Core / shell radio-nanoparticles useful for targeted radiotherapy

Abstract

The present invention relates to a core / shell radioactive nanoparticle comprising: - a porous silica-based core comprising one or more alpha-emitting radionuclides and one or more beta-emitting radionuclides, and - a metal shell. The present invention also relates to the use of this radioactive nanoparticle as a medicament, 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 two types of radionuclides, particularly for use in cancer radiotherapy. Advantageously, these nanoparticles can also be used in therapeutic diagnostic methods. 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 uses radiation, also known as ionizing radiation, to destroy and / or inhibit the growth of cancer cells. Typically, this radiation comes from sources outside the patient's body, such as when high-energy (>1 MeV) X-rays are used in external radiation therapy. This method is particularly suitable for localized or oligometastatic tumors. Radiation therapy can also be performed by administering a therapeutic radionuclide to the patient. This radionuclide specifically targets the tumor and emits short-range (<1.5 cm, beta radiation) or very short-range ionizing radiation (<100 µm alpha radiation or <10 µm Auger electrons). This is called internal radiation therapy and can be used for localized tumors as well as metastatic tumors. Other types of radionuclides (beta+ radiation) that can be visualized in imaging can be used for cancer diagnosis.

[0004] Whether used for imaging or therapy, the transport of radionuclides within the body is typically accomplished using specific carriers of the therapeutic target, such as antibodies, peptides, aptamers, or other small molecules. The resulting product is then called a radiopharmaceutical, and the coupling of the radionuclide to the carrier can thus be direct or via a bifunctional reagent. In a therapeutic context, this is called a therapeutic radiopharmaceutical, intended for use in vectorized radiotherapy practices. In a diagnostic context, this is called a diagnostic radiopharmaceutical.

[0005] 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).

[0006] However, while ionizing radiation used in radiotherapy (such as alpha particles) effectively destroys tumor cells to ensure tumor control, it can also kill healthy cells along its pathways and cause high toxicity. Toxicity issues arise in external radiotherapy, but also in internal carrier-based radiotherapy. For example, when an alpha-emitting radionuclide coupled to a carrier decays, the released daughter isotope may no longer bind to the carrier and can circulate in the body, irradiating healthy cells. Therefore, some of the advantages of carrier-based radiotherapy are lost.

[0007] Therefore, a system is needed to deliver therapeutic doses to tumor cells in order to control the tumor while avoiding irradiation and toxicity to healthy cells.

[0008] A key concept in internally carrier-based radiotherapy is the therapeutic diagnostic approach, which involves using the same carrier that can be coupled to a diagnostic or therapeutic radionuclide. The ability to visualize, in imaging, a diagnostic radionuclide associated with a carrier targeting tumor receptors allows for patient selection prior to the administration of therapeutic radiopharmaceuticals (including therapeutic radionuclides associated with the same carrier).

[0009] Therefore, it is important to be able to track the distribution of therapeutic radiopharmaceuticals in the body over time. In fact, quantifying the radiopharmaceuticals in different tumors and healthy tissues is used to determine the radiation dose delivered to tumors and healthy tissues. Dosimetry is crucial for predicting therapeutic efficacy and toxicity.

[0010] β-emission therapeutic radionuclides (e.g.) 177 Lu is useful in this method because the activity injected into the patient (tens of GBq) is compatible with SPECT imaging monitoring (γ emission of 177Lu) and the therapeutic target (β emission). Therefore, the distribution of β-emission therapeutic radionuclides in the body can be easily monitored.

[0011] Conversely, when using therapeutic alpha particle emitters, the applied activity (tens of MBq) is too low to achieve simple and high-quality imaging. Therefore, there is currently no solution for visualizing the distribution of alpha radionuclides in the body.

[0012] Therefore, it would be of interest to be able to combine alpha-particle-emitting radionuclides and diagnostic radionuclides within nanoparticles to monitor the biodistribution of therapeutic radiopharmaceuticals and determine the dose absorbed by tumor and healthy tissues. However, the development of such dual-function tools faces many challenges. In practice, radionuclides used for both imaging and therapy must be compatible with each other. Specifically, radionuclides must be chemically compatible, meaning they must not react with each other and alter their respective properties and stability. Radionuclides must also be physically compatible, possessing physical properties (e.g., half-life) that enable their combined use. Furthermore, radionuclides must be compatible for their medical applications. Moreover, the amount of each radionuclide within the nanoparticles must be strictly controlled so that each delivers a specific amount of radiation, allowing imaging and therapy to be performed with patient safety ensured. Summary of the Invention

[0013] Surprisingly, the inventors have developed tools in the form of core / shell nanoparticles capable of delivering effective doses of therapeutic radiation to treat tumors while limiting their impact on healthy cells. The nanoparticles of this invention are also suitable for therapeutic applications that meet the aforementioned requirements.

[0014] The first objective of this invention relates to radioactive core / shell nanoparticles comprising:

[0015] - A core based on a porous material, comprising one or more alpha-emitting radionuclides and one or more beta-emitting radionuclides, and

[0016] - Metal casing.

[0017] In particular, the nanoparticles of the present invention are characterized in that radionuclides are adsorbed into the porous material.

[0018] In some embodiments, the shell is made of a material selected from metals, metal oxides, metal alloys, mixtures thereof, and combinations thereof. In particular, it contains titanium oxide, and is especially composed of titanium oxide.

[0019] 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.

[0020] In some embodiments, one or more beta-emitting radionuclides are independently selected from the group consisting of beta+ emitting radionuclides, beta-emitting radionuclides, and combinations thereof.

[0021] In some embodiments, one or more beta-emitting radionuclides are selected from beta+-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.

[0022] In some embodiments, one or more beta-emitting radionuclides are selected from beta-emitting radionuclides, particularly 131 I, 89 Sr、 153 Sm、 32 P, 90 Y、 166 Ho、 177 Lu、 188 Re、 169 Er、 145 Pm, 67 Cu and 212 The group consisting of Pb.

[0023] A second objective of the present invention relates to a pharmaceutical composition comprising radioactive nanoparticles according to the invention and pharmaceutically acceptable excipients.

[0024] 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.

[0025] 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.

[0026] 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.

[0027] 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

[0028] Figure 1 SEM image of SiO2 NP (A), elemental mapping obtained by SEM-EDX of SiO2 NP (B).

[0029] Figure 2 High-resolution images obtained by transmission electron microscopy (TEM) of SiO2 / TiO2NP.

[0030] Figure 3High-resolution images of SiO2 / TiO2 NPs obtained at extremely small scales using transmission electron microscopy (TEM).

[0031] Figure 4 XPS spectra of SiO2 and SiO2-TiO2NP: (a) overview, (b) 2p Si, (c) 2p Ti and (d) 1s O.

[0032] Figure 5 PET images: (a) for S1, taken immediately after injection; (b) taken 24 h later; (c) for S2, taken immediately after injection; (d) taken 90 h later. Detailed Implementation

[0033] definition

[0034] 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".

[0035] The term "nanoparticle" (or NP) refers to spherical solid particles with a size (i.e., diameter) ranging from a few nanometers to hundreds of nanometers.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] Radiation therapy consists of treatments that use ionizing radiation to destroy cancer cells.

[0043] The activity of a radioactive source is expressed in becquerels (Bq). One Bq is equivalent to one decay per second.

[0044] 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.

[0045] 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 based on the nature of the radiation. In practice, for the same absorbed dose (in Gy), the risk to exposed living material varies depending on the type of radiation. For example, for the same absorbed dose, alpha radiation is approximately 4 to 5 times more cytotoxic 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.

[0046] Radioactive nanoparticles

[0047] 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.

[0048] The radioactive nanoparticles of the present invention have a core / shell structure as defined below.

[0049] -nuclear

[0050] 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.

[0051] 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 surface area allowing for the adsorption of a large number of radionuclides. 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 more or less radionuclides to be adsorbed, depending on the activity sought by the nanoparticles. The larger the pore size, the greater the amount of radionuclides adsorbed onto the silica.

[0052] In particular, the nucleus is biodegradable.

[0053] -shell

[0054] The core is encased in a metal shell, forming a uniform layer on the surface of the nanoparticles.

[0055] Specifically, the shell's function is to retain the radionuclide within the nanoparticle; in other words, to isolate the radionuclide and prevent its diffusion outside the nanoparticle, 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 shell's role is to prevent highly toxic radionuclides from circulating within the body, while allowing ionizing radiation that can be used for radiotherapy and medical imaging to pass through. The shell also enables the isolation of daughter isotopes produced by the degradation of the radionuclide initially present in the nanoparticle.

[0056] The shell is composed of materials selected from metals, metal oxides, metal alloys, mixtures thereof, and combinations thereof.

[0057] In some embodiments, the shell comprises or is made of a metal, such as gold, platinum, or combinations thereof. In other embodiments, the shell comprises or is composed of a metal oxide, such as titanium oxide, silicon dioxide, or combinations thereof. Preferably, the shell is composed of titanium oxide. Titanium oxide has the advantages of chemical inertness and ease of functionalization.

[0058] The metal shell typically has 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.

[0059] In some implementations, the shell is functionalizable. 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 a connector.

[0060] - Radionuclides

[0061] The radioactive nanoparticles according to the present invention comprise one or more alpha-emitting radionuclides and one or more beta-emitting radionuclides.

[0062] When a radioactive nanoparticle contains alpha-emitting radionuclides, it means that it contains a single type of alpha-emitting radionuclide. When a radioactive nanoparticle contains several types of alpha-emitting radionuclides, it means that it contains alpha-emitting radionuclides of different properties, i.e., different atomic elements. The same understanding applies to beta-emitting radionuclides.

[0063] Porous materials in which radioactive nuclides are adsorbed into the core of nanoparticles.

[0064] 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.

[0065] For example, alpha-emitting radionuclides are independently selected 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.

[0066] 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.

[0067] 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.

[0068] 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 and 177 Lu.

[0069] Therefore, in the first variant, 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 therapeutic applications, as they consist of both an imaging agent and a therapeutic agent, allowing for monitoring of the distribution of the nanoparticles in the body, and thus monitoring of the therapeutic dose applied to cells.

[0070] In this first variant, 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.

[0071] In a second variant, the radioactive nanoparticles of the present invention comprise one or more alpha-emitting radionuclides and one or more beta-emitting radionuclides, but contain no beta+ emitting radionuclides. Such nanoparticles are particularly useful in internally embodied radiotherapy and make it possible to deliver therapeutic doses of radiation to patients without toxicity. In fact, by combining these two types of radiation within the same nanoparticle, two types of particles can be combined that can have complementary effects on damage of different sizes.

[0072] In this second variant, the radioactive nanoparticles contain a single alpha-emitting radionuclide, specifically 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.

[0073] The amount of each radionuclide in the nanoparticle defines its activity, expressed in becquerel. Therefore, the nanoparticles of the present invention have defined alpha radiation activity and defined beta radiation activity. These activity levels are defined such that their combination results in therapeutic efficacy while limiting toxicity.

[0074] Therefore, the originality of the present invention lies in the fact that the nanoparticles initially comprise one or more alpha-emitting radionuclides and one or more beta-emitting radionuclides, wherein the beta-emitting radionuclides are not derived from those decaying from the alpha-emitting radionuclides, but are those contained in the NP.

[0075] 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.

[0076] 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、 223The 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.

[0077] 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.

[0078] Pharmaceutical Composition

[0079] This invention relates to pharmaceutical compositions comprising radioactive nanoparticles according to the invention and pharmaceutically acceptable excipients, and more particularly to radiopharmaceutical compositions.

[0080] 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 or 223 Ra) and single β+ emitting radionuclides (e.g. 89 Nanoparticles containing Zr and free of β-emitting radionuclides.

[0081] 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.

[0082] 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., 225Ac 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.

[0083] Pharmaceutically acceptable excipients must be compatible with the intended administration method and with the radioactive nanoparticles of this invention.

[0084] The pharmaceutical compositions according to the invention are specially formulated for intratumoral, intravenous, or topical application.

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] Applications of nanoparticles

[0093] -Therapeutic uses

[0094] The nanoparticles or pharmaceutical compositions of the present invention can be used as medicines, particularly for cancer prevention and / or treatment.

[0095] 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.

[0096] 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.

[0097] 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, regardless of whether they contain one or more beta- and / or beta+ emitting radionuclides, as they must contain one or more alpha-emitting radionuclides.

[0098] In a particular embodiment, the nanoparticles of the present invention, which can be used in radiotherapy, comprise one or more alpha-emitting radionuclides and one or more beta-emitting radionuclides. In this particular embodiment, they are particularly free of beta-emitting radionuclides.

[0099] In other embodiments, the nanoparticles of the present invention, which can be used in radiotherapy, comprise one or more alpha-emitting radionuclides and one or more beta-emitting radionuclides. In this particular embodiment, they are particularly free of beta+ emitting radionuclides. Preferably, they contain alpha-emitting radionuclides, such as those selected from... 225 Ac and 223 Ra, and β-emitting radionuclides, such as 90 Y、 67 Cu、 212 Pb or 177 Lu. These nanoparticles make it possible to deliver an effective dose of therapeutic radiation to patients 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 is less harmful to health.

[0100] 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.

[0101] 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.

[0102] 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:

[0103] -α-emitting radionuclides have an activity range of 1 MBq to 20 MBq, preferably 5 MBq to 10 MBq, and

[0104] - Where applicable, the activity range of β+ emitting radionuclides is 10 MBq to 300 MBq, preferably 30 MBq to 100 MBq, and / or

[0105] - Where applicable, the activity of the β-emitting radionuclide is from 1 GBq to 20 GBq, preferably from 5 GBq to 8 GBq.

[0106] 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.

[0107] - Used for imaging

[0108] β+ ionizing radiation is visible throughout the body in imaging. α and β- radiation are invisible in imaging.

[0109] 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.

[0110] The nanoparticles according to the invention, which can be used for imaging, may further contain one or more β-emitting radionuclides.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] - Used in therapeutic diagnostics

[0116] As mentioned in the introduction, therapeutic diagnostics refers to the simultaneous use of imaging and therapy.

[0117] 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.

[0118] The nanoparticles according to the invention, which can be used in therapeutic diagnostics, may further contain one or more β-emitting radionuclides.

[0119] 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.

[0120] 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.

[0121] 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.

[0122] - Used in dosimetry

[0123] 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.

[0124] 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.

[0125] 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:

[0126] i) Applying nanoparticles into the body, the nanoparticles having a known ratio of therapeutically radiative radionuclides to β+ radiative radionuclides;

[0127] ii) Visualize the nanoparticles, particularly through PET imaging, and determine the intensity of the signals emitted by β+-emitting radionuclides.

[0128] iii) Quantify the activity of β+ radionuclides by measuring the signal intensity in step ii).

[0129] iv) Quantify the activity of radionuclides emitting therapeutic radiation by means of the ratio of therapeutically radiated radionuclides to β+ radiated radionuclides.

[0130] 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.

[0131] 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.

[0132] 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.

[0133] Methods for preparing nanoparticles

[0134] The present invention also relates to a method for preparing the nanoparticles of the present invention, said nanoparticles comprising one or more alpha-emitting radionuclides and one or more beta-emitting radionuclides, the method comprising the following steps:

[0135] a) Preparation of nanoparticles based on sol-gel of porous materials.

[0136] b) Radiolabel the nanoparticles from step a) with one or more alpha-emitting radionuclides and one or more beta-emitting radionuclides.

[0137] c) Encapsulate the radioactive nanoparticles from step b) with a metal shell.

[0138] The radionuclides contained in the nanoparticles and metal shells are as described above.

[0139] 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.

[0140] 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.

[0141] 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. Thus, if the nanoparticles contain both alpha-emitting and beta-emitting radionuclides, a first radionuclide can be adsorbed onto the nanoparticles, and then in a subsequent step, the core of the nanoparticles can adsorb a second radionuclide. In the case where the nanoparticles contain several radionuclides of the same type (e.g., several alpha-emitting radionuclides), each radionuclide can be adsorbed individually and sequentially by the core of the nanoparticles. Advantageously, the adsorption order of the radionuclides depends on their half-lives. Radionuclides with longer half-lives can be adsorbed before those with shorter half-lives.

[0142] In the second variant, a radioactive nuclide is added simultaneously.

[0143] 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. This procedure is repeated for each radionuclide to be adsorbed by the nucleus of the nanoparticles.

[0144] The method for coating step c) depends on the properties of the metal shell applied to the surface of the nanoparticles. Based on the properties of the metal shell, those skilled in the art will be able to apply appropriate methods to perform the coating operation.

[0145] In a specific example, the coating step c) is performed by suspending radiolabeled nanoparticles in a solution containing a solvent (e.g., an alcohol such as ethanol) and a metal or metal oxide. For example, if the metal shell is composed of titanium dioxide, the solution contains tetrabutyl titanate. The nanoparticles are suspended in the solution for the duration required for the coating operation. The suspension time also depends on the half-life of the nanoparticles. The nanoparticles are then centrifuged and recovered.

[0146] 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.

[0147] On the other hand, preferably, steps b) and c) are performed sequentially over a short time span, based on the half-life of the adsorbed radionuclide.

[0148] Preferably, once step c) 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.

[0149] 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 limiting and should be used to determine step c) and the time period necessary for administration to the patient.

[0150] Example

[0151] 1) Synthesis of nanoparticles

[0152] 1.1. Synthesis of silica-based nanoparticles

[0153] SiO2 nanoparticles (NPs) were prepared using the sol-gel method. For this purpose, 8.75 mL of ethanol (99.9%) and 2.4 mL of milli-Q water were mixed for 5 minutes. Next, 65 µL of 99% tetraethyl orthosilicate (TEOS) 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.

[0154] 1.2. Use 223 Raand 89 Zr for radiolabeling

[0155] Through the synthesis of SiO2NP pairs 223 Radiolabeling 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 Ra、 89A solution of Zr and 2.5 μL of 2M Na2CO3 was added to the tube.

[0156] 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.

[0157] Since the initial activity of the radionuclide solution added to the NP SiO2 suspension is known, the adsorption yield of the radionuclide can be calculated by measuring the residual activity at the end of the step. This yield can be recalculated after the coating step to verify that the latter does not lead to a significant loss of activity.

[0158] 1.3. Coating SiO2with a TiO2layer 223 Ra- 89 Zr NP

[0159] After the radiolabeling process, SiO2 is coated with a TiO2 layer. 223 Ra- 89 Zr nanoparticles. For this purpose, 3 mg of SiO2 - 223 Ra- 89 Zr 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 h without stirring, which allowed for the formation of SiO2-. 223 Ra- 89 Zr-TiO2 nanoparticles. To remove reaggregates, centrifugation at 800 rpm for 1 minute was performed. The SiO2-- content was recovered. 223 Ra- 89 The supernatant of the Zr-TiO2 nanoparticles was collected and transferred to a new container, then centrifuged at 12,000 rpm for 5 minutes. The nanoparticles were then washed at 12,000 rpm for 3 minutes, once with ethanol and once with milli-Q water.

[0160] After separation and coating, each radionuclide exhibited an adsorption capacity of approximately 60%, which was determined by calibration curves previously obtained by measuring the radium and zirconium activities of each radionuclide at different known concentrations using a gamma counter.

[0161] 1.4. SiO2 NP coated with TiO2 layer

[0162] The same scheme as described in paragraph 1.3 was used to coat non-radioactively labeled SiO2 nanoparticles (from the scheme in paragraph 1.1) in order to study their physicochemical properties as well as the physicochemical properties of uncoated SiO2 NPs.

[0163] Scanning electron microscopy (SEM) analysis was performed to study the morphology of SiO2 nanoparticles. SEM images ( Figure 1 a) shows the presence of uniform spherical SiO2 nanoparticles. This confirms that the synthesis conditions produced regular and uniform nanoparticles. Importantly, it is noted that scanning electron spectroscopy primarily provides morphological information, such as particle shape and size. To better understand the properties of the obtained SiO2 NPs, transmission electron microscopy (TEM) analysis was performed. Figure 2 MET images of the nanoparticles are shown, with SiO2 Np particles having a size of approximately 150–220 nm. High-resolution MET studies were performed to determine the thickness of the TiO2 layer (see [link]). Figure 3 These results confirm that the formation of very thin TiO2 layers (between 1 nm and 10 nm) is sufficient to fill the pores and prevent the release of radionuclides.

[0164] Figure 1 The EDX spectrum in b confirms the presence of Ti on the SiO2-TiO2NP surface. This confirms the formation of a TiO2 layer around the SiO2 core.

[0165] To better understand the surface composition and bonding environment of SiO2-TiO2NP, X-ray photoelectron spectroscopy (XPS) was used for analysis.

[0166] The complete spectrum revealed the presence of Si and O elements in SiO2 nanoparticles, as well as the presence of Si, O, and Ti elements in SiO2-TiO2 nanoparticles. Figure 4 a). These results demonstrate the success of the synthesis method and the TiO2 coating of NPs on a silica core. Figure 4The high-resolution XPS spectra of the energy levels 2p Si, 2p Ti, and 1s O are shown in bd. The 2p Si spectrum of the SiO2 NP shows a single peak (104.3 eV) corresponding to the Si-O-Si bond. The same peak was detected in the SiO2-TiO2 NP spectrum, except for another peak at 102.2 eV, both corresponding to the Si-O-Ti bond energy. The 2p Ti spectrum shows peaks at 458.7 and 464.6 eV, corresponding to the 2p3 / 2 Ti orbital and the 2p1 / 2 Ti orbital, respectively. This indicates the presence of the oxidized Ti4+. The XPS spectrum of the 1s O of the SiO2 sample has a peak at 532.8 eV, which is attributed to Si-O. In the case of SiO2-TiO2, due to spectral asymmetry, it is deconvoluted into three peaks ( Figure 4 (b) The first peak at 530.3 eV is attributed to TiO2. The second peak at 532.6 eV is attributed to SiO2. The lowest peak at 530.9 eV is attributed to the Si-O-Ti bond energy. Therefore, these results indicate that TiO2 nanoparticles have been deposited on the surface of SiO2 nanoparticles, thus forming a coating layer.

[0167] 1.5. Use 89 Zr was radiolabeled and coated with a TiO2layer over SiO2- 89 Zr NPs

[0168] Perform the same procedure for radiolabeling as described in paragraph 1.2, and then perform the same procedure for coating as described in paragraph 1.3, using a radionuclide with an initial activity of 3 MBq. 89 Zr radiolabeled SiO2 NPs were then coated with TiO2 layers.

[0169] The adsorption yield after incubation was 95%. Only 3% loss was detected after two washing steps. Only 5% activity was lost during TiO2 coating. This coating step did not lead to any additional significant loss in the subsequent cleaning step. Release at different time intervals was studied using radiolabeled NPs. After 10 days, a very small percentage of 0.2% was observed to be released. Therefore, this study demonstrates the ability of SiO2-TiO2 nanoparticles to effectively encapsulate zirconium radionuclides with high adsorption rates and minimal activity loss during washing and coating steps. These results confirm the promising potential of these nanoparticles for applications such as medical imaging.

[0170] 1.6. Use 225 Ac- 124 I was radiolabeled and coated with a layer of SiO2- 225 Ac- 124 I NP

[0171] Perform the same procedure for radiolabeling as described in paragraph 1.2, and then perform the same procedure for coating as described in paragraph 1.3, to use radionuclides. 225 Ac and 124 I radiolabeled SiO2 NPs, and then coated them with TiO2 layers.

[0172] The adsorption yield of each radionuclide after incubation was 60%.

[0173] 1.7. Use 225 Ac -177 Lu for radiolabeling and coating with TiO2 layers on SiO2 - 225 Ac- 177 Lu NP

[0174] Implement the same procedure for radiolabeling as described in paragraph 1.2, and then implement the same procedure for coating as described in paragraph 1.3, to use 177 The initial activity of Lu was 60 MBq and 225 Ac radionuclides with an initial activity of 30 KBq 225 Ac and 177 Lu radiolabels SiO2 NP, then uses TiO2. 2 They are covered by layers.

[0175] The adsorption yield of each radionuclide after incubation was 60%.

[0176] 2) In vivo tumor imaging performance

[0177] The aim of this study was to evaluate the use of radioisotopes injected into mice. 89 Zr (used for imaging) and 223 The consequences of Ra (for therapeutic purposes) labeled SiO2-TiO2 nanoparticles. The aim of this study was to explore the feasibility of combining imaging and tumor growth inhibition by simultaneously using these radiolabels. For this purpose, mice (S1) received a dose of 125.8 kBq of Ra-labeled SiO2-TiO2 nanoparticles. 89 Zr-TiO2 nanoparticles were injected into one mouse, while another mouse (S2) received SiO2- 89 Zr- 223 The Ra-TiO2 nanoparticles were injected, with zirconium activity of 66.6 kBq and radium activity of 13.32 kBq.

[0178] Immediately after the administration of radiolabeled samples to the two mice, positron emission tomography (PET) imaging was performed on S1 after a 24-hour delay and on S2 after a 90-hour delay.

[0179] The results showed that using two types of radiolabeled NPs, namely Zr and Zr+Ra, allowed for active imaging of tumors and detection of tumor lesions. Furthermore, sufficient accumulation of these NPs was observed at the tumor site. Figure 5 Therefore, it is believed that when combined, SiO2-89 Zr-223 Ra-TiO2 nanoparticles constitute a powerful platform for tumor imaging and therapy.

Claims

1. Core / shell type radioactive nanoparticles, comprising: - A core based on a porous material, comprising one or more alpha-emitting radionuclides and one or more beta-emitting radionuclides, and - Metal casing.

2. The radioactive nanoparticles according to claim 1, characterized in that, The radionuclide is adsorbed onto the porous material.

3. The radioactive nanoparticles according to claim 1 or 2, characterized in that, The shell is composed of materials selected from metals, metal oxides, metal alloys, mixtures thereof, and combinations thereof.

4. The radioactive nanoparticles according to claim 3, characterized in that, The metal shell contains titanium oxide, and is particularly composed of titanium oxide.

5. The radioactive nanoparticles according to any one of claims 1 to 4, characterized in that, 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.

6. The radioactive nanoparticles according to any one of claims 1 to 5, characterized in that, The one or more β-emitting radionuclides are independently selected from the group consisting of β+-emitting radionuclides, β-emitting radionuclides, and combinations thereof.

7. The radioactive nanoparticles according to any one of claims 1 to 6, 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.

8. The radioactive nanoparticles according to any one of claims 1 to 6, characterized in that, The one or more β-emitting radionuclides are selected from β-emitting radionuclides, particularly 131 I, 89 Sr、 153 Sm、 32 P, 90 Y、 166 Ho、 177 Lu、 188 Re、 169 Er、 145 Pm, 67 Cu and 212 The group consisting of Pb.

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 nanoparticles according to any one of claims 1 to 8, 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 7, used as imaging agents, particularly for PET imaging.

13. The radioactive nanoparticles according to claim 7, used in combination with: -Tumor imaging, and - Cancer treatment and / or prevention.

14. The radioactive nanoparticles of claim 7, wherein the amount of therapeutic radiation absorbed by the therapeutic target is determined by PET imaging.

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