Ultrafine nanoparticles comprising a functionalized polyorganosiloxane matrix and including metal complexes; method for obtaining same and uses thereof in medical imaging and/or therapy
The invention relates to novel biocompatible hybrid nanoparticles of very small size, useful in particular for diagnostics and/or therapy. The purpose of the invention is to offer novel nanoparticles which are useful in particular as contrast agents in imaging (e.g. MRI) and/or in other diagnostic techniques and/or as therapeutic agents, which give better performance than the known nanoparticles of the same type and which combine both a small size (for example less than 20 nm) and a high loading with metals (e.g. rare earths), in particular so as to have, in imaging (e.g. MRI), strong intensification and a correct response (increased relaxivity) at high frequencies. The method for the production of these nanoparticles and the applications thereof in imaging and in therapy also form part of the invention.
1. A method for producing a nanoparticle having a diameter from 1 to 8 nm, wherein said method comprises:
a) synthesizing a metallic oxide core comprising a cationic form M n+ (n=2 to 6) selected from the group consisting of a rare earth element, an actinide element and a transition element, optionally doped with a dopant (D), selected from the group consisting of a rare earth element different from M, an actinide and/or a transition element;
said synthesizing comprises mixing a base with a salt of M dissolved in a solvent optionally selected from the group comprising alcohols;
b) coating of the core from (a) with polyorganosiloxane (POS) comprising employing a sol/gel technique for hydrolysis-condensation of silicic species and alkoxysilanes, in the presence of a base or of an acid;
c) functionalizing the coated core from (b) comprising bringing said coated core from (b) into contact with a precursor of chelating agent C1 that is capable of complexing a cationic form M n+ , and optionally D m+ (n=2 to 6), thereby obtaining functionalized precursor nanoparticle of a diameter d 0 ;
d) purification of the functionalized precursor nanoparticle of diameter d 0 , optionally by tangential filtration, dialysis and/or by precipitation/washing;
e) dissolving the cores M of the functionalized nanoparticle from (c) by placing said functionalized nanoparticle in aqueous solution, so that the diameter d 0 of said precursor nanoparticle is reduced to a value from 1 to 8 nm, thereby obtaining a nanoparticle with a diameter from 1 to 8 nm; and
f) optionally adding a cationic salt intended to be at least partly complexed by said chelating agent C1;
wherein (c), (d), (e), (f) can be carried out in a different order or at the same time.
2. The method of claim 1 , wherein the nanoparticle is comprised in an injectable liquid.
3. The method of claim 1 , wherein the nanoparticle is comprised in a suspension.
4. The method of claim 3 , wherein liquid is removed from the suspension to obtain a solid material, optionally liquid is removed by lyophilization.
5. The method of claim 3 , wherein the suspension is comprised in an injectable liquid.
6. The method of claim 4 , wherein the solid material is used to prepare an injectable liquid.
7. The method of claim 1 , wherein said chelating agent C1 is bound after step c) to the POS matrix by an —Si—C— covalent bound.
8. The method of claim 1 , wherein said precursor of chelating agent C1 is selected from polyaminated polycarboxylic acids.
9. The method of claim 1 , wherein M is a lanthanide and said precursor of chelating agent C1 is selected from complexing agents with complexation constant log(Kc 1 ) above 15.
10. The method of claim 1 , wherein said precursor of chelating agent C1 is DOTAGA anhydride.
11. The method of claim 1 , wherein the diameter d1 of the nanoparticle as obtained after the dissolution step e) is between 3 and 6 nm.
12. The method of claim 1 , wherein said M and, optionally D are selected from the groups of lanthanides.
13. The method of claim 1 , wherein M is Gd.
14. The method of claim 1 , wherein step e) further comprises bringing the functionalized nanoparticle into contact with a pH modifier and/or a chelating agent C2, identical or different to C1, that is capable of complexing at least said cationic forms M n+ and, optionally D m+ .