How does it work ?

With its hybrid nanostructured construction,  AGuIX® drug platform possesses three key actions against tumors: targeting, imaging and treating.

Targeting: Uptake in tumor

After their intravenous administration, AGuIX® nanoparticles circulate in blood vessels without extravasation in healthy tissues before their elimination by the kidneys. The nanoparticles can extravasate in tumoral tissue due to Enhanced Permeability and Retention (EPR) effect. It is due to the structural features of the tumor: hyperpermeable vasculature and impaired lymphatic drainage. The ultrasmall size of AGuIX nanoparticles allows a deep penetration in tumors and contrary to molecular agents, the AGuIX® particles are uptaken for long times in tumors allowing large therapeutic windows (>24 hours). In the particular case of brain tumors, one of the priority market of AGuIX®, the Blood Brain Barrier (BBB) is disrupted and the nanoparticles can accumulate for long times in tumors.

vaisseau et EPR

Imaging: MRI

Due to the presence of cyclic gadolinium chelates at the surface of the polysiloxane matrix, AGuIX® is a highly efficient MRI positive contrast agent, i.e. it increases the signal detected in MRI. This is due to the magnetic properties of gadolinium that possess seven unpaired electrons and a suitable electronic relaxation time. Commercial positive contrast agents are gadolinium chelates and are available for more than two decades. Nearly one third of MRI exams use gadolinium contrast agents. Among the different gadolinium chelates, cyclic ones are recognized for their thermodynamic stability and their kinetic inertness. In terms of efficacy, AGuIX® nanoparticles display relaxivities (i.e. capacity to enhance the MRI signal) two to three times higher than the commercial molecular agents. The following of the agent by MRI allows determining precisely its behavior in vivo and the best parameters for the irradiation protocol.

Treating: Radiosensitization

The principle of radiosensitization is to increase locally the radiobiological damages of irradiation. The radiosensitizer interacts with high energy radiation inside the tumor to produce harmful diffused photons, photoelectrons, Auger or Compton electrons and radical species. High Z elements like gadolinium are known to interact efficiently with primary and secondary species issued from X-Ray beams. The simulations performed on ultrasmall nanoparticles composed of this element show an important increase of the dose in the direct vicinity (few hundred nanometers) of the nano-objects.

nanodose

 The radiosensitization effect of AGuIX®  nanoparticles was validated  by  many in vitro tests performed at different concentrations in nanoparticles and on different cancerous cell lines under clinical irradiation. Even at small concentrations, a clear cytotoxic effect is observed when irradiation is performed in presence of AGuIX® nanoparticles.

The first in vivo proof of concept was obtained on a brain tumor model, demonstrating that after a single intravenous injection, the nanoparticles passively accumulate in brain tumors, allowing their detection by MRI, as well as a significant improvement of animal survival after irradiation.

The interest of the use of AGuIX® nanoparticles for cancer management was then demonstrated through different preclinical proofs of concepts on various clinical relevant tumor models (brain metastases, lung, pancreas, head and neck…).