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

Abstract

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.

Chemical and in vitro characterizations of a promising bimodal AGuIX probe able to target apoptotic cells for applications in MRI and optical imaging

“…In aqueous‐buffered suspension containing 2 mM [Gd 3+ ] at pH 7.4, approximately 50% of the longitudinal relaxivity at 60 MHz and 20 MHz is lost after 70 min, whereas the r 1,2 decrease of the 20 mM solution is lower than 10%. The kinetics of degradation is thus dependent on Gd 3+ concentration in suspension .…”

“…The synthesis of the core–shell nanoparticles (core gadolinium oxide and shell polysiloxane) in diethylene glycol (DEG) has been previously described by the present authors .…”

Orotracheal administration of contrast agents: a new protocol for brain tumor targeting

“…administration of Dotarem®. In addition, a previous study has shown that Dotarem® has a brain tumor residence time about half that of the USRPs . As a consequence, the contrast is probably eliminated from the tumor before reaching a relevant concentration able to generate a visible enhancement of the GBM.…”

Ultrasmall particles for Gd‐MRI and 68Ga‐PET dual imaging

“…Accuracy assessments, which showed percentages of radioactivity recovery over 97%, assured no further post‐purification steps were necessary. The nanoparticles are cleared rapidly from the blood to the urine via the kidneys, as established by the biodistribution analysis, due to the small size and the biodegradable properties of AGuIX . An extremely low residual activity in all untargeted tissues, especially in the critical organs such as the liver and lungs (<2% ID/g at 120 min p.i.)…”