Radiopaque monomer and embolisation microspheres comprising same

Abstract

The present invention relates to a compound of the following formula (A) mainly for use as a radiopaque monomer: The invention further relates to radiopaque embolisation microspheres based at least on: 20% to 90% hydrophilic monomer; 5% to 50% compound of formula (A); 1% to 15% non-biodegradable hydrophilic crosslinking monomer; and - 0.1% to 10% transfer agent. The invention also relates to a pharmaceutical composition comprising at least one embolisation microsphere according to the invention, in association with a pharmaceutically acceptable carrier, advantageously for parenteral administration. The invention further relates to a kit comprising a pharmaceutical composition according to the invention in association with a pharmaceutically acceptable carrier for parenteral administration, and to an injection means.

Description

[0001]Novel radiopaque monomer and embolization microspheres comprising it FIELD OF THE INVENTION The present invention relates to a novel halogenated radiopaque monomer, in particular for use within a crosslinked matrix used in the composition of embolization microspheres. PRIOR ART Therapeutic vascular occlusion (i.e. embolization) is used to prevent or treat certain pathological conditions in situ. It can be carried out using catheters allowing, under imaging control, the positioning of particulate occlusion agents (i.e. emboli or embolic agents) in the circulatory system. It has a variety of medical applications such as the treatment of vascular malformations, hemorrhagic processes, or tumors, including, for example, uterine fibroids, primary or secondary liver tumors.For example, vascular occlusion can cause tumor necrosis and avoid a more invasive operation. This occlusion technique can also be combined with the delivery of an anticancer agent as part of chemoembolization. This increases local concentration while limiting systemic drug exposure through targeted injection, as well as its residence time in the tumor. In the case of vascular malformations, vascular occlusion normalizes blood flow to normal tissues, aiding surgery by limiting the risk of hemorrhage. In hemorrhagic processes, vascular occlusion can lead to a decrease in flow, which promotes healing of the arterial wound. Furthermore, depending on the pathologies being treated, embolization can be used for temporary or permanent purposes.Embolization agents are typically introduced into a blood vessel via a catheter, particularly a microcatheter, whose diameter is smaller than that of the vessel to be treated. Embolization agents for vascular occlusion include, for example, embolization liquids (acrylic glues, gels), mechanical devices, particles, and polymeric embolization microspheres. The choice of a specific material depends on many factors, such as the type of lesion to be treated, the type of catheter to be used, and the need for temporary or permanent embolization. Polymer-based embolization microspheres are particularly useful for the aforementioned therapeutic purposes. They may be biodegradable for temporary embolization, as described in WO 2012 / 120139 and WO 2012 / 120138, or non-biodegradable for permanent embolization.For example, the Embosphere® product (Biosphere Medical) consists of non-biodegradable microspheres based on trisacryl (N-acryloyl-2-amino-2-hydroxymethylpropane-1,3 diol) and gelatin. Non-biodegradable microspheres based on acrylic copolymers and polyvinyl alcohol (PVA) have also been proposed for permanent embolization (Osuga et al. (2002) J. Vasc Interv Radiol. 13: 929-34). In addition, in order to be visible in X-ray imaging, the embolization microspheres can be made radiopaque by adding a radiopaque entity or monomer to their composition. Such radiopaque embolization microspheres are described in applications WO 2021 / 069527 and WO 2021 / 069528. The microspheres of these applications incorporate a radiopaque monomer called MAOETIB, with the following formula:. Radiopacity refers to the relative inability of electromagnetism, particularly X-rays, to penetrate dense materials, which are described as "radiopaque" appearing opaque / white in an X-ray image. Given the complexity of the content in an X-ray or fluoroscopic image, clinicians are sensitive to image quality with respect to the brightness or signal strength of the material in the image. The two main factors that contribute to the significance of radiopacity are density and atomic number. Polymer-based medical devices requiring radiopacity typically use a polymer blend that incorporates a small amount, by weight percentage, of a radiopaque element such as a heavy atom such as a halogen, particularly iodine.The ability of a device to be visualized by fluoroscopy depends on the amount or density of the radiopaque element mixed into the material. However, the addition of a radiopaque entity or monomer having halogenated groups appears to significantly decrease the hydrophilicity of the material. In addition, microspheres incorporating such radiopaque entities or monomers have an increased density, which impacts their suspendability properties in the injection medium. In summary, prior art iodine-loaded microspheres for X-ray visibility are typically more hydrophobic, dense, and rigid than non-X-ray microspheres and tend to form microsphere aggregates.As a result, (1) they are difficult to maintain in suspension for the duration of the injection in the catheter, and (2) they often block the catheter, even when their diameter is smaller than the internal diameter of the catheter (Duran 2016), for example because they agglomerate more easily between themselves (3) they tend to stick the walls of the catheter. It is therefore preferable to have radiopaque entities or monomers in the composition of the embolization microspheres which allow the latter to remain hydrophilic and flexible when swollen with water. It is also desirable that these microspheres have mechanical properties, in particular a swelling rate, elasticity and compressibility, adequate for injection via a catheter or microcatheter.It is also desirable that these microspheres can be kept suspended in the injection mixture (mixture composed of contrast agent and aqueous phase) for the duration of the injection into the catheter. Indeed, to be injectable and so that the practitioner can monitor the injection under X-ray control, the microspheres are generally suspended in a mixture of non-ionic iodinated contrast agent and aqueous phase. For this, radiologists generally use a solution of contrast agent and possibly physiological saline, bicarbonate buffer or phosphate buffer, advantageously a 100% solution of contrast agent. To guarantee their injectability, the microspheres must be kept homogeneously suspended in this solution.If the microspheres sediment or, on the contrary, float on the surface of the solution, the resulting suspension is non-homogeneous, unstable and therefore cannot be injected into the patient. Applications WO 2021 / 069527 and WO 2021 / 069528 describe halogenated radiopaque monomers which make it possible to meet these requirements satisfactorily. However, the need remains for new radiopaque entities or monomers intended for the preparation of embolization microspheres which make it possible to obtain better performances, for example in terms of stability or injectability of the suspensions comprising said microspheres, while remaining compatible with iodinated contrast agents as described above. SUMMARY OF THE INVENTION In this context, the inventors have developed a new halogenated radiopaque monomer of formula (A) leading to an improvement in the performances of the embolization microspheres comprising this monomer in their composition.For example, this new radiopaque monomer of formula (A) allows in particular the embolization microspheres comprising it to avoid aggregating with each other in the catheter or microcatheter before injection. The presence of this new halogenated radiopaque monomer of formula (A) in the embolization microspheres also prevents the latter from sticking to the walls of the catheter or microcatheter before injection. In addition, the suspendability and injectability properties of these microspheres are improved thanks to this new radiopaque monomer. By the expression "improved suspendability" is meant, within the meaning of the present invention, the capacity of the microspheres to form a suspension that is stable over a time compatible with their use, and homogeneous, that is to say with an identical distribution of the microspheres at all points in the volume of the suspension.By the expression "improved injectability properties" is meant, for the purposes of the present invention, the ability of the suspension to be injected via an injection system, such as a syringe or a catheter, without creating blockages and without requiring significant force on the part of the practitioner. The present invention therefore relates to a compound of the following formula (A):. This compound is also referred to as MAETIP in the present description. Another subject of the present invention relates to the use of the compound of formula (A) as defined above as a radiopaque halogenated monomer. Another subject of the invention relates to embolization microspheres comprising said halogenated radiopaque monomer of formula (A). The present invention therefore also relates to the use of this compound of formula (I) in embolization microspheres. The present invention further relates to a pharmaceutical composition comprising embolization microspheres as defined above, in association with a pharmaceutically acceptable vehicle, advantageously for administration by injection.The present invention also relates to a kit comprising a pharmaceutical composition as defined above and at least one means of injecting said composition, for administration of said composition by parenteral route. The present invention also relates to a kit comprising on the one hand a pharmaceutical composition as defined above and on the other hand a contrast agent for X-ray, magnetic resonance or ultrasound imaging, and optionally at least one means of injection for administration by parenteral route, advantageously said means of injection is the Vectorio® device as described in applications WO2016 / 166346, WO2016 / 166339, WO2017 / 005914 and WO2017 / 081178. DETAILED DESCRIPTION The main object of the present invention is therefore the compound of formula (A) below:. In the compound of formula (A), the iodine atoms are placed in positions 2, 4 and 6 of the phenyl ring. Due to the size of the iodine atoms and their homogeneous distribution on the phenyl ring, this compound has reduced spatial accessibility to the aromatic carbons (in positions 3 and 5 of the phenyl ring), compared to MAOETIB or compound (Vb) of application WO 2021 / 069528 (where the iodine atoms are in positions 2, 3 and 5 and the aromatic carbons in positions 4 and 6 of the phenyl ring). The restricted accessibility to the aromatic carbons in the compound of formula (A) appears to have the effect of reducing the lipophilic character of the molecule. Indeed, the inter- or intramolecular interactions of these carbons are reduced, or even zero, so as to limit the stickiness of the molecule. In other words, the spatial configuration of the compound of formula (A) makes it possible to limit the aggregation between them of the embolization microspheres integrating said compound.According to the present invention, this compound of formula (A) is advantageously used as a radiopaque halogenated monomer. Thus, the present invention also relates to the use of the compound of formula (A) as defined above as a radiopaque halogenated monomer. Furthermore, the present invention relates to embolization microspheres comprising said halogenated radiopaque monomer of formula (A). In particular, said embolization microspheres comprise a crosslinked polymer matrix comprising the halogenated radiopaque monomer of formula (A). In a particular embodiment, said crosslinked polymer matrix is ​​as defined in application WO2021 / 069528 with the exception of the halogenated radiopaque monomer of general formula (II) replaced by the compound of formula (A) according to the invention.In other words, said crosslinked polymer matrix is ​​based on at least: a) 20% to 90% of hydrophilic monomer chosen from N-vinylpyrrolidone and a monomer of the following formula (I): (CH2=CR1)-CO-D (I) in which: ^ D represents OZ or NH-Z, Z representing (C1-C6)alkyl, -(CR2R3)m-CH3, -(CH2-CH2-O)m- H, -(CH2-CH2-O)m-CH3, -C(R4OH)m or -(CH2)m-NR5R6 with m representing an integer from 1 to 30, preferably m is equal to 4 or 5 ^ R1, R2, R3, R4, R5 and R6 represent, independently of each other, H or a (C1-C6)alkyl; b) 5% to 50% of compound of the following formula (A):. c) 1% to 15% of linear or branched non-biodegradable hydrophilic crosslinking monomer having (CH2=(CR 16 ))- at each of its ends, each R 16independently representing H or a (C1-C6)alkyl; and d) 0.1% to 10% of transfer agent chosen from alkyl halides and cycloaliphatic or aliphatic thiols having in particular from 2 to 24 carbon atoms, and optionally having another functional group chosen from amino, hydroxy and carboxy groups, the percentages of monomers a) to c) being cited in moles relative to the total number of moles of monomers and the percentages of compound d) being cited in moles relative to the number of moles of the hydrophilic monomer a). The hydrophilic monomer of formula (I), the crosslinking monomer c) and the transfer agent d) are advantageously as defined in application WO2021 / 069528, in particular on pages 13 and 19-22. For the purposes of the present invention, the term "hydrophilic monomer" means a monomer having a strong affinity for water, i.e. tending to dissolve in water, to mix with water, to be wetted by water,or capable of swelling in water after polymerization. For the purposes of the present invention, the term "crosslinking monomer" means an at least bifunctional but also multifunctional monomer having a double bond at each polymerizable end. The crosslinking monomer, in combination with the other monomers in the mixture, allows the formation of a crosslinked network. The structure and quantity of crosslinking monomer(s) in the monomer mixture can be easily chosen by those skilled in the art to provide the desired crosslinking density. The crosslinker is also advantageous for the stability of the microspheres. The crosslinker prevents the microspheres from dissolving in any solvent. The crosslinker also improves the compressibility of the microspheres, which is favorable for embolization. For the purposes of the present invention, the term "non-biodegradable hydrophilic crosslinker" means a crosslinker as defined above,having a strong affinity for water and which cannot be degraded under the physiological conditions of the body of a mammal, in particular the human body. Indeed, the biodegradation of a molecule is permitted when it contains sufficient functional sites which can be cleaved under physiological conditions, in particular by the endogenous enzymes of the body of a mammal, in particular the human body, and / or at physiological pH (generally around 7.4). The functional sites which can be cleaved under physiological conditions include amide bonds, ester bonds and acetals. A molecule comprising an insufficient number of said functional sites will therefore be considered non-biodegradable. In the context of the present invention, the crosslinking monomer contains less than 20 functional sites which can be cleaved under physiological conditions, preferably less than 15 sites, more preferably less than 10 sites,even more preferably less than 5 sites. In the context of the present invention, the term "transfer agent" means a chemical compound having at least one weak chemical bond. This agent reacts with the radical site of a growing polymer chain and interrupts the growth of the chain. In the chain transfer process, the radical is temporarily transferred to the transfer agent which restarts the growth by transferring the radical to another polymer or monomer. By the expression "matrix based on", it is of course necessary to understand a matrix comprising the mixture and / or the product of the reaction between the base constituents used for the polymerization in a heterogeneous medium of this matrix, preferably only the product of the reaction between the different base constituents used for this matrix, some of which may be intended to react or capable of reacting with each other or with their close chemical environment,at least in part, during the various phases of the matrix manufacturing process, in particular during a polymerization step. Thus, the basic constituents are the reagents intended to react together during the polymerization of the matrix. The basic constituents are therefore introduced into a reaction mixture optionally further comprising a solvent or a mixture of solvents and / or other additives such as at least one salt and / or at least one polymerization initiator and / or at least one stabilizer such as PVA. In the context of the present invention, the reaction mixture comprises at least the monomers a), b), c) and the transfer agent d) cited in the present description as basic constituents, optionally a polymerization initiator such as, for example, t-butyl peroxide, benzoyl peroxide, azobiscyanovaleric acid (also called 4,4′-Azobis(4-cyanopentanoic acid)), AIBN (azobisisobutyronitrile), or 1,1'- Azobis(cyclohexane carbonitrile) or one or more thermal initiators such as 2-Hydroxy-4′-(2- hydroxyethoxy)-2-methylpropiophenone (106797-53-9); 2-Hydroxy-2- methylpropiophenone (Darocur® 1173, 7473-98-5); 2,2-Dimethoxy-2- phenylacetophenone (24650-42-8); 2,2-dimethoxy-2-phenyl acetophenone (Irgacure®, 24650-42-8) or 2-Methyl-4′-(methylthio)-2-morpholinopropiophenone (Irgacure®, 71868-10-5), and at least one solvent, preferably a solvent mixture comprising an aqueous solvent and an organic solvent such as an apolar aprotic solvent, for example an immiscible water / toluene system. Thus, according to the present invention, the matrix is ​​at least based on the monomers a), b), c) and the transfer agent d) cited in the present description, these compounds therefore being basic constituents. Thus, in the present description,expressions similar to "the [basic constituent X] is in particular added to the reaction mixture in an amount of YY% to YYY%" and to "the crosslinked matrix is ​​in particular based on the [basic constituent X] in an amount of YY% to YYY%" are interpreted in a similar manner. Similarly, expressions similar to "the reaction mixture comprises at least [the basic constituent X]" and to "the crosslinked matrix is ​​based on at least [the basic constituent X]" are interpreted in a similar manner. For the purposes of the present invention, the term "organic phase" of the reaction mixture means the phase comprising the organic solvent and the compounds soluble in said organic solvent, in particular the monomers, the transfer agent and the polymerization initiator. For the purposes of the present invention, the term "(CX-CY)alkyl" means a saturated, linear or branched monovalent hydrocarbon chain comprising X to Y carbon atoms,X and Y being integers between 1 and 36, preferably 1 and 18, in particular 1 and 6. By way of example, mention may be made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl groups. In the context of the present invention, the compound of formula (A) is in particular added to the reaction mixture in an amount of 5% to 50%, in particular in an amount greater than 7% and less than or equal to 50%, in particular in an amount greater than 10% and less than or equal to 50%, more particularly in an amount greater than 15% and less than or equal to 50%, preferably in an amount greater than 15% and less than or equal to 35%, and in particular from 20% to 30% per mole,relative to the total number of moles of monomers. The embolization microspheres comprising the crosslinked polymer matrix as defined above advantageously correspond to spherical particles having a diameter after swelling ranging from 20 to 1200 µm, for example from 20 to 100 µm, from 40 to 150 µm, from 100 to 300 µm, from 300 to 500 µm, from 500 to 700 µm, from 700 to 900 µm or from 900 to 1200 µm, as determined by optical microscopy. The microspheres advantageously have a diameter small enough to be injected by needles,a catheter or microcatheter with an internal diameter varying from a few hundred micrometers to more than one millimeter. The expression "after swelling" means that the size of the microspheres is considered after the polymerization and sterilization steps that occur during their preparation. The sterilization step involves, for example, passing the microspheres after the polymerization step into a high-temperature autoclave, typically at a temperature above 100°C, preferably at a temperature between 110°C and 150°C, preferably 121°C. During this sterilization step, the microspheres continue to swell in a controlled manner, i.e. with a controlled swelling rate. The swelling rate is defined as:, where mw is the weight in grams of 1 mL of sedimented microspheres and md is the weight in grams of 1 mL of sedimented microspheres which have then been lyophilized. In a particular embodiment according to the invention, the crosslinked polymer matrix of the microspheres is based solely on the basic constituents a), b), c) and d) as defined above, in the abovementioned proportions of monomers and transfer agent, no other basic constituent being added to the reaction medium. It is thus clear that the sum of the abovementioned proportions of monomers a), b) and c) must be equal to 100%.Preferably, the hydrophilic monomer of formula (I) is selected from the group consisting of N-vinylpyrrolidone, vinyl alcohol, 2-hydroxyethylmethacrylate, sec-butyl acrylate, n-butyl acrylate, t-butyl acrylate, t-butyl methacrylate, methylmethacrylate, N-dimethylaminoethyl(methyl)acrylate, N,N-dimethylaminopropyl-(meth)acrylate, t-butylaminoethyl(methyl)acrylate, N,N-diethylaminoacrylate, poly(ethylene oxide) (meth)acrylate, methoxy poly(ethylene oxide) (meth)acrylate, butoxy poly(ethylene oxide) (meth)acrylate, poly(ethylene glycol) (meth)acrylate, methoxy poly(ethylene glycol) (meth)acrylate, butoxy poly(ethylene glycol) methyl ether methacrylate and mixtures thereof. More preferably, the hydrophilic monomer a) is poly(ethylene glycol) methyl ether methacrylate (m-PEGMA).In the context of the present invention, the hydrophilic monomer a) is in particular added to the reaction mixture in an amount of 20% to 90%, preferably 30% to 80%, preferably 40% to 70%, in particular 45% to 65% per mole, relative to the total number of moles of monomers. Thus, in the context of the present invention, the crosslinked matrix in particular based on the hydrophilic monomer a) in an amount of 20% to 90%, preferably 30% to 80%, preferably 40% to 70%, in particular 45% to 65% per mole, relative to the total number of moles of monomers. Advantageously, the linear or branched non-biodegradable hydrophilic crosslinking monomer has (CH2=(CR. 16 ))CO- or (CH2=(CR 16 ))CO-O- at its at least two ends, each R 16independently representing H or a (C1-C6)alkyl. In particular, the crosslinker is of the following general formula (IIIa) or (IIIb): (CH2=(CR16))CO-NH-A-HN-OC((CR16)=CH2) (IIIa), (CH2=(CR 16 ))CO-OAO-OC((CR 16 )=CH2) (IIIb), in which each R16 independently represents H or a (C1-C6)alkyl, advantageously the radicals R16 are identical and represent H or (C1-C6)alkyl; and A represents, alone or with at least one of the atoms to which it is bonded, a (C1-C6)alkylene, a polyethylene glycol (PEG), a polysiloxane, a poly(dimethylsiloxane) (PDMS), a polyglycerol ester (PGE) or a bisphenol A. Advantageously, the crosslinker is of the following general formula (IIa) or (IIb): (CH2=(CR16))CO-NH-A-HN-OC((CR16)=CH2) (IIIa), (CH2=(CR 16 ))CO-OAO-OC((CR 16)=CH2) (IIIb), wherein each R16 independently represents H or a (C1-C6)alkyl, advantageously the radicals R16 are identical and represent H or (C1-C6)alkyl; and A preferably represents, alone or with at least one of the atoms to which it is bonded, a (C1-C6)alkylene or a polyethylene glycol (PEG), preferably a polyethylene glycol (PEG). Within the scope of the definitions of A above, the polyethylene glycol has a length ranging from 200 to 10000 g / mol, preferably from 200 to 2000 g / mol, more preferably from 500 to 1000 g / mol. Examples of crosslinking monomers that may be used in the context of the present invention include (but are not limited to): 1,4-butanediol diacrylate, pentaerythritol tetraacrylate, methylenebisacrylamide, glycerol 1,3-diglycerolate diacrylate and poly(ethylene glycol)dimethacrylate (PEGDMA).Advantageously, the crosslinking monomer is poly(ethylene glycol)dimethacrylate (PEGDMA), the polyethylene glycol unit having a length varying from 200 to 10000 g / mol, preferably from 200 to 2000 g / mol, more preferably from 500 to 1000 g / mol. In the context of the present invention, the crosslinking monomer is in particular added to the reaction mixture in an amount of 1% to 15%, preferably from 2% to 10%, in particular 2% to 7%, more particularly 2% to 5% per mole, relative to the total number of moles of monomers. Advantageously, said chain transfer agent is chosen from the group consisting of monofunctional or polyfunctional thiols, and alkyl halides. Among the alkyl halides that can be used as transfer agents, we find in particular bromotrichloromethane, tetrachloromethane and tetrabromomethane.Particularly advantageously, said chain transfer agent is a cycloaliphatic or aliphatic thiol typically having from 2 to about 24 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 6 carbon atoms, and optionally having an additional functional group chosen from amino, hydroxy and carboxy groups. Advantageously, the transfer agent is chosen from thioglycolic acid, 2-mercaptoethanol, dodecanethiol, hexanethiol and mixtures thereof. In the context of the present invention, the transfer agent is in particular added to the reaction mixture in an amount of 0.1% to 10%, preferably 0.5% to 8%, more preferably 1.5% to 6% and in particular 1.5% to 4.5% per mole, and in particular 3% per mole, relative to the number of moles of hydrophilic monomer a).In another particular embodiment of the invention, the polymeric crosslinked matrix of the microspheres of the invention is furthermore based on: - an ionized or ionizable monomer and / or - a colored monomer to make them visible to the naked eye, for example to check before injection that the suspension of microspheres is homogeneous in the syringe and to control the injection speed, and / or - at least one agent visible in magnetic resonance imaging (MRI) Said ionized or ionizable, colored monomer and agent visible in MRI are in particular as defined in application WO2021 / 069528, in particular on pages 22-25. In particular, the polymeric crosslinked matrix of the embolization microspheres of the invention may furthermore be based on at least one ionized or ionizable monomer of the following formula (IV): (CH2=CR. 17)-ME (IV) in which: ^ R17 represents H or a (C1-C6) alkyl; ^ M represents a single bond or a divalent radical having from 1 to 20 carbon atoms; ^ E represents a charged or ionizable group having 100 atoms at most, E being advantageously chosen from the group consisting of -COOH, -COO-, -SO3H, -SO3-, -PO3H2, -PO H-, -PO 2- , -NR + 3 3 18R19, -NR20R21R22 , ^ R18, R19, R20, R21 and R22 independently represent H or a (C1-C6)alkyl. For the purposes of the present invention, the term ionized or ionizable group means a group that is charged or that can be in charged form (in ion form), i.e. carrying at least one positive or negative charge, depending on the pH of the medium. For example, the COOH group may be ionized in COO- form and the NH2 group may be in ionized NH3 form +. The introduction of an ionized or ionizable monomer into the reaction mixture makes it possible to increase the hydrophilicity of the resulting microspheres, thus increasing the swelling rate of said microspheres, further facilitating their injection via catheters and microcatheters. In addition, the presence of an ionized or ionizable monomer allows the loading of active substances within the microsphere. According to a preferred variant, the ionized or ionizable monomer is of the following formula (IV-A): (CH2=CR 17)-C(O)-O-M'-E (IV) in which: ^ R17 and E are as defined above, and ^ M' a hydrocarbon chain comprising from 1 to 20 atoms. Preferably, the ionized or ionizable monomer is a cationic monomer, advantageously chosen from the group consisting of methacrylic acid, (methacryloyloxy)ethylphosphorylcholine, 2-(dimethylamino)ethyl (meth)acrylate, 2-(diethylamino)ethyl (meth)acrylate), 11-methacryloyloxyundecylphosphonic acid and 2-((meth)acryloyloxy)ethyl)-trimethylammonium chloride, advantageously, the cationic monomer is diethylamino)ethyl (meth)acrylate. Advantageously, the crosslinked matrix according to the invention is based on a cationic monomer mentioned above in quantities of between 1% and 40% by mole relative to the total number of moles of monomers.Preferably, the crosslinked matrix according to the invention is based on ionized or ionizable monomer in amounts of between 5% and 15%, preferably 10% by mole relative to the total number of moles of monomers, when the resulting microspheres are not intended to be loaded with an active substance. According to another embodiment, when the microspheres are intended to be loaded with an active substance, the crosslinked matrix according to the invention is obtained by adding to the reaction mixture between 20% and 40%, preferably by adding to the reaction mixture 20% to 30% by mole of ionized or ionizable monomer relative to the total number of moles of monomers.In another advantageous embodiment, the ionized or ionizable monomer is an anionic monomer advantageously chosen from the group consisting of acrylic acid, methacrylic acid, 2-carboxyethyl acrylate, 2-carboxyethyl acrylate oligomers, 3-sulfopropyl (meth)acrylate, potassium salt and 2-((methacryloyloxy)ethyl)dimethyl-(3-sulfopropyl)ammonium hydroxide. Advantageously, the crosslinked matrix according to the invention is based on an anionic monomer mentioned above in amounts of between 1% and 40% by mole based on the total amount of monomers. Preferably, the crosslinked matrix according to the invention is based on ionized or ionizable monomer in amounts of between 5% and 15%, preferably 10% by mole based on the total amount of monomers, when the resulting microspheres are not intended to be loaded with an active substance.According to another embodiment, when the microspheres are intended to be loaded with an active substance, the crosslinked matrix according to the invention is based on ionized or ionizable monomer in amounts of between 20% and 40%, preferably 20% to 30% of ionized or ionizable monomer based on the total amount of monomers. Particularly advantageously, the ionized or ionizable monomer is methacrylic acid (MA or AM). Advantageously, the crosslinked matrix according to the invention is based on methacrylic acid (MA) in amounts of between 10% and 30% by mole based on the total amount of monomers. Said crosslinked polymeric matrix may further be based on at least one colored monomer of the following general formula (VI):. in which, ^ Z1 and Z2 represent, independently of each other, H or OR 25 , R 25representing H or a (C1-C6)alkyl, advantageously Z1 and Z2 represent H; ^ X represents H or Cl, advantageously H; ^ R 23 represents H or a (C1-C6)alkyl, advantageously a (C1-C6)alkyl, in particular a methyl; and ^ R24 represents a group chosen from linear or branched (C1-C6)alkylene, (C5-C 36 )arylene, (C5-C 36 )arylene-OR 26 , (C5-C 36 )heteroarylene and (C5-C 36 )heteroarylene-OR 27 , R 26 and R 27 representing a (C1-C6)alkyl or a (C1-C6)alkylene, advantageously R 24represents a group -C6H4-O-(CH2)2-O or -C(CH3)2-CH2-O. By group "(CX-CY)alkylene" is meant, for the purposes of the present invention, a divalent, linear or branched hydrocarbon chain, comprising X to Y carbon atoms, X and Y being whole numbers between 1 and 36, preferably 1 and 18, in particular 1 and 6. By way of example, mention may be made of the methylene, ethylene, propylene, butylene, pentylene or hexylene groups. For the purposes of the present invention, the term "(CX-CY)heteroarylene" means a divalent aromatic group comprising from X to Y cyclic atoms, including one or more heteroatoms, advantageously 1 to 4 and even more advantageously 1 or 2, such as, for example, sulfur, nitrogen or oxygen atoms, the other cyclic atoms being carbon atoms. X and Y are integers between 5 and 36, preferably 5 and 18, in particular 5 and 10. For the purposes of the present invention, the term "divalent radical" means:a radical having a valence of 2, i.e. having two covalent, polar covalent or ionic chemical bonds. Said radical may comprise, for example, carbon and / or oxygen atoms. Advantageously, the colored monomer is of the following formula (VIa) or (VIb): More advantageously, the colored monomer is of formula (VIb) above. In the context of the present invention, the colored monomer is in particular added to the reaction mixture in an amount of 0% to 1%, preferably 0% to 0.5%, more particularly 0.02% to 0.2%, and even more particularly 0.04% to 0.1% per mole, relative to the total number of moles of monomers. Said crosslinked polymer matrix may further be based on elements visible in magnetic resonance imaging (MRI) such as iron oxide nanoparticles, gadolinium chelates or magnesium chelates, advantageously iron oxide nanoparticles. In the context of the present invention,the elements visible in MRI are advantageously added to the reaction mixture in an amount of 0% to 0.5%, preferably 0.025% to 0.4%, more preferably 0.025% to 0.25%, in particular 0.05%, by mass of element visible in MRI per volume of organic phase, so as to obtain microspheres visible and quantifiable by MRI. The polymeric crosslinked matrix of the embolization microspheres of the invention can be easily synthesized by numerous methods well known to those skilled in the art. For example, it can be obtained by suspension polymerization as described in application WO2021 / 069528, in particular on pages 27-29. In a particular embodiment, the embolization microspheres according to the present invention are loaded with active substances, thus making it possible to combine vascular occlusion and the delivery of an active principle. Said active substance may be chosen from a medicament,a diagnostic agent and macromolecules as defined in application WO2021 / 069528, in particular on pages 29-31. Preferably, the microspheres according to the invention may be loaded with an active substance chosen from anticancer agents, anti-inflammatory agents, local anesthetics, analgesics, antibiotics, steroids, antiseptics and mixtures thereof. The anticancer agent is preferably chosen from anthracyclines such as doxorubicin, epirubicin or idarubicin, platinum complexes, anthracycline-related compounds such as mitoxantrone and nemorubicin, antibiotics such as mitomycin C (Ametycine®), bleomycin and actinomycin D, other antineoplastic compounds such as irinotecan, 5-Fluoro-Uracil (Adrucil®), sorafenib (Nevaxar®), sunitinib (Sutent®), regorafenib, brivanib, orantinib, linsitinib, erlotinib, cabozantinib, foretinib,tivantinib, fotemustine, tauromustine (TCNU), carmustine, cytosine C, cyclophosphonamide, cytosine arabinoside (or cytarabine), paclitaxel, docetaxel, methotrexate, everolimus (Afinitor®), PEG-arginine deiminase, the combination tegafur / gimeracil / oteracil (Teysuno®), muparfostat, peretinoin, gemcitabine, bevacizumab (Avastin®), ramucirumab, floxuridine, immunostimulants such as GM-CSF (Granulocyte-macrophage colony-stimulating factor) and its recombinant forms: molgramostim or sargramostim (Leukine®), OK-432 (Picibanil®), interleukin-2, interleukin-4 and Tumor necrosis Factor-alpha (TNFalpha), antibodies, radioelements, complexes of these radioelements with chelates, nucleic acid sequences and a mixture of one or more of these compounds (preferably a mixture of one or more anthracyclines). Preferably, the anticancer agent is chosen from anthracyclines,immunostimulants, platinum complexes, antineoplastics and mixtures thereof. Even more preferably, the anticancer agent is chosen from anthracyclines, antibodies, antineoplastics and mixtures thereof. The antibodies are, for example, chosen from anti-PD-1, anti-PD-L1, anti-CTLA-4, anti-CEA (CarcinoEmbryonic Antigen) or a mixture thereof. Anti-PD-1 agents are, for example, nivolumab or pembrolizumab. Anti-PD-L1 agents are, for example, avelumab, durvalumab or atezolizumab. Anti-CTLA-4 agents are, for example, ipilimumab or tremelimumab. Even more advantageously, the anticancer agent is chosen from the group consisting of paclitaxel, doxorubicin, epirubicin, idarubicin, irinotecan, GM-CSF (Granulocyte-macrophage colony-stimulating factor), tumor necrosis factor-alpha (TNFalpha), antibodies, and mixtures thereof. Preferably, the local anesthetic is chosen from lidocaine,bupivacaine and mixtures thereof. The anti-inflammatory may be chosen from ibuprofen, niflumic acid, dexamethasone, naproxen and mixtures thereof. In the context of the present invention, the microspheres may be loaded, in particular by extemporaneous adsorption, with macromolecules chosen from the group consisting of enzymes, antibodies, cytokines, growth factors, coagulation factors, hormones, plasmids, antisense oligonucleotides, siRNA, ribozymes, DNA enzyme (also called DNAzyme), aptamers, anti-inflammatory proteins, bone morphogenic proteins (BMPs), pro-angiogenic factors, vascular endothelial growth factors (VEGF) and TGF-beta,and angiogenesis inhibitors or anti-tyrosine kinases and mixtures thereof. Anti-inflammatory proteins are, for example, infliximab or rilonacept and mixtures thereof. Pro-angiogenic factors are, for example, fibroblast growth factors (FGFs) and mixtures thereof. Angiogenesis inhibitors are, for example, bevacizumab, ramucirumab, nesvacumab, olaratumab, vanucizumab, rilotumumab, emibetuzumab, aflibercept, ficlatuzumab, pegaptanib and mixtures thereof. Examples of anti-tyrosine kinases are lenvatinib, sorafenib, sunitinib, pazopanib, vandetanib, axitinib, regorafenib, cabozantinib, fruquintinib, nintedanib, anlotinib, motesanib, cediranib, sulfatinib, dovetinib, linifanib and mixtures thereof. Advantageously, the microspheres may be loaded with macromolecules selected from anti-tyrosine kinases, TGF-beta,angiogenesis inhibitors and mixtures thereof. The active substance is typically adsorbed onto the crosslinked matrix by non-covalent interactions, optionally in the presence of pharmaceutically acceptable excipient(s) well known to those skilled in the art. This particular way of trapping active substances is called physical encapsulation. No particular requirements are imposed on the active substance to be loaded. Loading can be done by many methods well known to those skilled in the art such as passive adsorption (swelling of the crosslinked matrix in a drug solution) or by ionic interaction. These methods are for example described in international application WO 2012 / 120138,in particular from page 22 line 20 to page 26 line 7. The loading efficiency depends mainly on the compatibility between the two structures and / or favorable interactions. Another subject of the invention relates to a pharmaceutical composition comprising embolization microspheres according to the invention, in association with a pharmaceutically acceptable vehicle, advantageously for administration by injection. An example of a pharmaceutically acceptable vehicle includes, but is not limited to, water for injection, saline solution also called physiological serum, starch, hydrogel, polyvinylpyrrolidone, polysaccharide, hyaluronic acid ester, plasma, a contrast agent for X-ray, magnetic resonance or ultrasound imaging, a buffering agent, a preservative, a gelling agent, glucose and / or a surfactant. Advantageously,the pharmaceutically acceptable vehicle is physiological saline, water for injection, a contrast agent for X-ray, magnetic resonance or ultrasound imaging, or mixtures thereof. More preferably, the pharmaceutically acceptable vehicle is physiological saline, a contrast agent for X-ray, magnetic resonance or ultrasound imaging, or a mixture of physiological saline and a contrast agent for X-ray, magnetic resonance or ultrasound imaging. According to the present invention, the contrast agent is preferably a contrast agent for X-ray imaging. It is advantageously a non-ionic iodinated water-soluble contrast agent, such as for example iobitridol (Xenetix, ® ), iopamidol (Iopamiron ® , Isovue ® ), iomeprol (Iomeron ® ), ioversol (Optiray ® , Optiject ® ), iohexol (Omnipaque ®), iopentol (Imagopaque ® ), ioxitol (Oxilan®), iopromide (Ultravist ® ), and metrizamide (Amipaque ® ), iosarcol (Melitrast ® ), iotrolan (Isovist ® ), iodixanol (Visipaque ® ), iosiminol and iosimide (Univist ®) and a mixture thereof. According to another embodiment, the contrast agent is a contrast agent for magnetic resonance imaging (MRI). These are advantageously gadolinium chelates (Dotarem®, Gadopiclenol). According to another embodiment, the contrast agent is a contrast agent for ultrasound imaging. This is advantageously sulfur hexafluoride (Sonovue®). In a particular embodiment of the present invention, the pharmaceutical composition comprises embolization microspheres according to the invention, in association with physiological saline, said composition being intended to be mixed with at least one contrast agent for X-ray, magnetic resonance or ultrasound imaging as defined above, in particular for X-ray imaging, before administration by injection, such a mixture resulting in the suspension of the microspheres according to the invention.In a particular embodiment according to the invention, the pharmaceutical composition according to the invention comprises embolization microspheres according to the invention, in association with a mixture of physiological serum and a contrast agent as defined above, the physiological serum and the contrast agent being present in proportions of 70 / 30 to 20 / 80, advantageously from 50 / 50 to 20 / 80, preferably 50 / 50. The pharmaceutical composition must have an acceptable viscosity for injection. The embolization microspheres according to the invention can, as indicated above, be used for various biomedical purposes, which means that they must be compatible with the human body or the body of a mammal. More particularly, suitable biomedical materials do not possess hemolytic properties.The present invention also relates to a kit comprising a pharmaceutical composition as defined above and at least one means of injecting said composition, for administration of said composition by parenteral route. According to the present invention, the term "injection means" means any means allowing administration by parenteral route. Advantageously, said injection means is one or more syringes and / or one or more syringe(s) which can be pre-filled and / or one or more catheter(s) or microcatheter(s) for administration of said composition by injection. Advantageously, the pharmaceutical composition present in said kit comprises the microspheres according to the present invention in association with physiological saline, a contrast agent, or their mixture.More advantageously, said pharmaceutical composition comprises the microspheres according to the present invention in association with a mixture of physiological serum and a contrast agent in proportions of between 80 / 20 and 0 / 100, advantageously of between 70 / 30 and 40 / 60, preferably 50 / 50. Advantageously, the injection means present in the kit according to the invention is suitable for the parenteral administration of the pharmaceutical composition according to the invention. Thus, the size of the syringe(s) or (micro)catheter(s) will be adapted according to the size of the microspheres according to the invention and the volume to be injected for embolization. A person skilled in the art will know how to choose the appropriate injection means. According to a preferred embodiment, said injection means is the Vectorio® device as described in applications WO2016 / 166346, WO2016 / 166339, WO2017 / 005914 and WO2017 / 081178.The present invention also relates to a kit comprising on the one hand a pharmaceutical composition as defined above and on the other hand at least one contrast agent for X-ray, magnetic resonance or ultrasound imaging, and optionally at least one injection means for parenteral administration. The injection means is as defined above. In said kit, the pharmaceutical composition and the contrast agent are packaged separately and are intended to be mixed just before administration by injection. In said kit, the at least one contrast agent is as defined above in the description. In particular, the at least one contrast agent is a contrast agent for X-ray imaging as defined above in the description.In said kit, the pharmaceutical composition advantageously comprises the microspheres according to the present invention in association with a pharmaceutically acceptable vehicle for administration by injection. Said pharmaceutically acceptable vehicle may be, for example, but not limited to, water for injection, physiological saline, starch, hydrogel, polyvinylpyrrolidone, polysaccharide, hyaluronic acid ester, glucose and / or plasma. Preferably, in said kit, the pharmaceutical composition advantageously comprises the microspheres according to the present invention in association with physiological saline or water for injection. In said kit, the pharmaceutical composition is advantageously packaged directly in an injection means, in particular in a syringe, suitable for the injection of embolization microspheres by the parenteral route.In said kit, the contrast agent is advantageously packaged in a bottle or directly in an injection means, in particular a syringe, in particular suitable for the injection of embolization microspheres by parenteral route. In said kit, the proportions of pharmaceutically acceptable vehicle / contrast agent are between 50 / 50 and 0 / 100, advantageously between 40 / 60 and 0 / 100, preferably 30 / 70 to 0 / 100.EXAMPLES Example 1: Synthesis of MAETIP (compound of formula (A) according to the invention) Material and method Chemical products: - Magnesium sulfate (MgSO4, anhydrous, 98%, Sigma-Aldrich, ref: 230391, CAS: 10034-99-8) - 2,4,6 – triiodophenol (95-98%, BLDpharm, ref: A17145, CAS: 609-23-4) - 2-[2-(2-Chloroethoxy) ethoxy] ethanol (95-98%, TCI, ref: QF-8470, CAS: 5197-62-6) - Sodium iodide (NaI, >99%, OakwoodChemical, ref: QE-0904, CAS: 7681-82-5) - Sodium hydroxide (NaOH, anhydrous, >98%, Sigma-Aldrich, ref: S8045, CAS: 1310-73-2) - Anhydride methacrylate (AM, >94%, Sigma-Aldrich, ref: 276685, CAS: 760-93-0) - Triethylamine (TEA, >99.5%, Sigma-Aldrich, ref: 471283, CAS: 121-44-8) Solvents: - Absolute ethanol (EtOH, 99.96%, VWR, ref: 20821.310, CAS: 64-17-5) - Ethyl acetate (Anhydrous, 99.8%, Sigma-Aldrich, ref: 270989, CAS: 141-78-6) - Heptane (>99%, Sigma-Aldrich, ref: 34873, CAS: 142-82-5) - Dichloromethane (DCM, anhydrous, >99.8%, Sigma-Aldrich, ref: 270997, CAS: 75-09-2) - Distilled water (grade 2) Equipment: - Magnetic plate (Heidoplh, MR Hei-Satndard) - Rotary Evaporator (Buchi Rotavapor R-215) - Precision balance (d=0.1 mg, Sartorius) - Silica column: ChromatoFlash (Buchi) 1. O-alkylation. Intermediate 1 In a 10 mL round-bottomed flask, triiodophenol (200 mg; 0.42 mmol) is dissolved in 2.2 mL of ethanol. NaOH (15 mg; 0.375 mmol) is added, and the mixture is stirred for 30 minutes at room temperature. After stirring, evaporation is carried out under vacuum until a slightly yellow solid is obtained. In a three-necked flask, equipped with a condenser, placed under nitrogen, NaI (57 mg; 0.375 mmol) and 2-[(2-Chloroethoxy) ethoxy] ethanol (55 µL; 0.375 mmol) are added. The mixture is dissolved in 1.7 mL of ethanol until the NaI is completely dissolved. The triiodophenol derivative, previously dissolved in 0.7 mL of ethanol, is then added. The reaction medium is heated to reflux for 2 and a half days, ensuring a sufficiently high water flow rate in the condenser, so as to observe rapid condensation of the ethanol. The progress of the reaction is monitored by TLC (thin layer chromatography): Heptane / Ethyl acetate 5 / 5.At the end of the reaction, the reaction medium is evaporated under pressure, then the solid obtained is solubilized in a 6 mL NaOH (6M) solution. The aqueous phase is then washed with DCM (dichloromethane) (3 x 7 mL). The organic phases are dried under MgSO4. A yellowish solid is obtained. Purification is carried out on a silica column, via a Heptane / ethyl acetate co-elution system. Following purification, 0.133 mg of a white solid is obtained. Molar yield: 85% UV purity: 96% 2. Esterification of the alcohol. Intermediate 1 In a 25 mL three-necked flask equipped with a condenser, intermediate 1 (0.133 mg; 0.22 mmol) is dissolved in 12 mL of anhydrous THF. TEA (triethylamine) (0.10 mL; 0.66 mmol) is added dropwise. The reaction medium is cooled to a temperature below 5°C, then methacrylate anhydride (0.11 mL; 0.66 mmol) is added dropwise over a period of 5 minutes. Finally, the reaction medium is stirred for one hour at a temperature below 5°C, then refluxed overnight. The progress of the reaction is monitored by TLC: Heptane / Ethyl acetate 5 / 5. At the end of the reaction, the reaction medium is brought back to room temperature, then suspended in 90 mL of water for one hour. Wash with dichloromethane (3 x 20 mL).The organic phases are dried under MgSO4, then evaporated under pressure, until an orange oil is obtained which is then purified on a silica column, via a Heptane / Ethyl Acetate co-elution system. Following the purification, 89.7 mg of a transparent oil is obtained. Molar yield: 74.5% UV purity: 96.6% 3. Conclusion The synthesis of MAETIP was carried out with synthesis yields of approximately 54% (comparable to that of the synthesis of MAOETIB), with a purity of the final molecule of approximately 97%.Example 2: Synthesis by oil-in-water suspension polymerization (direct phase) of microspheres according to the invention based on MAETIP, of size 100-300 μm, 300-500 μm and 700-900 μm The synthesis parameters are adapted to the desired microsphere size (see table 1) a) Preparation of the aqueous phase An aqueous solution of hydrolyzed polyvinyl alcohol (PVA) and sodium chloride is prepared according to the following protocol: i) Dissolution of the PVA in 5L of pyrogen-free water and stirring overnight at 50°C. ii) Addition of NaCl and stirring at room temperature for 4 hours. b) Preparation of the organic phase v) Weighing of each reagent and toluene w) Dissolution of AIBN in a volume of toluene x) Dissolution in a volume of toluene (in a different container) of poly(ethylene glycol) methyl ether methacrylate (m-PEG. 300 MA) (hydrophilic monomer), poly(ethylene glycol) dimethacrylate (PEG 1000DMA) (crosslinker), methacrylic acid (AM or MA) (ionizable monomer), MAETIP (radiopaque monomer) and the dye then adding hexanethiol (transfer agent) y) Addition of the AIBN solution obtained in step w) to the monomer solution of step x) c) Synthesis of the microspheres according to the invention The aqueous solution of PVA and NaCl prepared in step a) is poured into a reactor and heated to 50°C. The organic phase obtained in step b) is then introduced into the reactor. Stirring is applied with a propeller-type stirrer to obtain dispersed phase droplets of the desired diameter. The temperature is then increased to 80°C and stirring is maintained for 8 hours. The mixture is then filtered through a 50 μm sieve and the microspheres are washed with acetone, then ethanol and then water before being sieved through sieves of size 50 μm, 100 μm, 300 μm and 500 μm, 700 μm, 900 μm and 1200 μm.Table 1 below summarizes the main parameters of the synthesis according to the size of the microspheres. *n = number of moles Table 1 Example 3: Measurement of the suspension time of the MS according to the invention and comparison with MS comprising a radiopaque monomer other than MAETIP The suspension time of the MS according to the invention synthesized in Example 1 in an injection medium (50 / 50 physiological saline / iodinated contrast agent) was studied and compared to that of control MS comprising a radiopaque monomer other than MAETIP. The control MS are synthesized according to the same protocol as that of Example 1 with the same constituents except for the radiopaque monomer. The following radiopaque monomers are used in the control MS: ^ MAOETIB of formula: ^ Compound Vb described in application WO 2021 / 069528 of formula: The suspension was carried out using the so-called "Falcon" method: Falcon method - 1 mL of radiopaque microspheres is added to a 15 mL Falcon® (or Axygen®) tube with an internal coating made of polypropylene (polystyrene), then the tube is filled to the "water level" (observation of an edge effect, in order to eject as much air as possible from the tube) with a 50 / 50 mixture of distilled water and contrast agent; - The microspheres are suspended by successively turning the tube over for 3 minutes; - The tube is left to rest, and the sedimentation (or creaming) time of the microspheres is measured. Results and discussion: a) A first test of suspending the microspheres was carried out in Axygen® tubes according to the protocol described previously. The results obtained are as follows: Table 2: Suspension time of MS according to the Falcon method in Axygen® tubes. Note that in each case, sedimentation of the microspheres is observed at the end of the suspension in the injection medium. b) A second test was carried out using the same parameters, in a Falcon® tube. The results obtained are as follows: Table 3: Suspension time of MS according to the Falcon method in Falcon® tubes In each case, sedimentation of the microspheres was observed at the end of the suspension in the injection medium. For both tests, it was observed that the suspension time of the MS according to the invention was much higher than that of the control MS. The results annotated with a “*” correspond to a suspension time greater than 600 seconds. It was not considered relevant to measure the suspension time beyond 600 seconds, the results obtained by the suspension comprising the MS according to the invention being much higher than the results observed for the control microspheres.

Claims

CLAIMS 1. Compound of the following formula (A):

2. Use of the compound of formula (A) as defined in claim 1 as a radiopaque halogenated monomer.

3. Radiopaque embolization microspheres comprising a crosslinked matrix, said matrix being based on at least: a) 20% to 90% of hydrophilic monomer chosen from N-vinylpyrrolidone and a monomer of the following formula (I): (CH2=CR1)-CO-D (I) in which: ^ D represents OZ or NH-Z, Z representing (C1-C6)alkyl, -(CR2R3) m -CH3, -(CH2-CH2-O) m - H, -(CH2-CH2-O)m-CH3, -C(R4OH)m or -(CH2)m-NR5R6 with m representing an integer from 1 to 30, preferably m is equal to 4 or 5 ^ R1, R2, R3, R4, R5 and R6 represent, independently of each other, H or a (C1-C6)alkyl; b) 5% to 50% of compound of the following formula (A): c) 1% to 15% of linear or branched non-biodegradable hydrophilic crosslinking monomer having (CH2=(CR16))- groups at each of its ends, each R 16independently representing H or a (C1-C6)alkyl; and d) 0.1% to 10% of transfer agent chosen from alkyl halides and cycloaliphatic or aliphatic thiols having in particular from 2 to 24 carbon atoms, and optionally having another functional group chosen from amino, hydroxy and carboxy groups, the percentages of monomers a) to c) being cited in moles relative to the total number of moles of monomers and the percentages of compound d) being cited in moles relative to the number of moles of the hydrophilic monomer a). 4.Embolization microspheres according to claim 3, wherein said matrix is ​​based on the compound of general formula (A) in an amount greater than 7% and less than or equal to 50%, advantageously in an amount greater than 10% and less than or equal to 50%, advantageously in an amount greater than 15% and less than or equal to 50%, more advantageously in an amount greater than 15% and less than or equal to 35%, and in particular from 20% to 30% per mole, relative to the total number of moles of monomers.

5. Embolization microspheres according to claim 3 or 4, wherein the hydrophilic monomer a) is selected from the group consisting of N-vinylpyrrolidone, vinyl alcohol, 2-hydroxyethylmethacrylate, sec-butyl acrylate, n-butyl acrylate, t-butyl acrylate, t-butyl methacrylate, methylmethacrylate, N-dimethylaminoethyl(methyl)acrylate, N,N-dimethylaminopropyl-(meth)acrylate, t-butylaminoethyl(methyl)acrylate, N,N-diethylaminoacrylate, poly(ethylene oxide) (meth)acrylate, methoxy poly(ethylene oxide) (meth)acrylate, butoxy poly(ethylene oxide) (meth)acrylate, poly(ethylene glycol) (meth)acrylate, methoxy poly(ethylene glycol) (meth)acrylate, butoxy poly(ethylene glycol) (meth)acrylate, poly(ethylene glycol) methyl ether methacrylate and mixtures thereof, advantageously the monomer a) is poly(ethylene glycol) methyl ether methacrylate. 6.Embolization microspheres according to any one of claims 3 to 5, in which the linear or branched non-biodegradable hydrophilic crosslinking monomer c) has (CH2=(CR. 16 ))CO- or (CH2=(CR 16 ))CO-O- at its at least two ends, each R 16independently representing H or a (C1-C6)alkyl.

7. Embolization microspheres according to any one of claims 3 to 6, wherein the transfer agent d) is chosen from thioglycolic acid, 2-mercaptoethanol, dodecanethiol, hexanethiol and mixtures thereof.

8. Embolization microspheres according to any one of claims 3 to 7, wherein said matrix is ​​further based on at least one ionized or ionizable monomer of the following formula (IV): (CH2=CR17)-ME (IV) in which ^ R17 represents H or a (C1-C6)alkyl; ^ M represents a single bond or a divalent radical having from 1 to 20 carbon atoms; ^ E represents a charged or ionizable group having 100 atoms at most, E being advantageously chosen from the group consisting of -COOH, -COO-, -SO3H, -SO3-, -PO3H2, -PO3H-, -PO3 2- , -NR 18 R 19 , -NR 20 R 21 R 22+ , ^ R18, R19, R20, R21 and R22 independently represent H or a (C1-C6)alkyl.

9. Embolization microspheres according to any one of claims 3 to 8, in which said matrix is ​​further based on at least one colored monomer of the following general formula (VI): in which, ^ Z1 and Z2 represent, independently of each other, H or OR25, R25 representing H or a (C1-C6)alkyl, advantageously Z1 and Z2 represent H; ^ X represents H or Cl, advantageously H; ^ R23 represents H or a (C1-C6)alkyl, advantageously a (C1-C6)alkyl, in particular a methyl; and ^ R24 represents a group selected from linear or branched (C1-C6)alkylene, (C5-C36)arylene, (C5-C36)arylene-O-R26, (C5-C36)heteroarylene and (C5-C36)heteroarylene-O-R27, R26 and R27 representing a (C1-C6)alkyl or a (C1-C6)alkylene, advantageously R24 represents a group -C6H4-O-(CH2)2-O or -C(CH3)2-CH2-O.

10. Embolization microspheres according to any one of claims 3 to 9, wherein said matrix is ​​further based on elements visible in magnetic resonance imaging (MRI) such as iron oxide nanoparticles, gadolinium chelates or magnesium chelates, advantageously iron oxide nanoparticles. 11.Microspheres according to any one of claims 8 to 10, loaded with an active substance advantageously chosen from the group consisting of anti-inflammatory agents, local anesthetics, analgesics, antibiotics, anticancer agents, steroids, antiseptics and a mixture thereof.

12. Embolization microspheres according to any one of claims 8 to 10, loaded with macromolecules selected from the group consisting of enzymes, antibodies, cytokines, growth factors, coagulation factors, hormones, plasmids, antisense oligonucleotides, siRNA, ribozymes, DNA enzymes, aptamers, anti-inflammatory proteins, bone morphogenic proteins (BMPs), pro-angiogenic factors, vascular endothelial growth factors (VEGF) and TGF-beta, and angiogenesis inhibitors or anti-tyrosine kinases and mixtures thereof. 13.Pharmaceutical composition comprising at least one embolization microsphere according to any one of claims 3 to 12, in association with a pharmaceutically acceptable vehicle, advantageously for parenteral administration.

14. Kit comprising a pharmaceutical composition as defined in claim 13, in association with a pharmaceutically acceptable vehicle for parenteral administration, and at least one injection means.

15. Kit comprising on the one hand a pharmaceutical composition as defined in claim 13 and on the other hand at least one contrast agent for X-ray, magnetic resonance or ultrasound imaging, and optionally at least one injection means for parenteral administration, the pharmaceutical composition and the at least one contrast agent being packaged separately.

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