Microbeam radiation therapy (MRT) can be enhanced by the prior administration of gadolinium-based nanoparticles to the patient. The nanoparticles have a radiosensitising effect that is activated by X-ray microbeams [1]. The nanoparticles also improve contrast in magnetic resonance imaging (MRI) permitting localisation of the tumour [2]. These two beneficial properties allow theranostic applications to be envisaged using the same drug as contrast and dose media.

The new technique has been tested at the ESRF’s biomedical beamline ID17. Following treatment, rats bearing very aggressive brain tumours survived five times longer than non treated rats. Figure 58 presents a summary of the results. The median survival time of non-treated tumour bearing rats was around 19 days while it reached 47 days for those treated by MRT alone. The median survival time increased even further to 93 days when the MRT treatment was carried out 20 minutes after an intravenous injection of gadolinium oxide nanoparticles.

Fig. 58: Survival curves for tumour bearing rats. Without treatment (grey curve, n=4 rats), treated by MRT only (blue curve, n = 7) and treated by MRT following intravenous injection of nanoparticles with delays of 5 minutes (red curve, n = 8) and 20 minutes (green curve, n = 8). The MRT irradiation was done in cross fire mode, using 50 µm wide X-ray beams with a spacing of 211 µm between the beams. The skin entrance dose was set up at 400 Gy for the peak and 20 Gy for the valley.

For treatments combining MRT with gadolinium based nanoparticles, the time delay between the administration of the nanoparticles and the subsequent MRT irradiation proved critical. When the time delay was 5 minutes, the median survival time fell to 35 days, i.e. lower than the survival time achieved with MRT alone. The variation in the survival time is most probably caused by the non-uniform distribution of the nanoparticles within the brain. MRI images reveal that the nanoparticles concentrate within and around the tumour tissue (Figure 59). The dependency of the survival time on the time delay post injection leads to the conclusion that the difference in gadolinium nanoparticle concentration between the tumour and healthy tissue is highly significant, and more important than achieving the ultimate dose within the tumour because healthy tissue can be equally damaged by the dose enhancement induced by the nanoparticles. In other words, even if the total concentration of nanoparticles in the tumour affected tissue (Figure 59, right hemisphere) is lower 20 minutes after injection than at 5 minutes after injection, the higher contrast between the nanoparticle concentration in tumour affected tissue and non affected tissue (Figure 59, left hemisphere) dominates by prolonging the survival time.

Fig. 59: MRI images of rat brain glioma before and 20 minutes after injection of gadolinium nanoparticles. The tumour and surrounding tissues are revealed by the effect of the particles on the MRI signal.

The gadolinium nanoparticles have also proven beneficial for MRI, which is the standard imaging technique used for the diagnosis of a brain tumour. The nanoparticles help to delineate the tumour and its surrounding vasculature because the nanoparticles leak from the vascular bed to the interstitial space between the tumour cells. This is demonstrated by Figure 59 where the tumour has better contrast than the healthy tissue. Gadolinium nanoparticles are therefore appealing as dual modality drugs for their beneficial effect on the treatment as well as for the possibility of performing imaging-guided therapy.

The nanoparticles were designed and produced by the Laboratoire de Chimie des Matériaux Luminescents (Université Claude Bernard, Lyon, France). First in vivo trials were performed at the ESRF in 2007 in preparation for the experiments presented here. Ongoing studies aim at a treatment where one injection will serve both diagnosis and therapy, using the remanence of the nanoparticles in the tissue up to and over 24 hours following injection.

 

Principal publication and authors

G. Le Duc (a), I. Miladi (b), C. Alric (b), P. Mowat (b), E. Brauer Krisch (a), A. Bouchet (a), E. Khalil (c), C. Billotey (b), M. Janier (b), F. Lux (b), T. Epicier (d), P. Perriat (e), S. Roux (b,d) and O. Tillement (b), ACS Nano 5, 9566-74 (2011).

(a) ESRF

(b) Laboratoire de Physico-Chimie des Matériaux Luminescents, UMR 5620 CNRS – Université Claude Bernard, Lyon (France)

(c) Faculty of Pharmacy, University of Jordan, Amman (Jordan)

(d) Institut UTINAM, UMR6213 CNRS-UFC, Université de Franche-Comté, Besançon (France)

(e) Matériaux, Ingéniérie et Sciences, UMR 5510 CNRS-INSA, Université Claude Bernard, Lyon (France)

 

References

[1] O. Tillement, S. Roux, G. Le Duc, P. Perriat, C. Mandon, B. Mutelet, C. Alric, C. Billotey, M. Janier and C. Louis, Utilisation de nanoparticules à base de lanthanides comme agents radiosensibilisants, Patent FR N 07 58348, 17 Oct 2007.

[2] F. Lux, A. Mignot, P. Mowat, C. Louis, S. Dufort, C. Bernhard, F. Denat, F. Boschetti, C. Brunet, R. Antoine, P. Dugourd, S. Laurent, L. Vander Elst, R. Muller, L. Sancey, V. Josserand, J.L. Coll, V. Stupar, E. Barbier, C. Rémy, A. Broisat, C. Ghezzi, G. Le Duc, S. Roux, P. Perriat and O. Tillement, Angew Chem Int Ed Engl. 50, 12299-303 (2011).