Long-term in vivo clearance of gadolinium-based AGuIX nanoparticles and their biocompatibility after systemic injection.

We previously reported the synthesis of gadolinium-based nanoparticles (NPs) denoted AGuIX (activation and guiding of irradiation by X-ray) NPs and demonstrated their potential as an MRI contrast agent and their efficacy as radiosensitizing particles during X-ray cancer treatment. Here we focus on the elimination kinetics of AGuIX NPs from the subcellular to whole-organ scale using original and complementary methods such as laser-induced breakdown spectroscopy (LIBS), intravital two-photon microscopy, inductively coupled plasma optical emission spectrometry (ICP-OES), transmission electron microscopy (TEM), and electrospray ionization mass spectrometry (ESI-MS). This combination of techniques allows the exact mechanism of AGuIX NPs elimination to be elucidated, including their retention in proximal tubules and their excretion as degraded or native NPs. Finally, we demonstrated that systemic AGuIX NP administration induced moderate and transient effects on renal function. These results provide useful and promising preclinical information concerning the safety of theranostic AGuIX NPs.

Advantages of gadolinium based ultrasmall nanoparticles vs molecular gadolinium chelates for radiotherapy guided by MRI for glioma treatment.

AGuIX nanoparticles are formed of a polysiloxane network surrounded by gadolinium chelates. They present several characteristics. They are easy to produce, they present very small hydrodynamic diameters (<5 nm) and they are biodegradable through hydrolysis of siloxane bonds. Such degradation was evaluated in diluted conditions at physiological pH by dynamic light scattering and relaxometry. AGuIX nanoparticles are also known as positive contrast agents and efficient radiosensitizers. The aim of this paper is to compare their efficiency for magnetic resonance imaging and radiosensitization to those of the commercial gadolinium based molecular agent: DOTAREM®. An experiment with healthy animals was conducted and the MRI pictures we obtained show a better contrast with the AguIX compared to the DOTAREM® for the same amount of injected gadolinium in the animal. The better contrast obtained after injection of Aguix than DOTAREM® is due to a higher longitudinal relaxivity and a residential time in the blood circulation that is two times higher. A fast and large increase in the contrast is also observed by MRI after an intravenous injection of the AGuIX in 9 L gliosarcoma bearing rats, and a plateau is reached seven minutes after the injection. We established a radiotherapy protocol consisting of an irradiation by microbeam radiation therapy 20 minutes after the injection of a specific quantity of gadolinium. After microbeam radiation therapy, no notable difference in median survival time was observed in the presence or absence of gadolinium chelates (38 and 44 days respectively). In comparison, the median survival time is increased to 102.5 days with AGuIX particles showing their interest in this nanomedicine protocol. This remarkable radiosensitizing effect could be explained by the persistent tumor uptake of the particles, inducing a significant nanoscale dose deposition under irradiation.