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

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.

Radiation-Induced Mitotic Catastrophe Enhanced by Gold Nanoparticles: Assessment with a Specific Automated Image Processing Workflow.

In recent years, the use of gold-based nanoparticles in radiotherapy has been extensively studied, and the associated radiosensitization mechanism has been evaluated in a variety of in vitro studies. Given that mitotic catastrophe is widely involved in radiation-induced cell death, we evaluated the effect of gold nanoparticles on this key event. Most of the methods currently used to visualize and quantify morphological changes and multinucleation are manual. To circumvent this time-consuming step, we developed and optimized an image processing workflow (based on freely accessible software and plugins) for the automated quantification of mitotic catastrophes. We validated this approach in three cell lines by comparing the number of radiation-induced mitotic catastrophes detected using the automated and manual methods in the presence and absence of nanoparticles. With the Bland-Altman analysis, the automated and manual counting methods were found to be fully interchangeable. The ultimate goal of this work was to determine whether mitotic catastrophe was critically involved in radiationinduced cell death after prior exposure to gold nanoparticles. In the radioresistant U87 cell line, exposure to gold nanoparticles was associated with a shorter time course for the events related to mitotic catastrophe, which peaked at 96 h postirradiation. Mitotic catastrophe was dose-dependent in both the presence and absence of gold nanoparticles. These results demonstrate that cell exposure to gold nanoparticles led to an increase in mitotic catastrophe events, and confirm the marked radiosensitizing effect observed in clonogenic assays.

Monte Carlo simulations guided by imaging to predict the in vitro ranking of radiosensitizing nanoparticles.

This article addresses the in silico-in vitro prediction issue of organometallic nanoparticles (NPs)-based radiosensitization enhancement. The goal was to carry out computational experiments to quickly identify efficient nanostructures and then to preferentially select the most promising ones for the subsequent in vivo studies. To this aim, this interdisciplinary article introduces a new theoretical Monte Carlo computational ranking method and tests it using 3 different organometallic NPs in terms of size and composition. While the ranking predicted in a classical theoretical scenario did not fit the reference results at all, in contrast, we showed for the first time how our accelerated in silico virtual screening method, based on basic in vitro experimental data (which takes into account the NPs cell biodistribution), was able to predict a relevant ranking in accordance with in vitro clonogenic efficiency. This corroborates the pertinence of such a prior ranking method that could speed up the preclinical development of NPs in radiation therapy.