Core / shell radioactive nanoparticles useful in targeted radiotherapy

Abstract

The present invention relates to a core / shell radioactive nanoparticle comprising: - a core based on a porous material, comprising one or more α-emitting radionuclide(s), - a first intermediate shell around the core, - optionally a second intermediate shell located between the first intermediate shell and the outer shell, and - an outer shell. The present invention also relates to the use of this radioactive nanoparticle as a drug, in particular in the prevention and / or treatment of cancer, and / or as an imaging agent.

Description

[0001] DESCRIPTION

[0002] CORE / SHELL-TYPE RADIOACTIVE NANOPARTICLES USEFUL IN TARGETED RADIOTHERAPY

[0003] FIELD OF THE INVENTION

[0004] The present invention relates to core / shell type nanoparticles encapsulating radionuclides with an improved retention rate, particularly useful in cancer radiotherapy.

[0005] STATE OF THE ART

[0006] In nuclear medicine, radioactive elements are used for the diagnosis or treatment of cancer.

[0007] Radiotherapy has been used for many decades to treat cancer. It uses radiation to destroy cancer cells and / or inhibit their growth. Often, this radiation is delivered from a source outside the patient's body, such as through the use of X-rays. Radiotherapy can also be delivered by administering a radionuclide to the patient, which will specifically target the tumor and emit short-range (beta-) or very short-range (alpha) ionizing radiation in a localized manner, destroying surrounding cancer cells. Other types of radionuclide (beta+ radiation), visible on imaging, are useful for cancer diagnosis.

[0008] Whether for imaging or therapy, the transport of radiopharmaceuticals within the body is generally carried out using vectors specific to the therapeutic target such as antibodies, peptides or aptamers. Nanoparticle (NP) systems enclosing the radionuclide have also been developed in recent years such as conjugated polymer NPs, liposomes, micelles or inorganic NPs (e.g. mesoporous silica NPs, iron oxide NPs, gold NPs or calcium phosphate NPs).

[0009] However, while radiotherapy can indeed limit the growth of cancer cells and destroy them, ionizing radiation, particularly alpha radiation, can be harmful to healthy cells. For example, when an alpha-emitting radionuclide decays, the released daughter isotope, which may itself be an alpha emitter, is likely to circulate within the body and affect healthy cells. This is particularly the case when the parent radionuclide is vectored to cancer cells using a specific vector such as an antibody; the released daughter isotope will not be bound to this antibody and will therefore be free to circulate throughout the body.

[0010] There is therefore a need for a system capable of delivering an effective dose of therapeutic ionizing radiation, in order to inhibit the growth of cancer cells while preventing the spread of this radiation to healthy cells, thus ensuring patient safety.

[0011] STATEMENT OF THE INVENTION

[0012] Surprisingly, the inventors have developed a tool in the form of a core / shell type nanoparticle, capable of delivering an effective dose of therapeutic radiation to treat a tumor, with a high retention rate of daughter radionuclides, thus limiting their impact on healthy cells.

[0013] A first object of the invention relates to a radioactive nanoparticle of the core / shell type comprising:

[0014] - a core based on a porous material comprising one or more a-emitting radionuclides,

[0015] - a first intermediate envelope around the heart,

[0016] - optionally a second intermediate envelope located between the first intermediate envelope and the external envelope and

[0017] - an external envelope.

[0018] In some embodiments, the intermediate shell(s) and the outer shell are independently made of a material selected from metals, metal oxides, metal alloys, a combination of multiple metals, a polymer, and a polymer blend.

[0019] In some embodiments, the outer shell and / or the intermediate shell(s) are made of a biodegradable material.

[0020] In some embodiments, at least one of the intermediate shell(s) and the outer shell is made of a material whose degradation products have antibacterial properties. In some embodiments, the intermediate shell(s) and the outer shell independently have a thickness ranging from 1 nm to 100 nm.

[0021] In some embodiments, the one or more a-emitting radionuclide(s) is (are) selected from the group consisting of 225 Ac, 223 Ra, 211 At, 212 Bi, 213 Bi, 227 Th, 224 Ra, 221 Fr and 213 Po.

[0022] In some embodiments, the core further comprises one or more p-emitting radionuclides independently selected from the group consisting of p+ emitting radionuclides, - emitting radionuclides, and a combination thereof.

[0023] A second subject of the present invention relates to a pharmaceutical composition comprising a radioactive nanoparticle according to the invention, and a pharmaceutically acceptable excipient.

[0024] A third subject of the invention relates to a radioactive nanoparticle according to the invention, or a pharmaceutical composition according to the invention, for its use as a medicament, in particular as a radiopharmaceutical in the treatment of cancer.

[0025] A fourth subject of the invention relates to a radioactive nanoparticle according to the invention, comprising one or more a-emitting radionuclides and one or more p+-emitting radionuclides, or a pharmaceutical composition according to the invention comprising such nanoparticles, for its use as an imaging agent.

[0026] A fifth subject of the invention relates to a radioactive nanoparticle according to the invention, comprising one or more a-emitting radionuclides and one or more p+-emitting radionuclides, or a pharmaceutical composition according to the invention comprising such nanoparticles, for its joint use for the imaging and treatment (and / or prevention) of cancer.

[0027] A sixth subject of the invention relates to a radioactive nanoparticle according to the invention, comprising one or more a-emitting radionuclides and one or more p+-emitting radionuclides, for determining by PET imaging a quantity of therapeutic radiation absorbed by a therapeutic target.

[0028] DESCRIPTION OF FIGURES

[0029] Figure 1: SEM images of SiC>2 NPs (A), SiO2-TiO2-Au NPs (B) and SiC>2-TiO2-Au-PEG NPs (C). Figure 2: Elemental mapping obtained by EDX of SiO2-TiO2-Au NPs.

[0030] Figure 3: Thermogravimetric curve of SiO2-TiO2-Au-PEG NPs

[0031] Figure 4: Representation of the release rate of 223 Ra after 5, 10, 20, 24 and 31 days in SiO2- NPs 223 Ra-TiO2 (dark gray, initial activity equal to 22.94 KBq) and in SiO2- NPs 223 Ra-TiO2-Au (light gray, initial activity equal to 38.85 KBq).

[0032] Figure 5: Representation of the release rate of 225 Ac after 5 and 12 days in SiO2 NPs- 225 Ac-TiO2 (dark gray) and in SiO2- NPs 225 Ac-TiO2-Au (light gray) (NP activity equal to 59.2 KBq).

[0033] DETAILED DESCRIPTION OF THE INVENTION

[0034] Definitions

[0035] For the purposes of the present invention, the expression “comprises a” means “comprises at least one” or “comprises one or more”. For example, the expression “comprising a radionuclide” means “comprises one or more radionuclides”.

[0036] The term "nanoparticle" (or NP) refers to a spherical solid particle with a size, that is, a diameter, ranging from a few nanometers to a few hundred nanometers.

[0037] The term "core / shell" (or "core / shell") nanoparticle refers to a nanoparticle whose core (the interior of the nanoparticle) is uniformly coated with a surface shell having a composition different from that of the core.

[0038] The term "radionuclide" (or radioisotope) refers to a radioactive atomic element, that is, unstable and capable of disintegrating into another element, called a daughter isotope, by emitting ionizing radiation. The daughter isotope may itself be a radionuclide (called a daughter radionuclide), or not. The daughter radionuclide does not necessarily emit the same type of ionizing radiation as the parent radionuclide from which it originates.

[0039] The half-life of a radionuclide is the time required for half of the radioactive nuclei initially present to have disintegrated. The activity of the radionuclide is then equal to half of the initial activity.

[0040] The term "ionizing radiation" refers to radiation, that is, the emission of particles of matter and energy, with an energy level high enough to cause the ionization of the matter it passes through. Ionizing radiation includes alpha radiation (a) consisting of helium nuclei, beta radiation (P) consisting of electrons or positrons, and gamma radiation (y) consisting of photons.

[0041] The term "α-emitting radionuclide" therefore refers to a radionuclide as defined above emitting α radiation (also referred to as an α particle) when it decays into a daughter isotope. It should be noted that the daughter isotope of an α-emitting radionuclide can also be an α-emitting radionuclide, or a radionuclide emitting another radiation, for example a β-emitting radionuclide.

[0042] The term "p-emitting radionuclide" therefore refers to a radionuclide as defined above emitting p radiation (also referred to as a P particle) when it decays into a daughter isotope. It should be noted that the daughter isotope of a p-emitting radionuclide can also be a p-emitting radionuclide, or a radionuclide emitting another radiation, for example an a-emitting radionuclide.

[0043] Radiotherapy is a treatment method that uses ionizing radiation to destroy cancer cells.

[0044] The activity of a radioactive source is expressed in Becquerel (Bq). One Bq is equivalent to one disintegration per second.

[0045] The absorbed radioactive dose corresponds to the amount of energy absorbed per unit mass of the exposed material. The dose is expressed in Gray (Gy) and 1 Gy = 1 Joule / kg.

[0046] The equivalent dose is a dosimetric quantity used to translate the harmfulness of a given absorbed dose (Gy) onto the same reference scale, in order to assess the actual risk of said absorbed dose. Indeed, for the same absorbed dose (in Gy), the risk to the exposed living matter is not the same depending on the type of radiation, the exposure time, and the sensitivity of the exposed living matter. For example, for the same absorbed dose, alpha radiation is approximately 4 to 5 times more toxic to cells than gamma or X-ray radiation. The equivalent dose is expressed in Sieverts (Sv) with 1 Sv = Dose (Gy) x Radiation Quality Factor. The equivalent dose value in Sieverts of alpha radiation will therefore be 4 to 5 times higher than the equivalent dose of gamma or X-ray radiation.

[0047] Radioactive nanoparticle The nanoparticle of the invention typically has a size ranging from 5 nm to 300 nm, preferably from 50 nm to 280 nm, more preferably from 100 nm to 250 nm and in particular from 180 nm to 250 nm.

[0048] The radioactive nanoparticle of the invention has a core / shell type structure as defined below.

[0049] - The heart

[0050] The radioactive nanoparticle of the invention has a core based on a porous material, for example mesoporous. “Based on a porous material” means that the porous material represents the main constituent of the core. The core is notably made of this porous material. The porous material is typically chosen from porous silica, zeolites such as aluminosilicates (clinoptilolite, chabazite or modernity), and MOFs (metal-organic frameworks) such as ZIFs (zeolitic imidazolate frameworks) for example ZIF-8. Preferably, the core is based on, notably made of, porous silica.

[0051] The core has a diameter in a range of 7 to 298 nm, preferably 50 to 280 nm.

[0052] In particular, silica is mesoporous, meaning it has pores smaller than 50 nm, ranging from 0.3 nm to 50 nm, which gives it a particularly large active surface area. In addition, the pores have numerous deprotonated Si-O- sites that facilitate and stabilize the adsorption of radionuclides within the pores. The size of the pores allows more or less radionuclides to be adsorbed, depending on the desired activity of the nanoparticle. The larger the pore diameter, the greater the quantity of radionuclides adsorbed on the silica.

[0053] The heart is notably biodegradable.

[0054] - The first intermediate envelope, the second intermediate envelope and the external envelope

[0055] The core is coated with a first intermediate shell forming a uniform layer around the core. This first intermediate shell is in direct contact with the core. The first intermediate shell is itself coated either with a second intermediate shell forming a uniform layer around the first, or directly with an outer shell forming a uniform layer on the surface of the nanoparticle. The outer shell is therefore in direct contact with either the first or the second intermediate shell.

[0056] In a particular embodiment, the nanoparticle may comprise additional intermediate shells, for example three, four or five intermediate shells. Preferably, however, the nanoparticle only comprises one or two intermediate shells.

[0057] The role of the intermediate and external envelopes is to retain within the nanoparticle, in other words to sequester, the radionuclides and prevent their diffusion outside the nanoparticle, while allowing the ionizing radiation emitted during the disintegration of the radionuclide to pass through. Since the nanoparticle is intended for use within the human body, the envelopes therefore have the role of preventing the circulation within the body of radionuclides, which present a high toxicity, while allowing the passage of ionizing radiation useful for radiotherapy and medical imaging. The envelopes also make it possible to sequester the daughter isotopes resulting from the degradation of the radionuclides initially present in the nanoparticle. The presence of a double or triple envelope makes it possible to reinforce this sequestration capacity and to drastically reduce the release rate of radionuclides compared to a single envelope.

[0058] The intermediate and outer shells are independently made of a material selected from metals, metal oxides, metal alloys, a combination of several metals, a polymer and a mixture of polymers.

[0059] When the intermediate or external shell comprises or is made of a metal, this is in particular gold, platinum or combinations thereof. When the intermediate or external shell comprises or is made of a metal oxide, this is in particular titanium oxide, silica or combinations thereof. When the intermediate or external shell comprises or is made of a polymer, it is in particular chosen from polysaccharides (for example starch or cellulose), polyethylene glycol (PEG), polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA) and a mixture thereof. The polymer may optionally be functionalized, for example to reinforce the stability of the nanoparticle. Preferably, only the external shell may comprise or be made of a polymer.

[0060] It is understood that each shell is different from the adjacent shell. Thus, when the nanoparticle contains a single intermediate shell and an outer shell, these two shells are different. When the nanoparticle contains two intermediate shells and an outer shell, the first intermediate shell is different from the second intermediate shell and the second intermediate shell is different from the outer shell, the outer shell and the first intermediate shell may be the same or different.

[0061] In some embodiments, the outer shell and / or the intermediate shell(s) are made of a biodegradable material. Preferably, at least the outer shell is made of a biodegradable material. In a particular embodiment, the intermediate shell(s) and the outer shell are all made of a biodegradable material. It is understood that even if the outer shell and possibly the intermediate shell(s) are made of a biodegradable material, the shells perform their role of retaining the radionuclide(s) at least during the longest half-life of the radionuclides present. In other words, the biodegradation takes place according to sufficiently slow kinetics so that it takes place once the half-life of the radionuclide(s) has elapsed (taking into account the longest half-life).Biodegradation of the envelope occurs in particular when the radionuclide is stable and no longer emits ionizing radiation. A person skilled in the art will be able to select the biodegradable material having degradability kinetics adapted according to the longest half-life of the radionuclide(s) encapsulated in the nanoparticle.

[0062] The biodegradation of the envelopes takes place thanks to the cellular environment of the nanoparticles, for example by enzymatic means.

[0063] Advantageously, the biodegradation of at least one of the envelopes leads to the formation of by-products having therapeutic properties, for example antibacterial properties. In other words, at least one of the envelopes is made of a material whose degradation products have antibacterial properties.

[0064] In certain advantageous embodiments, the first intermediate shell is made of titanium oxide. Titanium oxide has the advantage of being chemically inert and easily functionalizable. The degradation products of titanium oxide have the particular advantage of possessing antibacterial properties.

[0065] In certain advantageous embodiments, the outer shell or the second intermediate shell is made of gold or platinum. Gold and platinum have the particular advantage of being chemically stable, non-toxic and easily functionalized via existing methods. The degradation products of platinum have the particular advantage of possessing antibacterial properties.

[0066] In a first variant of the invention, the nanoparticle comprises a first intermediate shell and an outer shell but is devoid of a second intermediate shell. In this first variant, the intermediate shell and the outer shell are preferably as described above.

[0067] In a second variant of the invention, the nanoparticle comprises a first intermediate shell, a second intermediate shell and an outer shell. In this second variant, the intermediate shells and the outer shell are preferably as described above. In an advantageous embodiment of this second variant, the first intermediate shell is made of titanium oxide, the second intermediate shell is made of gold or platinum, and the outer shell is made of a polymer, in particular polyethylene glycol. In a particular example, the polymer is functionalized so as to be able to create covalent bonds with the second outer shell, making it possible to stabilize the multiple shells.

[0068] The intermediate shell(s) and the outer shell typically have, independently of each other, a thickness ranging from 1 nm to 100 nm, preferably from 1 nm to 50 nm, more preferably from 2 nm to 20 nm. The thinness of the shells facilitates their degradation when they are made of a biodegradable material.

[0069] In some embodiments, the outer shell is functionalized. In particular, it may be functionalized with one or more targeting molecules capable of targeting a site to be treated and leading the nanoparticle there (active targeting). For example, the targeting molecules are chosen from antibodies, peptides or proteins. They may be linked to the surface of the nanoparticle via a linker if necessary.

[0070] - Radionuclides

[0071] The radioactive nanoparticle according to the invention comprises one or more a-emitting radionuclide(s).

[0072] When the radioactive nanoparticle comprises an a-emitting radionuclide, this means that it contains only one type of a-emitting radionuclide. When the radioactive nanoparticle comprises several a-emitting radionuclides, this means that it comprises a-emitting radionuclides of different nature, i.e. different atomic elements. The same understanding applies to radionuclides emitting other types of radiation, such as p+ or p- radiation, in the case where such radionuclides are also present in the nanoparticle.

[0073] Radionuclides are adsorbed onto the porous material of the nanoparticle core.

[0074] The elements listed below are understood to be the radionuclides initially present within the nanoparticle. Of course, during the lifetime of the nanoparticle, the radionuclides initially present disintegrate, one or more times, depending on their half-life time and the duration during which the nanoparticle is administered, and the nanoparticle then comprises the daughter radionuclides resulting from this or these disintegrations. This means that the daughter radionuclides also remain sequestered within the nanoparticle of the invention.

[0075] The emitting radionuclides a are for example independently chosen from 225 Ac, 223 Ra, 211 At, 212 Bi, 213 Bi, 227 Th, 224 Ra, 221 Fr and 213 Po. Preferably, the emitting radionuclides a are chosen from 225 Ac and 223 Ra.

[0076] Furthermore, in addition to the a-emitting radionuclides, the nanoparticle may comprise one or more p-emitting radionuclides.

[0077] The p-emitting radionuclides are chosen from p+ emitting radionuclides and p- emitting radionuclides. The radioactive nanoparticle of the invention may comprise one or more p+ emitting radionuclides, one or more p- emitting radionuclides or a mixture of p+ and p- emitting radionuclides. Preferably, the radioactive nanoparticle of the invention comprises one or more p+ emitting radionuclides or one or more p- emitting radionuclides.

[0078] The p+ emitting radionuclides are for example chosen from 89 Zr, 18 F, 11 C, 13 N, 15 0, 68 Ga, 82 Rb, 64 Cu, 124 l and 207 Bi. Preferably, the p+ emitting radionuclides are chosen from 89 Zr and 64 Cu.

[0079] The p- emitting radionuclides are for example chosen from 131 1, 89 Sr, 153 Sm, 32 P, 90 Y, 166 Ho, 177 Read, 188 D, 169 Er, 145 Pm, 67 Cu and 212 Pb. Preferably, the P- emitting radionuclides are chosen from 90 Y, 67 Cu, 212 Pb and 177 Read.

[0080] In a preferred embodiment, the radioactive material of the invention comprises only one or more α-emitting radionuclides as defined above. Such a nanoparticle is particularly useful in targeted radiotherapy and makes it possible to deliver an effective dose of therapeutic radiation to the patient while ensuring their safety, α-radiation being the most effective against cancer cells, and the double envelope of the nanoparticle ensuring effective retention of the radionuclides.

[0081] In other embodiments, the radioactive nanoparticle of the invention comprises one or more α-emitting radionuclides and one or more p+-emitting radionuclides, and is devoid of p-emitting radionuclides. Such a nanoparticle is particularly useful in a theranostic approach, consisting of both an imaging agent and a therapeutic agent. In particular, such a nanoparticle makes it possible to perform efficient detection and visualization of cancer cells, while delivering a dose of therapeutic ionizing radiation sufficient to inhibit the growth of the cancer cells.

[0082] In these embodiments, the radioactive nanoparticle preferably comprises a single α-emitting radionuclide, notably chosen from 225 Ac and 223 Ra, and a single p+ emitting radionuclide, in particular 89 Zr.

[0083] In other embodiments, the radioactive nanoparticle of the invention comprises one or more α-emitting radionuclides and one or more p-emitting radionuclides, and is devoid of p+ emitting radionuclides. Such a nanoparticle is particularly useful in targeted radiotherapy and makes it possible to deliver an effective dose of therapeutic radiation to the patient while ensuring their safety. Indeed, by combining these two types of radiation within the same nanoparticle, it is possible to reduce the dose of alpha radiation delivered, which is the most dangerous, and to achieve the necessary therapeutic dose with beta- radiation, which is less harmful to health.

[0084] In these embodiments, the radioactive nanoparticle comprises a single α-emitting radionuclide, notably chosen from 225 Ac and 223 Ra, and a single p-emitting radionuclide, notably chosen from 90 Y, 67 Cu, 212Pb and 177 Read.

[0085] The quantity of each radionuclide in the nanoparticle defines its activity, expressed in Becquerel. Thus, the nanoparticle of the invention has an activity defined in alpha radiation and possibly an activity defined in beta radiation. These activity levels are defined so that their combination leads to therapeutic efficacy while limiting toxicities.

[0086] This simultaneous presence of two types of radionuclides in the nanoparticle at the start of its use, in particular at the time of its administration to the patient, makes it possible to obtain activity levels which could not be achieved if only the descendants resulting from the radioactive decay of an alpha emitter were considered.

[0087] For example, while a beta-emitting therapeutic radionuclide requires activities of several GBq (see for example the product Lutathera™) to lead to therapeutic efficacy, such activity levels will never be reached by the descendants (beta-emitters) resulting from the decay of an alpha-emitting parent radionuclide (eg 225 Ac ). Indeed, the activity of the emitting radionuclides has (eg 225 Ac, 223 Ra) administered is generally of the order of a few MBq. However, the disintegration of an a emitter with an activity of a few MBq can give rise to a maximum of a p- activity, equal to twice the initial alpha activity, but in no case of the same order of magnitude (a few GBq) as that required in RIV for p- emitters. The nanoparticles of the invention therefore make it possible to achieve activity levels compatible with a therapy and p- therapy.

[0088] The same reasoning applies to nanoparticles comprising a-radionuclides and p+ radionuclides. The disintegration of an a-emitting radionuclide will never allow a sufficient level of activity in gamma / x / p+ emission to be achieved to obtain imaging of sufficient quality, unless a very long acquisition time is planned and an image of average quality is accepted. The simultaneous presence in the nanoparticle of an a-emitting radionuclide and a p+ emitting radionuclide at the start of administration makes it possible to obtain compatible activity for the use of nanoparticles in a-therapy and imaging simultaneously.

[0089] Pharmaceutical composition

[0090] The present invention relates to a pharmaceutical composition, more precisely a radiopharmaceutical composition, comprising radioactive nanoparticles according to the invention, and a pharmaceutically acceptable excipient.

[0091] In a preferred embodiment, the pharmaceutical composition of the invention comprises nanoparticles comprising one or more α-emitting radionuclides, in particular nanoparticles comprising a single α-emitting radionuclide, such as 225 Ac or 223 Ra, and devoid of emitting radionuclides p.

[0092] In certain embodiments, the pharmaceutical composition of the invention comprises nanoparticles comprising one or more α-emitting radionuclides and one or more p+-emitting radionuclides, in particular nanoparticles comprising a single α-emitting radionuclide, such as 225 Ac or 223 Ra, and a single p+ emitting radionuclide, such that 89 Zr, and devoid of p- emitting radionuclide.

[0093] In other embodiments, the pharmaceutical composition of the invention comprises nanoparticles comprising one or more α-emitting radionuclides and one or more β-emitting radionuclides, in particular nanoparticles comprising a single α-emitting radionuclide, such as 225 Ac or 223 Ra, and a single p-emitting radionuclide, such that 90 Y, 67 Cu, 212 Pb or 177 Lu., and devoid of p+ emitting radionuclide.

[0094] In other embodiments, the pharmaceutical composition of the invention comprises nanoparticles comprising one or more α-emitting radionuclides, one or more p-emitting radionuclides and one or more p+ emitting radionuclides, in particular nanoparticles comprising a single α-emitting radionuclide, such as 225 Ac or 223 Ra, a single p+ emitting radionuclide, such that 89 Zr and a single p- emitting radionuclide, such that 90 Y,67 Cu, 212 Pb or 177 Read.

[0095] The pharmaceutically acceptable excipient must be compatible with the intended mode of administration and compatible with the radioactive nanoparticle of the invention.

[0096] The pharmaceutical composition according to the invention is in particular formulated for intratumoral, intravenous or topical administration.

[0097] The pharmaceutical composition is therefore advantageously in the form of a suspension of nanoparticles in a pharmaceutically acceptable solvent, in particular in a saline solution. The composition may further comprise additives such as pH buffers, emulsifiers, wetting agents or combinations thereof.

[0098] Alternatively, the composition may be deposited on or incorporated into a medical device. Such a medical device is, for example, suitable for in situ application at the therapeutic target, or for topical application.

[0099] The composition of the invention is advantageously formulated so as to possess the activities making it possible to deliver the doses as specified above according to the quantity of composition administered to humans.

[0100] Each radionuclide encapsulated within the NPs of the invention is provided in the form of a solution of this radionuclide, in particular a solution of a salt of this radionuclide, having a predefined volume activity (in Bq / mL). The activity of each NPs therefore depends on the volume activity of this radionuclide solution, the half-life time of the radionuclide and the size of the NPs.

[0101] For example, the composition administered to the patient has an emission activity a ranging from 1 MBq to 20 MBq, preferably from 5 MBq to 10 MBq per administration.

[0102] For example, when the nanoparticles of the composition comprise one or more p+ emitting radionuclides, the composition administered to the patient has a P+ emission activity ranging from 10 MBq to 300 MBq, preferably from 30 MBq to 100 MBq per administration.

[0103] For example, when the nanoparticles of the composition comprise one or more p- emitting radionuclides, the composition administered to the patient has a P- emission activity ranging from 1 GBq to 20 GBq, preferably from 5 GBq to 8 GBq per administration.

[0104] Use of nanoparticles

[0105] Therapeutic use The nanoparticles of the invention, or the pharmaceutical composition of the invention, are useful as a medicament, in particular for the prevention and / or treatment of cancer.

[0106] In other words, the present invention relates to the use of a radioactive nanoparticle according to the invention, or of a pharmaceutical composition according to the invention, as a medicament or for the manufacture of a medicament, in particular intended for the prevention and / or treatment of cancer.

[0107] In other words, the present invention relates to a method for preventing and / or treating cancer comprising administering at an effective dose to a person in need thereof a radioactive nanoparticle according to the invention, or a pharmaceutical composition according to the invention.

[0108] The nanoparticles of the invention, or the pharmaceutical composition of the invention, are particularly useful in radiotherapy, more particularly in targeted radiotherapy. α-ionizing radiation and p-ionizing radiation are effective in radiotherapy and can destroy cancer cells. Thus, the nanoparticles of the invention are useful in radiotherapy.

[0109] In targeted radiotherapy, the nanoparticles of the invention will specifically target the cancer cells to be treated and accumulate there. This targeting is carried out on the one hand by the size of the nanoparticles which will more easily accumulate on the cancer cells. This is called passive targeting. This targeting can also be carried out using a targeting molecule grafted onto the surface of the nanoparticles. This is called active targeting.

[0110] In particular, the local injection of the nanoparticles of the invention at the level of the tumor makes it possible to release ionizing radiation which will specifically destroy the surrounding cancer cells and / or limit their spread, while preserving healthy tissues.

[0111] In some embodiments, the nanoparticles of the invention for use in the prevention and / or treatment of cancer are administered to a person in need thereof with the following activities:

[0112] - an activity of the emitting radionuclides ranging from 1 MBq to 20 MBq, preferably from 5 MBq to 10 MBq, and

[0113] - if applicable, an activity of p+ emitting radionuclides ranging from 10 MBq to 300 MBq, preferably from 30 MBq to 100 MBq, and / or

[0114] - if applicable, an activity of the p- emitting radionuclides ranging from 1 GBq to 20 GBq, preferably from 5 GBq to 10 GBq. The cancers to be prevented and / or treated by the nanoparticles of the invention are, for example, chosen from pancreatic cancer, liver cancer, prostate cancer, breast cancer, ovarian cancer, vulvar cancer, vaginal cancer, brain cancer, skin cancer, neck cancer, head cancer, neuroendocrine tumors, leukemias and lymphomas.

[0115] Use in imaging

[0116] Ionizing p+ radiation is visible on imaging through the body. A and p- radiation are not visible on imaging.

[0117] Thus, only nanoparticles of the invention comprising one or more a-emitting radionuclides and one or more p+-emitting radionuclides, or a pharmaceutical composition comprising such nanoparticles, are useful as an imaging agent.

[0118] The nanoparticles according to the invention useful in imaging may further comprise one or more p-emitting radionuclides.

[0119] In a particular embodiment, the nanoparticles of the invention useful in imaging comprise one or more α-emitting radionuclides and one or more p+-emitting radionuclides, and are devoid of p-emitting radionuclides. Preferably, they contain an α-emitting radionuclide, for example chosen from 225 Ac and 223 Ra, and a p+ emitting radionuclide, for example 89 Zr.

[0120] In particular, this imaging agent is useful in PET (Positron Emission Tomography) imaging, which allows the visualization of radioactive nanoparticles comprising a p+ emitting radionuclide within the body.

[0121] As previously stated, the nanoparticles of the invention will specifically accumulate at the level of cancer cells via passive and possibly active targeting. Consequently, the accumulation of the imaging agent according to the invention at the level of a cancerous tumor will make it possible to visualize the latter and to evaluate its size. The distribution of the NPs in the tumor will also be visualized.

[0122] In particular, the nanoparticles according to the invention useful as an imaging agent make it possible to locate a tumor within the body, in particular the human body.

[0123] Use in theranostics

[0124] As stated in the introduction, theranostics refers to the simultaneous use of imaging and therapy.

[0125] The nanoparticles of the invention comprising one or more α-emitting radionuclides and one or more p+-emitting radionuclides, or a pharmaceutical composition comprising such nanoparticles, are useful in theranostics. In other words, the nanoparticles of the invention comprising one or more α-emitting radionuclides and one or more p+-emitting radionuclides, or a pharmaceutical composition comprising such nanoparticles, can be used together for the imaging and treatment (and / or prevention) of cancerous tumors. In particular, such nanoparticles allow for effective detection and visualization of cancerous cells, while delivering a dose of therapeutic ionizing radiation sufficient to inhibit the growth of cancerous cells.

[0126] The nanoparticles according to the invention useful in theranostics may further comprise one or more p- emitting radionuclides.

[0127] In a particular embodiment, the nanoparticles of the invention useful in theranostics comprise one or more α-emitting radionuclides and one or more p+-emitting radionuclides, and are devoid of p-emitting radionuclides. Preferably, they contain an α-emitting radionuclide, for example chosen from 225 Ac and 223 Ra, and a p+ emitting radionuclide, for example 89 Zr.

[0128] Use of the nanoparticles of the invention in theranostics makes it possible, in particular, to visualize the cancerous tumor, for example via PET, at the same time as the therapeutic action of the nanoparticles is exerted. It is thus possible to visualize the size of the cancerous tumor and to verify by imaging the cessation of tumor growth or the reduction in tumor size.

[0129] The nanoparticles of the invention useful jointly for imaging and treating (and / or preventing) cancerous tumors are as described for use as an imaging agent.

[0130] Use in dosimetry

[0131] The nanoparticles according to the invention comprising one or more a-emitting radionuclides and one or more p+ emitting radionuclides, or a pharmaceutical composition comprising such nanoparticles, are useful in dosimetry, i.e. for determining the dose of therapeutic radiation having reached the therapeutic target, i.e. the cancer cells. In other words, the nanoparticles according to the invention comprising one or more a-emitting radionuclides and one or more p+ emitting radionuclides, or a pharmaceutical composition comprising such nanoparticles, can be used to determine by PET imaging a quantity of therapeutic radiation absorbed by a therapeutic target. In practice, visualization by imaging, typically by PET imaging, of the distribution of the nanoparticles in the tumor makes it possible to quantify the dose of radiation absorbed by the tumor.Indeed, the intensity of the measured signal is a function of the number of photons visualized, and therefore of the number of p+ emitting radionuclides visualized in the tumor. It is possible from this data, and knowing the initial ratio of therapeutic radiation emitting radionuclides / p+ emitting radionuclides of the nanoparticles, to find the quantity of alpha emitting radionuclide distributed to the tumor. Indeed, the advantage of the nanoparticle of the present invention is to integrate the two types of radionuclides in a single nanoparticle, so that it is certain that the two radionuclides have the same distribution within the body. By visualizing the distribution of the P+ emitting radionuclides, the distribution of the therapeutic radiation emitting radionuclides is automatically obtained, and therefore the absorbed dose.By difference with the initially administered quantity, it is also possible to deduce the quantity of radiation distributed to healthy tissues and therefore to measure the possible toxicity of the nanoparticles.

[0132] The nanoparticles according to the invention comprising one or more a-emitting radionuclides and one or more p+ emitting radionuclides, or a pharmaceutical composition comprising such nanoparticles, can therefore be used in a method of dosimetry of therapeutic radiation having reached the therapeutic target comprising: i) administration of the nanoparticles into the body, the nanoparticles having a known ratio of therapeutic radiation emitting radionuclides / p+ emitting radionuclides;ii) visualization by imaging of the nanoparticles, in particular by PET imaging, and determination of the intensity of the signal emitted by the p+ emitting radionuclides iii) quantification of the activity of the p+ emitting radionuclides using the intensity of the signal determined in step ii) iv) quantification of the activity of the radionuclides emitting therapeutic radiation using the ratio of radionuclides emitting therapeutic radiation / radionuclides p+;

[0133] The nanoparticles according to the invention useful in dosimetry may further comprise one or more p- emitting radionuclides. In this case, the therapeutic radiation corresponds to a- radiation and p- radiation.

[0134] In a particular embodiment, the nanoparticles of the invention useful in dosimetry comprise one or more α-emitting radionuclides and one or more p+-emitting radionuclides, and are free of p-emitting radionuclides. Preferably, they contain an α-emitting radionuclide, for example chosen from 225 Ac and 223 Ra, and a p+ emitting radionuclide, for example 89 Zr. In this case, the therapeutic radiation corresponds to a radiation only.

[0135] In other words, the present invention therefore relates to a method for preventing and / or treating cancer as described above, in which the nanoparticles of the invention comprise one or more a-emitting radionuclides and one or more p+-emitting radionuclides, the method further comprising the determination, in particular by PET imaging, of a quantity of therapeutic radiation absorbed by a therapeutic target, i.e. the cancer cells.

[0136] Process for preparing nanoparticles

[0137] The present invention also relates to a method for preparing the nanoparticles of the invention comprising the following steps: a) Sol-gel preparation of nanoparticles based on porous material, b) Radiolabeling of the nanoparticles resulting from step a) with one or more a-emitting radionuclides and if applicable with one or more p+ emitting radionuclides and / or one or more p- emitting radionuclides, c) Coating of the radioactive nanoparticles resulting from step b) with an intermediate shell, d) Coating of the radioactive nanoparticles resulting from step c) with an external shell.

[0138] The radionuclides included in the nanoparticles and the intermediate and outer shells are as described above.

[0139] The method of the invention makes it possible to simultaneously encapsulate different radionuclides, via a universal approach, independent of the nature of each radionuclide.

[0140] The sol-gel process of step a) is well known to those skilled in the art. Typically, when the porous material is porous silica, the sol-gel process is carried out by placing in aqueous solution, preferably in the presence of a base, a silicon alkoxide, such as tetraethyl orthosilicate (TEOS). The silica-based nanoparticles are then formed by centrifugation of the resulting solution.

[0141] Radiolabeling step b) is carried out by physical adsorption of the radionuclides onto the nanoparticles from step a). In a first variant, each radionuclide is added separately and successively. In the case where the nanoparticle comprises several radionuclides of the same type, for example several α-emitting radionuclides, each will be adsorbed separately and successively by the core of the nanoparticle. The same applies in the case where the nanoparticle comprises an α-emitting radionuclide and a β-emitting radionuclide. Advantageously, the order of adsorption of the radionuclides depends on their half-life.

[0142] In a second variant, the radionuclides are added simultaneously.

[0143] Typically, a solution of a radionuclide, particularly a radionuclide salt, is added to a suspension of nanoparticles. The nanoparticles are, for example, suspended in a buffer solution at neutral pH. The mixture is heated, for example, between 50°C and 80°C, then centrifuged to recover the radiolabeled nanoparticles. An ultrasonication step of the mixture can also be carried out to improve adsorption. This protocol is repeated for each radionuclide to be adsorbed by the core of the nanoparticle in the case of successive adsorptions. In the case of simultaneous adsorptions, the solution in which the nanoparticles are suspended contains the radionuclides to be adsorbed.

[0144] The methodology of coating steps c) and d) depends on the nature of the intermediate and external envelopes. A person skilled in the art will know how to apply the appropriate protocol for carrying out the coating depending on the nature of the envelope.

[0145] In a particular example, both the intermediate shell and the outer shell are metallic. Coating step c) is carried out by suspending the radiolabeled nanoparticles from step b) in a solution containing a solvent, for example an alcohol such as ethanol, and a metal or metal oxide. For example, if the intermediate shell consists of titanium dioxide, the solution comprises titanium butoxide. The nanoparticles are left suspended in this solution for the time necessary for the coating to be carried out. The nanoparticles are then centrifuged and recovered. Step d) is then carried out by suspending the radiolabeled nanoparticles from step c) in a solution containing a solvent, and a metal or metal oxide. For example, if the outer shell consists of gold, the solution comprises potassium gold.The nanoparticles from step c) are first suspended in a hydrogen tetrachloroaurate solution before being suspended in the potassium-gold solution. The nanoparticles are left suspended in this potassium-gold solution for the time required for the coating to be achieved. The nanoparticles are then centrifuged and recovered. In each of steps c) and d), the suspension time must be less than the half-life of the encapsulated radionuclides.

[0146] The method for preparing nanoparticles may include an intermediate step a') between steps a) and b) of storing the nanoparticles. Indeed, nanoparticles based on porous material, for practical reasons, can be produced on a large scale, then stored for a significant time and / or transported, for example to the injection site.

[0147] On the other hand, steps b), c) and d) are preferably carried out successively within a short period of time depending on the half-life of the adsorbed radionuclides.

[0148] Preferably, once step d) is completed, the radioactive nanoparticles will be administered to the patient in need within a very short period of time depending on the half-life of the adsorbed radionuclides.

[0149] For example the half-life time of 223 Ra is 11.4 days and that of the 89 Zr is 78h (3d). In a nanoparticle comprising 223 Ra and the 89 Zr, the half-life time is 89 Zr is therefore limiting and will condition the durations in which steps c) and d) must be carried out, then administration to the patient.

[0150] EXAMPLES

[0151] 1) Synthesis of nanoparticles

[0152] 1. 1. Synthesis of silica-based nanoparticles

[0153] SiC>2 nanoparticles (NPs) are prepared using the sol-gel method. To do this, 8.75 mL of ethanol (99.9%) and 2.4 mL of milli-Q water are mixed for 5 minutes. Then, 65 pL of 99% tetraethylorthosilicate (TEOS) and 390 pL of ammonium hydroxide are added. The resulting mixture is stirred for 2 hours. The resulting solution is then transferred into 2 mL centrifuge tubes to separate the SiO2 nanoparticles by centrifugation at a rotation speed of 12,000 rpm for 5 min. A washing step is performed by centrifugation at 12,000 rpm for 5 minutes, once with ethanol and once with milli-Q water. Finally, the formed SiO2 NPs are dried in an oven at 70°C for 15 min.

[0154] 1.2. Radiomarguacie of S1O2 NPs with 223 R a

[0155] Radiolabeling was achieved by physical adsorption of 223Ra by the synthesized SiO2 NPs. Initially, 3 mg of SiO2 NPs were suspended in 1 mL of 10 mM HEPES buffer solution (pH 7.2), then a solution containing 223 Ra and 2.5 pL of 2M Na2COs solution were added to the tube.

[0156] The mixture was incubated at 70°C for 60 min with a rotation speed of 1000 rpm. The solution was suspended by ultrasonication for 15 min to enhance the adsorption of the radionuclide. Then, the labeled NPs were centrifuged at 12,000 rpm for 5 min and washed twice with milli-Q water. During the different steps, the supernatants were collected and the radioactivity was measured using a gamma counter.

[0157] 1.3. Radiolabeling of S1O2 NPs with 225 Ac

[0158] Radiolabeling is carried out by physical adsorption of 225Ac by the synthesized SiC>2 NPs. Initially, 3 mg of SiC>2 NPs are suspended in 1 mL of a 10 mM HEPES buffer solution (pH 7.2), then a solution containing [ 225 Ac] AcNO3 (solution in 0.1 M ultrapure HCl at 59.2 KBq) and 2.5 μL of 2M Na2COs solution are added to the tube. The mixture is incubated at 70°C for 60 min with a rotation speed of 1000 rpm. The solution is suspended by ultrasound for 15 min to improve the adsorption of the radionuclide. Then, the radiolabeled NPs are centrifuged at 12,000 rpm for 5 min and washed twice with milli-Q water. During the different steps, the supernatants are collected and the radioactivity is measured using a gamma counter.

[0159] 1.4. Coating of SiO2 NPs- 223 Ra with a TiO2 layer

[0160] After the radiolabeling process, the SiO2- nanoparticles 223Ra were coated with a layer of TiO2. For this, 3 mg of SiO2 NPs- 223 Ra are transferred into a 1.5 mL solution containing a mixture of titanium butoxide (Ti^HgO)^ and ethanol in a volumetric ratio of 1:75. The solution is then subjected to ultrasound to ensure the suspension of the particles. After 15 min, the solution is left at room temperature for 24 h without stirring, which allows the formation of the SiO2- nanoparticles. 223 Ra- TiO2. In order to remove heavy aggregates, centrifugation at 800 rpm for 1 min is carried out. The supernatant containing the SiO2- nanoparticles 223 Ra-TiO2 is recovered and transferred to a new container to be centrifuged at 12,000 rpm for 5 min. A wash at 12,000 rpm for 3 min is carried out once with ethanol and once with milli-Q water.

[0161] 1.5. Coating of SiO2 NPs- 223 Ra-TiO2 with a gold layer

[0162] The synthesis of SiO2- nanoparticles 223 Ra-TiO2-Au was carried out in three steps using hydrogen tetrachloroaurate (HAuCL) and SiO2- nanoparticles 223 Ra-TiO2 obtained previously. In the first step, a potassium-gold (K-gold) solution was prepared by dissolving potassium carbonate (K2CO3) in purified water at a concentration of 280 mg / L. Simultaneously, a 25 mM HAuCL solution was prepared while adjusting the acidity to pH 7 with 1 M NaOH. These two solutions were combined in a single tube containing 8 mL of K2CO3 and 120 μl of HAuCk and stirred in the dark for 12 hours. The second step involves suspending 3 mg of SiO2- nanoparticles 223Ra- TiO2 in 2 mL of 6.35 mM HAuCk (pH = 7). The resulting suspension was mixed at 96 °C for 15 minutes (1000 rpm). Then, these NPs were centrifuged at 12,000 rpm for 5 min and washed twice with ethanol and milli-Q water. Finally, in the third step, the K-gold solution was mixed with the nanoparticles obtained in step 2 containing the gold grains and a 0.0053 M NaBH4 solution was added as a reducing agent, and the mixture was stirred for 60 minutes at room temperature. The SiO2- nanoparticles 223 Ra-TiO2-Au were then centrifuged at 12,000 rpm for 5 min and washed twice with ethanol and milli-Q water.

[0163] 1.6. Coating of SiO2 NPs with a layer of TiQ2 and then a layer of gold

[0164] The coating protocol described in paragraphs 1.4 and 1.5 is applied to non-radiolabeled SiO2 NPs (from the protocol described in paragraph 1.1) to obtain SiO2-TiO2-Au NPs.

[0165] 1.7. Coating of SiO2-TiO2-Au NPs with a third polyethylene glycol layer

[0166] SiO2-TiO2-Au NPs were incubated at 4 °C for 1 h with stirring at 1000 rpm, in the presence of ortho-pyridyl-polyethylene glycol-succinimidyl valerate disulfide (OPSS-PEG-SVA), SH-PEG and 1 mL of PBS. The OPSS function allows the establishment of covalent sulfur-gold bonds. The addition of SH-PEG ensures optimal stabilization of the nanoparticles to limit their aggregation while preserving their surface properties for subsequent applications. After incubation, the nanoparticles were separated by centrifugation and then washed twice with ethanol and water to remove the ungrafted PEG on their surface.

[0167] 1.8. Coating of SiO2 NPs- 225 Ac with a layer of TiO2 then a layer of gold The coating protocol described in paragraphs 1.4 and 1.5 is applied to the NPs 225 Ac to give SiO2-NPs 225 Ac-TiO2-Au.

[0168] 1.9. Coating of SiO2 NPs- 225 Ac-TiO2-Au with a third layer of oolveth yleneolvcol

[0169] The coating protocol described in paragraph 1.7 is applied to SiO2- NPs 225 Ac-TiO2- Au to give SiO2- NPs 225 Ac-TiO2-Au-PEG.

[0170] 1.10. Characterization of NPs

[0171] Scanning electron microscopy (SEM) analysis was performed to study the morphology of SiO2, SiO2-TiO2.Au and SiO2-TiO2-Au-PEG nanoparticles. The SEM image (Figure 1A,B and C) shows the presence of SiO2, SiO2-TiO2.Au and SiO2-TiO2-Au-PEG nanoparticles with a homogeneous sphere shape. This confirms that the synthesis conditions allowed obtaining regular and uniform nanoparticles. Coating with an external gold layer does not affect the morphology of SiO2-TiO2 NPs. Similarly, coating with a PEG layer does not alter the morphology of the NPs.

[0172] EDX analysis (Figure 2) confirms the presence of the elements: Si, O, Ti and Au. This confirms the formation of a TiO2 layer and a gold layer around the SiC core.

[0173] Thermogravimetric analysis (TGA) of SiO2-TiO2-Au-PEG nanoparticles confirms the presence and thermal degradation of the grafted polyethylene glycol. The TGA profile (Figure 3) shows several stages of mass loss as a function of increasing temperature. The first mass loss, observed around 123.12 °C with a reduction of 9.291%, is attributed to the removal of adsorbed water and residual solvents on the nanoparticle surface. A second loss, of approximately 2.597% at 207.17 °C, corresponds to the initial degradation of the organic functional groups of PEG. Finally, a third significant loss of 4.330% at 374.60 °C reflects the complete decomposition of the grafted polymer. Beyond this temperature, the nanoparticles show remarkable thermal stability up to 1000 °C, without significant mass loss, indicating that the SiO2-TiO2-Au matrix remains intact.These results validate the success of PEG grafting onto nanoparticles and demonstrate that the modification does not alter their overall thermal stability.

[0174] 2) Study of the release of 223 Ra

[0175] Release tests were performed at 5, 10, 20, 24 and 31 days after the fabrication of the SiO2- NPs. 223 Ra-TiO2 and SiO2- 223 Ra-TiO2-Au to evaluate the radionuclide retention capacity of NPs and compare the efficiency of double-coated NPs compared to single-coated NPs. The retention efficiency was evaluated by measuring the activity of 223 Ra released at 5, 10, 20, 24 and 31 days after initial radiolabeling.

[0176] The results are illustrated in Figure 4.

[0177] SiO2-NPs 223 Ra-TiO2-Au NPs exhibit a lower release rate than SiO2- 223Ra-TiO2 during the 31 days of the study, although the concentration of 223Ra was higher in the SiO2- NPs 223 Ra-TiO2-Au (38.85 KBq) than in SiO2- NPs 223 Ra- TiO2.(22.94 KBq). The retention of the radionuclide is therefore improved thanks to the double envelope.

[0178] 3) Study of the release of 225 Ac

[0179] Release tests were performed at 5 and 12 days after the fabrication of the SiO2- NPs. 225 Ac-TiO2 and SiO2- 225 Ac-TiO2-Au to evaluate the radionuclide retention capacity of NPs and compare the efficiency of double-coated NPs compared to single-coated NPs. The retention efficiency was evaluated by measuring the activity of 225 Ac released at 5 and 12 days after initial radiolabeling.

[0180] The results are illustrated in Figure 5.

[0181] SiO2-NPs 225Ac-TiO2-Au NPs exhibit a lower release rate than SiO2- 223 Ra-TiO2 during the 12 days of the study. The retention of the radionuclide is therefore improved thanks to the double envelope.

[0182] After grafting PEG onto SiO2-TiO2-Au NPs, no actinium release was detected, highlighting the effectiveness of this modification in radionuclide stabilization. These observations highlight the interest of gold and PEG as essential elements for the design of stable SiO2 nanoparticles suitable for targeted radiotherapy applications.

Claims

CLAIMS 1. Radioactive core / shell nanoparticle comprising: - a core based on a porous material, comprising one or more a-emitting radionuclide(s), - a first intermediate envelope around the heart, - optionally a second intermediate envelope located between the first intermediate envelope and the external envelope, and - an external envelope.

2. Radioactive nanoparticle according to claim 1, characterized in that the intermediate envelope(s) and the external envelope are independently made of a material chosen from metals, metal oxides, metal alloys, a combination of several metals, a polymer and a mixture of polymers.

3. Radioactive nanoparticle according to claim 1 or 2, characterized in that the external envelope and / or the intermediate envelope(s) are made of a biodegradable material.

4. Radioactive nanoparticle according to any one of claims 1 to 3, characterized in that at least one of the intermediate envelope(s) and the external envelope is made of a material whose degradation products have antibacterial properties.

5. Radioactive nanoparticle according to any one of claims 1 to 4, characterized in that the intermediate envelope(s) and the external envelope have, independently of one another, a thickness ranging from 1 nm to 100 nm.

6. Radioactive nanoparticle according to any one of claims 1 to 5, characterized in that one or more emitting radionuclide(s) a is (are) chosen from the group consisting of 225 Ac, 223 Ra, 211At, 212 Bi, 213 Bi, 227 Th, 224 Ra, 221 Fr and 213 Po.

7. Radioactive nanoparticle according to any one of claims 1 to 6, characterized in that the core further comprises one or more p-emitting radionuclides independently chosen from the group consisting of p+ emitting radionuclides, p- emitting radionuclides and a combination thereof.

8. Radioactive nanoparticle according to claim 7, characterized in that one or more p-emitting radionuclide(s) is (are) chosen from the group consisting of p+ emitting radionuclide(s), in particular in particular 89 Zr, 18 F, 11 C, 13 N, 15 O, 68 Ga, 82 Rb, 64 Cu, 124 l and 207 Bi.

9. Pharmaceutical composition comprising a radioactive nanoparticle as described in any one of claims 1 to 8 and a pharmaceutically acceptable excipient.

10. Radioactive nanoparticle according to any one of claims 1 to 8, for use as a medicament.

11. Radioactive nanoparticle according to any one of claims 1 to 8, for use in the treatment and / or prevention of cancer, in particular pancreatic cancer, liver cancer, prostate cancer, breast cancer, ovarian cancer, vulvar cancer, vaginal cancer, brain cancer, skin cancer, neck cancer, head cancer, neuroendocrine tumors, leukemias and lymphomas.

12. Radioactive nanoparticle according to claim 8, for its use as an imaging agent, in particular for PET imaging.

13. Radioactive nanoparticle according to claim 8, for its joint use in: - imaging and - the treatment and / or prevention of tumors.

14. Radioactive nanoparticle according to claim 8, for determining by PET imaging a quantity of therapeutic radiation absorbed by a therapeutic target.

Images