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Marie-Thérèse Aloy,1,* Jacqueline Sidi Boumedine,2,* Agathe Deville,2,3 David Kryza,2 Arnaud Gauthier,1,4 Delphine Brichart-Vernos,1,5 Grégoire Ollier,1 Veronica La Padula,5 François Lux,5 Olivier Tillement,5 Claire Rodriguez-Lafrasse,1,4,* Marc Janier2,3,* 1Laboratory of Cellular and Molecular Radiobiology, UMR CNRS5822/IP2I, Lyon-Sud Medical School, Univ Lyon, Lyon 1 University, Oullins, France; 2CNRS, LAGEPP, UMR5007, IMTHERNAT, Lyon 1 University, Hospital Edouard Herriot, Lyon, France; 3Department of Nuclear Medicine, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France; 4Department of Biochemistry and Molecular Biology, Groupement Hospitalier Sud, Hospices Civils de Lyon, Pierre-Bénite, France; 5Light Matter Institut UMR CNRS 5306, Lyon 1 University, Villeurbanne, France*These authors contributed equally to this workCorrespondence: Marc Janier, Department of Nuclear Medicine, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, 69634, France, Tel +33472356999, Fax +33472357345, Email marc.janier@univ-lyon1.frPurpose: Chondrosarcomas (CHSs), which represent 20% of primary bone tumors in adults, are mostly resistant to radio- and chemotherapy. It is therefore essential that new therapeutic approaches, targeted to the tumour, be developed to improve the prognosis of patients. The effectiveness, as a radiosensitizing agent, of gadolinium oxide nanoparticles (GdoNP, AGuIX®) nanoparticles in CHS was evaluated in vitro, in spheroid CHS models allowing to reproduce cell-cell extracellular matrix interactions, and, in vivo, in a nude mouse model with heterotopic tumour xenograft.Methods: Spheroids from SW1353 and HEMC-SS cells were characterized by confocal microscopy with or without GdoNP treatment. Real-time microscopy enabled quantification of cell viability, cell migration and invasion. In vivo, the efficacy of the association of GdoNP combined with a single (4Gy) or fractionated (4x1Gy) irradiation was evaluated in HEMC-SS tumor-bearing mice by monitoring tumor growth, mouse survival and gene expression profile.Results: The expression of proteoglycans in the extra-cellular matrix (ECM) of spheroids demonstrated the relevance of the 3-D model. The combination of GdoNP with single or fractionated irradiation increased the lethal effects of irradiation on 2-D- and 3-D-cultured cells. In vivo, a single or a fractionated dose of 4 Gy associated with IT or IV injection of GdoNP decreased tumor growth significantly. Only IT injection increased mice survival. Unexpectedly, the radiosensitizing effect of GdoNP was associated, in vitro, with a significant decrease in invasion-migration capacities and, in vivo, with the decreased expression of PTX3, a protein involved in the epithelial-to-mesenchymal transition process, suggesting a potential impact of GdoNP on metastasis formation.Conclusion: These results provide the first proof of concept of the radiosensitizing effect of GdoNP in CHSs and opened the way for a multicentre, randomized Phase 2 trial evaluating the association of GdoNP with radiotherapy for the therapeutic management of patients with symptomatic inoperable musculoskeletal tumor lesions.Keywords: chondrosarcoma, AGuIX® nanoparticle, radiosensitization, PTX3