Ultrafine nanoparticles comprising a functionalized polyorganosiloxane matrix and including metal complexes; method for obtaining same and uses thereof in medical imaging and/or therapy
Inactive Publication Date: 2013-08-01
NANO H +2
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[0031]The high loading with magnetic complexes combined with the size and the rigidity of the object makes it possible to obtain a high r1 per object and per gadolinium atom (greater than th
Problems solved by technology
Unfortunately, the non-specificity, the low contrast that they produce, their rapid renal excretion and their field-dependent properties further restrict their application.
Moreover, the often low local concentration of gadolinium ions makes it difficult to detect medical abnormalities under a few centimetres in size.
All these aspects limit the usefulness of molecular compounds as contrast agents (the commercially available T1 agents described above are indeed molecular agents, this is not the case for the T2 agents but the latter are less interesting owing to the negative contrast that they provide).
Molecular compounds, because of their small size, do not generally allow combining several active agents, i.e. several properties within one and the same set (lack of space at the level of a molecular compound).
However, the element acting as T1 contrast agent in MRI in these nanopa
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example 1
Synthesis of the Gadolinium Oxide Core
[0260]A solution is prepared by dissolving a quantity of 11 g / L of gadolinium chloride salt (GdCl3, 6H2O) in a volume of 375 mL of diethylene glycol (DEG). 375 mL of a soda solution at 0.1 mol / L in DEG is added to the solution obtained, at room temperature, in 15 h.
[0261]The attached FIG. 3 shows the size distribution of the gadolinium oxide cores, measured in DEG by PCS; mean value: 3.6 nm.
example 2
Functionalization of the Gadolinium Oxide Cores with DTPABA
[0262]A layer of functionalized polysiloxane is synthesized by the sol-gel process around the gadolinium oxide cores from Example 1. For this purpose, the 750 mL solution of cores is heated to 40° C. in an oil bath, with stirring. 787 μL of APTES, 502 μL of TEOS and 1913 μL of an aqueous solution of triethylamine at 0.1 mol / L are added to the solution of cores. These additions are repeated a second time after waiting 24 h. The solution is then stirred at 40° C. for 48 h. Core-shell particles are obtained with a size of about 5 nm, with amine functions on the surface, FIG. 4 shows the size distribution of the polysiloxane-coated cores, measured in DEG by PCS; mean value: 4.9 nm.
[0263]Then 3.135 g of DTPABA is dispersed in 150 mL of dimethyl sulphoxide (DMSO). Then the 750 mL of solution of gadolinium oxide cores is added to the solution of DTPABA. The mixture is stirred for 24 h.
[0264]The nanoparticles are then precipitated b...
example 3
Dissolution of the Core of DTPABA-Functionalized Gadolinium Oxide Particles by Means of Hydrochloric Acid
[0270]Concentrated hydrochloric acid is added to the particles from Example 2, dispersed in water, until a pH equal to 2.5 is obtained. It is stirred overnight.
[0271]The solution is purified by tangential filtration, to remove the Gd3+ ions that were dissolved from the core of the particles. Particles are obtained with a size of about 3.5 nm. The attached FIG. 8 shows the size distribution of the particles reduced in size with hydrochloric acid, measured in water by PCS; mean value: 3.4 nm.
[0272]The signal from the particles in relaxornetry r1=1 / T1 decreased by 27%. Considerable chemical attack was observed with forced dissolution by acid attack. This is confirmed by the large decrease in relaxometry.
[0273]Moreover, chemical analysis by EDX gives a gadolinium / silicon atomic ratio of 22.1%. Relative to the particles from Example 2, it is observed that 54% of the gadolinium was dis...
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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 d1 between 1 and 20 nm, each comprise a polyorganosiloxane (POS) matrix including gadolinium cations optionally associated with doping cations; a chelating graft C1 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.
Description
TECHNICAL FIELD[0001]The invention relates to novel biocompatible hybrid nanoparticles of very small size, useful in particular for diagnostics and / or therapy.[0002]The invention also relates to the method for the production thereof and applications thereof.[0003]In the field of diagnostics, these may be probes for biological labelling endowed with magnetic, fluorescent or radioactive properties, contrast agents for magnetic resonance imaging (MRI), for imaging by SPECT (Single Photon Emission Computed Tomography) scintigraphy, for imaging by PET (Positron Emission Tomography) scintigraphy, for fluorescence imaging, for optical imaging, for X-ray scanner imaging or for multimodal imaging.[0004]In the field of therapeutics, the uses envisaged are as radiosensitizing or radioactive agents for radiotherapy (e.g. curietherapy), for neutron therapy, agents for PDT (photodynamic therapy), agents for the vectorization of molecules with a therapeutic effect or cellular labelling agents.[000...
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