학술논문
Proof of Concept of the Radiosensitizing Effect of Gadolinium Oxide Nanoparticles in Cell Spheroids and a Tumor-Implanted Murine Model of Chondrosarcoma
ORIGINAL RESEARCH
ORIGINAL RESEARCH
Document Type
Academic Journal
Author
Source
International Journal of Nanomedicine. December 31, 2022, Vol. 17, p6655, 19 p.
Subject
Language
English
ISSN
1178-2013
Abstract
Introduction Chondrosarcoma (CHS) is the second most common primary bone sarcoma in humans after osteosarcoma. Almost 90% of CHSs are of the conventional subtype. They are characterized by the production [...]
Purpose: 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[R]) 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[R] nanoparticle, radiosensitization, PTX3
Purpose: 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[R]) 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[R] nanoparticle, radiosensitization, PTX3