Classifications

• • C—CHEMISTRY; METALLURGY
  • C01—INORGANIC CHEMISTRY
  • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
  • C01B39/00—Compounds having molecular sieve and base-exchange properties, e.g. crystalline zeolites; Their preparation; After-treatment, e.g. ion-exchange or dealumination
  • C01B39/02—Crystalline aluminosilicate zeolites; Isomorphous compounds thereof; Direct preparation thereof; Preparation thereof starting from a reaction mixture containing a crystalline zeolite of another type, or from preformed reactants; After-treatment thereof
  • C01B39/32—Type L
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
  • B01J13/0004—Preparation of sols
  • B01J13/0008—Sols of inorganic materials in water
• • C—CHEMISTRY; METALLURGY
  • C01—INORGANIC CHEMISTRY
  • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
  • C01B39/00—Compounds having molecular sieve and base-exchange properties, e.g. crystalline zeolites; Their preparation; After-treatment, e.g. ion-exchange or dealumination
  • C01B39/02—Crystalline aluminosilicate zeolites; Isomorphous compounds thereof; Direct preparation thereof; Preparation thereof starting from a reaction mixture containing a crystalline zeolite of another type, or from preformed reactants; After-treatment thereof
  • C01B39/20—Faujasite type, e.g. type X or Y
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/51—Nanocapsules; Nanoparticles
  • A61K9/5107—Excipients; Inactive ingredients
  • A61K9/5115—Inorganic compounds
• • C—CHEMISTRY; METALLURGY
  • C01—INORGANIC CHEMISTRY
  • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
  • C01P2004/00—Particle morphology
  • C01P2004/60—Particles characterised by their size
  • C01P2004/64—Nanometer sized, i.e. from 1-100 nanometer
• • C—CHEMISTRY; METALLURGY
  • C01—INORGANIC CHEMISTRY
  • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
  • C01P2006/00—Physical properties of inorganic compounds
  • C01P2006/12—Surface area
• • C—CHEMISTRY; METALLURGY
  • C01—INORGANIC CHEMISTRY
  • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
  • C01P2006/00—Physical properties of inorganic compounds
  • C01P2006/14—Pore volume

Definitions

• the present invention relates to a process for the synthesis of zeolite nanoparticles, the nanoparticles thus obtained, suspensions of these nanoparticles in water or PBS buffer as well as a pharmaceutical composition and a combination product containing these nanoparticles.
• nanoparticles can be used in the medical field, in particular for the treatment of hypoxic solid tumors.
• TO4 Ti, Al or other heteroatoms
• the presence of the ACUI 5 ' ions gives the framework negative charges that must be compensated by cations (alkaline or alkaline-earth) called compensation, such as Na + , K + , Ca 2+ , Sr 2+ in order to maintain electrical neutrality.
• compensation such as Na + , K + , Ca 2+ , Sr 2+ in order to maintain electrical neutrality.
• the vacant space is defined by the aluminosilicate framework formed by these three-dimensional chains.
• the vacant spaces of the tetrahedral crystal lattice are connected to each other and occupied by alkali ions and water molecules.
• Zeolites also have a microporous network formed by cavities, channels connecting the cavities and pores connecting the channels or cavities with the outside. Zeolites can be natural or synthetic. There are currently more than 250 types of zeolites.
• Document W02015/101800 A describes a method for synthesizing faujasite nanocrystals (FAU-type zeolites), faujasite single crystals and a process for synthesizing a colloidal suspension of these nanocrystals.
• the faujasite nanocrystals have a size ranging from 5 to 400 nm, a Si/Al molar ratio ranging from 1 to 2.5 and a Si/Na molar ratio of 1.1 to 1.5.
• the total pore volume (total pore volume) ranges from 0.50 to 1.5 cm 3 /g.
• WO 2019/030200 A1 describes FAU and EMT type zeolite nanocrystals for which sodium ions have been replaced by Fe or Gd ions and which can be loaded with gaseous dioxygen. These nanocrystals can be used for the diagnosis and treatment of brain tumors, including glioblastoma.
• the publication of Anfray et al “nanosized zeolites as a gas delevery platfrom in a glioblasma model" describes a suspension of FAU type nano zeolites in water.
• the zeolite nanocrystals that are described in these documents are synthesized in water which restricts their medical uses. Indeed, in the long term and at high concentrations, these nanocrystals are likely to cause allergy-type problems. technical problem to be solved
• An aim of the present invention is therefore to propose new zeolite nanoparticles which can be used in the diagnosis and/or treatment of certain pathologies, in particular solid brain tumors.
• Another aim of the invention is to propose a new method of synthesizing such nanoparticles.
• Another aim of the invention is to provide colloidal suspensions of these nanoparticles.
• Another aim of the invention is to provide zeolite nanoparticles which have reduced toxicity and/or exhibit an improved oxygen adsorption and/or release capacity.
• a first aspect of the invention relates to a method for synthesizing nanoparticles consisting of or comprising at least one zeolite nanocrystal according to which:
• composition/solution 1 is prepared containing a source of aluminum and a source of an ion of an alkali metal M, in particular Na;
• composition/solution 2 comprising a source of silicon and a source of an ion of an alkali metal M, in particular Na, said compositions/suspensions 1 and 2 being free of any organic structuring agent;
• said first composition/solution 1 and said second composition/suspension 2 are each a composition/solution consisting of said source and an aqueous buffer (PBS), which consists of water and 137 mM/L of NaCl, 2.7 mM/L of KCl, 10 mM/L of Na 2 HPO 4 , 1.76 mM/L of KH2PO4 and having a pH equal to 7.2 and said mixture of solutions 1 and 2 has the following molar composition (I):
• the method of the invention is simple to implement and makes it possible to obtain zeolite nanoparticles forming a stable colloidal suspension in PBS.
• solutions 1 and 2 are prepared.
• the first composition/solution 1 can be prepared at room temperature.
• the second composition/solution is prepared, for example, at a temperature below 30°C and in particular equal to 25°C.
• the mixing of the two compositions/solutions can advantageously be carried out at a temperature equal to or greater than 0°C and equal to or less than 30°C and in particular equal to 0°C.
• the mixture must be left stirring at a temperature equal to or greater than 0°C and equal to or less than 30°C and in particular equal to 25°C for at least 2 hours and in particular 24 hours.
• the mixture can be crystallized at a temperature greater than or equal to 50°C.
• the aluminum source may be chosen from any aluminum source capable of providing monomeric oxyhydroxide species.
• any aluminum source capable of providing monomeric oxyhydroxide species means that this aluminum source does not provide polymeric aluminum oxyhydroxide species and makes it possible to dissolve all the aluminum in the clear aqueous solution 1.
• the aluminum source may be chosen among alumina, hydrated alumina, aluminum powder, Al, Al2(SO4)3, aluminum hydroxide AI(OH)3, sodium aluminate (NaAlCh), potassium aluminate (KAIO2) and kaolin clays.
• the silicon source may be selected from any silicon source capable of providing monomeric or Si2-Sie oxyhydroxide species. Thus, the amount of larger [SiOOH] n units is limited in the composition/suspension 2.
• the silicon source may be selected from silica hydrogel, silicic acid, colloidal silica, fumed silica, tetraalkyl orthosilicates, silica hydroxides, precipitated silica, silica fume and clays. Colloidal silica is preferred in all embodiments of the method of the invention.
• the alkali metal source M can be chosen in particular from a source of Na and a source of K.
• the hydroxides of these two alkali metals are preferred as sources of alkali metal.
• M Na
• said aluminum source is aluminum powder
• solutions 1 and 2 are prepared and before crystallizing said mixture of solutions 1 and 2, it is dehydrated under vacuum and the remaining solid fraction is then crystallized at a temperature greater than or equal to 30°C and less than or equal to 100°C and in particular equal to 50°C for a duration equal to or greater than 6 hours and equal to or less than 30 hours and in particular equal to 25 hours.
• FAU type zeolite nanoparticles are thus obtained. It should be noted that the process of the invention also allows the direct production of suspensions of zeolite nanoparticles in PBS.
• the purification of said nanoparticles is carried out using a membrane, in particular a dialysis membrane.
• a membrane in particular a dialysis membrane.
• the operation of this method is simple, inexpensive, generally carried out using commercially available membranes (dialysis membrane), and it also saves water.
• This technique also makes it possible to preserve the PBS in the nanoparticles.
• a second aspect of the invention relates to a method for manufacturing a colloidal suspension of nanoparticles, according to which nanoparticles are synthesized according to the method of the invention and said synthesized nanoparticles are dispersed in optionally sterile water or in an optionally sterile aqueous buffer solution consisting of water and 137 mM/L NaCI, 2.7 mM/L KCI, 10 mM/L Na2HPO4 and 1.76 mM/L KH2PO4 and having a pH equal to 7.2.
• a suspension of zeolite nanoparticles in water or in PBS is thus obtained.
• the zeolite nanoparticles are dispersed, having been previously filtered in order to eliminate the PBS.
• the present invention also relates to a nanoparticle consisting of or comprising a zeolite nanocrystal and obtainable according to the method of the invention.
• said zeolite is an aluminosilicate of the FAU type and it contains PBS ions, i.e. Na + , K + , H2PO4 2 ; HPCU' HsO + and Cl' ions and optionally water molecules. These ions are arranged on the surface of the crystal lattice and/or in the interstices of the crystal lattice and/or in the pore network of the particle. The surface of the crystal lattice may be the surface of the particle.
• the Na + and K + ions may be found in the interstices of the crystal lattice as compensation ions.
• Said nano zeolite may advantageously contain at least two species of the aforementioned ions. Depending on the pH, it can contain different quantities of the HPCU 2 ', H3O+, FhPCU' ions. These ions, whatever they may be, are located in its porous network and/or on its surface and/or in the interstices of its crystal network and/or on the surface of the crystal network, which can correspond to the surface of the particle.
• the inventors have demonstrated that nanoparticles synthesized in PBS saline buffer are less cytotoxic and therefore likely to be better accepted by the body.
• PBS has the same salt concentration as the human body; it also contains the dihydrogen phosphate/hydrogen phosphate pair which allows the maintenance of blood pH in the body. Without the inventors being bound to this explanation, it would seem that certain ions of the PBS contained in the crystal lattice and/or in the porous lattice and/or on the surface of the nanoparticle can stabilize the nanoparticles and prevent them from degrading in the biological environment, which reduces their toxicity potential. In addition, the ions of the PBS can also regulate the charge on the surface of the nanoparticles, which can influence their behavior and their interaction with biological cells and tissues.
• the nanoparticles obtained according to the method of the invention thus avoid or reduce the allergy phenomena described above.
• the nanoparticle can be a nanocrystal.
• This nanocrystal may have an average diameter greater than or equal to 10 nm and less than or equal to 100 nm and in particular equal to 30 nm.
• the zeolite has the following chemical composition:
• the number of moles of water is determined by thermogravimetric analysis.
• the number of Na, K, Si and Al atoms is determined by ICP, and the number of moles of oxygen is determined from the number of moles of the metals using the stoichiometry of the formula.
• the nanoparticle of the invention may have a total pore volume greater than or equal to 0.4 cm 3 /g and less than or equal to 1.5 cm 3 /g and/or a specific surface area SBET greater than or equal to 200 m 2 /g and less than or equal to 1000 m 2 /g.
• said nanoparticle has a total pore volume (cavity + pores + channels) greater than or equal to 0.6 cm 3 /g and less than or equal to 1.3 cm 3 /g and in particular equal to 0.93 cm 3 /g and/or a specific surface area SBET greater than or equal to 300 m 2 /g and less than or equal to 800 m 2 /g and in particular equal to 600 or 428 m 2 /g.
• This nanocrystal may have the chemical formula (II)
• porous network of the zeolite of the invention extends in the three directions of space
• a nanoparticle as mentioned above which further contains, in the cavities of its crystal lattice, cations of a metal chosen from Fe, Gd, Cu and Ce and in particular in an amount greater than or equal to 0.2% by mass and less than or equal to 5% by mass and/or a gas contained in its pore volume and chosen from oxygen, nitrogen, carbon dioxide and mixtures thereof.
• a metal chosen from Fe, Gd, Cu and Ce
• a gas contained in its pore volume and chosen from oxygen, nitrogen, carbon dioxide and mixtures thereof Some of these nanoparticles can be used in diagnosis (the Gd, Fe ions serving in particular as a labeling ion) in particular in magnetic resonance imaging (MRI) and in treatment when they are loaded with oxygen. Indeed, they then provide oxygen which they deliver into the cells and thus increase the reactivity of the cells of solid cancerous tumors to anticancer agents.
• MRI magnetic resonance imaging
• a suspension comprising or consisting of the nanoparticles of the invention and a dispersant chosen from water, a buffer consisting of water and 137 mM/L of NaCI, 2.7 mM/L of KCI, 10 mM/L of Na2HPO4, 1.76 mM/L KH2PO4 and having a pH of 7.2 (PBS), alcohols and their mixtures.
• a dispersant chosen from water, a buffer consisting of water and 137 mM/L of NaCI, 2.7 mM/L of KCI, 10 mM/L of Na2HPO4, 1.76 mM/L KH2PO4 and having a pH of 7.2 (PBS), alcohols and their mixtures.
• the present invention relates to a pharmaceutical composition containing as contrast agent or pharmaceutically active agent nanoparticles according to the invention, optionally suspended in a dispersant.
• the amount of nanoparticles is the amount suitable to obtain a therapeutic effect or to obtain a contrast allowing diagnosis.
• the dispersant is chosen from pharmaceutically acceptable solvents, in particular water, PBS, alcohols and their mixtures.
• composition of the invention can be administered orally, mucosally (in particular intranasally) or parenterally.
• the present invention also relates to a nanoparticle according to the invention, for its use as a medicament, in particular for the treatment of hypoxic solid brain tumors and in particular glioblastoma, or as a diagnostic agent, in particular as a contrast agent in MRI.
• the present invention also relates to a combination product comprising or consisting of the pharmaceutical composition of the invention or the suspension according to the invention and an anticancer agent, for their simultaneous or delayed administration.
• the nanoparticles according to the invention preferably contain oxygen in their porous network and are optionally suspended in a pharmaceutically acceptable dispersant.
• the dispersant is preferably chosen from water, PBS and mixtures thereof.
• the anticancer agent and the pharmaceutical composition of the combination product of the invention may be administered simultaneously or in a delayed manner, the anticancer agent being advantageously administered first.
• the anticancer agent may be chosen from temozolomide® (4-methyl-5-oxo-2,3,4,6,8-pentazabicyclo[4.3.0]nona-2,7,9-triene-9-carboxamide methazolastone), doxorubicin (8S,10S)-10-(4-amino-5-hydroxy-6-methyl-tetrahydro-2H-pyran-2-yloxy)-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-7,8,9,10-tetrahydrotetracene-5,12-dione), cisplatin (cis-diamminedichloroplatinum(ll)).
• average size designate for the purposes of the invention the average size (in number or in intensity) measured by dynamic light scattering.
• the average size corresponds to the diameter of the sphere which diffuses at the same speed as that of the particle being measured.
• the fundamental size distribution obtained by DLS is an intensity distribution. The operating conditions are as defined in the remainder of the application.
• nanoparticle designates any solid particle with a maximum dimension of less than 100 nm. It may be a single crystal or an aggregate of crystals.
• PBS refers to phosphate buffered saline which is an aqueous solution of NaCl (0.137 M), KCl (0.0027 M), sodium phosphate dibasic (0.01 M) and potassium phosphate monobasic (0.0018 M). Its pH is 7.2.
• FAU-type nanoparticle refers to nanoparticles comprising or consisting of a single crystal of FAU-type zeolite.
• FAU-type zeolite refers to an aluminosilicate that crystallizes in a face-centered cubic system. According to the invention, the terms include FAU X-type zeolites for which the Si/Al molar ratio is greater than or equal to 1 and less than or equal to 1.5 and FAU Y-type zeolites for which the Si/Al molar ratio is greater than or equal to 1.5 and less than or equal to 2.6.
• a chemical formula of a FAU-type zeolite nanocrystal is INa a Kb (H2O) C I(AI X Sii92-xO384), with Na + and K + ions being present to ensure the electrical neutrality of the nanocrystal. Water molecules may be absent from the nanocrystal.
• clear suspension means an aqueous suspension having substantially the same refractive index as water, i.e. a refractive index of approximately 1.333 ⁇ 0.030, measured under standard conditions.
• pore volume or “pore network” designate the set formed by the cavities, the channels connecting these cavities together and the pores which connect the channels and cavities to the outside of the nanoparticle.
• pharmaceutically active means an agent which confers curative or preventive therapeutic properties to the composition which contains it and which, if it presents harmful side effects, these are not preponderant in relation to the curative and/or preventive effects.
• composition means any homogeneous or inhomogeneous mixture of at least two compounds which may be present in different physical states; the term composition thus includes in particular solutions, suspensions and dispersions.
• - Fig. 1 represents the size distribution of the Na-FAU-PBS nanoparticles of the invention, the nanoparticles are dispersed in a PBS solution;
• FIG. 2A shows scanning electron microscope images of Na-FAU-PBS and Gd-FAU-PBS type nanoparticles (nanocrystals) with a scale of 500 nm
• Fig. 2B shows scanning electron microscope images of Na-FAU-PBS type nanoparticles (nanocrystals) with a scale of 100 nm and 40 nm;
• - Fig. 3 represents the quantity of adsorbed nitrogen as a function of the relative pressure obtained under the operating conditions described below for Na-FAU-PBS type nanoparticles;
• Fig. 4 shows a comparison of the viability of U87-MG cells exposed to two colloidal suspensions of nanoparticles containing respectively 10 pg/mL and 100 pg/mL of Na-FAU-Water or Gd-FAU-Water nanoparticles with that obtained for the same concentrations of Na-FAU-PBS and Gd-FAU-PBS nanoparticles;
• - Fig. 5 represents on the left the percentage of hemolysis as a function of the dose of nanoparticles (in pg/mL) of the Na-FAU and Gd-FAU type synthesized with water or PBS;
• - Fig. 6A represents the change in the oxygen concentration in water obtained by contacting Na-FAU-Water and Gd-FAU-Water particles, previously loaded with O2
• Fig. 6B the change in the oxygen concentration in PBS obtained by contacting with Na-FAU-PBS and Gd-FAU-PBS particles of the invention and previously loaded with O2;
• PBS Phosphate buffered saline
• the different zeolite materials obtained in the examples were characterized on different size scales.
• the morphology of the nanoparticles was examined by scanning electron microscopy (SEM) using a Tescan Mira I LMH instrument at a voltage of 20 kV.
• TEM Transmission electron microscopy
• the hydrodynamic diameters of the zeolite material in the different suspensions were determined with a Malvern Zetasizer Nano instrument.
• the surface charge of the samples was determined by measuring the zeta potential of the suspensions.
• the backscattering geometry (scattering angle 173°, HeNe laser with an output power of 3 mW at a wavelength of 632.8 nm) allows measurements at high sample concentration, since a complete penetration of the incident light through the sample is not necessary.
• the chemical composition of the zeolite samples was characterized by inductively coupled plasma mass spectrometry using Agilent Technologies 7900.
• the samples were prepared according to the following procedure: (i) 50 mg of zeolite sample was dissolved in 3 mL of hydrofluoric acid (HF) (Sigma-Aldrich 40-45%), (ii) 0.5 mL solution (HNO3/HCl equals 1:3 v/v) was added and the mixture was heated at 110 °C for 1 h in a polytetrafluoroethylene (PTFE) bottle (100 mL), and subsequently (iii) 96.5 mL of distilled water and 2 g of boric acid (H3BO3) were added. The resulting solution was stirred overnight to facilitate the dissolution of boric acid. Finally, 10 mL of the suspension was diluted 10 times with distilled water before analysis.
• HF hydrofluoric acid
• the colloidal suspension of FAU was synthesized hydrothermally from the molar composition cited with reference to the first mode of implementation of the process of the invention.
• a solution A of aluminum powder is prepared by dissolving 2.3 g of NaOH in 3 g of PBS followed by slow addition of 0.29 g of aluminum powder.
• Silicate solution B was prepared by mixing 10 g of colloidal silica (LUDOX® HS-30) with 1.1 g of NaOH and 1 g of PBS. This cloudy solution (suspension B) was heated for 6-7 min in an oven at 100°C to be transformed into a clear solution. Solution B was then added dropwise to solution A under a temperature of 0-3°C and rapid stirring, and then the mixture was aged for 24 h at room temperature.
• colloidal silica LUDOX® HS-30
• the initial molar composition of the mixture is as follows:
• the mixture obtained is dehydrated by lyophilization and then crystallized for 25 h in an oven at 50 ° C.
• the suspension is purified by dialysis membrane (Visking Dialysis Tubing, Code No. - DTV.12000.08 Size No.8 (25.4 mm, 30 m), Molecular weight 12-14000 Daltons), until a pH of 7.2 is reached.
• 60 - 75 mL (1.6 to 1.9 g) of a colloidal suspension containing 2.5% by mass of Na-FAU type zeolite nanocrystals in PBS are obtained.
• the nanoparticles contain PBS ions in their porous network and as an intercalated alkali ion in the network, Na + and K + ions.
• the final suspensions were sonicated for 2 h.
• crystal yield ranges from 53 to 63% (crystal yield is defined as the mass of product obtained X 100/mass of SiCh contained in solution B.
• Example 2 Synthesis of colloidal suspensions of nanoparticles according to the invention A given quantity of each of the types of nanoparticles of example 1 was dispersed in 10 mL of PBS under sonication for 2 hours. Colloidal solutions containing respectively 1%, 2%, 3% and 4% by mass of nanoparticles of the Na-FAU-PBS type dispersed in PBS are obtained.
• nanoparticles are stable in colloidal suspension at room temperature for at least one week.
• Example 3 Synthesis of zeolite nanoparticles charged with metal ions
• Example 2 Each of the colloidal aqueous suspensions obtained in Example 2 or Example 3 was then bubbled with O2, CO2 or carbogen at a flow rate of 800 mL/min for 30 minutes.
• Example 5 Morphological characterization of the nanoparticles obtained in examples 1, 2 and 4. Scanning/transmission electron microscopy (SEM)/(TEM) was used to determine the morphology and size of the synthesized Na-FAll-PBS and Gd-FAU-PBS nanoparticles.
• Fig. 1 The curve giving the size distribution of nanoparticles dispersed in PBS is shown in Fig. 1 for Na-FAU-PBS nanoparticles.
• the hydrodynamic size of nanoparticle aggregates in PBS solution measured by DLS is between 50-200 nm. It is observed that this is a monodisperse population.
• Scanning electron microscopy images of Na-FAU-PBS or Gd-FAU-PBS zeolite nanoparticles show nanoparticles with a quasi-spherical shape with a homogeneous size distribution and TEM transmission electron microscopy images (see Fig. 2B) show nanoparticles (nanocrystals) with an average size of 30 nm.
• nanoparticles are highly crystalline. These are nanoparticles each formed from a single nanocrystal.
• the chemical formula of the zeolite material of Na-FAU-PBS and Gd-FAU-PBS type nanoparticles is as follows (determined by ICP):
• the formula in parentheses corresponds to the crystal tetrahedral lattice, between the bars are the number of moles of compensating cations and the number of moles of water.
• the porosity of the Na-FAU-PBS and Gd-FAU-PBS zeolites synthesized in the above examples was characterized by nitrogen gas adsorption/desorption measurements.
• the textural properties of the nanoparticles obtained in Examples 1, 2 and 4 were determined by the adsorption/desorption isotherms of dinitrogen measured at a temperature of -196 °C using a surface characterization device "Micromeritics 3Flex". All samples were degassed at 250 °C under vacuum overnight before analysis. The external surface of the zeolite nanoparticles and the micropore volume of zeolite nanoparticles were evaluated by the t-plot method.
• Nitrogen adsorption/desorption measurements for both zeolites resulted in hybrid isotherms of type I and IV according to the IUPAC classification (see Fig. 3).
• the measurement of the SBET specific surface area, the total pore volume and the micropore volume of the zeolite nanoparticles are grouped in Table 1 below.
• a micropore is defined as a pore smaller than 0.08 mm.
• Table 2 below lists the chemical composition of the Na-FAU-PBS and Gd-FAU-PBS nanoparticles of the invention.
• Example 8 Toxicity test on human cell line.
• Cells used were derived from a human glioblastoma cell line, U87-MG purchased from American Type Culture Collection (ATCC). Cells were cultured in DMEM 1 g/L glucose (Sigma-Aldrich) supplemented with 10% fetal bovine serum (Eurobio), 2 mM glutamine (Sigma-Aldrich), and penicillin (100 U/mL)/streptomycin (100 pg/mL) (Sigma-Aldrich). Cells were maintained in culture at 37°C with 5% CO2 and 95% humidity. Cell viability was assessed 72 h after exposure to zeolite nanoparticles with the WST-1 test (Roche) according to the manufacturer's instructions.
• Example 9 Red blood cell viability test.
• Example 10 Study of oxygen release by zeolite nanoparticles in aqueous and hypoxic conditions.
• a hypoxia chamber (IN VIV02 500TM, 3M) was used to obtain a stable and precisely controlled gas composition of the atmosphere with an accuracy of 0.1% O2 by adjusting the amount of N2.
• the PBS solution (Sigma-Aldrich) was equilibrated with the gas mixture contained in the hypoxia chamber for 1 h before the experiment.
• the nanoparticles of the examples of different types and previously loaded with oxygen were then added to the system and the dissolved oxygen in the PBS solution was measured continuously for 1 h. The results are visible in Fig. 6A and 6B.
• the Gd-FAU-PBS nanoparticles of the invention previously loaded with oxygen exhibit a better release of dioxygen compared to the nanoparticles prepared in water (Gd-FAU-Water).
• the release kinetics are also increased, which is of interest for in vivo use.
• the release of oxygen is accelerated after 30 min, which is of considerable interest for in vivo use, the particle having time to reach the brain and deliver oxygen there.
• Concerning the Na-FAU-PBS nanoparticles it is noted that the release kinetics of dioxygen are slower compared to Na-FAU-Water.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• General Life Sciences & Earth Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Geology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Inorganic Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Materials Engineering (AREA)
• Dispersion Chemistry (AREA)
• Silicates, Zeolites, And Molecular Sieves (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=88068905

Family Applications (1)

Country Status (5)

Family Cites Families (2)

• 2024
  • 2024-03-19 JP JP2025555819A patent/JP2026511198A/ja active Pending
  • 2024-03-19 WO PCT/EP2024/057254 patent/WO2024200101A2/fr not_active Ceased
  • 2024-03-19 EP EP24712249.2A patent/EP4688656A2/de active Pending
  • 2024-03-19 CN CN202480019771.7A patent/CN120826370A/zh active Pending
  • 2024-03-19 AU AU2024245504A patent/AU2024245504A1/en active Pending

Also Published As

Similar Documents

Legal Events