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. Thus, the nanoparticles according to the invention, with diameter d 1 between 1 and 20 nm, each comprise a polyorganosiloxane (POS) matrix including gadolinium cations optionally associated with doping cations; a chelating graft C 1 DTPABA (diethylenetriaminepentaacetic acid bisanhydride) bound to the POS matrix by an —Si—C— covalent bond, and present in sufficient quantity to be able to complex all the gadolinium cations; and optionally another functionalizing graft Gf* bound to the POS matrix by an —Si—C— covalent bond (where Gf* can be derived from a hydrophilic compound (PEG); from a compound having an active ingredient PA1; from a targeting compound; from a luminescent compound (fluorescein). 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 nanoparticle comprising
(i) a polyorganosiloxane (POS) matrix,
(ii) a metallic cation Gd 3+ ,
(iii) a chelating graft C 1 which is obtained by functionalizing said POS matrix of the nanoparticle with DOTAGA anhydride of the following formula:
wherein Gd 3+ is complexed to the chelating graft C 1 , wherein a diameter d 1 of said nanoparticle is from 1 to 8 nm, said nanoparticle molecular weight (in kDa) is greater than or equal to 2 and less than or equal to 200, and wherein said nanoparticle does not comprise a crystallized core of gadolinium oxide.
2. The nanoparticle of claim 1 , wherein the atom-% ratio ((Gd/Si)×100) is comprised between 10 and 60.
3. The nanoparticle of claim 1 , wherein the diameter d 1 of said nanoparticle is from 1 to 5 nm.
4. The nanoparticle according to claim 1 , wherein an atom % ratio (Gd/Si) is from 10 to 60.
5. The nanoparticle according to claim 1 , wherein said chelating graft C 1 is in excess relative to said metallic cation Gd 3+ .
6. The nanoparticle according to claim 1 , wherein the nanoparticle further comprises another functionalizing graft Gf* bound to said POS matrix by an —Si—C—covalent bond, where Gf* can be derived from:
a hydrophilic compound,
a compound having an active ingredient PA1,
a targeting compound,
a luminescent compound.
7. The nanoparticle according to claim 1 , wherein a relaxivity r 1 per Gd 3+ ion is greater than 5 mM −1 (of Gd 3+ ion)·s −1 for a frequency of 20 MHz.
8. The nanoparticle according to claim 1 , wherein a relaxivity r 1 per Gd 3+ ion at 60 MHz is greater than relaxivity r 1 per Gd 3+ ion at 20 MHz.
9. A suspension of a nanoparticle according to claim 1 .
10. A solid material obtained by removal of the liquid, optionally by lyophilization, of said suspension according to claim 9 .
11. An injectable liquid comprising a nanoparticle according claim 1 .
12. An injectable liquid comprising a suspension according to claim 9 .
13. An injectable liquid prepared from the solid material according to claim 10 .