Radiosensitization with Gadolinium Chelate-Coated Gold Nanoparticles Prevents Aggressiveness and Invasiveness in Glioblastoma

Maxime Durand (1) , Alicia Chateau (1) , Justine Jubréaux (1) , Jérôme Devy (2) , Héna Paquot (1) , Gautier Laurent (3) , Rana Bazzi (3) , Stéphane Roux (3) , Nicolas Richet (4) , Aurélie Reinhard-Ruch (1) , Pascal Chastagner (1) , Sophie Pinel (1)

1 CRAN - Centre de Recherche en Automatique de Nancy
2 MEDyC - Matrice Extracellulaire et Dynamique Cellulaire - UMR CNRS 7369
3 UTINAM - Univers, Transport, Interfaces, Nanostructures, Atmosphère et environnement, Molécules (UMR 6213)
4 Plateau technique de cytométrie environnementale MOBICYTE

This study aimed to evaluate the radiosensitizing potential of Au@DTDTPA(Gd) nanoparticles when combined with conventional external X-ray irradiation (RT) to treat GBM. Methods: Complementary biological models based on U87 spheroids including conventional 3D invasion assay, organotypic brain slice cultures, chronic cranial window model were implemented to investigate the impact of RT treatments (10 Gy single dose; 5×2 Gy or 2×5 Gy) combined with Au@DTDTPA(Gd) nanoparticles on tumor progression. The main tumor mass and its infiltrative area were analyzed. This work focused on the invading cancer cells after irradiation and their viability, aggressiveness, and recurrence potential were assessed using mitotic catastrophe quantification, MMP secretion analysis and neurosphere assays, respectively. Results: In vitro clonogenic assays showed that Au@DTDTPA(Gd) nanoparticles exerted a radiosensitizing effect on U87 cells, and in vivo experiments suggested a benefit of the combined treatment "RT 2×5 Gy + Au@DTDTPA(Gd)" compared to RT alone. Invasion assays revealed that invasion distance tended to increase after irradiation alone, while the combined treatments were able to significantly reduce tumor invasion. Monitoring of U87-GFP tumor progression using organotypic cultures or intracerebral grafts confirmed the antiinvasive effect of Au@DTDTPA(Gd) on irradiated spheroids. Most importantly, the combination of Au@DTDTPA(Gd) with irradiation drastically reduced the number, the viability and the aggressiveness of tumor cells able to escape from U87 spheroids. Notably, the combined treatments significantly reduced the proportion of escaped cells with stem-like features that could cause recurrence. Conclusion: Combining Au@DTDTPA(Gd) nanoparticles and X-ray radiotherapy appears as an attractive therapeutic strategy to decrease number, viability and aggressiveness of tumor cells that escape and can invade the surrounding brain parenchyma. Hence, Au@DTDTPA(Gd)-enhanced radiotherapy opens up interesting perspectives for glioblastoma treatment.

Mots clés: gold nanoparticles radiotherapy brain tumor cancer cell invasion tumor recurrence; gold nanoparticles; radiotherapy; brain tumor; cancer cell invasion; tumor recurrence

Domaines: Sciences du Vivant [q-bio]

Maxime Durand, Alicia Chateau, Justine Jubréaux, Jérôme Devy, Héna Paquot, et al.. Radiosensitization with Gadolinium Chelate-Coated Gold Nanoparticles Prevents Aggressiveness and Invasiveness in Glioblastoma. International Journal of Nanomedicine, 2023, 18, pp.243-261. ⟨10.2147/IJN.S375918⟩. ⟨hal-03957559⟩