Ultrafine nanoparticles comprising a functionalized polyorganosiloxane matrix and including metal complexes; method for obtaining same and uses thereof in medical imaging and/or therapy

Abstract

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,
 (i) comprising:
 a polyorganosiloxane (POS) matrix including cations M n+  (n=2 to 6) optionally of a rare earth, optionally partly in the form of a metal oxide and/or oxohydroxide (M), optionally associated with doping cations D m+  (m=2 to 6), optionally a rare earth different from M, an actinide and/or a transition element; 
   a chelating functionalizing graft C 1  which is:
 derived from a chelating agent C1, 
 bound to said POS matrix by an —Si—C— covalent bond, 
 and in sufficient quantity to be able to complex all the cations M n+  and D m+ ; the graft C 1  optionally being in excess relative to said cations M n+  and D m+ ; said chelating agent C1 from which said graft C 1  is derived corresponding to at least one different species; 
   optionally 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; 
   (ii) wherein a diameter d 1  of said nanoparticle is from 1 to 20 nm, optionally from 1 to 10 nm; and   (iii) optionally said nanoparticle comprising an active ingredient PA2, identical to or different from PA1.   
     
     
         2 . The nanoparticle according to  claim 1 , wherein said POS matrix of said nanoparticle is obtained from a nanoparticle of diameter d 0  comprising:
 a core based on a metal oxide and/or oxohydroxide (M), optionally of a rare earth, at least partly in cationic form M n+  (n=2 to 6), optionally doped with a dopant (D), optionally a rare earth different from M, an actinide and/or a transition element;   at least one coating layer based on said POS; and   optionally an overcoating based on a functionalizing agent, optionally selected from functionalizing said chelating agents C1 capable of sequestering cations and/or said targeting compound and/or said compound comprising an active ingredient PA1 and/or said hydrophilic compound and/or said luminescent compound; and   
       said nanoparticle being subjected to dissolution of the core M, optionally by means of a pH modifier and/or of a chelating agent C2, identical to or different from C1, capable of complexing at least one of said cations M n+  and D m+ , so that the diameter d 0  of the nanoparticle is reduced to a value d 1  from 1 to 20 nm, optionally from 1 to 10 nm. 
     
     
         3 . The nanoparticle according to  claim 1 , wherein said nanoparticle molecular weight (in kDa) is greater than or equal to, in increasing order of preference, 2, 3, 5, and less than or equal to, in decreasing order of preference, 200, 100, 50, 20, 10. 
     
     
         4 . The nanoparticle according to  claim 1 , comprising formula:
   [C 1 ] a [R] b Si[O] c [OH] d [M n+ ] e [D m+ ] f [Gf*] g      
       where:
 C 1  are chelating functionalizing grafts formed by monovalent hydrocarbon radicals, identical to or different from one another, and each connected to the Si by an Si—C bond; 
 R are monovalent radicals, identical to or different from one another, constituting a functionalizing graft connected to the Si by an Si—C bond, and optionally comprising a hydrophilic group and at least one N or O atom; 
 M n+  are metal cations, identical to or different from one another, with n=2 to 6; 
 D m+  are metal cations, identical to or different from one another, with m=2 to 6; 
 Gf* are functionalizing grafts other than C 1 , formed by monovalent hydrocarbon radicals, identical to or different from one another, each connected to the Si by an Si—C bond, and which can be derived from:
 a hydrophilic compound; 
 a compound having an active ingredient PA1; 
 a targeting compound; 
 a luminescent compound; 
 
 a greater than or equal to 0.01 and less than or equal to 0.8; optionally with a≧d+e; 
 b less than or equal to 0.7; 
 c greater than or equal to 0.5 and less than 1.9; 
 g greater than or equal to 0 and less than 0.3; 
 e+f greater than or equal to 0.01 and less than or equal to 0.8; 
 e+f less than or equal to a; 
 a+b+2c+d+g=4; 
 a+b+g from 0.25 to 0.95. 
 
     
     
         5 . The nanoparticle according to  claim 1 , wherein at least 1% and optionally at least 10% of said chelating agents C 1  are not complexed by said cations M n+  and/or D m+ . 
     
     
         6 . The nanoparticle according to  claim 1 , wherein said M and/or D is an active agent in imaging and/or in therapy. 
     
     
         7 . The nanoparticle according to  claim 2 , wherein said cations M n+  and/or D m+  are located on the surface of the nanoparticle. 
     
     
         8 . The nanoparticle according to  claim 1 , wherein said nanoparticle does not comprise a crystallized core. 
     
     
         9 . The nanoparticle according to  claim 1 , wherein an atom-% ratio [(M/Si)×100] from 10 to 60, optionally from 25 to 40. 
     
     
         10 . The nanoparticle according to  claim 1 , wherein relaxivity r 1  per M n+  ion is greater than 5 mM −1  (of M n+  ion)·s −1  optionally 10 mM −1  (of M n+  ion)·s −1  for a frequency of 20 MHz. 
     
     
         11 . The nanoparticle according to  claim 1 , wherein relaxivity r 1  per M n+  ion at 60 MHz is greater than relaxivity r 1  per M n+  ion at 20 MHz. 
     
     
         12 . A method for producing a nanoparticle according to  claim 1 , wherein said method comprises:
 a Synthesis of cores based on a metal oxide and/or oxohydroxide (M), optionally of a rare earth, at least partly in cationic form M n+  (n=2 to 6), optionally doped with a dopant (D), optionally a rare earth different from M, an actinide and/or a transition element;
 said synthesis comprising mixing a base with a salt of M dissolved in a solvent optionally selected from the group comprising alcohols; 
   b Coating of the cores 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 and optionally of an active ingredient PA1 and/or PA2;   c Functionalizing overcoating of the coated cores from (b) comprising bringing said coated cores from (b) into contact with a precursor of functionalizing grafts C 1 , and optionally into contact with a functionalizing graft Gf*;   d Purification of the overcoated/functionalized nanoparticles of diameter d 0 , optionally by tangential filtration, dialysis and/or by precipitation/washing;   e Dissolution of the cores M of the overcoated/functionalized nanoparticles from (c) comprising bringing them into contact with a pH modifier and/or a chelating agent C2 that is capable of complexing at least one of said cations M n+  and D m+ , so that the diameter d 0  of said nanoparticle is reduced to a value d 1  from 1 to 20 nm, optionally from 1 to 10 nm; and   f Optional addition of a cationic salt intended to be at least partly complexed by said chelating agent C 1 ;   
       Wherein (c), (d), (e), (f) can be carried out in a different order or at the same time. 
     
     
         13 . A suspension of a nanoparticle according to  claim 1 . 
     
     
         14 . A solid material obtained by removal of the liquid, optionally by lyophilization of said suspension according to  claim 13 . 
     
     
         15 . An injectable liquid comprising a nanoparticle according  claim 1 . 
     
     
         16 . A suspension of a nanoparticle obtained according to the method according to  claim 12 . 
     
     
         17 . An injectable liquid comprising a nanoparticle obtained by the method of  claim 12 . 
     
     
         18 . An injectable liquid comprising a suspension according to  claim 13 . 
     
     
         19 . An injectable liquid prepared from the solid state material according to  claim 14 .