TWI833803B - Use of high-z element containing nanoparticles in the manufacture of a medicament for treating a tumor - Google Patents

Abstract

The disclosure relates to methods for treating tumors. In particular, the disclosure relates to a method of treating a tumor by ionizing radiations in a subject in need thereof, said method comprising the steps of: (i) injecting a first therapeutically effective amount of high-Z element containing nanoparticles as radiosensitizing agents in said subject in need thereof within a period between 2 and 7 days prior to the first irradiation of the tumor, (ii) injecting a second therapeutically effective amount of the same or different high-Z element containing nanoparticles within a period between 1 hour to 12 hours prior to the first irradiation of the tumor, and, (iii) irradiating the tumor of said subject with a therapeutically efficient dose of radiations; wherein said high-Z element containing nanoparticles are nanoparticles containing an element with an atomic Z number higher than 40 and said nanoparticles have a mean hydrodynamic diameter below 10 nm.

Description

Nanoparticles containing high Z elements are used in the preparation of drugs for treating tumors. way

This disclosure relates to methods of treating tumors. Specifically, the present disclosure relates to a method of treating tumors by ionizing radiation in a subject in need thereof, the method comprising the following steps: (i) a period between 2 days and 10 days before first irradiation of the tumor Injecting a first therapeutically effective amount of nanoparticles containing high Z elements as a radiosensitizer into a subject in need thereof, (ii) within a period between 1 hour and 12 hours before the first irradiation of the tumor , injecting a second therapeutically effective amount of nanoparticles containing the same or a different high-Z element, and (iii) irradiating the subject's tumor with a therapeutically effective dose of radiation, wherein the nanoparticles containing the high-Z element are nanoparticles containing elements with an atomic number Z higher than 40, and the nanoparticles have an average hydrodynamic diameter below 10 nm.

Radiation therapy (also known as radiation therapy) is one of the most commonly used anti-tumor strategies. More than half of all cancer patients are treated with ionizing radiation (IR) alone or in combination with surgery or chemotherapy. ¹ The latest advances achieved in medical physics (through the development of low/high energy radiation, the execution of single-shot, low-fraction or high-fraction protocols and the diversification of dose rates used) and innovative medical technologies (such as 3D- The research and development of 3D-conformational radiotherapy (3D-CRT), intensity modulated radiation therapy (IMRT), stereotactic radiosurgery (SRS) and functional imaging) helps to treat tumors Better delivery of effective doses of radiation while avoiding damage to surrounding healthy tissue, which is the most common side effect of radiation therapy. ² Several applications of nanomedicine, such as radioisotope labeling or metal nanoparticles, have been developed to improve this therapeutic index by using nanomaterials as contrast agents or contrast agents to better deliver the radiation dose to the tumor. in-site and/or as a radiosensitizer to enhance dose deposition in the tumor and reduce radiation-related side effects. ^3,4,5,6,7 Taking into account that the radiation dose absorbed by any tissue is related to the square of the relative atomic number (Z ² ) of the material (where Z is the atomic number) ⁸ , containing high Z atoms (such as gold or chromium ) nanoparticles have been extensively studied for their potential to improve radiotherapy. After exposure to ionizing radiation, heavy metal-based nanoparticles generate photons and Auger electrons, which improve the total dose rate deposition on tumors, induce the production of reactive oxygen species (ROS) and lead to Cell destruction of many tumors including, for example, melanoma, glioblastoma, breast cancer, and lung cancer. ^9,10,11 Although there are several preclinical animal models revealing the fact that the combination of heavy metal-based nanoparticles and ionizing radiation can reduce tumor growth, there is still a need to improve the use of radiosensitizing nanoparticles in combination with ionizing radiation in anticancer therapy. Use of particles.

Specifically, an important success rule for therapeutic strategies involving radiosensitizing nanoparticles is to optimize the concentration and distribution of radiosensitizing nanoparticles in the tumor to be treated while preserving surrounding healthy tissue.

In the present disclosure, the inventors now unexpectedly discovered that more than 10% of the Gd-based nanoparticles initially targeted to the tumor were still visible in the tumor 8 days after the initial injection. This unexpectedly long persistence of nanoparticles in human tumors allowed the inventors to devise new protocols for administering nanoparticles as radiosensitizers in combination with radiation therapy in human patients. The methods of the present disclosure comprise at least two injections of nanoparticles prior to irradiation, one or more of the injections typically occurring less than 24 hours prior to irradiation, but further comprising the first injection being between 2 days and 10 days prior to the first irradiation of the tumor. carried out within the period.

Accordingly, the present disclosure relates to a method of treating tumors by ionizing radiation in a subject in need thereof, the method comprising: (i) between 2 days and 10 days before first irradiation of the tumor, preferably between 2 days and Within a period of 7 days, inject a first therapeutically effective amount of a radiosensitizer containing Nanoparticles of high-Z elements; (ii) inject a second therapeutically effective amount of nanoparticles containing the same or different high-Z elements within a period between 1 hour and 12 hours before the first irradiation of the tumor; and (iii) irradiating the subject's tumor with a therapeutically effective dose of radiation; wherein the nanoparticles containing high-Z elements are nanoparticles containing elements having an atomic number Z higher than 40, preferably higher than 50, and The nanoparticles have an average hydrodynamic diameter below 10 nm, preferably below 6 nm, for example between 2 nm and 6 nm.

In specific embodiments of the methods, the nanoparticles are injected intravenously.

In certain embodiments, the nanoparticles include rare earth metals, or mixtures of rare earth metals, as high-Z elements. In more specific embodiments, the nanoparticles include as high-Z elements gallium, bismuth, or mixtures thereof.

Typically, the nanoparticles include chelates of high-Z elements, such as chelates of rare earth elements.

In certain embodiments, the nanoparticles used in the above methods comprise: (i) a polyorganosiloxane; (ii) a chelate covalently bound to the polyorganosiloxane; and (iii) by Chelates are used to complex high Z elements.

In particular embodiments, the nanoparticles used in the above methods comprise: (i) a polyorganic polyorganosulfide having a silicon weight ratio of at least 8%, preferably between 8% and 50%, based on the total weight of the nanoparticles. siloxane; (ii) chelates covalently bound to the polyorganosiloxane in a ratio of between 5 and 100, preferably between 5 and 20, per nanoparticle; and (iii) complexing High Z elements to chelates.

In specific embodiments, the nanoparticles used in the above methods may include chelates for complexing high-Z elements by grafting one or more of the following chelating agents onto the nanoparticles particles Come up and get: DOTA, DTPA, EDTA, EGTA, BAPTA, NOTA, DOTAGA, and DTPABA, or their mixtures.

In a particularly preferred embodiment, the nanoparticles are chelated polysiloxane nanoparticles of the following formula:

Wherein PS is the matrix of polysiloxane, and n includes between 5 and 50, preferably between 5 and 20, and the average hydrodynamic diameter includes between 2nm and 6nm.

In specific embodiments, the nanoparticles are AGuIX nanoparticles.

In certain embodiments, the nanoparticles are lyophilized powders contained in prefilled vials for reconstitution in aqueous solution for intravenous injection.

In specific embodiments, the nanoparticles used in the above methods are included in the injectable solution at a concentration of between 50 and 150 mg/mL, and preferably between 80 and 120 mg/mL, such as 100 mg/mL.

Typically, a therapeutically effective amount administered at each injection step may comprise between 50 mg/kg and 150 mg/kg, typically between 80 and 120 mg/kg, such as 100 mg/kg.

In certain embodiments, the tumor to be treated is a solid tumor, preferably selected from the group consisting of: glioblastoma, brain metastasis, meningioma, or cervical cancer, rectal cancer, lung cancer, head and neck cancer, prostate cancer , primary tumors of colorectal cancer, liver cancer, and pancreatic cancer. Typically, the tumor is a brain metastasis, usually from melanoma, lung cancer, breast cancer, kidney cancer, or primary cancer of the colon.

In certain embodiments, the subject is exposed to whole brain radiation therapy at step (iii). For example, the whole-brain radiation therapy consists of exposing the subject to a total dose of ionizing radiation of between 25 and 35 Gy, such as 30 Gy. Typically, subjects are exposed to a dose of approximately 3 Gy per fraction of ionizing radiation, and the total dose is preferably administered in a maximum of 10 fractions.

In certain embodiments, the method includes injecting a third therapeutically effective amount of nanoparticles containing the same or a different high-Z element within 5-10 days after the second injection step, such as within 7 days after the second injection step. steps.

In a specific embodiment, the method further includes the step of imaging the tumor by magnetic resonance imaging (MRI) after the first injection step of the nanoparticles, wherein the nanoparticles are used as the T1 of the MRI Contrast agent.

Figure 1 shows MRI enhancement compared to the administered dose. Each point on the graph corresponds to the MRI enhancement value measured in metastases with a longest diameter greater than 1 cm. MRI enhancement was found to be statistically different between doses, combined 15-30 mg/kg, combined 50-75 mg/kg and 100 mg/kg.

Figure 2 shows MRI enhancement compared to AGuIX concentration. Each point on the graph corresponds to the measured MRI enhancement and AGuIX concentration values in patient #13's metastasis with the longest diameter greater than 1 cm. The black curve corresponds to linear regression applied to a series of points. The dashed curve corresponds to the 95% confidence band.

Figure 3 shows MRI enhancement one week after nanoparticle administration. A portion of the signal enhancement map (color coded) of Patient #13 was superimposed onto the original 3D T ₁ -weighted images obtained 2 hours after the patient's iv injection (left image) and one week later (right image). Arrow points to AGuIX-enhanced transfer.

Figure 4 shows a summary of the Phase II clinical studies and objectives.

This disclosure arises, in part, from the unexpected discovery by the present inventors of the longer persistence of certain nanoparticles used as radiosensitizers in cancer radiation therapy in human tumors. now.

The beneficial effects of the treatment method of the present disclosure are particularly related to two characteristics of the nanoparticles: (i) they contain high-Z elements, usually complexes of high-Z cations with radiosensitizing properties; (ii) they have Smaller mean hydrodynamic diameter.

As used herein, the term "radiosensitizing" is readily understood by those of ordinary skill in the art and generally refers to an increase in the response of cancer cells to radiation therapy (e.g., photon radiation, electron radiation, proton radiation, heavy ion radiation, and the like) ) sensitivity process.

The high Z element as used herein is an element having an atomic number Z above 40, for example above 50.

In a specific embodiment, the high Z element is chosen between heavy metals, and more preferably Au, Ag, Pt, Pd, Sn, Ta, Zr, Tb, Tm, Ce, Dy, Er, Eu, La, Nd, Pr, Lu, Yb, Bi, Hf, Ho, Pm, Sm, In, and Gd, and mixtures thereof.

High-Z elements are preferably cationic elements, which are included in the nanoparticles in the form of oxides and/or chalcogenides or halides or in complexes with chelating agents such as organic chelating agents.

The size distribution of nanoparticles is measured, for example, using a commercial particle sizer such as the Malvern Zêtasizer Nano-S particle sizer based on PCS (Photon Correlation Spectroscopy).

For the purposes of the present invention, the term "mean hydrodynamic diameter" or "average diameter" is intended to mean the harmonic mean of the diameters of the particles. The method of measuring this parameter is also described in the standard ISO 13321:1996.

Nanoparticles having a mean hydrodynamic diameter, for example, between 1 and 10 nm, and even better, between 1 and 8 nm, or, for example, between 2 nm and 6 nm, or typically about 3 nm, are suitable for the methods disclosed herein. Specifically, it has been shown to provide excellent passive targeting in tumors, including brain tumors, and rapid renal elimination (and thus low toxicity) following intravenous injection.

In another embodiment, which can be combined with the previous embodiment, nanoparticles can also advantageously be used As a contrast agent or contrast agent, for example, in image-guided radiation therapy.

As used herein, the term "contrast agent" is intended to mean an agent that artificially increases contrast so that a specific anatomical structure (eg, certain tissues or organs) or a pathological anatomical structure (eg, a tumor) can be observed relative to adjacent or non-pathological structures. Any product or composition intended for use in medical imaging. The term "contrast agent" is intended to mean a substance used in medical imaging for the purpose of producing a signal that allows the observation of a specific anatomical structure (such as certain tissues or organs) or a pathological anatomical structure (such as a tumor) relative to adjacent or non-pathological structures. any product or composition used in. How contrast media or contrast agents work depends on the imaging technique used.

In some embodiments, imaging is performed using magnetic resonance imaging (MRI), computerized tomography, positron emission tomography, or any combination thereof.

Advantageously, the use of nanoparticles in the treatment methods of the present disclosure may be combined with in vivo detection of tumors by MRI, enabling, for example, monitoring of therapeutic treatments, as described in the present disclosure.

Preferably, only lanthanide elements include at least 50% by weight of gallium (Gd), dysprosium (Dy), 鑥 (Lu), bismuth (Bi) or 鈥 (Ho), or mixtures thereof (relative to the nanoparticles) (total weight of high-Z elements), for example at least 50% by weight of rhodium is selected as the high-Z element in the nanoparticles.

In a particularly preferred embodiment, the nanoparticles used in the methods of the present disclosure are gallium-based nanoparticles.

In specific embodiments, the high-Z elements are cationic elements complexed by organic chelating agents, such as chelating agents selected from the group consisting of carboxylic acid, amine, thiol, or phosphonate groups.

In preferred embodiments, the nanoparticles further comprise a biocompatible coating in addition to high-Z elements and optional chelating agents. Agents suitable for such biocompatibility include, but are not limited to, biocompatible polymers such as polyethylene glycol, polyethylene oxide, polyacrylamide, biopolymers, polysaccharides, or polysiloxanes.

In specific embodiments, the nanoparticles are selected such that they have a relaxivity r1 (at 37°C and 1.4T) of between 50 and 5000mM ⁻¹ .s ⁻¹ per particle and/or at least 5%, e.g. Gd weight ratio between 5% and 30%.

In a particular embodiment, the nanoparticles having a very small average hydrodynamic diameter, for example between 1 and 10 nm, preferably between 2 nm and 6 nm, are chelates containing high Z elements, such as rare earth elements. Chelate nanoparticles. In certain embodiments, the nanoparticles comprise chelates of gium or bismuth.

In certain embodiments that can be combined with any of the previous embodiments, the high-Z element-containing nanoparticles comprise: ‧polyorganosiloxane; ‧a chelating agent covalently bound to the polyorganosiloxane; High Z elements complexed by chelating agents.

As used herein, the term "chelating agent" refers to a group capable of complexing one or more metal ions.

Exemplary chelating agents include (but are not limited to): 1,4,7-triazacyclononanetriacetic acid (NOTA), 1,4,7,10-tetraazacyclododecane-1,4,7 ,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODAGA), ethylenediaminetetraacetic acid (EDTA), diethylene glycol Triaminepentaacetic acid (DTPA), cyclohexyl-1,2-diaminetetraacetic acid (CDTA), ethylene glycol-0,0'-bis(2-aminoethyl)-N,N,N', N'-tetraacetic acid (EGTA), N,N-bis(hydroxybenzyl)-ethylenediamine-N,N'-diacetic acid (HBED), trisethylenetetraminehexaacetic acid (TTHA), hydroxyethylenediamine Amine triacetic acid (HEDTA), 1,4,8,11-tetraazacyclotetradecane-N,N',N",N'''-tetraacetic acid (TETA), and 1,4,7,10 -Tetraaza-1,4,7,10-tetraaza-(2-aminomethylmethyl)-cyclododecane (TCMC) and 1,4,7,10-tetraazacyclododecane, 1-(Glutaric acid)-4,7,10-triacetic acid (DOTAGA).

In some embodiments, the chelating agent is selected between:

Where the wavy bond indicates the bond connecting the chelating agent to the linking group forming the biocompatible coating of the nanoparticle.

In a particular embodiment, which may preferably be combined with the previous embodiments, the chelates of rare earth elements are chelates of gallium and/or bismuth, preferably DOTA or DOTAGA chelating Gd ³⁺ and/or Bi .

In certain and preferred embodiments, the ratio of high Z elements per nanoparticle, such as the ratio of rare earth elements such as gallium (optionally chelated by DOTAGA) per nanoparticle, is between 3 and 100 between, preferably between 5 and 20, usually about 10.

For imaging by scintigraphy, the nanoparticles may additionally contain radioactive isotopes, which can be used for scintigraphy and are preferably selected from the group consisting of radioactive isotopes of In, Tc, Ga, Cu, Zr, Y or Lu, for example: ¹¹¹ In, ^99m Tc, ⁶⁷ Ga, ⁶⁸ Ga, ⁶⁴ Cu, ⁸⁹ Zr, ⁹⁰ Y or ¹⁷⁷ Lu.

For fluorescence in the near-infrared range, the nanoparticles may additionally contain a lanthanide element selected from Nd, Yb or Er.

For fluorescence in the visible range, the nanoparticles may additionally contain a lanthanide selected from Eu or Tb which may be used.

For fluorescence in the near-infrared range, the nanoparticles may additionally contain organic fluorophores selected from Cyanine 5.5, Cyanine 7, Alexa 680, Alexa 700, Alexa 750, Alexa 790, Bodipy, ICG.

In certain embodiments, the hybrid nanoparticles are core-shell type. Nanoparticles of the core-shell type based on a core consisting of rare earth oxides and with an optionally functionalized polyorganosiloxane matrix are known (see in particular WO 2005/088314, WO 2009/053644).

Nanoparticles can be further developed by allowing targeted delivery of nanoparticles to specific tissues. molecules for functionalization. These agents can be coupled to the nanoparticles by covalent coupling, or captured by non-covalent bonding, such as by encapsulation or hydrophilic/hydrophobic interactions or the use of chelating agents.

In a specific embodiment, hybrid nanoparticles are used that comprise: - a polyorganosiloxane (POS) matrix, which includes rare earth cations M ⁿ⁺ , n being an integer between 2 and 4, as appropriate Partly in the form of metal oxides and/or oxyhydroxides, these rare earth cations are optionally associated with doping cations D ^m+ , m being an integer between 2 and 6, D preferably being a rare earth metal other than M , actinides and/or transition elements; - chelates covalently bound to POS via covalent bonds -Si-C-, - M ⁿ⁺ cations and optionally D ^m+ cations are complexed by chelates.

In the case of a core-shell structure, the POS matrix forms a surface layer surrounding a core based on metal cations. Its thickness can vary from 0.5 to 10nm and can account for 25% to 75% of the total volume.

The POS matrix acts as a protection for the core relative to the external medium (especially protection against hydrolysis) and it optimizes the properties of the contrast agent (eg, fluorescence). It also allows functionalization of nanoparticles via grafting chelators and targeting molecules.

[Ultra-fine nanoparticles]

In a specific embodiment, the nanoparticles are chelated polysiloxane nanoparticles of the formula:

Where PS is the matrix of polysiloxane, and n includes 5 and 50, usually between 5 and 20, And the average hydrodynamic diameter is between 2nm and 6nm.

More specifically, the gallium-chelated polysiloxane nanoparticles as described in the above formula are AGuIX ultrafine nanoparticles as described in the next section.

Such ultrafine nanoparticles that can be used according to the methods of the present disclosure can be obtained or can be obtained by a top-down synthesis route including the following steps: a. Obtaining a metal (M) oxide core, where M is High Z elements as previously described, preferably gallium; b. Add a polysiloxane shell around the M oxide core, for example via the sol-gel method; c. Graft the chelating agent to the POS shell so that the chelating agent Bind to the POS shell by -Si-C- covalent bond, thereby obtaining core-shell precursor nanoparticles; and d. purify the core-shell precursor nanoparticles and transfer them to an aqueous solution; wherein The grafted reagent is in an amount sufficient to dissolve the metal (M) oxide core and complex the cationic form (M) in step d., thereby reducing the average hydrodynamic diameter of the resulting mixed nanoparticles to less than 10 nm, eg, between 1 nm and 8 nm, is typically less than an average diameter of 6 nm, eg, between 2 nm and 6 nm.

The nanoparticles obtained according to the method described above do not contain a core of metal oxide encapsulated by at least one coating. More details on the synthesis of these nanoparticles are given below.

This top-down synthesis method yields observed sizes typically between 1 nm and 8 nm, more specifically between 2 nm and 6 nm. So the term used in this article is ultrafine nanoparticles.

Alternatively, another "one-pot" synthesis is described below to prepare such coreless nanoparticles with an average diameter of less than 10 nm, eg, between 1 nm and 8 nm, typically between 2 nm and 6 nm.

Further details about such ultrafine or coreless nanoparticles, their synthesis processes and their uses are described in patent applications WO2011/135101, WO2018/224684 or WO2019/008040, which applications are incorporated by reference.

[Process for Obtaining Preferred Embodiments of Nanoparticles for Use in accordance with the Disclosure]

In general, one skilled in the art can readily produce nanoparticles for use in accordance with the present invention. More specifically, the following elements will be mentioned.

For core-shell nanoparticles based on a core of lanthanide oxides or oxyhydroxides, production processes using alcohols as solvents can be used, as for example in P. Perriat et al., J. Coll. Int. Sci, 2004, 273, 191; O. Tillement et al., J. Am. Chem. Soc., 2007, 129, 5076 and P. Perriat et al., J. Phys. Chem. C, 2009, 113, 4038.

For POS substrates, several techniques derived from those pioneered by Stoeber (Stoeber, W; J. Colloid Interf Sci 1968, 26, 62) can be used. The process for coating can also be used, as described in Louis et al. (Louis et al., 2005, Chemistry of Materials, 17, 1673-1682) or in the international application WO2005/088314.

In practice, the synthesis of ultrafine nanoparticles is described, for example, in Mignot et al. Chem. Eur. J. 2013, 19, 6122-6136: Usually, core/shell type precursor nanoparticles are prepared with lanthanide oxides. A core (via modified polyol route) and a polysiloxane shell (via sol/gel) are formed; the object has an average hydrodynamic diameter of, for example, about 5-10 nm. Therefore, lanthanide oxide cores of extremely small size (tunable below 10 nm) can be produced in alcohols by means of one of the processes described in the following publications: P. Perriat et al., J. Coll. Int. Sci, 2004, 273, 191; O. Tillement et al., J. Am. Chem. Soc., 2007, 129, 5076 and P. Perriat et al., J. Phys. Chem. C, 2009, 113, 4038.

Such cores may be coated with a polysiloxane layer according to the protocol described, for example, in the following publications: C. Louis et al., Chem. Mat., 2005, 17, 1673 and O. Tillement et al., J. Am .Chem.Soc.,2007,129,5076.

A chelating agent specific for a specified metal cation (such as DOTAGA for Gd ³⁺ ) is grafted onto the surface of the polysiloxane; part of it can also be inserted into the interior of the layer, but the control of the polysiloxane is formed are complex, and simple external grafting at these very small scales can give adequate proportions of grafting.

Nanoparticles can be separated from synthesis residues by means of methods such as dialysis or tangential filtration on membranes containing pores of appropriate size.

The core is destroyed by dissolution (eg by changing the pH or by introducing complex molecules into the solution). This destruction of the core then allows the dissipation of the silicone layer (according to the mechanism of slow erosion or collapse), so that ultimately polysiloxane objects with complex morphologies can be obtained, with characteristic dimensions being the thickness of the silicone layer orders of magnitude, that is, much smaller than the objects produced until now.

Therefore, removing the core allows reducing the particle size from about 5-10 nanometers in diameter to below 8 nm, for example to a size between 2-6 nm. Furthermore, this operation allows to increase the number of M (eg gallium) per nm ³ compared to theoretical polysiloxane nanoparticles of the same size but containing M (eg gallium) only at the surface. The number of M for a certain nanoparticle size can be evaluated with the help of the M/Si atomic ratio measured by EDX. Typically, this number of M per ultrafine nanoparticle may be comprised between 5 and 50.

In a specific embodiment, nanoparticles according to the present disclosure include a chelating agent with acid functionality, such as DOTA or DOTAGA. The acid functionality of the nanoparticles is achieved in the presence of an appropriate amount of targeting molecules, such as using EDC/NHS (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydrosuccinimide). amine) to activate. The nanoparticles thus grafted are then purified, for example by tangential filtration.

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4。 Alternatively, nanoparticles according to the present disclosure may be obtained or obtainable by a synthetic method ("one-pot synthesis") that involves adding at least one hydroxysilane or alkoxy group that is negatively charged at physiological pH. The silane and at least one chelating agent selected from polyaminopolycarboxylic acids are mixed with: - at least one hydroxysilane or alkoxysilane that is neutral at physiological pH, and/or - at least one hydroxysilane or alkoxysilane that is neutral at physiological pH Positively charged hydroxysilanes or alkoxysilanes containing amine functionality, where: - The molar ratio A of neutral silanes to negatively charged silanes is defined as follows: 0

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4。 According to a more specific embodiment of this one-pot synthesis method, the method includes mixing at least one alkoxysilane that is negatively charged at physiological pH with APTES-DOTAGA, TANED, CEST and mixtures thereof, - an alkoxysilane that is at least neutral at physiological pH, the alkoxysilane is selected between TMOS, TEOS and mixtures thereof, and/or - is positively charged at physiological pH APTES, where: - The molar ratio A between neutral silane and negatively charged silane is defined as follows: 0

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4。 According to a particular embodiment, the one-pot synthesis involves mixing APTES-DOTAGA, which is negatively charged at physiological pH, with: - at least one alkoxysilane that is neutral at physiological pH, the alkoxysilane Choose between TMOS, TEOS and their mixtures, and/or - Positively charged APTES at physiological pH, where: - The molar ratio A of neutral silane to negatively charged silane is defined as follows: 0

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[AGuIX Nanoparticles]

In a more specific embodiment, the nanoparticles based on chelated polysiloxane are core-less ultrafine AGuIX nanoparticles of the following formula:

Where PS is polysiloxane and n averages about 10, and has an average hydrodynamic diameter of 4±2 nm and a mass of about 10±1 kDa.

The AGuIX nanoparticles can also be described by the average chemical formula: (GdSi _4-7 C _24-30 N _5-8 O _15-25 H _40-60 ,5-10 H ₂ O) _x

[Pharmaceutical formulations of nanoparticles for use according to the disclosed methods]

When used as pharmaceuticals, compositions containing such high-Z nanoparticles for use as provided herein can be administered in the form of pharmaceutical formulations of suspensions of nanoparticles. Such formulations may be prepared as described herein or elsewhere, and may be administered by various routes, depending on whether local or systemic treatment is desired and the area to be treated.

Specifically, such pharmaceutical formulations for use as described herein contain as active ingredients a suspension containing high-Z nanoparticles as provided herein, and one or more pharmaceutically acceptable The carrier (excipient). In making the pharmaceutical formulations provided herein, the nanoparticle compositions may be mixed with or diluted by excipients, for example. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material that serves as a vehicle, carrier, or medium for the nanoparticle composition.

Thus, pharmaceutical formulations may be in the form of powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols (either in solid form or in liquid media), sterile injectable solutions, sterile packaged powders, and the like. form.

In certain embodiments, the pharmaceutical formulation for use described herein is a sterile lyophilized powder contained in a prefilled vial for reconstitution, eg, in aqueous solution, for intravenous injection. In certain embodiments, the lyophilized powder includes as an active ingredient an effective amount of such high-Z nanoparticle-containing nanoparticles, generally nanoparticles based on chelated polysiloxane, and more specifically as described herein. AGuIX nanoparticles. In certain specific embodiments, the lyophilized powder contains between about 200 mg and 15 g of AGuIX per vial, such as between 280 mg and 320 mg per vial, typically 300 mg of AGuIX per vial or between about 800 mg and 1200 mg, such as per vial 1g of AGuIX.

This powder may further contain one or more additional excipients, and in particular _CaCl2 , for example between 0.5 mg and 0.80 mg of _CaCl2 , typically 0.66 mg of _CaCl2 .

The lyophilized powder can be reconstituted in an aqueous solution, usually water for injection. Accordingly, in a specific embodiment, the pharmaceutical solution for use according to the present disclosure is an injectable solution that contains as an active ingredient an effective amount of such high-Z nanoparticle-containing nanoparticles, typically based on chelated polysilica. Nanoparticles of oxane, and more specifically AGuIX nanoparticles as described herein.

For example, the injectable solution for use in the methods as disclosed herein is between 50 mg/mL and 150 mg/mL, such as between 80 mg/mL and 120 mg/mL, typically 100 mg/mL, based on chelated polysiloxane. rice particles, typically a solution of AGuIX nanoparticles, optionally containing one or more additional pharmaceutically acceptable excipients, such as CaCl ₂ between 0.1 mg/mL and 0.3 mg/mL, typically 0.22 mg/mL of CaCl ₂ .

[How to use this disclosure]

The present invention relates to a method of treating tumors in a subject in need thereof, the method comprising: (i) within a period between 2 days and 10 days, preferably between 2 days and 7 days, before the first irradiation of the tumor, Inject the first therapeutically effective amount of nanoparticles containing high-Z elements as radiosensitizers into the subject in need; (ii) Inject the second therapeutically effective amount between 1 hour and 12 hours before the first irradiation of the tumor. 2. A therapeutically effective dose of nanoparticles containing the same or different high-Z elements; and (iii) a therapeutically effective dose of radiation to irradiate the subject's tumor; wherein the nanoparticles containing high-Z elements are those containing high-Z elements. Nanoparticles of an element with an atomic number Z between 40 and preferably above 50, and the nanoparticles have an average hydrodynamic diameter below 10 nm, preferably below 6 nm, for example between 2 nm and 6 nm.

The present disclosure also relates to nanoparticles containing high Z elements for use in a method of treating tumors in a subject in need thereof, the method comprising: (i) between 2 days and 10 days before first irradiation of the tumor, whichever is less Preferably within a period between 2 days and 7 days, inject a first therapeutically effective amount of nanoparticles containing high Z elements as a radiosensitizer into the subject in need; (ii) before the first irradiation of the tumor Injecting a second therapeutically effective amount of nanoparticles containing the same or different high-Z elements within a period between 1 hour and 12 hours; and (iii) irradiating the subject's tumor with a therapeutically effective dose of radiation; wherein the Nanoparticles containing high Z elements are nanoparticles containing elements with an atomic number Z higher than 40, preferably higher than 50, and these nanoparticles have a diameter below 10 nm, preferably below 6 nm, such as Average hydrodynamic diameter between 2nm and 6nm.

The present disclosure further relates to nanoparticles containing high Z elements for use in the manufacture of a drug for treating tumors in a subject in need thereof, the method comprising: (i) between 2 days and 10 days before first irradiation of the tumor, Preferably within a period between 2 and 7 days, in Inject the first therapeutically effective amount of nanoparticles containing high-Z elements as radiosensitizers into the subject in need; (ii) Inject the second therapeutically effective amount between 1 hour and 12 hours before the first irradiation of the tumor. 2. A therapeutically effective dose of nanoparticles containing the same or different high-Z elements; and (iii) a therapeutically effective dose of radiation to irradiate the subject's tumor; wherein the nanoparticles containing high-Z elements are those containing high-Z elements. Nanoparticles of an element with an atomic number Z between 40 and preferably above 50, and the nanoparticles have an average hydrodynamic diameter below 10 nm, preferably below 6 nm, for example between 2 nm and 6 nm.

As used herein, the term "treatment" refers to one or more of the following: (1) Suppression of a disease; e.g., suppression of a disease, condition, or disorder in an individual who is experiencing or exhibiting pathology or symptoms of the disease, condition, or condition (also i.e., arresting the further development of pathology and/or symptoms); and (2) ameliorating disease; e.g., ameliorating (i.e., reversing) a disease, condition, or condition in an individual who is experiencing or exhibiting pathology or symptoms of the disease, condition, or condition. pathology and/or symptoms), such as reducing the severity of the disease or reducing or alleviating one or more symptoms of the disease. Specifically, with respect to treating a tumor, the term "treating" may mean inhibiting the growth of the tumor, or reducing the size of the tumor.

The terms "patient" and "subject" are used interchangeably herein to refer to any member of the animal kingdom, including mammals and invertebrates. For example, mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, fish, and humans. Preferably, the subject is a mammal, or human, including, for example, a subject suffering from a tumor.

In specific embodiments, the tumor is a solid tumor, preferably selected from the group consisting of: glioblastoma, brain metastasis, meningioma, or cervical cancer, rectal cancer, lung cancer, head and neck cancer, prostate cancer, colorectal cancer Primary tumors of cancer, liver cancer, and pancreatic cancer. Specifically, the tumor is a brain metastasis, usually from melanoma, lung cancer, breast cancer, or primary renal cancer.

In specific embodiments, the subject is selected from a human patient suffering from multiple brain metastases. In other specific embodiments, the subject is selected from a population not suitable for localization by surgery or stereotactic radiation. Partially treated human patients with multiple brain metastases.

Methods of the present disclosure for treating cancer include at least two steps of administering an effective amount of the nanoparticles to a tumor in a subject.

Nanoparticles can be administered to a subject using different possible routes, such as local (intratumoral (IT)), intraarterial (IA), subcutaneous, intravenous (IV), intradermal, airway (inhalation), intraperitoneal, intramuscular Intrathecal, intraocular, or oral routes.

In specific embodiments, the nanoparticles are administered intravenously. Indeed, nanoparticles as disclosed herein are advantageously targeted for delivery to human tumors through passive targeting, such as through enhanced permeability and entrapment effects.

When appropriate, further injections or administrations of nanoparticles can be performed. Typically, when fractionated radiation therapy is used, nanoparticles can be further injected once a week during radiation therapy. For example, in one particular embodiment, a method as disclosed herein further comprises injecting a third therapeutically effective amount of a compound containing the same or a different high concentration within 5-10 days after the second injection step, such as within 7 days after the second injection step. The steps of Z element nanoparticles.

In particular embodiments, the nanoparticles are chelated polysiloxane-based nanoparticles and the therapeutically effective amount administered at each injection step may comprise between 50 mg/kg and 150 mg/kg, typically 80 mg /kg and 120mg/kg, such as 100mg/kg.

Advantageously, the same nanoparticles can be used as a theranostic agent for detecting tumors by MRI before they are used as radiosensitizers. Therefore, the method further includes the step of imaging the tumor by magnetic resonance imaging (MRI) after the first injection step of the nanoparticles, wherein the nanoparticles are used as T1 contrast agents for the MRI. The results in the Examples provide evidence of excellent signal enhancement in detecting tumors such as brain metastases by MRI in human patients after injection of these high-Z containing nanoparticles.

[Steps of irradiating tumors]

Methods using nanoparticles include targeting cancer-specific radiation therapy to those in need. A step of irradiating a subject's tumor, wherein the nanoparticles advantageously enhance the dose efficacy of radiation therapy.

As used herein, radiation therapy or radiotherapy is the medical use of radiation, also known as ionizing radiation, as part of cancer treatment to control malignant cells. It is used as a palliative treatment or as a therapeutic treatment. Radiation therapy is recognized as an important standard therapy for the treatment of various types of cancer.

As used herein, the term "radiation therapy" is used for the treatment of diseases of a neoplastic nature by irradiation corresponding to ionizing radiation. Ionizing radiation deposits energy that damages or destroys cells in the area to be treated (target tissue) by damaging their genetic material, making it impossible for these cells to continue to grow.

In certain embodiments, methods of the present disclosure include exposing a tumor to be treated to an effective dose of ionizing radiation, wherein the ionizing radiation is photons, such as X-rays. Depending on their energy, these rays can be used to destroy cancer cells on the surface or deeper within the body. The higher the energy of the X-ray beam, the deeper the X-rays can penetrate into the target tissue. Linear accelerators and beta accelerators produce X-rays of increasing energy. Using a machine to focus radiation, such as X-rays, on the cancer site is called external beam radiation therapy.

In alternative embodiments of treatment methods according to the present disclosure, gamma rays are used. Gamma rays are produced spontaneously when certain elements, such as radium, uranium, and cobalt-60, release radiation as they break down or decay.

Ionizing radiation is typically 2keV to 25000keV, especially 2keV to 6000keV (ie 6MeV) or 2keV to 1500keV (such as a cobalt 60 source).

Those skilled in the field of radiation therapy know how to determine appropriate dosage and administration regimens depending on the nature of the disease and the patient's constitution. Specifically, this person knows how to assess dose-limiting toxicities (DLT) and, accordingly, how to determine the maximum tolerated dose (MTD).

The amount of radiation used in radiation therapy is measured in Grays (Gy) and varies depending on the type and stage of cancer being treated. For responsive cases, the typical total of solid tumors Doses ranged from 20Gy to 120Gy. Radiation oncologists consider many other factors when selecting doses, including whether the patient is receiving chemotherapy, the patient's comorbid conditions, whether radiation therapy is given before or after surgery, and the success of the surgery.

The total dose is usually given in divided doses (spread out over time). Amount and schedule (planning and delivery of ionizing radiation, fractionated doses, fractionated delivery mode, total dose alone or in combination with other anticancer agents, etc.) are defined for any disease/anatomic site/disease stage patient situation/age and constitutes the standard of care in any particular situation.

A typical conventional fractionated dose regimen for adults using the disclosed method may be 2.5Gy to 3.5Gy per day, five days per week, for example, for 2 to 8 weeks. In certain embodiments, the radiation therapy consists of exposing the subject to a total dose of ionizing radiation of between 25 Gy and 35 Gy, such as 30 Gy.

In other specific embodiments, the subject is exposed to a dose of about 2 Gy to 8 Gy per fraction, and the total dose is preferably administered in a maximum of 10 fractions.

In certain embodiments in which the subject suffers from brain cancer, such as multiple brain metastases, the radiation therapy employed at step (iii) of the methods disclosed herein is whole brain radiation therapy (WBRT). The most common dosing/fractionation regimen used in WBRT is to deliver 30 Gy in 10 fractions over the course of 2 weeks, as used, for example, in Example 2.

[Combination therapy of methods disclosed in this disclosure]

Nanoparticles for use disclosed herein may be administered as the sole active ingredient or in combination with other agents, such as cytotoxic, anti-proliferative, or other anti-neoplastic agents, for example, used to treat or prevent the cancer disorders described above, for example, as administered with an adjuvant or combination.

Suitable cytotoxic, antiproliferative or antineoplastic agents may include, but are not limited to, cisplatin, doxorubicin, taxol, etoposide, irinotecan, topotecan ), paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide cyclophosphamide, tipifarnib, Gefitinib, erlotinib, imatinib, gemcitabine, uracil mustard, chlormethine, ifosfate ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, busulfan, carmustine , lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fluorine Fludarabine phosphate, oxaliplatin, folinic acid, pentostatin, vinblastine, vincristine, vinblastine Vindesine, bleomycin, dactinomycin, daunorubicin, epirubicin, idarubicin, mithramycin ), deoxycoformycin, mitomycin-C, L-aspartase, teniposide.

In some embodiments, additional therapeutic agents are administered concurrently with the compositions provided herein. In some embodiments, the additional therapeutic agent is administered after administration of a composition provided herein. In some embodiments, the additional therapeutic agent is administered prior to administration of a composition herein. In some embodiments, compositions provided herein are administered during a surgical procedure. In some embodiments, compositions provided herein are administered during a surgical procedure in combination with additional therapeutic agents.

Additional therapeutic agents provided herein are effective over a wide dosage range and are generally administered in effective amounts. However, it is understood that the actual amount of therapeutic agent administered will generally be determined by the physician based on the relevant circumstances, including the condition to be treated, the route of administration chosen, the actual compound administered, the age, weight, and age of the individual patient. reactions, severity of patient symptoms, and similar circumstances.

Other aspects and advantages of the methods of the present disclosure will become apparent in the following examples, which are given for illustrative purposes only.

[Example]

Example 1: First human trial of Gd-based theranostic nanoparticles: patients with 4 Absorption and biodistribution in patients with various types of brain metastases

[1.1 Materials and methods]

[Research Design]

This study is part of a prospective dose-escalation Phase Ib clinical trial to evaluate the tolerability of radiosensitized AGuIX nanoparticles administered intravenously in combination with whole-brain radiation therapy for the treatment of brain metastases. The Nano-Rad test (radiosensitization of multiple brain metastases using AGuIX gallium-based nanoparticles) is registered as NCT02820454. In this article, we report the findings of an MRI protocol applied to 15 recruited patients. The objectives assigned to this MRI ancillary study were i) to assess the distribution of AGuIX nanoparticles in brain metastases and surrounding healthy tissue and ii) to measure T ₁ -weighted contrast enhancement and brain imaging following intravenous administration of AGuIX nanoparticles. Nanoparticle concentration in metastasis and surrounding healthy tissue (Verry C et al. BMJ Open. 9 : e023591 (2019)).

[Patient selection]

Recruitment is not suitable for patients with multiple brain metastases who are treated locally by surgery or stereotactic radiation. Inclusion criteria included: i) minimum age 18 years, ii) secondary brain metastases from histologically confirmed solid tumors, iii) no previous brain irradiation, iv) no renal failure (glomerular filtration rate >60 mL/ min/1.73m ² ), v) normal liver function (bilirubin <30 μmol/L; alkaline phosphatase <400UI/L; aspartate aminotransferase (AST) <75UI/L; alanine aminotransferase (ALT)<175UI/L).

[Experimental design]

The main steps of the test plan are as follows. At D0, the patient underwent the first imaging session (see MRI protocol in the next paragraph), which consisted of an intravenous bolus injection of Dotarem (meglumine meglumine) at a dose of 0.2 mL/kg (0.1 mmol/kg) of body weight. Give the patient intravenously at a dose of 15 mg/kg, 30 mg/kg, 50 mg/kg, 75 mg/kg, or 100 mg/kg of body weight between 1 day and 21 days after the first imaging session (depending on patient availability and radiation therapy plan). Administer the solution of AGuIX nanoparticles. The date of AGuIX nanoparticle administration is referred to as D1.

[Synthesis of AGuIX nanoparticles]

AGuIX nanoparticles were obtained through a six-step synthesis. The first step is to form a gallium oxide core by adding soda ash to gallium trichloride in diethylene glycol. The second step is to grow the polysiloxane shell by adding TEOS and APTES. After maturation, DOTAGA anhydride is added to react with free amine functional groups present on the surface of the inorganic matrix. After transfer to water, dissolution of the gallium oxide core was observed and chelation of the gallium by DOTAGA at the surface of the matrix was observed. Then, fragmentation of the polysiloxane matrix in the ultrasmall AGuIX nanoparticles was observed. The final step is freeze-drying of the nanoparticles.

Theranostic agents consist of a polysiloxane network surrounded by cylindrium cyclic ligands covalently grafted to the polysiloxane matrix. These ligands are DOTA(1,4 , 7,10-tetraazacyclododecanoic acid-1,4,7,10-tetraacetic acid) derivatives. Its average hydrodynamic diameter is 4±2nm, its mass is about 10kDa and its average chemical formula is (GdSi _4-7 C _24-30 N _5-8 O _15-25 H _40-60 ,5-10H ₂ O) _x to describe. On average, each nanoparticle exhibits 10 DOTA ligands on its surface, which chelate core gallium ions. The longitudinal relaxation rate r ₁ at 3 Tesla is equal to 8.9mM ^-1 .s ^-1 per Gd ³⁺ ion, resulting in a total r ₁ of 89mM ^-1 .s ^-1 per AGuIX nanoparticle. Two hours after nanoparticle administration, the same MRI procedure was performed without injection of meglumine meglumine. The patient then underwent whole-brain radiation therapy (30Gy delivered in 10 sessions of 3Gy). Similar MRI procedures were performed on each patient 7 days (D8) and 4 weeks (D28) after administration of AGuIX nanoparticles.

[MRI plan]

MRI acquisitions were performed on a 3 Tesla Philips scanner. Uses a 32-channel Philips head coil. The patient underwent the same imaging protocol including the following MRI sequences: i) 3D T ₁ -weighted gradient echo sequence, ii) 3D FLASH sequence with multiple tilt angles, iii) susceptibility-weighted imaging (SWI) sequence, iv) Fluid Attenuated Inversion Recovery (Fluid Attenuated Inversion Recovery; FLAIR) sequence, v) Diffusion-weighted imaging (DWI) sequence. Some of these contrast-enhanced sequences are recommended when following the RECIST (Response Evaluation Criteria in Solid Tumors) and RANO (Response Assessment in Neuro-Oncology) criteria for assessing brain metastasis response after radiation therapy (24, 25). 3D T ₁ -weighted imaging sequences provide high-resolution contrast-enhanced images of healthy tissue and brain metastases after administration of MRI contrast agent. The 3D FLASH sequence is repeated several times with different tilt angles in order to calculate the _T1 relaxation time and contrast agent concentration. SWI sequences are used to detect the presence of hemorrhage. The FLAIR sequence should be used to monitor the presence of inflammation or edema. Ultimately, DWI sequences can be applied to detect abnormal water diffusion in tissue or brain metastases. The total acquisition time ranges between 30 and 40 minutes depending on patient-adjusted angiographic parameters. The key features and main acquisition parameters of these imaging sequences are detailed in the supporting material section.

[Image processing and quantization pipeline]

MRI analysis was performed using an in-house computer program called MP ³ (https://github.com/nifm-gin/MP3) developed by GIN Laboratory (Grenoble, France) and running on ^Matlab® software. Image analysis includes calculation and measurement of transfer, quantification of contrast enhancement, relaxation time, and nanoparticle concentration. Following RECIST and RANO criteria, only metastases with a longest diameter greater than 1 cm were considered measurable and retained in subsequent analyses. MRI enhancement expressed as a percentage is defined as the ratio of the MRI signal amplitude after contrast agent administration to the MRI signal amplitude before contrast agent administration; MRI signal amplitude is measured in a 3D T ₁ -weighted image data set. The T ₁ relaxation time is derived from 3D FLASH images obtained at four different tilt angles. The concentration of nanoparticles in brain metastases is derived from the change in _T1 relaxation time before and after administration of contrast agent and from the known relaxation rate of the nanoparticles.

3D image rendering is performed using the BrainVISA/Anatomist software (http://brainvisa.info) developed by NeuroSpin (CEA, Saclay, France). In order to better observe the location of different metastases, BrainVISA's Morphologist pipeline was used to generate meshes of the brain and head of each patient.

[statistical analysis]

All analyzes were performed using GraphPad Prism (GraphPad Software Inc.). Unless specified, significance is fixed at the 5% probability level. Unless otherwise specified, all data are presented as mean ± SD.

[1.2 Results]

[Administered AGuIX Gd-based nanoparticles induced MRI contrast enhancement in all four types of brain metastases]

Patient recruitment resulted in the inclusion of four types of brain metastases, namely NSCLC (non-small cell lung cancer) N=6, breast cancer N=2, melanoma N=6 and colon cancer N=1. At each escalating step in dose administered (N=3 for 15 mg/kg, 30 mg/kg, 50 mg/kg, 75 mg/kg, and 100 mg/kg body weight), all patients were treated with theranostic nanoparticles AGuIX (as in as described in Materials and Methods) for successful injection.

At D1, two hours after AGuIX injection, MRI signal enhancement was observed for all types of brain metastases, for all patients, and for all doses administered. Within the region of interest mapped around each metastasis, MRI signal enhancement was found to increase with dose of AGuIX nanoparticles administered (Figure 1). The signal enhancement averaged across all measurable metastases (longest diameter greater than 1 cm) was equal to 26.3± for AGuIX doses of 15 mg/kg, 30 mg/kg, 50 mg/kg, 75 mg/kg and 100 mg/kg body weight respectively 15.2%, 24.8±16.3%, 56.7±23.8%, 64.4±26.7% and 120.5±68%. MRI enhancement was found to be linearly related to injected dose (slope 1.08, R ² =0.90) (data not shown).

[Gd-based nanoparticles show MRI enhancement of brain metastases that is equivalent to MRI enhancement of clinically used contrast agents]

For each patient, MRI enhancement was also measured at D0, 15 min after injection of a clinically approved Gd-based contrast agent (Dotarem ^® , Guerbet, Villepinte, France). Averaged over all measurable metastases with a longest diameter greater than 1 cm, MRI enhancement was equal to 182.9 ± 116.2%. This MRI enhancement observed 15 min after injection was of the same order of magnitude compared to the MRI enhancement observed 2 h after administration of the highest dose of AGuIX nanoparticles.

The detection sensitivity of AGuIX nanoparticles, defined by their ability to enhance MRI signals in measurable brain metastases, was evaluated for all administered doses and compared with the sensitivity of the clinically used contrast agent ^Dotarem® . For injection doses of 15 mg/kg, 30 mg/kg, 50 mg/kg, 75 mg/kg, and 100 mg/kg body weight, the AGuIX nanoparticle sensitivities expressed as a percentage of Dotarem sensitivity were equal to 12.1%, 19.5%, 34.2%, and 31.8%, respectively. and 61.6%.

AGuIX nanoparticle concentration can be quantified in brain metastasis

Multi-tilt angle 3D FLASH acquisition was successfully used to calculate a pixel-by-pixel map of _T1 values (data not shown) and enabled the quantification of longitudinal relaxation times over regions of interest. The reduction in _T1 relaxation time in brain metastases induced by uptake of AGuIX nanoparticles is clearly shown in these _T1 spectra. As expected, decreases in _T1 values colocalized with contrast-enhancing brain metastases.

The concentration of AGuIX nanoparticles in contrast-enhanced transfer was calculated based on the change in _T1 value after its administration. For patients administered a dose of 100 mg/kg body weight, measurements of AGuIX concentrations were performed in metastases with a longest diameter greater than 1 cm. In patients #13, #14, and #15, the mean AGuIX concentrations in brain metastases were measured to be 57.5±14.3 mg/L, 20.3±6.8 mg/L, and 29.5±12.5 mg/L, respectively.

For patients with the highest (100 mg/kg) administered dose, the correlation between MRI enhancement and nanoparticle concentration was evaluated. The correlation is illustrated in Figure 2 by MRI data from patient #13 with NSCLC metastasis. A strong positive correlation between the two MRI parameters was observed, with the relationship approaching linearity over the range of measured values.

For each patient, MRI enhancement and _T1 values were assessed in brain regions of interest without visible metastases (three representative regions of interest per patient, of similar size for all patients). No significant MRI enhancement and no _T1 changes were observed in any of these healthy brain regions.

[Observe MRI enhancement one week after nanoparticle administration]

For patients administered the highest dose (100 mg/kg body weight), measurable metastases (longest diameter greater than 1 cm) were found at D8, up to one week after administration of AGuIX nanoparticles as shown in Figure 3 Persistence of MRI enhancement. For patients #13, #14, and #15, the mean MRI enhancement in metastases was measured to be equal to 32.4±10.8%, 14±5.8%, and 26.3±9.7%, respectively. As a point of comparison, for patients #13, #14, and #15, the mean MRI enhancement at D1 was equal to 175.8±45.2%, 58.3±18.4%, and 154.1±61.9%, respectively. Due to the lower _T1 variation, the concentration of AGuIX nanoparticles could not be calculated. Based on the observed correlation between MRI enhancement and nanoparticle concentration, an upper limit of 10 mM for MAGuIX concentration in brain metastases can be estimated at D8. At D28, no significant MRI enhancement was observed in any patient 4 weeks after administration of AGuIX nanoparticles.

[Discuss]

The occurrence of brain metastases is a common event in the history of cancer and adversely affects the life expectancy of patients. For patients with multiple brain metastases, whole-brain radiation therapy (WBRT) remains the standard of care. However, the median overall survival is less than six months and new approaches need to be developed to improve treatment outcomes for these patients. Therefore, the use of radiosensitizers has received great attention. The in vivo theranostic properties (radiosensitization and diagnosis by multimodal contrast imaging) of AGuIX nanoparticles were previously demonstrated in preclinical studies performed in eight tumor models in rodents (F. Lux et al. Br J Radiol. 18 :20180365 (2018)), and especially in brain tumors (G. Le Duc et al. ACS Nano. 5 , 9566-9574 (2011), C. Verry C et al. Nanomedicine 11 , 2405-2417 (2016) ). Clinical evaluation of the diagnostic value of AGuIX nanoparticles for brain metastasis is one of the secondary goals of the clinical trial Nano-Rad. The target dose for radiotherapy applications of AGuIX nanoparticles in patients is 100 mg/kg and for this reason, the conclusions and perspectives of this study are essentially focused on this dose.

The maximum dose of AGuIX nanoparticles administered to a patient (100 mg/kg body weight or 100 μmol/kg body weight Gd ³⁺ ) corresponds to a dose of chelated chromium ion Gd ³⁺ injected in a clinically used MRI contrast agent such as ^Dotarem® Amount (100mmol/kg body weight Gd ³⁺ ). It is therefore appropriate to compare the MRI enhancement observed in metastases using the maximum AGuIX dose with the dose of Gd-based contrast agents used in clinical practice.

In this study, there was a 2-hour delay between administration of the nanoparticles and MRI acquisition to monitor the patient's response to the injection. With an average nanoparticle plasma half-life of approximately 1 hour, this delay resulted in an 86% reduction in nanoparticle concentration in plasma. In comparison, there was only a 15-minute delay between ^Dotarem® injection and MRI acquisition. Despite this significant clearance of nanoparticles and reduced concentration in the patient's bloodstream, MRI enhancement at the highest nanoparticle dose was close to that observed using clinical contrast agents.

This remarkable diagnostic performance of AGuIX nanoparticles in enhancing MRI signals in brain metastases can be attributed to two independent factors. The first factor is related to the inherent magnetism of nanoparticles. As compared to clinical Gd-based contrast agents, their larger diameter and molecular weight lead to a higher longitudinal relaxation coefficient r ₁ and thus to an increased ability to change the intensity of the MRI signal. Specifically, under a magnetic field of 3 Tesla, the r ₁ values of AGuIX nanoparticles and Dotarem ^® are respectively equal to 8.9 and 3.5mM ^-1 .s ^-1 per Gd ³⁺ ion (BRSmith, SSGambhir. Chem Rev. 117,901-986 (2017)).

The second factor may be related to the ability of AGuIX nanoparticles to passively accumulate in brain metastases. This passive targeting phenomenon exploits the so-called enhanced permeability and retention (EPR) effect, which postulates that the accumulation of nanoobjects in tumors is due to defective and leaky tumor blood vessels and is due to the lack of effective lymphatic drainage (A. Bianchi, et al. MAGMA. 27 , 303-316 (2014)). Passive targeting of tumors by AGuIX nanoparticles has been consistently observed in previous studies in animal cancer models. In a mouse model of multiple brain melanoma metastases, AGuIX nanoparticles have been reported to be internalized in tumor cells and the presence of nanoparticles in brain metastases was still observed 24 hours after intravenous injection into the animals. (Kotb, A. et al. Theranostics 6 (3): 418-427 (2016)). At the highest dose of 100 mg/kg, all metastases with a diameter greater than 1 cm remained contrast enhanced up to 7 days after nanoparticle administration.

The persistence of MRI signal enhancement in metastases one week after administration suggests this accumulation and delayed clearance of nanoparticles from metastases. To the best of the inventors' knowledge, such late MRI enhancement in metastases after administration of clinically used Gd-based contrast agents has not been reported in the literature.

Dose escalation was included in the design of this first-in-human clinical trial, and thus patients were administered five ascending dose levels of AGuIX nanoparticles. Based on the linear correlation observed between signal enhancement in metastasis and the concentration of administered nanoparticles, it can be concluded that the dose of nanoparticles in the range of doses studied is not a limiting factor for passive targeting of metastases . What's important is that Although a limited number of patients participated in this first clinical study, these initial results show that nanoparticle uptake and signal enhancement are present in the four types of metastases studied (NSCLC, melanoma, breast cancer, and colon cancer), regardless of whether What is the injection dose of rice granules?

Given the radiosensitizing properties of AGuIX nanoparticles, it is critical to assess and possibly quantify the local concentration of nanoparticles that accumulate in metastases. To this end, the MRI protocol consists of a T ₁ enantiography sequence from which the nanoparticle concentration is derived. Concentration values obtained in this clinical study can be compared to concentration values obtained in preclinical studies in animal tumor models. The calculated concentrations of AGuIX nanoparticles in NSCLC and breast cancer metastases in the three patients injected with the highest doses varied between 8 mg/L and 63 mg/L, which corresponded to Gd ³ between 8 mg/L and 63 mM in brain metastases. ⁺ Concentration range of ions. In the three aforementioned patients, % ID/g ranged between 8% and 63%. The same order of magnitude of % ID/g was found in the two aforementioned MRI preclinical studies, which had 28% and 45% ID/g respectively. Of interest, these concentrations were obtained with a post-injection delay (several hours) compatible with the course of radiotherapy.

In this study, we also evaluate the relationship between nanoparticle concentration and MRI signal enhancement SE obtained using robust T ₁ -weighted 3D MRI sequences. A linear relationship between MRI enhancement and nanoparticle concentration was observed with the acquisition protocol used in this study over the range of measurable nanoparticle concentrations in metastasis. Therefore, with the specific protocol used in this study, MRI enhancement can be used as a robust and simple indicator for assessing the concentration of AGuIX nanoparticles.

Although metastatic targeting is beneficial for diagnostic and radiosensitization purposes, it requires keeping nanoparticles at low concentrations in healthy surrounding tissue. In this regard, no MRI enhancement was observed in metastasis-free brain tissue two hours after administration of the highest dose of AGuIX nanoparticles. This lack of enhancement is consistent with the rapid clearance of nanoparticles measured in patient plasma and is a positive indication of the harmlessness of nanoparticles in healthy brains.

In conclusion, the preliminary results of the clinical trials reported in this article demonstrate that intravenous injection of Gd-based nanoparticles can effectively enhance different types of brain metastases in patients. The results of these first clinical investigations The results, that is, pharmacokinetics, passive targeting, and concentrations in metastasis are consistent with observations previously obtained in preclinical studies of animal models of brain tumors and indicate the success of this theranostic agent from the preclinical level. Translated to clinical level.

Additionally, preliminary results from the Nano-Rad Phase 1 clinical trial demonstrate that intravenous injection of AGuIX nanoparticles is well tolerated up to the 100 mg/kg dose selected for this study.

Finally, the persistence of nanoparticles in tumors at D8 supports a strategy that includes a first injection between days 2 and 7 before the first irradiation in order to optimize tumor concentration and distribution within the tumor. , while minimizing the presence of nanoparticles in surrounding healthy tissue.

All these results and observations provide strong and reliable support for the Phase 2 clinical trial (NANORAD2, NCT03818386), as disclosed in Example 2 below.

Example 2: Radiation therapy of multiple brain metastases using AGuIX chelated polysiloxane-based nanoparticles: a prospective randomized phase II clinical trial

[2.1 Research hypothesis and expected results]

Preliminary results from the Phase Ib trial Nanorad confirm the importance of combining AGuIX nanoparticles with radiation therapy for the treatment of cancer patients, especially those with brain metastases.

The purpose of this randomized phase II study was to evaluate the efficacy of the combination of AGuIX and WBRT and demonstrate increased intracranial response rates compared with WBRT alone. Additionally, an increase in intracranial progression-free survival is expected, as well as an improvement in patients' quality of life. Additionally, because gium is the positive contrast agent _T1 in MRI, MRI studies were performed to evaluate the distribution of this product in brain metastases and surrounding healthy tissue.

The selected target group is patients with brain metastases who are suitable for treatment with whole-brain radiation therapy, regardless of their primary cancer.

Target groups were selected based on: - the relevance of intravenous administration of radiosensitizers to the multifocal nature of brain metastases; - preclinical in vivo studies, and for inclusion in the Phase I Nanorad trial Differences in tissue enhancement between tumor lesions and healthy brain in patients in (EudraCT2015-004259-30; NCT02820454); - No treatment alternatives exist for patients with a life expectancy of approximately 4.5 months treated with standard radiation therapy .

Other tumor sites may also benefit from the increased dose efficacy associated with the radiosensitizing effect of nanoparticles.

[2.2 Research plan/method]

This is a prospective, randomized, blinded endpoint phase II clinical trial to evaluate the efficacy of AGuIX in combination with whole-brain radiation therapy compared with whole-brain radiation therapy alone for the treatment of brain metastases (Blood Press. 1992 Aug; 1( 2): 113-9. Prospective randomized open blinded end-point (PROBE) study. A novel design for intervention trials. Prospective Randomized Open Blinded End-Point. Hansson L) (Hansson et al., 1992) .

1或>1)、顱內局部治療史(是或否)、免疫療法治療(是或否)、在納入時用皮質類固醇治療(是或否)、執行海馬迴保護之意向(是或否)。 After a center-performed minimization procedure, patients were assigned to one of two treatment groups in order to balance potential prognostic factors between treatment groups. The minimization algorithm takes into account the following factors: center, age (as a continuous variable), tissue structure of the primary cancer (lung or breast or melanoma or other cancer), DS-GPA score (

1 or >1), history of intracranial local therapy (yes or no), immunotherapy treatment (yes or no), treatment with corticosteroids at inclusion (yes or no), intention to perform hippocampal protection (yes or no) .

The study was adaptive: an interim analysis was planned after enrolling 20 patients in each treatment group (WBRT and AGuIX+WBRT), in order to discard a priori identification of subgroups in the absence of differences between groups. The two differential groups selected midterm were (i) patients with melanoma brain metastases and (ii) patients with brain metastases from all other primary cancers (lung, breast, kidney...).

In each of the two subgroups, contingency tables describe response rates and any group with no response or poor response (i.e., the same or worse best objective intracranial response rate compared to the reference group) can be given up.

[2.3 Eligibility criteria/subject characteristics]

[Inclusion criteria]

- Patients with brain metastases from histologically confirmed solid tumors eligible for WBRT

- At least 18 years old

- Sign informed consent

ECOG (Eastern Cooperative Oncology Group) performance status 0-2

- Extracranial diseases:

‧Complete or partial response or stability under systemic treatment

‧No extracranial disease

‧Or first-line treatment

- Life expectancy greater than 6 weeks

- All patients of childbearing potential should use effective contraception

- Affiliated to a Social Security program or its beneficiary

[Non-inclusion criteria]

- Leptomeningeal metastasis

- Metastasis with signs of recent major bleeding

- Progressive and threatening extracranial disease under systemic therapy

- Previous cranial irradiation (other than stereotactic irradiation)

- Known contraindications, sensitivities or allergies to chromium

- Known contraindications to MRI

50mL/min/1.73m²) - Renal failure (glomerular filtration rate

50mL/min/1.73m ² )

- Incorporated into another clinical trial protocol

- Pregnant or breastfeeding

- Subjects who are in the exclusion period of another study

- Subjects under administrative or judicial control

[2.4 Treatments/Procedures Allowed]

Maintaining or discontinuing systemic cancer therapy prior to brain irradiation is at the discretion of the individual investigator and must adhere to current recommendations.

The following treatments are contraindicated during radiotherapy: GEMZAR®, AVASTIN®, VEMURAFENIB® and tyrosine kinase inhibitors. According to current recommendations, they must be stopped before irradiation.

Subject to these restrictions, the patient's usual treatment is permitted and is listed in each patient's CRF.

As a precaution, radiation therapy should not be administered less than 2 hours after administration of AGuIX. The plasma half-life of the particles in humans is 1.08 hours (0.75 to 2 hours). Premature radiation therapy can increase the effects of radiation therapy in healthy brain tissue, but the amount of nanoparticles in healthy brain tissue remains low in animal models (Verry, C. et al. (2016). Glioma MRI-guided clinical 6-MV radiosensitization uses unique gallium-based nanoparticle injection. Nanomedicine (Lond).

[2.5 Treatments used in this study]

Drug/Treatment Name and Trade Name: AGuIX.

Chemical name (DCI): Nanoparticles based on chelated polysiloxane.

Pharmaceutical form: Sterile lyophilized off-white powder containing 300 mg AGuIX as active ingredient (300 mg AGuIX/vial). Each vial contains 0.66 mg of _CaCl as the inactive ingredient. The drug product is supplied in single-use 10 mL clear glass vials with bromobutyl rubber stoppers.

Preparation procedure: Reconstitute the solution with 3 mL of water for injection to obtain a 100 mg/mL AGuIX solution. The pH of the solution is then at 7.2±0.2.

One hour after reconstitution with water for injection, place the reconstituted solution in a syringe, prior to injection using a syringe pump.

Administer for a minimum of 1 hour after reconstitution and within a maximum of 24 hours.

The AGuIX solution is administered within half a day after reconstitution, however, the nanoparticles must be stored in [+2°C; +8°C] and administered within a maximum of 24 hours after reconstitution.

Intravenous administration was performed by slow infusion (2 mL/min) using a syringe pump.

Dose for each administration: 100mg/kg, 1mL/kg.

[2.6 Treatment and related procedures]

Radiation therapy: Whole brain radiation therapy:

- Dosimetry scanners and individual competition shields

- Allowed irradiation techniques:

○Configuration of 6MV photons, equidistant, 2 transverse beams

○IMRT (tomotherapy or VMAT)

- dosage

○Prescription dose: 30Gy

○The dose per dose is 3Gy

○Number of doses: 10

○Dose per day: 1

○Total treatment duration should not exceed 3 weeks

Target volume:

Clinical target volume (CTV) = brain + brainstem + cerebellum

Planning target volume (PTV)=CTV+3mm

Organs at risk:

Eyes, lens, retina, hippocampus, inner ear and cochlea

Dosage Limitations:

PTV: V95%>95, D max<107%

Avoid damaging the hippocampus:

Avoiding disruption of the hippocampus is recommended when possible, but is not mandatory. In the case of intensity-modulated irradiation to avoid damage to the hippocampus, it is necessary to coordinate the dosimetry scanner with the reference Fusion occurs between MRIs. Bilateral hippocampal outlines were manually generated on the fused MRI-CT image set and extended 5 mm to create hippocampal avoidance areas. Planning target volume (PTV) is defined as the clinical target volume excluding the hippocampal avoidance area. IMRT is delivered to a dose of 30 Gy in 10 fractions to cover the PTV while avoiding the hippocampus. The dose delivered to 100% of the hippocampus may not exceed 9 Gy, and the maximum hippocampal dose may not exceed 16 Gy.

[2.7 Visit during treatment]

V experimental treatment group: AGuIX+WBRT

Day 0 (before starting WBRT, between days 2 and 7):

- Patient hospitalized in a mobile unit

- Clinical examination to determine ECOG OMS performance status, pain, weight and constants (heart rate, blood pressure, temperature)

- Neurological examination

- Place a peripheral intravenous catheter for AGuIX® injection

- Biological tests: complete blood count, serum electrolytes, renal function, liver function

- First investment in AGuIX(H0) between day 2 and day 7 before starting WBRT

- Perform brain MRI* one hour after injection

- Security assessment

Week 1 of Radiation Therapy Treatment:

Process 1:

- Patient hospitalized in a mobile unit

- Clinical examination to determine ECOG OMS performance status, pain, weight and constants (heart rate, blood pressure, temperature)

- Neurological examination

- Place a peripheral intravenous catheter for AGuIX® injection

- Biological tests: complete blood count, serum electrolytes, renal function, liver function. Physicians must Confirm that the patient has no changes in renal function before performing AGuIX® injections.

- Second investment in AGuIX(H0)

- Radiotherapy course n°1, performed between 3 and 5 hours after the second AGuIX injection

- (As a precaution, radiation therapy should not be performed less than 2 hours after administration of AGuIX)

- Security assessment

Process 2/Process 3/Process 4/Process 5:

Mobile radiotherapy procedures n°2, n°3, n°4 and n°5

Week 2 of Radiation Therapy Treatment:

Course 6 (before radiotherapy course n°6):

- Patient hospitalized in a mobile unit

- Clinical examination to determine ECOG OMS performance status, pain, weight and constants (heart rate, blood pressure, temperature)

- Neurological examination

- Place a peripheral intravenous catheter for AGuIX® injection

- Biological tests: complete blood count, serum electrolytes, renal function, liver function. Physicians must Confirm that the patient has no changes in renal function before performing AGuIX injections.

- The third investment in AGuIX(H0)

- Radiotherapy course n°6, performed between 3 and 5 hours after the second AGuIX injection.

- (As a precaution, radiation therapy should not be performed less than 2 hours after administration of AGuIX)

- Security assessment

Process 7/Process 8/Process 9/Process 10:

- Mobile radiotherapy procedures n°7, n°8, n°9 and n°10

V control treatment group: WBRT

Radiotherapy Treatment Week 1

Process 1:

- Clinical examination to determine ECOG OMS performance status, pain, weight and constants (heart rate, blood pressure, temperature)

- Neurological examination

- Biological tests: complete blood count, serum electrolytes, renal function, liver function

- Radiotherapy process n°1

- Security assessment

Process 2/Process 3/Process 4/Process 5:

Mobile radiotherapy procedures n°2, n°3, n°4 and n°5

Week 2 of Radiation Therapy Treatment:

Course 6 (before radiotherapy course n°6):

- Clinical examination to determine ECOG OMS performance status, pain, weight and constants (heart rate, blood pressure, temperature);

- neurological examination;

- Biological tests: complete blood count, serum electrolytes, renal function, liver function;

- radiotherapy course n°6;

- Security assessment.

Process 7/Process 8/Process 9/Process 10:

- Mobile radiotherapy procedures n°7, n°8, n°9 and n°10

[Follow-up visit]

The follow-up visit schedule was the same regardless of treatment group (i.e., experimental treatment AGuIX+WBRT and control treatment WBRT).

Follow-up visits occurred 6 weeks after the start of radiation therapy and then at 3, 6, 9, and 12 months (+/- one week).

end-of-study visit

For both treatment groups (i.e., experimental treatment group AGuIX+WBRT and control treatment group WBRT), the end of the study occurred 12 months after the start of radiation therapy.

The research protocol and objectives are also summarized in Figure 4 .

[Reference]

1. Schaue D, McBride WH. Opportunities and challenges of radiotherapy for treating cancer. Nat Rev Clin Oncol 2015, 12 (9): 527-540.

2. Beasley M, Driver D. Dobbs HJ. Complications of radiotherapy: improving the therapeutic index. Cancer Imaging 2005, 5 : 78-84.

3. Hainfeld JF, O'Connor MJ, Dilmanian FA, Slatkin DN, Adams DJ. Smilowitz HM. Micro-CT enables microlocalisation and quantification of Her2-targeted gold nanoparticles within tumour regions. Br J Radiol 2011. 84 (1002): 526 -533.

4. Dorsey JF. Sun L. Joh DY. Witztum A. Kao GD, Alonso-Basanta M. et al. Gold nanoparticles in radiation research: potential applications for imaging and radiosensitization. Transl Cancer Res 2013, 2 (4): 280- 291.

5. Taupin F. Flaender M. Delorme R, Brochard T. Mayol JF. Amaud J. et al. Gadolinium nanoparticles and contrast agent as radiation sensitizers. Phys Med Biol 2015, 60 (11): 4449-4464.

6. McQuaid HN. Muir MF. Taggart LE, McMahon SJ, Coulter JA, Hyland WB. et al. Imaging and radiation effects of gold nanoparticles in tumour cells. Sci Rep 2016. 6 : 19442.

7. Zhu J. Zhao L. Cheng Y. Xiong Z. Tang Y. Shen M. et al. Radionuclide (131)I-labeled multifunctional dendrimers for targeted SPECT imaging and radiotherapy of tumors. Nanoscale 2015. 7(43): 18169 -18178.

8. Mi Y. Shao Z. Vang J. Kaidar-Person O. Wang AZ. Application of nanotechnology to cancer radiotherapy. Cancer Nanotechnol 2016. 7 (1): 11.

9. Le Duc G, Miladi I, Alric C, Mowat P. Brauer-Krisch E. Bouchet A. et al. Toward an image-guided microbeam radiation therapy using gadolinium-based nanoparticles. ACS Nano 2011, 5 (12): 9566 -9574.

10. Dufort S. Bianchi A, Henry M. Lux F, Le Duc G, Josserand V. et al. Nebulized gadolinium-based nanoparticles: a theranostic approach for lung tumor imaging and radiosensitization. Small 2015, 11 (2): 215- 221.

11. Hainfeld JF. Slatkin DN, Smilowitz HM. The use of gold nanoparticles to enhance radiotherapy in mice. Phys Med Biol 2004. 49 (18): N309-315.

Claims (18)

The use of nanoparticles containing high Z elements in the preparation of drugs for treating tumors, wherein the drugs are used in a method of treating the tumors by ionizing radiation in subjects in need, and the method includes the following steps : Step (i) within a period between 2 days and 10 days before the first irradiation of the aforementioned tumor, inject a first therapeutically effective amount of nanometers containing high Z elements as a radiosensitizer into the aforementioned subject if necessary particles; step (ii) injecting a second therapeutically effective amount of nanoparticles containing the same or different high Z elements within a period between 1 hour and 12 hours before the first irradiation of the aforementioned tumor; and step (iii) injecting a therapeutically effective dose Radiation is used to irradiate the aforementioned tumor of the aforementioned subject; wherein the aforementioned nanoparticles containing high Z elements are chelated polysiloxane nanoparticles of the following formula:

Wherein PS is a polysiloxane matrix, and n includes between 5 and 50, and wherein the average hydrodynamic diameter includes between 2 and 6 nm. The use as described in claim 1, wherein in the aforementioned step (i), within a period between 2 days and 7 days before the first irradiation of the aforementioned tumor, the first therapeutically effective amount is injected into the aforementioned subject before the need arises. Nanoparticles containing high Z elements as radiosensitizers Rice grains. The use as described in claim 1, wherein the aforementioned nanoparticles are injected intravenously. The use as described in claim 1, wherein the nanoparticles comprise polyorganosiloxane with a silicon weight ratio between 8% and 50% of the total weight of the nanoparticles. The purpose described in claim 1, where n includes between 5 and 20. The use as described in any one of claims 1 to 5, wherein the aforementioned nanoparticles are freeze-dried powders contained in prefilled vials so as to be reconstituted in aqueous solution for intravenous injection. The use as described in any one of claims 1 to 5, wherein the aforementioned nanoparticles are included in the injectable solution at a concentration between 50 mg/mL and 150 mg/mL. The use as described in claim 7, wherein the aforementioned nanoparticles are included in the injectable solution at a concentration between 80 mg/mL and 120 mg/mL. The use as described in any one of claims 1 to 5, wherein the therapeutically effective dose administered at each injection step contains a concentration between 50 mg/kg and 150 mg/kg, or between 80 and 120 mg/kg. The use as described in any one of claims 1 to 5, wherein the aforementioned tumor is a solid tumor. The use as described in any one of claims 1 to 5, wherein the aforementioned tumor is a solid tumor selected from the group consisting of: glioblastoma, brain metastasis, meningioma, or cervical cancer, rectal cancer, lung cancer, Primary tumors of head and neck cancer, prostate cancer, colorectal cancer, liver cancer, and pancreatic cancer. The use as described in claim 11, wherein the aforementioned tumor is brain metastasis. The use as described in claim 12, wherein the aforementioned brain metastasis is from melanoma, lung Cancer, breast cancer, or brain metastasis from primary renal cancer. The use as described in claim 12 or 13, wherein the subject is exposed to whole-brain radiation therapy in step (iii). The use as described in claim 14, wherein the whole-brain radiation therapy consists of exposing the subject to a total dose of ionizing radiation between 25Gy and 35Gy. The use as described in claim 15, wherein the subject is exposed to a dose of ionizing radiation of about 3 Gy per fraction, and the total dose is administered in a maximum of 10 fractions. The use as described in any one of claims 1 to 5, wherein the aforementioned method includes injecting a third therapeutically effective amount of nanometers containing the same or different high-Z elements within 5 to 10 days after the aforementioned injection in step (ii). Particle steps. The use as described in any one of claims 1 to 5, wherein the aforementioned method further includes the step of imaging the aforementioned tumor by magnetic resonance imaging (MRI) after the injection of the aforementioned nanoparticles in step (i), The aforementioned nanoparticles are used as the T1 contrast agent for the aforementioned magnetic resonance imaging (MRI).

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