nanoparticle is between 3 and 100, preferably between 5 to 20, typically about 10.
  • the chelating agent is advantageously selected from those whose complexing constant log (KC1) is greater than 15, preferably 20.
  • complexing agents lanthanides which may be mentioned are those comprising a unit of diethylene triamine penta acetic acid (DTPA), of 1, 4,7,10-tetraazacyclododecane-1, 4,7,10-tetra acetic acid (DOTA) or of ′ 1,4,7,10-tetraazacyclododecance-1, glutaric anhydrous-4,7,10-triacetic acid (DOTAGA).
  • the nanoparticles which can be used according to the invention are obtained by the following method:
  • At least one coating layer (shell) comprising polysiloxanes for example by a sol gel method
  • the core-shell precursor nanoparticle into an aqueous solution in which the grafting agent is in sufficient quantity to dissolve the metal oxide core and to complex the metal cation so that the average diameter of the nanoparticle thus obtained is reduced to a value of less than 10 nm, preferably less than 5 nm, for example between 1 and 5 nm.
  • nanoparticles obtained according to the method described above do not include a core encapsulated by at least one coating. Further details on the synthesis of these nanoparticles are given in the following section.
  • the chelating agents can be grafted on the surface of the polysiloxane particles or directly inserted within the POS matrix. Some or all of these chelating agents are intended to complex metal cations (e.g. gadolinium, bismuth).
  • these nanoparticles can be modified (function) at the surface by hydrophilic compounds (PEG) and / or loaded differently to adapt their bio-distribution within the organism and / or allow a good cell labeling, in particular for monitoring cell therapy.
  • PEG hydrophilic compounds
  • They can for example be functionalized at the surface by grafting molecules targeting lung tissue, or, due to their passage through the blood, by grafting molecules targeting certain areas of interest of the body, in particular areas tumor.
  • the functionalization can also be carried out by compounds comprising another active principle and / or luminescent compounds (fluorescein).
  • fluorescein a radiosensitizing agent
  • neutron therapy as a radioactive agent for brachytherapy treatments
  • PDT photodynamic therapy
  • vectoring molecules with a therapeutic effect a radioactive agent for vectoring molecules with a therapeutic effect.
  • ultrafine nanoparticles Another characteristic of these ultrafine nanoparticles is the maintenance of the rigid character of the objects and of the overall geometry of the particles after injection.
  • This high three-dimensional rigidity can be ensured by a polysiloxane matrix, where the majority of silicones are linked to 3 or 4 other silicon atoms via an oxygen bridge.
  • the combination of this rigidity with their small size makes it possible to increase the relaxivity of these nanoparticles for intermediate frequencies (20 to 60 MHz) compared to commercial compounds (complexes based on Gd-DOTA for example), but also for frequencies greater than 100 MHz present in new generation high-field MRIs.
  • the nanoparticles according to the invention have a relaxivity n per metal cation M n + which is greater than 5 mM 1 .s 1 (of M n + ion). preferably 10 mM 1 .s 1 (of M n + ion). for a frequency of 20 MHz.
  • they have a relaxivity n per nanoparticle of between 50 and 5000 mM 1 .s 1 .
  • these nanoparticles have a relaxivity n per M n + ion at 60 MHz which is greater than or equal to the relaxivity n per M n + ion at 20 MHz.
  • the nanoparticles which can be used according to the invention are polysiloxane nanoparticles chelated with gadolinium.
  • they are polysiloxane nanoparticles chelated with gadolinium, which do not include a gadolinium oxide core and whose diameter is between 1 and 10 nm, preferably between 2 and 8 nm.
  • Such nanoparticles are in particular the nanoparticles known as AGulX of general formula I below: n in which PS is a polysiloxane matrix and n is between 5 and 50, preferably between 5 and 20, and in which the hydrodynamic diameter is between 1 and 10 nm, for example between 2 and 8 nm, in particular 5 nm .
  • the AGulX nanoparticles can have a mass of about 15 kDa ⁇ 10 kDa.
  • AGulX nanoparticles can also be described by formula II below: (GdSÎ3-8C24-34N5-80i5-3oH4o-6o, 1-10 hhOJn
  • a person skilled in the art can easily manufacture nanoparticles used according to the invention.
  • POS matrix several techniques can be used, derived from those initiated by Stoeber (Stoeber, W; J. Colloid Interf Sci 1968, 26, 62). It is also possible to use the method employed for the coating as described in Louis et al. (Louis et al., 2005, Chemistry of Materials, 17, 1673-1682) or international application WO 2005/088314. In practice, the synthesis of ultrafine nanoparticles is for example described in Mignot et al. Chem. Eur. J. 2013, 19: 6122-6136.
  • a core / shell type nanoparticle is formed with a lanthanide oxide core (by modified polyol route) and a polysiloxane shell (by sol / gel), this object for example has a size around 10 nm ( preferably 5 nanometers).
  • a lanthanide oxide core of very small size can thus be produced in an alcohol by one of the methods described in the following publications: P. Perriat et al., J. Coll. Int. S ci, 2004, 273, 191; O. Tillement et al., J. Am. Chem. Soc, 2007, 129, 5076 and P. Perriat et al., J. Phys. Chem.
  • Chelating agents specific for the targeted metal cations are grafted onto the surface of the polysiloxane; it is also possible to insert a part of it inside the layer but the control of the formation of the polysiloxane is complex and the simple external grafting gives, at these very small sizes, a sufficient grafting proportion.
  • the nanoparticles are separated from the synthesis residues by a dialysis or tangential filtration method, on a membrane comprising pores of suitable size.
  • the heart is destroyed by dissolution (for example by modifying the pH or by providing complexing molecules in the solution).
  • This destruction of the core then allows a scattering of the polysiloxane layer (according to a collapse or slow corrosion mechanism), which ultimately makes it possible to obtain a polysiloxane object of complex morphology, the characteristic dimensions of which are of the order of magnitude of the thickness of the polysiloxane layer, that is to say much smaller than the objects so far developed.
  • Removing the core thus makes it possible to go from a particle size of about 5 nanometers in diameter to a size of about 3 nanometers.
  • this operation makes it possible to increase the number of metal cations (e.g.
  • gadolinium per nm in comparison with a theoretical polysiloxane nanoparticle of the same size but comprising metal (e.g. gadolinium) only at the surface.
  • the number of metal cations for a nanoparticle size can be evaluated using the M / Si atomic ratio measured by EDX.
  • nanoparticles it is possible to graft targeting molecules, for example by means of coupling by peptide bond on an organic constituent of the nanoparticle, as described in Montalbetti, CAGN, F alga B. Tetrahedron 2005, 61, 10827-10852. It is also possible to use a coupling method using “click chemistry” Jewett, JC; Bertozzi, CR Chem. Soc. Rev. 2010, 39, 1272-1279, and involving groups of the type: -N3, -CN, -CoCH, or one of the following groups: ⁇ ; ⁇
  • the nanoparticle according to the invention comprises a chelating agent having an acid function, for example DOTA.
  • the acid function of the nanoparticle is activated, for example using EDC / NHS (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / N-hydrosuccinimide) in the presence of a quantity appropriate targeting molecules.
  • the nanoparticles thus grafted are then purified, for example by tangential filtration.
  • the nanoparticles according to the present invention are obtained by a synthesis method (“one-pot synthesis method") comprising the mixture of at least one hydroxysilane or alkoxysilane which is negatively charged at a pH physiological and at least one chelating agent chosen from polyaminopolycarboxylic acids with:
  • the molar ratio A of neutral silanes to negatively charged silanes is defined as follows: 0 ⁇ A ⁇ 6, preferably 0.5 ⁇ A ⁇ 2;
  • the molar ratio B of positively charged silanes to the charged silanes negatively is defined as follows: 0 ⁇ B ⁇ 5, preferably 0.25 ⁇ B ⁇ 3;
  • the molar ratio C of the positively charged and neutral silanes to the negatively charged silanes is defined as follows: 0 ⁇ C ⁇ 8, preferably 1 ⁇ C ⁇ 4.
  • the "one pot" synthesis method comprises the mixture of at least one alkoxysilane which is negatively charged at a physiological pH, said alkoxysilane being chosen from APTES-DOTAGA, TANED, CEST, and their mixtures with:
  • alkoxysilane which is neutral at physiological pH
  • said alkoxysilane being chosen from TMOS, TEOS and their mixtures, and / or
  • the molar ratio A of neutral silanes to negatively charged silanes is defined as follows: 0 ⁇ A ⁇ 6, preferably 0.5 ⁇ A ⁇ 2;
  • the molar ratio B of positively charged silanes to the negatively charged silanes is defined as follows: 0 ⁇ B ⁇ 5, preferably 0.25 ⁇ B ⁇ 3;
  • the molar ratio C of the positively charged and neutral silanes to the negatively charged silanes is defined as follows: 0 ⁇ C ⁇ 8, preferably 1 ⁇ C ⁇ 4.
  • the "one pot" synthesis method comprises the mixture of APTES-DOTAGA which is negatively charged at physiological pH with:
  • alkoxysilane which is neutral at physiological pH
  • said alkoxysilane being chosen from TMOS, TEOS and their mixtures, and / or
  • the molar ratio A of neutral silanes to negatively charged silanes is defined as follows: 0 ⁇ A ⁇ 6, preferably 0.5 ⁇ A ⁇ 2;
  • the molar ratio B of positively charged silanes to the negatively charged silanes is defined as follows: 0 ⁇ B ⁇ 5, preferably 0.25 ⁇ B ⁇ 3;
  • the molar ratio C of the positively charged and neutral silanes to the negatively charged silanes is defined as follows: 0 ⁇ C ⁇ 8, preferably 1 ⁇ C ⁇ 4.
  • the nanoparticles as described above are administered into the tumor or near the tumor region of a patient. They can also be administered by intravenous, intramuscular injection or by inhalation. The radiofrequency radiation treatment of the patient then induces hyperthermia of said tumor and reduces tumor growth.
  • Nanoparticles as defined above are used as a sensitizing agent to radiofrequency radiation to target tumor cells specifically.
  • the radiofrequency radiation sensitizing agents as used in the present application refer to a composition which makes it possible to induce a greater absorption of quantity of energy from a radiofrequency signal thus creating an increase in the higher temperature in the zone comprising this composition.
  • the sensitizing agents in the present application are characterized by their ability to target and bind to a target cell, here a tumor cell, and to make the target cell more sensitive to the increase in temperature induced by radiofrequency radiation.
  • the present invention thus relates to the nanoparticles as defined above for use in the treatment of a tumor in a patient undergoing treatment with radiofrequency radiation.
  • patient or “subject” is meant any member of the animal kingdom, preferably a mammal or a human including, for example, a subject having a tumor.
  • treatment refers to any act which aims to improve the state of health of a patient, such as therapy, prevention, prophylaxis, and the delay of a disease. In some cases, these terms refer to the amelioration or eradication of a disease or symptoms associated with the disease. In other embodiments, these terms refer to the reduction in the spread or aggravation of disease resulting from the administration of one or more therapeutic agents to a subject afflicted with such disease.
  • nanoparticles are used for the treatment of solid tumors, in particular brain cancer (primary and secondary, glioblastoma, etc.), hepatic cancers (primary and secondary), pelvic tumors (cancer of the cervix, prostate cancer, anorectal cancer, colorectal cancer), upper aerodigestive tract cancers, lung cancer, esophageal cancer, breast cancer, pancreatic cancer.
  • solid tumors in particular brain cancer (primary and secondary, glioblastoma, etc.), hepatic cancers (primary and secondary), pelvic tumors (cancer of the cervix, prostate cancer, anorectal cancer, colorectal cancer), upper aerodigestive tract cancers, lung cancer, esophageal cancer, breast cancer, pancreatic cancer.
  • the present invention relates to a method of treating tumors with radiofrequency radiation comprising the steps of administering an effective dose of nanoparticles as described above into the tumor of a patient and exposing the tumor to radiation. radio frequency.
  • an effective dose of nanoparticles reference is made to the amount of nanoparticles as described above which, administered to a patient, is sufficient to be localized in the tumor and to induce hyperthermia following treatment with radiofrequency radiation.
  • This dose is determined and adjusted according to factors such as the age, sex and weight of the subject.
  • the administration of the nanoparticles as described above can be carried out intratumoral, subcutaneous, intramuscular, intravenous, intradermal, intraperitoneal, oral, sublingual, rectal, vaginal, intranasal, by inhalation or by transdermal application.
  • composition is in a pharmaceutical form suitable for a chosen administration.
  • the nanoparticles are administered intravenously and the nanoparticles will specifically target tumors, by passive targeting, for example by increasing the effect of permeability and retention.
  • a single dose of between 20 mg / kg and 500 mg / kg of nanoparticles is administered intravenously into a subject.
  • the nanoparticles are administered into the patient's tumor such that the nanoparticles are present at a concentration between 0.1 mg / L and 50 mg / L, preferably 1 and 10 mg / L in the region of the tumor which will be treated by radiofrequency.
  • Nanoparticles act as sensitizers and are used to target tumor cells specifically. The emission of radio waves near tumor cells comprising the nanoparticles then leads to the elimination of the tumor cells.
  • Radiofrequency radiation induces oscillating movements of the charged species at frequencies in the range from 3 kHz to 300 GHz. Following these electromagnetic excitations, ionic agitation triggers molecular frictional movements responsible for thermal elevation in cells. The heat rise then leads to the elimination of cells.
  • Radiofrequency radiation is generated between a transmission head and a reception head different from the transmission head.
  • the transmitting and receiving head are arranged on either side of the tumor site or the patient's body and the radio frequency signal is emitted to induce hyperthermia in target cells, such as tumor cells.
  • target cells such as tumor cells.
  • Many devices are known to emit radio waves.
  • the treatment with radiofrequency radiation according to the invention is preferably a non-invasive treatment.
  • non-invasive as used in this application means that no needle, wire, electrodes or other objects are inserted into the patient or the tumor of the patient to be treated.
  • the radio frequency signal is emitted such that the target tumor reaches a temperature between 37.5 and 45 ° C, preferably between 42 and 44 ° C.
  • the radiofrequency treatment is carried out at a frequency less than 1 GHz between 1 and 1000 MHz, preferably between 1 and 100 MHz.
  • the radiofrequency signal must be high enough to make it possible to induce hyperthermia of the tumor cells and thus to induce their cell death or at least the damage of the target cells.
  • the radiofrequency treatment can be carried out by simple exposure or successive exposures to radiofrequency radiation.
  • the duration of each exposure to radiofrequency radiation is between 1 and 60 min, preferably between 10 and 60 min.
  • the frequency and the time of the radiofrequency treatment can be optimized, for example according to the patient, the type of cancer, the gender, the size of the individual.
  • the temperature of the target area can be measured using a device well known to those skilled in the art.
  • the temperature can be measured using an infrared camera, a non-contact thermometer, a thermal probe or by thermal magnetic resonance imaging. These probes are thermally and electrically inert to radiofrequency treatment.
  • the treatment with radiofrequency radiation can comprise one exposure to radiofrequency radiation per week, or several exposures per week.
  • the hyperthermia induced by radiofrequency radiation will also make cancer cells more sensitive to radiotherapy or anti-cancer drugs.
  • the nanoparticles as described above for use in the treatment of a tumor with radiofrequency radiation can thus be used in combination with one or more anti-cancer agents or with radiotherapy.
  • Chemotherapy agents can be DNA replication inhibitors such as DNA binding agents, in particular alkylating or intercalating drugs, anti-metabolite agents such as polymerase or topoisomerase I inhibitors or II, or anti-mitotic agents such as alkaloids.
  • Non-limiting examples of chemotherapy agents are: 5-FU, oxaliplatin, cisplatin, carboplatin, irinotecan, cetuximab, erlotinib, docetaxel, doxorubicin and paclitaxel.
  • Immunotherapy agents are compounds which indirectly or directly enhance or stimulate the immune response against tumor cells.
  • the nanoparticles can also be used in addition as a radio-sensitizing agent for radiotherapy, as a photosensitizing agent for phototherapy or as an agent for beam therapy.
  • the nanoparticles used for the treatment of tumors by radiofrequency are also used as a contrast agent or an imaging agent for visualizing the tumor in vivo, by medical imaging allowing for example monitoring of the therapy.
  • the term “contrast agent” is understood to mean any product or composition used in medical imaging with the aim of artificially increasing the contrast allowing a particular anatomical structure to be visualized (for example certain tissues or organs) or a pathological anatomical structure (eg tumors) relative to neighboring or non-pathological structures.
  • imaging agent means any product or composition used in medical imaging with the aim of creating a signal making it possible to visualize a particular anatomical structure (for example certain tissues or organs) or a pathological anatomical structure (for example tumors). compared to neighboring or non-pathological structures. How the contrast or imaging agents work depends on the imaging techniques used.
  • Medical imaging is preferably chosen from the following techniques: nuclear magnetic resonance, X-ray scanners, fluorescence imaging, by SPECT scintigraphy, by PET scintigraphy, more preferably the tumor is visualized in vivo by resonance nuclear magnetic, in particular in dynamic magnetic resonance imaging (MRI) (ie DCE for Dynamic Contrast Enhanced sequence).
  • MRI dynamic magnetic resonance imaging
  • a subject of the present invention is also a pharmaceutical composition
  • a pharmaceutical composition comprising a nanoparticle as defined above and a pharmaceutically acceptable vehicle, a carrier substance and / or a adjuvant for use in the treatment of a tumor with radiofrequency radiation in a patient as previously described.
  • Pharmaceutically acceptable vehicles, a carrier substance and / or an adjuvant are those conventionally used.
  • the AGulX nanoparticles (50 mM per bottle) are obtained by Dr. O. Tillement via Dr. V. Lysenko.
  • the nanoparticles are dissolved in a physiological solution at a concentration of 20 mM (per Gd).
  • Radio-frequency electromagnetic radiation is generated by a UVCH-60 medical device (MedTeeko Ltd., Russia) operating at 27 MHz with a power of up to 60 W.
  • Lewis lung carcinoma transplant is performed by homogenizing Lewis lung carcinoma tumor tissue in a sterile solution of Medium 199 (Merck).
  • the donor animals are sacrificed, and pieces of tumor are excised without a necrotic site and then homogenized in medium 199.
  • the tumor mass is diluted in medium 199 and administered intramuscularly into the right hip of C57BI / 6 mice at a volume of 0.3 mL.
  • mice are divided into four groups, a group of control mice injected with saline solution (A), a group of mice injected with saline solution and treated with radiofrequency radiation for 10 min (B), a group of mice injected with AGulX and not treated with radiofrequency radiation (C), and a group of mice injected with AGulX and treated with radiofrequency radiation (D) (Table 1).
  • the saline solutions and AGulX (0.2 ml) are injected intramuscularly six days after inoculation of the tumor, when the tumor reaches a size of 70 ⁇ 15 mm 3 .
  • Table 1 description of the different groups of mice 4.
  • MRI monitoring of the biodistribution of AGulX is carried out using a Bruker BioSpec 7 T MRI scanner (Briker BioSpin GmbH, Germany) with a gradient system of 105 mT / m using ParaVision 5.0 software.
  • Figure 3 shows the MRI images of a mouse before and after the intratumoral injection of the AGulX solution. AGulX nanoparticles are seen in the tumor region at least one hour after injection.
  • Group B and D mice are treated with radiofrequency radiation with a power of about 10 W for 10 min.
  • Thermal monitoring of mice during treatment with radiofrequency radiation is performed with a Seek Thermal thermal imager.
  • a maximum temperature of around 43-45 ° C in the tumor is measured 5 to 10 minutes after the start of the radiofrequency treatment ( Figure 4).
  • the survival of the injected mice is then monitored 65 days after the Lewis lung carcinoma transplant. Mouse survival is improved in mice injected with AGulX and treated with radiofrequency radiation ( Figure 6).
  • the AGulX nanoparticles act as hyperthermia sensitizers following treatment with radiofrequency radiation.
  • the AGulX nanoparticles injected intratumorally are located in the region of the tumor for at least 1 hour after the injection.

Abstract

The present disclosure relates to a method for treating tumours. In particular, the invention relates to a new therapeutic use of nanoparticles as a radiofrequency-radiation-sensitizing agent. More particularly, the invention relates to the use of the nanoparticles in combination with radiofrequencies for the treatment of tumours, the radiofrequencies inducing hyperthermia of said tumour comprising the nanoparticles in the patient.

Description

Nanoparticules pour le traitement du cancer par rayonnement de radiofréquence Nanoparticles for the treatment of cancer by radiofrequency radiation
Domaine technique Technical area
[0001] La présente divulgation concerne une méthode pour traiter les tumeurs. En particulier, l’invention concerne une nouvelle utilisation thérapeutique des nanoparticules en tant qu’agent sensibilisant au rayonnement de radiofréquence. L’invention concerne plus particulièrement l’utilisation des nanoparticules en combinaison avec des rayonnements de radiofréquence pour le traitement de tumeurs, les radiofréquences induisant une hyperthermie de ladite tumeur comprenant les nanoparticules chez le patient. [0001] The present disclosure relates to a method for treating tumors. In particular, the invention relates to a novel therapeutic use of nanoparticles as a sensitizing agent for radiofrequency radiation. The invention relates more particularly to the use of nanoparticles in combination with radiofrequency radiation for the treatment of tumors, the radiofrequencies inducing hyperthermia of said tumor comprising the nanoparticles in the patient.
Technique antérieure Prior art
[0002] En dépit de grandes avancées dans le traitement des cancers, les traitements utilisés en particulier dans les tumeurs solides présentent de nombreux effets secondaires considérables voire délétères. [0002] Despite great advances in the treatment of cancers, the treatments used in particular in solid tumors exhibit numerous considerable or even deleterious side effects.
[0003] L’utilisation de la radiofréquence est de plus en plus proposée comme traitement alternatif. [0003] The use of radiofrequency is increasingly proposed as an alternative treatment.
[0004] Les ondes radio pénètrent facilement les différents tissus et des zones profondes peuvent être atteintes. Les ondes induisent localement une agitation ionique qui déclenche des mouvements de friction moléculaire responsables d’une élévation thermique qui est transmise dans les tissus adjacents conduisant à une augmentation de la température interne des tissus entraînant l’endommagement voire la mort des cellules. La radiofréquence peut donc être utilisée soit pour induire une hyperthermie localisée dans la tumeur via une sonde spécifique conduisant à l’ablation des cellules tumorales, soit pour permettre de rendre la tumeur plus sensible à certains traitements. [0004] The radio waves easily penetrate the various tissues and deep areas can be reached. The waves locally induce ionic agitation which triggers molecular frictional movements responsible for thermal elevation which is transmitted to adjacent tissues leading to an increase in the internal temperature of the tissues leading to cell damage or even death. The radiofrequency can therefore be used either to induce localized hyperthermia in the tumor via a specific probe leading to the ablation of tumor cells, or to make the tumor more sensitive to certain treatments.
[0005] Bien que les cellules tumorales soient plus sensibles aux changements de température que les cellules saines, le traitement par rayonnement de radiofréquence ne permet pas de cibler une zone très spécifique. [0005] Although tumor cells are more sensitive to changes in temperature than healthy cells, treatment with radiofrequency radiation does not make it possible to target a very specific area.
[0006] Pour remédier à cet inconvénient, des agents permettant d’absorber l’énergie des ondes et augmenter l’hyperthermie locale peuvent être utilisés. Ces agents, appelés agents sensibilisants sont par exemple les nanoparticules de silicium ou d’or ou des nanotubes de carbones (Tamarov K. P. et al. 2014, Scientific Reports, 4 :7034 ; Rejinov N. J. et al. 2015, Journal of Controlled Release, 204 :84- 97). Les agents sont insérés dans les tumeurs et permettent ainsi suite au traitement par rayonnement de radiofréquence, une augmentation locale de la température spécifiquement au niveau des cellules tumorales. To remedy this drawback, agents making it possible to absorb the energy of the waves and to increase the local hyperthermia can be used. These agents, called sensitizing agents are for example silicon or gold nanoparticles or carbon nanotubes (Tamarov KP et al. 2014, Scientific Reports, 4: 7034; Rejinov NJ et al. 2015, Journal of Controlled Release, 204: 84-97). The agents are inserted into the tumors and thus allow, following treatment by radiofrequency radiation, a local increase in temperature specifically in the tumor cells.
[0007] Cependant, ces agents présentent de nombreux inconvénients. Ils sont de taille élevée et ne ciblent pas spécifiquement les cellules tumorales. Ces agents doivent donc être injectés dans la tumeur. Par ailleurs, ces agents sont peu biocompatibles et difficiles à éliminer. De plus, ces agents ne sont pas adaptés pour une administration intraveineuse. [0007] However, these agents have many drawbacks. They are large in size and do not specifically target tumor cells. These agents must therefore be injected into the tumor. Moreover, these agents are not very biocompatible and difficult to eliminate. In addition, these agents are not suitable for intravenous administration.
[0008] Il reste donc un besoin de développer des agents sensibilisants ne présentant pas tous ces inconvénients. [0008] There therefore remains a need to develop sensitizing agents which do not have all of these drawbacks.
Résumé de l’invention Summary of the invention
[0009] De façon surprenante, les inventeurs ont montré que des nanoparticules comprenant une matrice non-conductrice et non-magnétique fonctionnalisée en surface par des cations métalliques tels que le gadolinium peuvent interagir de façon favorable avec des radiofréquences et provoquer une augmentation locale de la température, en particulier des cellules cancéreuses comprenant ces nanoparticules et bloquer ainsi la croissance tumorale. Surprisingly, the inventors have shown that nanoparticles comprising a non-conductive and non-magnetic matrix functionalized at the surface by metal cations such as gadolinium can interact favorably with radiofrequencies and cause a local increase in the temperature, in particular cancer cells comprising these nanoparticles and thus block tumor growth.
[00010] Ainsi, il est proposé une nanoparticule pour une utilisation dans le traitement d’une tumeur par un rayonnement de radiofréquence chez un patient induisant une hyperthermie de ladite tumeur, caractérisée en ce que ladite nanoparticule comprend une matrice non-conductrice et non-magnétique et des cations métalliques ayant un numéro atomique Z supérieur à 40, ladite nanoparticule étant administrée avant le dit traitement par un rayonnement de radiofréquence. De préférence, ladite matrice est une matrice en polysiloxane. De manière avantageuse, ladite nanoparticule pour l’utilisation telle que décrite précédemment comprend au moins un agent chélatant, de préférence le DOTA, DTPA, DOTAGA ou un de ses dérivés destiné à complexer les cations métalliques. Dans un mode particulier, les cations métalliques de ladite nanoparticule représentent plus de 10% de la masse de ladite nanoparticule, de préférence moins de 50 % de la masse de ladite nanoparticule, de manière encore plus préférée, les cations métalliques sont disposés à la surface de ladite matrice. Lesdits cations métalliques sont de préférence le gadolinium ou le bismuth. De manière avantageuse, la nanoparticule pour l'utilisation telle que décrite précédemment a une taille inférieure à 10 nm, de préférence inférieure à 5 nm. [00010] Thus, there is proposed a nanoparticle for use in the treatment of a tumor by radiofrequency radiation in a patient inducing hyperthermia of said tumor, characterized in that said nanoparticle comprises a non-conductive and non-matrix. magnetic and metal cations having an atomic number Z greater than 40, said nanoparticle being administered before said treatment with radiofrequency radiation. Preferably, said matrix is a polysiloxane matrix. Advantageously, said nanoparticle for the use as described above comprises at least one chelating agent, preferably DOTA, DTPA, DOTAGA or one of its derivatives intended for complexing metal cations. In a particular embodiment, the metal cations of said nanoparticle represent more than 10% of the mass of said nanoparticle, preferably less than 50% of the mass of said nanoparticle, even more preferably, the metal cations are placed on the surface of said matrix. Said metal cations are preferably gadolinium or bismuth. Advantageously, the nanoparticle for the use as described above has a size of less than 10 nm, preferably less than 5 nm.
[00011] En particulier, la nanoparticule est utilisée pour le traitement d’une tumeur, de préférence solide, et avantageusement sélectionnée parmi le groupe consistant en une tumeur rénale, une tumeur des poumons, une tumeur hépatique, une tumeur du sein, une tumeur des os, ladite nanoparticule étant de préférence sous une forme adaptée pour une administration par voie intraveineuse, intratumorale ou par inhalation. In particular, the nanoparticle is used for the treatment of a tumor, preferably solid, and advantageously selected from the group consisting of a renal tumor, a lung tumor, a hepatic tumor, a breast tumor, a tumor. bones, said nanoparticle preferably being in a form suitable for intravenous, intratumoral or inhalation administration.
[00012] L’invention concerne également un agent sensibilisant hyperthermique par radiofréquence comprenant ladite nanoparticule telle que décrite précédemment. [00012] The invention also relates to a radiofrequency hyperthermic sensitizing agent comprising said nanoparticle as described above.
Brève description des dessins Brief description of the drawings
[00013] D’autres caractéristiques, détails et avantages apparaîtront à la lecture de la description détaillée ci-après, et à l’analyse des figures annexées, sur lesquelles : [00013] Other characteristics, details and advantages will become apparent on reading the detailed description below, and on analyzing the appended figures, in which:
Fig. 1 Fig. 1
[00014] [Fig. 1] représente la température de transition de l’eau déionisée (carré noir), d’un milieu salin (triangle), d’un milieu salin en présence d’albumine (triangle renversé) et de la solution d’AGulX (losange) sous un traitement par un rayonnement de radiofréquence à 27MHz. [00014] [Fig. 1] represents the transition temperature of deionized water (black square), of a saline medium (triangle), of a saline medium in the presence of albumin (inverted triangle) and of the AGulX solution (diamond) under treatment with radiofrequency radiation at 27 MHz.
Fig. 2 Fig. 2
[00015] [Fig. 2] représente la température de transition de l’eau déionisée, d’un milieu comprenant de l’yttrium, du gadolinium, du bismuth, du terbium, de l’AGulX sous un traitement par un rayonnement de radiofréquence à 27 MHz. [00015] [Fig. 2] represents the transition temperature of deionized water, of a medium comprising yttrium, gadolinium, bismuth, terbium, AGulX under treatment with radio frequency radiation at 27 MHz.
Fig. 3 Fig. 3
[00016] [Fig. 3] représente des images en IRM de souris avant et après une injection intratumorale d’une solution saline d’AGulX. [00017] [Fig. 4] représente des images thermiques d’une souris pendant le traitement par un rayonnement en radiofréquence pendant 1, 5 et 10 min. [00016] [Fig. 3] shows MRI images of mice before and after intratumoral injection of AGulX saline solution. [00017] [Fig. 4] shows thermal images of a mouse during treatment with radiofrequency radiation for 1, 5 and 10 min.
Fig. 5 [00018] [Fig. 5] est un graphique (A) représentant la taille de la tumeur à différents temps après le traitement par un rayonnement de radiofréquence des différents groupes de souris contrôles (rond noir), injectées par voie intra-tumorale avec une solution comprenant des AGulX (rond), injectées par voie intra-tumorale avec une solution comprenant des AGulX suivi d’un traitement radiofréquence (carré), (B) représentant la taille de la tumeur après le traitement par radiofréquence de souris injectées par voie intratumorale avec une solution saline suivi d’un traitement radiofréquence (carré), et de souris injectées par voie intra-tumorale avec une solution comprenant des AGulX suivi d’un traitement par un rayonnement de radiofréquence (rond). Fig. 6 Fig. [00018] [Fig. 5] is a graph (A) representing the size of the tumor at different times after the treatment with radiofrequency radiation of the different groups of control mice (black circle), injected intratumorally with a solution comprising AGulX (round ), injected intratumorally with a solution comprising AGulX followed by radiofrequency treatment (square), (B) representing the size of the tumor after radiofrequency treatment of mice injected intratumorally with saline solution followed by radiofrequency treatment (square), and of mice injected intratumorally with a solution comprising AGulX followed by treatment with radiofrequency radiation (round). Fig. 6
[00019] [Fig. 6] est un graphique représentant la survie à différents temps après la greffe du carcinome pulmonaire de Lewis des différents groupes de souris injectées par voie intra-tumorale avec une solution saline (carré noir), injectées par voie intratumorale avec une solution saline suivi d’un traitement radiofréquence (triangle renversé), injectées par voie intratumorale avec une solution comprenant des AGulX (rond), injectées par voie intratumorale avec une solution comprenant des AGulX suivi d’un traitement radiofréquence (triangle). [00019] [Fig. 6] is a graph showing the survival at different times after the Lewis lung carcinoma transplant of the different groups of mice injected intratumorally with saline solution (black square), injected intratumorally with saline followed by radiofrequency treatment (inverted triangle), injected intratumorally with a solution comprising AGulX (round), injected intratumorally with a solution comprising AGulX followed by radiofrequency treatment (triangle).
Description des modes de réalisation Description of embodiments
[00020] Les inventeurs ont montré que l’administration de nanoparticules comprenant une matrice de polymère non-magnétique et non conductrice et des cations métalliques ayant un numéro atomique supérieur à 40 conduit à une diminution de la croissance tumorale in vivo chez les souris. [00020] The inventors have shown that the administration of nanoparticles comprising a matrix of non-magnetic and non-conductive polymer and metal cations having an atomic number greater than 40 leads to a decrease in tumor growth in vivo in mice.
[00021] Les nanoparticules selon l’invention sont déposées dans la tumeur et vont agir comme agent sensibilisant au traitement par radiofréquence. En effet, suite au traitement par radiofréquence les nanoparticules présentes dans la tumeur vont absorber une grande quantité d’énergie et entraîner une dissipation plus importante d’énergie conduisant à une hyperthermie locale dans la tumeur et à l’élimination des cellules tumorales. [00021] The nanoparticles according to the invention are deposited in the tumor and will act as a sensitizing agent for radiofrequency treatment. In fact, following radiofrequency treatment, the nanoparticles present in the tumor will absorb a large amount of energy and cause greater energy dissipation leading to local hyperthermia in the tumor and elimination of tumor cells.
[00022] Par hyperthermie, on entend des températures supérieures à la température du corps, en particulier supérieures à 37°C chez l’homme. [00022] By hyperthermia is meant temperatures above body temperature, in particular above 37 ° C in humans.
[00023] Dans un mode particulier, par hyperthermie, on entend une température corporelle locale comprise entre 37.5°C et 45°C, de préférence 39 et 45°C L’hyperthermie va permettre d’éliminer ou endommager les cellules cibles ou les sensibiliser pour un autre traitement, en particulier radiothérapie ou chimiothérapie. [00023] In a particular embodiment, by hyperthermia is meant a local body temperature of between 37.5 ° C and 45 ° C, preferably 39 and 45 ° C. Hyperthermia will make it possible to eliminate or damage the target cells or to sensitize them for other treatment, in particular radiotherapy or chemotherapy.
Nanoparticules Nanoparticles
[00024] La présente invention concerne ainsi les nanoparticules comprenant une matrice non-magnétique et non-conductrice et des cations métalliques ayant un numéro atomique Z supérieur à 40 pour une utilisation dans le traitement d’une tumeur par un rayonnement en radiofréquence chez un patient, ladite nanoparticule étant administrée avant ledit traitement par un rayonnement en radiofréquence. [00024] The present invention thus relates to nanoparticles comprising a non-magnetic and non-conductive matrix and metal cations having an atomic number Z greater than 40 for use in the treatment of a tumor by radiofrequency radiation in a patient , said nanoparticle being administered before said treatment with radiofrequency radiation.
[00025] Les nanoparticules sont des particules de taille de l’ordre du nanomètre. [00025] Nanoparticles are particles on the order of one nanometer.
[00026] Dans un mode particulier, les nanoparticules sont administrées chez le sujet par voie intraveineuse. Dans ce cas-là, les nanoparticules doivent être suffisamment petites pour pouvoir cibler les cellules tumorales via le système vasculaire et être éliminées rapidement par les reins. Ainsi, dans un mode particulier de l’invention, les nanoparticules ont un diamètre inférieur à 20 nm, de préférence inférieur à 10 nm. In a particular embodiment, the nanoparticles are administered to the subject by the intravenous route. In this case, the nanoparticles must be small enough to be able to target tumor cells via the vascular system and be eliminated quickly by the kidneys. Thus, in a particular embodiment of the invention, the nanoparticles have a diameter of less than 20 nm, preferably less than 10 nm.
[00027] Plus particulièrement, les nanoparticules sont des particules dont le diamètre moyen est compris entre 1 et 20 nm, de préférence entre 1 et 10 nm et encore plus préféré entre 2 et 5 nm, ou encore entre 1 et 6 nm. [00027] More particularly, the nanoparticles are particles whose average diameter is between 1 and 20 nm, preferably between 1 and 10 nm and even more preferably between 2 and 5 nm, or alternatively between 1 and 6 nm.
[00028] Selon l’invention, on utilisera avantageusement des nanoparticules de très faible diamètre par exemple compris entre 1 et 10 nm, de préférence entre 2 et 5 nm. [00028] According to the invention, use will advantageously be made of nanoparticles of very small diameter, for example between 1 and 10 nm, preferably between 2 and 5 nm.
[00029] La distribution de taille des nanoparticules est par exemple mesurée à l’aide d’un granulomètre commercial, tel qu’un granulomètre Malvern Zetasizer Nano-S basé sur la PCS (Photon Corrélation spectroscopy). Cette distribution est caractérisée par un diamètre hydrodynamique moyen. [00029] The size distribution of the nanoparticles is for example measured using a commercial particle size analyzer, such as a Malvern Zetasizer Nano-S particle size analyzer based on PCS (Photon Correlation spectroscopy). This distribution is characterized by an average hydrodynamic diameter.
[00030] Au sens de l’invention, par « diamètre moyen » on entend la moyenne harmonique des diamètres des particules. Une méthode de mesure de ce paramètre est également décrite dans la norme ISO 13321 :1996. [00030] For the purposes of the invention, by "mean diameter" is meant the harmonic mean of the diameters of the particles. A method for measuring this parameter is also described in ISO 13321: 1996.
[00031] Les nanoparticules selon l’invention sont des nanoparticules comprenant une matrice organique ou hybride (organique-inorganique) non-magnétique et non- conductrice. [00031] The nanoparticles according to the invention are nanoparticles comprising a non-magnetic and non-conductive organic or hybrid matrix (organic-inorganic).
[00032] Par matrice non-conductrice, on entend une matrice isolante c’est-à-dire une matrice qui ne conduit pas l’électricité. De préférence, la matrice ne contient pas de matériaux conducteurs tels que les métaux sous leur forme métallique (au degré d’oxydation zéro). [00032] By non-conductive matrix is meant an insulating matrix, that is to say a matrix which does not conduct electricity. Preferably, the matrix does not contain conductive materials such as metals in their metallic form (at zero oxidation).
[00033] Par matrice non-magnétique, on entend une matrice qui n’est pas attirée vers le champ magnétique. Avantageusement, la nanoparticule selon l’invention comprend une matrice non-ferromagnétique et/ou non super-paramagnétique, et de préférence ne comprend pas ou moins de 5 % de Fer, de Cobalt ou de Nickel de la masse de la matrice. [00033] By non-magnetic matrix is meant a matrix that is not attracted to the magnetic field. Advantageously, the nanoparticle according to the invention comprises a non-ferromagnetic and / or non-super-paramagnetic matrix, and preferably does not comprise or less than 5% of iron, cobalt or nickel of the mass of the matrix.
[00034] De préférence, la nanoparticule comprend une matrice non-magnétique et non-conductrice qui est un polymère biocompatible tels que le polyéthylène glycol, le polyéthylèneoxide, polyacrylamide, biopolymères, polysaccharides ou polysiloxane, de préférence le polysiloxane. [00034] Preferably, the nanoparticle comprises a non-magnetic and non-conductive matrix which is a biocompatible polymer such as polyethylene glycol, polyethylene oxide, polyacrylamide, biopolymers, polysaccharides or polysiloxane, preferably polysiloxane.
[00035] Les nanoparticules telles que décrites précédemment comprennent en outre des cations métalliques ayant un numéro atomique supérieur à 40 permettant d’agir comme agents sensibilisants aux radiofréquences. Plus particulièrement, les cations métalliques sont choisis parmi les métaux lourds, de préférence parmi le groupe constitué de : Pt, Pd, Sn, Ta, Zr, Tb, Tm, Ce, Dy, Er, Eu, La, Nd, Pr, Lu, Yb, Bi, Hf, Ho, Sm, In et Gd, ou un mélange de ces derniers. De préférence, les cations métalliques sont du Bi et/ou Gd. [00035] The nanoparticles as described above further comprise metal cations having an atomic number greater than 40 making it possible to act as sensitizing agents to radiofrequencies. More particularly, the metal cations are chosen from heavy metals, preferably from the group consisting of: Pt, Pd, Sn, Ta, Zr, Tb, Tm, Ce, Dy, Er, Eu, La, Nd, Pr, Lu , Yb, Bi, Hf, Ho, Sm, In and Gd, or a mixture of these. Preferably, the metal cations are Bi and / or Gd.
[00036] De préférence, la nanoparticule pour l’utilisation selon l’invention a un rapport massique en cation métallique, en particulier de Bi et/ou Gd de plus de 10%, de préférence compris entre 10 et 50%. [00037] Les cations métalliques peuvent être couplés à la matrice par des couplages covalents ou piégés par liaison non-covalente, par exemple par encapsulation ou interaction hydrophile/hydrophobe ou à l’aide d’un agent chélatant. Preferably, the nanoparticle for the use according to the invention has a mass ratio of metal cation, in particular of Bi and / or Gd, of more than 10%, preferably between 10 and 50%. The metal cations can be coupled to the matrix by covalent couplings or trapped by non-covalent bond, for example by encapsulation or hydrophilic / hydrophobic interaction or using a chelating agent.
[00038] Dans un mode préféré, les cations métalliques sont situés à la surface de la matrice de la nanoparticule. [00038] In a preferred embodiment, the metal cations are located at the surface of the matrix of the nanoparticle.
[00039] De manière préférée, les nanoparticules qui peuvent être utilisées selon l’invention comprennent des agents chélatants qui sont liés de façon covalente à la matrice et permettent de complexer les cations métalliques. De préférence les chélatants sont greffés en surface de la matrice de la nanoparticule de façon à complexer les cations métalliques à la surface de la matrice. [00039] Preferably, the nanoparticles which can be used according to the invention comprise chelating agents which are covalently linked to the matrix and make it possible to complex the metal cations. Preferably, the chelating agents are grafted to the surface of the matrix of the nanoparticle so as to complex the metal cations at the surface of the matrix.
[00040] De préférence, la nanoparticule pour l’utilisation selon l’invention comprend une matrice de polysiloxane, un agent chélatant lié de manière covalente à ladite matrice et un cation métallique compléxé par l’agent chélatant. [00040] Preferably, the nanoparticle for use according to the invention comprises a polysiloxane matrix, a chelating agent covalently bonded to said matrix and a metal cation complemented by the chelating agent.
[00041] Avantageusement, l’agent chélatant est choisi parmi les produits suivants :[00041] Advantageously, the chelating agent is chosen from the following products:
- les produits du groupe des acides polycarboxyliques polyaminés et leurs dérivés et plus préférentiellement dans le sous-groupe comprenant : DOTA (acide 1 ,4,7,10- tétraazacyclododécane-N,N’,N”,N’”-téracétique), DTPA (acide diéthylène triamine penta-acétique), EDTA (acide 2,2',2",2"'-(ethane-1 ,2-diyldinitrilo)tétraacétique), EGTA (acide éthylène glycol-bis(2-aminoéthyléther)-N,N,N',N'-tétraacetique), BAPTA (acide 1 ,2-bis(o-aminophénoxy)éthane-N,N,N',N'-tétraacetique), NOTA (acide 1 ,4,7-triazacyclononane-1 ,4,7-triacétique), DOTAGA (acide 2-(4,7,10- tris(carboxymethyl)-1 ,4,7,10-tétraazacyclododécan-1 -yl)pentanedioïque), DTPABA acide 2-(bis(2-(2,6-dioxomorpholino)éthyl)amino) acétique, leurs dérivés amides comme par exemple le DOTAM (1 ,4,7,10-tetrakis(carbamoylméthyl)-1 ,4,7,10 tetraazacyclododécane) ou le NOTAM (1 ,4,7-tetrakis(carbamoylméthyl)-1 ,4,7- triazacyclononane), leurs dérivés phosphoniques comme par exemple le DOTP (1 ,4,7,10- tetraazacyclododecane1 ,4,7,10-tetrakis(methylène phosphonate)) ou le NOTP (1 ,4,7-tetrakis(methylène phosphonate)-1 ,4,7-triazacyclononane) et leurs mélanges, - products of the group of polyaminated polycarboxylic acids and their derivatives and more preferably in the subgroup comprising: DOTA (1, 4,7,10-tetraazacyclododecane-N, N ', N ”, N'” - teracetic acid), DTPA (diethylene triamine penta-acetic acid), EDTA (2,2 ', 2 ", 2"' - (ethane-1, 2-diyldinitrilo) tetraacetic acid), EGTA (ethylene glycol-bis (2-aminoethyl ether) acid) - N, N, N ', N'-tetraacetic), BAPTA (1, 2-bis (o-aminophenoxy) ethane-N, N, N', N'-tetraacetic acid), NOTE (1, 4,7- acid triazacyclononan-1, 4,7-triacetic), DOTAGA (2- (4,7,10- tris (carboxymethyl) -1, 4,7,10-tetraazacyclododecan-1 -yl) pentanedioic acid), DTPABA acid 2- ( bis (2- (2,6-dioxomorpholino) ethyl) amino) acetic, their amide derivatives such as for example DOTAM (1, 4,7,10-tetrakis (carbamoylmethyl) -1, 4,7,10 tetraazacyclododecane) or NOTAM (1, 4,7-tetrakis (carbamoylmethyl) -1, 4,7- triazacyclononane), their phosphonic derivatives such as for example DOTP (1, 4,7,10- tetraazacyclododecane1, 4,7,10-tetrakis (met hylene phosphonate)) or NOTP (1, 4,7-tetrakis (methylene phosphonate) -1, 4,7-triazacyclononane) and their mixtures,
- les produits du groupe comprenant la porphyrine, la chlorine, 1 ,10-phénanthroline, bipyridine, terpyridine, cyclam, triazacyclononane, et leurs dérivés, comme par exemple les dérivés du cyclam tels que le TETA (1 ,4,8,11- tetraazacydotetradecane-N,N',N'',N"'- tetraacetic acid), TETAM (1 ,4,8,11- tetraazacyclotetradecane-N,N',N'',N"'- tetrakis(carbamoylméthyl)), TETP (1 ,4,8,11- tetraazacyclotetradecane-N,N',N'',N"'- tetrakis(methylène phosphonate)), et leurs mélanges, - products from the group comprising porphyrin, chlorine, 1, 10-phenanthroline, bipyridine, terpyridine, cyclam, triazacyclononane, and their derivatives, such as for example cyclam derivatives such as TETA (1, 4,8,11- tetraazacydotetradecane-N, N ', N'', N "' - tetraacetic acid), TETAM (1, 4,8,11- tetraazacyclotetradecane-N, N ', N'',N"' - tetrakis (carbamoylmethyl)), TETP (1, 4,8,11- tetraazacyclotetradecane-N, N ', N'', N "' - tetrakis (methylene phosphonate)), and mixtures thereof,
- et leurs mélanges. - and their mixtures.
[00042] Selon un mode de réalisation particulier, l’agent chélatant est choisi parmi le DOTA, DTPA, EDTA, EGTA, BAPTA, NOTA, DOTAGA, DTPABA, DOTAM, DOTP, NOTP et leurs mélanges. [00042] According to a particular embodiment, the chelating agent is chosen from DOTA, DTPA, EDTA, EGTA, BAPTA, NOTA, DOTAGA, DTPABA, DOTAM, DOTP, NOTP and their mixtures.
[00043] Dans un mode préféré, lorsque la nanoparticule comprend un cation métallique Gd ou Bi, l’agent chélatant est le DOTA, DTPA, DOTAGA ou un de ses dérivés, de préférence le DTPA, DOTAGA ou un de ses dérivés tels que par exemple le DOTAM ou le NOTAM. [00043] In a preferred embodiment, when the nanoparticle comprises a Gd or Bi metal cation, the chelating agent is DOTA, DTPA, DOTAGA or one of its derivatives, preferably DTPA, DOTAGA or one of its derivatives such as by example DOTAM or NOTAM.
[00044] Dans un mode particulier et préféré, le ratio des cations métalliques par nanoparticule, par exemple le ratio des éléments de terre rare, par exemple le gadolinium (optionnellement chélaté avec le DOTAGA) par nanoparticule est entre 3 et 100, de préférence entre 5 à 20, typiquement environ 10. In a particular and preferred embodiment, the ratio of metal cations per nanoparticle, for example the ratio of rare earth elements, for example gadolinium (optionally chelated with DOTAGA) per nanoparticle is between 3 and 100, preferably between 5 to 20, typically about 10.
[00045] Si le cation métallique est un lanthanide, par exemple le gadolinium, l’agent chélatant est avantageusement sélectionné parmi ceux dont la constante de complexation log(KC1) est supérieure à 15, de préférence 20. Comme exemple préférés de chélatants, complexant des lanthanides, on peut citer ceux comprenant un motif d’acide diéthylène triamine penta acétique (DTPA), d’acide 1 ,4,7,10- tetraazacyclododécane-1 ,4,7,10-tetra acétique (DOTA) ou d’acide 1 ,4,7,10- tetraazacyclododecance-1 ,glutarique anhydre-4,7,10-triacetique (DOTAGA). If the metal cation is a lanthanide, for example gadolinium, the chelating agent is advantageously selected from those whose complexing constant log (KC1) is greater than 15, preferably 20. As preferred example of chelating agents, complexing agents lanthanides, which may be mentioned are those comprising a unit of diethylene triamine penta acetic acid (DTPA), of 1, 4,7,10-tetraazacyclododecane-1, 4,7,10-tetra acetic acid (DOTA) or of ′ 1,4,7,10-tetraazacyclododecance-1, glutaric anhydrous-4,7,10-triacetic acid (DOTAGA).
Nanoparticules ultrafines fonctionnalisées « sans cœur » Ultrafine functionalized “heartless” nanoparticles
[00046] Dans un mode de réalisation plus particulièrement préféré, en raison notamment de leur très faible dimension, les nanoparticules utilisables selon l'invention sont obtenues par la méthode suivante : In a more particularly preferred embodiment, in particular because of their very small size, the nanoparticles which can be used according to the invention are obtained by the following method:
- obtenir un cœur comprenant un oxyde métallique, M étant un élément métallique,- obtain a heart comprising a metal oxide, M being a metal element,
- ajouter au moins une couche d'enrobage (coquille) comprenant des polysiloxanes par exemple par une méthode sol gel; - Add at least one coating layer (shell) comprising polysiloxanes, for example by a sol gel method;
- greffer un agent chélatant à la couche de polysiloxanes, l’agent chélatant étant lié à ladite couche de polysiloxane par une liaison covalente -Si-C-, pour obtenir une nanoparticule précurseur noyau-coquille - grafting a chelating agent to the polysiloxane layer, the chelating agent being bound to said polysiloxane layer by a covalent bond -Si-C-, to obtain a core-shell precursor nanoparticle
- purifier et transférer la nanoparticule précurseur noyau-coquille dans une solution aqueuse dans laquelle l’agent de greffage est en quantité suffisante pour dissoudre le cœur d’oxyde métallique et pour complexer le cation métallique de sorte que le diamètre moyen de la nanoparticule ainsi obtenue est réduit à une valeur de moins de 10 nm, de préférence de moins de 5 nm, par exemple entre 1 et 5 nm. - purify and transfer the core-shell precursor nanoparticle into an aqueous solution in which the grafting agent is in sufficient quantity to dissolve the metal oxide core and to complex the metal cation so that the average diameter of the nanoparticle thus obtained is reduced to a value of less than 10 nm, preferably less than 5 nm, for example between 1 and 5 nm.
[00047] Ces nanoparticules obtenues selon le mode décrit ci-dessus ne comprennent pas de cœur encapsulé par au moins un enrobage. De plus amples détails sur la synthèse de ces nanoparticules sont donnés dans la section suivante. [00047] These nanoparticles obtained according to the method described above do not include a core encapsulated by at least one coating. Further details on the synthesis of these nanoparticles are given in the following section.
[00048] Il en résulte des nanoparticules de tailles observées comprises entre 1 et 8 nm, par exemple entre 1 et 5 nm. On parle alors de nanoparticules ultrafines. [00048] This results in nanoparticles with sizes observed of between 1 and 8 nm, for example between 1 and 5 nm. We then speak of ultrafine nanoparticles.
[00049] Alternativement, une autre méthode de synthèse « one-pot » permettant de préparer des nanoparticules sans cœur avec un diamètre moyen de moins de 10 nm, typiquement entre 1 et 8 nm, par exemple entre 1 et 5 nm, est décrite dans la section suivante. [00049] Alternatively, another “one-pot” synthesis method making it possible to prepare coreless nanoparticles with an average diameter of less than 10 nm, typically between 1 and 8 nm, for example between 1 and 5 nm, is described in the next section.
[00050] Les chélatants peuvent être greffés en surface des particules de polysiloxane ou directement insérés au sein de la matrice POS. Une partie ou la totalité de ces chélatants sont destinés à complexer des cations métalliques (e.g. du gadolinium, du bismuth). The chelating agents can be grafted on the surface of the polysiloxane particles or directly inserted within the POS matrix. Some or all of these chelating agents are intended to complex metal cations (e.g. gadolinium, bismuth).
[00051] Outre la fonctionnai isation chélatante, ces nanoparticules peuvent être modifiées (fonctionnai isation) en surface par des composés hydrophiles (PEG) et/ou chargées différemment pour adapter leur bio-distribution au sein de l'organisme et/ou permettre un bon marquage cellulaire, en particulier pour le suivi des thérapies cellulaires. [00051] In addition to the chelating function, these nanoparticles can be modified (function) at the surface by hydrophilic compounds (PEG) and / or loaded differently to adapt their bio-distribution within the organism and / or allow a good cell labeling, in particular for monitoring cell therapy.
[00052] Elles peuvent être par exemple fonctionnalisées en surface par greffage de molécules ciblant les tissus pulmonaires, ou, du fait de leur passage dans le sang, par greffage de molécules ciblant certaines zones d'intérêt de l'organisme, en particulier de zones tumorales. They can for example be functionalized at the surface by grafting molecules targeting lung tissue, or, due to their passage through the blood, by grafting molecules targeting certain areas of interest of the body, in particular areas tumor.
[00053] La fonctionnai isation peut se faire également par des composés comportant un autre principe actif et/ou des composés luminescents (fluorescéine). Il en résulte des possibilités d’utilisations thérapeutiques comme agent radiosensibilisant, des neutronthérapies, comme agent radioactif pour des traitements de curiethérapie, comme agent pour la PDT (photodynamic therapy) ou comme agent de vectorisation de molécules à effet thérapeutique. [00053] The functionalization can also be carried out by compounds comprising another active principle and / or luminescent compounds (fluorescein). This results in possibilities of therapeutic uses as a radiosensitizing agent, neutron therapy, as a radioactive agent for brachytherapy treatments, as an agent for PDT (photodynamic therapy) or as an agent for vectoring molecules with a therapeutic effect.
[00054] Une autre caractéristique de ces nanoparticules ultrafines est le maintien du caractère rigide des objets et de la géométrie globale des particules après injection. Cette forte rigidité tridimensionnelle peut être assurée par une matrice en polysiloxane, où la majorité des siliciums sont liés à 3 ou 4 autres atomes de silicium via un pont oxygène. La combinaison de cette rigidité avec leur petite taille permet d’augmenter la relaxivité de ces nanoparticules pour les fréquences intermédiaires (20 à 60 MHz) par rapport aux composés commerciaux (complexes à base de Gd- DOTA par exemple), mais aussi pour des fréquences supérieures à 100 MHz présentes dans les IRM haut champ de nouvelle génération. Another characteristic of these ultrafine nanoparticles is the maintenance of the rigid character of the objects and of the overall geometry of the particles after injection. This high three-dimensional rigidity can be ensured by a polysiloxane matrix, where the majority of silicones are linked to 3 or 4 other silicon atoms via an oxygen bridge. The combination of this rigidity with their small size makes it possible to increase the relaxivity of these nanoparticles for intermediate frequencies (20 to 60 MHz) compared to commercial compounds (complexes based on Gd-DOTA for example), but also for frequencies greater than 100 MHz present in new generation high-field MRIs.
[00055] Cette rigidité, non présente dans les polymères, est aussi un atout pour la vectorisation et l’accessibilité des molécules ciblantes. [00055] This rigidity, not present in polymers, is also an asset for the vectorization and accessibility of targeting molecules.
[00056] De préférence, les nanoparticules selon l'invention, et en particulier selon le présent mode de réalisation, ont une relaxivité n par cation métallique Mn+ qui est supérieure à 5 mM 1.s 1 (d'ion Mn+). préférentiellement 10 mM 1.s 1 (d'ion Mn+). pour une fréquence de 20 MHz. Par exemple, elles ont une relaxivité n par nanoparticule compris entre 50 et 5000 mM 1.s 1. Mieux encore, ces nanoparticules ont une relaxivité n par ion Mn+ à 60 MHz qui est supérieure ou égale à la relaxivité n par ion Mn+ à 20 MHz. La relaxivité n considérée ici est une relaxivité par ion Mn (par exemple gadolinium) n est extrait de la formule suivante : 1 /Ti = [1/Ti]eau + n[Mn+]. Preferably, the nanoparticles according to the invention, and in particular according to the present embodiment, have a relaxivity n per metal cation M n + which is greater than 5 mM 1 .s 1 (of M n + ion). preferably 10 mM 1 .s 1 (of M n + ion). for a frequency of 20 MHz. For example, they have a relaxivity n per nanoparticle of between 50 and 5000 mM 1 .s 1 . Better still, these nanoparticles have a relaxivity n per M n + ion at 60 MHz which is greater than or equal to the relaxivity n per M n + ion at 20 MHz. The relaxivity n considered here is a relaxivity per Mn ion (for example gadolinium) n is extracted from the following formula: 1 / Ti = [1 / Ti] water + n [M n + ].
[00057] Plus de détails concernant ces nanoparticules ultrafines, leurs procédés de synthèse et leurs applications sont décrits dans la demande de brevet WO201 1/135101 , WO2018/224684 ou WO2019/008040 qui sont incorporées ici par référence. [00057] More details concerning these ultrafine nanoparticles, their synthesis methods and their applications are described in patent application WO201 1/135101, WO2018 / 224684 or WO2019 / 008040 which are incorporated here by reference.
[00058] Selon un mode de réalisation préféré, les nanoparticules utilisables selon l’invention sont des nanoparticules de polysiloxane chélatées avec du gadolinium. En particulier, il s’agit de nanoparticules de polysiloxane chélatées avec du gadolinium, qui ne comprennent pas de cœur d’oxyde de gadolinium et dont le diamètre est compris entre 1 et 10 nm, de préférence entre 2 et 8 nm. De telles nanoparticules sont notamment les nanoparticules dites AGulX de formule générale I ci-dessous : n dans laquelle PS est une matrice en polysiloxane et n est compris entre 5 et 50, de préférence entre 5 et 20, et dans laquelle le diamètre hydrodynamique est compris entre 1 et 10 nm, par exemple entre 2 et 8 nm, notamment 5 nm. [00058] According to a preferred embodiment, the nanoparticles which can be used according to the invention are polysiloxane nanoparticles chelated with gadolinium. In particular, they are polysiloxane nanoparticles chelated with gadolinium, which do not include a gadolinium oxide core and whose diameter is between 1 and 10 nm, preferably between 2 and 8 nm. Such nanoparticles are in particular the nanoparticles known as AGulX of general formula I below: n in which PS is a polysiloxane matrix and n is between 5 and 50, preferably between 5 and 20, and in which the hydrodynamic diameter is between 1 and 10 nm, for example between 2 and 8 nm, in particular 5 nm .
[00059] Selon ce mode de réalisation, les nanoparticules AGulX peuvent avoir une masse d’environ 15 kDa ± 10 kDa. [00059] According to this embodiment, the AGulX nanoparticles can have a mass of about 15 kDa ± 10 kDa.
[00060] Toujours selon ce mode de réalisation préféré, les nanoparticules AGulX peuvent également être décrites par la formule II ci-après : (GdSÎ3-8C24-34N5-80i5-3oH4o-6o, 1-10 hhOJn [00060] Still according to this preferred embodiment, the AGulX nanoparticles can also be described by formula II below: (GdSÎ3-8C24-34N5-80i5-3oH4o-6o, 1-10 hhOJn
Méthode de préparation nanoparticules Nanoparticle preparation method
[00061] D'une façon générale, l'homme du métier pourra aisément fabriquer des nanoparticules utilisées selon l'invention. [00062] Pour la matrice POS, plusieurs techniques peuvent être employées, dérivées de celles initiées par Stoeber (Stoeber, W ; J. Colloid Interf Sci 1968, 26, 62). On peut également utiliser le procédé employé pour l'enrobage comme décrit dans Louis et al (Louis et al. ,2005, Chemistry of Materials, 17, 1673-1682) ou la demande internationale WO 2005/088314. [00063] En pratique, la synthèse de nanoparticules ultrafines est par exemple décrite dans Mignot et al. Chem. Eur. J. 2013, 19 :6122-6136. Typiquement, on forme une nanoparticule de type cœur/coquille avec un cœur d'oxyde de lanthanide (par voie polyol modifiée) et une coquille de polysiloxane (par sol/gel), cet objet a par exemple une taille aux alentours de 10 nm (préférentiellement 5 nanomètres). Un cœur d'oxyde de lanthanide de taille très petite (adaptable inférieure à 10 nm) peut ainsi être élaboré dans un alcool par un des procédés décrits dans les publications suivantes : P. Perriat et al., J. Coll. Int. S ci, 2004, 273, 191 ; O. Tillement et al., J. Am. Chem. Soc, 2007, 129, 5076 et P. Perriat et al., J. Phys. Chem. C, 2009, 113, 4038. Ces cœurs peuvent être enrobés par une couche de polysiloxane en suivant par exemple un protocole décrit dans les publications suivantes : C. Louis et al., Chem. Mat., 2005, 17, 1673 et O. Tillement et al., J. Am. Chem. Soc, 2007, 129, 5076. In general, a person skilled in the art can easily manufacture nanoparticles used according to the invention. [00062] For the POS matrix, several techniques can be used, derived from those initiated by Stoeber (Stoeber, W; J. Colloid Interf Sci 1968, 26, 62). It is also possible to use the method employed for the coating as described in Louis et al. (Louis et al., 2005, Chemistry of Materials, 17, 1673-1682) or international application WO 2005/088314. In practice, the synthesis of ultrafine nanoparticles is for example described in Mignot et al. Chem. Eur. J. 2013, 19: 6122-6136. Typically, a core / shell type nanoparticle is formed with a lanthanide oxide core (by modified polyol route) and a polysiloxane shell (by sol / gel), this object for example has a size around 10 nm ( preferably 5 nanometers). A lanthanide oxide core of very small size (adaptable less than 10 nm) can thus be produced in an alcohol by one of the methods described in the following publications: P. Perriat et al., J. Coll. Int. S ci, 2004, 273, 191; O. Tillement et al., J. Am. Chem. Soc, 2007, 129, 5076 and P. Perriat et al., J. Phys. Chem. C, 2009, 113, 4038. These cores can be coated with a layer of polysiloxane, for example by following a protocol described in the following publications: C. Louis et al., Chem. Mat., 2005, 17, 1673 and O. Tillement et al., J. Am. Chem. Soc, 2007, 129, 5076.
[00064] On greffe à la surface du polysiloxane des chélatants spécifiques des cations métalliques visés (par exemple DOTAGA pour Gd3+); on peut également en insérer une partie à l'intérieur de la couche mais le contrôle de la formation du polysiloxane est complexe et le simple greffage extérieur donne, à ces très faibles tailles, une proportion de greffage suffisante. [00064] Chelating agents specific for the targeted metal cations (for example DOTAGA for Gd 3+ ) are grafted onto the surface of the polysiloxane; it is also possible to insert a part of it inside the layer but the control of the formation of the polysiloxane is complex and the simple external grafting gives, at these very small sizes, a sufficient grafting proportion.
[00065] On sépare les nanoparticules des résidus de synthèse par une méthode de dialyse ou de filtration tangentielle, sur une membrane comportant des pores de taille adaptée. The nanoparticles are separated from the synthesis residues by a dialysis or tangential filtration method, on a membrane comprising pores of suitable size.
[00066] Le cœur est détruit par dissolution (par exemple en modifiant le pH ou en apportant des molécules complexantes dans la solution). Cette destruction du cœur permet alors un éparpillement de la couche de polysiloxane (selon un mécanisme d'effondrement ou de corrosion lente), ce qui permet d'obtenir en final un objet en polysiloxane de morphologie complexe dont les dimensions caractéristiques sont de l'ordre de grandeur de l'épaisseur de la couche de polysiloxane, c'est-à-dire beaucoup plus petit que les objets jusqu'à présent élaborés. Le fait de retirer le cœur permet ainsi de passer d'une taille de particules d'environ 5 nanomètres de diamètre à une taille d'environ 3 nanomètres. De plus, cette opération permet d'augmenter le nombre de cations métalliques (e.g. gadolinium) par nm en comparaison d'une nanoparticule de polysiloxane théorique de même taille mais comprenant du métal (e.g. gadolinium) uniquement en surface. Le nombre de cations métalliques pour une taille de nanoparticule est évaluable grâce au rapport atomique M/Si mesuré par EDX. [00066] The heart is destroyed by dissolution (for example by modifying the pH or by providing complexing molecules in the solution). This destruction of the core then allows a scattering of the polysiloxane layer (according to a collapse or slow corrosion mechanism), which ultimately makes it possible to obtain a polysiloxane object of complex morphology, the characteristic dimensions of which are of the order of magnitude of the thickness of the polysiloxane layer, that is to say much smaller than the objects so far developed. Removing the core thus makes it possible to go from a particle size of about 5 nanometers in diameter to a size of about 3 nanometers. In addition, this operation makes it possible to increase the number of metal cations (e.g. gadolinium) per nm in comparison with a theoretical polysiloxane nanoparticle of the same size but comprising metal (e.g. gadolinium) only at the surface. The number of metal cations for a nanoparticle size can be evaluated using the M / Si atomic ratio measured by EDX.
[00067] Sur ces nanoparticules, on peut greffer des molécules ciblantes, par exemple à l'aide de couplage par liaison peptidique sur un constituant organique de la nanoparticule, comme décrit dans Montalbetti, C.A.G.N, F algue B. Tetrahedron 2005, 61, 10827-10852. On pourra également utiliser une méthode de couplage utilisant la « click chemistry » Jewett, J.C.; Bertozzi, C.R. Chem. Soc. Rev. 2010, 39, 1272-1279, et faisant intervenir des groupements du type : -N3, -CN, -CºCH, ou l'un des groupements suivants : ~ ;~ On these nanoparticles, it is possible to graft targeting molecules, for example by means of coupling by peptide bond on an organic constituent of the nanoparticle, as described in Montalbetti, CAGN, F alga B. Tetrahedron 2005, 61, 10827-10852. It is also possible to use a coupling method using “click chemistry” Jewett, JC; Bertozzi, CR Chem. Soc. Rev. 2010, 39, 1272-1279, and involving groups of the type: -N3, -CN, -CºCH, or one of the following groups: ~ ; ~
[00068] Dans un mode de réalisation spécifique, la nanoparticule selon l'invention comprend un chélatant présentant une fonction acide, par exemple le DOTA. On procède à l’activation de la fonction acide de la nanoparticule, par un exemple à l'aide d'EDC/NHS (l-éthyl-3-(3-diméthylaminopropyl)carbodiimide/N- hydrosuccinimide) en présence d'une quantité appropriée de molécules ciblantes. Les nanoparticules ainsi greffées sont ensuite purifiées, par exemple par filtration tangentielle. [00068] In a specific embodiment, the nanoparticle according to the invention comprises a chelating agent having an acid function, for example DOTA. The acid function of the nanoparticle is activated, for example using EDC / NHS (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / N-hydrosuccinimide) in the presence of a quantity appropriate targeting molecules. The nanoparticles thus grafted are then purified, for example by tangential filtration.
[00069] Dans un mode particulier, les nanoparticules selon la présente invention sont obtenues par une méthode de synthèse (« one-pot synthesis method ») comprenant le mélange d’au moins un hydroxysilane ou d’alcoxysilane qui est chargé négativement à un pH physiologique et au moins un agent chélatant choisi parmi les acides polyaminopolycarboxyliques avec: In a particular embodiment, the nanoparticles according to the present invention are obtained by a synthesis method ("one-pot synthesis method") comprising the mixture of at least one hydroxysilane or alkoxysilane which is negatively charged at a pH physiological and at least one chelating agent chosen from polyaminopolycarboxylic acids with:
- au moins un hydroxysilane ou alcoxysilane qui est neutre à un pH physiologique, et/ou - at least one hydroxysilane or alkoxysilane which is neutral at physiological pH, and / or
- au moins un hydroxysilane ou alcoxysilane qui est chargé positivement à un pH physiologique et comprend une fonction amine, dans lequel: - at least one hydroxysilane or alkoxysilane which is positively charged at a physiological pH and comprises an amine function, in which:
- le ratio molaire A de silanes neutres sur les silanes chargés négativement est défini comme suit: 0<A<6, de préférence 0.5<A<2; - the molar ratio A of neutral silanes to negatively charged silanes is defined as follows: 0 <A <6, preferably 0.5 <A <2;
- le ratio molaire B de silanes chargés positivement sur les silanes chargés négativement est défini comme suit: 0<B<5, de préférence 0.25<B<3; - the molar ratio B of positively charged silanes to the charged silanes negatively is defined as follows: 0 <B <5, preferably 0.25 <B <3;
- le ratio molaire C des silanes chargés positivement et neutres sur les silanes chargés négativement est définit comme suit: 0<C<8, de préférence 1<C<4. - the molar ratio C of the positively charged and neutral silanes to the negatively charged silanes is defined as follows: 0 <C <8, preferably 1 <C <4.
[00070] Dans un mode plus particulier, la méthode de synthèse «one pot» comprend le mélange d’au moins un alcoxysilane qui est chargé négativement à un pH physiologique, ledit alcoxysilane étant choisi parmi l’APTES-DOTAGA, TANED, CEST, et leurs mélanges avec: [00070] In a more particular embodiment, the "one pot" synthesis method comprises the mixture of at least one alkoxysilane which is negatively charged at a physiological pH, said alkoxysilane being chosen from APTES-DOTAGA, TANED, CEST, and their mixtures with:
- au moins un alcoxysilane qui est neutre à un pH physiologique, ledit alcoxysilane étant choisi parmi le TMOS, TEOS et leurs mélanges, et/ou - at least one alkoxysilane which is neutral at physiological pH, said alkoxysilane being chosen from TMOS, TEOS and their mixtures, and / or
- APTES qui est chargé positivement à un pH physiologique, dans lequel: - APTES which is positively charged at physiological pH, in which:
- le ratio molaire A de silanes neutres sur les silanes chargés négativement est défini comme suit: 0<A<6, de préférence 0.5<A<2; - the molar ratio A of neutral silanes to negatively charged silanes is defined as follows: 0 <A <6, preferably 0.5 <A <2;
- le ratio molaire B de silanes chargés positivement sur les silanes chargés négativement est défini comme suit: 0<B<5, de préférence 0.25<B<3; the molar ratio B of positively charged silanes to the negatively charged silanes is defined as follows: 0 <B <5, preferably 0.25 <B <3;
- le ratio molaire C des silanes chargés positivement et neutres sur les silanes chargés négativement est défini comme suit: 0<C<8, de préférence 1<C<4. the molar ratio C of the positively charged and neutral silanes to the negatively charged silanes is defined as follows: 0 <C <8, preferably 1 <C <4.
[00071] Selon un mode particulier, la méthode de synthèse « one pot » comprend le mélange de APTES-DOTAGA qui est chargé négativement à pH physiologique avec : According to a particular embodiment, the "one pot" synthesis method comprises the mixture of APTES-DOTAGA which is negatively charged at physiological pH with:
- au moins un alcoxysilane qui est neutre à un pH physiologique, ledit alcoxysilane étant choisi parmi le TMOS, TEOS et leurs mélanges, et/ou - at least one alkoxysilane which is neutral at physiological pH, said alkoxysilane being chosen from TMOS, TEOS and their mixtures, and / or
- APTES qui est chargé positivement à un pH physiologique, dans lequel : - APTES which is positively charged at physiological pH, in which:
- le ratio molaire A de silanes neutres sur les silanes chargés négativement est défini comme suit : 0<A<6, de préférence 0.5<A<2 ; - the molar ratio A of neutral silanes to negatively charged silanes is defined as follows: 0 <A <6, preferably 0.5 <A <2;
- le ratio molaire B de silanes chargés positivement sur les silanes chargés négativement est défini comme suit : 0<B<5, de préférence 0.25<B<3 ; the molar ratio B of positively charged silanes to the negatively charged silanes is defined as follows: 0 <B <5, preferably 0.25 <B <3;
- le ratio molaire C des silanes chargés positivement et neutres sur les silanes chargés négativement est définit comme suit : 0<C<8, de préférence 1<C<4. Méthode thérapeutique - the molar ratio C of the positively charged and neutral silanes to the negatively charged silanes is defined as follows: 0 <C <8, preferably 1 <C <4. Therapeutic method
[00072] Les nanoparticules telles que décrites précédemment sont administrées dans la tumeur ou à proximité de la région de la tumeur d’un patient. Elles peuvent également être administrées par injection intraveineuse, intramusculaire ou par inhalation. Le traitement par un rayonnement de radiofréquence du patient induit alors une hyperthermie de ladite tumeur et réduit la croissance tumorale. [00072] The nanoparticles as described above are administered into the tumor or near the tumor region of a patient. They can also be administered by intravenous, intramuscular injection or by inhalation. The radiofrequency radiation treatment of the patient then induces hyperthermia of said tumor and reduces tumor growth.
[00073] Les nanoparticules telles que définies précédemment sont utilisées comme agent sensibilisant aux rayonnements de radiofréquence pour cibler des cellules tumorales spécifiquement. [00074] Les agents sensibilisant aux rayonnements de radiofréquence tels qu’utilisés dans la présente demande se réfèrent à une composition qui permet d’induire une plus grande absorption de quantité d’énergie à partir d’un signal de radiofréquence créant ainsi une augmentation de la température plus élevée dans la zone comprenant cette composition. Les agents sensibilisants sont dans la présente demande caractérisés par leur capacité à cibler et se lier à une cellule cible, ici une cellule tumorale, et permettre de rendre la cellule cible plus sensible à l’augmentation de température induite par un rayonnement de radiofréquence. Nanoparticles as defined above are used as a sensitizing agent to radiofrequency radiation to target tumor cells specifically. The radiofrequency radiation sensitizing agents as used in the present application refer to a composition which makes it possible to induce a greater absorption of quantity of energy from a radiofrequency signal thus creating an increase in the higher temperature in the zone comprising this composition. The sensitizing agents in the present application are characterized by their ability to target and bind to a target cell, here a tumor cell, and to make the target cell more sensitive to the increase in temperature induced by radiofrequency radiation.
[00075] La présente invention concerne ainsi les nanoparticules telles que définies précédemment pour une utilisation dans le traitement d’une tumeur chez un patient subissant un traitement par un rayonnement de radiofréquence. [00075] The present invention thus relates to the nanoparticles as defined above for use in the treatment of a tumor in a patient undergoing treatment with radiofrequency radiation.
[00076] Par « patient » ou « sujet », on entend n’importe quel membre du règne animal, de préférence un mammifère ou un être humain incluant par exemple un sujet ayant une tumeur. By "patient" or "subject" is meant any member of the animal kingdom, preferably a mammal or a human including, for example, a subject having a tumor.
[00077] Les termes « traitement », « thérapie », se réfèrent à n’importe quel acte qui a pour but d’améliorer l’état de santé d’un patient, tel que la thérapie, la prévention, la prophylaxie, et le retardement d’une maladie. Dans certains cas, ces termes se réfèrent à l’amélioration ou l’éradication d’une maladie ou des symptômes associés à la maladie. Dans d’autres modes de réalisation, ces termes se réfèrent à la réduction de la propagation ou l’aggravation de la maladie résultant de l’administration d’un ou plusieurs agents thérapeutiques à un sujet atteint d’une telle maladie. [00078] En particulier, les nanoparticules sont utilisées pour le traitement des tumeurs solides, en particulier le cancer du cerveau (primaires et secondaires, le glioblastome...), les cancers hépatiques (primaires et secondaires), les tumeurs pelviennes (cancer du col de l’utérus, cancer de la prostate, cancer anorectal, cancer colorectal), les cancers des voies aérodigestives supérieures, le cancer des poumons, le cancer de l’œsophage, le cancer du sein, le cancer du pancréas. The terms "treatment", "therapy" refer to any act which aims to improve the state of health of a patient, such as therapy, prevention, prophylaxis, and the delay of a disease. In some cases, these terms refer to the amelioration or eradication of a disease or symptoms associated with the disease. In other embodiments, these terms refer to the reduction in the spread or aggravation of disease resulting from the administration of one or more therapeutic agents to a subject afflicted with such disease. [00078] In particular, nanoparticles are used for the treatment of solid tumors, in particular brain cancer (primary and secondary, glioblastoma, etc.), hepatic cancers (primary and secondary), pelvic tumors (cancer of the cervix, prostate cancer, anorectal cancer, colorectal cancer), upper aerodigestive tract cancers, lung cancer, esophageal cancer, breast cancer, pancreatic cancer.
[00079] La présente invention concerne une méthode de traitement des tumeurs par un rayonnement de radiofréquence comprenant les étapes d’administration d’une dose efficace de nanoparticules telles que décrites précédemment dans la tumeur d’un patient et exposition de la tumeur à un rayonnement de radiofréquence. The present invention relates to a method of treating tumors with radiofrequency radiation comprising the steps of administering an effective dose of nanoparticles as described above into the tumor of a patient and exposing the tumor to radiation. radio frequency.
[00080] Par « dose efficace » de nanoparticules, il est fait référence à la quantité de nanoparticules telles que décrites précédemment qui administrée à un patient est suffisante pour être localisées dans la tumeur et induire une hyperthermie suite au traitement par un rayonnement de radiofréquence. [00080] By “effective dose” of nanoparticles, reference is made to the amount of nanoparticles as described above which, administered to a patient, is sufficient to be localized in the tumor and to induce hyperthermia following treatment with radiofrequency radiation.
[00081] Cette dose est déterminée et ajustée en fonction de facteurs tels que l’âge, le sexe et le poids du sujet. This dose is determined and adjusted according to factors such as the age, sex and weight of the subject.
[00082] L'administration des nanoparticules telles que décrites précédemment peut être réalisée par voie intratumorale, sous-cutanée, intramusculaire, intraveineuse, intradermique, intrapéritonéale, orale, sublinguale, rectale, vaginale, intranasale, par inhalation ou par application transdermique. [00082] The administration of the nanoparticles as described above can be carried out intratumoral, subcutaneous, intramuscular, intravenous, intradermal, intraperitoneal, oral, sublingual, rectal, vaginal, intranasal, by inhalation or by transdermal application.
[00083] La composition se présente sous une forme galénique adaptée à une administration choisie. [00083] The composition is in a pharmaceutical form suitable for a chosen administration.
[00084] De préférence, les nanoparticules sont administrées par voie intraveineuse et les nanoparticules vont cibler spécifiquement les tumeurs, par un ciblage passif par exemple en augmentant l’effet de perméabilité et de rétention. [00084] Preferably, the nanoparticles are administered intravenously and the nanoparticles will specifically target tumors, by passive targeting, for example by increasing the effect of permeability and retention.
[00085] Des administrations répétées peuvent être réalisées. [00085] Repeated administrations can be performed.
[00086] Dans un mode particulier, une dose unique comprise entre 20 mg/kg et 500 mg/kg de nanoparticules est administrée par voie intraveineuse dans un sujet. In a particular embodiment, a single dose of between 20 mg / kg and 500 mg / kg of nanoparticles is administered intravenously into a subject.
[00087] Dans un mode particulier, les nanoparticules sont administrées dans la tumeur du patient de telle sorte que les nanoparticules sont présentes à une concentration comprise entre 0.1 mg/L et 50 mg/L, préférentiellement 1 et 10 mg/L dans la région de la tumeur qui sera traitée par radiofréquence. [00087] In a particular embodiment, the nanoparticles are administered into the patient's tumor such that the nanoparticles are present at a concentration between 0.1 mg / L and 50 mg / L, preferably 1 and 10 mg / L in the region of the tumor which will be treated by radiofrequency.
[00088] Les nanoparticules agissent comme des agents sensibilisants et sont utilisées pour cibler des cellules tumorales spécifiquement. L’émission d’ondes radio à proximité de cellules tumorales comprenant les nanoparticules conduit alors à l’élimination des cellules tumorales. [00088] Nanoparticles act as sensitizers and are used to target tumor cells specifically. The emission of radio waves near tumor cells comprising the nanoparticles then leads to the elimination of the tumor cells.
[00089] Les méthodes de traitement par un rayonnement de radiofréquence de cancer sont bien connues et les paramètres utilisés pour traiter les tumeurs par radiofréquence de manière non-invasive peuvent être optimisés par l’homme du métier. [00089] The methods of radiofrequency radiation treatment of cancer are well known and the parameters used to treat tumors by radiofrequency in a non-invasive manner can be optimized by those skilled in the art.
[00090] Un rayonnement de radiofréquence induit des mouvements oscillants des espèces chargées aux fréquences dans le domaine de 3 kHz à 300 GHz. Suite à ces excitations électromagnétiques, une agitation ionique déclenche des mouvements de friction moléculaire responsables d’une élévation thermique dans les cellules. L’élévation thermique conduit alors à l’élimination des cellules. [00090] Radiofrequency radiation induces oscillating movements of the charged species at frequencies in the range from 3 kHz to 300 GHz. Following these electromagnetic excitations, ionic agitation triggers molecular frictional movements responsible for thermal elevation in cells. The heat rise then leads to the elimination of cells.
[00091] Un rayonnement de radiofréquence est généré entre une tête de transmission et une tête de réception différente de la tête de transmission. La tête de transmission et de réception sont disposées de part et d’autre du site de la tumeur ou du corps du patient et le signal de radiofréquence est émis pour induire l’hyperthermie des cellules cibles, telles que les cellules tumorales. De nombreux dispositifs sont connus pour émettre des ondes radio. [00091] Radiofrequency radiation is generated between a transmission head and a reception head different from the transmission head. The transmitting and receiving head are arranged on either side of the tumor site or the patient's body and the radio frequency signal is emitted to induce hyperthermia in target cells, such as tumor cells. Many devices are known to emit radio waves.
[00092] Le traitement par un rayonnement de radiofréquence selon l’invention est de préférence un traitement non-invasif. Le terme « non-invasif » tel qu’utilisé dans la présente demande signifie qu’aucune aiguille, fil, électrodes ou autres objets sont insérés chez le patient ou la tumeur du patient qui doit être traité. [00092] The treatment with radiofrequency radiation according to the invention is preferably a non-invasive treatment. The term "non-invasive" as used in this application means that no needle, wire, electrodes or other objects are inserted into the patient or the tumor of the patient to be treated.
[00093] Le signal de radiofréquence est émis de telle sorte que la tumeur cible atteint une température comprise entre 37,5 et 45°C, de préférence entre 42 et 44 °C. The radio frequency signal is emitted such that the target tumor reaches a temperature between 37.5 and 45 ° C, preferably between 42 and 44 ° C.
[00094] Le traitement par radiofréquence est réalisé à une fréquence inférieure à 1 GHz comprise entre 1 et 1000 MHz, de préférence entre 1 et 100 MHz. [00095] Le signal de radiofréquence doit être suffisamment élevé pour permettre d’induire l’hyperthermie des cellules tumorales et ainsi induire leur mort cellulaire ou du moins l’endommagement des cellules cibles. [00094] The radiofrequency treatment is carried out at a frequency less than 1 GHz between 1 and 1000 MHz, preferably between 1 and 100 MHz. [00095] The radiofrequency signal must be high enough to make it possible to induce hyperthermia of the tumor cells and thus to induce their cell death or at least the damage of the target cells.
[00096] Le traitement par radiofréquence peut être réalisé par une simple exposition ou des expositions successives à un rayonnement de radiofréquence. Dans un mode particulier, la durée de chaque exposition à un rayonnement de radiofréquence est comprise entre 1 et 60 min, de préférence entre 10 et 60 min. [00096] The radiofrequency treatment can be carried out by simple exposure or successive exposures to radiofrequency radiation. In a particular embodiment, the duration of each exposure to radiofrequency radiation is between 1 and 60 min, preferably between 10 and 60 min.
[00097] La fréquence et le temps du traitement par radiofréquence peuvent être optimisés par exemple en fonction du patient, du type de cancer, du genre, de la taille de l’individu. [00097] The frequency and the time of the radiofrequency treatment can be optimized, for example according to the patient, the type of cancer, the gender, the size of the individual.
[00098] La température de la zone cible peut être mesurée en utilisant un dispositif bien connu de l’homme du métier. Par exemple la température peut être mesurée en utilisant une caméra infra-rouge, un thermomètre sans contact, une sonde thermique ou par imagerie par résonance magnétique thermique. Ces sondes sont inertes thermiquement et électriquement au traitement par radiofréquence. [00098] The temperature of the target area can be measured using a device well known to those skilled in the art. For example the temperature can be measured using an infrared camera, a non-contact thermometer, a thermal probe or by thermal magnetic resonance imaging. These probes are thermally and electrically inert to radiofrequency treatment.
[00099] Dans un mode particulier, le traitement par un rayonnement de radiofréquence peut comprendre une exposition à un rayonnement de radiofréquence par semaine, ou plusieurs expositions par semaine. [00099] In a particular embodiment, the treatment with radiofrequency radiation can comprise one exposure to radiofrequency radiation per week, or several exposures per week.
[000100] L’hyperthermie induite par un rayonnement de radiofréquence va également rendre les cellules cancéreuses plus sensibles à la radiothérapie ou aux drogues anti-cancéreuses. Les nanoparticules telles que décrites précédemment pour une utilisation dans le traitement d’une tumeur par un rayonnement de radiofréquence peuvent ainsi être utilisées en combinaison avec un ou plusieurs agents anti-cancer ou de la radiothérapie. [000100] The hyperthermia induced by radiofrequency radiation will also make cancer cells more sensitive to radiotherapy or anti-cancer drugs. The nanoparticles as described above for use in the treatment of a tumor with radiofrequency radiation can thus be used in combination with one or more anti-cancer agents or with radiotherapy.
[000101] Les agents de chimiothérapie peuvent être des inhibiteurs de la réplication de l’ADN comme des agents liant l’ADN, en particulier des drogues alkylantes ou intercalantes, des agents anti-métabolites tels que des inhibiteurs de polymérase ou de topoisomérase I ou II, ou des agents anti-mitotiques tels que les alcaloïdes. Des exemples non-limitatifs d’agents de chimiothérapie sont : 5-FU, oxaliplatine, cisplatine, carboplatine, irinotecan, cetuximab, erlotinib, docetaxel, doxorubicine et le paclitaxel. [000102] Les agents d’immunothérapie sont des composés qui améliorent ou stimulent indirectement ou directement la réponse immunitaire contre les cellules tumorales. [000101] Chemotherapy agents can be DNA replication inhibitors such as DNA binding agents, in particular alkylating or intercalating drugs, anti-metabolite agents such as polymerase or topoisomerase I inhibitors or II, or anti-mitotic agents such as alkaloids. Non-limiting examples of chemotherapy agents are: 5-FU, oxaliplatin, cisplatin, carboplatin, irinotecan, cetuximab, erlotinib, docetaxel, doxorubicin and paclitaxel. [000102] Immunotherapy agents are compounds which indirectly or directly enhance or stimulate the immune response against tumor cells.
[000103] Les nanoparticules peuvent également être utilisées en outre comme agent radio-sensibilisant pour la radiothérapie, comme agent photosensibilisant pour la photothérapie ou comme agent pour la thérapie par faisceau. [000103] The nanoparticles can also be used in addition as a radio-sensitizing agent for radiotherapy, as a photosensitizing agent for phototherapy or as an agent for beam therapy.
[000104] Avantageusement, les nanoparticules utilisées pour le traitement des tumeurs par radiofréquence sont également utilisées comme agent de contraste ou agent d’imagerie pour visualiser la tumeur in vivo, par imagerie médicale permettant par exemple un monitorage de la thérapie. [000104] Advantageously, the nanoparticles used for the treatment of tumors by radiofrequency are also used as a contrast agent or an imaging agent for visualizing the tumor in vivo, by medical imaging allowing for example monitoring of the therapy.
[000105] Au sens de l'invention, on entend par « agent de contraste » tout produit ou composition utilisé en imagerie médicale dans le but d'augmenter artificiellement le contraste permettant de visualiser une structure anatomique particulière (par exemple certains tissus ou organes) ou une structure anatomique pathologique (par exemple les tumeurs) par rapport aux structures voisines ou non-pathologiques. On entend par « agent d’imagerie » tout produit ou composition utilisé en imagerie médicale dans le but de créer un signal permettant de visualiser une structure anatomique particulière (par exemple certains tissus ou organes) ou une structure anatomique pathologique (par exemple les tumeurs) par rapport aux structures voisines ou non-pathologiques. La manière dont les agents de contrastes ou d’imagerie agissent dépend des techniques d’imagerie utilisées. [000105] For the purposes of the invention, the term “contrast agent” is understood to mean any product or composition used in medical imaging with the aim of artificially increasing the contrast allowing a particular anatomical structure to be visualized (for example certain tissues or organs) or a pathological anatomical structure (eg tumors) relative to neighboring or non-pathological structures. The term “imaging agent” means any product or composition used in medical imaging with the aim of creating a signal making it possible to visualize a particular anatomical structure (for example certain tissues or organs) or a pathological anatomical structure (for example tumors). compared to neighboring or non-pathological structures. How the contrast or imaging agents work depends on the imaging techniques used.
[000106] L’imagerie médicale est de préférence choisie parmi les techniques suivantes : résonance magnétique nucléaire, les scanners X, l’imagerie par fluorescence, par scintigraphie SPECT, par scintigraphie TEP, de manière encore préférée la tumeur est visualisée in vivo par résonnance magnétique nucléaire, notamment en imagerie par résonance magnétique (IRM) dynamique (i.e. DCE pour Dynamic Contrast Enhanced sequence). L'IRM permet notamment d'obtenir une précision spatio-temporelle particulièrement avantageuse pour la mise en œuvre de la présente invention. [000106] Medical imaging is preferably chosen from the following techniques: nuclear magnetic resonance, X-ray scanners, fluorescence imaging, by SPECT scintigraphy, by PET scintigraphy, more preferably the tumor is visualized in vivo by resonance nuclear magnetic, in particular in dynamic magnetic resonance imaging (MRI) (ie DCE for Dynamic Contrast Enhanced sequence). MRI makes it possible in particular to obtain a particularly advantageous spatio-temporal precision for the implementation of the present invention.
[000107] La présente invention a également pour objet une composition pharmaceutique comprenant une nanoparticule telle que définie ci-dessus et un véhicule pharmaceutiquement acceptable, une substance porteuse et/ou un adjuvant pour une utilisation dans le traitement d’une tumeur par un rayonnement de radiofréquence chez un patient tel que décrit précédemment. Des véhicules pharmaceutiquement acceptables, une substance porteuse et/ou un adjuvant sont ceux classiquement utilisés. [000107] A subject of the present invention is also a pharmaceutical composition comprising a nanoparticle as defined above and a pharmaceutically acceptable vehicle, a carrier substance and / or a adjuvant for use in the treatment of a tumor with radiofrequency radiation in a patient as previously described. Pharmaceutically acceptable vehicles, a carrier substance and / or an adjuvant are those conventionally used.
[000108] La présente divulgation ne se limite pas aux exemples suivants, mais elle englobe toutes les variantes que pourra envisager l’homme de l’art dans le cadre de la protection recherchée. [000108] The present disclosure is not limited to the following examples, but it encompasses all the variations that a person skilled in the art may envisage in the context of the protection sought.
Exemples Examples
1. Echantillons 1. Samples
[000109] Les nanoparticules AGulX (50 mM par bouteille) sont obtenues par le Dr. O. Tillement via le Dr. V. Lysenko. [000109] The AGulX nanoparticles (50 mM per bottle) are obtained by Dr. O. Tillement via Dr. V. Lysenko.
[000110] Les nanoparticules sont dissoutes dans une solution physiologique à une concentration de 20mM (par Gd). [000110] The nanoparticles are dissolved in a physiological solution at a concentration of 20 mM (per Gd).
2. Traitement par un rayonnement de radiofréquence 2. Treatment with radiofrequency radiation
[000111] Les radiations électromagnétiques de radiofréquence sont générées par un appareil médical UVCH-60 (MedTeeko Ltd., Russie) opérant à 27 MHz avec une puissance allant jusqu’à 60 W. [000111] Radio-frequency electromagnetic radiation is generated by a UVCH-60 medical device (MedTeeko Ltd., Russia) operating at 27 MHz with a power of up to 60 W.
[000112] Différentes cuvettes contenant de l’eau, une solution saline, une solution saline avec de l’albumine 50 g/L et une solution saline avec de l’albumine 50 g/L et 7.5 mM de nanoparticule d’AGulX (Gd) sont traitées par un rayonnement de radiofréquence pendant une durée de 20 à 30 min. Les températures des solutions sont mesurées sans contact à l’aide d’un thermomètre. [000112] Different cuvettes containing water, a saline solution, a saline solution with albumin 50 g / L and a saline solution with albumin 50 g / L and 7.5 mM of AGulX nanoparticle (Gd ) are treated with radiofrequency radiation for a period of 20 to 30 min. The temperatures of the solutions are measured without contact using a thermometer.
[000113] Ensuite différentes cuvettes contenant de l’eau, du Yttrium (Y) (10,3 mM), Gadolinium (Gd) (10,2 mM), Bismuth (Bi) (9,9 mM), Terbium (Tb) (10,5 mM), de l’AGulX sont traitées par un rayonnement de radiofréquence comme décrit précédemment. [000113] Then various cuvettes containing water, Yttrium (Y) (10.3 mM), Gadolinium (Gd) (10.2 mM), Bismuth (Bi) (9.9 mM), Terbium (Tb) (10.5 mM), AGulX are treated with radiofrequency radiation as described above.
[000114] Les expériences réalisées avec des cuvettes de 10 mL remplies de nanoparticules AGulX et des liquides de référence montrent que le traitement par un rayonnement de radiofréquence permet une élévation plus importante de la température dans les solutions d’AGulX que dans les solutions de référence. Les nanoparticules d’AGulX agissent comme un agent sensibilisant important au traitement par un rayonnement de radiofréquence (Figures 1 et 2). [000114] The experiments carried out with 10 mL cuvettes filled with AGulX nanoparticles and reference liquids show that the treatment with radiofrequency radiation allows a greater rise in temperature in the AGulX solutions than in the reference solutions . The AGulX nanoparticles act as an important sensitizing agent for treatment with radiofrequency radiation (Figures 1 and 2).
3. Etudes in vivo 3. In vivo studies
[000115] Des souris C57BI/6, BDF1 présentant un carcinome pulmonaire de Lewis sont utilisées. La greffe du carcinome pulmonaire de Lewis est réalisée en homogénéisant le tissu de la tumeur du carcinome pulmonaire de Lewis dans une solution stérile de milieu 199 (Merck). [000115] C57BI / 6, BDF1 mice exhibiting Lewis lung carcinoma are used. Lewis lung carcinoma transplant is performed by homogenizing Lewis lung carcinoma tumor tissue in a sterile solution of Medium 199 (Merck).
[000116] Les animaux donneurs sont sacrifiés, et des morceaux de tumeurs sont excisés sans site nécrotique et ensuite homogénéisés dans du milieu 199. La masse tumorale est diluée dans le milieu 199 et administrée intramusculairement dans la hanche droite de souris C57BI/6 à un volume de 0.3 mL. [000116] The donor animals are sacrificed, and pieces of tumor are excised without a necrotic site and then homogenized in medium 199. The tumor mass is diluted in medium 199 and administered intramuscularly into the right hip of C57BI / 6 mice at a volume of 0.3 mL.
[000117] Les souris sont divisées en quatre groupes, un groupe de souris contrôle injectées avec une solution saline (A), un groupe de souris injectées avec une solution saline et traitées par un rayonnement de radiofréquence pendant 10 min (B), un groupe de souris injectées avec AGulX et non traitées par un rayonnement de radiofréquence (C), et un groupe de souris injectées avec AGulX et traitées par un rayonnement de radiofréquence (D) (Tableau 1). [000117] The mice are divided into four groups, a group of control mice injected with saline solution (A), a group of mice injected with saline solution and treated with radiofrequency radiation for 10 min (B), a group of mice injected with AGulX and not treated with radiofrequency radiation (C), and a group of mice injected with AGulX and treated with radiofrequency radiation (D) (Table 1).
[000118] Les solutions salines et AGulX (0.2 mL) sont injectées intramusculairement six jours après l’inoculation de la tumeur, quand la tumeur atteint une taille de 70 ± 15 mm3. [000118] The saline solutions and AGulX (0.2 ml) are injected intramuscularly six days after inoculation of the tumor, when the tumor reaches a size of 70 ± 15 mm 3 .
[000119] Toutes les expériences sur les animaux sont réalisées en accord avec les principes de travail avec les animaux de laboratoire (Règles NIH N° 85-23, révisée en 1985) et la convention Européenne de la protection des animaux utilisés à des fins expérimentales ou à d’autres fins scientifiques (Strasbourg, 18.111.1986, protocole ETS 170). [000120] [Tableau 1] [000119] All animal experiments are carried out in accordance with the principles of working with laboratory animals (NIH Rules No. 85-23, revised in 1985) and the European convention for the protection of animals used for experimental purposes or for other scientific purposes (Strasbourg, 18.111.1986, ETS 170 protocol). [000120] [Table 1]
Tableau 1 : description des différents groupes des souris 4. Monitorage par IRM [000121] Le monitorage par IRM de la biodistribution des AGulX est réalisé en utilisant un scanner IRM 7 T Bruker BioSpec (Briker BioSpin GmbH, Allemagne) avec un système de gradient de 105 mT/m utilisant le logiciel ParaVision 5.0. [000122] La Figure 3 montre les images en IRM d’une souris avant et après l’injection intratumorale de la solution d’AGulX. Les nanoparticules d’AGulX sont observées dans la région tumorale au moins une heure après l’injection. Table 1: description of the different groups of mice 4. MRI monitoring [000121] MRI monitoring of the biodistribution of AGulX is carried out using a Bruker BioSpec 7 T MRI scanner (Briker BioSpin GmbH, Germany) with a gradient system of 105 mT / m using ParaVision 5.0 software. [000122] Figure 3 shows the MRI images of a mouse before and after the intratumoral injection of the AGulX solution. AGulX nanoparticles are seen in the tumor region at least one hour after injection.
[000123] Les souris du groupe B et D sont traitées par un rayonnement de radiofréquence avec une puissance d’environ 10 W pendant 10 min. Le monitorage thermique des souris durant le traitement par un rayonnement de radiofréquence est réalisé avec une caméra thermique Seek Thermal. Une température maximale d’environ 43-45°C dans la tumeur est mesurée 5 à 10 minutes après le début du traitement par radiofréquence (Figure 4). La survie des souris injectées est ensuite suivie 65 jours après la greffe du carcinome pulmonaire de Lewis. La survie des souris est améliorée chez les souris injectées avec de l’AGulX et traitées par un rayonnement de radiofréquence (Figure 6). Conclusions [000123] Group B and D mice are treated with radiofrequency radiation with a power of about 10 W for 10 min. Thermal monitoring of mice during treatment with radiofrequency radiation is performed with a Seek Thermal thermal imager. A maximum temperature of around 43-45 ° C in the tumor is measured 5 to 10 minutes after the start of the radiofrequency treatment (Figure 4). The survival of the injected mice is then monitored 65 days after the Lewis lung carcinoma transplant. Mouse survival is improved in mice injected with AGulX and treated with radiofrequency radiation (Figure 6). Conclusions
[000124] Les nanoparticules AGulX agissent comme des agents sensibilisants à l’hyperthermie suite au traitement par un rayonnement de radiofréquence. Comme le montre les données en IRM, les nanoparticules AGulX injectées par voie intra tumorale sont situées dans la région de la tumeur pendant au moins 1h après l’injection. [000124] The AGulX nanoparticles act as hyperthermia sensitizers following treatment with radiofrequency radiation. As As shown by the MRI data, the AGulX nanoparticles injected intratumorally are located in the region of the tumor for at least 1 hour after the injection.
[000125] L’injection de nanoparticules AGulX suivi du traitement par radiofréquence permet de supprimer la croissance du carcinome pulmonaire de Lewis par hyperthermie (Figure 5) et d’améliorer la survie des souris (Figure 6). La croissance du carcinome pulmonaire de Lewis est surveillée à l’aide de caméra thermique. [000125] The injection of AGulX nanoparticles followed by radiofrequency treatment suppresses the growth of Lewis lung carcinoma by hyperthermia (Figure 5) and improves the survival of the mice (Figure 6). The growth of Lewis lung carcinoma is monitored using a thermal imager.
[000126] Pour améliorer l’effet des agents sensibilisants à l’hyperthermie par un rayonnement de radiofréquence, différentes voies d’optimisation peuvent être proposées : (i) prolonger le temps de traitement par radiofréquence (plus d’une heure) après une seule injection, (ii) des traitements répétés (injection d’AGulX suivi du traitement par radiofréquence, (iii) administration des nanoparticules AGulX par voie intraveineuse en surveillant l’accumulation maximale dans les tumeurs suivi du traitement par un rayonnement de radiofréquence. [000126] To improve the effect of hyperthermia sensitizers by radiofrequency radiation, various optimization routes can be proposed: (i) extend the radiofrequency treatment time (more than one hour) after a single injection, (ii) repeated treatments (injection of AGulX followed by radiofrequency treatment, (iii) administration of AGulX nanoparticles by intravenous route monitoring maximum accumulation in tumors followed by treatment with radiofrequency radiation.

Claims

Revendications Claims
[Revendication 1] Nanoparticule pour une utilisation dans le traitement d’une tumeur par un rayonnement de radiofréquence chez un patient induisant une hyperthermie de ladite tumeur, caractérisée en ce que ladite nanoparticule comprend une matrice non-conductrice et non-magnétique et des cations métalliques ayant un numéro atomique Z supérieur à 40, ladite nanoparticule étant administrée avant ledit traitement par un rayonnement de radiofréquence. [Claim 1] Nanoparticle for use in the treatment of a tumor by radiofrequency radiation in a patient inducing hyperthermia of said tumor, characterized in that said nanoparticle comprises a non-conductive and non-magnetic matrix and metal cations having an atomic number Z greater than 40, said nanoparticle being administered prior to said treatment with radiofrequency radiation.
[Revendication 2] Nanoparticule pour une utilisation selon la revendication 1 caractérisée en ce que la nanoparticule comprend une matrice en polysiloxane. [Claim 2] Nanoparticle for use according to claim 1 characterized in that the nanoparticle comprises a polysiloxane matrix.
[Revendication 3] Nanoparticule pour une utilisation selon la revendication 1 ou 2 caractérisée en ce que ladite nanoparticule comprend au moins un agent chélatant, de préférence le DOTA, DTPA, DOTAGA ou ses dérivés, destiné à complexer les cations métalliques. [Claim 3] Nanoparticle for use according to claim 1 or 2 characterized in that said nanoparticle comprises at least one chelating agent, preferably DOTA, DTPA, DOTAGA or its derivatives, intended to complex metal cations.
[Revendication 4] Nanoparticule pour une utilisation selon les revendications 1 à 3 caractérisée en ce que les cations métalliques représentent plus de 10 % de la masse de ladite nanoparticule et de préférence moins de 50 % de la masse de la dite nanoparticule. [Claim 4] Nanoparticle for use according to claims 1 to 3 characterized in that the metal cations represent more than 10% of the mass of said nanoparticle and preferably less than 50% of the mass of said nanoparticle.
[Revendication 5] Nanoparticule pour une utilisation selon les revendications 1 à 4 caractérisée en ce que les cations métalliques sont disposés à la surface de ladite matrice. [Claim 5] Nanoparticle for use according to claims 1 to 4 characterized in that the metal cations are disposed on the surface of said matrix.
[Revendication 6] Nanoparticule pour une utilisation selon les revendications 1 à 5 caractérisée en ce que les cations métalliques sont le gadolinium ou le bismuth. [Claim 6] Nanoparticle for use according to claims 1 to 5 characterized in that the metal cations are gadolinium or bismuth.
[Revendication 7] Nanoparticule pour une utilisation selon les revendications 1 à 6 caractérisée en ce que ladite nanoparticule a une taille inférieure à 10 nm, de préférence inférieure à 5 nm. [Claim 7] Nanoparticle for use according to claims 1 to 6 characterized in that said nanoparticle has a size less than 10nm, preferably less than 5nm.
[Revendication 8] Nanoparticule pour une utilisation selon les revendications 1 à 7 caractérisée en ce que la tumeur est sélectionnée parmi le groupe consistant en une tumeur rénale, une tumeur des poumons, une tumeur hépatique, une tumeur du sein, tumeur des os. [Claim 8] Nanoparticle for use according to claims 1 to 7 characterized in that the tumor is selected from the group consisting of renal tumor, lung tumor, liver tumor, breast tumor, bone tumor.
[Revendication 9] Nanoparticule pour une utilisation selon les revendications 1 à 8 caractérisée en ce que ladite nanoparticule est sous une forme adaptée pour une administration par voie intraveineuse, intra-tumorale ou par inhalation. [Claim 9] Nanoparticle for use according to claims 1 to 8 characterized in that said nanoparticle is in a form suitable for intravenous, intratumoral or inhalation administration.
[Revendication 10] Nanoparticule pour une utilisation selon les revendications 1 à 9, caractérisée en ce qu’elle présente la formule générale I ci-dessous : n dans laquelle PS est une matrice en polysiloxane, et n est compris entre 5 et 50, de préférence entre 5 et 20, et dans laquelle le diamètre hydrodynamique est compris entre 1 et 10 nm, par exemple entre 2 et 8 nm, notamment 5 nm. [Claim 10] Nanoparticle for use according to claims 1 to 9, characterized in that it has the general formula I below: n in which PS is a polysiloxane matrix, and n is between 5 and 50, preferably between 5 and 20, and in which the hydrodynamic diameter is between 1 and 10 nm, for example between 2 and 8 nm, in particular 5 nm.
[Revendication 11] Agent sensibilisant hyperthermique par radiofréquence comprenant une nanoparticule comprenant une matrice non-conductrice et non magnétique et des cations métalliques avec un numéro atomique Z supérieur à 40. [Claim 11] A radiofrequency hyperthermic sensitizer comprising a nanoparticle comprising a non-conductive and non-magnetic matrix and metal cations with an atomic number Z greater than 40.
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