EP2823016A1 - Particules d'oxyde à base de terres rares et utilisation notamment en imagerie - Google Patents

Particules d'oxyde à base de terres rares et utilisation notamment en imagerie

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Publication number
EP2823016A1
EP2823016A1 EP13715291.4A EP13715291A EP2823016A1 EP 2823016 A1 EP2823016 A1 EP 2823016A1 EP 13715291 A EP13715291 A EP 13715291A EP 2823016 A1 EP2823016 A1 EP 2823016A1
Authority
EP
European Patent Office
Prior art keywords
particles
formula
imaging
particle
use according
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.)
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Application number
EP13715291.4A
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German (de)
English (en)
French (fr)
Inventor
Markus SCHOEFFEL
Antigoni Alexandrou
Cédric BOUZIGUES
Thierry Gacoin
Jean-Pierre Boilot
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Ecole Polytechnique
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Ecole Polytechnique
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Publication of EP2823016A1 publication Critical patent/EP2823016A1/fr
Withdrawn legal-status Critical Current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
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
    • A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
    • C09K11/08—Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials
    • C09K11/77—Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials containing rare earth metals
    • C09K11/7783—Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials containing rare earth metals containing two or more rare earth metals one of which being europium
    • C09K11/7794—Vanadates; Chromates; Molybdates; Tungstates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y15/00—Nanotechnology for interacting, sensing or actuating, e.g. quantum dots as markers in protein assays or molecular motors
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the present application relates to multimodal composite products for imaging, in particular for diagnostic imaging, and optionally for therapy, in particular composite products capable of being used as contrast agents, in particular in magnetic resonance imaging (MRI ), and / or in imaging techniques, such as optical imaging, optical oxidant detection, positron emission tomography (PET), computed tomography (CT) and / or ultrasound imaging and optionally simultaneously usable in therapy.
  • MRI magnetic resonance imaging
  • PET positron emission tomography
  • CT computed tomography
  • ultrasound imaging optionally simultaneously usable in therapy.
  • These products are based on a particle comprising or consisting of a part provided with a contrast agent activity and / or a paramagnetic activity, and a part provided with a luminescent activity and optionally with a detection activity. oxidant.
  • Magnetic Resonance Imaging is essentially used to image different types of soft tissue.
  • the contrast is determined by proton relaxation times ⁇ (longitudinal relaxation) and T 2 (transverse relaxation) (Abragam, 1983 and Levitt, 2008).
  • CAs contrast agent
  • ACs can be divided into two classes: positive AC 7i or AC that act primarily on longitudinal relaxation time, and negative AC T 2 or AC that shorten the transverse relaxation time (Bottrill). et al., 2006).
  • the performances of a contrast agent are characterized by the normalized concentration relaxivity ( ⁇ ) (Lauffer, 1987):,, -,
  • index p denotes the pure paramagnetic contribution of the CA.
  • the value of the relaxivity ratio ( ⁇ ): allows to determine which of the effect or T 2 is dominant.
  • a low ⁇ ratio of about 1 indicates a positive AC, while a ratio ⁇ significantly greater than 1 means that the compound acts as a negative AC.
  • the improvement in paramagnetic relaxation of water protons is the result of temporal fluctuations in the coupling between the magnetic moment of the electrons of the metal ion and the nuclear magnetic moment of the proton (Kowalewski et al., 1985, Banci et al. 1991, Bertini and Luchinat, 1996). At least two contributions can be differentiated: an inner sphere mechanism and an outer sphere mechanism. Inner sphere relaxation refers to solvent molecules directly coordinated to the metal center, while outer sphere relaxation refers to water molecules in a second coordination sphere or even more distantly around the complex.
  • the inverse relaxation time observed is a function of the inverse relaxation times for the two processes (Caravan et al., 1999):
  • nanoparticles based on iron oxide are used as AC T 2 . They have the disadvantage of showing an effect of extinction of the signal which makes the interpretation of the images difficult, since the resulting dark regions can not always be unambiguously attributed to the presence of the AC.
  • the high susceptibility of the iron oxide material introduces magnetic field distortions in neighboring tissues, known as the susceptibility artifact or "glare artifact,” which generate obscured images and affect the bottom around the actual location of the agent (Bulte and Kraitchman, 2004).
  • Nanoparticles are interesting candidates for CAs because of the increase in available surface area of interaction between Gd 3+ ions and water protons (Na et al., 2009).
  • Nanoparticulate ACs can be made from an inorganic core structure bearing binding structures for paramagnetic ions (Na et al., 2009). The application of these particles results in a high local concentration of paramagnetic ions and therefore in a strong contrast.
  • the maximum number of Gd 3+ ions is limited by the binding sites on the surface.
  • Another disadvantage lies in their synthesis complex involving several steps, at least the production of the core structure, the addition of the binding sites to the surface and the chelation of Gd 3+ ions in these binding sites.
  • Bridot et al. (2007) designed the preparation of Gd 2 0 3 nanoparticles of different core diameters integrated into a polysiloxane (GadoSiPEG) envelope that can also carry organic fluorophores for bi-modal magnetic resonance and fluorescence imaging.
  • imaging such as optical imaging, optical detection of oxidants, positron emission tomography (PET), computed tomography (CT) and / or ultrasound imaging, and optionally simultaneously used in therapy.
  • PET positron emission tomography
  • CT computed tomography
  • FFiigguurree 11 :: TTeemmppss rreellaaxxaattiioonn ooff ooff pprroottoonnss iinn pprréésseennccee uu pcuprttiiccuulleess YYoo .. 66 EEuuoo..44VVOO44 // GGddVVOO44 iinn FFuunnccttiioonn tthhee ccoonncceennttrraattiioonn iinn GGdd 33 ++ .. ((AA)) :: TT11 ;; ((BB)) :: TT 22 ..
  • FFiigguurree 22 : SSppeeccttrree dd''éémmiissssiioonn ooff ooff lluummiinneesscceennccee pplorttiiccuulleess YYoo .. 66 .. EEuuoo..44VVOO44 // GGddVVOO44 TThhee
  • Ffiigguurree 33 DDeetteeccttiioonn of the Hydrogen Hydroxygen of the Hydrogelenee with the Pcarrttiiccuulleess YYoo .. 66 EEuuoo..44VVOO44 // GGddVVOO44 ..
  • Figure 4 Schematic representation of a particle according to the invention, in section.
  • Figure 5 Schematic representation (in section) of a coated particle according to the invention.
  • the application relates to a particle that can be used both as a contrast agent, in particular MRI, and as a luminescent agent (at least a bimodal agent).
  • This particle comprises or consists of a portion provided with the luminescent activity and a portion provided with the contrast agent activity (at least bipartite particle).
  • the nanoparticles according to the invention can thus advantageously be paramagnetic and luminescent, and in a particular embodiment, they comprise or consist on the one hand of a luminescent part and on the other hand. on the other hand a paramagnetic part, the paramagnetic part being preferably neutral in terms of luminescence.
  • the shell is paramagnetic and neutral in terms of luminescence, that is to say that it emits no light as a result of light excitation or emits light with a quantum yield of less than 1%.
  • the particle of the invention can be used as a contrast agent, in particular MRI, as a luminescent agent and as an oxidizing substance sensor (at least a trimodal agent).
  • the particle of the invention is further provided with a coating.
  • the particle of the invention comprises or consists of at least two parts, a portion of formula X a L b (M p O q ), wherein:
  • M is at least one element capable of associating with oxygen (O) to form an anion
  • - L corresponds to one or more lanthanide ion (s) luminescent (s);
  • - X corresponds to one or more ion (s) neutral (s) in terms of luminescence
  • the values of p, q, a and b are such that the electroneutrality of X a L b (M p O q ) is respected, the fraction of the luminescent element, defined by the ratio b / (b + a), being from 1 to 75%; and
  • M ' is at least one element capable of associating with oxygen (O) to form an anion
  • - A corresponds to one or more lanthanide ions (s) paramagnetic (s);
  • the values of p ', q', e and, if appropriate, f are such that the electroneutrality of A e X ' f (M' p O q ) is respected, the paramagnetic element fraction, defined by the ratio e / (e + f), being from 80 to 100%.
  • the part of formula X a L b (MpO q ) is luminescent, and the part of formula A e X ' f (M'pO q ) (or A e (M'pO q ) defined more low) is paramagnetic and neutral in terms of luminescence.
  • the particle of the invention comprises or consists of at least two parts, a part of formula X a L b (MpO q ), in which:
  • M is at least one element capable of associating with oxygen (O) to form an anion
  • - L corresponds to one or more lanthanide ion (s) luminescent (s);
  • - X corresponds to one or more ion (s) neutral (s) in terms of luminescence
  • the values of p, q, a and b are such that the electroneutrality of X a L b (MpO q ) is respected, the fraction of the luminescent element, defined by the ratio b / (b + a), being 1 to 75%; and
  • M ' is at least one element capable of associating with oxygen (O) to form an anion
  • - A corresponds to one or more lanthanide ions (s) paramagnetic (s);
  • the values of p ', q', e and f are such that the electroneutrality of A e X ' f (M'pO q ) is respected, the fraction of paramagnetic element, defined by the ratio e / (e + f), being from 80 to 100%.
  • the particle of the invention comprises or consists of at least two parts, a part of formula X a L b (MpO q ), in which:
  • M is at least one element capable of associating with oxygen (O) to form an anion
  • - L corresponds to one or more lanthanide ion (s) luminescent (s);
  • - X corresponds to one or more ion (s) neutral (s) in terms of luminescence
  • the values of p, q, a and b are such that the electroneutrality of X a L b (M p O q ) is respected, the fraction of the luminescent element, defined by the ratio b / (b + a), being from 1 to 75%; and
  • M ' is at least one element capable of associating with oxygen (O) to form an anion
  • - A corresponds to one or more lanthanide ions (s) paramagnetic (s);
  • M, M ', L, X, p, q, a, b, A, X' p ', q', e and f are more particularly defined as follows M and M 'are, independently of one another, at least one (preferably 1 or 2) element capable of associating with oxygen (O) to form an anion.
  • O oxygen
  • M and M 'are independently of one another, of valence + V or + VI.
  • M and M 'are each an ion chosen, independently of one another, in the group consisting of V, P, W, Mo and As.
  • M and M' are independently from each other, P or V, preferably M and M 'are V.
  • M and / or M' represents, one and / or the other, two independently selected ions. from each other, in the group consisting of V, P, W, Mo and As.
  • M can represent V V P 1 -V (v ranging from 0 to 1).
  • M ' may represent VyPi.v (v' ranging from 0 to 1).
  • L is one or more (preferably 1 or 2) lanthanide ion (s) luminescent (s).
  • lanthanide (or Ln) defines the elements whose atomic number is 57 to 71 in the Periodic Table of Elements.
  • L has a valence between +11 and + IV, and preferably +111.
  • L is an ion selected from the group consisting of Ce, Pr, Nd, Pm, Sm, Eu, Tb, Dy, Ho, Er, Tm and Yb.
  • L is Eu, in particular Eu 3+ .
  • L is Ce, in particular Ce 3+ .
  • L is Tb, in particular Tb 3+ .
  • L represents a plurality of ions (preferably 2) selected from the group consisting of Ce, Pr, Nd, Pm, Sm, Eu, Tb, Dy, Ho, Er, Tm and Yb.
  • L represents the ions Ce and Tb, or the ions Er and Yb.
  • X corresponds to one or more (preferably 1 or 2) ion (s) neutral (s) in terms of luminescence.
  • ion neutral is meant that the X-ion (s) are not capable of emitting light upon excitation or emit with a quantum yield of less than 1%.
  • X is of valence + III.
  • X is selected from the group consisting of lanthanides and Bi.
  • X is selected from the group consisting of La, Y, Gd and Bi.
  • X is selected from the group consisting of La, Y, and Bi.
  • X is the Yttrium element (Y).
  • X is La.
  • X is as defined above and furthermore is not Gd.
  • L is Eu and X is Y, so that X a L b is Y a Eu b .
  • L is Ce and X is La, so that X a L b is La a Ce b .
  • L is Tb and X is La, so that X a L b is La a Tb b .
  • L represents Ce and Tb, and x is the, so that X is L b has the (Ce, Tb) b.
  • p is 0 or 1, and preferably 1.
  • q is between 2 and 5, and is preferably 4.
  • M is P or V
  • p is 1, and q is 4, so that (M p O q) is P0 4 3 "or 4 V0 3" in another example, p is 0 and X is Y, so that X (M p O q) is Y 2 0 3.
  • M represents the ions V and P
  • p is equal to 1
  • q is equal to 4 so that (M p O q ) is (V v P 1 -v ) 0 4 .
  • the fraction of luminescent elements is from 1 to 75%, in particular from 10 to 60% or 20 to 50%, in particular of the order of 30% or more. the order of 40% ( ⁇ 5%). In one embodiment, the ratio b / (b + a) is less than or equal to 75%, less than or equal to 60%, less than or equal to 50%, less than or equal to 40%, less than or equal to 30% or less than or equal to 20%.
  • b / b + a is greater than 10%, preferably greater than 20%, preferably greater than 25%. In a particular embodiment, b / (b + a) ranges from 10 to 75% or alternatively from 20 to 75% or else from 25 to 75% or else from 25 to 45%.
  • the prior art recommends low doping, less than 10%, and makes the choice because, in massive materials and nanoparticles especially when they are synthesized at high temperature, a quenching effect between Eu 3+ ions appears at higher rates, which decreases quantum yield; when these nanoparticles are excited in the UV (vanadate absorption band), the quantum yield of the Eu 3+ emission is optimal for doping values between 0.1 and 10%.
  • the element L for example Eu 3+ ions
  • the number of excited ions is proportional to the number of ions Eu 3+ available in the nanoparticle.
  • the number of photons collected is optimal for high and specific doping values. It is advantageous to have a maximum L rate without a drop in quantum efficiency. It has been found that with low temperature syntheses the quenching effect only appears at higher concentrations.
  • L Eu
  • the optimum of b / b + a is between about 20 and 40%.
  • the quantum yield is optimal for doping values between 20 and 40%. Since the intended applications according to the invention are biomedical applications, a visible excitation is preferable to an excitation in the UV, more harmful for the cells and more absorbed by the tissues.
  • L is Eu and the ratio b / (b + a) is 40%, so that X a L b is Xo. 6 Eu 0 4 .
  • L is Eu
  • X is Y
  • the ratio b / (b + a) is 40%, so that X a L b is Y 0 . 6 Eu 0 . 4 .
  • X is Y
  • L is Eu
  • M is V or P
  • the ratio b / (b + a) is 1 to 75%, preferably 10 to 75%, more preferably 20 to 75%.
  • X is Y, L is Eu, M is V and the ratio b / (b + a) is 1 to 75%, preferably 10 to 75%, more preferably 20 to 75%.
  • X is Y, L is Eu, M is V, and the ratio b / (b + a) is 40%, so that X a L b (M p O q ) is Y 0 .6Euo .4 (V0 4 ).
  • L is Eu and X is Y, M is V and / or P, and the ratio b / (b + a) is 1 to 75%, preferably 10 to 75%, more preferably preferred 20 to 75%.
  • L is Ce and X is La, M is V and / or P, and the ratio b / (b + a) is 1 to 75%,%, preferably 10 to 75%, so still preferred 20 to 75%.
  • L is Ce and Tb, and X is La, M is V and / or P, and the ratio b / (b + a) is 1 to 75%,%, preferably 10 to 75%. more preferably 20 to 75%.
  • A represents one or more (preferably 1 or 2) paramagnetic ions of the family of lanthanides.
  • the term "paramagnetic" is understood here according to the usual meaning, more particularly according to Langevin's definition of paramagnetism.
  • A is a paramagnetic ion selected from the group consisting of Ce, Pr, Nd, Eu, Gd, Tb, Ho, Er, Tm and Yb.
  • A is Gd.
  • L and A are different.
  • A represents a plurality of paramagnetic ions (preferably 2) selected from the group consisting of Ce, Pr, Nd, Eu, Gd, Tb, Ho, Er, Tm and Yb.
  • A represents Gd and Eu ions.
  • A is different from L by the number and / or nature of the ions.
  • a particular advantage lies in the invention in the choice of a majority element in the matrix that is not luminescent in the matrix, the paramagnetic shell being neutral in terms of luminescence.
  • the paramagnetic elements used according to the invention in the form Gd 3+ , GdV0 4 and GdP0 4 but also Gd 2 0 3 and other salts and oxides of Gd 3+ are neutral in terms of luminescence in the form of nanoparticles or even shells in core-shell systems.
  • the elements of the shell are neutral in terms of luminescence.
  • X ' when present, corresponds to one or more ion (s) (preferably 1 or 2) neutral (s) in terms of paramagnetic properties.
  • neutral in terms of paramagnetic properties it is meant that the ion (s) X 'has (have) no unpaired electronic spin in the ground state.
  • the "neutrality in terms of paramagnetic properties" of the ion (s) X ' is understood here according to the usual meaning, more particularly according to the definition of Langevin paramagnetism.
  • X ' is of valence + III.
  • X ' is selected from the group consisting of lanthanides and Bi.
  • X ' is selected from the group consisting of La, Y and Bi.
  • X ' is the element Yttrium (Y).
  • ⁇ ', q', e and, where appropriate, f are such that the electroneutrality of A e X ' f (M' p O q ') is respected.
  • p ' is 0 or 1, and preferably 1.
  • q' is between 2 and 5, and is preferably 4.
  • the paramagnetic element fraction defined by the ratio e / (e + f), is 80 to 100%, in particular 90 to 100% or 95 to 100%. In one embodiment, the ratio e / (e + f) is greater than or equal to 80%, 90% or 95%. In one embodiment, the ratio e / (e + f) is greater than or equal to 80%, 90% or 95%, and less than 100%.
  • the ratio e / (e + f) is 100%, i.e., f is 0, so that A e X ' f (M'pO q ) is A e (M'pO q ), the values of p ', q' and e being such that the electroneutrality of A e (M'pO q ) is respected.
  • A is Gd and the ratio e / (e + f) is 100%, so that A e X ' f (M'pO q ) is Gd (M' p O q ).
  • M is V
  • A is Gd
  • the ratio e / (e + f) is 100%, so that A e X ' f (M'pO q ) is Gd (V0 4 ).
  • the particle of the invention may also be defined as comprising or consisting of two parts:
  • a e X ' f (M'pO q ) in which M', A, X 'when it is present, p', q ', e and if appropriate f are as defined above , and chosen so that the portion A e X ' f (M'pO q ) has a contrast agent activity, in particular MRI and / or paramagnetic activity.
  • a particle or composition comprising particles which is capable of emitting light, following excitation.
  • the luminescence activity of a particle can be evaluated by calculating the luminescence quantum yield (Q), which corresponds to the ratio between the number of photons emitted and the number of photons absorbed (the higher the Q, the more the particle is luminescent ).
  • Q luminescence quantum yield
  • a particle in its uncoated form) will be considered as an effective luminescence agent when the value of Q will be greater than or equal to 10%, preferably at least 20% (see Example 1.7).
  • contrast agent activity or “usable as a contrast agent” is meant a particle (or composition comprising particles) which decreases the relaxation times ⁇ and / or T 2 when used in MRI.
  • the values r 1 and r 2 are defined by the slopes of the straight lines of the relaxation velocities 1 / ⁇ and 1 / T 2 , respectively, as a function of the concentration of the particles (see examples 1.5 and 1.6).
  • the particles of the invention can be used as a Ti contrast agent, that is to say have a preponderant effect.
  • a particle will be considered an effective ⁇ contrast agent, when the r- ⁇ and r 2 values will be at least about 4 mM "V 1, and the ratio r 2 / r ( ⁇ ) will be of the order of 1, preferably in a range of 1 to 2, in particular 1 to 1.5.
  • the application also relates to a particle of the invention that can be used as a contrast agent, in particular MRI, as a luminescent agent and as an oxidizing substance sensor (at least a trimodal agent).
  • the particle of the invention comprises or consists of two parts, a part provided with the luminescent activity and the activity of detecting oxidizing substances, and another part provided with the activity as a contrast agent.
  • the particle is defined as comprising or consisting of two parts:
  • a e X 'f (M'po q') has a contrast agent activity, in particular MRI.
  • the particle of the invention comprises or consists of at least two parts, a part being of formula X a Eu b (V p O q ) and a part being of formula A e X ' f (M' p O q ) , in which :
  • X corresponds to one or more, preferably one or two, neutral ion (s) in terms of luminescence
  • the values of p, q, a and b are such that the electroneutrality of X has Eu b (V p O q ) is respected, the fraction of the luminescent element, defined by the ratio b / (b + a), being from 1 to 75%; and
  • M ' is at least one element capable of associating with oxygen (O) to form an anion
  • A corresponds to one or more, preferably one or two, paramagnetic lanthanide ion (s); - ⁇ ', when present, corresponds to one or more neutral ions in terms of paramagnetic properties; and
  • the values of p ', q', e and, if appropriate, f are such that the electroneutrality of A e X ' f (M'pO q ) is respected, the paramagnetic element fraction, defined by the ratio e / (e + f), being from 80 to 100%.
  • an agent for detecting oxidizing substances or “for detecting oxidizing substances” is meant a particle (or composition comprising particles) which is capable of detecting, quantitatively, the concentration of oxidizing substances (such as hydrogen peroxide, H 2 O 2 , hypochlorite anion), intracellularly or in vivo.
  • the detection of the concentration of oxidizing substances is dynamic, that is to say that it is possible to detect the concentration as a function of time.
  • the particles of the invention are used as a hydrogen peroxide sensor.
  • a particle will be considered as an effective sensor of oxidizing substances, in particular hydrogen peroxide, when the luminescent ions can be reversibly oxidized by the oxidizing substances producing a modulation of their luminescence intensity at a wavelength band. given.
  • the luminescent ions are photoreduced by irradiation prior to their use for the detection of oxidizing substances (Casanova et al., 2009).
  • the photoreduction induces a decrease in the luminescence of the luminescent ion which is at least 10%, preferably greater than or equal to 20%, greater than or equal to 30%, greater than or equal to 40% or greater or equal to 50%.
  • the luminescent ions are already in a valence state such that they are susceptible to oxidation.
  • the modulation of the luminescence intensity produced by oxidant concentrations at physiological and pathophysiological concentrations must be sufficiently large, greater than the noise, to be detectable (see example 1 .8).
  • the ratio between the luminescence recovery signal and the noise is greater than 1, preferably greater than 2 or preferably greater than 5.
  • the characteristic time necessary to obtain this recovery is of the order of one minute, preferably less than 5 min, preferably less than 1 min or preferably less than 30 s.
  • the particle of the invention corresponds to a formula X a L b (MpO q ) / A e X ' f (M'pO q ') or a formula X a L b (MpO q ) / A e (M'p ' O q '), in particular a formula X a EU b (VpO q ) / A e X' f (M'pO q ') or a formula X a EU b (VpO q ) / A e (M'p'O q ').
  • the particle of the invention corresponds to a formula X a Eu b (V0 4 ) / AeX ' f (M'pO q ) or a formula X a Eu b (V0 4 ) / A e (M'pO q ).
  • the particle of the invention has a formula selected from the group consisting of YaEUb (V04) Gd (V0 4), Y has EUB (P04) / Gd (V0 4), Y has EUB ( V04) / Gd (P0 4 ) and Y has EUb (PO 4 ) / Gd (PO 4 ), the ratio b / (b + a) being from 1 to 75%, in particular from 10 to 60% or 20 to 50%, in particular of the order of 30% or of the order of 40% ( ⁇ 5%).
  • the particle of the invention is of formula Yo. 6 Euo .4 (V0 4 ) / Gd (V0 4 ).
  • L is in the form of a radioisotope, for example 86 Y.
  • the surface of the nanoparticles is functionalized with organic chelators, for example with the DOTA ligand, in order to allow the binding of a suitable radioisotope to a positron emission, such as 64 Cu or 86 Y.
  • the functionalization of the surface is carried out with organic molecules containing, for example, 11 C ions, 13 N, 18 F, also suitable for positron emission.
  • the term "part" means a structure of formula as indicated above, regardless of its spatial arrangement with the other party, excluded the homogeneous mixture of the two parts. It is in this that the particles are defined as composites.
  • the at least two parts of formula X a L b (M p O q ) and AeX ' f (M'pO q ') or of formula X a L b (M p O q ) and A e (M'pO q ) constituting respectively the luminescent part and the paramagnetic part of the particle of the invention are juxtaposed, that is to say that they are in contact with one another, without the two parts being mixed together or in such a way that only a tiny proportion of the whole is mixed (less than 10% for each of the parts).
  • one of the phases may be at least partially dispersed in the other.
  • the at least two moieties of formula X a L b (M p O q ) and AeX ' f (M'pO q ') or of formula X a L b (M p O q ) and A e (M'pO q ) constituting at least one zone of the particle of the invention are arranged in a gradient structure, so that at least one zone of the particle consists of 100% of a part, that another zone consists of 100% of the other part, and between these two zones there is a mixture of the two parts in which the proportion of one of the parts decreases when the proportion of the other part increases, according to a gradient.
  • the at least two parts of formula X a L b (M p O q ) and A e X ' f (M'pO q ) or of formula X a L b (M p O q ) and A e (M'pO q ) constituting the particle of the invention are arranged according to a so-called core / shell structure, generally spherical or spheroidal, in which one of the parts is found in the center of the particle and in shape the heart, completely surrounded by the other part called shell (Figure 4A).
  • the portion forming the heart is without mixing with the shell.
  • at the edge of the heart and the shell is an intermediate zone where is mixed with the other a tiny proportion of each of the two parts (less than 10% for each of the two parts). parts).
  • the part of formula X a L b (MpO q ) [in particular the part of formula X a Eu b (V p O q )] constitutes the core of the particle, and the part of formula A e X ' f (M'pO q ) or of formula A e (M'pO q ) constitutes the shell of the particle.
  • the portion Yo for a particle Yo.6Euo.4 formula (V04) / Gd (V0 4), the portion Yo.
  • Nanoparticles having a part Y has Eub (P, V) O 4 and a part Gd (P, V) O 4 and in which b / b + a is greater than 10 and goes up to 75% or ranges from 20 to 75% or else 25 to 75% or 25 to 45% are particularly preferred, and more particularly these nanoparticles YaEub (V, P) 0 4 / Gd (V, P) 0 4 where the part of formula Y has Eub (P, V) 0 4 constitutes the heart of the particle, and the part of formula Gd (V0 4 ) constitutes its shell.
  • the core is neutral in terms of paramagnetism and / or the neutral shell in terms of luminescence.
  • the volumetric fraction of the shell (% vol), that is to say the volume of the shell relative to the total volume of the nanoparticle, is between 5% and 95%, preferably between 25% and 75%, preferably between 50% and 60%. In a particular embodiment, the volumetric fraction of the shell does not exceed 60%. In a particular embodiment, the volumetric fraction of the shell is of the order of 58 ⁇ 5% of the total volume of the nanoparticle.
  • the volumetric fraction of the core [with respect to the whole of the particle] can vary from 5% to 95%, preferably from 25% to 75%, preferably from 40% to 50%. In a particular embodiment, the volume fraction of the core does not exceed 50%.
  • the application also relates to a composition
  • a composition comprising particles of formula X a L b (MpO q ) / A e X ' f (M'pO q ') or of formula X a L b (MpO q ) / A e (M'pO q ').
  • the particles have the same composition, i.e. the nature of X, L, M, X 'when present, A and M' and the value of p, q , p ', q', e and f are identical for all particles of the composition, the value of a and b may vary.
  • the particles have the same composition and the same nature, that is, the nature of X, L, M, X 'when present, A and M' and the value.
  • p, q, p ', q', a, b, e and f are identical for all the particles of the composition.
  • the composition comprises different particles of the invention, which may vary in the nature of X, L, M, X 'when present, A and / or M', and / or in the value of a, b, p, q, p ', q', e and / or f.
  • the particles of the invention differ only in the nature of X and X 'when present, and possibly the values of a and b.
  • the particles of the invention contained in the composition differ only in the nature of L, and possibly the values of a and b.
  • the particles of the invention differ only in the nature of X, and possibly the values of a and b.
  • the parts of the particle of the invention may contain one or more crystalline zones of the metal oxide (s).
  • the structure of one and / or the other of the parts of the particle is not monocrystalline. If several crystalline domains are present within the particle, these domains are preferably crystals of the same direction.
  • more than 50%, more than 70%, more than 80% or more than 90%, more than 95%, more than 98%, more than 99% or 100% of the particles have a crystalline structure.
  • more than 50%, more than 70%, more than 80%, more than 90%, more than 95%, more than 98%, more than 99% or 100% of the volume of the particle has a crystalline structure.
  • the particles of the invention may be porous or non-porous, that is to say that the particles have the ability or not, respectively, to let in particular water into the particle.
  • the particles according to the invention are porous.
  • more than 50%, more than 70%, more than 80%, more than 90%, more than 95%, more than 98%, more than 99% % or 100% of the particles are porous.
  • a fraction of the volume of each particle may be porous.
  • the invention also relates to a particle of the invention consisting of two parts X a L b (MpO q ) and A e X ' f (M'pO q ) or consisting of two parts X to L b (MpO q ) and A e (M'pO q ) as defined herein (constituting the particle in its uncoated form), further provided with a third portion, to give a coated particle.
  • the third part surrounds the uncoated particle.
  • the coated particle consists of a heart surrounded by a shell, itself surrounded by this third part ( Figure 5A).
  • This third part comprises at least one, preferably one, two or three, layer (s) chosen from among a preparation layer, a layer carrying functional groups and a layer consisting of biologically active molecules, layers as defined herein. -after.
  • this third part consists of a preparation layer, so that the non-coated particle of the invention is coated only with a preparation layer.
  • this third part consists of a preparation layer and a layer carrying functional groups, so that the uncoated particle of the invention is coated with a preparation layer and a bearing layer.
  • functional groups functionalized particles
  • the preparation layer is internal with respect to the layer carrying functional groups, that is to say that the preparation layer is applied to the non-coated particle, and that the layer carrying functional groups. is applied on the preparation layer.
  • this third part consists of a preparation layer and a layer consisting of biologically active molecules, so that the non-coated particle of the invention is only coated with a preparation layer and a layer consisting of biologically active molecules.
  • the preparation layer is internal with respect to the layer consisting of biologically active molecules, that is to say that the preparation layer is applied to the non-coated particle, and that the layer consisting of molecules biologically active is applied to the preparation layer.
  • this third part consists of a preparation layer, a layer carrying functional groups and a layer consisting of biologically active molecules, so that the non-coated particle of the invention is coated with a layer. of preparation, a layer carrying functional groups and a layer consisting of biologically active molecules.
  • the preparation layer is internal with respect to the layer carrying functional groups, and the layer carrying functional groups is itself internal with respect to the layer consisting of biologically active molecules, ie say that the layer of preparation is applied to the uncoated particle, that the layer carrying functional groups is applied to the preparation layer, and that the layer consisting of biologically active molecules is applied to the layer carrying functional groups.
  • this third part has neither contrast agent activity nor luminescent activity, and where appropriate, nor activity of detecting oxidizing substances which are specific to it.
  • this third part has neither contrast agent activity, and where appropriate, nor activity of detecting oxidizing substances, but has a luminescent activity which is distinct from those of luminescent ions (L). contained in the particle of the invention.
  • this distinct luminescence activity is exerted by molecules (in particular fluorophores) contained in one of the three layers of the coating, preferably in the preparation layer or in the layer carrying groups. functional. This distinct luminescence activity differs from the luminescence activity of the luminescent ions (L) contained in the particles, by its color, its photophysical properties and / or its sensitivity to environmental factors, such as pH or ion concentration as the Ca 2+ .
  • biologically active molecule is meant any molecule of natural or synthetic origin, such as chemical compounds, proteins, polypeptides or polynucleotides, which is or are selected according to the desired activity.
  • the one or more biologically active molecule are targeting molecules, that is to say molecules that will allow the specific targeting of the particle according to the invention to a specific molecule.
  • organ for example blood
  • cell type for example, platelets, lymphocytes, monocytes, tumor cells, ...) or a cell compartment.
  • this specific targeting can be accomplished using monoclonal or polyclonal antibodies, or protein or polypeptide ligands of cellular receptors.
  • TGF / TGFR TGF / TGFR
  • EGF / EGFR TNF ⁇ / TNFR
  • interferon / interferon receptor interleukin / interleukin receptor
  • GMCSF / receptor GMCSF GMCSF
  • MSCF / MSCF receptor GCSF / GCSF receptor.
  • Protein fragments or detoxified toxins and their cellular receptors may also be mentioned as ligands.
  • these will be chosen according to the antigen or antigens against which the antibody is directed.
  • antibodies recognizing antigens located on monocytes, lymphocytes, platelets for example antibodies marketed by Santa Cruz Biotechnology (http://www.scbt.com/) may be used.
  • the biologically active molecule (s) are fluorescent molecules, and for example are in the form of fusion proteins with fluorescent proteins.
  • the biologically active molecule (s) are stealth agents, such as polyethylene glycol (PEG) or dextran, to render the particles stealthy in the body and thereby increase their circulation time in the blood.
  • stealth agents such as polyethylene glycol (PEG) or dextran
  • the one or more biologically active molecule are molecules with therapeutic activity, in particular anticancer (chemotherapeutic) molecules.
  • chemotherapeutic molecules are: Cisplatin, Methotrexat, Bleomycin, Cyclophosphamid, Mitomycin, 5-Fluoruracil, Doxorubicin / Adriamycin, Docetaxel.
  • the use of the particle of the invention as a transport vehicle of therapeutic molecules (drug) has several advantages: the particles encapsulating drugs generally have a circulation time in the body longer than the molecular drugs, and the particles can eliminate the multiple-drug resistance effect of tumor cells where molecular drugs are readily pumped out of the cell by membrane pumps (Kim et al., 2009).
  • the particle according to the invention carries at its surface at least two, preferably two or three types of biologically active molecules chosen from those described above.
  • the particle carries targeting molecules and stealth molecules as defined above.
  • the particle carries targeting molecules and therapeutic molecules as defined above, and optionally stealth molecules as defined above.
  • the biologically active molecules may be attached, on the surface of the particle or, where appropriate, to the preparation layer, directly or via a layer carrying functional groups, by covalent bonding. or non-covalent.
  • the attachment of these biologically active molecules is achieved by conventional techniques of oxidation, halogenation, alkylation, acylation, addition, substitution or amidation of the surface of the particle, the preparation layer and / or the layer bearing groups. functional, with biologically active molecules.
  • the preparation layer is applied directly to the particle, either by covalent bonding or by adsorption. This preparation layer may be hydrophilic or hydrophobic. In a particular embodiment, this preparation layer is amorphous.
  • the preparation layer consists of molecules, non-covalently bound to the particle, whose charge is opposite to that of the non-coated particle according to the invention.
  • binding molecules are anionic, cationic, or zwitterionic detergents, peptides, acidic or basic proteins, polyamines, polyamides, and polysulfonic or polycarboxylic acids. These binding molecules can be adsorbed on the surface of the particle by coincubation.
  • the preparation layer consists of silica (SiO 2 ) (silicate particles).
  • the silica layer may be formed by the condensation of a suitable precursor containing the silicon atom around the particle according to the invention.
  • the silica layer is bonded to the particle according to the invention by electrostatic forces.
  • the silica layer is formed from sodium metasilicate (Na 2 SiO 3 ) according to the following reaction (where "RE" represents A and / or X 'in the context of a particle according to invention):
  • the layer carrying the functional groups when present, provides the link between the preparation layer, on the one hand, and the layer carrying the biologically active molecules, on the other hand. It consists of organic groups, for example organosilanes carrying amine, thiol or carboxylic functions.
  • a particle carrying a preparation layer and a layer with functional groups, as described herein, is said to be a functionalized particle.
  • the layer carrying the functional groups is formed from (3-aminopropyl) triethoxysilane (APTES) which is carrying amino groups.
  • APTES (3-aminopropyl) triethoxysilane
  • the amino groups are added to the particle according to the invention, in the first step, by the hydrolysis of the ethoxy groups of the APTES to generate hydroxyl groups which can, in a second step, condense with the hydroxyl groups of the preparation layer to form a covalent bond, according to the reaction scheme below (where "RE" represents A and / or X 'in the context of a particle according to the invention):
  • the particle thus functionalized can be linked to biologically active molecules (to form the layer consisting of biologically active molecules), by any means known to those skilled in the art, for example by a weak chemical bond, such as for example by electrostatic force, Van der Waals strength, hydrogen bonding, hydrophobic bonds, or by a strong chemical bond, for example by ionic, covalent or metallic bonding, or by means of a coupling agent, such as for example coupling agents bearing dual functions making it possible to set on the one hand functions (for example amine functions or carboxylic acid functions) present on the surface of the particle and, on the other hand, on functions of the targeting molecule (for example functions amino or sulfhydryl functions).
  • a weak chemical bond such as for example by electrostatic force, Van der Waals strength, hydrogen bonding, hydrophobic bonds, or by a strong chemical bond, for example by ionic, covalent or metallic bonding
  • a coupling agent such as for example coupling agents bearing dual functions making it possible to set on the one hand functions (for example
  • the functionalized particle and the biologically active molecule (s) may also be linked using, for example, high affinity biological interactions, such as biotin-streptavidin interaction (or ligand-receptor interaction or interaction antibody-antigen), and multi-step coupling, i.e. first coupling streptavidin (or biotin) to the functionalized particle and coupling biotin (or streptavidin) to the to the biologically active molecule (s) and then interaction of the two coupling products.
  • Mention may also be made of coupling techniques between, for example, a carboxy group and a carbodiimide, an amine and a ⁇ -hydroxysuccinimide or an imidoester, and a thiol and a maleimide.
  • binding agents such as (1) Bis (sulfosuccinimidyl) suberate (BS 3 ), homobifunctional linker, which by its / V-ester hydroxysulfosuccinimide (NHS) groups, binds with amino groups carried by different molecules, (2) 1-ethyl 3- (3-Dimethylaminopropyl) carbodiimide (EDC), carbodiimide linker, which activates carboxyl groups for spontaneous reaction with primary amines, and (3) Sulfosuccinimidyl-4 - ((V-maleimidomethyl) cyclohexane-1 -carboxylate (Sulfo-SMCC), which by its ester group Sulfo-NHS binds the molecules containing a primary amine, and by its
  • the functionalized particle of the invention may be coupled to a protein or polypeptide having amine functions on its surface by bis (sulfosuccinimidyl) suberate (BS 3 ).
  • the coupling method described in detail by Casanova et al. (2007), includes:
  • the ratio of the concentrations of the particles of the invention and the proteins or polypeptides is chosen according to the number of proteins or polypeptides that it is desired to couple per particle. When it is desired to fix a single molecule on the particle and when the reaction of step iv) has an efficiency close to 100%, a ratio of the concentrations of particles and proteins of interest, close to 1: 1 is retained. , for carrying out step iv).
  • the concentration of the particles coupled to the BS 3 and proteins or polypeptides before the implementation of step iv) can be determined by their absorption. After performing this step iv), as the absorption of the proteins or polypeptides and particles is superimposed, the concentration of the proteins or polypeptides can be determined by standard tests such as the Bradford test.
  • the functionalized particle of the invention can be coupled to aminated PEG, in particular to make the particles stealthy.
  • Steps i) to v) described above are repeated identically, the PEG replacing the protein or polypeptide to be coupled from step iv).
  • a PEG / particulate ratio of 10: 1, 20: 1 or 40: 1 will be considered, in order to ensure complete recovery of the surface of the particle by PEG.
  • the second reaction will take place, for example, between a concentration C of particles, a concentration of 2C of proteins and 10C of PEG.
  • the particle in its uncoated, coated or functionalized form, may have a spheroidal shape (including a spherical particle), or any other irregular shape.
  • the size of the particles of the invention (defined as the diameter for spherical particles and as the largest dimension when the particle has a spheroidal shape), is between 1 and 500 nm.
  • the particle size is less than 200 nm, in particular less than 100, less than 50, less than 25 or less than 10 nm.
  • the size will be greater than that of an uncoated particle, and less than 200 nm, in particular less than 100 nm, less than 50 nm or less than 25 nm.
  • Particles can be defined as nanoparticles (NP).
  • the particle size may be uniform (or monodispersed), that is to say more than 75%, in particular more than 80% or more than 90% of the particles. have a size that differs from the average particle size of the aggregate of the composition by not more than 50 nm, not more than 40 nm, not more than 30 nm, not more than 20 nm, or not more than 10 nm.
  • the size distribution of more than 75%, especially more than 80% or more than 90% of the particles is within a size range of ⁇ 40%, ⁇ 30%, ⁇ 20% or ⁇ 10% of the average particle size.
  • Particles in composition whose size does not meet one of the two definitions below, are said to be polydispersed.
  • the present application also relates to a process for preparing the particles according to the invention, which comprises or consists of:
  • the aqueous solution containing the elements X and L is in the form of chlorides, nitrates or acetates.
  • the aqueous solution containing the elements X and L may also contain complexing agents of these elements such as citrate in order to limit the size of the particles.
  • the aqueous solution containing an oxo-hydroxo salt of the element M is in the form of a salt of sodium, potassium or ammonium.
  • the pH of the aqueous solution containing an oxo-hydroxo salt of element M is adjusted so that the precipitation reaction leads to the synthesis of the part of formula X a L b (M p O q ) [or particles of formula X to L b (M p O q )].
  • the oxidation states of elements X, L and M are those of these elements in the final particle.
  • the aqueous solution containing the elements X 'and A (or containing the element A), is in the form of chlorides, nitrates or acetates.
  • the aqueous solution containing the elements A and X '(or containing the element A) may also contain complexing agents of these elements such as citrate in order to limit the particle size.
  • the aqueous solution containing an oxo-hydroxo salt of the element M ' is in the form of a salt of sodium, potassium or ammonium.
  • the pH of the aqueous solution containing an oxo-hydroxo salt of the element M ' is adjusted so that the precipitation reaction leads to the coating of the part of the formula X a L b (M p O q ) by a part of formula A e X ' f (M' p O q ) or a part of formula A e (M ' p O q ).
  • the oxidation states of elements A, X 'and M' will be those of these elements in the final particle.
  • Step (2) is carried out in the presence of the parts of formula X a L b (M p O q ) synthesized in (1), that is to say that step (2) is implemented in particular in the dispersion of parts of formula X a L b (M p O q ) as obtained at the end of step (1), or after the dispersion of parts of formula X a L b (M p O q ) as obtained at the end of step (1) has been purified to remove the counterion salts.
  • the aqueous solution containing elements X 'and A (or containing element A) and the aqueous solution containing element M' are successively added to the dispersion of parts of formula X a L b (M p O q ) as obtained at the end of step (1), the second solution being added by means of a slow drip.
  • the aqueous solution containing elements X 'and A (or containing element A) and the aqueous solution containing element M' are added simultaneously to the dispersion of parts of formula X a L b ( M p O q ) as obtained at the end of step (1), each of the two solutions being slowly added dropwise.
  • the mode of addition of the two solutions in the dispersion of parts of formula X to L b (M p O q ) as obtained after step (1) and their concentration are controlled so that the coating of the parts of formula X to L b (M p O q ) is preferably carried out with the separate precipitation of parts of formula A e X ' f (M' p O q ) or of parts of formula A e (M ') p O q ).
  • Those skilled in the art may modify the modes of addition described above or vary the dilution of the added solutions.
  • the coprecipitation reaction for the synthesis of the parts of formula X a L b (M p O q ) and the coprecipitation reaction for coating the parts of formula X a L b (M p O q ) by the part of formula A e X ' f (M' p O q ) or of formula A e (M ' p O q ) succeed each other directly and without interruption.
  • the dispersion of parts of formula X a L b (M p O q ) obtained directly at the end of their synthesis may contain a quantity of M ions (or M ') sufficient for the coating of the parts of formula X to L b (M p O q ) by the part of formula A e X' f (M ' p O q ) or the part of formula A e X' f ( M ' p O q ), so that only one an aqueous solution containing the elements X 'and A (or containing the element A) is added in step (2).
  • step (3) comprises or consists of a purification of the particles, in order to remove the counterion salts.
  • the method comprises an ultimate step of sorting the particles according to their size, by centrifugation.
  • the application also relates to particles having the above definition, in particular particles of formula X a L b (MpO q ) / A e X ' f (M'pO q ') or of formula X a L b (MpO q ) / A e (M'pO q '), obtained by the method described above.
  • the application also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising particles as defined in the present application or a composition as defined in the present application, and a pharmaceutically and / or physiologically acceptable vehicle.
  • pharmaceutical composition is meant a composition intended for diagnostic use and / or therapeutic use, not only in humans but also in animals, in particular in mammals and / or pets (veterinary use ).
  • pharmaceutically and / or physiologically acceptable carrier is meant an agent suitable for the use of the pharmaceutical composition in contact with a living being (for example a non-human mammal, and preferably a human being), and is therefore preferentially non-toxic, such as excipients.
  • physiologically and / or pharmaceutically acceptable vehicles are, for example, water, a saline solution, in particular a physiological solution, water-miscible solvents, sugars, binders, pigments, vegetable or mineral oils, polymers soluble in water, surfactants, thickeners or gelling agents, preservatives, basifying or acidifying agents.
  • Excipients that may be contained in the pharmaceutical composition according to the invention include sugars, such as lactose, sucrose, mannitol, or sorbitol, cellulose-based preparations, for example corn starch, wheat starch, rice starch, or corn starch.
  • the excipients or vehicles are intended for the preparation of a pharmaceutical composition of the invention as an injectable solution, in particular as an injectable solution intravenously.
  • the pharmaceutical composition comprises, as active product, between 0.1 and 1 g / ml of particles according to the invention, in particular between 0.1 and 0.6 g / ml or between 0 and , 2 and 0.5 g / ml.
  • the pharmaceutical composition according to the invention is formulated in the form of an injectable solution, in particular in the form of a solution for injection by injection. intravenous (IV), and in particular is in the form of vials or pre-filled syringes.
  • the application also relates to the use of particles, compositions or pharmaceutical compositions according to the invention in imaging, in particular in medical imaging, in particular in diagnostic imaging.
  • the particles, compositions or pharmaceutical compositions according to the invention can be used in vitro, in particular on a cell culture or on an organ previously removed ex vivo, or preferably in vivo. In vivo use includes use in animals, particularly in mammals, particularly in pets (veterinary use), or in humans (patients).
  • the application relates to the use of particles, compositions or pharmaceutical compositions according to the invention in imaging, in particular on laboratory animals (mice, rats, primates, etc.), in particular for purposes of research or investigation, or for the purpose of developing molecules for diagnostic and / or therapeutic purposes.
  • the application also relates to the use of particles, compositions or pharmaceutical compositions according to the invention as diagnostic agents, in a patient or an animal, preferably a mammal (diagnostic use).
  • the particles, compositions or pharmaceutical compositions according to the invention are used for diagnostic purposes only, excluding their use for therapeutic purposes.
  • the application relates to the use, in particular in vivo, of particles, compositions or pharmaceutical compositions according to the invention in the implementation of at least one imaging technique (in particular one, or the combination of two or three techniques) selected from the group consisting of MRI, Optical Imaging, Optical Oxidant Detection, Positron Emission Tomography (PET), Computed Tomography (CT) and Ultrasound Imaging (for example, ultrasound)
  • imaging technique in particular one, or the combination of two or three techniques
  • PET Positron Emission Tomography
  • CT Computed Tomography
  • Ultrasound Imaging for example, ultrasound
  • the acquisition of the signals (in particular images) of the imaging technique (s) is carried out following a single injection of the particles, compositions or pharmaceutical compositions according to the invention, or at most following two injections of the same particles, same compositions or same pharmaceutical compositions according to the invention [if the acquisition of the signals must be longer than the residence time of the particles in the subject (patient or animal, preferably mammalian, subject of investigation.]
  • the acquisition of signals by different imaging techniques respectively implemented may be slightly shifted in time, provided that the imaging techniques are implemented during the same investigation session, particularly diagnostic investigation.
  • the combination of different imaging techniques using particles, compositions or pharmaceutical compositions according to the invention allows the collocation of the signals or images respectively acquired by these multiple techniques.
  • the application relates to the use of particles, compositions or pharmaceutical compositions according to the invention in MRI (or for diagnosis by MRI, or for the diagnosis using the MRI technique).
  • the application also relates to the use of particles, compositions or pharmaceutical compositions according to the invention as multimodal agents (in particular bimodal or trimodal agents) in the diagnosis using at least two imaging techniques chosen from the group consisting of MRI. , optical imaging, optical oxidant detection, positron emission tomography, computed tomography and ultrasound imaging.
  • the application relates to the use of particles, compositions or pharmaceutical compositions according to the invention as multimodal agents (in particular bimodal or trimodal) in imaging, in particular in MRI in combination with at least one, in particular an imaging technique selected from the group consisting of optical imaging, optical oxidant detection, positron emission tomography, computed tomography and ultrasound imaging.
  • MRI in combination with at least one, in particular, an imaging technique selected from the group consisting of optical imaging, optical oxidant detection, positron emission tomography, computed tomography and Ultrasound imaging includes the use of particles, compositions or pharmaceutical compositions according to the invention, in MRI in combination with optical imaging, in MRI in combination with optical oxidant detection, in MRI in combination with tomography positron emission, MRI in combination with computed tomography or MRI in combination with ultrasound imaging (bimodal imaging).
  • the particles, compositions or pharmaceutical compositions according to the invention are used in MRI in combination with optical imaging.
  • the use of a particle according to the invention (having properties of MRI contrast agents and luminescent properties) can reduce scanning times by contrast enhancement and simultaneously allow rapid optical imaging, by combining the complementary advantages of optical techniques in terms of speed of acquisition and sensitivity at low concentrations with the deep penetration of MRI tissues.
  • the particles, compositions or pharmaceutical compositions according to the invention are used in MRI in combination with the optical detection of oxidants.
  • the use of a particle according to the invention (having properties of MRI contrast agents and of oxidant detection properties) can make it possible to image the tissues by MRI and detect the production of bound oxidants. for example, at an ignition site by injecting a single product.
  • the luminescent ions of the particle must already be in a state of valence such that they are susceptible to oxidation.
  • the particles, compositions or pharmaceutical compositions according to the invention are used in MRI in combination with positron emission tomography.
  • the positron emission by radioisotopes suitable for positron emission such as 11 C, 13 N, 15 0, 18 F, 64 Cu, 86 Y or 124 I is followed by a reaction with electrons and ⁇ -photon emission whose depth of penetration is unlimited on the scale of biological samples, which makes PET the imaging technique with the highest sensitivity, allowing the determination of the local concentration of the radioisotope, and the detection of a single abnormal cell (Hahn et al., 201 1). PET is therefore appropriate for detecting the onset of cancer before any macroscopic changes can be visualized.
  • a particle according to the invention (having properties of contrast agents in MRI and carrying a radioisotope) makes it possible to combine the high sensitivity of the PET with a localization of the PET signal in the body of the animal or patient examined by MRI.
  • the particles, compositions or pharmaceutical compositions according to the invention are used in MRI in combination with computed tomography.
  • the contrast generated by CT is essentially between the bones and other parts of the body.
  • CT can therefore provide additional information to MRI where contrast is generated between regions containing water, ie between different types of tissue.
  • CT can provide three-dimensional images with a resolution comparable to that of MRI (Frullano and Meade, 2007).
  • A the paramagnetic lanthanide ion
  • Gd the high electron density of the gadolinium atom makes the particles according to the invention an appropriate contrast agent for CT in combination with the implementation of the invention.
  • MRI the paramagnetic lanthanide ion
  • the particles, compositions or pharmaceutical compositions according to the invention are used in MRI in combination with ultrasound imaging.
  • the particles of the invention are contained, in large numbers, in microspheres or polymeric microbubbles prepared prior to their administration concerning the investigation (Hahn et al. 201 (1).
  • MRI in combination with at least one, particularly one, imaging technique selected from the group consisting of optical imaging, optical oxidant detection, positron emission tomography, computed tomography and "Ultrasonic imaging” includes the use of particles, compositions or pharmaceutical compositions according to the invention, in MRI in combination with two imaging techniques selected from optical imaging, optical oxidant detection, positrons, computed tomography and ultrasound imaging (trimodal imaging).
  • the particles, compositions or pharmaceutical compositions according to the invention are used, in MRI in combination with optical oxidant detection and optical imaging, in MRI in combination with the optical detection of oxidant and positron emission tomography, MRI in combination with optical oxidant detection and computed tomography or MRI in combination with optical oxidant detection and ultrasound imaging.
  • the invention also covers:
  • particles, compositions or pharmaceutical compositions for their use in imaging in particular as diagnostic agents, as multimodal agents (in particular bimodal or trimodal) diagnostics or in the diagnosis using one or a combination of several, in particular 2 or 3, imaging technique (s) according to the definitions given above.
  • the invention also relates to a method for acquiring a signal, in particular image (s), by MRI, optical imaging, optical detection of oxidant, PET, CT or ultrasound imaging, or by a combination of at least two (in particular two or three) of these techniques as defined above, in an animal, in particular a mammal, or in a patient, using particles, compositions or pharmaceutical compositions according to the invention comprising :
  • the invention also relates to a method for acquiring a signal, in particular image (s), by MRI, optical imaging, optical detection of oxidant, PET, CT or ultrasound imaging, or by a combination of at least two (in particular two or three) of these techniques as defined above, in an animal, in particular a mammal, or in a patient, using particles, compositions or pharmaceutical compositions according to the invention comprising:
  • Excitation means the application of a magnetic field (MRI), an X-ray beam scan (TDM), a light at a particular wavelength (optical imaging) and / or ultrasound (ultrasound imaging) on the subject (animal or patient), depending on the imaging technique (s) used in the diagnosis.
  • MRI magnetic field
  • TDM X-ray beam scan
  • optical imaging optical imaging
  • ultrasound ultrasound imaging
  • medium containing the particles is meant the biological fluid or tissue in which the particles of the invention have been administered, or the biological fluid or tissue in which the particles of the invention are located or concentrated ( particularly because of targeting) after their administration.
  • the diagnostic applications of the particles, compositions or pharmaceutical compositions according to the invention are numerous and correspond to conventional applications of MRI techniques, optical imaging, optical detection of oxidant, CT, PET or ultrasound imaging.
  • the particles, compositions or pharmaceutical compositions are used in the implementation of the imaging techniques defined above, for the diagnosis of numerous disorders, in particular, without being limiting, the disorders linked to the brain.
  • the spinal cord large vessels, artery, intrathoracic organs (eg the heart), spine, digestive and pelvic viscera, joint muscles and adjacent structures, tendons, ligaments and peripheral nerves, and tumor cells.
  • the particles, compositions or pharmaceutical compositions are used, without being limiting, and depending on the imaging technique or the combination of imaging techniques used, for the diagnosis of coronary heart disease, valvular diseases, cardiomyopathies, congenital heart disease, pericardial diseases, congenital heart defects, tumors (bone, heart, lymphoma, pulmonary nodules, upper aerodigestive tract, hepatic localization of digestive cancers, melanoma, breast cancer, gynecological cancers), Inflammatory neurological diseases, herniated discs, discosomatic pathologies, traumatic spinal and spinal injuries, infectious spondylodiscitis, arteriovenous malformations and degenerative brain diseases such as Alzheimer's and Parkinson's.
  • valvular diseases congenital heart disease
  • pericardial diseases congenital heart defects
  • tumors bone, heart, lymphoma, pulmonary nodules, upper aerodigestive tract, hepatic localization of digestive cancers, melanoma, breast
  • the application also relates to the use of particles, compositions or pharmaceutical compositions according to the invention, in imaging, in particular in medical imaging, in particular in diagnosis or in diagnostic imaging, as defined above, and simultaneously as a medicament or in therapy.
  • “simultaneous” or “simultaneously” it is meant that the acquisition of the signals (in particular images) of the imaging technique (s) and the therapeutic stage of the treatment of the subject (animal or patient) are carried out , in the same subject, during the same investigation session, that is to say following a single injection of the particles, compositions or pharmaceutical compositions according to the invention.
  • the particles of the invention may also be used as a medicament or in therapy, the active ingredient possibly being the particle itself or a molecule therapeutic related to the particle.
  • the particle of the invention in its uncoated form itself constitutes, at least in part, the active ingredient of the drug.
  • A is Gd
  • the neutron capture therapy (TCN) can be implemented, based on the gigantic neutron absorption section by the Gd, in particular its 157 Gd isotope.
  • the nucleus of 157 Gd carries out a nuclear reaction 157 Gd + n ⁇ 158 Gd * ⁇ 158 Gd + ⁇ + ze " which causes the rapid emission of a high energy ⁇ radiation with an energy of up to 7.8 MeV and several electrons, including z electrons, mainly of the Auger type from the internal conversion with energies ⁇ 41 keV (De Stasio et al., 2001) Auger electrons are highly ionizing on These electrons may cause breaks in the double-stranded DNA in the tumor cells and lead to necrosis, and it is therefore advantageously possible to couple via a particle according to the invention in which A is Gd, MRI and TCN imaging (see Bridot et al (2009) on particles with a Gd 2 0 3 nucleus) TCN is suitable for the treatment of brain tumors, in particular glioblastoma multiforme In a mode of Particular embodiment, the particles, compositions or
  • the particle of the invention in its coated form constitutes the active principle of the drug, the particle being used in particular as a drug transport vehicle.
  • the particles according to the invention which carry therapeutic molecules (for example anticancer molecules) and optionally targeting molecules and / or stealth agents.
  • therapeutic molecules for example anticancer molecules
  • Therapeutic benefits have the advantage of allowing the monitoring of the progression and / or the accumulation of the drug at the target site by MRI and thus the adjustment of doses and administration intervals for maximum effect. This use is particularly suitable for the treatment of disorders that can be diagnosed by the imaging techniques mentioned above, in particular by MRI.
  • the particles, compositions or pharmaceutical compositions according to the invention are used as a diagnostic agent or as a contrast agent in MRI and in the treatment of tumors.
  • the invention also covers:
  • the particles, compositions or pharmaceutical compositions according to the invention for their simultaneous use in imaging, in particular as a diagnostic agent or as an MRI contrast agent, and as a medicament;
  • the particles, compositions or pharmaceutical compositions according to the invention for their simultaneous use in imaging, in particular as a diagnostic agent or as an MRI contrast agent, and as a medicament in the treatment of tumors;
  • the invention also relates to a method for the treatment of a subject, in particular the treatment of a subject suffering from tumor (s), comprising:
  • the doses used will be those commonly recommended for MRI techniques.
  • the dose administered to the subject ranges from 0.01 to 0.5 mmol / kg, in particular from 0.05 to 0.3 or 0.01 to 0.2 mmol / kg (in mmol of ion or paramagnetic ions).
  • Heart / shell type particles containing a core of formula Y 0 . 6 Eu 0 . 4 VO 4 and a shell of formula GdV0 4 were synthesized. Particles having a size of about 40 nm (ie a radius of 20 nm) were obtained.
  • the volume ratio between the core volume (c) and the shell volume (V s ) was calculated using a value of 5 nm for the thickness of the shell.
  • V NP is the volume of the particle The following volumetric ratio is obtained:
  • the solution of lanthanides in the core is itself a mixture of 60% (vol / vol) solution Y (N0 3 ) 3 and 40% (vol / vol) solution Eu (N0 3 ) 3 .
  • the shell a pure solution of Gd (N0 3 ) 3 was used.
  • the resulting crude particle dispersion was purified by dialysis or centrifugation to remove counterions in solution. Dialysis was performed in Spectra / Por regenerated cellulose dialysis membranes (MWCO 12-14 kDa, Spectrum Labs, Collinso Dominguez, CA, USA) against ultrapure water until the conductivity of the dispersion of particles less than 100 ⁇ 8 ⁇ " ⁇ " 1 . For large volumes, purification by centrifugation was performed. The dispersion was centrifuged at 26323 g for 20 minutes. The supernatant was removed and the precipitate redispersed in ultrapure water. The centrifugation-redispersion steps were repeated 3 to 5 times depending on the concentration factor and until a conductivity of the dispersed particles smaller than 100 ⁇ g ⁇ - ⁇ - 1 was reached.
  • the size selection was performed by two centrifugation steps.
  • the dispersion was first centrifuged at 500 g for 2 min and the supernatant thus obtained was centrifuged again at 1000 g for 2 min to remove aggregates and very large particles.
  • the supernatant contained a particle dispersion having a good compromise between a small size distribution and a high yield. Characterization by technique of the dynamic scattering of light gave (number average values) a hydrodynamic diameter of 55 nm with a width of the distribution of 16 nm
  • the spectrometer was calibrated using standard water / oil mixtures having a known component ratio according to the manufacturer's instructions.
  • the pre-diluted samples were further diluted directly in 10mm NMR (Nuclear Magnetic Resonance) tubes, in a series containing 10 1 ml samples. All dilutions were performed using ultrapure water.
  • Relaxivities per particle were determined by first calculating the volume of a particle.
  • the nanoparticles were considered to be homogeneous in size and spherical with a diameter equal to the number average diameter determined by DLS (dynamic light scattering).
  • DLS dynamic light scattering
  • the diameter of the uncovered (i.e. unmodified) particles was used.
  • the particle relaxivity was then obtained by multiplying the Gd ion relaxivity by the number of Gd ions per particle. 1.7. Acquisition of the luminescence spectra The dispersion of particles was pre-diluted so that it appeared almost transparent and was transferred to a 2 mm quartz cuvette QS 100 (Hellma, Mullheim, Germany). The emission spectra were recorded using a Hitachi F-4500 fluorescence spectrophotometer (Hitachi, High-Tech, Tokyo, Japan). Slots with a spectral width of 2.5 nm were used in the excitation and emission path, and scanning was performed at a rate of 240 nm / min.
  • a high-pass filter GG-375 Schott, Mainz, Germany
  • the luminescence was excited at 280 nm and the emission was recorded from 500 to 750 nm.
  • absorbance measurements for determination of the quantum yield at 280 nm when the absorbance exceeded 0.3, the sample was further diluted.
  • a dense particle layer was deposited by spin by adding 100 ⁇ of a 94 mM suspension (ion concentration 4 V0 3 ") Yo.6Euo particles. 4 (V04) / Gd (V0 4 ) on a quartz slide
  • the luminescence was recorded at an excitation intensity of 1.6 kW / cm 2 at an acquisition rate of 1 fps for 10 min. the photoreduction step, and for an excitation intensity of 0.3 kW / cm 2 at an acquisition rate of 1 image / 3 s for 10 min during the recovery, respectively.
  • the luminescence signals were normalized to a value of 1 for the first image analyzed during each acquisition cycle, the photoreduction and recovery values are given in the form of a circular region with homogeneous particle coverage. a percentage compared to this first re image.
  • Lai xEu x P0 4 / GdPO4 nanoparticles Lai-xEuxPO nanoparticles GdPCU, La1.xEuxPyVi.yO4 Gd PO4 nanoparticles and Y1.xEuxPyVi nanoparticles.
  • yO4 GdVO4 with x ranging from 10% to 75% and y ranging from 0.1 to 99% by adapting as above the nanoparticle synthesis protocols Lai.xEu x P0 4 , GdP0 4 , La1.xEUxPyV1.yO4, GdP y Vi.
  • Table 2 a number average diameter obtained by dynamic light scattering (DDL).
  • CC means coordination complex Yo particles. 6 Euo.4VO4 / GdVO4 (in a core / shell organization) are more efficient at inducing proton relaxation (rV 0 "and r 2 ' on than or equal to 4) than homogeneous GdV0 4 particles and Gdo homogeneous particles. These results are attributed to the fact that more magnetically active Gd ions are found near the surface in the Yo 6 Euo.4VO4 / GdVO4 particles and can thus interact more effectively with the water protons. in comparison with the Gd ion in homogeneous particles (GdV0 4 and Gd. Euo.4VO4 6) where a part of Gd ions are located within the particle. the latter does not have direct contact with the water.
  • the ratio of relaxivity r 2 / ri observed with the particles Yo.6Euo.4VO4 / GdVO4 is of the same order of magnitude as that obtained with Dotarem TM and free Gd 3+ ions (about 1, 2), only particles consisting of pure and homogeneous GdV0 4 having a higher ratio.
  • the luminescence spectrum of a suspension of nanoparticles Yo.6Euo.4VO4 / GdVO4 (in an organization heart / uille cock) is shown in Figure 2.
  • This spectrum shows a peak at 593 nm bound to the transition 5 D 0 ⁇ 7 F ⁇ , a double and strong main peak at 616 nm ( 5 D 0 ⁇ 7 F 2 ), a very weak peak at 650 nm ( 5 D 0 ⁇ 7 F 3 ), and another double peak at 699 nm ( 5 D 0 ⁇ 7 F 1 ).
  • This spectrum corresponds to the spectra found for YV0 4 doped with Eu in the literature (Huignard et al., 2000).
  • a calibration curve for determining quantum yield was obtained from the organic rhodamine 6G fluorophore.
  • the relative error of the adjustment is 2%.
  • the absorption of the nanoparticle dispersion at 280 nm is obtained as a peak on a background resulting from the scattering of incident light by the particles.
  • the measurement of the value of the absorbance at 280 nm / 2 8o, is not very accurate because of the contribution of diffusion. A total error in determining the quantum yield of the order of 5% therefore seems reasonable.
  • Yo.6Euo.4VO4 GdVO4 particles were spin coated on a quartz slide and excited at high laser intensity.
  • the corresponding time-dependent luminescence intensity is shown in Figure 3A.
  • the decreasing luminescence intensity observed confirms that a photoreduction of Eu 3+ ions takes place in the particles
  • Yo particles. 6 Euo.4VO4 / GdVO4 in their core-shell organization, are a powerful agent especially for multimodal imaging purposes. They can be used both as a luminescent marker, as an oxidant sensor and as a contrast agent for MRI. They combine a high luminescence quantum yield, particularly necessary for the detection of high sensitivity hydrogen peroxide, with a better MRI contrast than that obtained with conventional contrast agents.

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