Core / shell radio-nanoparticles useful for 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 alpha-emitting radionuclides, - a first intermediate shell surrounding 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

Technical Field

[0001] This invention relates to core / shell nanoparticles encapsulating radionuclides with improved retention rates, particularly for use in cancer therapy. Background Technology

[0002] In nuclear medicine, radioactive elements are used to diagnose or treat cancer.

[0003] Radiation therapy has been used to treat cancer for decades. It involves radiation to destroy cancer cells and / or inhibit their growth. Typically, this type of radiation is delivered via a source outside the patient's body, such as through the use of X-rays. Radiation therapy can also be performed by administering a radionuclide to the patient, which specifically targets the tumor and emits short-range (beta-radiation) or very short-range (alpha-radiation) ionizing radiation in a targeted manner to destroy surrounding cancer cells. Other types of radionuclides (beta+ radiation) that can be visualized in imaging can be used to diagnose cancer.

[0004] Whether used for imaging or therapy, the delivery of radiopharmaceuticals into the body is typically accomplished using specific carriers of the therapeutic target, such as antibodies, peptides, or aptamers. In recent years, nanoparticle (NP) systems encapsulating radionuclides have also been developed, such as NPs of conjugated polymers, liposomes, micelles, or inorganic NPs (e.g., mesoporous silica NPs, iron oxide NPs, gold NPs, or calcium phosphate NPs).

[0005] However, while radiation therapy can limit the growth of cancer cells and destroy them, ionizing radiation, especially alpha radiation, can be harmful to healthy cells. For example, when an alpha-emitting radionuclide decays, the released daughter isotopes (which can themselves be alpha-emitting isotopes) can circulate in the body and affect healthy cells. This is especially true when a parent radionuclide is vectorized into cancer cells using specific carriers such as antibodies; the released daughter isotopes may not bind to the antibody and can therefore circulate freely in the body.

[0006] Therefore, there is a need for a system for delivering effective doses of therapeutic ionizing radiation to inhibit the growth of cancer cells and prevent the radiation from spreading to healthy cells, thereby ensuring patient safety. Summary of the Invention

[0007] Surprisingly, the inventors have developed tools in the form of core / shell nanoparticles that can deliver effective doses of therapeutic radiation to treat tumors, with high retention rates of radionuclides, thus limiting their effects on healthy cells.

[0008] The first objective of this invention relates to core / shell type radioactive nanoparticles comprising:

[0009] -Based on a porous material core containing one or more alpha-emitting radionuclides.

[0010] -The first intermediate shell surrounding the core

[0011] -Optionally, a second intermediate shell located between the first intermediate shell and the outer shell, and

[0012] -shell.

[0013] In some embodiments, the intermediate shell and the outer shell are independently composed of materials selected from metals, metal oxides, metal alloys, combinations of several metals, polymers, and polymer mixtures.

[0014] In some implementations, the outer shell and / or intermediate shell are composed of biodegradable materials.

[0015] In some embodiments, at least one of the intermediate shell and the outer shell is composed of a material whose degradation products have antibacterial properties.

[0016] In some implementations, the intermediate shell and the outer shell have thicknesses ranging from 1 nm to 100 nm, which are independent of each other.

[0017] In some implementations, one or more alpha-emitting radionuclides are selected from 225 Ac、 223 Ra、 211 At、 212 Bi、 213 Bi、 227 Th、 224 Ra、 221 Fr and 213 The group consisting of Po.

[0018] In some embodiments, the nucleus further comprises one or more beta-emitting radionuclides, independently selected from the group consisting of beta+ emitting radionuclides, beta-emitting radionuclides, and combinations thereof.

[0019] A second objective of the present invention relates to pharmaceutical compositions comprising radioactive nanoparticles according to the invention and pharmaceutically acceptable excipients.

[0020] A third objective of the present invention relates to radioactive nanoparticles according to the invention or pharmaceutical compositions according to the invention, which are used as medicines, particularly as radiopharmaceuticals in cancer treatment.

[0021] A fourth objective of the present invention relates to radioactive nanoparticles according to the invention or pharmaceutical compositions comprising such nanoparticles according to the invention, which are used as imaging agents, said radioactive nanoparticles comprising one or more alpha-emitting radionuclides and one or more beta-emitting radionuclides.

[0022] A fifth objective of the present invention relates to radioactive nanoparticles according to the invention or pharmaceutical compositions comprising such nanoparticles according to the invention for combined use in imaging and cancer treatment (and / or prevention), said radioactive nanoparticles comprising one or more alpha-emitting radionuclides and one or more beta-emitting radionuclides.

[0023] A sixth objective of the present invention relates to radioactive nanoparticles according to the invention, the amount of therapeutic radiation absorbed by a therapeutic target determined by PET imaging, said radioactive nanoparticles comprising one or more alpha-emitting radionuclides and one or more beta-emitting radionuclides. Attached Figure Description

[0024] Figure 1 SEM images of SiO2 NP (A), SiO2-TiO2-Au NP (B) and SiO2-TiO2-Au-PEG NP (C).

[0025] Figure 2 Elementary mapping of SiO2-TiO2-Au NP obtained by EDX.

[0026] Figure 3 Thermogravimetric curves of SiO2-TiO2-Au-PEG NP.

[0027] Figure 4 : SiO2-223Ra-TiO2 NP (dark gray, initial activity equal to 22.94 KBq) and SiO2- 223 Representation of the release rates of 223Ra after 5, 10, 20, 24 and 31 days in Ra-TiO2-Au NP (light gray, initial activity equal to 38.85 KBq).

[0028] Figure 5 SiO2- 225 Ac-TiO2 NP (dark gray) and SiO2- 225 Expression of the release rate of 225Ac in Ac-TiO2-Au NP (light gray) after 5 and 12 days (NP activity equal to 59.2 KBq). Detailed Implementation

[0029] definition

[0030] For the purposes of this invention, the term "comprising one" means "comprising at least one" or even "comprising one or more". For example, the term "comprising a radionuclide" means "comprising one or more radionuclides".

[0031] The term "nanoparticle" (or NP) refers to spherical solid particles with a size (i.e., diameter) ranging from a few nanometers to several hundred nanometers.

[0032] The term "core / shell nanoparticle" (or "core / coating") refers to a nanoparticle in which the core (the interior of the nanoparticle) is uniformly coated with a surface shell that has a different composition from the core.

[0033] The term "radionium" (or radioisotope) refers to a radioactive atomic element, that is, an unstable element that can decay into another element by emitting ionizing radiation, called a daughter isotope. A daughter isotope may or may not be a radionuclide (it may be called a daughter radionuclide). A daughter radionuclide does not necessarily emit the same type of ionizing radiation as its parent radionuclide.

[0034] The half-life of a radionuclide corresponds to the time required for half of the initially present radionuclides to decay. The activity of the radionuclide is then equal to half of its initial activity.

[0035] The term "ionizing radiation" refers to radiation with a sufficiently high energy level to ionize matter it passes through; that is, the emission of matter particles and energy. Within ionizing radiation, alpha radiation (α), beta radiation (β), and gamma radiation (γ) are specifically distinguished: alpha radiation consists of helium nuclei, beta radiation consists of electrons or positrons, and gamma radiation consists of photons.

[0036] Therefore, the term "alpha-emitting radionuclide" refers to a radionuclide as defined above that emits alpha radiation (also known as alpha particles) when it decays into a daughter isotope. It should be noted that the daughter isotopes of an alpha-emitting radionuclide can also be alpha-emitting radionuclides, or radionuclides that emit another type of radiation, such as beta-emitting radionuclides.

[0037] Therefore, the term "β-emitting radionuclide" refers to a radionuclide as defined above that emits β radiation (also known as β particles) when it decays into a daughter isotope. It should be noted that a daughter isotope of a β-emitting radionuclide can also be a β-emitting radionuclide, or a radionuclide that emits another type of radiation, such as an α-emitting radionuclide.

[0038] Radiation therapy consists of treatments that use ionizing radiation to destroy cancer cells.

[0039] The activity of a radioactive source is expressed in becquerels (Bq). One Bq is equivalent to one decay per second.

[0040] The absorbed radioactive dose corresponds to the amount of energy absorbed per unit mass of exposed material. The dose is expressed in gray (Gy), where 1 Gy = 1 Joule / kg.

[0041] Equivalent dose is a dosimetric measure used to convert the hazard of a given absorbed dose (Gy) onto the same reference scale to assess the actual risk of that absorbed dose. In practice, for the same absorbed dose (in Gy), the risk to exposed living material varies depending on the type of radiation, the duration of exposure, and the sensitivity of the exposed living material. 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. Equivalent dose is expressed in Sieverts (Sv), where 1 Sv = dose (Gy) x radiation quality factor. Therefore, the Sievert equivalent dose value for alpha radiation can be 4 to 5 times higher than that for gamma or X-ray radiation.

[0042] Radioactive nanoparticles

[0043] The nanoparticles of the present invention typically have 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 particularly from 180 nm to 250 nm.

[0044] The radioactive nanoparticles of the present invention have a core / shell structure as defined below.

[0045] -nuclear

[0046] The radioactive nanoparticles of the present invention have a core based on a porous, such as a mesoporous, material. "Based on a porous material" means that the porous material represents the main component of the core. Specifically, the core is composed of such a porous material. Porous materials are typically selected from porous silica, zeolites such as aluminosilicates (clinoptilolite, chalcogenide, or modernite), and MOFs (metal-organic frameworks) such as ZIFs (zeolite imidazolium ester frameworks), for example, ZIF-8. Preferably, the core is based on porous silica, particularly composed of porous silica.

[0047] The diameter of the nucleus ranges from 7 to 298 nm, preferably from 50 to 280 nm.

[0048] In particular, silica is mesoporous, meaning it has pores smaller than 50 nm, especially in the range of 0.3 nm to 50 nm, which provides it with a particularly large active specific surface area. Furthermore, the pores contain numerous Si-O-deprotonation sites, which promote and stabilize the adsorption of radionuclides within the pores. The pore size allows for the adsorption of more or fewer radionuclides, depending on the activity sought by the nanoparticles. Larger pore sizes result in a higher amount of radionuclides adsorbed onto silica.

[0049] The nucleus is particularly biodegradable.

[0050] - First intermediate shell, second intermediate shell, and outer shell

[0051] The core is encapsulated by 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 itself is encapsulated by a second intermediate shell, forming a uniform layer around the first intermediate shell, or it is directly encapsulated by an outer shell, forming a uniform layer on the surface of the nanoparticle. Therefore, the outer shell is in direct contact with either the first or second intermediate shell.

[0052] In certain embodiments, the nanoparticles may contain additional intermediate shells, such as three, four, or five intermediate shells. However, preferably, the nanoparticles contain only one or two intermediate shells.

[0053] Specifically, the intermediate and outer shells serve to retain the radionuclide within the nanoparticles; in other words, they isolate the radionuclide and prevent its diffusion outside the nanoparticles, while allowing ionizing radiation emitted during the radionuclide's decay to pass through. Since the nanoparticles are intended for use within the human body, the shells prevent highly toxic radionuclides from circulating within the body, while allowing ionizing radiation suitable for radiotherapy and medical imaging to pass through. The shells also enable the isolation of daughter isotopes produced by the degradation of the radionuclide initially present in the nanoparticles. Compared to a single shell, the presence of double or triple shells makes it possible to enhance this isolation capability and significantly reduce the rate of radionuclide release.

[0054] The intermediate shell and outer shell are independently composed of materials selected from metals, metal oxides, metal alloys, combinations of several metals, polymers, and polymer mixtures.

[0055] When the intermediate shell or outer shell contains or is composed of a metal, this is particularly gold, platinum, or combinations thereof. When the intermediate shell or outer shell contains or is composed of a metal oxide, this is particularly titanium dioxide, silicon dioxide, or combinations thereof. When the intermediate shell or outer shell contains or is composed of a polymer, it is particularly selected from polysaccharides (e.g., starch or cellulose), polyethylene glycol (PEG), polylactic acid (PLA), poly(lactic-co-hydroxyacetic acid) (PLGA), and mixtures thereof. The polymer may optionally be functionalized, for example, to enhance the stability of the nanoparticles. Preferably, only the outer shell may contain or be composed of a polymer.

[0056] It should be understood that each shell is different from its adjacent shell. Therefore, when a nanoparticle contains a single intermediate shell and an outer shell, these two shells are different. When a 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, wherein the outer shell and the first intermediate shell can be the same or different.

[0057] In some embodiments, the outer shell and / or intermediate shell are composed of a biodegradable material. Preferably, at least the outer shell is composed of a biodegradable material. In certain embodiments, both the intermediate shell and the outer shell are composed of a biodegradable material. It should be understood that even if the outer shell and possibly the intermediate shell are composed of a biodegradable material, the shell ensures its retention of the radionuclide's function at least during the longest half-life of the radionuclide present. In other words, biodegradation occurs kinetically, and the kinetics are slow enough that it occurs after the half-life of the radionuclide (considering the longest half-life) has ended. In particular, the biodegradation of the shell occurs when the radionuclide is stable and no longer emits ionizing radiation. Those skilled in the art will be able to select biodegradable materials having degradation kinetics adapted according to the longest half-life of the radionuclide encapsulated in the nanoparticles.

[0058] The biodegradation of the shell occurs within the cellular environment of the nanoparticles, for example, through enzymatic pathways.

[0059] Advantageously, the biodegradation of at least one shell results in the formation of byproducts with therapeutic properties, such as antibacterial properties. In other words, at least one shell is composed of a material whose degradation products possess antibacterial properties.

[0060] In some advantageous embodiments, the first intermediate shell is composed of titanium dioxide. Titanium dioxide has the advantages of being chemically inert and readily functionalizable. In particular, the degradation products of titanium dioxide have the advantage of possessing antibacterial properties.

[0061] In some advantageous embodiments, the outer shell or second intermediate shell is composed of gold or platinum. Gold and platinum have the particular advantages of being chemically stable, non-toxic, and easily functionalizable using existing methods. In particular, the degradation products of platinum have the advantage of possessing antibacterial properties.

[0062] In a first variant of the invention, the nanoparticles comprise a first intermediate shell and an outer shell, but do not contain a second intermediate shell. In this first variant, the intermediate shell and outer shell are preferably as described above.

[0063] In a second variant of the invention, the nanoparticles comprise a first intermediate shell, a second intermediate shell, and an outer shell. In this second variant, the intermediate shell and outer shell are preferably as described above. In an advantageous embodiment of this second variant, the first intermediate shell is composed of titanium oxide, the second intermediate shell is composed of gold or platinum, and the outer shell is composed of a polymer, particularly polyethylene glycol. In certain instances, the polymer is functionalized to form covalent bonds with the second outer shell, making it possible to stabilize multiple outer shells.

[0064] The intermediate shell and the outer shell typically have a thickness ranging from 1 nm to 100 nm, preferably from 1 nm to 50 nm, and more preferably from 2 nm to 20 nm, independent of each other. When the shell is composed of a biodegradable material, the thinness of the shell is beneficial to its degradation.

[0065] In some implementations, the shell is functionalized. Specifically, it can be functionalized with one or more targeting molecules capable of targeting the therapeutic site and driving the nanoparticles therein (active targeting). For example, the targeting molecules are selected from antibodies, peptides, or proteins. If necessary, they can be attached to the surface of the nanoparticles via connectors.

[0066] - Radionuclides

[0067] The radioactive nanoparticles according to the present invention contain one or more alpha-emitting radionuclides.

[0068] When a radioactive nanoparticle contains an alpha-emitting radionuclide, it means that it contains a single type of alpha-emitting radionuclide. When a radioactive nanoparticle contains several alpha-emitting radionuclides, it means that it contains alpha-emitting radionuclides of different properties, i.e., different atomic elements. The same understanding applies to radionuclides that emit other types of radiation, such as beta+ or beta- radiation, when such radionuclides are also present in the nanoparticle.

[0069] Porous materials in which radioactive nuclides are adsorbed into the core of nanoparticles.

[0070] The elements listed below should be understood as radionuclides initially present within the nanoparticles. Of course, during the lifetime of the nanoparticles, the initially present radionuclides decay once or multiple times, depending on their half-lives and the time of application of the nanoparticles, and the nanoparticles therefore contain daughter radionuclides derived from such or such decays. This means that the daughter radionuclides also remain isolated within the nanoparticles of this invention.

[0071] Alpha-emitting radionuclides, for example, independently selected from 225 Ac、 223 Ra、 211 At、 212 Bi、 213 Bi、 227 Th、 224 Ra、 221 Fr and 213 Po. Preferably, the alpha-emitting radionuclide is selected from... 225 Ac and 223 Ra.

[0072] In addition to alpha-emitting radionuclides, nanoparticles may also contain one or more beta-emitting radionuclides.

[0073] The β-emitting radionuclides are selected from β+-emitting radionuclides and β-emitting radionuclides. The radioactive nanoparticles of the present invention may contain one or more β+-emitting radionuclides, one or more β-emitting radionuclides, or a mixture of β+ and β-emitting radionuclides. Preferably, the radioactive nanoparticles of the present invention contain one or more β+-emitting radionuclides or one or more β-emitting radionuclides.

[0074] β+ radioactive nuclides, for example, selected from 89 Zr、 18 F, 11 C 13 N、 15 O、 68 Ga、 82 Rb、 64 Cu、 124 I and 207 Bi. Preferably, the β+ emitting radionuclides are selected from... 89 Zr and 64 Cu.

[0075] β-emitting radionuclides, for example, selected from 131 I, 89 Sr、 153 Sm、 32 P, 90 Y、 166 Ho、 177 Lu、 188 Re、 169 Er、 145 Pm, 67 Cu and 212 Pb. Preferably, the β-emitting radionuclide is selected from... 90 Y、 67 Cu、 212 Pb and177 Lu.

[0076] In a preferred embodiment, the radioactive nanoparticles of the present invention contain only one or more alpha-emitting radionuclides as defined above. Such nanoparticles are particularly useful in targeted radiotherapy and make it possible to deliver an effective dose of therapeutic radiation to a patient while ensuring its safety, as alpha radiation is most effective against cancer cells, and the double shell of the nanoparticles ensures the effective retention of the radionuclides.

[0077] In other embodiments, the radioactive nanoparticles of the present invention comprise one or more alpha-emitting radionuclides and one or more beta+-emitting radionuclides, but do not contain beta-emitting radionuclides. Such nanoparticles are particularly useful in therapeutic methods that consist of both imaging agents and therapeutic agents. In particular, such nanoparticles enable the effective detection and visualization of cancer cells while delivering a therapeutic dose of ionizing radiation sufficient to inhibit cancer cell growth.

[0078] In these embodiments, the radioactive nanoparticles preferably contain a single alpha-emitting radionuclide, particularly selected from... 225 Ac and 223 Ra, and single β+ emitting radionuclides, especially 89 Zr.

[0079] In other embodiments, the radioactive nanoparticles of the present invention comprise one or more alpha-emitting radionuclides and one or more beta-emitting radionuclides, and contain no beta+-emitting radionuclides. Such nanoparticles are particularly useful in targeted radiotherapy and make it possible to deliver an effective dose of therapeutic radiation to a patient while ensuring their safety. In fact, by combining both types of radiation within the same nanoparticle, it is possible to reduce the dose of delivered alpha radiation (which is the most dangerous) and achieve the necessary therapeutic dose through beta radiation, which poses less health risk.

[0080] In these embodiments, the radioactive nanoparticles contain a single alpha-emitting radionuclide, particularly selected from... 225 Ac and 223 Ra, and single β-emitting radionuclides, especially those selected from 90 Y、 67 Cu、 212 Pb and 177 Lu.

[0081] The amount of each radionuclide in the nanoparticle defines its activity, expressed in becquerels. Therefore, the nanoparticles of the present invention possess a defined alpha radiation activity and, possibly a defined β radiation activity. These activity levels are defined such that their combination results in therapeutic efficacy while limiting toxicity.

[0082] When starting to use nanoparticles, especially when administering them to patients, the simultaneous presence of two types of radionuclides in the nanoparticles makes it possible to obtain activity levels that cannot be achieved when only the daughter bodies of radioactive decay derived from alpha emitters are considered.

[0083] For example, although therapeutic beta-emitting radionuclides require an activity of several GBq (see, for example, product Lutathera) TM To produce therapeutic effects, but derived from alpha emitter parent radionuclides (e.g. 225 The daughter bodies of Ac) decay (β emitters) will never reach such activity levels. In fact, the applied α-emitting radionuclides (e.g., 225 Ac、 223 The activity of α-emitters (Ra) is typically on the order of several MBq. However, the decay of an α-emitter with an activity of several MBq can at most produce a β-activity equal to twice the initial α-activity, but can never reach the same order of magnitude (several GBq) required for β-emitters in RIV. Therefore, the nanoparticles of the present invention can achieve activity levels compatible with both α- and β-therapies.

[0084] The same reasoning applies to nanoparticles containing both alpha and beta radionuclides. Aside from providing very long acquisition times and receiving moderate-quality images, the decay of alpha radionuclides will never allow for sufficient activity levels in gamma / x / beta+ emission to achieve adequate imaging quality. The simultaneous presence of alpha and beta radionuclides within the nanoparticles at the start of application makes it possible to obtain compatible activities for both alpha therapy and imaging.

[0085] Pharmaceutical Composition

[0086] This invention relates to pharmaceutical compositions comprising radioactive nanoparticles according to the invention and pharmaceutically acceptable excipients, and more particularly to radiopharmaceutical compositions.

[0087] In a preferred embodiment, the pharmaceutical composition of the present invention comprises nanoparticles containing one or more alpha-emitting radionuclides, particularly a single alpha-emitting radionuclide, for example... 225 Ac or 223 Ra, and does not contain beta-emitting radionuclides.

[0088] In some embodiments, the pharmaceutical composition of the present invention comprises nanoparticles containing one or more alpha-emitting radionuclides and one or more beta-emitting radionuclides, particularly containing a single alpha-emitting radionuclide (e.g. 225 Ac or223 Ra) and single β+ emitting radionuclides (e.g. 89 Nanoparticles containing Zr and free of β-emitting radionuclides.

[0089] In other embodiments, the pharmaceutical composition of the present invention comprises nanoparticles containing one or more alpha-emitting radionuclides and one or more beta-emitting radionuclides, particularly containing a single alpha-emitting radionuclide (e.g. 225 Ac or 223 Ra) and single β-emitting radionuclides (e.g. 90 Y、 67 Cu、 212 Pb or 177 Nanoparticles containing Lu and free of β+ radioactive nuclides.

[0090] In other embodiments, the pharmaceutical composition of the present invention comprises nanoparticles containing one or more alpha-emitting radionuclides, one or more beta-emitting radionuclides, and one or more beta+ emitting radionuclides, particularly containing a single alpha-emitting radionuclide (e.g., 225 Ac or 223 Ra), a single β+ emitting radionuclide (e.g. 89 Zr) and single β-emitting radionuclides (e.g. 90 Y、 67 Cu、 212 Pb or 177 Lu) nanoparticles.

[0091] Pharmaceutically acceptable excipients must be compatible with the intended administration method and with the radioactive nanoparticles of this invention.

[0092] The pharmaceutical compositions according to the invention are specially formulated for intratumoral, intravenous, or topical application.

[0093] Therefore, advantageously, the pharmaceutical composition is in the form of a suspension of nanoparticles in pharmaceutically acceptable solvents, particularly saline solutions. The composition may further comprise additives, such as pH buffers, emulsifiers, wetting agents, or combinations thereof.

[0094] Alternatively, the composition can be deposited onto or incorporated into a medical device. For example, such a medical device is suitable for in-situ application at a therapeutic target or for topical application.

[0095] Advantageously, the compositions of the present invention are formulated to have an activity that allows delivery of the doses described herein, depending on the amount of the composition administered to a human.

[0096] Each radionuclide encapsulated within the NP of the present invention is provided in the form of a solution of that radionuclide, particularly a solution of a salt of that radionuclide, having a predetermined volumetric activity (in Bq / mL). Therefore, the activity of each NP depends on the volumetric activity of the radionuclide solution, the half-life of the radionuclide, and the size of the NP.

[0097] For example, the composition administered to a patient has an α-emission activity ranging from 1 MBq to 20 MBq, preferably from 5 MBq to 10 MBq, per administration.

[0098] For example, when the nanoparticles of the composition contain one or more β+ emitting radionuclides, the composition administered to a patient has a β+ emission activity ranging from 10 MBq to 300 MBq, preferably from 30 MBq to 100 MBq per administration.

[0099] For example, when the nanoparticles of the composition contain one or more β-emitting radionuclides, the composition administered to a patient has a β-emitting activity ranging from 1 GBq to 20 GBq, preferably from 5 GBq to 8 GBq per administration.

[0100] Applications of nanoparticles

[0101] -Therapeutic uses

[0102] The nanoparticles or pharmaceutical compositions of the present invention can be used as medicines, particularly for cancer prevention and / or treatment.

[0103] In other words, the present invention relates to the use of radioactive nanoparticles or pharmaceutical compositions according to the present invention as medicines or for the preparation of medicines, particularly for cancer prevention and / or treatment.

[0104] In other words, the present invention relates to methods for preventing and / or treating cancer, comprising administering radioactive nanoparticles according to the invention or pharmaceutical compositions according to the invention to a person in need at an effective dose.

[0105] The nanoparticles or pharmaceutical compositions of the present invention are particularly useful in radiotherapy, and more particularly in targeted radiotherapy. Alpha and beta ionizing radiation are effective in radiotherapy and enable the destruction of cancer cells. Therefore, the nanoparticles of the present invention can be used in radiotherapy.

[0106] In targeted radiotherapy, the nanoparticles of this invention can specifically target and accumulate on cancer cells to be treated. This targeting is achieved, in one aspect, by the size of the nanoparticles, which makes it easier for them to accumulate on cancer cells. This is called passive targeting. This targeting can also be achieved using targeting molecules grafted onto the surface of the nanoparticles. This is called active targeting.

[0107] In particular, local injection of the nanoparticles of the present invention into a tumor site makes it possible to release ionizing radiation that can specifically destroy surrounding cancer cells and / or limit their spread while preserving healthy tissue.

[0108] In some embodiments, the nanoparticles of the present invention, used for cancer prevention and / or treatment, are applied to a person in need of them, the nanoparticles having the following activity:

[0109] -α-emitting radionuclides have an activity range of 1 MBq to 20 MBq, preferably 5 MBq to 10 MBq, and

[0110] - Where applicable, the activity range of β+ emitting radionuclides is 10 MBq to 300 MBq, preferably 30 MBq to 100 MBq, and / or

[0111] - Where applicable, the activity of the β-emitting radionuclide is from 1 GBq to 20 GBq, preferably from 5 GBq to 10 GBq.

[0112] Cancers that can be prevented and / or treated by the nanoparticles of the present invention are selected from, for example, pancreatic cancer, liver cancer, prostate cancer, breast cancer, ovarian cancer, vulvar cancer, vaginal cancer, brain cancer, skin cancer, cervical cancer, head cancer, neuroendocrine tumors, leukemia, and lymphoma.

[0113] - Used for imaging

[0114] β+ ionizing radiation is visible throughout the body in imaging. α and β- radiation are invisible in imaging.

[0115] Therefore, only the nanoparticles of the present invention containing one or more alpha-emitting radionuclides and one or more beta-emitting radionuclides, or pharmaceutical compositions containing such nanoparticles, can be used as imaging agents.

[0116] The nanoparticles according to the invention, which can be used for imaging, may further contain one or more β-emitting radionuclides.

[0117] In certain embodiments, the nanoparticles of the present invention, which can be used for imaging, comprise one or more alpha-emitting radionuclides and one or more beta+-emitting radionuclides, and do not contain beta-emitting radionuclides. Preferably, they contain alpha-emitting radionuclides, for example selected from... 225 Ac and 223 Ra, and β+ emitting radionuclides, for example 89 Zr.

[0118] In particular, this imaging agent can be used for PET imaging (positron emission tomography), which makes it possible to visualize radioactive nanoparticles containing β+-emitting radionuclides in vivo.

[0119] As previously described, the nanoparticles of the present invention can specifically accumulate at cancer cells via passive and potentially active targeting. Therefore, the accumulation of the imaging agent according to the present invention at cancerous tumors makes it possible to visualize and assess the size of the tumor. The distribution of NPs within the tumor can also be visualized.

[0120] In particular, the nanoparticles according to the invention, which can be used as imaging agents, make it possible to locate tumors in vivo, especially in the human body.

[0121] - Used in therapeutic diagnostics

[0122] As mentioned in the introduction, therapeutic diagnostics refers to the simultaneous use of imaging and therapy.

[0123] The nanoparticles of the present invention comprising one or more alpha-emitting radionuclides and one or more beta-emitting radionuclides, or pharmaceutical compositions comprising such nanoparticles, can be used in therapeutic diagnostics. In other words, the nanoparticles of the present invention comprising one or more alpha-emitting radionuclides and one or more beta-emitting radionuclides, or pharmaceutical compositions comprising such nanoparticles, can be used in combination for imaging and treatment (and / or prevention) of cancerous tumors. In particular, such nanoparticles enable the effective detection and visualization of cancer cells while delivering a therapeutic dose of ionizing radiation sufficient to inhibit cancer cell growth.

[0124] The nanoparticles according to the invention, which can be used in therapeutic diagnostics, may further contain one or more β-emitting radionuclides.

[0125] In certain embodiments, the nanoparticles of the present invention, which can be used in therapeutic diagnostics, comprise one or more alpha-emitting radionuclides and one or more beta+-emitting radionuclides, and do not contain beta-emitting radionuclides. Preferably, they contain alpha-emitting radionuclides, for example selected from... 225 Ac and 223 Ra, and β+ emitting radionuclides, for example 89 Zr.

[0126] In particular, the therapeutic and diagnostic applications of the nanoparticles of the present invention make it possible to visualize cancerous tumors, for example via PET, while exerting the therapeutic effects of the nanoparticles. Therefore, the size of cancerous tumors can be visualized, and imaging can be used to verify that tumor growth has stopped or that the tumor size has decreased.

[0127] The nanoparticles of the present invention, used in conjunction with imaging and treatment (and / or prevention) of cancerous tumors, are used as imaging agents as described.

[0128] - Used in dosimetry

[0129] Nanoparticles according to the invention comprising one or more alpha-emitting radionuclides and one or more beta-emitting radionuclides, or pharmaceutical compositions comprising such nanoparticles, can be used in dosimetry, i.e., to determine the dose of therapeutic radiation that has reached the therapeutic target (i.e., cancer cells). In other words, nanoparticles according to the invention comprising one or more alpha-emitting radionuclides and one or more beta-emitting radionuclides, or pharmaceutical compositions comprising such nanoparticles, can be used to determine the dose of therapeutic radiation absorbed by the therapeutic target via PET imaging.

[0130] In practice, visualization of the distribution of nanoparticles in tumors (typically in PET imaging) makes it possible to quantify the radiation dose absorbed by the tumor. In fact, the intensity of the measured signal depends on the number of visualized photons, and therefore on the number of visualized β+ radionuclides in the tumor. Based on this data, and knowing the initial ratio of therapeutic radionuclides to β+ radionuclides in the nanoparticle, the amount of α-radionuclides distributed in the tumor can be found. In fact, the advantage of the nanoparticles of this invention is that they integrate two types of radionuclides into a single nanoparticle, thereby determining that both radionuclides have the same distribution in vivo. By visualizing the distribution of β+ radionuclides, the distribution of therapeutic radionuclides is automatically obtained, and thus the absorbed dose is obtained. By the difference from the initially administered amount, the amount of radiation distributed to healthy tissue can also be inferred, and thus the potential toxicity of the nanoparticles can be measured.

[0131] Therefore, nanoparticles according to the invention comprising one or more alpha-emitting radionuclides and one or more beta-emitting radionuclides, or pharmaceutical compositions comprising such nanoparticles, can be used in a dosimetry method for therapeutic radiation that has reached a therapeutic target, the method comprising:

[0132] i) Applying nanoparticles into the body, the nanoparticles having a known ratio of therapeutically radiative radionuclides to β+ radiative radionuclides;

[0133] ii) Visualize the nanoparticles, particularly through PET imaging, and determine the intensity of the signals emitted by β+-emitting radionuclides.

[0134] iii) Quantify the activity of β+ radionuclides by measuring the signal intensity in step ii).

[0135] iv) Quantify the activity of radionuclides emitting therapeutic radiation by means of the ratio of therapeutically radiated radionuclides to β+ radiated radionuclides.

[0136] The nanoparticles according to the invention, which can be used in dosimetry, may further comprise one or more beta-emitting radionuclides. In this case, therapeutic radiation corresponds to alpha and beta radiation.

[0137] In certain embodiments, the nanoparticles of the present invention, which can be used in dosimetry, comprise one or more alpha-emitting radionuclides and one or more beta+-emitting radionuclides, and do not contain beta-emitting radionuclides. Preferably, they contain alpha-emitting radionuclides, for example selected from... 225 Ac and 223 Ra, and β+ emitting radionuclides, for example 89 Zr. In this case, therapeutic radiation corresponds only to alpha radiation.

[0138] In other words, the present invention therefore relates to a method for preventing and / or treating cancer, as previously described, wherein the nanoparticles of the present invention comprise one or more alpha-emitting radionuclides and one or more beta-emitting radionuclides, and the method further comprises determining the amount of therapeutic radiation absorbed by the therapeutic target (i.e., cancer cells), particularly by PET imaging.

[0139] Methods for preparing nanoparticles

[0140] The present invention also relates to a method for preparing the nanoparticles of the present invention, the method comprising the following steps:

[0141] a) Preparation of nanoparticles based on sol-gel of porous materials

[0142] b) Radiolabel the nanoparticles from step a) with one or more alpha-emitting radionuclides and, where applicable, one or more beta+-emitting radionuclides and / or one or more beta-emitting radionuclides.

[0143] c) Encapsulate the radioactive nanoparticles from step b) with an intermediate shell.

[0144] d) Encapsulate the radioactive nanoparticles from step c) with a shell.

[0145] The radionuclides contained in the nanoparticles and the intermediate and outer shells are as described above.

[0146] The method of the present invention makes it possible to simultaneously encapsulate different radionuclides via a common method, regardless of the properties of each radionuclide.

[0147] The sol-gel method of step a) is well known to those skilled in the art. Typically, when the porous material is porous silica, the sol-gel method is carried out by placing a silanol, such as tetraethyl orthosilicate (TEOS), into an aqueous solution (preferably in the presence of an alkali). The resulting solution is then centrifuged to form silica-based nanoparticles.

[0148] The radiolabeling step b) is carried out by physically adsorbing radionuclides onto nanoparticles derived from step a). In the first variant, each radionuclide is added individually and sequentially. In the case where the nanoparticles contain several radionuclides of the same type (e.g., several alpha-emitting radionuclides), the core of the nanoparticles can adsorb each radionuclide individually and sequentially. The same is true in the case where the nanoparticles contain both alpha-emitting and beta-emitting radionuclides. Advantageously, the adsorption order of the radionuclides depends on their half-lives.

[0149] In the second variant, a radioactive nuclide is added simultaneously.

[0150] Typically, a solution of a radionuclide, particularly a radionuclide salt, is added to a suspension of nanoparticles. For example, the nanoparticles are suspended in a buffer solution with a neutral pH. The mixture is heated, for example, between 50°C and 80°C, and then centrifuged to recover the radiolabeled nanoparticles. A sonication step can also be performed on the mixture to improve adsorption. In cases of simultaneous adsorption, the solution of suspended nanoparticles contains the radionuclide to be adsorbed.

[0151] The methods used in encapsulation steps c) and d) depend on the properties of the intermediate shell and the outer shell. Those skilled in the art will be able to apply appropriate schemes to perform the encapsulation operation based on the properties of the shell.

[0152] In a specific instance, both the intermediate shell and the outer shell are metallic. Coating step c) is performed by suspending the radiolabeled nanoparticles from step b) in a solution containing a solvent (e.g., an alcohol such as ethanol) and a metal or metal oxide. For example, if the intermediate shell is composed of titanium dioxide, the solution contains tetrabutyl titanate. The nanoparticles are suspended in this solution for the time necessary for the coating operation. The nanoparticles are then centrifuged and recovered. Step d) is then performed 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 is composed of gold, the solution contains potassium-gold. The nanoparticles from step c) are pre-suspended in a tetrachloroauric acid trihydrate solution, and then suspended in a potassium-gold solution. The nanoparticles are suspended in this potassium-gold solution for the time necessary for the coating operation. 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 radionuclide.

[0153] The method for preparing nanoparticles may include an intermediate step a' of storing the nanoparticles between steps a) and b). In practice, for practical reasons, nanoparticles based on porous materials can be mass-produced and then stored for a considerable period of time and / or transported, for example, to an injection site.

[0154] On the other hand, based on the half-life of the adsorbed radionuclide, steps b), c), and d) are preferably performed sequentially over a short time span.

[0155] Preferably, once step d) is completed, the radioactive nanoparticles can be administered to patients in need within a very short time span, depending on the half-life of the adsorbed radionuclide.

[0156] For example, 223 The half-life of Ra is 11.4 days. 89 The half-life of Zr is 78 hours (3 days). Therefore, in the presence of... 223 Ra and 89 In Zr nanoparticles, 89 The half-life of Zr is finite, and the duration of steps c) and d) must be determined before it can be administered to a patient.

[0157] Example

[0158] 1) Synthesis of nanoparticles

[0159] 1.1. Synthesis of silica-based nanoparticles

[0160] SiO2 nanoparticles (NPs) were prepared using the sol-gel method. For this, 8.75 mL of 99.9% ethanol and 2.4 mL of milli-Q water were mixed for 5 minutes. Next, 65 µL of 99% tetraethyl orthosilicate (TES) and 390 µL of ammonium hydroxide were added. The resulting mixture was stirred for 2 hours. The resulting solution was then transferred to 2 mL centrifuge tubes to separate the SiO2 nanoparticles by centrifugation at 12,000 rpm for 5 minutes. A washing step was performed by centrifugation at 12,000 rpm for 5 minutes, once with ethanol and once with milli-Q water. Finally, the formed SiO2 NPs were dried in an oven at 70°C for 15 minutes.

[0161] 1.2. use 223 Ra radiolabels SiO2 NP

[0162] Through the synthesis of SiO2NP pairs 223Radiolabeling was performed using the physical adsorption of Ra. Initially, 3 mg of SiO2 NP was suspended in 1 mL of 10 mM HEPES buffer (pH 7.2), and then... 223 A solution of Ra and 2.5 μL of 2M Na2CO3 solution were added to the tube.

[0163] The mixture was incubated at 70°C and 1000 rpm for 60 minutes. The solution was then sonicated for 15 minutes to improve the adsorption of the radionuclide. The labeled NPs were then centrifuged at 12,000 rpm for 5 minutes and washed twice with milli-Q water. During each step, the supernatant was collected and radioactivity was measured using a gamma counter.

[0164] 1.3. use 225 Ac radiolabels SiO2 NP

[0165] Through the synthesis of SiO2 NP pairs 225 Ac was radiolabeled via physical adsorption. Initially, 3 mg SiO2 NP was suspended in 1 mL of 10 mM HEPES buffer (pH 7.2), and then […]. 225 A solution of Ac]AcNO3 (ultrapure 0.1 M HCl solution, 59.2 KBq) and 2.5 μL of 2 M Na2CO3 solution were added to the tube. The mixture was incubated at 70°C and 1000 rpm for 60 minutes. The solution was resuspended by sonication for 15 minutes to improve the adsorption of the radionuclide. The labeled NP was then centrifuged at 12,000 rpm for 5 minutes and washed twice with milli-Q water. During the different steps, the supernatant was collected and the radioactivity was measured using a gamma counter.

[0166] 1.4. SiO2- coated with TiO2 layer 223 Ra

[0167] Following the radiolabeling process, SiO2- 223 Ra nanoparticles are already coated with a TiO2 layer. Therefore, 3 mg of SiO2- 223 Ra NP was transferred to 1.5 mL of a solution containing a mixture of tetrabutyl titanate (Ti(C4H9O)4) and ethanol at a volume ratio of 1:75. The solution was then sonicated to ensure particle suspension. After 15 minutes, the solution was left to stand at room temperature for 24 hours without stirring to allow SiO2- to form. 223 Ra-TiO2 nanoparticles. To remove reaggregates, centrifugation at 800 rpm for 1 minute was performed. The SiO2-- content was recovered. 223RaThe supernatant of TiO2 was collected and transferred to a new container, then centrifuged at 12,000 rpm for 5 minutes. The mixture was then washed at 12,000 rpm for 3 minutes, once with ethanol and once with milli-Q water.

[0168] 1.5. SiO2- coated with gold 223 Ra-TiO2

[0169] Using tetrachloroauric acid trihydrate (HAuCl4) and previously obtained SiO2- 223 Ra-TiO2 particles were synthesized into SiO2 in three steps. 223 Ra-TiO2-Au particles. In the first step, a potassium-gold (K-gold) solution was prepared by dissolving potassium carbonate (K2CO3) at a concentration of 280 mg / L in purified water. Simultaneously, a 25 mM HAuCl4 solution was prepared, and the pH was adjusted to 7 with 1 M NaOH. These two solutions were combined in a single tube containing 8 mL of K2CO3 and 120 μL of HAuCl4 and stirred in the dark for 12 hours. The second step involved adding 3 mg SiO2- 223 Ra-TiO2 nanoparticles were suspended in 2 mL of 6.35 mM HAuCl4 (pH=7). The resulting suspension was mixed at 96°C for 15 minutes (1000 rpm). Then, these nanoparticles were centrifuged at 12,000 rpm for 5 minutes and washed twice with ethanol and milli-Q water. Finally, in the third step, the K-gold solution was mixed with the gold-containing nanoparticles obtained in step 2, and 0.0053 M NaBH4 solution was added as a reducing agent. The mixture was stirred at room temperature for 60 minutes. Then, SiO2- 223 Ra-TiO2-Au nanoparticles were centrifuged at 12,000 rpm for 5 minutes and washed twice with ethanol and milli-Q water.

[0170] 1.6. A TiO2 layer was used, followed by a gold layer to coat the SiO2 NP.

[0171] The coating schemes described in paragraphs 1.4 and 1.5 are applied to non-radioactively labeled SiO2 NPs (from the scheme described in paragraph 1.1) to obtain SiO2-TiO2-Au NPs.

[0172] 1.7. SiO2 was coated with a third layer of polyethylene glycol. 2- TiO2-Au NP

[0173] SiO2-TiO2-Au NPs were incubated at 4°C for 1 hour with stirring at 1000 rpm in the presence of o-pyridyl polyethylene glycol succinimide valerate (OPSS-PEG-SVA), SH-PEG, and 1 mL PBS. The OPSS function enabled the formation of covalent sulfur-gold bonds. The addition of SH-PEG ensured optimal stability of the nanoparticles, limiting 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 ungrafted PEG from their surface.

[0174] 1.8. A TiO2 layer was used, followed by a gold layer to coat the SiO2- 225 Ac NP

[0175] The coating schemes described in paragraphs 1.4 and 1.5 are applied to SiO2- 225 Ac NP to generate SiO2- 225 Ac-TiO2-Au NP.

[0176] 1.9. SiO2- was coated with a third layer of polyethylene glycol. 225 Ac-TiO2-Au NP

[0177] The coating scheme described in paragraph 1.7 is applied to SiO2- 225 Ac-TiO2-Au NP to generate SiO2- 225 Ac-TiO2-Au-PEG NP.

[0178] 1.10. Characterization of NP

[0179] Scanning electron microscopy (SEM) analysis was performed to investigate the morphology of SiO2, SiO2-TiO2-Au, and SiO2-TiO2-Au-PEG nanoparticles. SEM images ( Figure 1 Images A, B, and C show the presence of uniform spherical SiO2, SiO2-TiO2-Au, and SiO2-TiO2-Au-PEG nanoparticles. This confirms that the synthesis conditions produced regular and uniform nanoparticles. The outer gold coating does not affect the morphology of the SiO2-TiO2 NPs. Similarly, the PEG coating does not impair the morphology of the NPs.

[0180] EDX analysis Figure 2 The presence of the following elements was confirmed: Si, O, Ti, and Au. This confirmed the formation of a TiO2 layer and a gold layer around the SiO2 core.

[0181] Thermogravimetric analysis (TGA) of SiO2-TiO2-Au-PEG nanoparticles confirmed the presence and thermal degradation of grafted polyethylene glycol. TGA spectra ( Figure 3The results show several stages of mass loss as temperature increases. The first mass loss (reduction of 9.291%) observed at approximately 123.12°C is attributed to the removal of adsorbed water and residual solvent from the nanoparticle surface. The second loss of approximately 2.597% at 207.17°C corresponds to the initial degradation of the PEG organic functional groups. Finally, the third significant loss of 4.330% at 374.60°C reflects the complete decay of the grafted polymer. Above this temperature, the nanoparticles exhibit significant 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 the nanoparticles and demonstrate that modification does not compromise their overall thermal stability.

[0182] 2) 223 Research on Ra release

[0183] In the preparation of SiO2- 223 Ra-TiO2 and SiO2- 223 Release tests were performed on Ra-TiO2-Au NPs at 5, 10, 20, 24, and 31 days after initial radiolabeling to assess the NPs' ability to retain radionuclides and to compare the effectiveness of double-coated NPs versus single-coated NPs. The release was measured at 5, 10, 20, 24, and 31 days after initial radiolabeling. 223 The activity of Ra was used to assess the effectiveness of retention.

[0184] exist Figure 4 The results are shown in the image.

[0185] In a 31-day study, SiO2- 223 Ra-TiO 2- Au NP is more than SiO2- 223 Ra-TiO2NP exhibits a lower release rate, although SiO2- 223 Ra-TiO 2- The concentration of 223Ra in Au NP (38.85 KBq) is higher than that in SiO2- 223 Ra-TiO 2. The concentration of NPs is higher in NPs (22.94 KBq). Therefore, the retention of radionuclides is improved due to the double shell.

[0186] 3) 225 Research on Ac release

[0187] In the preparation of SiO2- 225 Ac-TiO2 and SiO2- 225 Ac-TiO 2-Release tests were performed 5 and 12 days after Au NP to assess the NP's ability to retain radionuclides and to compare the effectiveness of double-coated NPs versus single-coated NPs. The release was measured at 5 and 12 days after initial radiolabeling. 225 Ac activity was used to assess the effectiveness of retention.

[0188] exist Figure 5 The results are displayed in the image.

[0189] In a 12-day study, SiO2- 225 Ac-TiO2-Au NP is more compatible with SiO2- 223 Ra-TiO2NP exhibits a lower release rate. Therefore, due to the double shell, the retention of radionuclides is improved.

[0190] Grafting PEG onto SiO2-TiO2-Au NP resulted in no detectable actinium release, highlighting the effectiveness of this modification in stabilizing radionuclides. These observations underscore the importance of gold and PEG as fundamental elements for designing stable SiO2 nanoparticles suitable for targeted radiotherapy applications.

Claims

1. Core / shell type radioactive nanoparticles, comprising: - A core based on a porous material, containing one or more alpha-emitting radionuclides. -A first intermediate shell surrounding the core. - Optionally, a second intermediate shell located between the first intermediate shell and the outer shell, and -shell.

2. The radioactive nanoparticles according to claim 1, characterized in that, The intermediate shell and the outer shell are independently composed of materials selected from metals, metal oxides, metal alloys, combinations of several metals, polymers, and polymer mixtures.

3. The radioactive nanoparticles according to claim 1 or 2, characterized in that, The outer shell and / or the intermediate shell are composed of biodegradable materials.

4. The radioactive nanoparticles according to any one of claims 1 to 3, characterized in that, At least one of the intermediate shell and the outer shell is composed of a material whose degradation products have antibacterial properties.

5. The radioactive nanoparticles according to any one of claims 1 to 4, characterized in that, The intermediate shell and the outer shell have thicknesses ranging from 1 nm to 100 nm, independent of each other.

6. The radioactive nanoparticles according to any one of claims 1 to 5, characterized in that, The one or more alpha-emitting radionuclides are selected from 225 Ac、 223 Ra、 211 At、 212 Bi、 213 Bi、 227 Th、 224 Ra、 221 Fr and 213 The group consisting of Po.

7. The radioactive nanoparticles according to any one of claims 1 to 6, characterized in that, The nucleus further comprises one or more beta-emitting radionuclides, which are independently selected from the group consisting of beta+-emitting radionuclides, beta-emitting radionuclides, and combinations thereof.

8. The radioactive nanoparticles according to claim 7, characterized in that, The one or more β-emitting radionuclides are selected from β+ emitting radionuclides, particularly 89 Zr、 18 F, 11 C 13 N、 15 O、 68 Ga、 82 Rb、 64 Cu、 124 I and 207 The group consisting of Bi.

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

10. The radioactive particles according to any one of claims 1 to 8, which are used as a drug.

11. The radioactive nanoparticles according to any one of claims 1 to 8, for the treatment and / or prevention of cancer, particularly pancreatic cancer, liver cancer, prostate cancer, breast cancer, ovarian cancer, vulvar cancer, vaginal cancer, brain cancer, skin cancer, cervical cancer, head cancer, neuroendocrine tumors, leukemia, and lymphoma.

12. The radioactive nanoparticles according to claim 8, used as imaging agents, particularly for PET imaging.

13. The radioactive nanoparticles according to claim 8, used in combination with: -Tumor imaging, and - Cancer treatment and / or prevention.

14. The radioactive nanoparticles of claim 8, wherein the amount of therapeutic radiation absorbed by the therapeutic target is determined by PET imaging.

Images