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Purpose 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 anti-invasive 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.

Introduction Metal-based nanoparticles with radiosensitizing aim have promising prospects in the field of radiotherapy. Due to their high X-ray absorption capacity, nanomaterials with high atomic number may indeed improve radiation therapy efficacy in cancer treatment. Clinical trials are ongoing to evaluate the benefit of nanoparticle enhanced radiotherapy. The objective of the present study was to validate the potential of gold nanoparticle enhanced radiotherapy to treat glioblastoma using in silico, in vitro and in vivo approaches. Material and methods Among a panel of 5 gold nanoparticles (AuNPs), an innovative Monte Carlo simulation approach was used to rank the most promising nanoparticles according to their theoretical radiosensitizing effect. In U87-MG glioblastoma cells, the radiosensitizing effect of the selected nanoobjects was confirmed by clonogenic assays and cell death processes such as apoptosis, senescence, and mitotic catastrophes were investigated. A brain tumour window model, allowing fluorescence-based imaging was used to evaluate the tumour tissue selectivity of Cy5-labelled nanoparticles. Results and discussions A radiosensitizing effect was determined for 3 among 5 tested AuNPs with a dose modifying factor (DMF) from 0.4 to 0.5 (i.e. a DMF equal to 0.5 means the treatment is twice as efficient). Our results showed an inverse relationship between the radiosensitizing effects and the AuNPs sizes. Moreover, the nature of the coating influences the triggered cell death process. In case of PVP-coated AuNPs, the cell death was characterised by a radio-induced senescence in relation with a 1.5-fold increase of the reactive oxygen species production. In contrast, smallest PEG-coated AuNPs triggered post-RX mitotic catastrophes, leading to a delayed cell death. For in vivo experiments, a most promising AuNP (i.e. Au@DTDTPA:Gd) was selected, showing an interesting U87-tumour tissue selectivity. Conclusion After validating the in vitro radiosensitizing effect of small-sized AuNPs, an innovative design was selected for in vivo experiments. Tumour tissue accumulation and selectivity were evidenced for this innovative nanoparticle. We still have to validate the in vivo radiosensitizing effect using an orthotopic U87 model. We will suggest optimised treatment modalities.