Crystallized hafnium oxide nanoparticles, their manufacturing process and their uses

Abstract

Crystallized hafnium oxide nanoparticles, their manufacturing process and their uses The invention relates to crystallized hafnium oxide nanoparticles, characterized in that they carry on their surface molecules of amide(s) and / or at least one amide degradation product chosen from a carboxylic acid, an amine or an amino acid and / or residues of said molecules.

Description

Title of the invention: Crystallized hafnium oxide nanoparticles, their manufacturing process and their uses

[0001] The present invention relates to crystallized hafnium oxide nanoparticles, their manufacturing process, in particular in aqueous colloidal solution, and their uses.

[0002] Hafnium oxide nanoparticles (HfO2) are nanoparticles with high electron density (ZHf=72) which are of great interest in the field of response to ionizing radiation such as scintillation, whether for the detection of this ionizing radiation or the treatment of certain cancers by radiotherapy. Having highly concentrated colloidal solutions can be a definite advantage with regard to the detection of ionizing radiation. This concerns, for example, the densification of all liquid scintillators, as for calorimetry, in particular in the physics of so-called high-energy particles, or the metrology of the measurement of activities of certain radionuclides. This also includes the construction of complex architectures such as porous aerogels, particularly suitable for the detection of radionuclides present in fluids (gas, liquid).Regarding the use of these nanoparticles as an anti-cancer treatment, the objective is to amplify the energy deposition and the radiobiological effects induced during radiotherapy sessions. These effects will be due to the generation of secondary photons and electrons (photoelectrons and Auger electrons in particular) in the local area where the nanoparticles are accumulated. The injection of HfO2 nanoparticles in the form of a colloidal solution into a cancerous tumor thus makes it possible to improve the therapeutic index of radiotherapy. As a result, either the dose of X-rays to be delivered to the patient can be reduced while maintaining the same therapeutic efficacy but reducing the side effects of conventional radiotherapy caused by the irradiation of healthy tissues, or the local efficacy is improved for the same dose of radiation delivered to the tumor, which allows for better treatment efficacy.Due to their small size, these nanoparticles are not metabolized by the liver and can be eliminated through the kidneys.

[0003] Hafnium oxide nanoparticles also have high refractive indices of 1.94 at 400 nm and 1.88 at 800 nm, and can be used in the field of optics. Hafnium oxide also has high thermal stability and a high permittivity - between 17 and 25 - which makes it interesting in the field of microelectronics.

[0004] From the point of view of applications involving ionizing radiation, the main advantage of the HfO2 structure is the presence of atoms with a very high atomic number (72) and its high density (9.68g / cm3). It is therefore one of the most absorbent materials for ionizing radiation. The possibility of obtaining it in very high mass concentration in solution opens the way to several application possibilities: - In “passive” use, it would initially allow it to play the role of absorber in liquid scintillators, particularly in high-energy physics where the radiation to be measured is at very high energy. - In “active” use, by doping these particles with active elements (Cerium for example), they retain their role as absorber, but also contribute to the emission of light (scintillation). - In a radioactivity metrology situation, it could enhance the ionizing radiation absorption properties of certain radionuclides by standard liquid scintillators. - In complex architectures such as scintillating aerogels, the preparation of which requires a very high concentration colloidal solution, these solutions would allow the density of the material (capacity to absorb ionizing radiation) and its optical index (optical transparency) to be modulated at will depending on the fluids to be measured. Doped, they could actively contribute to the scintillation process. - These nanoparticles can be used as contrast agents for X-ray imaging. This can of course be applied to medical imaging, once the nanoparticles are functionalized to make them biocompatible and potentially with a targeting strategy. This could be applied to industrial imaging for leak detection for example. - Finally, in the case of targeting and therefore internalization in tumors, they could be combined with radiotherapy and give rise to a local dose increase of ionizing rays in the tumor. This dose increase can produce several effects. First, there is emission of secondary ionizing radiation (photoelectron and Auger electrons in particular) with a very low mean free path, capable of destroying the genetic material of the tumor. With the help of judicious doping and by combining the surface grafting of molecules with photosensitizing properties (generation of cytotoxic species under light excitation), the nanoparticle can become an active therapeutic agent under ionizing radiation (photodynamic therapy induced by ionizing radiation such as X-rays for example). - Hafnium oxide has also been tested for several years as a radiotherapy amplifier in the treatment of solid cancers (see reference: S Bonvalot et al., “LBA66A phase II / III trial of hafnium oxide nanoparticles activated by radiotherapy in the treatment of locally advanced soft tissue sarcoma of the extremity and trunk wall”, Annals of Oncology, vol. 29, suppl. 8, 2018).

[0005] Whatever the intended application of the nanoparticles, it is desirable to obtain colloidal solutions with a very high concentration, i.e. with a very high dry extract.

[0006] In particular, it could be interesting to have aqueous colloidal solutions having very high dry extracts. Such colloidal solutions highly concentrated in nanoparticles in any solvent of interest can be more easily transferred from the place of their production to the place of their use while preserving their stability. Furthermore, in the case in particular of the use of hafnium oxide nanoparticles in the treatment of cancer, a highly concentrated colloidal solution of these nanoparticles would make it possible to inject, in a small volume, a significant quantity of nanoparticles into the tumor to reduce the dose of X-rays delivered to healthy tissues or to enhance the therapeutic effect at an equivalent dose.

[0007] There is also a need to be able to disperse the nanoparticles in any solvent of interest such as water, alcohols, amides, ketones, hydrocarbons, physiological serums, etc.

[0008] The present invention meets all these objectives.

[0009] To this end, the present invention relates to crystallized nanoparticles of hafnium oxide, characterized in that they carry on their surface molecules of amide(s) and / or at least one amide degradation product chosen from a carboxylic acid, an amine or an amino acid and / or residues of said molecules.

[0010] The amide(s) may be chosen from the compounds of formula (I):

[0011] [Chem.l] Q (D

[0012] in which: - Ri and R2 and R3, identical or different, each independently represent one of: • hydrogen • C1-C6 alkyl, linear or branched, optionally substituted; • optionally substituted C3-C7 cycloalkyl; • optionally substituted phenyl; and • hetero-cycloalkyl consisting of C3-C7 cycloalkyl, the hydrocarbon links of which are interrupted by at least one of -O-, -S- or

[0013] [Chem.2] —H H , with R4 representing H or linear or branched C1-C6 alkyl, said hetero-cycloalkyl group also being able to be substituted; - R1 and R2 may also be linked together to form an optionally substituted C2-C6 alkanediyl chain, and R2 and R3 may be linked together to form an optionally substituted C2-C5 alkanediyl chain, provided that, when R1 and R2 are linked together to form an alkanediyl chain, R3 cannot be linked to R2, and that, when R2 and R3 are linked together to form an alkanediyl chain, R1 cannot be linked to R2,

[0014] where, in the case where an alkyl, cycloalkyl, phenyl or heterocycloalkyl group falling within the definition of Rh R2 and R3 is substituted, it may be substituted by at least one substituent chosen in particular from halogen, C1-C6 alkyl, phenyl, hydroxyl and C1-C6 alkoxy,

[0015] or a compound of formula (II):

[0016] [Chem.3] (II)

[0017] in which R2 and R3 are as defined above and n = 10 to 100,000, in particular from 20 to 10,000.

[0018] In particular, the amide(s) may be chosen from the compounds of formula (I) in which: Ri represents H, C1-C6 alkyl, linear or branched, optionally substituted; and • R2 and R3 are linked together to form an alkanediyl group -(CH2)3-.

[0019] In particular, the amide(s) may be chosen from pyrrolidone, N-methyl-2-pyrrolidone or 1-(2-hydroxyethyl)-2-pyrrolidone, or a compound of formula:

[0020] [Chem.4] rx NO h]Mh 1 ■' ft with n = 20 to 10,000.

[0021] In particular, the amide(s) may be chosen from the compounds of formula (I) in which: • R1 and R2 each independently represent H or C1-C6 alkyl, linear or branched; and • R3 represents H.

[0022] In particular, the amide(s) may be chosen from formamide or N,N-diethylformamide.

[0023] The hafnium oxide nanoparticles according to the invention may have a size of 3 to 300 nm, in particular 3 to 60 nm, in particular 3 nm.

[0024] The hafnium oxide nanoparticles according to the invention can be in the form of an aqueous dispersion.

[0025] The present invention also relates to a method for manufacturing crystallized hafnium oxide nanoparticles, characterized in that the following successive steps are carried out: a. in a solvent consisting of at least one amide or a mixture of at least one amide with water, a hafnium precursor is dissolved; b. solvothermal treatment in an autoclave is carried out on the solution obtained in (a); c. the solution obtained in (b) is brought into contact with a precipitation solvent and the precipitated hafnium oxide nanoparticles are collected.

[0026] A solvothermal synthesis is defined as a synthesis that takes place in a solvent at a temperature greater than or equal to the boiling temperature of the solvent in a sealed container. It can also take place at a temperature slightly lower than the boiling temperature of the solvent. This method allows precise control of the particle size distribution, shape, and crystallinity by adjusting the reaction parameters. In this process, if the solvent is water, it is also called a hydrothermal process, while if it is solvents other than water, such as alcohol, then it is called a solvothermal process. This process is usually performed in a sealed container called an autoclave which is made of a metal body so that it can tolerate the pressure that usually develops during the temperature rise. The autoclave further consists of a Teflon insert which provides a chemically inert container for the reaction and also protects the metal body of the autoclave from corrosion.

[0027] Hafnium oxychloride may be used as a hafnium precursor. In particular, hafnium oxychloride in the form HfOCl2.8H2O may be used.

[0028] At least one of the compounds of formula (I) may be used as amide:

[0029] [Chem.5]

[0030] in which: - Ri and R2 and R3, identical or different, each independently represent one of: • hydrogen • C1-C6 alkyl, linear or branched, optionally substituted; • optionally substituted C3-C7 cycloalkyl; • optionally substituted phenyl; and • hetero-cycloalkyl consisting of C3-C7 cycloalkyl, the hydrocarbon links are interrupted by at least one of -O-, -S- or

[0031] [Chem.6] —H X , with R4 representing H or linear or branched C1-C6 alkyl, said hetero-cycloalkyl group also being able to be substituted; - R1 and R2 may also be linked together to form an optionally substituted C2-C6 alkanediyl chain, and R2 and R3 may be linked together to form an optionally substituted C2-C5 alkanediyl chain, provided that, when R1 and R2 are linked together to form an alkanediyl chain, R3 cannot be linked to R2, and that, when R2 and R3 are linked together to form an alkanediyl chain, R1 cannot be linked to R2,

[0032] where, in the case where an alkyl, cycloalkyl, phenyl or heterocycloalkyl group falling within the definition of Rb R2 and R3 is substituted, it may be substituted by at least one substituent chosen in particular from halogen, C1-C6 alkyl, phenyl, hydroxyl and C1-C6 alkoxy,

[0033] or a compound of formula (II):

[0034] [Chem.7] n (II)

[0035] in which R2 and R3 are as defined above and n = 10 to 100,000, in particular from 20 to 10,000.

[0036] As a compound of formula (I), a compound in which R 1 represents H, linear or branched C 1 -C 6 alkyl, optionally substituted; and R 2 and R 3 are linked together to form an alkanediyl group -(CH 2 ) 3 - may be used. In particular, 2-pyrrolidone, N-methyl-2-pyrrolidone or 1-(2-hydroxyethyl)-2-pyrrolidone may be used, or a compound of formula:

[0037] [Chem.8] with n = 20 to 10,000.

[0038] As compound of formula (I), a compound in which R1 and R2 each independently represent H or linear or branched C1-C6 alkyl, and R3 represents H may be used. In particular, formamide or N,N-diethylformamide may be used.

[0039] In step (a), the amide and the hafnium precursor can be brought together in a molar ratio of 2 to 100, in particular 3 to 40, the number of moles of the hafnium precursor being indicated in moles of Hf.

[0040] In step (b), the solution obtained in (a) can be heated to a temperature above 150°C.

[0041] In step (b), the solution obtained in (a) can be heated for a period of time greater than or equal to 1 / 2h.

[0042] In step (c), acetone can be used as precipitation solvent.

[0043] In step (c), the nanoparticles can be collected by centrifugation, followed by a dispersion of these nanoparticles in water to obtain said nanoparticles in aqueous colloidal solution, said aqueous colloidal solution possibly having a dry extract of at least 50% by mass, in particular a dry extract of at least 80% by mass.

[0044] After step (c), the nanoparticles can be redispersed in water and step (c) can be repeated, and if necessary, the redispersion in water followed by step (c) is repeated at least once more to obtain nanoparticles, then followed by a dispersion of these nanoparticles in water to obtain said nanoparticles in aqueous colloidal solution, said aqueous colloidal solution possibly having a dry extract of at least 50% by mass, in particular a dry extract of at least 80% by mass.

[0045] The method according to the present invention can lead to nanoparticles whose size is from 3 to 300 nm, in particular from 3 - 60, in particular 3 nm.

[0046] The present invention also relates to the use of nanoparticles as defined above or prepared by the method as defined above, as an agent improving the therapeutic index of radiotherapy.

[0047] The following Examples illustrate the present invention without, however, limiting its scope. Examples 1 to 8 I - General operating procedure

[0048] a) Obtaining a hafnium + amide precursor reaction medium

[0049] x mL (x'g)(x”mole) of an amide solvent (Solvant Amide) was placed in the Teflon pot of a Z mL autoclave, then yg (y' mole of Hf) of hafnium oxychloride (HfOCl2.8H2O) was added with stirring. The mixture was stirred for 5 min, which resulted in a slightly diffusing or even transparent solution. b) Solvothermal treatment

[0051] The Teflon pot was then slid into the metal casing of the autoclave. The latter was closed and heated to 200°C for 3 hours, with a temperature rise of 5°C / min to obtain a reaction product. c) Precipitation of hafnium oxide particles

[0052] After cooling the autoclave, the reaction product obtained in (b) was purified: Cl) Acetone precipitation

[0053] For this, 70 mL of the reaction product was poured into 100 mL of acetone. The HfO2 nanoparticles precipitated and were recovered by centrifugation (5 min at 6000 g). The centrifugation pellet was white and the supernatant was perfectly clear and slightly yellow. C2) Reprecipitation with acetone

[0054] The pellet was then dispersed in 10 mL of deionized water using an ultrasonic bath. A translucent, very slightly yellow colloidal solution was then obtained.

[0055] To this solution, 20 mL of acetone was added, which caused the precipitation of the nanoparticles.

[0056] These were recovered by centrifugation (5 min at 6000 g). The centrifugation pellet was white, and the supernatant was perfectly clear and colorless. C3) Reprecipitation with acetone

[0057] The pellet was then dispersed in 10 mL of deionized (DI) water using an ultrasonic bath. A translucent, very slightly yellow colloidal solution was then obtained.

[0058] To this solution, 20 mL of acetone was added, which caused the precipitation of nanoparticles.

[0059] These were recovered by centrifugation (5 min at 6000 g). The centrifugation pellet was white, and the supernatant was perfectly clear and colorless. C4) Final purification

[0060] The pellet was then dispersed in 7 mL of DI water using an ultrasonic probe.

[0061] The solution obtained was vacuum-drawn so as to eliminate traces of acetone and a certain volume of water to adjust the dry extract.

[0062] A perfectly transparent or opalescent colloidal solution was then obtained depending on the size of the nanoparticles, presenting a dry extract of 50% by mass up to 80% by mass. II - Analysis of HfO2 nanoparticles

[0063] The nanoparticles obtained were analyzed by FTIR (Fourier Transform Infrared spectroscopy), DLS (Dynamic Light Scattering), TEM (Transmission Electron Microscopy) and DRX (X-ray Diffraction).

[0064] After isolation of a small portion of the HfO2 nanoparticles, an X-ray diffraction (XRD) pattern was systematically recorded using a Panalytical Empyrean diffractometer equipped with an X-ray tube with a copper anticathode to ensure the crystallinity of the particles. The pattern is shown in the figure as indicated in the Table below. The prepared nanoparticles have a monoclinic structure (P21 / c, a=0.51 nm, b=0.52 nm, c=0.53 nm, b=99, 19°, JCPDS-ICDD 00-043-1017).

[0065] The infrared spectrum (FTIR) of the isolated nanoparticles is represented each time in the figure as indicated in the Table below. This spectrum shows the presence of solvent molecules and organic molecules which result from the degradation of the solvent molecules.

[0066] The graph obtained by DLS (Dynamic Light Scattering) is represented each time in the figure as indicated in the Table below. It represents the distribution (in number) in size of the nanoparticles.

[0067] The size of the nanoparticles was also measured by transmission electron microscopy (TEM). The resulting photo is each time shown in the figure as indicated in the Table below. It shows that the size of the HfO2 particles is around 5 nm. For the smallest, the size is around 3 nm. These particles can assemble into larger units (homogeneous in size). TEM observations also make it possible to observe the crystallinity of the nanoparticles.

[0068] [Tables 1] Example Solvent A mide x( mL) x' (g) x” (mole) y( g) y' (mole of Hf) Z( ml) FTIR DLS TEM XRD 1 N-methyl-2-pyrolidone 72 0.747 14, 74 0.036 100 Fig 1 Fig 2 Fig 3 Fig 4 2 Pyrrolidone 14 16 0.1 888 2.95 0.0 072 20 Fig 5 Fig 6 Fig 7-8 Fig 9 3* Pyrrolidone 1.8 2 0.0 238 2.95 0.0 072 20 Fig 10 Fig 11 Fig 12-13 Fig 14 4* N-methyl-2-pyrrolidone 1.8 1.87 0.019 2.95 0.0 072 20 Fig 15 Fig 16 Fig 17-18 Fig 19 5** N-methyl-2-pyrrolidone 14.4 14.8 0.1 494 2.95 0.0 072 20 Fig 20 Fig 21 Fig 22 Fig 23 6 N,N-diethyl Iformamide 14 12.7 2.95 0.0 072 20 Fig 24 Fig 25 Fig 26-27 Fig 28 7 l-(2-Hydrox yethyl)-2-pyrrolidone 14 16 0.124 2.95 0.0 072 20 Fig 29 Fig 30 Fig 31-32 Fig 33 8 Formamide 12 13, 61 0.302 2.95 0.0 072 20 Fig 34 Fig 35 Fig 36-37 Fig 38

[0069] * Instead, a mixture of this amide solvent with 12.2 mL of water (0.678 mole)

[0070] ** The autoclave was heated to 200°C for one hour instead of three hours.

[0071] In [Fig.l], the IR spectrum of bare HfO2 particles (calcined particles from which the organic part was removed by heating at 600°C) is shown with the IR spectrum of the nanoparticles obtained in Example 1.

[0072] The IR spectrum of the nanoparticles obtained in Example 1 shows the presence of organic residues on the surface of the particles by the presence of the representative bands indicated in the attribution table below.

[0073] Table of allocation of peaks of the IR spectra of Examples 1, 2, 6, 7 and 8

[0074] [Tables2] Example Nombre d'onde (cm1) Attribution Example 1 3200 v (OH) 2800 v (CH) 1622 ô (H-OH) 1555 v (C=O—Hf) 1450, 1413 ô (CH3), ô (CH2) 1333 v (CN) 742 Vibration HfO2 monoclinique Example 2 3200-3400 v (OH), v (NH), 2928 v (CH) 1678 v (C=O) 1629 ô (H-OH) 1555 v (C=O—Hf) 1450, 1407 ô (CH3), ô (CH2) 1315 v (CN) 748 Vibration HfO2 monoclinique Example 6 3365 v (OH) 2873 v (CH) 1580 v (C=O—Hf) 1370 v (CN) 1302 ô (CH) 754 Vibration of monoclinic HfO2 Example 7 3285 v (OH) 2930 v (CH) 1635 ô (H-OH) 1549 v (C=O—Hf) 1450, 1413 ô (CH2) 1321 v (CN) 1075 v (CO) 748 Vibration of monoclinic HfO2 Example 8 3359 v (OH) 1650 ô (H-OH), v (C=O) 1590 ô (NH2) 1525 v (C=O—Hf) 1370 v (CN) 742 Vibration of monoclinic HfO2 Comparative example 9

[0075] Hafnium oxychloride was added to a 100 mL flask into which N-methylpyrrolidone had been previously added. The mixture was stirred for 15 min until a very slightly diffusing solution formed. The solution was then heated to 200°C (bath temperature) and atmospheric pressure. When the bath temperature reached 200°C, the solution became transparent, then gradually became opaque over time.

[0076] The solution was heated for 3 hours. The temperature of the solution is set by the boiling temperature of the solvent (the solution is at reflux).

[0077] The reaction product was isolated as in Example 1.

[0078] A portion of the product was analyzed by X-ray diffraction. The product is amorphous. It begins to crystallize from 500°C as shown in the diagrams in [Fig.39].

[0079] A comparison of the diffraction patterns of the products obtained in autoclave and in flask (Comparative Example 9) is shown in [Fig.40].

[0080] These diagrams show the importance of solvothermal treatment. Indeed, synthesis at atmospheric pressure did not allow the production of crystallized nanoparticles which cannot be used as is. Example 10

[0081] 0.8 g of polyvinylpyrrolidone (0.0072 mole of pyrrolidone unit) (PVP) was weighed

[0082] [Chem.9]

[0083] n=number of repeating units

[0084] of mass average molar mass of 10000.

[0085] 2.95g of HfOCl2.8H2O (0.0072 mole of Hf) were weighed.

[0086] PVP was introduced into the Teflon pot of the 20mL autoclave. 13 mL of water was were then introduced into the pot. The solution was stirred until completely dissolved of PVP and obtaining a clear solution. Hafnium oxychloride was then introduced into the PVP solution and after stirring, a clear solution was obtained. The Teflon pot was then slid into the metal jacket of the 20mL autoclave. The closed autoclave was heated to 200°C for 3 hours. The temperature rise was 5°C / min.

[0087] The purification was carried out as in the general procedure of Examples 1 to 8.

[0088] The infrared spectrum, the graph obtained by DLS and the X-ray diffraction diagram are presented in Figures 41, 42 and 43 respectively.

[0089] The following table shows the allocation of peaks in the IR spectrum.

[0090] [Tables3] Wavenumber (cm1) Allocation 3200 v (OH) 2922 v (CH) 1653 ô (H-OH), v (C=O) 1560 v (C=O—Hf) 1432 ô (CH3), ô (CH2) 1290 v (CN) 742 Monoclinic HfO2 vibration Example 11

[0091] In order to evaluate the influence of temperature on the formation of HfO2 nanoparticles, three syntheses were carried out according to the general procedure of Examples 1 to 8 with x'= 13 g of N-methylpyrrolidone (x” =0.3133 mole) and y = 2.95 g (y'=0.0072 mole) of hafnium oxychloride, the only difference being the heating temperature of the autoclave of 100, 150 and 200°C respectively.

[0092] The purification is identical to that described in the general procedure of Examples 1 to 8.

[0093] [Fig.44] shows the diffraction patterns recorded for these different syntheses. We see that the monoclinic phase is obtained for a temperature close to 200°C.

[0094] This series of syntheses shows that for a given heating mode it is important to provide sufficient energy to ensure the crystallization of the particles. Example 12

[0095] In order to evaluate the influence of the solvothermal treatment time on the formation of HfO2 nanoparticles, three syntheses were carried out according to the general procedure of Examples 1 to 8 with x'= 13 g of N-methylpyrrolidone (x”=0.3133 mole) and y = 2.95 g (y'=0.0072 mole) of hafnium oxychloride, the only difference being the heating time of 30 minutes, 1 hour and 3 hours respectively.

[0096] The purification is identical to that described in the general procedure of Examples 1 to 8.

[0097] [Fig.45] shows the diffraction patterns recorded for these different syntheses. It can be seen that the monoclinic phase is obtained for a treatment time greater than 1 hour.

[0098] For a given temperature and a given heating mode, the heating time must be sufficient to ensure the crystalline arrangement. Example 13

[0099] In order to evaluate the influence of the heating mode during the solvothermal treatment on the formation of HfO2 nanoparticles, two syntheses were carried out at 200°C: - Heating the autoclave in an oven, treatment time 3 hours. - Microwave heating, treatment time 1 / 2h.

[0100] The other parameters are those of the general procedure of Examples 1 to 8 with x'= 13 g of N-methylpyrrolidone (x”=0.3133 mole) and y = 2.95 g (y'=0.0072 mole) of hafnium oxychloride

[0101] The purification is identical to that described in the general procedure of Examples 1 to 8.

[0102] [Fig.46] shows the diffraction patterns recorded for these different syntheses. It can be seen that the monoclinic phase is obtained after 1 / 2h of microwave treatment. Traditional heating is mainly carried out by conduction and generates significant temperature gradients within the reactor. In the case of microwave heating, all the solvent molecules are excited and participate in the rapid and efficient heating of the entire reaction medium.

[0103] [Fig.47] is a TEM view of the particles obtained by microwave treatment. The particles obtained are crystallized and have an average size of the order of 3nm. Example 14

[0104] In order to test other hafnium precursors for the solvothermal synthesis of HfO2 nanoparticles, two syntheses were carried out at 200°C for 3 h with: - Hafnium chloride HfCl4, y=2.31 g (y'=0.0072 mole) - Hafnium ethoxide Hf(OC2H5)4, y=2.58 g (y'=0.0072 mole).

[0105] The other parameters are those of the general procedure of Examples 1 to 8 with x'= 13 g of N-methylpyrrolidone (x”=0.3133 mole).

[0106] In either case the hafnium precursor does not dissolve in N-Methyl-2-pyrrolidone.

[0107] The purification is identical to that described in the general procedure of Examples 1 to 8.

[0108] [Fig.48] shows the diffraction patterns recorded for these different syntheses.

[0109] Among the precursors hafnium chloride and hafnium ethoxide, the monoclinic phase is obtained only for hafnium chloride. For comparison, the diffraction pattern recorded for HfO2 obtained with hafnium oxychloride has been reported in [Fig.47]. The HfO2 nanoparticles obtained with hafnium chloride disperse with difficulty in water with an extremely low extract (a few percent by mass).

[0110] Hafnium oxychloride makes it possible to obtain crystallized nanoparticles while leading to colloidal solutions with high dry extracts. Even if crystallized nanoparticles are obtained from hafnium chloride, it is not possible to obtain a highly concentrated colloidal solution. Example 15

[0111] Due to their composition (presence of atoms with a high atomic number, Z=72), HfO2 nanoparticles are of great interest for increasing the effect of radiotherapy. Indeed, if the tumors are loaded with heavy elements, the X-rays from radiotherapy will be more strongly absorbed by the nanoparticles. In addition, many secondary particles (e.g. photoelectrons and Auger electrons) created by the primary interaction of X-rays with the nanoparticles locally increase the generation of reactive oxygen species (ROS), including hydroxyl radicals (OH*). These radicals are associated with the therapeutic effect of radiotherapy: the more OH* radicals are created, the greater the effectiveness of radiotherapy.

[0112] A chemical probe, aminophenyl fluorescein (APF), whose fluorescence increases with OH* concentration, was used to measure the increase in OH* generation in the presence of the HfO2 nanoparticles of Example 1. For this, the fluorescence of APF in two samples was compared: i) a sample containing only water and APF and ii) a sample containing 10 mg / mL of HfO2 nanoparticles of Example 1 in water and APF. The results obtained are shown in [Fig.49].

[0113] It appears clearly that the HfO2 nanoparticles very strongly stimulate the generation of OH* radicals. Indeed, the fluorescence signal of the APF is multiplied by a factor ranging from 4.3 to 8.5 depending on the radiation dose used, between the sample containing only water and APF (standard radiotherapy effect) and the sample containing water and nanoparticles of Example 1 (standard radiotherapy effect + nanoparticle-induced dose-increasing effect). These results therefore demonstrate the strong potential of the HfO2 nanoparticles according to the invention to stimulate the creation of OH* radicals, and thus, the effect of radiotherapy.

Claims

Claims

1. - Crystallized hafnium oxide nanoparticles, characterized by the fact that they carry on their surface molecules of amide(s) and, where appropriate, molecules of at least one amide degradation product chosen from a carboxylic acid, an amine or an amino acid and / or residues of said molecules.

2. - Hafnium oxide nanoparticles according to claim 1, characterized in that the amide(s) are chosen from the compounds of formula (I): [Chem. 11] (I) in which: - Ri and R2 and R3, identical or different, each independently represent one of: • hydrogen • C1-C6 alkyl, linear or branched, possibly substituted; • optionally substituted C3-C7 cycloalkyl; • optionally substituted phenyl; and • hetero-cycloalkyl consisting of C3-C7 cycloalkyl, the hydrocarbon links of which are interrupted by at least one of -O-, -S- or [Chem. 12] , with R4 representing H or linear or branched C1-C6 alkyl, said hetero-cycloalkyl group also being able to be substituted; - R1 and R2 may also be linked together to form an optionally substituted C2-C6 alkanediyl chain, and R2 and R3 may be linked together to form an optionally substituted C2-C5 alkanediyl chain, provided that, when R1 and R2 are linked together to form an alkanediyl chain, R3 cannot be linked to R2, and that, when R2 and R3 are linked together to form an alkanediyl chain, R1 cannot be linked to R2, wherein, in the case where an alkyl, cycloalkyl, phenyl or heterocycloalkyl group falling within the definition of R2 and R3 is substituted, it may be substituted by at least one substituent chosen in particular from halogen, C1-C6 alkyl, phenyl, hydroxyl and C1-C6 alkoxy, or a compound of formula (II): [Chem. 13] Rv in ' h K “ n (II) in which R2 and R3 are as defined above and n = 10 to 100,000, in particular from 20 to 10,000.

3. - Hafnium oxide nanoparticles according to claim 2, characterized in that the amide(s) are chosen from the compounds of formula (I) in which: • Ri represents H, linear or branched C1-C6 alkyl, optionally substituted; and • R2 and R3 are linked together to form an alkanediyl group -(CH2)3-.

4. - Hafnium oxide nanoparticles according to claim 2, characterized in that the amide(s) are chosen from pyrrolidone, N-methyl-2-pyrrolidone or l-(2-hydroxyethyl)-2-pyrrolidone, or a compound of formula: [Chem. 14] k J n with n = 20 to 10,000.

5. - Hafnium oxide nanoparticles according to claim 2, characterized in that the amide(s) are chosen from the compounds of formula (I) in which: • R1 and R2 each independently represent H or linear or branched C1-C6 alkyl; and • R3 represents H.

6. - Hafnium oxide nanoparticles according to claim 5, characterized in that the amide(s) are chosen from formamide or N,N-diethylformamide.

7. - Hafnium oxide nanoparticles according to one of claims 1 to 6, characterized in that they have a size of 3 to 300 nm, in particular of 3 to 60 nm, in particular of 3 nm.

8. - Nanoparticles as defined in one of claims 1 to 7, in the form of aqueous dispersion.

9. - Process for the manufacture of crystallized hafnium oxide nanoparticles, in particular as defined in one of claims 1 to 8, characterized in that the following successive steps are carried out: a. in a solvent consisting of at least one amide or a mixture of at least one amide with water, a hafnium precursor is dissolved; b. a solvothermal treatment in an autoclave of the solution obtained in (a) is carried out; c. the solution obtained in (b) is brought into contact with a precipitation solvent and the precipitated hafnium oxide nanoparticles are collected.

10. - Process according to claim 9, characterized in that hafnium oxychloride is used as hafnium precursor.

11. - Process according to claim 10, characterized in that a hafnium oxychloride is used in the form HfOCl2.8H2O.

12. - Process according to one of claims 9 to 11, characterized in that at least one of the compounds of formula (I) as defined in one of claims 2 to 6 is used as amide.

13. - Process according to one of claims 9 to 12, characterized in that in step (a), the amide and the hafnium precursor are brought together in a molar ratio of 2 to 100, in particular of 3 to 40, the number of moles of the hafnium precursor being indicated in moles of Hf.

14. - Method according to one of claims 9 to 13, characterized in that in step (b), the solution obtained in (a) is heated to a temperature above 150°C.

15. - Method according to one of claims 9 to 14, characterized in that in step (b), the solution obtained in (a) is heated for a period of time greater than or equal to 1 / 2h.

16. - Method according to one of claims 9 to 15, characterized in that in step (c), acetone is used as precipitation solvent.

17. - Method according to one of claims 9 to 16, characterized in that in step (c), the nanoparticles are collected by centrifugation, then followed by a dispersion of these nanoparticles in water to obtain said nanoparticles in aqueous colloidal solution, said aqueous colloidal solution possibly having a dry extract of at least 50% by mass, in particular a dry extract of at least 80% by mass.

18. - Method according to one of claims 9 to 17, characterized in that after step (c), the nanoparticles are redispersed in water and step (c) is repeated, and if necessary the redispersion in water followed by step (c) is repeated at least once more to obtain nanoparticles, then followed by a dispersion of these nanoparticles in water to obtain said nanoparticles in aqueous colloidal solution, said aqueous colloidal solution possibly having a dry extract of at least 50% by mass, in particular a dry extract of at least 80% by mass.

19. - Use of nanoparticles as defined in one of claims 1 to 8 or prepared by the process as defined in one of claims 9 to 18, as an agent improving the therapeutic index of radiotherapy.

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