Abstract LB-104: Gadolinium-based nanoparticles sensitize head and neck carcinoma stem and nonstem cells to low and high LET radiation.

Abstract

Abstract Head and neck squamous cell carcinoma (HNSCC) is an aggressive and recurrent malignancy owing to intrinsic radioresistance and lack of induction of apoptosis. Several strategies aiming at radiosensitizing these tumors are currently being developed, one of these relying on the use of nanoparticles including high Z elements such as gadolinium (Z=64). Once delivered to the tumor, gadolinium-based nanoparticles (GBNs) should amplify the efficacy of radiotherapy through the generation of electron Auger cascades and secondary electrons. This study aims at demonstrating the in vitro and in vivo radiosensitizing effect of sub-5 nm GBNs (composed of a core of gadolinium oxide, a shell of polysiloxane, and functionalized by diethylene triaminepentaacetic acid) in a SQ20B radioresistant HNSCC model. Owing to the crucial role of cancer stem cells in tumor initiation, disease recurrence and radioresistance, the radiosensitizing effect of GBNs was also tested in SQ20B stem-like cells. The association of 0,6 mM GBNs with a photon or a 33.6 keV/µm carbon ion irradiation decrease significantly SQ20B cell survival. Radiosensitization goes through the increase in non-reparable DNA double-strand breaks, the shortening of G2/M phase blockage, the inhibition of cell proliferation, each contributing to the commitment into apoptosis. The combined treatment of GBNs with irradiation can also overcome the resistance of SQ20B stem-like cells. Using an SQ20B tumor-bearing mouse model, we also demonstrate that GBNs in conjunction with photon irradiation significantly retard tumor growth compared with the radiation alone, with complete remission in some mice. Significantly, an increase in apoptosis and decrease in cell proliferation are also detected inside tumors in the combined treatment group. These results suggest the interesting potential of GBNs in sensitizing resistant HNSCC tumors to radiotherapy and their possible contribution towards overcoming limitations of current cancer treatment. This project was conducted under the framework of LANTHARAD (PDC019 CLARA 2010), PRRH-ETOILE and LABEX PRIMES (2012) Citation Format: Marie-Thérèse Aloy, Imen Miladi, Emma Armandy, Claire Billotey, Olivier Tillement, François Lux, Pascal Perriat, Marc Janier, Claire Rodriguez-Lafrasse. Gadolinium-based nanoparticles sensitize head and neck carcinoma stem and nonstem cells to low and high LET radiation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-104. doi:10.1158/1538-7445.AM2013-LB-104