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 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...

AI Technical Summary

Benefits of technology

The present invention relates to nanoparticles that can be used as contrast agents in imaging techniques such as MRI. The nanoparticles have several advantages over existing nanoparticles, including better performance in imaging, higher loading with metals, and better molecular rigidity. Additionally, the nanoparticles have good biocompatibility, can be easily functionalized, and can be used as a platform for combining multiple functions. The invention also provides a method for producing the nanoparticles and new compositions for diagnostics, therapy, and cellular labelling based on the nanoparticles.

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 nanoparticles, namely for example gadolinium present at the centre of the core of lanthanide oxide, is far less accessible to water than that on the surface or than that which would be complexed with DTPA or DOTA within or on the surface of the layer of polysiloxane.

This leads to a lower efficacy of the object per atom of gadolinium for these nanoparticles of the core / shell type.

This may result in problems of dissolution of the core connected with the reduced protection provided by a thinner layer of polysiloxane.

This leads to risks of toxicity connected with the high local concentrations of gadolinium.

However, their size of several tens of nanometers is a serious handicap in terms of elimination in vivo.

The prior art does not disclose nanoparticles combining a very small size, for example less than 20 nm, and a high level of loading with constant agent, e.g. T1 for MRI (gadolinium).

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