METHOD FOR PREPARING NANOPARTICLES

1 . A process for preparing a colloidal solution of nanoparticles, each nanoparticle comprising chelating groups grafted onto a polymer matrix, one portion only of the chelating groups being complexed with a metal cation, the other portion being uncomplexed, said process comprising

(1) the synthesis or the provision of a colloidal solution of precursor nanoparticles, said precursor nanoparticles having the following formula [Ch-M 1 ] n -PS wherein:

PS is an organic or inorganic polymer matrix, for example a polysiloxane matrix,

[Ch-M 1 ] is a chelating group complexed with a metal cation M 1 with a high atomic number Z greater than 40, and preferably greater than 50,

Ch is covalently grafted to the surface of the polymer matrix, for example, a polysiloxane matrix,

n is between 5 and 100, and,

the average hydrodynamic diameter of the nanoparticles is between 1 and 50 nm, preferably between 2 and 20 nm, and more preferentially between 2 and 8 nm,

(2) a step of treating the colloidal solution in an acid medium, for example by adding a hydrochloric acid solution, in order to obtain a pH preferably below 2.0, preferably below 1.0, for a time sufficient to obtain a partial release of the metal cations M 1 ,

(3) where appropriate, a step of diluting the colloidal solution, for example with water,

(4) a purification step to separate the nanoparticles obtained in step (2) from the metal cations M 1 released,

(5) where appropriate, a step of concentrating the solution of the nanoparticles obtained in step (4),

(6) where appropriate, repeating steps (3), (4) and (5),

(7) where appropriate, freezing and/or freeze-drying the solution of nanoparticles obtained in one of steps (4), (5) or (6).

2 . The process as claimed in claim 1 , wherein M 1 is chosen from metal cations selected from radiosensitizers and/or contrast agents for magnetic resonance imaging (MRI), for example M 1 is chosen from gadolinium and bismuth.

3 . The process as claimed in claim 1 , wherein the chelating group Ch is chosen from macrocyclic agents, preferably from 1,4,7-triazacyclononane-triacetic acid (NOTA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODAGA), and 1,4,7,10-tetraazacyclododecane, 1-(glutaric acid)-4,7,10-triacetic acid (DOTAGA), 2,2′,2″,2′″-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetamide (DOTAM), and 1,4,8,11-tetraazacyclotetradecane (Cyclam), 1,4,7,10-tetraazacyclododecane (Cyclen) and deferoxamine (DFO).

4 . The process as claimed in claim 1 , wherein the chelating group Ch is DOTAGA of formula (I) below:

5 . The process as claimed in claim 1 , wherein PS is a polysiloxane matrix.

6 . The process as claimed in claim 5 , wherein the precursor nanoparticles have the following characteristics:

the weight ratio of silicon to the total weight of the nanoparticle is between 5% and 25%,

the total number n of chelating groups grafted to the polymer is between 5 and 50 per nanoparticle, preferably between 10 and 30, and,

the nanoparticle has an average diameter of between 2 and 8 nm.

7 . The process as claimed in claim 1 , wherein the precursor nanoparticles have the following characteristics:

(i) PS is a polysiloxane matrix,

(ii) Ch is a DOTAGA chelating group of the following formula [Chem. 1]

and grafted to the polysiloxane matrix by Si—C bond,

(iii) M 1 is the gadolinium cation Gd 3 ,

(iv) n is between 5 and 50, preferably between 10 and 30, and

(v) the average hydrodynamic diameter is between 2 and 8 nm.

8 . A process for preparing a colloidal solution of nanoparticles, each nanoparticle comprising chelating groups grafted onto a polymer matrix, a first fraction f1 of the chelating groups being complexed with a metal cation M 1 , a second fraction f2 being being-complexed with a cation M 2 , and a third fraction f3 being uncomplexed, said process comprising

(1) the synthesis or the provision of a colloidal solution of precursor nanoparticles, said precursor nanoparticles having the following formula [Ch-M 1 ] n -PS wherein:

PS is an organic or inorganic polymer matrix,

Ch is a chelating group complexed with a metal cation M 1 with a high atomic number Z greater than 40, and preferably greater than 50,

Ch is grafted onto the polymer matrix,

n is between 5 and 100, and,

the average hydrodynamic diameter of the nanoparticle is between 1 and 50 nm, preferably between 2 and 20 nm, and more preferentially between 2 and 8 nm

(2) a step of treating the colloidal solution in an acid medium, for example by adding a hydrochloric acid solution, in order to obtain a pH below 2.0, preferably below 1.0, for a time sufficient to obtain a partial release of the metal cations M 1 ,

(3) where appropriate, a step of diluting the solution, for example with water,

(4) a purification step to separate the nanoparticles obtained in step (2) from the free metal cations M 1 ,

(5) where appropriate, a step of concentrating the solution of the nanoparticles obtained in step (4),

(6) where appropriate, repeating steps (3), (4) and (5),

(7) optionally, a step of partial recomplexation of the nanoparticles obtained in step (2), (3), (4), (5) or (6) with a determined amount of metal cation M 1 in order to obtain a determined amount of chelating group Ch complexed with the metal cation M 1 ,

(8) bringing the solution of nanoparticles obtained in step (4), (5), (6) or (7) into contact with a sufficient amount of cation M 2 , preferably with a high atomic number Z greater than 40, and preferably greater than 50, for example a metal cation different from the metal cations M 1 or a radioisotope, to complex at least some of the chelating groups Ch1 freed in step (2) and,

(9) where appropriate, freezing and/or freeze-drying the solution of nanoparticles obtained in step (8).

9 . The process as claimed in claim 8 , wherein M 1 and/or M 2 are chosen from metal cations selected from radiosensitizers and/or contrast agents for magnetic resonance imaging (MRI), for example gadolinium or bismuth.

10 . The process as claimed in claim 8 , wherein the chelating group Ch is chosen from macrocyclic agents, preferably from 1,4,7-triazacyclononane-triacetic acid (NOTA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODAGA), and 1,4,7,10-tetraazacyclododecane, 1-(glutaric acid)-4,7,10-triacetic acid (DOTAGA), 2,2′,2″,2′″-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetamide (DOTAM), and 1,4,8,11-tetraazacyclotetradecane (Cyclam), 1,4,7,10-tetraazacyclododecane (Cyclen) and deferoxamine (DFO).