International audienc

New, ultrasmall nanoparticles with sizes below 5 nm have been obtained. These small rigid platforms (SRP) are composed of a polysiloxane matrix with DOTAGA (1,4,7,10-tetraazacyclododecane-1-glutaric anhydride-4,7,10-triacetic acid)-Gd(3+) chelates on their surface. They have been synthesised by an original top-down process: 1) formation of a gadolinium oxide Gd2O3 core, 2) encapsulation in a polysiloxane shell grafted with DOTAGA ligands, 3) dissolution of the gadolinium oxide core due to chelation of Gd(3+) by DOTAGA ligands and 4) polysiloxane fragmentation. These nanoparticles have been fully characterised using photon correlation spectroscopy (PCS), transmission electron microscopy (TEM), a superconducting quantum interference device (SQUID) and electron paramagnetic resonance (EPR) to demonstrate the dissolution of the oxide core and by inductively coupled plasma mass spectrometry (ICP-MS), mass spectrometry, fluorescence spectroscopy, (29)Si solid-state NMR, (1)H NMR and diffusion ordered spectroscopy (DOSY) to determine the nanoparticle composition. Relaxivity measurements gave a longitudinal relaxivity r1 of 11.9 s(-1)  mM(-1) per Gd at 60 MHz. Finally, potentiometric titrations showed that Gd(3+) is strongly chelated to DOTAGA (complexation constant logβ110 =24.78) and cellular tests confirmed the that nanoconstructs had a very low toxicity. Moreover, SRPs are excreted from the body by renal clearance. Their efficiency as contrast agents for MRI has been proved and they are promising candidates as sensitising agents for image-guided radiotherapy.

Since radiotherapy is widely used in cancer treatment, it is essential to develop strategies which lower the irradiation burden while increasing efficacy and become efficient even in radio resistant tumors. Our new strategy is relying on the development of solid hybrid nanoparticles based on rare-earth such as gadolinium. In this paper, we then evidenced that gadolinium-based particles can be designed to enter efficiently into the human glioblastoma cell line U87 in quantities that can be tuned by modifying the incubation conditions. These sub-5 nm particles consist in a core of gadolinium oxide, a shell of polysiloxane and are functionalized by diethylenetriaminepentaacetic acid (DTPA). Although photoelectric effect is maximal in the [10-100 keV] range, such particles were found to possess efficient in-vitro radiosensitizing properties at an energy of 660 keV by using the "single-cell gel electrophoresis comet assay," an assay that measures the number of DNA damage that occurs during irradiation. Even more interesting, the particles have been evidenced by MTT assays to be also efficient radiosensitizers at an energy of 6 MeV for doses comprised between 2 and 8 Gy. The properties of the gadolinium-based particles give promising opening to a particle-assisted radio-therapy by using irradiation systems already installed in the majority of hospitals.

Gadolinium based Small Rigid Plaforms (SRPs) have previously demonstrated their efficiency for multimodal imaging and radiosensitization. Since the RGD sequence is well-known to be highly selective for αvβ3 integrins, a cyclic pentapeptide containing the RGD motif (cRGDfK) has been grafted onto the SRP surface. An appropriate protocol led to the grafting of two targeting ligands per nano-object. The resulting nanoparticles have demonstrated a strong association with αvβ3 integrins in comparison with cRADfK grafted SRPs as negative control. Flow cytometry and fluorescence microscopy have also been used to highlight the ability of the nanoparticles to target efficiently HEK293(β3) and U87MG cells. Finally the grafted radiosensitizing nanoparticles were intravenously injected into Nude mice bearing subcutaneous U87MG tumors and the signal observed by optical imaging was twice as high for SRP-cRGDfK compared to their negative analogue.

Ultraklein, aber multifunktionell: Starre Bildgebungspartikel mit Größen unter 5 nm wurden durch einen Top‐down‐Prozess ausgehend von einer Kern‐Schale‐Struktur erhalten (Kern: Gadoliniumoxid; Schale: Polysiloxan). Es sind die ersten multifunktionellen Siliciumdioxid‐Partikel, die hinreichend klein sind, um sich der hepatischen Clearance zu entziehen, und die eine In‐vivo‐Bildgebung mit vier komplementären Techniken ermöglichen.

Small Rigid Platforms (SRPs) are sub-5 nanometre gadolinium based nanoparticles that have been developed for multimodal imaging and theranostic applications. They are composed of a polysiloxane network surrounded by gadolinium chelates. A covalent coupling with quinoxaline derivatives has been performed. Such derivatives have proven their affinity for melanin frequently expressed in primary melanoma cases. Three different quinoxaline derivatives have been synthesised and coupled to the nanoparticles. The affinity of the grafted nanoparticles for melanin has then been shown in vitro by surface plasmon resonance on a homemade melanin grafted gold chip.

Ultrasmall gadolinium based particles have been functionalized with positively charged pyridinium quaternary ammonium and labelled with (111)In. Evidence of their active targeting properties towards proteoglycans has been demonstrated in vivo after intravenous injection into rats opening thus a route to cancer imaging and therapy.

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