Dialysate composition comprising a specific compound

Abstract

The present invention relates to a dialysate composition having a composition having a composition allowing for a balance with blood comprising mineral salts and a pH buffer, and comprising at least one iron oxide nanoparticle (Fe2+ and / or Fe3+) coated with at least one polymeric compound.

Description

[0001] DIALYSATE COMPOSITION COMPRISING A SPECIFIC COMPOUND

[0002] The present invention concerns a dialysate composition having a composition allowing for a balance with blood, said composition comprising mineral salts, pH buffer and optionally at least one osmotic compound, and comprising at least one iron oxide nanoparticle (Fe2+ / Fe3+) coated with at least one polymeric compound. Typically, the polymeric compound act as a surfactant.

[0003] Chronic kidney disease (CKD), characterized by a progressive loss of kidney function over time, is currently a major health problem worldwide, with 75 million people suffering from CKD in Europe. This syndrome leads to the accumulation in the blood of uremic toxins and phosphate that are normally regularly eliminated by healthy kidneys, resulting in the development of toxic symptoms, persistent inflammation, oxidative stress and endothelial dysfunction, which eventually lead to major clinical complications, including cardiovascular disease and death. Patients suffering from end-stage renal failure therefore cannot survive without renal replacement therapy, i.e. transplantation or dialysis. Transplantation is the best option for patients, but the waiting list can be long and most patients require some form of dialysis while waiting for a transplant. Dialysis can be carried out in two ways: haemodialysis (HD) and peritoneal dialysis (PD).

[0004] Haemodialysis consists in purifying the blood via extracorporeal circulation, where the blood is filtered using a machine. In peritoneal dialysis, the process is different: the dialysate is introduced into the patient’s peritoneal cavity and it is through the peritoneum that exchanges take place. By diffusion and osmosis / convection mechanisms mostly through the capillaries, toxins and excess water pass into the dialysate. The composition of the dialysate is balanced with that of the blood within a few hours.

[0005] Whilst dialysis remains an effective means of treating chronic kidney disease, current processes do not eliminate phosphates and toxins in sufficiently large quantities. This imbalance in phosphate in the blood leads to very high cardiovascular mortality and bone disorders in patients. In order to control the phosphataemia, patients with CKD must follow a restrictive diet, which can lead to malnutrition and greatly reduce their life quality or ingest phosphate binders, which are not always well tolerated or effective.

[0006] Thus, there is an urgent need to improve the treatment of chronic kidney disease, to control the accumulation of phosphate in blood, and to prevent hyperphosphatemia. Moreover, there is notably a need to find a better dialysate composition to capture phosphates from the blood more effectively and if possibly to improve also the removal of other toxins.

[0007] The present invention fulfills these needs. Indeed, as shown in the examples, the inventors have discovered that formulating new dialysates by adding nanomaterials based on iron oxide nanoparticles improve the elimination of phosphate and potentially toxins from blood and biological fluids.

[0008] A first object of the present invention is to provide a dialysate allowing for a balance with blood, said composition comprising mineral salts and a pH buffer, and comprising at least one iron oxide nanoparticle (Fe2+and / or Fe3+) coated with at least one polymeric compound. Preferably, the dialysate composition further comprises at least one osmotic compound.

[0009] Another object of the present invention is a composition for use as a medicament, more preferably for use as a dialysate for blood purification.

[0010] Dialysate composition

[0011] A first object of the present invention is a dialysate composition allowing for a balance with blood, said composition comprising mineral salts, pH buffer and optionally at least one osmotic compound, and comprising at least one iron oxide nanoparticle (Fe2+and / or Fe3+) coated with at least one polymeric compound.

[0012] By “dialysate composition”, it is meant an aqueous composition comprising at least one mineral salt (also called “electrolyte”), a pH buffer and optionally at least one osmotic compound. The purpose of said dialysate composition is to pull the toxins and phosphates from the blood to the dialysate.

[0013] The dialysate composition of the invention is a composition that can be used in peritoneal dialysis and / or in hemodialysis.

[0014] Preferably, the dialysate composition according to the invention has a composition similar to that of blood.

[0015] By “composition similar to that of blood” it is meant that the composition comprises at least one mineral salt in a concentration similar to those of blood and a pH buffer. Optionally said composition further comprises at least one osmotic compound especially in a concentration that allows it to be in balance with the blood and allows exchanges by diffusion and convection / osmose between the dialysate and the blood.

[0016] Specifically, the dialysate composition is prepared in such a way as to facilitate exchange by diffusion and convection / osmose between the blood and the dialysate.

[0017] By “blood”, it is meant liquids that are present in a mammalian body. Preferably, the blood is human blood.

[0018] Preferably, the dialysate composition according to the invention comprises at least one mineral salt. Preferably, the mineral salt is selected from the group consisting of calcium, phosphorus, potassium, sodium, chloride, magnesium, iron, zinc, iodine, chromium, copper, fluoride, molybdenum, manganese, sulphur, selenium and mixtures thereof. More preferably, the mineral salt is selected from the group consisting of sodium, chloride, calcium, magnesium, potassium, sulphur and mixtures thereof. In a preferred embodiment, the mineral salt is selected among sodium, magnesium, potassium, calcium and mixtures thereof.

[0019] In a more preferred embodiment, the mineral salt is selected among sodium, potassium and mixtures thereof.

[0020] Typically, the amount of sodium in the dialysate composition is comprised between 120 and 150 mM. Typically, the amount of calcium in the dialysate composition is comprised between 1.2 and 1.9 mM. Typically, the amount of magnesium in the dialysate composition is comprised between 0.2 and 1.5 mM.

[0021] Typically, the amount of potassium in the dialysate composition is comprised between 0 and 5 mM, especially in the case of hemodialysis.

[0022] Typically, the amount of chloride in the dialysate composition is comprised between 90 and 110 mM, especially in the case of peritoneal dialysis.

[0023] Preferably, the dialysate composition according to the invention comprise at least one pH buffer. Preferably, the pH buffer is selected in the group consisting of acetate buffer, bicarbonate buffer, citrate buffer, lactate buffer and mixtures thereof.

[0024] More preferably, the pH buffer is selected in the group consisting of bicarbonate buffer, lactate buffer and mixtures thereof. All buffers containing phosphates such as PBS are not suitable, as phosphates will interact with nanoparticles, as well as buffers containing cationic elements such as Na, Ca which may strongly perturbate the blood element balance (sodium : 136-146 mmol / l) such as DMEM.

[0025] Typically, the amount of bicarbonate buffer in the dialysate composition is comprised between 0 and 45 mM.

[0026] Typically, the amount of lactate buffer in the dialysate composition is comprised between 0 and 40 mM, especially in the case of peritoneal dialysis.

[0027] Preferably, the pH of the dialysate composition is comprised between 4 and 8, preferably between 5 and 8 and more preferably between 5.5 and 7.5.

[0028] Preferably, the dialysate composition has an osmolarity or osmotic concentration comprised between 250 mOsm / L and 600 mOsm / L, more preferably between 250 mOsm / L and 350 mOsm / L. By “osmolarity”, it is meant a measure of the concentration of a solution, colloid or chemical compound, expressed as the number of "osmotically active" particles (osmoles) per litre.

[0029] By “osmotically active” it is meant particles that are responsible for other properties of solutions, such as osmotic pressure, freezing point depression and water vapor pressure.

[0030] These quantities are all linearly related to osmolality, making it possible to measure it.

[0031] The dialysate composition according to the invention may comprise at least one osmotic compound.

[0032] By “osmotic compound”, it is meant an osmotically active ion or molecule in the peritoneal cavity and thereby forcing intraluminal water retention to maintain isotonicity with plasma.

[0033] Preferably, the osmotic compound is selected from the group consisting of maltodextrin, sucrose, glucose, polyethylene glycol, mannitol, sorbitol, icodextrin, amino acids and mixtures thereof.

[0034] Preferably, the amino acid is selected in the group consisting of L-tyrosine, L- tryptophan, L-phenylalanine, L-threonine, L-serine, L-proline, glycine, L-alanine, L-valine, L-methionine, L-isoleucine, L-leucine, L-histidine, L-arginine, L-lysine (and its hydrochloride salt) and mixtures thereof.

[0035] Specifically, the dialysate composition that comprises at least one osmotic compound is mostly used for peritoneal dialysis.

[0036] Iron oxide nanoparticles

[0037] According to the invention, the composition comprises at least one iron oxide nanoparticle (Fe2+ / Fe3+) coated with at least one polymeric compound.

[0038] By ‘iron oxide nanoparticle”, it is meant a nanoparticle made up of an iron oxide derivative with one dimension being below 100 nm and possibly having different shapes.

[0039] By “iron oxide derivative”, it is meant a compound comprising at least iron and oxygen as constituting elements.

[0040] Iron oxides are a complex group of materials that have structure-dependent properties that are still not yet fully understood. Depending on how the nanoparticles are formed, their character may be one or more of the many different iron oxide species, including:

[0041] - Iron(ll) oxide, wustite (FeO),

[0042] - Iron(ll,lll) oxide, magnetite (Fe3 04),

[0043] - Iron(lll) oxides (Fe2 03) :

[0044] ■ alpha phase, hematite (a-Fe2 03), ■ beta phase, (P-Fe2 03),

[0045] ■ gamma phase, maghemite (y-Fe2 03), or

[0046] ■ epsilon phase, (e-Fe2 03).

[0047] - Iron hydroxides

[0048] ■ Iron(lll) oxide-hydroxide or ferric oxyhydroxide FeO(OH)

[0049] ■ Iron(ll) hydroxide or ferrous hydroxide : Fe(0H)2

[0050] ■ Iron(lll) hydroxide or ferric hydroxide : : Fe(0H)3

[0051] - Doped iron oxides : MxFe3-xO4 with M being a metallic element such as Al, Mn, Co, Zn, Y, In, Cr, or Nd.

[0052] Preferably, the iron oxide nanoparticles are made with magnetite or maghemite phase.

[0053] Typically, nanosized magnetite is usually oxidized on its surface, so the composition of iron oxide nanoparticles usually consists of a magnetite core covered by an oxide layer mainly composed of maghemite phase. Such nanoparticles can also be oxidized after synthesis so that they consist only of the maghemite phase.

[0054] The iron oxide nanoparticles according to the invention are coated with at least one polymeric compound.

[0055] The polymeric compound should ensure the colloidal stability of nanoparticles in dialysates, an anchoring on the surface of nanoparticles weaker than that of phosphates, a biocompatibility and non-cytotoxicity (in the hypothesis that they can be desorbed during dialysis), a mean hydrodynamic size in the range 20-300 nm, a zeta potential value ensuring no strong interaction with the peritoneal membrane (e.g. from about -50mV to 10mV).

[0056] It should be added with an optimized amount to keep free adsorption sites. Their composition may favor the adsorption of toxins.

[0057] Specifically, the surface of the nanoparticles is functionalized by at least one polymeric compound.

[0058] Without being bound by any theory, the inventors have discovered that functionalizing these nanoparticles with a polymer or polymer mixture improves their stability in dialysis solution.

[0059] Preferably, the iron oxide nanoparticles are coated with one polymeric compound or a mixture of polymeric compounds.

[0060] Specifically, the polymeric compound functionalizing the nanoparticles is chosen as a function of the amount of phosphate that needs to be extracted from the blood.

[0061] Preferably, the dialysate composition according to the invention comprises at least one iron oxide nanoparticle functionalized with a mixture of polymeric compounds.

[0062] Typically, the polymeric compound act as a surfactant. The polymer may be chosen from anionic, cationic, nonionic, amphoteric and zwitterionic polymers and mixtures thereof.

[0063] Preferably, the polymeric compound is chosen from the group consisting of: polymers bearing catechol groups such as gallic acid, anionic polyphenol, tannic acid, dopamine and polydopamine; polymers bearing carboxylate groups such as polyAcrylic acid, carboxymethyl dextran, hyaluronic acid, polyacrylates, polyethelylene glycol carboxylates; gluconic acid, glucuronic acid polysaccharides or polycarbohydrates or chitosan, preferably bearing functional groups to interact with iron oxide surface such as catechol, carboxylate, .. polyalcohol based polymers such as polyvinyl alcohol (PVA); cationic polymers such PolyEthylenelmine (PEI), PolyDiAllylDiMethylAmmonium Chloride (PDADMAC); chitosan biomolecules based such as peptide or proteins.

[0064] By “polysaccharide”, it is meant a long-chain polymeric carbohydrate composed of monosaccharide units bound together by glycosidic linkages such as dextran, cellulose, amidon, hyaluronic acid and / or glucose, chitosan.

[0065] Preferably, the polymers used for coating the nanoparticles are biocompatible and are not cytotoxic.

[0066] Preferably, the polymeric compound is chosen from anionic polymers and cationic polymers.

[0067] Preferably, the polymeric compound is chosen from tannic acid, polyacrylic acid, carboxymethyl dextran, hyaluronic acid and mixtures thereof.

[0068] According to another embodiment, the polymeric compound is a cationic polymer.

[0069] According to this embodiment, the polymeric compound is chosen from polyethyleneimine (PEI), polydiallyldimethylammonium chloride (PDADMAC), chitosan and mixtures thereof.

[0070] Preferably, the iron oxide nanoparticle is coated with a polymeric compound selected from the group consisting of tannic acid, polyacrylic acid, PDADMAC, PEI, chitosan, gluconic acid, glucuronic acid and mixtures thereof.

[0071] According to an embodiment, the iron oxide nanoparticle is prepared by the polyol or polyol solvothermal method as described in :

[0072] Low Oxidation State and Enhanced Magnetic Properties Induced by Raspberry Shaped Nanostructures of Iron Oxide, O. Gerber, B. P. Pichon, C. Ulhaq, J.-M. Greneche, C. Lefevre, I. Florea, O. Ersen, D. Begin, S. Lemonnier, E. Barraud, S. Begin-Colin, J. Phys. Chem. C 2015, 119 (43), 24665-24673 ; and - Synthesis Engineering of Iron Oxide Raspberry Shaped Nanostructures, O. Gerber, B. P. Pichon, D. Ihiawakrim, I. Florea, S. Moldovan, O. Ersen, D. Begin, J.-M. Greneche, S.Lemonnier, E. Barraud, S. Begin-Colin, Nanoscale, 2017, 9, 305-313.

[0073] Typically this synthesis protocol has been modified to perform the synthesis in the presence of polymer such as tannic acid and directly formed in situ polymer / tannic acid coated nanoparticles.

[0074] - Impact of Tannic Acid on Iron Oxide Nanosclusters Synthesized by a Polyol Solvothermal Method, J. Vaz-Ramos, T. Lucante, J.-M. Greneche, C. Leuvrey, V. Papaefthymiou, S. Zafeiratos, A. Carton, D. Begin, S. Le Calve, S. Begin-Colin, Colloids and Surfaces A: Physicochemical and Engineering Aspects, 2024, 689, 133658.

[0075] In brief, the polyol method involves suspending the metal precursor and polymeric compound, preferably iron chloride hexahydrate in a polyol solvent and subsequently heating the solution to a refluxing temperature (polyol method) or in an autoclave (solvothermal polyol method). This technique has been used to synthesize metallic, oxide, and semiconductor NPs.

[0076] This method is further described in the experimental section.

[0077] Mono-metallic and metallic alloy NPs have been synthesized with this technique.

[0078] According to a second embodiment, the iron oxide nanoparticles is prepared by coprecipitation followed or not by a hydrothermal treatment as described in:

[0079] - Daou, T. J.; Pourroy, G.; Begin-Colin, S.; Greneche, J. M.; Ulhaq-Bouillet, C.; Legare, P.; Bernhardt, P.; Leuvrey, C.; Rogez, G. Hydrothermal Synthesis of Monodisperse Magnetite Nanoparticles. Chemistry of Materials 2006, 18 (18), 4399-4404; and

[0080] - Magnetic Iron oxide nanoparticles in 10-40 nm range: composition in terms of magnetite / maghemite ratio, and effect on the magnetic properties, J. Santoyo Salazar, L. Perez, O. de Abril, L. Truonc Phuoc, D. Ihiawakrim, M. Vazquez, J-M. Greneche, S. Begin- Colin, G. Pourroy Chem. Mater. 2011, 23(6), 1379-1386.

[0081] In brief, the co-precipitation method is a liquid phase synthesis method that involves mixing two solutions to obtain an insoluble compound (mixed oxides) by precipitation reaction. The polymeric compound could be introduced during or after the coprecipitation step and by using other bases such as ammoniac or NaOH.

[0082] This method is further described in the experimental section.

[0083] Preferably, this synthesis protocol has been modified to perform the synthesis in the presence of tannic acid or PAA and directly formed in situ tannic acid or PAA coated nanoparticles.

[0084] Preferably, after this synthesis protocol, the nanoparticles are coated with gluconic acid or glucuronic acid by putting them in the presence of gluconic acid and glucuronic acid. According to a third embodiment, the iron oxide nanoparticle is prepared by the thermal decomposition method as described in:

[0085] - Size-Dependent Properties of Magnetic Iron Oxide Nanocrystals, A. Demortiere, P. Panissod, B. Pichon, G. Pourroy, D. Guillon, B. Donnio, S. Begin-Colin, Nanoscale, 3 (2011) 225-232

[0086] - Baaziz, W.; Pichon, B. P.; Fleutot, S.; Liu, Y.; Lefevre, C.; Greneche, J.-M.; Toumi, M.; Mhiri, T.; Begin-Colin, S. Magnetic Iron Oxide Nanoparticles: Reproducible Tuning of the Size and Nanosized-Dependent Composition, Defects, and Spin Canting. The Journal of Physical Chemistry C 2014, 118 (7), 3795-3810.

[0087] In brief, the thermal decomposition method is the thermal decomposition of a iron precursor in a high boiling point organic solvent in presence of surfactants. The polymeric compound could be introduced during (if it solubilizes in organic solvent) or after the thermal decomposition step but rather after.

[0088] This method is further described in the experimental section.

[0089] In a preferred embodiment, the iron oxide nanoparticle is coated with PAA, gluconic acid, glucuronic acid, or tannic acid.

[0090] Preferably, the coated iron oxide nanoparticle has a molar ratio polymer : iron (i.e. polymer: Fe) ranging from 0.001 to 0.5, preferably from 0.005 to 0.3 and more preferably from 0.005 to 0.15.

[0091] Preferably, when the polymer is PAA, the iron oxide nanoparticle has a mass ratio polymer PAA : iron ranging from 0.05 and 1.5, preferably from 0.1 and 0.5.

[0092] Note: mass ratio PAA : Fe actually calculated in our experiments = 1.04 (before synthesis) or 0.28 (effectively on surface after synthesis)

[0093] Preferably, when the polymer is TA, the iron oxide nanoparticle has a mass ratio polymer TA : iron ranging from 0.1 and 2.5, preferably from 0.2 and 2.0.

[0094] Note: mass ratio TA : Fe actually calculated in our experiments = 0.30 (before synthesis) or 1.91 (effectively on surface after synthesis).

[0095] Preferably, when the polymer is gluconic acid, the iron oxide nanoparticle has a mass ratio polymer gluconic acid : iron ranging from 0.1 and 1.5, preferably from 0.2 and 0.5. Note: mass ratio gluconic acid : Fe actually calculated in our experiments = 0.35 (before synthesis) or 1.09 (effectively on surface after synthesis).

[0096] Preferably, when the polymer is glucuronic acid, the iron oxide nanoparticle has a mass ratio polymer glucuronic acid : iron ranging from 0.1 and 2.0, preferably from 0.2 and 0.5.

[0097] Note: mass ratio glucuronic acid : Fe actually calculated in our experiments = 0.35 (before synthesis) or 1.38 (effectively on surface after synthesis). Preferably, when the polymer is PDADMAC, the iron oxide nanoparticle has a molar ratio polymer PDADMAC : iron ranging from 2.5 and 15, preferably from 10 and 15.

[0098] Preferably, when the polymer is PDADMAC, the iron oxide nanoparticle has a molar ratio polymer PDADMAC : iron ranging from 43 and 54 (functionalization), preferably from 0.8 and 1.2 (effectively on surface, via1H-NMR relaxometry and TGA measurements). Note: molar ratio PDADMAC : Fe actually calculated in our experiments = 1.06.

[0099] Preferably, when the polymer is PDADMAC, the iron oxide nanoparticle has a mass ratio polymer PDADMAC : iron ranging from 80 and 100 (functionalization), preferably from 2.5 and 3 (effectively on surface, via1H-NMR relaxometry and TGA measurements).

[0100] Note: mass ratio PDADMAC : Fe actually calculated in our experiments = 2.73.

[0101] Preferably, the iron nanoparticle has an average hydrodynamic diameter ranging from 10 nm and 300 nm, preferably from 20 nm and 200 nm, more preferably from 30 nm and 150 nm, and most preferably from 30 nm and 100 nm.

[0102] The hydrodynamic diameter in suspension is measured by dynamic light scattering (DLS) and the diameter of iron oxide nanoparticle (without coating) is measured by transmission electron microscopy (TEM), which are measurements well-known by the skilled person.

[0103] Note that the diameter that is measured in DLS is a value that refers to how a particle moves within a fluid so it is referred to as a hydrodynamic diameter. The diameter that is obtained by this technique is the diameter of a sphere that has the same translational diffusion / moving coefficient as the particle.

[0104] The particle translational diffusion coefficient will depend not only on the size of the particle "core", but also on any surface structure that will affect the diffusion / moving speed, as well as the concentration and type of ions in the medium. Factors that can affect the diffusion / moving speed discussed in the following sections.

[0105] The zeta potential measurement (performed on the same apparatus than for DLS measurements) allows evaluating the colloidal stability of suspensions of coated nanoparticles. Zeta potential (or electro kinetic potential) is a measure of the magnitude of the electrostatic repulsion / attraction between particles and is one of the fundamental parameters known to affect stability of dispersed systems. It is calculated from the electrophoretic mobility with solvent dielectric constant, viscosity and other constants using the Henry equation. Its measurement brings detailed insight into the causes of dispersion, aggregation or flocculation and can be applied to improve the formulation of dispersion, emulsions and suspensions.

[0106] Absolute zeta potential values higher than 30 mV are expected to have a good colloidal stability induced by electrostatic interactions. However, charged polymers may provide a good colloidal stability at lower absolute zeta potential values by introducing steric interactions and allowing thus combining both electrostatic and steric interactions.

[0107] Preferably, the coated iron oxide nanoparticle has a specific surface area from 5 m2 / g to 1000 m2 / g, preferably from 10 m2 / g to 500 m2 / g and more preferably from 50 m2 / g to 500 m2 / g.

[0108] By “specific surface area” it is meant the total surface area of the coated iron oxide nanoparticle available for chemical or physical processes to take place. As physical or chemical processes, one can particularly cite absorption or adsorption.

[0109] The specific surface area can be determined by nitrogen adsorption-desorption isotherms using the BET method with Tristar equipment from Micromeritics. Prior to analysis, the sample was degassed under vacuum at 150 °C.

[0110] Preferably, the dialysate composition according to the invention has a concentration of coated iron oxide nanoparticles from 0.2 g.L'1to 100 g.L'1, preferably from 0.2 g.L'1to 5 g.L'1, more preferably from 0.2 g.L-1to 3 g.L-1.

[0111] Preferably, the dialysate composition according to the invention has a concentration of coated iron oxide nanoparticles from 0.04 mmol.L'1to 4 mol.L'1, preferably from 0.04 mmol.L'1to 0.4 mol.L-1, and even more preferably from 0.04 mmol.L'1to 20 mmol.L'1.

[0112] Specifically, the concentration of coated iron oxide nanoparticles in the composition according to the invention can be adjusted according to the patient's needs.

[0113] Preferably, the dialysate composition according to the invention is a composition for hemodialysis.

[0114] Specifically, it is meant a composition meeting the requirements to be used for hemodialysis.

[0115] Hemodialysis is a process of purifying the blood of a person whose kidneys are not working normally. This type of dialysis achieves the extracorporeal removal of toxic products such as creatinine and urea and free water from the blood when the kidneys are in a state of kidney failure.

[0116] Precisely, hemodialysis utilizes counter current flow, where the dialysate is flowing in the opposite direction to blood flow in the extracorporeal circuit. Counter-current flow maintains the concentration gradient across the membrane at a maximum and increases the efficiency of the dialysis. Fluid removal is achieved by altering the hydrostatic pressure of the dialysate compartment, causing free water and some dissolved solutes to move across the membrane along a created pressure gradient.

[0117] Preferably, the dialysate composition according to the invention is for hemodialysis, and comprises:

[0118] (a) at least one pH buffer, (b) at least one mineral salt, and

[0119] (c) at least one iron oxide nanoparticle (Fe2+and / or Fe3+) coated with at least one polymeric compound.

[0120] According to another embodiment, the dialysate composition according to the invention is a composition for peritoneal dialysis.

[0121] Specifically, it is meant a composition meeting the requirements to be used for peritoneal dialysis.

[0122] Peritoneal dialysis is a way to remove toxic products from the blood. During peritoneal dialysis, a cleaning fluid flows through a tube into part of the abdominal area. The inner lining of the abdomen, known as the peritoneum, acts as a filter and removes toxic products from blood. After a set amount of time, the fluid with the filtered toxic flows out of the abdomen and is thrown away. By diffusion and convection (pressure gradients) mechanisms through the capillaries, toxins and water in excess pass into the dialysate. The dialysate is then drained outside the body before the subsequent provision of new dialysis fluid. The duration of the exchanges varies according to the needs of the patient and the chosen technique.

[0123] Peritoneal dialysis differs from a more-common procedure as it works inside the body to clean the blood.

[0124] However, peritoneal dialysis requires that iron oxide nanoparticles (lONPs) do not cross the peritoneal membrane. This membrane surrounds all the organs of the abdominal cavity, delimiting a peritoneal cavity.

[0125] The peritoneal membrane is composed by a layer of flattened cells and an underlying area of varying thickness (the interstitium) containing lymphatic vessels, blood capillaries, and nerves. The exchange between the blood and the peritoneal cavity needs to cross the endothelium of the capillaries, flattened cells (mesothelial cells), and the space between both. The mechanism of passage through the membrane may be described by the three- pores model.

[0126] This model of peritoneal transport is used extensively for modeling peritoneal fluid and solute transport. This model characterized the passage through the membrane through three various sized pores. i) Ultra-small pores with a radius of 2 to 4 A. These are the most numerous and correspond to aquaporins. They only allow the passage of water by osmosis, through the cells. ii) Small pores with a radius of 40 to 55 A, allowing water and solutes of low to medium molecular weight to pass through convection (osmotic and hydrostatic pressure gradient) and diffusion (concentration gradient) processes. iii) Large pores with radius of 250 to 300 A allowing the transport of large molecules by convection (hydrostatic pressure gradient) and diffusion processes.

[0127] Therefore, to avoid transfer of lONPs from dialysis solution to blood vessels, they need a large mean diameter.

[0128] Preferably, the composition according to the invention is for peritoneal dialysis, and comprises:

[0129] (a) at least one pH buffer,

[0130] (b) at least one mineral salt,

[0131] (c) at least one osmotic agent, preferably selected form the group consisting of glucose, icodextrin and mixtures thereof; and

[0132] (d) at least one iron oxide nanoparticle (Fe2+and / or Fe3+) coated with at least one polymeric compound.

[0133] The composition according to the invention may further comprise another type of nanoparticles containing iron oxide selected from the group consisting of inorganic nanoparticles, polymeric nanoparticles, polymeric capsules, organic-inorganic hybrid nanoparticles and organic-inorganic hybrid capsules.

[0134] Preferably, the dialysate composition may further comprise one or more active ingredient chosen from anti-cancer agents, analgesic agents, antibacterial agents, antibiotics, antiseptics, antivirals agents and hormones.

[0135] The present invention also relates to the use of the dialysate composition as described above as a medicament.

[0136] The composition according to the invention may be used as a dialysate for biological fluid and / or blood purification.

[0137] By “blood purification”, it is meant removing toxic products from the blood such as toxins and phosphate that are normally regularly eliminated by healthy kidneys.

[0138] After blood purification, the range of said toxic product(s) is(are) typically reduced to a level at which it (they) is(are) no longer toxic to the human body.

[0139] Preferably, the range of phosphate in blood is comprised between 0.85 mg / L and 1.5 mg / L.

[0140] Preferably, the range of phosphate in children’s blood is less than 2.5 mg / L.

[0141] Preferably, the range of phosphate removed by the dialysate composition after hemodialysis or peritoneal dialysis is more than 50%, preferably 60% and even more preferably 70% of the initial phosphate range in the human body.

[0142] Typically, hemodialysis session lasts from 3 to 5 hours, during which the patient is connected to the device and cannot move. At least, 3 sessions per week are necessary to allow an effective purification. PD session is usually performed over night when using a cycler (automated peritoneal dialysis). In case of continuous ambulatory peritoneal dialysis, the patient does not need to be branched to a machine, he can process to the infusion and then disconnects the system and therefore has movement liberty, the possibility of being autonomous in the treatment. PD has numerous advantages: fewer hospitalizations are needed, no anti-coagulants are necessary and therefore, the patients have less side effects and there is the possibility to perform the treatment during the night / sleep with a cycler. It allows for less diet and fluid restriction for the patient and a better vascular preservation compared to HD. Finally, this method is the sole dialysis process especially for infants weighing less than 6-8 kg and new -born babies where intermittent chronic HD is difficult to perform due to their too low blood volume.

[0143] By “toxic products” it is meant products from the blood which need to be removed. By biological fluids or toxic blood products, it is generally mentioned phosphate or uremic toxins.

[0144] In parallel, the accumulation of toxins has also negative effects on physiological functions, resulting in a gradual endogenous intoxication and in a progressive deterioration of the clinical conditions of the patients.

[0145] Uremic toxins are classified in three groups associated with their molecular weight and chemical features:

[0146] - free water-soluble compounds (WS) with a molecular weight less than 500 Dalton, such as creatinine and urea;

[0147] -middle molecular weight compounds (MM) with a molecular weight comprised between 500 to 60 000 Da. These compounds are typically peptides and proteins; such as p2- microglobulin; and

[0148] -protein-bound uremic toxins (PBUTs), which are relatively low molecular weight molecules that bind strongly to proteins in the blood, such as albumin. The main molecules in this group, which have a higher than 90% protein bound percentage, are indoxyl sulfate (IS) and p-cresyl sulfate (PCS).

[0149] It is also described a method of treatment to purify a patient's blood or a biological fluid, preferably to remove phosphate and at least one toxin, comprising the following steps:

[0150] - providing a composition as described above; and

[0151] - administering the composition according to the invention to the patient via a device designed for haemodialysis.

[0152] It is also described a method of treatment to purify a patient's blood, preferably to remove phosphate, comprising the following steps:

[0153] - providing a composition as described above; and - administering the composition according to the invention to the patient via a device designed for peritoneal dialysis.

[0154] By “patient” it is meant a mammal with kidney function problems, preferably a human having chronic kidney disease.

[0155] The present invention is now illustrated by the following figures and examples.

[0156] Figure 1 : Phosphate isotherm adsorption experiment on the surface of (a) raspberryshaped nanostructures obtained by polyol solvothermal method coated with the anionic polyphenol tannic acid, (b) iron oxide nanoparticles obtained by coprecipitation method coated with the cationic polymer PDADMAC, (c) iron oxide nanoparticles obtained by coprecipitation method coated with the anionic polymer PAA and (d) iron oxide nanoparticles obtained by coprecipitation method coated with tannic acid and (e) iron oxide nanoparticles obtained by coprecipitation method coated with the anionic polymer PAA.

[0157] Figure 2: Phosphate kinetic adsorption experiment on the surface of Raspberry-Shaped Nanostructures obtained by polyol solvothermal method without or with coating of tannic acid (a) at pH 3, (b) at pH 7 and (c) at pH 7 quantified by VetTest and molylbdenum blue methods.

[0158] Figure 3: Isotherm adsorption experiments of uremic toxins - (a) creatinine, (b) urea, (c) indoxyl sulfate and (d) p-cresol - and beneficial compounds - (e) glucose and (f) calcium - on the surface of Raspberry-Shaped Nanostructures obtained by polyol solvothermal method, without or with coating of tannic acid.

[0159] Figure 4: Diffusion rate over time of methylthioninium chloride (MB), fluorophore-labeled glucose (marked glucose) and fluorescein isothiocyanate labelled bovine serum albumin (BSA-FITC) in cassette mode experiments through a 20 kDa membrane made of regenerated cellulose.

[0160] Figure 5: Phosphate removal over time at room temperature for different dialysis and dialysate compositions in (a) tubing mode experiment and (b) cassette mode experiment.

[0161] Figure 6: Phosphate removal rate over time in cassette mode experiment with different parameters mimicking physiological conditions.

[0162] Figure 7: (a) Phosphate removal rate over time in tubing mode experiment in the presence of iron oxide nanostructures coated with different surfactant in the dialysate compartment and (b) additional quantity of phosphate diffused per mass unit of material at 4h in comparison with reference experiment.

[0163] Figure 8: Phosphate removal rate over time in cassette mode experiment in the presence of iron oxide nanostructures coated with different surfactant in the dialysate compartment. Figure 9: Phosphate removal rate over time in cassette mode experiment for different dialysate solution composition, performed at room temperature, in the presence of Iron Oxide Nanoparticles obtained by coprecipitation method, coated with tannic acid in the dialysate compartment.

[0164] Figure 10: Batch mode: Phosphate kinetic adsorption experiment at a concentration of 1 g.L'1as a function of time, in ultrapure water or in PD solution at pH 7 - 7.5 at room temperature with a phosphate concentration of 50 P-mg.L'1except in (e) 150 P-mg.L'1on the surface of (a) raspberry-shaped nanostructures obtained by polyol solvothermal method coated with the anionic polyphenol tannic acid (RSN@TA), (b) iron oxide nanoparticles obtained by coprecipitation method coated with the cationic polymer PDADMAC (IO- CP@PDADMAC), (c) iron oxide nanoparticles obtained by coprecipitation method coated with the anionic polymer PAA (IO-CP@PAA), (d) iron oxide nanoparticles obtained by coprecipitation method coated with tannic acid (IO-CP@TA) and (e) iron oxide nanoparticles obtained by thermal decomposition method coated with the anionic polyphenol tannic acid.

[0165] Figure 11 : Batch mode: Phosphate isotherm adsorption experiments at a concentration of 1 g.L-1as a function of phosphate concentration at equilibrium in ultrapure water or in PD solution at pH 7 - 7.5 for 4 h at room temperature on the surface of (a) raspberry-shaped nanostructures obtained by polyol solvothermal method coated with the anionic polyphenol tannic acid, (b) IO-CP@PDADMAC, (c) IO-CP@PAA and (d) IO-CP@TA and (e) iron oxide nanoparticles obtained by thermal decomposition method coated with the anionic polyphenol tannic acid.

[0166] Figure 12: Batch mode: Adsorption of uremic toxins and beneficial compounds on RSNs@TA at a concentration of 1 g.L'1in ultrapure water for a duration of 4 h: (a) creatinine, indoxyl sulfate, p-cresol and calcium and (b) glucose and urea. Experiments were grouped by close values of equilibrium concentration of compounds.

[0167] Figure 13: Tubing mode: D / P ratio as a function of time, the blood solution containing phosphates in ultrapure water at concentration 50 P-mg.L'1and the dialysate solution containing ultrapure water or PD solution, without or with (a) RSNs@TA, (c) IO-CP@PAA, (e) IO-CP@TA and (g) IO-CP+PDADMAC at concentration 1 g.L'1and additional amount of phosphate transported out of the blood solution as a function of time due to (b) RSNs@TA, (d) IO-CP@PAA, (f) IO-CP@TA and (h) IO-CP+PDADMAC in the dialysate solution.

[0168] Figure 14: Tubing mode: D / P ratio as a function of time for tubing-mode experiments with blood = 50 P-mg.L'1phosphate solution in pH 7 - 7.5 ultrapure water versus dialysate = 1 g.L'1suspensions of nanoparticles in pH 7 - 7.5 (a) ultrapure water or (c) PD solution and additional amount of phosphate transported out of the blood solution as a function of time due to nanoparticles in (b) water or (d) PD solution.

[0169] Figure 15: Tubing mode with a higher scale and closer to the DP process conditions (scale 1 / 6). Phosphate transport over time with ultrapure water, the blood solution containing phosphates at concentration 50 P-rng.L'1and the dialysate solution containing ultrapure water or PD solution, without or with 1 g.L'1IO-CP@PAA.-

[0170] Figure 16: (a) Scheme of cassette mode and (b) reduction ratio as a function of time of methylthioninium chloride (methylene blue), fluorophore-labelled glucose (marked glucose) and fluorescein isothiocyanate-labelled bovine serum albumin (BSA-FITC) in cassettemode experiments through a 20 kDa regenerated cellulose membrane.

[0171] EXAMPLES

[0172] Example 1 : Preparation of iron oxide nanoparticles coated with a polymeric compound or not

[0173] 1.1. Polyol solvothermal synthesis conditions of nanoparticles without and with surfactants

[0174] The iron oxide raspberry-shaped nanoclusters (RSN) without and with surfactant, RSNs and RSN@TA, were synthesized using a polyol solvothermal method, respectively according to a previously established protocol (Gerber et al Nanoscale 2017) and by a modified version of this protocol (Vaz Ramos et al Colloids and Surfaces A 2024). Briefly, iron(lll) chloride hexahydrate (1.63 g, 6 mmol), succinic acid (0.24 g, 2 mmol) and urea (3.6 g, 60 mmol) were added to ethylene glycol (60 mL, 1.1 mol) and placed under strong magnetic stirring. After dissolution of previous reagents (~5 min stirring), tannic acid (0.1 g, 0.06 mmoL) was optionally added to the reaction medium in order to obtain RSNs@TA. In both protocols, stirring was continued for 2 h. The reaction mixture was then placed in an ultrasonic bath for 3 cycles of 20 minutes sonication, cooling down the bath water with ice between each cycle. For solvothermal treatment, the reaction mixture was sealed in a stainless-steel autoclave lined with an inner Teflon reactor (75 mL capacity) and placed inside a programmable oven. The reaction mixture was heated from room temperature to 200°C at 1.5 °C. min-1, then maintained at 200°C for 10.5 h before being left to cool outside the oven for 3 h. The obtained nanostructures were magnetically separated from the supernatant and washed with a mixture of 50 % ethanol I 50 % acetone nine times interspersed with 4 min sonication in an ultrasound bath. The washed nanostructures were stored in ethanol until further characterization or use. [1] Gerber, O.; Pichon, B. P.; Ihiawakrim, D.; Florea, I.; Moldovan, S.; Ersen, O.; Begin, D.; Greneche, J.-M. Lemonnier, S.; Barraud, E.; Begin-Colin, S. Synthesis Engineering of Iron Oxide Raspberry-Shaped Nanostructures. Nanoscale 2017, 9 (1), 305-313

[0175] [2] Impact of Tannic Acid on Iron Oxide Nanosclusters Synthesized by a Polyol Solvothermal Method, J. Vaz-Ramos, T. Lucante, J.-M. Greneche, C. Leuvrey, V. Papaefthymiou, S. Zafeiratos, A. Carton, D. Begin, S. Le Calve, S. Begin-Colin, Colloids and Surfaces A: Physicochemical and Engineering Aspects, 2024, 689, 133658.

[0176] 1.2. Synthesis of functionalized iron oxide nanoflowers (or Flower-shaped nanostructures - FSN) by a polyol synthesis at atmospheric pressure

[0177] Synthesis of naked iron oxide nanoflowers. Naked iron oxide nanoflowers were synthesized based on the protocol of Bertuit etal.'* Iron(lll) chloride hexahydrate (0.648 g) was dissolved in a mixture of diethylene glycol (16 mL) and N-methyldiethanolamine (16 mL) under magnetic stirring for 15 h. Separately, sodium hydroxide (0.256 g) was dissolved in a mixture of diethylene glycol (8 mL) and N-methyldiethanolamine (8 mL) under magnetic stirring for 24 h. The two previous solutions were then mixed into a two-neck round-bottom flask (100 mL capacity) under magnetic stirring for 1 h. Stirring was then stopped, followed by the addition of water to the mixture (0.2 mL). The mixture was then heated under reflux to 220°C with a temperature ramp of 2°C.min-1and maintained at this temperature for 2 h before being left to cool down to room temperature. The suspension was then recovered in ethanol (50 mL) and washed six times by magnetic separation in 50:50 mixtures of ethanol and acetone, interspersed with 4 min in an ultrasound bath. The resulting suspension was stored at 4°C in ethanol until further characterization or use.

[0178] Post-synthesis functionalization of naked iron oxide nanoflowers. Naked iron oxide nanoflowers were functionalized with various surfactants (namely gluconic acid; glucuronic acid; tannic acid and polyacrylic acid) following the same procedure. Suspensions of 2 g.L-1nanoflowers in 10 mL of water at pH 10 were first prepared. Their pH was then adjusted to 2 with a fast injection of a hydrochloric acid solution (2 mol.L-1) to promote protonation of the iron oxide surface hydroxyl groups. This was followed by a 15 min disaggregation step in an ultrasonic bath, then mechanical agitation for 1 h. The pH of the suspension was then carefully adjusted to 5 with a sodium hydroxide solution (0.2 mol.L-1), followed by a 15-min disaggregation step and mechanical agitation for 1 h. In parallel, 10 mL aqueous solutions containing 2, 20 or 200 times the amount of surfactant required to coat the nanoflower surface were prepared and their pH carefully adjusted to 5 (required quantities were calculated on the basis of the specific surface area of nanoflowers obtained by BET measurement and the area of a surfactant molecule). Nanoflower suspensions and surfactant solutions at different concentrations were then mixed and mechanically stirred for 15 h. The functionalized nanoparticle suspensions selected were those exhibiting the highest colloidal stability for the minimum surfactant introduced. The selected suspensions were stored at 4°C until further characterization or use.

[0179] [1] Enzo Bertuit; Emilia Benassai; Guillaume Meriguet; Greneche, J.-M.; Baptiste, B.; Neveu, S.; Wilhelm, C.; Hassan, A. A. Structure-Property-Function Relationships of Iron Oxide Multicore Nanoflowers in Magnetic Hyperthermia and Photothermia. ACS Nano 2021. https: / / doi.org / 10.1021 / acsnano.1c06212.

[0180] 1.3. Preparation of iron oxide nanoparticles coated with tannic acid, polyacrylic acid, gluconic acid or glucuronic acid by coprecipitation and with introduction of the polymeric compound during the synthesis

[0181] One-pot synthesis of non-coated iron oxide nanoparticles (IO-CP), coated with polyacrylic acid (IO-CP@PAA), with tannic acid (IO-CP@TA), with gluconic acid (IO- CP@GIA) or with glucuronic acid (IO-CP@GlcA)

[0182] IO-CP were synthesized using the coprecipitation method according to a previously established protocol1while IO-CP@TA, IO-CP@PAA, IO-CP@GIA and IO-CP@GlcA were synthesized using modified versions of this protocol. Briefly, iron(ll) chloride tetrahydrate (1.0 g, 5.0 mmol) and iron(lll) chloride hexahydrate (2.7 g, 10 mmol) were mixed in 12.5 mL of a 2 mol.L-1hydrochloric acid solution under magnetic stirring for 10 min. For IO-CP@TA synthesis, only iron(lll) chloride hexahydrate (4.1 g, 15 mmol) and tannic acid (0.256 g, 0.150 mmol) were mixed in 12.5 mL of a 2 mol.L-1hydrochloric acid solution under magnetic stirring for 1 h. For IO-CP@GIA and IO-CP@GlcA, gluconic acid (0.295 g) or glucuronic acid (0.292 g) were added to the initial mixture containing iron(ll) chloride tetrahydrate and iron(lll) chloride hexahydrate in hydrochloric acid. The mixture was then transferred to a 100 mL three-neck round-bottom flask and deoxidized with nitrogen for 15 minutes. For IO- CP@PAA synthesis, polyacrylic acid (0.874 g, 8.56 mmol) was added directly to the three- neck round-bottom flask, after the mixture had been deoxidized with nitrogen for 1 h. Under a nitrogen atmosphere and mechanical stirring using a Teflon paddle rotating at 250 rpm with a motor, the mixture was heated to 70°C before the introduction of 26 mL of a 25 wt. % tetramethylammonium hydroxide solution at a flow rate of 0.7 mL.min-1with a pump (Optos Pump 3HI, Eldex). The resulting suspension was left to cool in the flask at room temperature for 30 min. For IO-CP, the suspension was recovered and diluted in 120 mL of distilled water, then washed by centrifugation in 4 x 10 min cycles at 10,000 rpm before being recovered in 50 mL of distilled water. The IO-CP suspension was finally stored at basic pH (> 10) at 4°C until further characterization or use. For IO-CP@TA and IO- CP@PAA, suspensions were recovered and diluted in 400 mL of distilled water. After storage and natural sedimentation for 7 days, the supernatant was collected and pH adjusted to 7 with a 2 mol.L-1hydrochloric acid solution. The resulting suspension was then concentrated in 20 mL and washed 3 times by ultrafiltration in a stirred cell (Amicon Stirred Cell 50 mL, Merck Millipore) equipped with an ultrafiltration membrane (Ultrafiltration discs, PLTK, Ultracel regenerated cellulose, PMNL 30 kD, 44.5 mm, Merck Millipore) with distilled water before being placed in an ultrasonic bath for 15 min to promote de-aggregation of the nanoparticles. The washed suspensions were then placed at 4°C until further characterization or use.

[0183] 1.4. Two-step synthesis of iron oxide nanoparticles coated with poly(diallyldimethylammonium chloride) (IO-CP+PDADMAC), gluconic acid and glucuronic acid : Preparation of iron oxide nanoparticles by coprecipitation and then coating with PDADMAC, gluconic acid and glucuronic acid

[0184] IO-CP+PDADMAC were obtained by functionalizing already synthesized IO-CP obtained with the protocol described above1. Aqueous solutions of PDADMAC at concentration 60 g.L-1, pH 7 and IO-CP suspensions at concentration 15 g.L-1, pH 10 were prepared separately. Then, 25 mL suspensions of IO-CP in PDADMAC solutions were obtained in several centrifuge tubes by combining the above preparations to achieve a mass ratio of PDADMAC: Fe3O4 = 100. The centrifuge tubes were then placed on a roller mixer for 15 h before the suspensions were recovered and washed by centrifugation in 4 x 10 min cycles at 10,000 rpm. The washed suspensions were finally recovered in 20 mL distilled water, placed in an ultrasound bath for 15 min to promote de-aggregation of the nanoparticles and placed at 4°C until further characterization or use.

[0185] IO-CP+GIA and IO-CP@GlcA were obtained by post-synthesis functionalization of naked IO-CP following the same procedure. Suspensions of 2 g.L-1IO-CP in 10 mL of water at pH 10 were first prepared. Their pH was then adjusted to 2 with a fast injection of a hydrochloric acid solution (2 mol.L-1) to promote protonation of the iron oxide surface hydroxyl groups. This was followed by a 15 min disaggregation step in an ultrasonic bath, then mechanical agitation for 1 h. The pH of the suspension was then carefully adjusted to 5 with a sodium hydroxide solution (0.2 mol.L-1), followed by a 15-min disaggregation step and mechanical agitation for 1 h. In parallel, 10 mL aqueous solutions containing 2, 20 or 200 times the amount of surfactant required to coat the IO-CP surface were prepared and their pH carefully adjusted to 5 (required quantities were calculated on the basis of the specific surface area of IO-CP obtained by BET measurement and the area of a surfactant molecule). Surface specific area of IO-CP was 101 m2.g-1. One time the quantity required was 15.2 mg for gluconic acid and 13.5 mg for glucuronic acid. IO-CP suspensions and surfactant solutions at different concentrations were then mixed and mechanically stirred for 15 h. The functionalized nanoparticle suspensions selected were those exhibiting the highest colloidal stability for the minimum surfactant introduced. The selected suspensions were stored at 4°C until further characterization or use.

[0186] [1] Daou, T. J.; Pourroy, G.; Begin-Colin, S.; Greneche, J. M.; Ulhaq-Bouillet, C.; Legare, P.; Bernhardt, P.; Leuvrey, C.; Rogez, G. Hydrothermal Synthesis of Monodisperse Magnetite Nanoparticles. Chemistry of Materials 2006, 18 (18), 4399-4404.

[0187] 1.5. Preparation of iron oxide nanoparticles coated with tannic acid by thermal decomposition and with introduction of the polymeric compound after the synthesis

[0188] The 10 nm sized iron oxide nanoparticles are prepared by a thermal decomposition method, following a previously established method1. In a standard synthesis 1.83 g of iron(lll) stearate and 1.24 g of oleic acid are added to 20 mL of dioctyl ether in a balloon flask and placed on a heater connected to a computer controlling the temperature rise using a system of thermocouples. The reaction mixture is placed under magnetic stirring while being heated at 100°C for 1 h. After retrieving the magnetic stirrer and connecting a cooler, the reaction mixture is heated from 100°C to 292°C at 5°C / min then held at 292°C for 2 h. The reaction mixture is then let to cool to room temperature. The synthesized materials are separated magnetically and washed 3 times in 400 mL of warm acetone stirred with a stirring blade connected to a motor. After washing, the synthesized material (IO-TD) is stored in tetra hydrofuran until further characterization or use, or chloroform for immediate use.

[0189] For the synthesis of 5 nm sized nanoparticles, the solvent was hexadecene and the iron precursor was iron II stearate.

[0190] During a coating process with the surfactant tannic acid (IO-TD+TA), suspensions of 47 mL of iron oxide nanoparticles at concentration 0.1 or 0.2 mg(Fe3O4) / mL are prepared in tetra hydrofuran and placed in an ultrasound bath for ensuring deagglomeration of nanoaggregates. A solution of 3 mL of tannic acid in dimethylformamide at concentration 0.0025 mmol is then added to the nanoparticles suspension followed by 0.25 mmol of a solution of 2-(2-aminoethoxy)ethanol. The mixture is placed under magnetic stirring in an oil bath and the temperature adjusted to 50°C for 18 h. After the functionalization step, the suspension is precipited in diethyl ether and centrifuged. The precipitate is then washed and centrifuged with tetra hydrofuran to remove free molecules of octyl ether. The material (IO-TD+TA) is then suspended in distilled water until further characterization or use. 1.6. Elaboration of capsules containing iron oxide nanoparticles

[0191] Layer by layer (LbL) methodology for the formation of polymer capsules (hollow polymer capsules with lONPs in the inside).

[0192] This approach involves the sequential adsorption of alternating layers of oppositely charged polymers (polycations and polyanions) on the surface of nanoparticles. The adsorption is driven by electrostatic interactions between the layers of polymers. Parameters like the thickness, the composition and the properties of the surface can be modulated based on the choice of the polymers and on the amount of layers deposited. The process can be repeated as many as desired. During the steps, the zeta potential will change constantly between negative and positive values. The growth is followed by DLS measurements because the hydrodynamic diameter will increase with the number of layers. Polyanion: Tannic Acid crosslinked (TA*)

[0193] Polycation: poly-(diallyl dimethylammonium chloride) (PDAD)

[0194] Nanoparticles: Iron Oxide Nanoparticles with a shell of mesoporous silica IONPs@mSiC>2 (NP)

[0195] 100mg of IONPs@mSiO2were first mixed with 25 mL of 10mg / mL PDAD solution and sonicated for 10’. The mixture was then stirred for 80’ at room temperature (RT) with three subsequent washes using water. Next, 25 mL of 2 mg / mL of TA solution were added to NP@PDAD and sonicated for 10’. The resulting suspension was again stirred for 80’ minutes at RT, followed by three washes with water. For the cross-linking (*) of TA, 5 mL of NP@PDAD@TA suspension were mixed with 10 mL of Phosphate buffer (pH 7) and 10 pL of 40 wt% FeCl3.6H2O. The mixture was left for complexation for 6 hours, followed by three washes with water. Subsequently, the same protocol was repeated to add in total, 4 layers of polymers on the top of the NP.

[0196] Example 2: Characterization of all polymer-coated and uncoated iron oxide nanoparticles

[0197] 2.1. Materials and methods

[0198] Fourier Transform Infrared Spectroscopy (FTIR) was used to identify the chemical groups present in nanoparticles. The IR spectra were recorded in a Perkin Elmer Spectrum 100 spectrometer for wavenumbers between 4000 and 400 cm-1. For the preparation of the samples, a few drops of the suspension of composites in ethanol were mixed with dry KBr and after the evaporation of the solvent, pellets were prepared and FTIR transmittance spectra were obtained. X-Ray Diffraction (XRD) was used to identify the crystalline phases present. The X- Ray Diffractometer was a Bruker D8 Discover, equipped with a Lynx-Eye detector in the 20-70° (20) range with a scan step of 0.03° and the sample rotates at 30 rpm during the measure. Silicon powder was used as internal standard. The diffraction peaks were compared to JCPDS database. Profile matching with the software Fullprof was used to obtain estimates of the crystallite size and lattice parameter.

[0199] Scanning Electronic Microscopy (SEM) was used to obtained images of the synthesized nanoclusters, using a Zeiss Gemini SEM 500 electronic microscope operating at 3.00 kV. The materials were deposited in silicon wafers and posteriorly observed by SEM.

[0200] Transmission Electronic Microscopy (TEM) was performed to obtain images of the synthesized materials. For this, a high-resolution transmission electron microscope Topcon 002B operating at 200 kV was used. The samples were deposited on carbon-coated copper grids. After the image acquisition, the software Image J was used to obtain the size distribution of the iron oxide nanostructures.

[0201] Thermal Gravimetric Analysis (TGA) was performed on a SDT 600 from TA Instruments to measure the loss mass of the sample when the temperature changed and quantify the amount of tannic acid present in the nanoclusters. The measurements were performed under air flow, from room temperature until 900°C with a heating rate of 5°C / min. The materials were previously dried, before analysis.

[0202] Dynamic Light Scattering. Dynamic Light Scattering measurements were performed on a Zetasizer Nano ZS from Malvern Panalytical to assess the colloidal stability of the nanoparticles suspensions in water or in dialysates and to determine their mean hydrodynamic diameter (Dh). The electrophoretic mobility was also recorded using the same equipment in order to obtain the zeta potential value at the pH of the solution and to determine the isoelectric point of the nanoparticles. The zeta potential measurements were performed 3 times at 25°C. The nanoparticles were suspended in ultrapure water or PD solution to reach similar concentration, and sonicated for 10 minutes before being left to cool to room temperature, prior to analysis. The pH was adjusted with HCI and NaOH 0.1 M solutions.

[0203] X-ray photoelectron spectroscopy (XPS) was used to analyse the surface chemical state of tannic acid and nanostructures. Experiments were conducted in a VSW-Scientific spectrometer equipped with a twin anode source. XPS spectra were obtained using Al Ka radiation and pass energies of 90 and 22 eV for survey and high-resolution spectra, respectively. All XPS spectra were referenced to the C 1s peak, at 285 eV. Spectra analysis was done with the Casa-XPS software, with the application of Shirley background subtraction and a combination of Gaussian-Lorentzian symmetric and asymmetric line shapes for the peak fitting.

[0204] 2.2. Characterization of nanomaterials The characteristics of the different nanoclusters deduced from, DLS, IR SEM and

[0205] TEM images are also summarized in Table 3.

[0206]

[0207] Table 3. Summary of the microstructural characteristics of samples Example 3: Adsorption studies of phosphate on nanomaterials

[0208] 3.1. Quantification of phosphates using VetTest method

[0209] This method relies on the diverted use of a IDEXX VetTest 8008 blood biochemistry analyzer device which was initially designed for the simultaneous quantification of multiple compounds in plasma samples taken from animals. This equipment allows the quantification of compounds in a sample deposited on multilayered proprietary wafers using the reflectometry phenomenon, the inner system being composed of 3 reflectometers working on 6 wavelengths using LEDs for its visible light wavelength and mercury vapor bulbs for UV wavelength.

[0210] A measurement procedure with the VetTest consists of the equipment-assisted sampling and dispensing of a fixed volume of sample on one or multiple wafers previously loaded in the device. The concentration of the compound is then displayed directly on an integrated screen and corrected using a calibration curve previously constructed with standards.

[0211] 3.2. Adsorption experiments in batch-mode

[0212] Batch adsorption isotherm experiments were performed to evaluate the adsorption capacity of materials with phosphates, uremic toxins and beneficial compounds at concentration ranges observable in the blood of a patient with CKD.

[0213] Experiments were carried out by preparing suspensions of nanomaterials (nanoparticles coated with polymer) at a fixed concentration (1000 rng.L'1) in contact with adsorbate solutions of varying concentration. All the experiments were performed at room temperature. The contact duration between material and adsorbates was fixed at the one of a session of a standard PD process (4 h). Supernatant were then recovered and filtered to ensure the absence of material and free / unabsorbed adsorbates (phosphate, toxins...) were quantified to deduce their quantity adsorbed on the surface of the nanomaterials.

[0214] Nanomaterials adsorption capacity and adsorbate removal efficiency were calculated using the following formula: with QE the adsorption capacity at equilibrium, i.e. the mass of adsorbate captured per mass unit of adsorbent, Co the initial adsorbate concentration, CE the adsorbate concentration at equilibrium in the supernatant, V the suspension volume and mads the mass of adsorbent. For each sample, a blank solution of identical adsorbate concentration was prepared, containing no materials. Blanks concentrations were taken as the reference value Co in the calculations.

[0215] 3.3. Phosphate adsorption kinetics experiments

[0216] Phosphate adsorption kinetics experiments were performed by mixing nanostructure suspensions at fixed concentration 1 g(Fe3C>4).L'1with phosphate solutions at fixed concentration 50 P-mg.L'1for various durations. All experiments were performed at room temperature.

[0217] In a standard experiment, 10 mL nanostructure suspensions at concentration 2 g(Fe3C>4).L'1in ultrapure water or in PD solution at pH 7 - 7.5 were prepared in clear glass flasks 96.5 mL capacity by dilution of a stock nanostructure suspension in ultrapure water. For dilution in PD solution, suspensions containing 20 mg of nanostructures in ultrapure water were prepared then magnetically separated before the addition of 10 mL of PD solution.

[0218] Separately, a stock solution of phosphates was prepared by dilution of a commercial solution of orthophosphoric acid in ultrapure water and its pH was adjusted to 7 - 7.5 with NaOH solutions of various concentrations. Homogeneity was ensured by placing the stock solution under magnetic stirring for 1 h. A working phosphate solution at concentration 100 P-mg.L'1was prepared by diluting the phosphate stock solution with ultrapure water or with PD solution and placed under magnetic stirring. For the preparation of phosphate in PD solution, the change in concentration of solutes in the PD solution was minimized by diluting between 0.1 - 0.2 mL of phosphate solution in ultrapure water of suitable concentration in 10 mL of PD solution.

[0219] Nanostructures suspensions were placed in an ultrasonic bath for 10 min to promote their dispersion, then left to cool to room temperature before their mixing with 10 mL of phosphate solutions to obtain suspensions at concentrations 1 g.L'1nanostructures and 50 P-mg.L-1phosphates at pH 7 - 7.5.

[0220] Suspensions were mechanically stirred for 4 h on a roller mixer before recovery of supernatants by magnetic separation and filtration using a 0.20 pm porosity filter (CHROMAFIL© PA Xtra syr. Adaptator filters, 25 mm diameter, Carl Roth). Filtered supernatants were homogenized few seconds on a vortex and free phosphates were immediately quantified by VetTest method.

[0221] Adsorption capacity of the nanostructures was then calculated using the following formula: with qtthe adsorption capacity at time t in P-mg.g(Fe3C>4)'1, Cothe initial phosphate concentration (P-mg.L'1), Ctthe phosphate concentration at time t in the supernatant (P- mg.L'1), V the suspension volume (L) and mNSthe mass of nanostructures (g).

[0222] 3.4. Phosphate adsorption isotherm experiments

[0223] Adsorption isotherm experiments were carried out by mixing nanoparticles suspensions at fixed concentration 1 g(Fe3C>4).L'1with phosphate solutions of varying concentrations between 10 - 300 P-mg.L'1for 4 h in ultrapure water or in PD solution at pH 7 - 7.5. All experiments were performed at room temperature.

[0224] To this aim, 10 mL suspensions of materials with a mass concentration 2000 mg(Fe3C>4).L'1in ultrapure water or commercial dialysate (BICAVERA 1.5% GLUCOSE, 1.75 mmol / L calcium, solution for peritoneal dialysis) were prepared in clear glass flasks 96.5 mL capacity by dilution of a stock material suspension in ultrapure water whose concentration was previously determined by relaxometry measurement. pH of the suspensions was adjusted if necessary to 7-7.5 with HCI solutions of varying concentrations (0.02, 0.2 and / or 2 mol. L'1).

[0225] Separately, a stock solution of phosphates was prepared by dilution of a commercial solution of orthophosphoric acid (H3PO4, 85+%, Analytical Reagent, for analysis, Fisher Chemical) in ultrapure water and its pH was adjusted to 7-7.5 with NaOH solutions of varying concentration (0.02, 0.2 and / or 2 mol.L'1). The stock solution was then placed under magnetic stirring for 1 h to ensure homogeneity. Working solutions at concentrations of 20; 100; 200; 300 and 600 P-mg.L'1(milligrams of phosphorus per liter of solution) were prepared by diluting the stock solution with ultrapure water and placed as well under magnetic stirring.

[0226] Nanomaterial suspensions were placed in an ultrasonic bath for 10 min to promote dispersion of the aggregates, then allowed to cool to room temperature before the introduction of 10 mL of phosphate solution to obtain suspensions with concentrations of 1000 mg / L nanomaterials and 10, 50, 100, 150 and 300 P-mg.L'1phosphate.

[0227] Suspensions were mechanically stirred for 4 h, then the supernatants were recovered by magnetic separation (nanomaterials obtained by solvothermal polyol method) and filtered using a 0.20 pm porosity filter (CHROMAFIL© PA Xtra syr. Adaptator filters, 25 mm diameter, Carl Roth) or by ultrafiltration (nanomaterials obtained by coprecipitation method) with a stirred cell (Amicon® Stirred Cell 50 mL capacity, Merck Millipore) equipped with a 10 kDa porosity ultrafiltration membrane (Ultracel® 10 kDa Ultrafiltration Discs, 44.5 mm diameter, Merck Millipore). Filtered supernatants were briefly homogenized by mechanical agitation on a vortex and free phosphates immediately quantified by VetTest or molybdenum blue methods.

[0228] 3.5. Phosphate transport experiments in tubing mode

[0229] Experimental set-ups were developed to study phosphate transport from a solution located in a first compartment, referred as the “blood compartment”, to a solution in a second one, the “dialysate compartment”. Solutions contained in blood and dialysate compartments were referred to as blood and dialysate solutions respectively, regardless of their composition. These experiments were designed to simulate, on a reduced scale, the transport of phosphates during a PD process from the blood capillaries to the dialysate in the peritoneal cavity through the peritoneal membrane.

[0230] Membrane choice for dialysis tubing Membranes have been selected to reproduce the apparent permeability of the peritoneal membrane that behaves as a semi-permeable membrane. Its porosity is often described by the three-pore model which describes the presence of three pore size: aquaporins (2 - 4 A) allowing only water molecules to be transported by osmosis; small pores (40 - 55 A) representing 99.5 % of pore surface, enabling water molecules and solutes of low to medium molecular weight to pass through by convection and diffusion; and finally, large pores (250 - 300 A) permitting the transport by convection and diffusion of large molecules. Thus, commercially available dialysis tubing with regenerated cellulose membranes of 10 kDa (~50 A) and 20 kDa (~70 A) porosity41respectively were chosen for transport experiments.

[0231] The validation of the membrane by the tubing mode was not adapted and so the validation has been performed in cassette mode. By sampling in the cassette, it was observed that both methylene blue and marked glucose concentration decreased over time, being effectively transported through the membrane (Figure 16). Indeed, 48 % and 68 % of initial concentrations of methylene blue and marked glucose respectively were transported out of the cassette after 3 h experiment. In addition, BSA-FITC concentration remained constant over the experiment duration, confirming its retention in the cassette by the membrane.

[0232] These experiments confirmed the expected behavior of dialysis cassette membrane for simulating the apparent permeability of the peritoneal membrane to solutes as a function of their size.

[0233] 3.6. Phosphate transport experiments

[0234] Experiments involving a dialysis tubing (“tubing-mode”) were designed to approximate on a reduced scale the volume ratio of dialysate (2 L) to blood (5 L) in the body of a patient during a PD process. This ratio was mimicked by shaping the internal volume of a dialysis tubing (SnakeSkin™ Dialysis Tubing, 10K MWCO, 35 mm I.D., Thermo Scientific) filled with a dialysate solution (6 mL) and by completely immerging it in a shape-adapted glassware containing a minimum volume of blood solution (15 mL). In this configuration, phosphates were transported from the tubing external volume, towards its internal volume through the tubing membrane. All experiments were performed at room temperature.

[0235] Dialysate solution preparation. Experimentally, 6 mL of ultrapure water or PD solution, both optionally containing nanostructures at concentration 1 g(Fe3C>4).L'1was poured into the dialysis tubing. In experiments carried out in the presence of nanostructures in PD solution, suspension in ultrapure water containing 6 mg of nanostructures was initially prepared then magnetically separated before the addition of 6 mL of PD solution to prevent dilution of its solutes. Nanostructure suspension was sonicated during 10 min and let to cool to room temperature before introduction in dialysis tubing.

[0236] Blood solution preparation. Separately, a stock solution of phosphates was prepared by dilution of a solution of orthophosphoric acid in ultrapure water and its pH was adjusted to 7 - 7.5 with NaOH solution. The stock solution was then placed under magnetic stirring for 1 h. Working phosphate solution at a concentration of 50 P-rng.L'1was obtained by diluting the stock solution with ultrapure water and placed under magnetic stirring before the addition of 15 mL in a shape-adapted glassware (here, a test tube with the narrowest possible diameter to hold the dialysis tube).

[0237] Volumes of 0.3 mL were drawn from the blood solution at various times until 4 h after removal of the tubing and homogenization of the phosphate solution by mechanical stirring with a glass rod. Free phosphates in samples were immediately quantified using the VetTest method.

[0238] Phosphate transport rate from blood to peritoneal compartment was evaluated using D / P measurement, a ratio widely used in clinical tests and quantifying the deviation of a system from equilibrium. To measure D / P values, the phosphate concentration in the dialysate solution was calculated from the concentration measured in the blood solution. Two approaches were then adopted.

[0239] First, by considering the volumes of dialysate solution and blood fixed overtime. Thus, a possible ultrafiltration, predicting fluid movement from the blood compartment to the dialysate compartment when in the presence of osmotic agent, could therefore not be considered. The equation for the D / P quantity using this approach is: with Cband Cdthe phosphate concentrations in blood and dialysate solutions respectively (P-mg.L'1), Vbthe volume in blood solution (L), Cb 0the initial phosphate concentration in blood solution (P-mg.L'1), and Vb 0and Vd 0the initial volume of blood and dialysate solutions respectively (L).

[0240] Thus, the D / P ratio varies from 0 when Cb= Cb 0to 1 when the equilibrium state is reached, i.e. when phosphate concentrations on both sides of the membrane are equal.

[0241] In the second approach, the mass of blood solution was measured before and after the transport experiment. The difference in mass observed at the end of a reference experiment including ultrapure water in the blood and dialysate compartments was then considered as a systematic loss of mass (notably the mass of solution at the surface of the dialysis tubing at the end of the experiment) which would not be due to a possible ultrafiltration. For subsequent experiments involving PD solution and / or nanostructures in the dialysate compartment, the difference in mass of the blood solution before and after the experiment was deducted from the systematic mass loss, and the net mass loss was considered to be entirely due to ultrafiltration. This phenomenon was then implemented in the D / P equation as follows: with Vosmthe quotient of net mass loss over the number of samplings multiplied by the density of the blood solution (ultrapure water), in L. i is an index ranging from 0 to the number of samplings, enabling the volume of solvent transported by osmosis to be distributed over the duration of the experiment.

[0242] In each approach, volume variations in the blood solution due to successive withdrawals were considered in the calculation while the masses of phosphate successively removed were considered negligible. Indeed, in a typical tubing-mode experiment, the total mass of phosphate withdrawn due to sampling represented less than 0.3 % of the mass present in the blood solution after 4 h.

[0243] Example 4: Adsorption studies of uremic toxins and compounds on nanomaterials in batch-mode

[0244] 4.1. Methods for the quantification of creatinine, indoxyl sulfate and p-cresol were developed on an ultra high performance liquid chromatography system equipped with a UV-visible spectroscopy detector (UHPLC-UV / VIS).

[0245] The LIHPLC system was a Shimadzu Nexera XR model and the column containing the stationary phase was a Restek Force Cis 3 pm 150 x 2.1 mm with a Restek Force 5 pm 5 x 2.1 mm guard column. For each method developed, the flow rate was set at 0.3 mL.min'1, the oven temperature was 30°C and the injection volume was 5 pL. Composition of the mobile phase was 50 % acetonitrile 150 % water for creatine and indoxyl sulfate and 70 % methanol 130 % water for p-cresol. Retention times in the column were 4.8 min (creatinine), 4.2 min (indoxyl sulfate) and 6.3 min (p-cresol). Detections were performed at the maximum absorption wavelengthsabs= 235 nm (creatinine), 219 nm (indoxyl sulfate) and 221 nm (p-cresol). Calibration curves were constructed in triplicate from standard solutions over the range 10 - 500 rng.L'1(creatinine), 1 - 100 rng.L'1(indoxyl sulfate) and 10 - 250 rng.L'1(p- cresol).

[0246] Limit of detection (LCD) and limit of quantification (LOQ) are estimated based on a blank samples approach30, using the following formulas:

[0247] With b the calibration curve slope and syibthe standard deviation of the blank signals.

[0248] The LCD I LOQ calculated with formulas (1) and (2) were 2.718.8 rng.L'1(creatinine), 1.4 / 4.5 rng.L'1(indoxyl sulfate) and 2.2 17.3 rng.L'1(p-cresol).

[0249] Urea, glucose and calcium were quantified using the VetTest device and the LOD I LOQ values calculated from the calibration curves using formulas (1) and (2) were 31 1 95 rng.L'1(urea), 111 / 335 rng.L'1(glucose) and 9.2 128 rng.L'1(calcium).

[0250] 4.2. Adsorption isotherm experiments with uremic toxins and beneficial compounds

[0251] Experiments with uremic toxins - creatinine, indoxyl sulfate, p-cresol and urea - and beneficial compounds - glucose and calcium - were similar to those carried out with phosphate. Only the preparation of the adsorbate solutions and their method of quantification were adapted.

[0252] Creatinine. A creatinine stock solution was prepared by dissolution of a suitable mass of anhydrous creatinine (C4H7N3O, anhydrous, >98%, Sigma-Aldrich) in ultrapure water. Working solutions of concentrations 20; 50; 100; 150; 200; 500 and 1000 rng.L'1creatinine were prepared by dilutions of the stock solution in ultrapure water. The resulting suspensions after introduction of the adsorbate solutions contained 20 mL with 1000 rng.L'1material and 10; 25; 50; 75; 100; 250 and 500 rng.L'1creatinine. Free creatinine in filtered supernatant was quantified by VetTest methods and / or by UV-visible spectroscopy using a detector coupled with a liquid chromatography system.

[0253] Indoxyl sulfate. An indoxyl sulfate stock solution was prepared by dissolution of a suitable mass of indoxyl sulfate potassium salt (C8H6NO4SK, Sigma-Aldrich) in ultrapure water. Working solutions of concentrations 20; 50; 100; 200; 500 and 1000 rng.L'1were prepared by diluting the stock solution in ultrapure water. The resulting suspensions after introduction of the adsorbate solutions contained 20 mL of 1000 mg.L'1material and 10; 25; 50; 100; 250 and 500 mg.L'1indoxyl sulfate. Free indoxyl sulfate in filtered supernatant was quantified by UV-visible spectroscopy using a detector coupled with a liquid chromatography system. p-cresol. A p-cresol stock solution was prepared by dissolution of a suitable mass of p-cresol in powder form (CyHsO, 99%, Sigma-Aldrich) in ultrapure water. Working solutions of concentrations 20; 50; 100; 200; 500 and 1000 mg.L'1were prepared by diluting the stock solution in ultrapure water. The resulting suspensions after introduction of the adsorbate solutions contained 20 mL of 1000 mg.L'1material and 10; 25; 50; 100; 250 and 500 mg.L'1p-cresol. Free p-cresol contained in the filtered supernatants was quantified by UV-visible spectroscopy using a detector coupled with a liquid chromatography system.

[0254] Urea. A urea stock solution was prepared by dissolution of a suitable mass of urea in powder form (CH4N2O, 99.3+%, Alfa Aesar) in ultrapure water. Working solutions of concentrations 400; 600; 800; 1000; 1500; 2000; 3000 and 4000 mg.L'1were prepared by diluting the stock solution in ultrapure water. The resulting suspensions after introduction of the adsorbate solutions contained 20 mL of 1000 mg.L'1material and 200; 300; 400; 500; 750; 1000; 1500 and 2000 mg.L'1urea. Free urea contained in the filtered supernatants was quantified using the VetTest method.

[0255] Glucose. A glucose stock solution was prepared by dissolution of a suitable mass of D-(+)-Glucose in powder form (CeH^Oe, 99%, Alfa Aesar) in ultrapure water. Working solutions of concentrations 500; 1000; 2000; 3000; 4000; 5000 and 6000 mg.L'1were prepared by diluting the stock solution in ultrapure water. The resulting suspensions after introduction of the adsorbate solutions contained 20 mL of 1000 mg.L'1material and 250; 500; 1000; 1500; 2000; 2500 and 3000 mg.L'1glucose. Free glucose contained in the filtered supernatants was quantified using the VetTest method.

[0256] Calcium. A calcium stock solution was prepared by dissolution of a suitable mass of calcium chloride in powder form (CaCh, Prolabo) in ultrapure water. Working solutions of concentrations 20; 50; 100; 200 and 300 mg.L'1in calcium cation Ca2+were prepared by diluting the stock solution in ultrapure water. The resulting suspensions after introduction of the adsorbate solutions contained 20 mL of 1000 mg.L'1material and 10; 25; 50; 100 and 150 mg / L mg.L'1Ca2+cation. Free Ca2+contained in the filtered supernatants was quantified using the VetTest method.

Claims

CLAIMS1. A dialysate composition allowing for a balance with blood, said composition comprising at least one mineral salt and at least one pH buffer, and comprising at least one iron oxide nanoparticle (Fe2+and / or Fe3+) coated with at least one polymeric compound, wherein said at least on pH buffer is selected from the group consisting of acetate buffer, bicarbonate buffer, citrate buffer, lactate buffer and mixtures thereof.

2. The dialysate composition according to claim 1 , which further comprises at least one osmotic compound.

3. The dialysate composition according to claim 1 or 2, wherein the iron oxide nanoparticle is coated with one polymeric compound or mixture of polymeric compounds.

4. The dialysate composition according to claim 1 to 3, wherein the iron oxide nanoparticle is coated with a polymeric compound selected from the group consisting of tannic acid, polyacrylic acid, carboxymethyl dextran, PDADMAC, PEI, glucuronic acid, gluconic acid and mixtures thereof.

5. The dialysate composition according to any one of the claims 1 to 4, wherein the iron oxide nanoparticle has a molar ratio polymeric: iron (i.e. polymer: Fe) ranging from 0.001 to 5, preferably from 0.01 to 2.

6. The dialysate composition according to any one of the claims 1 to 5, wherein the iron nanoparticle has an average hydrodynamic diameter ranging from 10 nm and 300 nm, preferably from 20 nm and 200 nm, and more preferably from 30 nm and 150 nm.

7. The dialysate composition according to any one of the claims 1 to 6, wherein the pH is comprised between 4 and 8, preferably between 6 and 8 and more preferably between 6.5 and 7.

8. The dialysate composition according to any one of the claims 1 to 7, wherein the concentration of iron oxide nanoparticles in said dialysate composition is from 0.04 mmol.L-1to 4 mol.L-1, preferably from 0.04 mmol.L-1to 0.4 mol.L-1, and even more preferably from 0.04 mmol.L-1to 20 mmol.L-1.

9. The dialysate composition according to any one of the claims 1 to 8, for use for hemodialysis or peritoneal dialyses.

10. The dialysate composition according to any one of the claims 1 to 9, further comprising another nanoparticle selected from the groups consisting of inorganic nanoparticles, polymeric nanoparticles, polymeric capsules, organic-inorganic hybrid nanoparticles and organic-inorganic hybrid capsules.

11. The dialysate composition according to any one of the claims 1 to 10, for use as a medicament.

12. The dialysate composition for use according to claim 11, wherein the medicament is for delivering through the peritoneal membrane.

13. The dialysate composition according to any one of the claims 1 to 10, for use as a dialysate for blood purification or biological fluid purification.

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