Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
  • A61K51/1241—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins
  • A61K51/1255—Granulates, agglomerates, microspheres
• • 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
  • A61K41/009—Neutron capture therapy, e.g. using uranium or non-boron material
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the present invention relates to the assembly of elements, so as to produce radioactive devices.
• One of the potential applications lies in the injection into the human body, for diagnostic or curative purposes, of this type of device as such, or as part of a system used in curative medicine or for diagnostic.
• Radionuclides are commonly used in various fields of technology, in biology but also in other fields, either as markers or tracers for the purpose of characterization or diagnosis of media, or as therapeutic agents in nuclear medicine, and more specifically in radiotherapy.
• markers or tracers When used as tracers, including in non-biological applications, the question of the reliability of the measured results may arise in some cases, and hence the interpretation that is made of these results as to the characterization of the medium studied.
• radionuclides like other types of tracers such as fluorescent markers for example, are likely to interact with the surrounding environment. in which they are placed. These interactions, especially when the surrounding environment is not well known or controlled, can disrupt or even distort the interpretation of the measurements.
• radionuclides are also used in nuclear medicine as therapeutic agents, and more specifically in targeted radiotherapy.
• Targeted radiotherapy uses the biological differences between the cancer cells constituting a tumor and the healthy cells, so as to selectively deliver the radionuclides so that the tumor receives a greater amount of radiation than the healthy cells. Therefore, we try to bring the radionuclides near the cancer cells, in order to deliver the maximum dose.
• radionuclides In brachytherapy, this is achieved by physically implanting physical elements (seeds) loaded with radionuclides.
• These elements are usually in the form of rods, a few millimeters long and less than a millimeter in diameter. They are implanted in the human body by a surgical act.
• the radio-nuclides are linked to molecular vectors, that is to say to chemical or biological, natural or synthetic molecules such as antibodies, and in particular monoclonal antibodies, or fragments of these antibodies, or peptides, lipids and saccharides with a recognized affinity for markers (receptors at the cell surface) specific to certain types of cancer cells.
• Radionuclides are ordered to a company, and the precursors (vectors) to other companies.
• radioactive atoms per molecular vector is very small. Usually one can bind a single radioactive atom per vector. However, radio-chemists have very recently developed configurations of dendrimer-type molecules, in order to increase the number of atoms grafted by vector. 3. In the case of treatment of large tumors, the problem arises to treat both the periphery and the center of the tumor as effectively. 4. It is not possible to visualize by a traditional method, such as magnetic resonance, the biodistribution of "graft drugs" in the body or in certain organs.
• the present invention aims to propose a solution that makes it possible to overcome the problems of the state of the art mentioned above.
• the present invention aims to propose a solution that increases the radioactivity of the devices concerned, whether for particular uses in the therapeutic or non-therapeutic field.
• the present invention aims to provide a solution in the context of targeted radiotherapy.
• the present invention aims to provide a solution that is compatible with this application, that is to say that is not radiotoxic for the human body and / or animal.
• the present invention aims to provide a solution for effectively removing cancer cells from a patient.
• the present invention aims to propose a solution for eradicating the largest number of cancer cells to avoid any risk of subsequent recurrence or dissemination, while preserving as much as possible the healthy cells surrounding said cancer cells.
• the present invention aims to provide a solution that allows a specific elimination of cancer cells.
• the present invention also aims at providing a sufficiently flexible solution that effectively eliminates cancer cells regardless of their stage of development and regardless of their accessibility in the body of the patient, that is to say say whatever their location in the patient's body, periphery or depth.
• the present invention also aims at providing a modular solution as a function of time.
• the present invention also aims at providing a solution for visualizing and therefore to locate the therapeutic agents in the body of the treated patient.
• the present invention also aims to provide a solution to avoid the problem of opsonization that could occur in the case where a molecule, not produced by the human body, is used as a therapeutic agent.
• the present invention aims to propose monitoring the biodistribution of grafted biomarkers, and this with the aid of appropriate monitoring devices.
• Radioactivity is defined in the present invention as the property of an unstable or radioactive atomic nucleus to spontaneously transform into a or several nuclei of other elements emitting during this transformation a radioactive radiation.
• the term "radionuclide” is used in the present invention to designate an atom having an unstable atomic nucleus. It is therefore to be understood that in the present invention the terms “radio-nuclide” and “radioactive atom” are equivalent.
• a radio-nuclide is defined as a radioactive atom characterized by its number of protons (Z) and neutrons (A-Z) or by its mass number (A).
• a radioisotope is defined as a radioactive isotope of a particular element of the Mendeleev Table (same number of protons (Z) but mass number (A), and therefore number of neutrons, different).
• Z protons
• A mass number
• neutrons different.
• 125 I and 131 I are radioisotopes of iodine.
• the nanostructure is radioactive or radioactivatable. More precisely, at least the core of the nanostructure is radioactive or radioactivable, that is to say that it is capable of producing radioactive radiation, at least under certain conditions.
• radioactive radiation includes alpha type radiation, beta type radiation, and gamma type radiation, and mixtures thereof.
• alpha type radiation or "alpha radiation”, a particle of radiation corresponding to a helium nucleus, 2 protons and 2 neutrons.
• radioactive radiation also includes heavy particle radiation (neutron radiation and proton radiation).
• beam type radiation or “beta radiation” means a particle radiation corresponding to an electron ( ⁇ - radiation) or a positron
• gamma-type radiation or "gamma radiation”, an undulatory radiation corresponding to a photon.
• gamma-type radiation or "gamma radiation”
• RX radiation which correspond to photons emitted by the electrons of atoms.
• gamma rays like X-rays, are electromagnetic radiation.
• radioactive radiation is extended also to Auger electrons.
• a radio-nuclide is characterized by its "half-life” also called “half-life time”, that is to say the time after which half of a quantity of this radio-nuclide is disintegrated.
• L 1 "activity" of a radioactive substance at a given time is defined as the number of disintegrations per second at this time, ie the intensity of its radioactivity. It is expressed in Becquerels.
• the term “nanostructure” an assembly of at least several atoms, having a diameter less than 1 micron, and preferably between about 0.5 nm and 1 micron.
• nuclear structure and “nanocluster” are equivalent.
• type or “species” is meant radioactive nuclides of the same chemical nature (same number of protons Z) and the same molecular weight (A) and derivatives derived from the disintegration. (ex: 103 Pd * ⁇ 103 Rh + Gamma + RX, 103 Pd * and 103 Rh represent the same type of radionuclide).
• LET Linear Energy Transfer
• the present invention relates to a radioactive or radioactivatable nanostructure comprising a core, said core comprising at least two atoms, at least one of which is radioactive or radioactivable, and an envelope encasing said core and chosen from a material selected in such a way that at most 20% of the radioactive radiation produced by the core is stopped or absorbed by the envelope.
• the core comprises at least two radioactive or radioactivatable atoms.
• the core may comprise from 2 to 20,000 atoms.
• the thickness and the chemical nature of the material of the envelope are chosen so that at most 20% of the radioactive radiation produced by the core is stopped or absorbed by the envelope.
• the envelope of the nanostructure is designed in such a way that it allows at least 80% of the radioactive radiation produced by the heart to pass through the medium. surrounding the nanostructure and are therefore likely to be used in controlled radiotherapy or detection.
• the envelope of the nanostructure according to the invention is to a certain extent "transparent" to radioactive radiation.
• the envelope of the nanostructure according to the invention may be selected to be "transparent" to wave radiation whose energy is in a range from 10 -2 eV to 10 7 eV. can come from the disintegration of an atom of the heart (in versus out) or from the external environment to the nanostructure [0052]
• the design of the envelope (its composition and its thickness) is such that it prevents, if possible, the chemical exchanges between the inside of the nanostructure (internal cavity) and the external environment (chemical sealing).
• the envelope as a selective barrier which is used to control the exchanges between the interior of the nanostructure and its environment.
• the size of the envelope of the nanostructure is limited.
• the envelope of the nanostructure according to the invention advantageously has a thickness of less than 50 nm, and preferably less than 20 nm.
• This thickness may be obtained depending on the case either by structuring the envelope as a single layer, or in the form of several layers, and particularly advantageously in the form of at least three layers.
• the envelope of the nanostructure consists of a bio-compatible material that is to say, tolerated by the animal or human organism
• the envelope essentially comprises a material selected from the group consisting of amorphous carbon or graphite, metals and their derivatives and polymers, and mixtures thereof.
• the envelope consists of a material selected from the group consisting of amorphous carbon or graphite, metals and their derivatives and polymers, and mixtures thereof.
• the envelope may thus comprise aluminum oxides and / or titanium.
• the envelope of the nanostructure surrounds and delimits an internal cavity.
• the envelope "coats” or “encapsulates” the radioactive core of the nanostructure.
• the internal cavity corresponds to said core.
• the envelope "coats” or “encapsulates” the heart.
• the core of the nanostructure has a radius less than 1 micron.
• the core of the nanostructure has a radius of between about 0.5 nm and about
• 950 nm and preferably between about 0.5 nm and 500 nm, and preferably between about 0.5 nm and 100 nm, and preferably between about 0.5 nm and 20 nm, and preferably between about 2 nm and 20 nm.
• the core of the nanostructure has a diameter of less than 1 micron.
• the core of the nanostructure has a diameter of between about 0.5 nm and about 950 nm, and preferably between about 0.5 nm and 500 nm, and preferably between about 0.5 nm and 100 nm, and preferably between about 0.5 nm and 20 nm, and preferably between about 2 nm and 20 nm.
• the nanostructure has a radius less than 1 micron.
• the nanostructure has a radius of between about 0.5 nm and about 950 nm, and preferably between about 0.5 nm and 500 nm, and preferably between about 0.5 nm and 100 nm, and preferably between about 0.5 nm. and 20 nm, and preferably between about 2 nm and 20 nm.
• the nanostructure has a diameter of less than 1 micron.
• the nanostructure has a diameter of between about 0.5 nm and about 950 nm, and preferably between about 0.5 nm and 500 nm, and preferably between about 0.5 nm and 100 nm, and preferably between about 0.5 nm. and 20 nm, and preferably between about 2 nm and 20 nm.
• the thickness of the radioactive heart is significantly larger.
• the radioactive thickness represents in volume at least 60%, and preferably at least 70%, and preferably at least 80%, and preferably at least 90%, of the nanostructure. Note that in size, compared to the envelope, the radioactive heart occupies most of the volume of the nanostructure.
• the radioactive core represents in volume at least 60%, and preferably at least 70%, and preferably at least 80%, and preferably at least 90%, of the nanostructure.
• the atoms of the core are of the same type, that is to say that they have the same atomic number Z, defined as the number of protons (or electrons), and the same mass number A, defined as the total number of nucleons, that is, the number of protons and neutrons.
• the atoms of the core are of different types, that is to say that their atomic number Z and / or their mass number A are different.
• the radioactive radiation produced by the core is selected from the group consisting of alpha radiation, beta radiation, gamma radiation, X-rays, Auger electrons.
• the radioactive radiation produced by the core is selected from the group consisting of alpha radiation, beta radiation and gamma radiation.
• the atoms of the heart can also produce the same type of radiation, but with different energies.
• the different types of atoms of the heart are chosen so that they have different half-life times.
• the radioactive or radioactivatable atoms are selected from the group consisting of the following radionuclides: 18 F, 90 Y, 192 Ir, 194 Ir, 142 Pr, 188 Re, 32 P, 166 Ho, 89 Sr, 123 Sn, 149 Pm, 165 Dy, 73 Ga, 109 Pd, 110 Ag, 111 Ag, 112 Ag, 113 Ag, 186 Re, 170 Tm, 198 Au, 143 Pr, 173 Tm, 159 Gd, 153 Gd, 153 Sm, 197 Pt, 77 As, 161 Tb, 131 I, 114m In , 141 Ce, 195m Pt, 47 Sc, 67 Cu, 64 Cu, 117111 Sn, 105 Rh , 177 Lu, 113 Sn, 113tn In,: '5 Yb, 167 Tm, 121 Sn, 199 In, 169 Yb, 103 Ru, 169 Er, 33 P
• the radioactive atoms are selected from the group consisting of 14 C, 32 P, 33 P, 35 S, 36 Cl, 51 Cr, 55 Co, 60 Co, 63 Ni, 64 Cu, 67 Cu,
• the radioactive atoms are selected from the group of radioelements consisting of Pd, Ga, In, Cu, Y, P, Au, I, Lu, Re, At, Bi, W, Tc.
• the core or envelope of the nanostructure may further comprise at least one imaging element corresponding to a contrast agent.
• the contrast agent is chosen bet elements having a very high electronic magnetic moment selected for example from transition metals (Z between 21 and 30, 39 and 48, 72 and 80, 104 and 109 ), the lanthanides (Z between 57 and 71) and the actinides (Z between 89 and 103) as well as some elements belonging to the non-metals among the atomic numbers: 13, 31, 32, 49, 50, 51, 81, 82, 83, 84. Examples: Cr, Mn, Mg, Fe, Gd, Dy.
• the contrast agent may be chosen from gallium-based alloys, transition metals, actinides, iron oxides and their derivatives.
• This contrast agent can be grafted chemically on the envelope (the shell molecules) or physically, for example by adsorption. It will be appreciated that the nanostructure may further comprise a targeting agent, preferably located at the level of the envelope.
• targeting agent refers, in the field of biology, to an agent capable of directing the nanostructure towards specific targets within the patient, be it target cells, or within the cell to intracellular-target compartments.
• the targeting agent may be an antibody, and in particular a monoclonal antibody, or a peptide, or any other type of protein known to those skilled in the art. It can also be a lipid or a nucleic acid.
• the antibody may in particular be an antibody targeting at least one target molecule involved in angiogenesis, preferably a VEGF receptor, the integrin ⁇ v ⁇ 3, the endoglin (CD105) or annexin Al.
• the envelope of the nanostructure is at least partly functionalized by one or more functionalization (chemical) groups, such as OH, NH 2 , COOH, SH, ... well known to the human art, for the purpose of binding said envelope to one or more molecules.
• the nanostructure is advantageously in solid form, even if the internal cavity may contain one or more gases such as Xenon for example.
• the envelope may be in amorphous form or in crystalline form or a mixture of both.
• the different atoms of the core of the nanostructure can interact with each other via non-covalent bonds, such as bonds. ionic, metallic, electrostatic,
• the different atoms of the core of the nanostructure can interact with the envelope (the molecules of the envelope) via non-covalent bonds, such as ionic type bonds. , metallic, electrostatic, Van der Vaals, or hydrogen. This last type of interaction may also be of the covalent bond type.
• Another object of the present invention relates to the nanostructure as described for use as a therapeutic agent.
• the present invention also relates to the nanostructure for use as an antitumor agent, and in particular for use as an anticancer agent.
• the present invention also covers the use of the nanostructure as a diagnostic agent.
• Another object of the present invention relates to the nanostructure for the treatment or prevention against tumors, such as cancerous tumors, including metastasized cancers.
• the present invention is adapted to targeted radiotherapy but excludes brachytherapy as such as defined above.
• the invention also relates to a pharmaceutical composition comprising the nanostructure according to the invention and a pharmaceutically suitable excipient or vehicle.
• the invention also covers the use of the nanostructure and / or of this pharmaceutical composition for the manufacture of a medicament for the treatment of and / or the prevention against tumor diseases, such as cancers.
• the invention also relates to a method of therapeutic treatment of a disease in a patient comprising administering the nanostructure or the pharmaceutical composition according to the invention. [0109]
• said method comprises the following steps:
• the establishment of a preliminary diagnosis including the establishment of the characteristics of said disease, including the stage of evolution in the patient;
• the estimation of the irradiation profile to be obtained in situ in the patient type of radioactive radiation, biodistribution of the dose, intensity, duration, ...) as a function of these characteristics;
• the selection of the nanostructure or the pharmaceutical composition according to this profile including the selection the appropriate envelope type as well as the number and type of radioactive atoms to be used in the core, the number and type of targeting agents to be used, as well as the number and type of suitable contrast agents;
• the invention also relates to a method for manufacturing a nanostructure, comprising the following steps: obtaining the core by synthesis according to a method selected from the physical processes by material flow generated under vacuum and condensing on a substrate and chemical processes, or by co-milling its constituents; coating said core with an envelope by means of ion beams, or with a plasma or by pyrolysis of gas, such as the pyrolysis of carbonaceous gases; collecting the nanostructure thus obtained by dissolving the substrate in a solvent or by mechanical harvesting, such as scraped or by a derivative method.
• this process comprises between the step of coating the core and the collection of the nanostructure obtained, an additional step called “functionalization step”, during which the envelope is functionalized by one or more chemical groups by atomic beams of nitrogen, and / or carbon and / or oxygen, or by plasma in a reactive atmosphere, according to the selected chemical group or groups.
• functionalization step during which the envelope is functionalized by one or more chemical groups by atomic beams of nitrogen, and / or carbon and / or oxygen, or by plasma in a reactive atmosphere, according to the selected chemical group or groups.
• Figures 1 and 2 describe the deposition of a core of a few atoms of 103 Pd on a carbon substrate, at low pressure ( Figure 1) and at high pressure ( Figure 2).
• Figure 3 expresses the number of 103 Pd atoms that can be placed in the core of its size (expressed in nm).
• FIG. 4 shows, depending on the size of the core (uncoated envelope), the present activity.
• the nanostructure according to the invention, and more particularly its envelope, are designed to have the following advantageous characteristics:
• nanostructures obtained they can be introduced into the human body in various ways:
• radionuclides emitting radiation of different types are then collected and encapsulated.
• radiation eg beta
• Auger a setting to promote radiation
• this configuration makes it possible to combine a type of radiation used for diagnostic purposes (e.g. 99ra Te) and a radiation used for curative purposes (e.g. 225 As). In doing so, it is possible to follow the regression of the tumors in real time.
• Radionuclides emitting radiation of the same type (X, Beta or Auger) but of different energies are then collected and encapsulated.
• Radionuclides emitting radiation of the same type (X, Beta or Auger) but of different energies are then collected and encapsulated.
• concentration within the nanoclusters there is a setting that makes it possible, for example, to promote a weak radiation. energy compared to a highly energetic radiation.
• this configuration makes it possible to efficiently and uniformly treat millimeter-scale dispersed tumors.
• 90 Y beta radiation with an average energy of 934 keV
• 199 Au beta radiation with an average energy of 115 keV
• a radio-nuclide with a short half-life gives a "boost" to the treatment and can be mixed with a radionuclide with a longer half-life used as a background treatment. This modulation must obviously be studied according to the radio-toxicity of the cells.
• the 103 Pd (half-life time of 17 days) associated with the 181 W (half-life time of 121 days) can be cited.
• contrast agents may be magnetic materials, such as iron oxides, Gd and Ga, which allow the use in magnetic resonance imaging (MRI) to allow the localization of nanostructures.
• radioactive materials of the heart The following table shows a nonlimiting list of some radioactive materials for curative purposes.
• PET Single Photon Emission Computed Tomography
• SPECT Single Photon Emission Computed Tomography
• the table below compares by way of example the number of radioactive atoms of the same species that can be placed in a core for a nanostructure of 1 nm in diameter, depending on the species.
• Figure 3 shows the evolution of the number of radioactive atoms that can be placed in a heart depending on the size of the heart, in the particular case where these radioactive atoms are 103 Pd atoms.
• FIG. 4 shows, for a core comprising atoms of 103, Pd and not surrounded by an envelope, how the ratio between the activity outside the heart and the activity at the inside the heart varies according to the radius (in ⁇ m) of the heart.
• the preferred material for the coating (the envelope) of the nanotructure will be carbon.
• other biocompatible materials can also be envisaged: Ta, Ti, Al 2 O 3 , ...
• polymers organic and / or inorganic could also be suitable.
• Other materials described in the literature, for example of the PEG type (polyethylene glycol, PEO (polyethylene oxide), poloxomers, polyoxamines, or saccharide derivatives (dextran) can also be envisaged.
• results have shown that depending on the chemical nature of the material, the size of the envelope can be selected so that, within a certain range of values, the fraction of radioactive radiation produced by the the heart capable of crossing the nanostructure is optimal, that is to say that at least 80% of this radiation passes through the nanostructure and can thus be used, for example for therapeutic purposes.
• the coating material that is to say the envelope
• the coating material may be functionalized with groups well known to those skilled in the art such OH, COOH, NH 2 .
• This functionalization will make it possible to graft it to chemical or biological molecules, but also to render the surface hydrophilic, in particular to reduce the phenomenon of opsonization, if necessary.
• the functionalization may also be considered to bind the targeting agent as defined above to the nanostructure, and more specifically to the envelope.
• FIGS. 1 and 2 relate to the production of a Pd core (potentially 103 radioactive Pd) of average diameter of 5 nm. 2) Embedding the core with the envelope by methods using beams of ions, plasma or pyrolysis of carbonaceous gases.
• the measurement of the number of radioactive atoms incorporated can be done on the basis of the size of the nanoclusters and their image by electron microscopy, or atomic force, but also (easier) thanks to the use of the radiation emitted by radioactive materials that are directly proportional to the number of atoms incorporated.
• radioactive element As indicated above, the incorporation of a single radioactive element can be envisaged. However, the combination of several radioactive elements will be preferred in the context of this invention.
• a long-range radio-nuclide RX or ⁇ emission
• a short-range nuclide ⁇ or
• radionuclides emitting the same type of radiation will be combined: 90 Y ( ⁇ ) / 199 Au ( ⁇ ), 103 Pd (RX) / 181 W (RX).
• Another configuration would be to combine diagnostic radio-nuclides ( 99m Tc or 18 F) with curative radionuclides ( 211 At (ot) + 90 Y (Z?)).
• Another configuration would be to combine radionuclides with contrast agents (iron oxide, Gd, etc.).
• contrast agents iron oxide, Gd, etc.
• the present invention presents, among other things, the following advantages with respect to conventional targeted radiotherapy as it has been proposed up to now, in particular when the envelope comprises / consists of carbon:
• Nanostructures of a few nanometers can contain up to 1000 atoms. Therefore, by grafting a nanostruture on a targeting agent, the specific activity is much greater than that of current products.
• a radionuclide can be combined to treat the outside of the tumor and another radio-nuclide of greater "reach" to treat its center. The same is true for weakly vascularized tumors (occlusions). 4. These nanostructures may contain both radio-nuclides for functional imaging and therapeutic radionuclides.
• the nanostructure comprises diagnostic radionuclides (18F, 99m Tc, 7)
• PET camera or SPECT the help for example PET camera or SPECT.
• Another advantage associated with the previous one is that, in a curative way, by using nanostructures comprising both diagnostic radionuclides and therapeutic radionuclides, it is possible to make effective internal dosimetry. -line ". More precisely, thanks to the simultaneous (simultaneous) use of these two kinds of radionuclides within the same nanostructure, it is possible to know at any moment how many nanostructures are fixed on the cancerous cells and to calculate thereby, knowing the number of radioactive atoms in a nanostructure, the dose that these nanostructures will deliver locally to the cancer cells.
• the doses delivered to the diseased cells by adapting the type of radiation and its energy to the size and distribution of cancer cells, as well as their location in the body, or to combine a radionuclide with high dose rate (boost) with a low dose rate (background treatment)). In doing so, it will be easier to offer these treatments first or second line.
• boost high dose rate
• background treatment background treatment

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