EP2788036A1 - Mri-visible hydrophobic copolymer - Google Patents

Abstract

The invention relates to a hydrophobic thermoplastic copolymer which is in particular of use for manufacturing and/or coating medical devices, in particular implantable medical devices, characterized in that it is obtained by copolymerization, and in that it comprises at least one first monomer unit and at least one second monomer unit onto which is grafted a paramagnetic-ion-chelating ligand which can complex with such a paramagnetic ion or a paramagnetic-ion-chelating ligand which is complexed with such a paramagnetic ion, wherein the second monomer unit is grafted in sufficient amount for the copolymer to be visible in magnetic resonance imaging when it is complexed with said paramagnetic ion. The invention also relates to a method for obtaining said hydrophobic thermoplastic copolymer.

Description

 COPOLYMER H YDROPHOB E VISIBLE IN MRI

 The present invention relates to the field of medical devices, in particular implantable, visible in magnetic resonance imaging.

 The present invention relates more particularly to a novel thermoplastic copolymer, having the property of being hydrophobic and insoluble in biological fluids, useful for the manufacture and / or coating of medical devices, in particular implantable, visible temporarily or sustainably in magnetic resonance imaging.

 The invention furthermore relates to a process for the preparation of such a copolymer and to a process for the preparation of a medical device, in particular an implantable device, detectable by magnetic resonance imaging comprising such a copolymer in its mass and / or as a coating.

 The invention also relates to particles obtained from such copolymers.

 The present invention relates ultimately to the medical device, in particular implantable, resulting therefrom.

 Magnetic Resonance Imaging (MRI) is a medical imaging tool that makes it possible to make images of the human body through the presence of hydrogen atoms.

 In order to increase the signal intensity and the quality of the images obtained, many contrast agents are used, most of them soluble in biological fluids, allowing better visualization in the body.

 However, MRI can not visualize a large majority of prostheses or medical devices based on polymer implanted in the body in order to mitigate certain pathologies, and therefore to monitor the fate of these in the body .

 However, there is a need to be able to follow the fate of these prostheses or implanted medical devices to evaluate the quality and durability of fixation, for example, the cellular integration, as well as possibly the degradation of the prosthesis.

The grafting of contrast agents on water-soluble polymers, ie having no vocation to remain in the body, has already been described. Such polymers In particular, water-soluble agents substituted with complexing agents can in particular improve the targeting and / or retention at the level of the organs to be studied by MRI.

 Thus, in US2007 / 0202047, a polyamine substituted with complexing agents having an affinity for tumor cells is described.

 Similarly, Irma Perez-Baena et al., "Single-chain polyacrylic nanoparticles with multiple Gd (III) centers as potential MRI contrast agents," Journal of Materials Chemistry, 2010, 20, 6916-6922, discloses a contrast for MRI with improved relaxivity due to its macromolecular construction in which Gd (III) ions are incorporated via complexation.

 Also known are Biomaterials 32 (2011) 6595-6605,

Biomacromolecules 2007, 8, 3126-3134 and Journal of Applied Polymer Science, Vol. 120, 2596-2605 amphiphilic copolymers optionally in the form of micelles, on which are grafted paramagnetic ion complexes.

 This grafting technique has for the moment been little used for long-lasting visualisations of implants intended to remain in the body.

 Document WO2011 / 004332 discloses, however, a technique aiming at a durable application of visualization of solid objects implanted in the body, implementing a chemical grafting of contrast agents on a polymer chain. Thus, this document relates to a hydrophobic polymer, characterized in that it comprises at least one monomer unit on which is grafted a chelating ligand of a paramagnetic ion complexed with such a paramagnetic ion, said monomeric unit having at least one group carbonyl, said monomer unit comprising, before grafting, at least one hydrogen atom in at least one of said at least one carbonyl group and said grafting of the chelating ligand operating at said at least one hydrogen atom in at least one of said at least one carbonyl group .

 However, because of the necessity of the presence of a hydrogen atom at a carbonyl group, this technique is limited in the choice of the nature of the polymeric material used. Moreover, the copolymer is obtained by modification of the main chain and not by copolymerization of two distinct monomer units.

Also known from US 2008/0073272 and WO 2008/034911 are hydrophobic copolymers visible by magnetic resonance imaging. These copolymers are nevertheless crosslinked, and consequently insoluble in all types of solvent. In other words, they belong to the class of thermosets or resins, not included in the present application.

 There is therefore a need to find thermoplastic hydrophobic polymers, in particular soluble in hydrophobic solvents, visible by magnetic resonance imaging that can be implemented either in bulk or on the surface of implantable medical devices, the associated technique of preparation of said polymers being simple, easy to make, especially on a variety of polymers compatible with the medical application.

 WO99 / 60920 discloses coatings for medical devices to make them visible in MRI. The copolymers described in this document are obtained by surface functionalization of certain units of the polymer, and not by copolymerization of two distinct monomer units. This technique does not control the amount of paramagnetic ions.

 There is thus a need to find such thermoplastic hydrophobic polymers which allow control of the amount of detectable paramagnetic ions on medical devices, in particular by controlling the substitution rate of the contrast agent.

 Thus, according to a first of its aspects, the present invention relates to a hydrophobic copolymer, in particular useful for the manufacture and / or coating of medical devices, in particular implantable, characterized in that it comprises at least a first monomer unit and at least one minus a second monomer unit on which is grafted a chelating ligand of a paramagnetic ion capable of complexing with such a paramagnetic ion or a chelating ligand of a paramagnetic ion complexed with such a paramagnetic ion, the second monomeric unit being grafted in an amount sufficient to that the copolymer is visible in magnetic resonance imaging when it is complexed with said paramagnetic ion.

The present invention relates in particular to a hydrophobic thermoplastic copolymer, especially useful for the manufacture and / or coating of medical devices, in particular implantable, characterized in that it is obtained by copolymerization, that it comprises at least a first monomer unit and at least one second monomer unit on which is grafted a chelating ligand of a paramagnetic ion capable of complexing with such a paramagnetic ion or a chelating ligand of a paramagnetic ion complexed with such a paramagnetic ion, the second monomer unit being grafted in an amount sufficient for the copolymer to be visible in magnetic resonance imaging when complexed with said paramagnetic ion.

 By "sufficient amount" is meant the minimum amount to achieve the desired effect, namely, visibility in magnetic resonance imaging.

 By "thermoplastic copolymer" is meant a linear or branched copolymer forming a mono or two-dimensional network, characterized by a softening temperature. Thus, the definition of "thermoplastic copolymers", resins, crosslinked or thermoset copolymers are excluded.

 In particular, the thermoplastic copolymers are soluble in hydrophobic solvents while the thermoset copolymers are insoluble in all types of solvent.

 By "copolymerization" within the meaning of the invention is meant a polymerization reaction between at least two different monomers.

 The subject of the invention is also a process for preparing said copolymer as defined above, comprising (i) at least one step of preparation by copolymerization of a copolymer comprising at least a first monomer unit and at least a second monomer unit comprising a functional group capable of forming a bond, especially a stable bond, with a complex of a paramagnetic ion or with a chelating ligand of a paramagnetic ion capable of complexing with such a paramagnetic ion, optionally by click chemistry and (ii) at at least one grafting step on said second monomer unit of a complex of a paramagnetic ion or a chelating ligand of a paramagnetic ion capable of complexing with such a paramagnetic ion.

 When step (ii) consists of a grafting step on said second monomer unit of a chelating ligand of a paramagnetic ion capable of complexing with such a paramagnetic ion, said method comprises a step (iii) of complexing said paramagnetic ion with said chelating ligand.

It also relates to a medical device characterized in that it comprises at least one copolymer as defined above in its mass and / or as a coating and / or as a marking, in particular with a view to traceability as set forth above. after. The subject of the invention is also a method for preparing a medical device, in particular an implantable device, detectable by magnetic resonance imaging, characterized in that it comprises at least one coating step with a copolymer as defined above, in particular by dipping or spraying, in a solution comprising said polymer according to the invention.

 It further relates to the compound of formula (A) below or formula (B) below

 in which

M represents - (CHR) x- or - (CH ₂ -CHR-O) _y where x and y independently represent an integer from 1 to 18 for x and from 1 to 1000 for y,

 Y being one of the functions capable of reacting with anhydride groups, for example the hydroxyl, amine or thiol groups,

 R being a (C 1 -C 18) alkyl group or a hydrogen atom,

 especially useful as complexing agent of a paramagnetic ion.

The subject of the invention is also the corresponding complex of formula (Α ') following formed from (A):

the corresponding complex of formula (Β ') following formed from (B) (Β ')

 in which M and Y are as defined above, and

 PA denotes a paramagnetic ion, especially gadolinium.

 The copolymer which is the subject of the present invention, by the possible control of the degree of functionalization provided by incorporation of the second functionalized monomeric unit, thus makes it possible to adapt the content of complex, and thus, as a contrast agent, to the nature of the both the copolymer used and both the final implant, and this in order to obtain the desired viewing conditions, namely an optimal contrast at the image.

 The present invention also relates to particles comprising at least one copolymer according to the invention having a mean size ranging from 1 nm to 1000 μιη, preferably from 10 nm to 500 μιη and in particular from 20 to 250 μιη.

 In the context of the present invention, the following terms mean:

 - to understand the polymer "in its mass", the fact that the object concerned comprises within it such a polymer, and for example is essentially or partially constituted of said polymer,

 the term "polymeric chain" designates a macromolecule or a part of a macromolecule comprising a linear or branched sequence of consecutive units situated between two consecutive consecutive units which may each be a terminal group, a branch point or a characteristic characteristic of the macromolecule,

 the term "polymeric main chain" designates the part of the polymer chain as defined above, before the grafting step.

 the term "monomer" covers a molecule capable of being converted into a polymer by combination with itself or with other molecules of the same type,

a "monomeric unit" or "monomeric unit" denotes the smallest constitutive unit whose repetition leads to a regular macromolecule, a "complexed monomeric unit" designates a monomeric unit on which a complex is grafted,

 a "hydrolytically degradable" material, denotes a material which degrades in the presence of water following the breaking of the bond which connects the monomer units by hydrolysis and for which there is evidence that the degradation products of the material have masses number-average molars lower than the number average molecular weights of the polymeric chains of the starting material.

 - a "bio-resorbable" or "absorbable" material, means a material that degrades enzymatically or hydrolytically and for which there is evidence that the degradation products are integrated into biomass and / or removed from the body by metabolism or filtration kidney,

 - "block" means a part of a macromolecule comprising several identical or different constituent units and which have at least one particular constitution or configuration to distinguish it from its adjacent parts,

 the terms "complexing agent of a paramagnetic ion", "chelating agent of a paramagnetic ion" or "chelating ligand of a paramagnetic ion" are equivalent, and denote molecules carrying one or more chemical functions allowing them to to bind to one or more paramagnetic ions via a non-covalent interaction, for example of the Lewis acid / Lewis base type, electrostatic or other,

 the term "complex" designates one or more cations surrounded by one or more ligands which delocalise a part of their electronic density on the cation (s) thus forming non-covalent chemical bonds, for example of the Lewis acid / base type; Lewis, with this or these. In the context of the present invention, said cations are paramagnetic ions.

 - the terms "between ... and ..." and "vary from ... to ..." mean that the terminals are also described,

 "Hydrophobic polymer" means a polymer for which a contact angle of between 40 and 180 ° and more preferably between 50 and 150 ° is measured, for example according to the measurement protocol detailed below. Amphiphilic or micelle-forming polymers are not part of the invention.

In other words, the copolymers according to the invention are insoluble in biological fluids. Protocol for measuring a contact angle

 The measurement of contact angle can be made with a tensiometer, for example KRUSS Kl 00 sold by the company KRUSS.

 According to the Wihelmy method, a clean, dry microscope glass slide is immersed in a solution of copolymer according to the present invention, with a concentration of 5 g / L dissolved in tetrahydrofuran (THF), corresponding to an immersion of 1 cm in water, this operation being carried out at 20 ° C.

 The tensiometer measures the surface tension between the water and the copolymer-coated blade, and calculates the resulting contact angle with the water.

NEW HYDROPHOBIC COPOLYMERS

 The hydrophobic thermoplastic copolymer according to the present invention is characterized in that it is a copolymer obtained by copolymerization of at least one first monomer and at least one second functionalized monomer, on which is grafted after the step of copolymerization, a complex of a paramagnetic ion or a ligand capable of complexing a paramagnetic ion, optionally by click chemistry.

 In the context of the present invention, the copolymer thus comprises at least first units, called monomer units A, derived from the first monomer, and at least second units, called monomer units BF, from the second monomer, in which B is a monomeric unit and F is a functional group capable of forming a bond with a complex of a paramagnetic ion or a ligand capable of complexing a paramagnetic ion.

 In the context of the present invention, the expression "functional group" intends to designate a group of atoms forming a reactive function.

 By "functionalization rate" is meant in the context of the present invention the number content in monomer unit B-F, relative to the total number of monomer units of the copolymer.

In the case where said grafting step has been carried out by click chemistry as explained below, "functionalization rate" also refers to the content of number of monomer units grafted to a chelating ligand of a paramagnetic ion which can complex with a paramagnetic ion or a chelating ligand of a paramagnetic ion complexed with paramagnetic ion relative to the total number of monomer units of the copolymer.

 In the following examples, the influence of the degree of functionalization has been illustrated by the mass percentage of paramagnetic ion in the copolymer, that is to say the weight content of paramagnetic ion relative to the total weight of the copolymer considered. .

 According to a particular embodiment, the degree of functionalization is between 0.01 and 50%, especially between 0.1 and 10%, or even between 0.1 and 5%.

 Preferably, the hydrophobic thermoplastic copolymers according to the invention are soluble in at least one hydrophobic solvent. Example 14 below illustrates in particular the solubility of a copolymer according to the invention in dichloromethane. The thermoplastic copolymers according to the invention may, for example, be soluble in chloroform, dimethylsulfoxide, Ν, Ν-dimethylformamide, acetone, tetrahydrofuran and / or ethyl acetate.

 This solubility allows the copolymers according to the invention to be easily used as a coating or in compositions for airbrushing.

 The copolymers according to the invention may be linear, branched and / or star-shaped. According to a particular embodiment, the copolymers according to the invention are linear.

 The invention relates to hydrophobic thermoplastic copolymers as defined above which may have various degradation profiles. In other words, depending on the nature of the copolymer envisaged, as is detailed below, it can be bioabsorbable or degradable hydrolytically or not. This property can thus be easily modulated according to the intended application, which is one of the advantages of the present invention. Advantageously, this property can be evaluated by implementing the following degradation test.

Degradation test

This test makes it possible to determine whether a polymer is bioabsorbable or hydrolytically degradable in accordance with the definition given above. This test consists in studying the evolution, for example by steric exclusion chromatography, of molar masses number average under conditions mimicking a physiological situation (PBS buffer at pH 7.4, mechanical stirring at 37 ° C).

The percent decrease in number average molar mass at different times is expressed by the following equation: number average molar mass at T ₀ - number average molar mass at T

average molar mass in number at T _c

As an indication, according to the present invention:

 for a time T = 2 months, the percentage decrease in the number-average molar mass may be between 0 and 50%, preferably between 0 and 25%.

 for a time T = 6 months, the percentage decrease in the number-average molar mass can be between 0 and 75%, preferably between 5 and 50%.

 for a time T = 1 year, the percentage decrease in the number-average molar mass may be between 5 and 100%, preferably between 10 and 80%.

 for a time T = 2 years, the percentage decrease in the number-average molar mass may be between 10 and 100%, preferably between 20 and 90%.

 An illustration of the implementation of the test is given in the examples below with regard to a copolymer according to the present invention. First monomer

 In the case where the first monomer gives a degradable polymer, the first monomer must be biocompatible.

 For the purposes of the present invention, "biocompatibility" is the ability of a material to induce an appropriate response from the host in a specific application. Furthermore, it is within the scope of the present invention the monomers imparting hydrophobic properties to the resulting copolymer.

 Finally, because the targeted implantation may be permanent or temporary, the copolymers used in the context of the present invention may be biostable or bioabsorbable. Therefore, the first monomer may be selected from the monomers for obtaining biostable or bioresorbable homopolymers.

According to a particular embodiment, the first monomer is a monomer useful for the preparation of a polymer as defined below. Useful monomers for the preparation of biostable homopolymers

 Among the monomers useful for the preparation of biostable homopolymers, mention may be made of:

 · Monomers useful for the preparation of polyolefins.

The polyolefins are linear, hydrophobic aliphatic polymers represented by the following formula - (CH ₂ -C (R ')) - in which R and R' may be hydrogen atoms or alkyl groups, more particularly groups (Ci -Cig) alkyl. Semi-crystalline thermoplastics such as poly (ethylene) (PE) and polypropylene (PP) are the most widely used in the biomedical field. PE is chemically inert, resistant to oxidation and its density may vary depending on the method of manufacture.

• Monomers useful for the preparation of fluoro-polymers.

Fluoropolymers are characterized by their chemical inertness and very weak intermolecular interactions. Perfluorinated chains are more hydrophobic and more stable than their hydrogenated counterparts. Polytetrafluoroethylene (PTFE) is the most widely used fluoropolymer in medicine. The anti-adhesive properties of PTFE prostheses are used for specific applications. · Monomers useful for the preparation of acrylic and methacrylic polymers.

 In the biomedical field, poly (methyl methacrylate) (PMMA) and poly (methyl acrylate) are the most representative of methacrylic and acrylic derivatives. PMMA is a thermoplastic especially used in orthopedic surgery for its mechanical properties close to the bone. Its optical properties are also used for the design of intraocular implants.

• Monomers useful for the preparation of vinyl polymers. · Monomers useful for the preparation of semi-aromatic polyesters.

Semi-aromatic polyesters are non-degradable polyesters. In this category and in the biomedical field, poly (ethylene terephthalate) (PET) and poly (butylene terephthalate) (PBT) are mainly used. PET found in the amorphous (transparent) or semi-crystalline (x = 30%) state has a low water absorption rate, a chemical inertness and good mechanical strength properties. · Monomers useful for the preparation of polyurethanes (PUR).

 Polyurethanes are block copolymers composed of flexible units and rigid units. They are light, flexible at low temperatures and resistant to hydrolysis. Since the 1970s, PURs, thanks to their stability and biocompatibility properties, have many applications in surgery.

• Monomers useful for the preparation of silicones.

Silicones or polysiloxanes include polymers with very varied properties, whose common point is the siloxane unit unit - (Si (R ₂ ) -O) -,

with R independently representing a (C1-C18) alkyl group.

 The strong silicon / oxygen bond of the pattern gives the silicones good chemical stability and resistance to aging. The adhesion properties of the silicones can be modulated according to the nature of the substituents R. Thus, liquid compounds or gels, in the form of gum (bandages) or in hard form can be obtained.

Useful monomers for the preparation of bioresorbable homopolites

 Aliphatic polyesters are the most used resorbable materials in the biomedical field. They belong to a family of polymers which comprises both compounds produced by the bacterial route, poly (-hydroxyacids), and synthetic compounds obtained either by polycondensation of hydroxy acids or diacids and diols, or by opening of heterocycles of lactone type.

In reality depending on the nature of the polyester, the resorption can last from 1 month to 10 years. In the context of the present invention, the polyesters having a resorption time measured according to the above-mentioned protocol greater than 1 month, or even 6 months, are more particularly targeted. Mention may in particular be made of polyester polymers consisting wholly or in part of identical or different monomeric units, each of these units having the following formula (II):

 O

-0 - ^ - CHR ₂ - ^ CR ₄ R ^

 (Π)

in which :

R ₂ , R ₃ and P 4 independently represent a hydrogen atom, a (C 1 -C 12) alkyl group or a (C 1 -C 8) cycloalkyl group optionally substituted by a (CC ₁₂ ) alkyl group,

 x represents an integer between 0 and 12, for example between 0 and 6, and

 y represents an integer between 0 and 8, for example between 0 and 6, it being understood that x and y are not zero simultaneously.

In general, the polyesters of formula (II) can be obtained:

 a) by polycondensation of a hydroxy acid on itself, or

 b) by lactone ring opening polymerization.

Among these polymers comprising monomeric units of formula (II), mention is made in particular of polyesters consisting in whole or in part of identical or different monomeric units, each unit having the following formula (III)

in which R ₃ represents a (C ₁ -C ₂ ) alkyl group.

 Among the monomers useful for preparing polyesters include hydroxybutyric acid, hydroxyvaleric acid, hydroxyhexanoic acid and hydroxyoctanoic acid.

The following table gives the correspondence between the meaning of the R ₃ group and the full name of the polymer of formula (III). ₃ Polymer name

CH ₃ Polyhydroxybutyrate (PHB)

C ₂ H ₅ Polyhydroxyvalerate (PHV)

C ₃ H ₆ Polyhydroxyhexanoate (PHHx)

 CsHg Polyhydroxyoctanoate (PHO)

By way of illustration of other polyesters comprising monomeric units of formula (II), mention may be made of the polyesters obtained by opening lactone rings of formula (IV)

in which :

 q represents an integer which can vary between 2 and 9,

R5 is (Ci-C ₁₂₎ alkyl, and

n is an integer between 0 and 2, it being understood that when n is equal to 2, the two groups R ₅ may not only be different but may also be on the same or on two different carbon atoms.

 When q is 5 and n is 0, it is caprolactone or ε-caprolactone.

 The polyesters thus obtained are polycaprolactone or poly (ε-caprolactone). Among the lactones of formula (IV) that may be suitable for the present invention, mention may also be made of δ-valerolactone, γ-butyrolactone, ε-decalactone, pivalolactone and diethylpropriolactone.

By way of illustration of other polyesters comprising monomeric units of formula (II), mention is made of lactic acid polymers (PLA) consisting in whole or in part of identical or different monomeric units, each of these units having the following formula:

Generally, the lactic acid polymers are obtained from the lactide monomer, for example by ring-opening polymerization or from lactic acid or lactic acid derivatives by polycondensation. Due to the chiral nature of lactic acid, there are poly-L-lactide (PLLA) and poly-D-lactide (PDLA), poly (D, L lactide), poly-meso-lactide and all the stereoisomers that are part of the conforming polymers for the present invention.

By way of illustration of still other polyesters of formula (II), glycolic acid or poly (glycolide) polymers consisting wholly or in part of identical or different monomeric units are mentioned, each of these units having the following formula

Among the polyesters comprising monomer units of formula (II) that can be used in the context of the invention, mention may also be made of homopolymers and copolymers of p-dioxanone (1,4-dioxan-2-one); 1,4-dioxepan-2-one (including its 1,5,8,1,2-tetraoxacyclotetradecane-7,1,4-dione dimers); 1,4-dioxepan-5-one;

1.5- dioxepan-2-one; 6,6-dimethyl-1-4-dioxan-2-one; 2,5-diketomorpholine; 3-methyl-1,4-dioxane-2,5-dione; 3,3-diethyl-1,4-dioxan-2,5-dione;

6.6-dimethyl-dioxepan-2-one and their polymer mixtures.

Table below lists the main types of aliphatic polyesters:

Poly (lactide) (PLA), poly (glycolide) (PGA), poly (8-caprolactone) (PCL) and their copolymers are the most widely used poly (hydroxy acids) because of their biocompatibility and diversity. properties.

According to one particular embodiment of the invention, ε-caprolactone is used as the first monomer. Certain aliphatic polyamides, particularly polypeptides, are also a class of potentially hydrophobic degradable polymers within the scope of the present invention.

Functionalized monomer

 As the functionalized monomer, a monomer capable of comprising a functional group allowing the grafting of a complex of a paramagnetic ion or of a ligand capable of complexing said paramagnetic ion, via this functional group, optionally by click chemistry, is chosen.

 Said functionalized monomer may be hydrophobic or not.

 The monomer taken without the functional group may be chosen from any of the monomers mentioned as the first monomer.

 According to a particular embodiment, the functionalized monomer taken without the functional group is selected from a monomer useful for the preparation of a polyester, as described above for the first monomer.

 In the context of the present invention, the functional group can be any reactive functional group known to those skilled in the art, and in particular an azide, alkyne, nitrile, carboxylic acid, ester, anhydride, acid halide, amide, iso ( thio) cyanate, epoxide, thiol, amine, aziridine, ketone, aldehyde, diene, alkene or hydroxyl protected or not.

 The grafting step is described below.

 As the functionalized monomer, it is possible to use propargylated ε-caprolactone (αPr sCL) or 5-NHZ-δ-valerolactone (5-NHZ-6-VL).

Complexing agent / functionalized complex

 The complexing agent is chosen according to the type of grafting envisaged.

 Thus, according to a particular embodiment, when a click chemistry graft according to the Huisgen reaction is envisaged, the complex of a paramagnetic ion must comprise at least one azide function if the functionalized monomer contains an alkyne function.

The complexing agent before complexation may be used in the context of the present invention may have at least one carboxylic acid function. As such, we In particular, mention is made of diethylene triamine penta-acetic acid (DTPA), tetraazacyclododecane tetraacetic acid (DOTA) and tetraazacyclotetradecane tetracetic acid (TETA).

 The paramagnetic ion suitable for the present invention is a multivalent paramagnetic metal including, but not limited to, lanthanides and transition metals such as iron, manganese, chromium, cobalt and nickel.

 In a preferred manner, this paramagnetic ion is a lanthanide which is highly paramagnetic and, even more preferably, is a gadolinium (III) ion.

By way of example of complexing agent, mention may be made of the novel compounds DTPA-monoN ₃ and DTPA-diN ₃ , which form part of the invention. The corresponding complexes [Gd (DTPA-monoN ₃ )] and [Gd (DTPA-diN ₃ )] are also new, and form part of the invention. DTPA-diN ₃ and [Gd (DTPA-diN ₃ )] are as shown below:

with R = - (CH ₂ ) ₃ N ₃

and DTPA-monoN ₃ and [Gd (DTPA-monoN ₃ )] are as shown below

The galodinium complex [Gd (DTPA-diN ₃ )] can be obtained by bringing the DTPA-diN ₃ chelating ligand into contact with GdCl ₃ in water containing pyridine, in the presence or absence of a solvent such as DMF, DMSO, for example at a temperature of between 20 and 60 ° C., for example at 40 ° C., for a duration that can be between 30 minutes and 1 week, for example for a duration of 24 hours.

Other examples of complexes of a paramagnetic ion include complexes of europium salts (Eu ³⁺ ). Copolymer according to the invention

 In the context of the present invention, the copolymers according to the invention may have a number-average molecular weight of between 1,000 and 500,000, especially between 2,000 and 100,000, and for example between 3,000 and 50,000 g / mol. .

 The nature of the first and second monomers is advantageously chosen so that the latter can give rise to a copolymerization reaction, which is a matter of general knowledge of those skilled in the art.

 According to a particular embodiment of the invention, the copolymer is a bioabsorbable copolymer.

 The copolymer may be a random copolymer or a block copolymer or a graft copolymer.

 All of these copolymers can be made according to protocols and conditions known to those skilled in the art.

 By way of example of copolymer according to the present invention, mention may be made in particular of the following copolymers:

 - Caprolactone copolymer (CL) and propargylated caprolactone

 (CL-propargylated or Pr-CL) statistical,

 - Caprolactone copolymer (CL) and propargylated caprolactone

 (CL-propargylated or Pr-CL) block,

- Caprolactone (CL) and 5-NH ₃ ⁺ -δ-valerolactone copolymer

(5-NH ₃ ⁺ -ô-VL) statistics, or

Caprolactone (CL) and 5-NH ₃ ⁺ -δ-valerolactone (5-NH ₃ ⁺ -δ-VL) block copolymer. According to a particular embodiment of the invention, the copolymer is a random copolymer.

 According to a first particular embodiment of the invention, A and B are identical.

 According to a sub-embodiment of the invention of this first embodiment, A and B are both derived from cyclic esters as defined above.

In particular, the copolymer obtained by copolymerization of an ε-caprolactone and an α-propargylated ε-caprolactone can be mentioned as a copolymer according to the following scheme:

The copolymer can be obtained by contacting the two monomers in the presence of a catalyst such as Sn (Oct) ₂ (where "Oct" is octanoate) and in the presence or absence of an initiator such as isopropanol and a solvent such as toluene, at a temperature which can be between 0 and 200 ° C, for example at 140 ° C for a period of between 1 min and 1 week, for example for 3.5 hours.

 According to an even more particular embodiment of the invention, the polymer according to the invention is a copolymer of α-caprolactone and α-propargylated ε-caprolactone having a number-average molar mass of between 1,000 and 500,000, in particular between 3,000 and 50,000 g / mol.

According to another sub-mode of this first particular embodiment of the invention, A and B are both derived from methyl acrylate.

 In particular, the copolymer obtained by copolymerization of methyl acrylate and propargyl acrylate may be mentioned as copolymer according to the following scheme:

 The copolymer can be obtained by contacting the two monomers, for example via a conventional radical polymerization or a controlled radical polymerization (RAFT or ATRP).

In the case of a conventional polymerization, this can be carried out in the presence of a radical generator such as, for example, le or benzoyl peroxide in a solvent, especially of the toluene or dioxane type, at temperatures may be between 60 and 110 ° C. The reaction time can be between 5 minutes and 15 hours.

 In the case of a so-called controlled radical polymerization, for example ATRP, the polymerization can be carried out in the presence of a halogenated initiator such as, for example, alpha-isobutyryl bromide, a copper-based catalytic system such as the CuBr / PMDETA complex in a solvent, for example, toluene at temperatures between 60 and 90 ° C. The reaction time can be between 1 and 5 hours.

 According to an even more specific embodiment of the invention, the polymer according to the invention is a copolymer of methyl acrylate and propargyl acrylate with a number-average molar mass of between 5,000 and 100,000 g / mol. .

 When said copolymer has been obtained by a conventional radical polymerization, the number-average molecular weight may be between 60,000 and 100,000 g / mol, in particular between 70,000 and 90,000 g / mol.

 When said copolymer has been obtained by a controlled radical polymerization, the number-average molar mass may be between 5,000 and 20,000 g / mol.

According to a second particular embodiment of the invention, A and B are different.

 According to a sub-embodiment of this second embodiment of the invention, A and B are both derived from cyclic esters as defined above.

In particular, the copolymer poly (5-NH ₃ ⁺ -6-valerolactone-co-s-caprolactone) copolymer obtained by copolymerization of a ε-caprolactone and an δ-valerolactone amine can be mentioned according to the following scheme:

γ ν ^ The copolymer can be obtained by contacting the two monomers in the presence of a catalyst such as Sn (Oct) ₂ and in the presence or absence of an initiator such as benzyl alcohol and a solvent such as tetrahydrofuran at a temperature which may be between 0 and 200 ° C, for example at 110 ° C for a period of between 1 min and 1 week, for example for 24 hours.

 Deprotection of the amine functions in ammonium functions can be carried out according to protocols and conditions known to those skilled in the art, for example by reaction of the protected copolymer with hydrobromic acid in a solvent such as dichloromethane at room temperature for 20 minutes. minutes.

 According to an even more specific embodiment of the invention, the polymer according to the invention is a copolymer of ε-caprolactone and aminated δ-valerolactone having a number-average molar mass of between 1,000 and 500,000, in particular between 3,000 and 50,000 g / mol.

 The rate of functionalization, whatever the embodiment, can be modulated.

 In particular, in the case of a copolymer of ε-caprolactone and α-propargylated ε-caprolactone or of a copolymer of ε-caprolactone and δ-valerolactone, the degree of functionalization may vary between 0.01 and 50%, especially between 0.1 and 10%, or even between 0.1 and 5%.

 As is apparent from the reading of the examples, it has been found that, under comparable conditions of synthesis of the copolymer and of the environment, the rate of functionalization influences the proton relaxation time in NMR. On the other hand, at the MRI visualization stage, the functionalization rate influences the contrast of the image obtained. Thus, it has been observed that beyond a certain value of the functionalization rate, the contrast of the image is not improved.

According to a particular embodiment, the copolymer according to the present invention may also comprise additional monomer units, also biocompatible. These additional monomer units may take the form of additional blocks. Among these, mention may be made especially of the following polymer blocks: poly (ethylene glycol), poly (propylene glycol) or poloxamer. According to a variant of the invention, the additional block is a poly (ethylene glycol) or PEG block of formula H (OCH ₂ CH ₂ ) _p OH, where p varies from 5 to 600.

METHOD FOR GRAFTING CHELATING LIGAND OR

THE COMPLEX AGENT WITH A PARAMAGNETIC ION

 The grafting method generally consists in coupling a ligand complexed or not with a paramagnetic ion with the functionalized monomer units of the copolymer obtained by copolymerization of at least one first monomer and at least one functionalized monomer.

 During said grafting, it may for example be the formation of a binding function or a covalent bond.

 The term "binding function" is intended to denote a chemical function whose formation makes it possible to connect, by covalent bonding, two originally distinct chemical entities.

 According to a particular embodiment, the grafting is ensured by means of one or more non-hydrolyzable bonds in a physiological medium. In other words, stable links are preferred for the implementation of the present invention.

 According to one particular embodiment, the binding function or the bond between the complexing agent and the monomer to which it is attached is at least as stable as the bonds of the main chain, that is to say that There is no elimination of the body from at least one functionalized complex before the polymer degrades itself.

 In the context of the present invention, the term "stable bond" means a bond which is not destroyed following the submission to the stability test as described below:

 Stability test

A defined amount of copolymer complexed with the paramagnetic ion (eg Gd ³⁺ ), for example 50 mg for each tube, is added to 30 tubes in which 5 ml of phosphate buffered saline or PBS is added. These tubes are then put in an oven at 37 ° C with stirring to mimic physiological conditions.

 3 tubes correspond to a degradation time:

 7 days - 150 days

15 days - 210 days 30 days - 270 days

 60 days - 330 days

 90 days - 400 days

At each sampling, a plasma torch or ICPMS spectrometry of the aqueous phase is carried out which measures the quantity of paramagnetic ion released into the aqueous phase in complexed or free form. In the absence of a paramagnetic ion assayed in the release medium it is the proof that the polymer-complex bond is stable, in particular at least as stable as the intra-copolymer bond, and that the complex is not uninhibited .

According to a particular embodiment of the invention, the grafting is carried out by a simple coupling, for example by click chemistry.

 The grafting can moreover be carried out according to any simple alternative method to click chemistry, in particular by amidifications or esterifications.

 Furthermore according to a particular embodiment, the present invention also comprises copolymers comprising a linker between the ligand and the functionalized monomer unit. It may be included in the copolymer structure to move the ligand away from the main chain. The following groups may especially be mentioned as linkers: alkyl chains, polymer chains, in particular polyether chains, in particular PEG or pluronic chains.

As a link function resulting from a click chemistry reaction (Lclick), there may be mentioned triazole, tetrazole, thioether, carbamate or urea.

 For example, an Lclick bonding function can be derived, according to the invention, from the click chemistry reaction between a functional group Y and a complementary functional group F, and make it possible to connect a complex of a paramagnetic ion or a chelating ligand. a paramagnetic ion capable of complexing with such a paramagnetic ion according to the invention and a copolymer according to the invention.

For example, the click chemistry reaction may be represented by the following scheme, in the case where the complexing agent is of monodentate type. χ-γ

 (A) - (B-F) (A) - (B)

Lclick

in which

 n and m represent the number of monomer units A and B-F respectively, with n being able to vary from 5 to 4500, for example from 10 to 1000 and m varying from 1 to 500, for example from 1 to 10,

 A represents a first monomer unit,

 B-F represents a second monomeric unit, in which the functional group F is the functional group which reacts with the functional group Y by click chemistry to form the Lclick binding function.

 Lclick represents the link function obtained by click chemistry between functional groups F and Y, and

 XY represents a complex of a paramagnetic ion or a chelating ligand of a paramagnetic ion capable of complexing with such a paramagnetic ion in which the functional group Y is the functional group which reacts with the functional group F by click chemistry to form the function of Lclick link.

According to one embodiment, the click chemistry reaction implemented according to the invention can be:

 a cycloaddition reaction of unsaturated species, in particular a 1,3-dipolar cycloaddition reaction or a Diels-Alder type reaction;

 a nucleophilic substitution reaction, in particular an opening reaction of constrained electrophilic heterocycles such as epoxides, aziridines, aziridinium ions and episulfonium ions;

a reaction on the carbonyls with the exception of the aldol chemistry, in particular a formation reaction of ureas, thioureas, aromatic heterocycles, oximes ether, hydrazones or amides ; or an addition reaction on multiple carbon-carbon bonds, in particular an epoxy, dihydroxylation, aziridination, sulfenyl halide addition, thiol addition or addition reaction reaction; Michael type. In the case of a cycloaddition reaction, an azide group can be reacted either with an alkyne group leading to the formation of a triazole bonding function, or with a nitrile group, leading to the formation of a tetrazole.

 The most widespread reaction in click chemistry that can be used in the context of the present invention is the Huisgen reaction "cycloaddition of alkynes on azides", described in R. Huisgen Angew. Chem. 1963, 75, 604 according to the following scheme:

 And according to another catalyzed version described in V. V. Rostovtsev, L. Green G., V. V. Fokin, K. B. Sharpless, Angew. Chem. Int. Ed. 2002, 41, 2596 and C. W. Torne, C. Christensen, M. Meldal, J. Org. Chem. 2002, 67, 3057 according to the following scheme:

Cu (l) _R1 ^

R1 - N = N = N + R2-≡ * ^■ \ ^

 R2

Thus, according to a particular embodiment of the invention, it is intended to form a copolymer comprising a monomeric unit functionalized with a propargyl functional group.

Therefore, by reaction of a complex of an azotic functionalized paramagnetic ion, or of an azide functionalized ligand capable of complexing said paramagnetic ion with the functionalized monomeric units with a propargyl functional group, a copolymer is obtained which is a complex of a paramagnetic ion or can complex a paramagnetic ion. MEDICAL DEVICE

 The present invention extends to a medical device comprising at least one polymer according to the present invention.

 The polymer according to the present invention may be an integral part of the medical device itself; it is in other words included in its mass or is on the surface of said device in the form of a coating of a thickness such as to make the medical device visible magnetic resonance imaging.

 Typically, the coating may form a thickness between 1 and 1000 μιη, for example between 10 and 100 μιη.

 In the alternative of coating the medical device, various methods can be employed known to those skilled in the art. As such, there may be mentioned electro-spinning, soaking, the implementation of a spray drying or airbrush or spray.

 Of course, the present application extends to medical devices having undergone another type of mass treatment and / or surface of a different nature than that considered in the present invention. By way of example, mention may be made of bacterial and fungal anti-adhesive treatments, treatments allowing the release of active principles such as antibiotics, antibacterials, antifungals, anti-inflammatories, and any kind of active ingredients that can be released in if you.

 As medical devices particularly suitable for the present invention, mention may be made of medical devices which are more particularly applicable in the field of gynecology, for example for trellises or prostheses for genital prolapse. According to another aspect, the present invention extends to a method of marking a medical device, characterized in that it comprises at least one deposition step, in particular on a targeted area of the medical device, on the surface of the material of a polymer according to the invention.

According to this aspect, the polymer according to the invention is thus deposited on the prostheses, in particular in the form of an inscription in order to carry out a postoperative follow-up thanks to the direct marking on the material. More particularly, the marking may be intended for the traceability of the medical device. The medical device can be identified throughout its life, whether during manufacture, distribution or once laid. Thus the marking can take any form or surface on the medical device.

 Even more particularly, the inscriptions may take the form of numbers, letters or any other type of characters useful for traceability.

By way of examples, the marking may be carried out according to one of the following methods:

depositing a homogeneous surface of polymer according to the invention on the surface of the material, in which the characters are etched.

 depositing the characters on the surface of the material by micro-printing techniques, in which the polymer according to the invention represents the ink.

 CE 1899

This aspect of the invention is particularly advantageous insofar as the marking is thus integral with the medical device and no longer the packaging thereof as is usually the case.

 The invention also extends to a medical device provided with a marking made using a polymer according to the present invention.

The copolymer according to the present invention can also find application in any medical field where MRI is used.

 These different areas can be classified by surgical specialty or by type of particularly implantable materials that are used in several medical fields.

Ranking by medical-surgical specialties:

 Gynecology:

• retaining mesh in the course of prolapse genito urinary and rectal (vaginal and abdominal surgery) • tubal sterilization clips

 • endo-luminal tubal obstruction devices

 • cervical banding tape

 • intraperitoneal and endo-uterine anti-adhesive devices

 Urology:

 • Artificial Urinary Sphincter

 • penile prosthesis

 • reinforcement patch of corpora cavernosa (penis curvature cure, Lapeyronie's disease)

 • periurethral balloons

 • injectable devices in the peri-urethral area

 • strips under urethral

 • stent, endo-urethral prostheses

 • urinary diversion probes (transcutaneous and natural).

 Orthopedics:

 • synthetic ligaments

 • neo cartilage or articulation

 • synthetic intervertebral discs

 • femoral head

 • acetabulum (femur and humerus)

 • tibial plateau

 • humeral head.

 QRL:

 • cochlear implants

 • prostheses of the inner ear, bone substitutes.

 Endocrinology:

 • implantable pumps.

 Vascular:

 • endovascular prostheses

 • arterial and venous prostheses

• devices for closing and haemostasis first vascular trans-arterial • Implantable vascular chambers and catheters.

 Neurology:

 • Vascular stents

 • aneurysm occlusion devices and arterial vascular dissection

 • electrostimulation probes

 • patches and reinforcements of hard mother and meningeal.

 Ophthalmology:

 • synthetic corneas.

 Digestive Surgery :

 • reinforcement plates (trellis) hernia (diaphragmatic, parietal, inguinal, crural)

• gastric rings

 • splenic nets

 • esophageal prostheses

 • biliary and digestive tract stents (hail, colon, rectum) stent

 • parenteral nutrition probes

 • artificial anal sphincter.

 Cardiology:

 • coronary stents

 • Pace Maker cases and probes

 • systolic training probes

 Radiology:

 • vascular embolization agents, vascular occlusions (arterial or venous) (temporal or definitive.

Implantable materials used in several medical fields:

 • Surgical suture threads.

 • Venous and arterial (central and peripheral) catheters.

 • Endo body heat probes.

 • Surgical, tubular and blade drains, drainage ditches.

• Synthetic staples for approximation, identification, digestive anastomosis and prosthetic fixation. • Tissue engineering: Matrix of stem cell support in reconstructive surgery.

 The copolymer according to the invention can finally find an application in the very enclosure of the MRI apparatus.

 The working environment in the MRI room necessitates the absence of metals capable of disturbing the magnetic field of the MRI. This environment includes the development of ventilation equipment and resuscitation without metal, compatible MRI. We can cite as such the following equipment: table, headrest, neck brace, splint, harpoons, supports and calluses allowing the positioning and tracking in MRI.

As specified above, the subject of the present invention is also particles comprising at least one copolymer according to the invention having a mean size ranging from 1 nm to 1000 μιη, preferably from 10 nm to 500 μιη and in particular from 20 nm. at 250 μιη).

Any method for obtaining nanoparticles and / or microparticles known to those skilled in the art is conceivable for obtaining the particles according to the invention. By way of example, mention may in particular be made of the nebulization-drying method or the nanoprecipitation method.

 Obtaining the particles according to the invention by the nanoprecipitation method can be carried out as follows:

 Said particles can be obtained via the preparation of two solutions, followed by mixing them with stirring.

 The first solution may contain a copolymer according to the invention, and possibly the same copolymer before grafting the ligand if it is desired to obtain particles with a lowered gadolinium level. This solution may also contain a surfactant such as sorbitan mono- (9Z) -9-octadecenoate for example and a solvent. Any solvent for solubilizing the copolymer is suitable, such as acetone, for example.

 The second solution may contain a surfactant such as monooleate

Polyoxyethylene (20) sorbitan for example and a solvent. Any solvent in which the copolymer is not soluble is suitable, such as distilled water for example. The two solutions can then be homogenized with magnetic stirring for a period ranging, for example, from 1 hour to 10 hours. The first solution can then be poured dropwise into the second with magnetic stirring. The mixture is left stirring for a period ranging from 1 to 10 hours and then the volatile solvent (s) such as acetone for example can be evaporated (s) under vacuum at room temperature. The solution can then be dialyzed for a period ranging from 6 hours to 1 week, for example against distilled water before lyophilization.

The examples which follow illustrate the invention without limiting its scope.

Examples

 In the examples that follow, as well as throughout this application:

 "Pr" denotes propargyl,

 "CL" means caprolactone,

 "SC" refers to ε-caprolactone

"PCL" means poly (8-caprolactone)

 "P" means poly

 "Co" means copolymer

 "VL" means valerolactone

EXAMPLE 1 Preparation of an Azide (or DTPA-DiN ₃ ) 2 Diethyl Triamine Pentaacetic Acid (DTPA) Ligand

Step 1: Synthesis of 1-azido-3-aminopropane 1

The synthesis is carried out according to the following reaction scheme:

NaN ₃ This compound was obtained according to a synthesis previously described by Carboni, B. et al. (Macromolecules, Vol.40, No. 16, 2007 / Carboni, B. Benanlil, A. Vaultier, MJ Org Chem 1993, 58, 3736). An aqueous solution (30 mL) of 3-chloropropylamine hydrochloride (4 g, 30.8 mmol) and sodium azide (6 g, 92.3 mmol, 3 equiv) was heated at 80 ° C for 17 h. After evaporation of the water, the reaction mixture is placed in an ice bath. 50 ml of diethyl ether and 4 g of potassium hydroxide are added. The phases are separated. The product is extracted from the aqueous phase with 20 ml of diethyl ether. The organic phase is then dried over magnesium sulfate and filtered. After evaporation, the oil obtained is purified by distillation under reduced pressure. (2.46 g, 80% yield, colorless oil)

1 H NMR (300 MHz, CDCl ₃ ), δ (ppm): 3.33 (t, 2H, CH ₂ N ₃ ); 2.55 (t, 2H, CH ₂ NH ₂ ); 2.34 (s, 2H, NH ₂ ); 1.55 (q, 2H, CH ₂ CH ₂ CH ₂ ).

FT-IR (ATR, cm ^-1 ): 2100 (N ₃ ) Step 2: Synthesis of DTPA-DiN 2

 The synthesis is carried out according to the following reaction scheme:

This compound was obtained according to a procedure described by I. Perez-Baena et al. (J. Mater Chem., 2010, 20, 6916-6922).

 DTPA dianhydride (1 g, 2.8 mmol) and 1-azido-3-aminopropane (0.616 g, 6.2 mmol, 2.2 equiv) are solubilized in anhydrous dimethylformamide (DMF) (20 mL) and left behind. with stirring for 24 hours at room temperature under argon. Then the DMF is evaporated, the crude reaction is taken up in water and freeze-dried. A white solid is then obtained (1.48 g, yield: 95%).

1 H NMR (300 MHz, DMSO), δ (ppm): 3.4 (6H, CH ₂ CO ₂ H); 3.1 (12H, N (CH ₂ ) ₂ N and

NCH ₂ C (O)); 2.8 (8H, CH ₂ NHC (O) and CH ₂ N ₃ ); 1.7 (4H, CH ₂ CH ₂ N ₃ ).

FT-IR (ATR, cm- ¹ ): 2100 (N ₃ )

LC-MS (ES +, m / z): 558.4 [M + H ⁺ ] (calcined 558.27) Example 2 Preparation of a complex [Gd (DTPA-diN ₃ ) H ₂ 0] 3

 The synthesis is carried out according to the following reaction scheme:

with R = (CH ₂ ) ₃ N ₃

To an aqueous solution of ligand (2; 1 g; 1.79 mmol) was added pyridine (1.44 mL, 17.9 mmol). After stirring for 10 minutes at room temperature, GdCl ₃ -6H ₂ O (1.33 g, 3.58 mmol, 2 equiv) is added to the reaction medium which is then left stirring for 24 h at 40 ° C. Water and pyridine are evaporated and the product is purified by passage over Chelex resin. The absence of free Gd is verified by an MTB test. Finally, the product is lyophilized and obtained in the form of a glossy white solid (1.26 g, yield: 99%).

FT-IR (ATR, cm- ¹ ): 2100 (N ₃ )

MALDI-TOF (dithranol, m / z): 713.16 [M + H ⁺ ]; 1423.33 [2M + H ⁺ ] (calcd. 713.17 and 1425.34)

 % Gd (ICP-MS): 15.4% (calculated 22.09%)

Example 3: Preparation of a P (α-β-CL-α-Cl) Copolymer Step 1: Synthesis of q-propargyl-ε-caprolactone 4

 The synthesis is carried out according to the following reaction scheme

To a solution of 2M lithium diisopropyl amide (12 mL, 24.1 mmol) in tetrahydrofuran (80 mL) at -78 ° C is added dropwise under an atmosphere. inert a solution of ε-caprolactone (sCL) (2.5 g, 21.9 mmol) in anhydrous tetrahydrofuran (10 mL). After one hour at -78 ° C, propargyl bromide (2.92 mL, 26.3 mmol) and hexamethylphosphoramide (5 mL) are added to the lactone enolate. After 3 hours at -30 ° C., the reaction medium is neutralized with an ammonium chloride solution. The product is extracted with dichloromethane (100 mL) and washed with a solution of ammonium chloride and an aqueous solution of sodium chloride. The organic phase is dried over magnesium sulfate, filtered and evaporated under reduced pressure. The product is purified by chromatographic column on silica gel (heptane / ethyl acetate: 7/3, v / v).

 A colorless oil is then obtained (2.01 g, 13.2 mmol, yield: 60%).

1 H NMR (300 MHz, CDCl 3) δ (ppm) = 4.21 (m, 2H, CH ₂ O), 2.73 (m, 1H, COCHCH ₂ ), 2.57 (m, 1H, CH ₂ -C ≡CH), 2.29 (m, 1H, CH ₂ -C≡CH), 1.99 (m, 2H, CH ₂ CH ₂ 0), 1.95 (td, 1H, C≡CH), 1, 65 (m, 1H, CH ₂ CH ₂ CH ₂ 0), 1.4 (m, 2H, COCHCH ₂ ).

¹³ C NMR (75 MHz, CDCl ₃ ) δ (ppm) = 176.2 (C = O), 82.2 (C≡CH), 69.75 (CH ₂ O), 68.81 (C≡CH) , 42.60 (COCHCH ₂ ), 28.96, 28.89, 28.38, 22.04 (CH ₂ -C≡CH).

IR (ATR cm ^-1 ): 3280 (C≡CH), 1720 (C = O).

MS (ES,%): m Z = 153.1 (40) [M + H ⁺ ]; 305.2 (100) [2M ⁺ + H].

Step 2: Synthesis of polv (α-propargyl-8-caprolactone-co-8-caprolactone) (or P (aPrsCL-co-sCL) in mass

 The synthesis is carried out according to the following reaction scheme:

 5

 The polymerization reactions were carried out in bulk, using the conventional Schlenk procedure under an argon inert atmosphere.

Example of a protocol for the synthesis of PfaPreCL-co-eCL) 10% (that is to say comprising 10% of monomeric units functionalized with a propargyl group relative to the total number of monomer units):

SCL (2.66 g, 29.6 mmol, 90 equiv), lactone 4 (0.5 g, 3.29 mmol, 10 equiv), tin octanoate (66.4 mg, 0.164 mol, 0.5 equiv) and isopropanol (25 μl, 0.328 mmol, 1 equiv) are placed in a Schlenk. The solution is degassed by three freeze-thaw cycles. The reaction mixture is stirred under argon for 3.5 h at 140 ° C. The polymerization is stopped with 1N HCl solution. The polymer is purified by precipitation in methanol, filtered and dried under vacuum to give a white powder. 1 H NMR (300 MHz, CDCl 3) δ (ppm) = 4.96 (m, (CH ₃ ) ₂ CH), 4.02 (t, CH ₂ O), 3.60 (m, CH ₂ OH), 2 50 (m, COCHCH2), 2.26 (t, COCH _2), 1.96 (m, C≡CH), 1.49 to 1.70 (m, CH ₂ - CH ₂ -CH ₂ -CH ₂ -0-), 1.29-1.42 (m, COCH ₂ CH ₂ ), 1.18 (d, (CH ₃ ) ₂ CH).

IR (ATR cm ^-1 ): 3280 (C≡CH), 1720 (C = O).

The following table shows the evolution of the number average molar masses and the polydispersity index of the polymer (determined by CES, in THF medium on PL-gel mixed C columns (Polymer Laboratories)) as a function of the degree of functionalization ( determined by proton NMR).

functionalization (g.mor ¹ )

 0% 37000 1.9

 2% 34000 2.3

 5% 25000 1.9

 10% 18000 1.7

Example 4 Preparation of Functional Copolymer PCL- [Gd (DTPA)] 6

 The synthesis is carried out according to the following reaction scheme:

with R = (CH ₂ ) ₃ N ₃ 5, the complex 3 (3 equiv / aPreCL unit) and CuBr (2equiv / aPreCL unit) are solubilized in a minimum of DMF. The solution is degassed by three freeze-thaw cycles. Then pentamethyldiethylenetriamine (PMDETA) (2equiv / unit aPrCL), previously degassed by bubbling argon, is added to the medium. The schlenk is stirred at room temperature for 48 hours. The crude reaction product is taken up in THF and dialysed (pore 3500 g mol ^-1 ) against distilled water.

 After evaporation of the THF, the polymers are dried under vacuum and analyzed.

Determination of the mass percentage of gadolinium per polymer:

Given the structure of the [Gd (DTPA-diN ₃ ) H ₂ O] 3 complex, it can react with one or two propargyl functionalized entities of the polymer.

 In the following table the calculation of weight percent of theoretical gadolinium was carried out considering that each complex reacted with 2 functionalized propargyl entities.

The following table also presents the mass percentages of gadolinium obtained by elemental analysis ICP-MS (ICP-MS with quadrupole filter VG Plasmaquad II Turbo and Element XR, samples degraded by a solution of nitric acid and taken up in the ultrapure water then introduced by a micro-fogger at a flow rate of 0.2 ml.min ^-1 ) depending on the degree of functionalization of the polymers.

Nature of the PCL polyester PCL-g- [Gd (DTPA)]

 % of functionalization

 initial (units CL- 0% 2% 5% 10% propargylated)

 % mass of Gd

 Theoretical 0 0,910 2,097 3,712

% mass of Gd

 0 1,035 2,655 3,545 measured by ICP-MS

Example 5: NMR Experiments

 Prior to PCL- [Gd (DTPA)] 6 visibility experiments in MRI, 1H NMR experiments were performed to estimate the significance of gadolinium-induced perturbations on surrounding protons.

Indeed, MRI is based on the phenomenon of nuclear magnetic resonance and the abundance of water in the body makes hydrogen the most studied atom by this technique. Protons subjected to a magnetic field and a short radio frequency wave are excited and their return to equilibrium or relaxation induces a signal electromagnetic which after treatment gives an MRI image. The image and the contrast are mainly a function of the proton density: p and the two components of relaxation: longitudinal relaxation (Tl) and transverse relaxation (T2).

These 3 parameters are the main and determine the brightness (intensity) of each voxel (volume unit studied) and the contrast (difference in intensity between neighboring voxels). Gadolinium, like all paramagnetic contrast agents, induces a dipolar interaction between its electronic magnetic moment and the nearby nuclear magnetic moment of the protons. It therefore acts indirectly. By shortening the T1 and T2 relaxation times of the tissues in which it is found, gadolinium modifies the intensity of their signal. The T1 effect is preponderant on the T2 effect, so it is called Tl contrast agent or positive contrast agent because of the enhancement of signal it entails.

Measuring the proton relaxation times of the various PCL- [Gd (DTPA)] 6 polyesters having weight percentages of gadolinium of 1; 2.6 and 3.5% as well as PCL and PCL 5 propargylated controls was carried out using 1H NMR 400 MHz in organic medium (DMSO d ₆ ).

The samples were prepared at a concentration of 11 mg.mL ^"1 in DMSO The analyzes were carried out at 80 ° C. The measurement of the relaxation times shows a clear perturbation of the protons of the polymer by the complex subjected to the magnetic field A considerable reduction in the relaxation times (Tl) of all the protons is proven with the presence of gadolinium, and this, especially as the polymer has a significant functionalization.

Relaxation time (ms)

 proton S (ppm) PCL 1 PCL 2 PCL 3 PCL 4 PCL 5

 A 4,031 1554 1558 536.53 273.6 252.9

 B 2,284 1,687 1694,562, 127,289.4346.2

 C 1, 585, 1514, 1505, 553, 936, 291, 196, 399.

 D 1, 353 1512 1502 551, 918 298.991 289.2

PCL 1: PCL

 PCL 2: Propargylated PCL 5

PCL 3: PCL- [Gd (DTPA)] 1%

PCL 4: PCL- [Gd (DTPA)] 2.6%

PCL 5: PCL- [Gd (DTPA)] 3.5%

The protons A, B, C and D correspond to the 4 types of protons of the PCL. Overall, all protons are affected by the presence of gadolinium. Blanquer et al. (WO2011 / 004332 already cited) have visualized in MRI polymers that had relaxation times around 500 ms, which suggests that the PCL analyzed have mass percents of gadolinium for visualization in MRI.

An excessively high mass percentage of gadolinium causes a disturbance such that the calculation of the absolute relaxation times of the protons of the polymers becomes difficult. These relaxation time values are therefore to be used with caution and rather as relative values. Thus, if the curve representing the relative values of the Tl protons of the PCL- [Gd (DTPA)] is established, it appears that the reduction of the ratio Τ / Τ1 (Tl protons PCL- [Gd (DTPA)] / Tl protons of PCL) is a non-linear function of gadolinium concentration. However, the gadolinium used during MRI examination induces a contrast by decreasing the Tl of the tissues in which it is located. Therefore an enhancement of the signal in MRI of the PCL- [Gd (DTPA)] is expected but a priori, from a certain amount of gadolinium, the signal will not be better (above a mass percentage of 2.6 %).

 Figure 1 in the appendix shows the relative variation of Tl (ΤΓ / Τ1) PCL- [Gd (DTPA)] as a function of gadolinium concentration. Example 6: MRI Visualization

 The synthesized polymers were subjected to MRI (7T) experiments (7T Bruker DRX300SWB imager, with a 144mT / m "mini-imaging" gradient configuration, 30mm or 64mm "bird cage" resonator, echo sequence 3D spin) to verify the ability of PCL- [Gd (DTPA)] prepared to enhance the MRI signal but also to determine the mass percentages of gadolinium inducing optimal visualization in MRI.

 Films of about 10 mg containing 30 μg of gadolinium were prepared by mixing unmodified PCLs and PCL- [Gd (DTPA)] containing 1; 2.6 or 3.5% gadolinium.

PCL and PCL- [Gd (DTPA)] were solubilized in a dichloromethane / methanol mixture before being deposited in molds and dried in order to obtain films. Sample 2 was obtained by mixing PCL and PCL- [Gd (DTPA)] with a weight percent gadolinium of 1%.

 Sample 5 was obtained by mixing PCL and PCL- [Gd (DTPA)] with a mass percentage of gadolinium of 2.6%.

 Sample 8 was obtained by mixing PCL and PCL- [Gd (DTPA)] with a mass percentage of gadolinium of 3.5%.

Figure 2, which is in the appendix, presents the results obtained in MRI for the 3 samples 2, 5 and 8 included in agarose gels (Bruker DRX300SWB 7T imager, with a 144mT / m gradient mini-imaging configuration, bird cage resonator 30 mm or 64 mm, 3D spin echo sequence).

 The three images per sample correspond to 3 longitudinal sections of the agarose gel containing the sample.

All films tested enhance the signal in spin echo. On the other hand, a higher signal increase is observed for sample 5. These results confirm those obtained by NMR: beyond 2.6% of gadolinium, there is no longer any effect on the relaxation time protons. In MRI, the signal enhancement is optimal at this mass percentage.

Example 7 Preparation of Nanoparticles of PCL- [Gd (DTPA)] 6

 For the preparation of nanoparticles of PCL and PCL- [Gd (DTPA)] containing 0.1% of gadolinium, two solutions are prepared:

 a solution containing 477.5 mg of PCL, 2.5 mg of PCL- [Gd (DTPA)],

181.2 mg of sorbitan mono- (9Z) -9-octadecenoate (SPAN 80) in 90 mL of acetone.

 a solution containing 362.3 mg of Polyoxyethylene (20) sorbitan monooleate (TWEEN 80) in 181.2 mL of distilled water.

Both solutions are homogenized with magnetic stirring for 3 hours. The first solution is then poured dropwise into the second with magnetic stirring. The mixture is stirred for 3 hours and then acetone is evaporated under vacuum at room temperature. The solution is then dialyzed for 24 hours against distilled water before lyophilization.

 Figure 3, which is in the appendix, shows the size distribution of the nanoparticles obtained. The nanoparticles were characterized by DLS analysis on a NanoZS (Malvern) apparatus at 25 ° C (mean diameter 170 nm).

Example 8 Visualization of Nanoparticles of PCL- [Gd (DTPA)] 6

 The nanoparticles obtained in Example 7 were visualized on an Imager 7T Bruker BIOSPEC 70/20 type apparatus. The nanoparticles were incorporated into a 1% agarose gel. The 2D sequence (a = 60 °, TR / TE = 110 / 3.2ms) was performed.

 Figure 4, in the appendix, shows aggregates of nanoparticles visualized in an agarose gel (2D gradient echo, a = 60 °, TR / TE = 1 10 / 3.2ms.

Example 9: Stability study

 PCL and PCL- [Gd (DTPA)] 6 films are prepared by mixing the various polymers, dissolving in dichloromethane and then evaporating the solvent. The mixture is made to obtain a final gadolinium concentration of 0.4% by weight. 10 mg samples are cut from the obtained films and placed in the release medium. In parallel, a PCL film containing no gadolinium is prepared as a negative control.

 In order to evaluate the influence of the presence of proteins and ions present in physiological concentration and which can modify the gadolinium complexation equilibrium, the chosen release medium contains 3 g of albumin and 0.25 mg of zinc chloride. in 75 ml of PBS IX (phosphate buffered saline with identical pH and ionic strengths in the physiological medium). Each sample is placed in 10 ml of medium and then stirred at 37 ° C. 1 mL aliquots are taken after 1, 3, 7, 15, 30, 90 days. At each sample, the medium containing the films is adjusted to 10 ml with 1 ml of fresh medium to maintain the sink conditions.

These conditions are achieved when the volume of the dissolution medium is at least 3 to 10 times the saturation volume. (European Pharmacopoeia 7.5 page 721: 5.17.1 recommendations for the dissolution test) The release of Gd ⁺ ions is evaluated by ICP-MS analysis. For greater accuracy, a release medium assay is also performed as a second negative control.

 Figure 5 in the appendix shows the curve giving the release of gadolinium ions as a function of time for the PCL and PCL- [Gd (DTPA)] film containing 0.4% by mass of gadolinium. The curve labeled PBS control represents the release of gadolinium ions as a function of time for the film containing the release medium (it is a control)

 The graph in FIG. 5 thus shows that the film containing gadolinium does not release more gadolinium over time than the films containing none (PCL film and PBS film). This film is therefore stable in the release medium.

Example 10 Synthesis of benzyl 6-oxotetrahydro-2H-pyran-3-ylrbamate (5-amino-6-valerolactone = 5-NHZ-6-VL) monomer (9)

a- Synthesis of tert-butyl-4- (benzyloxycarbonylamino) -5-hydroxypentanoate (8)

The selective reduction of the main chain acid of N-benzyloxycarbonyl-glutamic acid ester γ-tert-butyl (ZGlu (OtBu) OH), (7) is carried out by formation of an ester-type intermediate activated by reaction with benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP). Typically, a solution of Ν, Ν-diisopropylethylamine (DIPEA) (1.17 mL, 7.1 mmol) and BOP (2.87 g, 6.5 mmol) in 10 mL of THF is slowly added to a suspension of 7 (2.02 g, 6 mmol) in 20 mL of THF at room temperature. After stirring for 10 minutes, NaBH ₄ (1.1 g, 30 mmol) is slowly added to the reaction medium and then the reaction is left stirring for 2 hours at room temperature. The mixture obtained is diluted in CH ₂ Cl ₂ (150 mL) and then washed with a 5% solution of HCl (5 × 100 mL), followed by washing with a saturated solution of NaHCO ₃ ( ₃ × 100 mL) and then saturated with NaCl (3 × 100 mL). The organic phase is then dried over MgSO ₄ and concentrated by evaporation of the solvent to obtain a clear oil. Final purification is carried out by flash column with CH ₂ Cl ₂ as eluent and then ethyl acetate. (yield: 90%).

1 H NMR (300 MHz, CDCl ₃ ): δ (ppm) = 7.3 (m, 5H, Ph), 5.1 (m, 1H, NH), 5.0 (s, 2H, OCH ₂ Ph), 3.8-3.7 (m, 1H, CH-NHZ), 3.6-3.5 (m, 2H, CH ₂ -OH), 2.3-2.2 (m, 2H, CH ₂ - CH ₂ -CH), 1.9-1.7 (m, 2H, CH ₂ -COOtBu), 1.4 (s, 9H, tBu). HPLC: 1.52 min.

Calculated monoisotopic mass (C ₁₇ H ₂₅ NO ₅ ) 323.17 g / mol, ES-MS (70 eV, m / z): 324.3 [M + H] ⁺ , 346.3 [M + Na] ⁺ b - Synthesis of benzyl 6-oxotetrahydro-2H-pyran-3-ylcarbamate (9)

The lactonization of 8 is carried out in two simultaneous steps by removal of the tert-butyl group and intramolecular cyclization of the intermediate thus formed. Typically, 8 (2 g) is dissolved in a mixture of trifluoroacetic acid (10 mL) and CH ₂ Cl ₂ (10 mL) and then stirred for 3 hours at room temperature. After reaction, cold water (80 mL) and CH ₂ Cl ₂ (80 mL) are added. The organic phase is washed with water (5 × 50 ml), dried over MgSO 4, filtered and concentrated by evaporation. Purification by column chromatography eluting with AcOEt / Et ₂ 0 (5: 5) results in the production of compound 9 (0.85 g, yield: 55%) as white crystals and a minimum purity of 98 %.

 Tm = 65 ° C. (DSC Perkin Elmer DSC 6000 Thermal Analyzer).

1 H NMR (300 MHz, DMSO-d ₆ ): δ (ppm) = 7.6 (m, 1H, NH), 7.4-7.3 (m, 5H, Ph), 5.05 (s, 2H) , OCH ₂ Ph), 4.3-4.2 (m, 1Ha, CH ₂ -O), 4.1-4.0 (m, 1Hb, CH ₂ -O), 3.9-3.8 ( m, 1H, CH-NH 2), 2.6-2.4 (m, 2H, CH ₂ -CO), 2.1-2.0 (m, 1H a, CH ₂ -CH ₂ -CH), 1, 8 to 1.7 (m, LHB, CH ₂ - CH ₂ -CH).

¹³ C NMR (75 MHz, DMSO-d6): δ (ppm) = 171 (s, C (O) O), 156.2 (s, NHC (O) O), 137.5 (s, CH ₂ CCH) ), 128.8-127.6 (m, CH), 70.6 (s, CH ₂ O), 65.9 (s, CH ₂ C (O) ONH), 44.3 (s, CHNH), 27.5 (s, CH ₂ CHNH), 24.5 (s, CH ₂ C (O)). HPLC: 1.23 min.

Calculated monoisotopic mass (C ₁₃ H ₁₅ NO ₄ ) 249.10 g / mol, ES-MS (70 eV, m / z): 250.2 [M + H] ⁺ , 499.4 [2M + H] ⁺ . )

 1) Synthesis of poly (5-Z-amino-6-valerolactone-co-s-caprolactone) or P (5-NHZ-6-VL-co-s-CL) (10)

Typically, 9 (500 mg, 2 mmol) and ε-CL (11.3 mg, 0.10 mmol) are placed in a schlenk under an inert atmosphere. The catalyst (Sn (Oct) ₂ , 5 mol%) and the initiator (benzyl alcohol (BzOH), 2.6 M in THF, 0.5 mol%) are added through a septum. The reaction is carried out for 24 hours at 110 ° C. under an inert atmosphere. The reaction is then stopped by adding 3 mL of THF, followed by precipitation in cold methanol. The polymer obtained is filtered and then dried. The comonomer ratios of the copolyester are determined by 1H NMR by comparing the intensities of the characteristic signals at 4.95 ppm (s, 2H, OCH ₂ Ph, 9, NHZVL) and 4.00 ppm (t, 2H, OCH ₂ -CH ₂ , ε-CL) and (m, 1Ha, CH ₂ -0, NHZVL).

1H NMR (300 MHz, DMSO-d ₆ ): δ (ppm) = 7.40-7.30 (m, 5H, Ph, NHZVL), 7.20 (m, 1H, NH, NHZVL), 4.95 (s, 2H, OCH ₂ Ph, NH ₂ VL), 3.95-4.00 (m, 1H a, CH ₂ -O, NH ₂ VL and 2H, CH ₂ -O, ε-CL), 3.85 (m, 1Hb). , CH ₂ -0, NHZVL), 3.65 (m, 1H, CH-NHZ, NHZVL), 2.2-2.3 (m, 2H, CH ₂ -CO, NHZVL and 2H, CH ₂ -CO, ε-CL), 1.65 (m, 1Ha, CH ₂ -CH ₂ -CH, NHZVL), 1.50 (m, 1Hb, CH ₂ -CH ₂ -CH, NHZVL and 4H, CH ₂ -CH ₂ - CH _2, ε-CL), 1.30 (m, 2H, -CH ₂ - CH ₂ -CH _2, ε-CL).

2) Synthesis of poly (5-NH ₃ ⁺ -δ-valerolactone-co-s-caprolactone) or

P (5-NH ₃ ⁺ -δ-VL-co-s-CL) (11)

The amine functions are deprotected in acidic medium to generate the corresponding polymer bearing pendant ammonium groups. Typically, a solution of hydrobromic acid (3 eq per protective group) in acetic acid (33 m%) is added slowly with stirring to a suspension of copolymer to be deprotected (10% m: v) in dichloromethane. Deprotection is performed at room temperature and then stopped after 20 minutes. The reaction medium is precipitated and then washed with diethyl ether and water to remove excess salts.

1H NMR: (300 MHz, DMSO-d ₆ ): δ (ppm) = 4.20 (m, 1H a, CH ₂ -0, NH ₃ ⁺ VL), 4.10 (m, 1Hb, CH ₂ -O, NH ₃ ⁺ VL), 4.00 (2H, CH ₂ -0, ε-CL), 3.5 (m, 1H, CH ₃ NH ₃ ⁺ , NH ₃ ⁺ VL), 2.60 (m, 2H, CH ₂ -CO, NH ₃ ⁺ VL), 2.30 (m, 2H, CH ₂ -CO, ε-CL), 1.90 (m, 2H, CH ₂ -CH ₂ -CH, NH ₃ ⁺ VL) 1.55 (m, 4H, CH ₂ -CH ₂ -CH ₂ , ε-CL), 1.30 (m, 2H, -CH ₂ -CH ₂ -CH ₂ , ε-CL).

Example 12 Synthesis of poly (5-DTPA-δ-valerolactone-co-ε-caprolactone) (P (DTPA-VL-co-CL)) (12)

DTPA dianhydride (5 mg; 4,14.10 ^"moles) predissolved in anhydrous DMF (3 mL) was added dropwise to a solution Ρ (5-ΝΗ ₃ ⁺ -δ- VL-co-ε- CL) 11 (25 mg, 1.05 × 10 ^-5 mol) in anhydrous DMF (4 mL) in the presence of triethylamine (6 μL · 3,17 × 10 ^-5 mol) The reaction mixture is stirred at room temperature for 24 hours. After evaporation of the DMF, the polymer is precipitated in methanol and dried before analysis.

 The superimposed chromatograms (CES, THF, double refractometric detection and UV) of the polymers 11, 12 and of the polymer 11 coupled to a phthalic anhydride (UV marker) confirm the grafting of DTPA on the copolymer (FIG. 6 in the appendix illustrating the graphs obtained from the steric exclusion chromatography).

The degree of functionalization determined by 1 H NMR is 5%. In contrast to Example 4, each DTPA dianhydride reacts with a single amino group herein to form an amide bond. xample 13: Gadolinium complexation with 12

12 13

The copolymer 12 (30 mg;. 1.15 10 ^-5 mol) is dissolved in a minimum of DMSO (5 mL). GdCl ₃ -6H ₂ O (8.4 mg, 2.5 × 10 ^-5 mol) is then added to the medium After 4 days, with stirring and at room temperature, the complexed polymer is purified by dialysis against methanol.

 Gadolinium mass percentage of 13 measured by ICP-MS: 2% Percentage mass of gadolinium calculated as a percentage of gadolinium compared to the expected gross formula: 5.7%

Example 14: Visibility of P [Gd (DTPA) / VL-co-CL] 13

 A film of PCL and P [Gd (DTPA) / VL-co-CL] 13 was prepared by mixing the various polymers, dissolving in dichloromethane and then evaporating the solvent. The mixture is made so as to obtain a final gadolinium concentration of 1% by weight. The visualization of the film was performed on an Imager 7T Bruker BIOSPEC 70/20 type apparatus on films incorporated in a 1% agarose gel. The 2D sequences (a = 60 °, TR / TE = 110 / 3.2ms), and 3D in echo gradient echo (three weightings a = 75 °, 30 ° and 15 °) and RARE (Rapid Acquisition with Relaxation Enhancement) have been realized.

 Figure 7 in the appendix shows two snapshots (a and b) from the 3D reconstruction of the images.

Figure 8 in the appendix shows that the visualized object is in the form of a cup, which corresponds to the shape of the mold. This proves that PCL and P [Gd (DTPA) / VL-co-CL] are soluble in dichloromethane since the visualized object took the form of the mold. This experiment shows the interest of using thermoplastic polymers in the present invention. Indeed, their solubility in solvents hydrophobes makes it possible to coat an object by simple dissolution in a solvent followed by evaporation of the solvent.

Example 15 Synthesis of poly (methyl acrylate-propargyl co-acrylate)

 a- Preparation of the copolymer P (MA-co-PA) 5% (that is to say comprising 5% of acrylate monomer units functionalized with a propargyl group relative to the total number of acrylate monomer units)

Methyl acrylate MA (5 g, 58.1 mmol, 95 equiv) acrylate, propargyl PA (0.337 g, 3.06 mmol, 5 equiv), AIBN (10 mg, 64,9x l0 ^{" 3} mmol, 0.2% wt) and toluene (20 ml) are placed in a Schlenk The solution is degassed by three freeze-thaw cycles The reaction mixture is stirred under argon for 4 hours at 65 ° C. The polymer is purified by precipitation in heptane, filtered and dried under vacuum to give a colorless solid.

1 H NMR (300 MHz, CDCl 3) δ (ppm) = 4.60 (O-CH ₂ -C≡CH), 3.59 (O-CH ₃ ), 1.91 (O-CH ₂ -COCH 2) -0.5 (CH ₂ -CH)

b- Synthesis of Functionalized Poly (Methyl Acrylate) P (MA-Co-PA) - [Gd (DTPA)]

In a Schlenk tube equipped with a magnetic bar are added the 5% P (MA-co-PA) copolymer, the 3 complex (3 equiv / propargyl acrylate monomer unit), the CuBr (2 equiv / unit). propargyl acrylate monomer), and a minimum of DMF. The solution is degassed by three freeze-thaw cycles. Then pentamethyldiethylenetriamine (PMDETA) (2 equiv / propargyl acrylate monomer unit), previously degassed by bubbling with argon, is added to the reaction medium. The schlenk is stirred at room temperature for 48 hours. The gross The reaction mixture is taken up in THF and dialyzed (pore 6000-8000 g mol ^-1 ) against distilled water.

 After evaporation of the solvent, the polymers are dried under vacuum and analyzed.

Claims

1. Hydrophobic thermoplastic copolymer, especially useful for the manufacture and / or coating of medical devices, in particular implantable, characterized in that it is obtained by copolymerization, it comprises at least a first monomer unit and at least a second monomer unit on which is grafted a chelating ligand of a paramagnetic ion capable of complexing with such a paramagnetic ion or a chelating ligand of a paramagnetic ion complexed with such a paramagnetic ion, the second monomeric unit being grafted in an amount sufficient for the copolymer is visible in magnetic resonance imaging when complexed with said paramagnetic ion.

 2. Copolymer according to claim 1, characterized in that the first monomer unit is chosen from monomers useful for the preparation of biostable homopolymers, in particular that can be chosen from:

 Monomers useful for the preparation of polyolefins,

 • Monomers useful for the preparation of fluoro-polymers,

• Monomers useful for the preparation of acrylic resins,

• Monomers useful for the preparation of semi-aromatic polyesters,

• Monomers useful for the preparation of polyurethanes (PUR), and

• Monomers useful for the preparation of silicones;

 or selected from monomers useful for the preparation of bioresorbable homopolymers, in particular that may be chosen from aliphatic polyesters such as poly (α-hydroxy acids), poly (β-hydroxy acids), poly (γ-hydroxy acids), poly (8-hydroxyacids), hydroxy acids), poly (1,4-dioxane-2,3-diones) or even poly (para-dioxanones).

3. Copolymer according to one of claims 1 or 2, characterized in that the second monomer unit is functionalized by an azide, alkyne, nitrile, carboxylic acid, ester, anhydride, acid halide, amide, iso (thio) function. cyanate, epoxide, thiol, amine, aziridine, ketone, aldehyde, diene, alkene or hydroxyl protected or not.

4. Copolymer according to any one of the preceding claims, characterized in that it is obtained from a copolymer selected from the following copolymers: caprolactone copolymer (CL) and propargylated caprolactone (CL-propargylée or Pr-CL) statistical, caprolactone copolymer (CL) and propargylated caprolactone (CL-propargylated or Pr-CL) block, caprolactone copolymer (CL) and 5-NH3 ⁺ -δ-valerolactone (5-NH ₃ ⁺ -δ-VL) statistical, or alternatively caprolactone copolymer (CL) and 5-ΝΉ3 ⁺ -δ-valerolactone (5-NH ₃ ⁺ -δ-VL) block.

 5. Copolymer according to any one of the preceding claims, characterized in that it comprises at least one additional block selected from the following polymer blocks: poly (ethylene glycol), poly (propylene glycol) or poloxamer.

 6. Copolymer according to any one of the preceding claims, characterized in that it is bioabsorbable.

 7. Copolymer according to any one of the preceding claims, characterized in that the grafting is ensured by means of a binding function selected from triazole, tetrazole, carbamate, urea and thioether.

 8. Copolymer according to any one of the preceding claims, characterized in that the complex of a paramagnetic ion comprises a chelating ligand having at least one carboxylic acid function and is in particular chosen from diethylene triamine penta-acetic acid (DTP). A), tetraazacyclododecane tetraacetic acid (DOTA) and tetraazacyclotetradecane tetraacetic acid (TETA).

 9. Copolymer according to any one of the preceding claims, characterized in that the degree of functionalization is between 0.01 and 10%, or even between 0.1 and 5%.

Process for the preparation of a copolymer according to any one of the preceding claims, comprising (i) at least one step of preparing a copolymer comprising at least a first monomer unit and at least a second monomer unit comprising a functional group capable of forming a bond, in particular a stable bond, with a complex of a paramagnetic ion or with a chelating ligand of a paramagnetic ion capable of complexing with such a paramagnetic ion, optionally by click chemistry and (ii) at least one step of grafting on said second monomer unit a complex of a paramagnetic ion or a chelating ligand of a paramagnetic ion capable of complexing with such a paramagnetic ion.

 11. Medical device, especially implantable, detectable magnetic resonance imaging, characterized in that it comprises a copolymer as defined in any one of claims 1 to 9, in its mass and / or as a coating and / or as marking.

 12. Process for the preparation of a medical device, in particular an implantable device detectable by magnetic resonance imaging, characterized in that it comprises at least one coating step with a copolymer as defined according to any one of Claims 1 to 9, in particular by dipping or spraying, in a solution comprising said copolymer.

 13. A method of marking a medical device, characterized in that it comprises at least one deposition step, in particular on a targeted area of the medical device, on the surface of the material, a copolymer as defined in the any of claims 1 to 9.

 14. Compound of following formula (A) or formula (B)

in which

M represents a group - (CHR) _X - or - (CH ₂ -CHR-O) _y where x and y independently represent an integer from 1 to 18 for x and from 1 to 1000 for y.

Y being one of the functions capable of reacting with anhydride groups, for example hydroxyl, amine or thiol groups,

 R is a (Ci-Cg) alkyl group or a hydrogen atom,

especially useful as complexing agent of a paramagnetic ion.

15. Complex of formula (Α ') following formed from (A): (Α ') and,

complex of formula (Β ') following formed from (B):

_(B > _}

wherein M and Y are as defined in claim 14, and PA is a paramagnetic ion, especially gadolinium.

 16. Particles comprising at least one copolymer according to any one of claims 1 to 9, having an average size ranging from 1 nm to 1000 μιη, preferably from 10 nm to 500 μιη and in particular from 20 nm to 250 μιη .