Systemic antitumor immune response of doped yttria nanoscintillators under low-dose x-ray irradiation
Menée in vitro et à l'aide de xénogreffes de tumeurs pancréatiques sur des modèles murins, cette étude met en évidence l'effet antitumoral d'un nouveau complexe nanoscintillateur-photosensibilisateur capable, sous de faibles doses de rayons X, de générer des espèces réactives de l'oxygène
Inadequate light penetration in tissues restricts photodynamic therapy to treating only superficial tumors. To enable x-ray–excited photodynamic therapy (XPDT) that targets deep-seated tumors, we synthesized a nanoscintillator-photosensitizer complex containing 5% Eu-doped Y2O3 fluorescing at 611 nanometers and decorated with SiO2 containing the scintillation-coupled photosensitizer methylene blue and a polyethylene glycol coating [PEGylated Y2O3:Eu@SiO2-methylene blue (pYSM)]. When irradiated, pYSMs generate singlet oxygen species in vitro, causing cytotoxicity with hallmarks of immunogenic cell death (calreticulin translocation to the cell membrane). Intravenously administered pYSMs home passively to pancreatic tumor xenografts and, upon 10 gray irradiation, cause significant tumor regression (P < 0.01). On combining XPDT with anti-PD1 immunotherapy, a distant nonirradiated tumor also regresses via an increase in intratumoral activated CD8+ cytotoxic T cells. Collectively, we advance a systemically delivered XPDT strategy that mediates an antitumor effect in both irradiated and nonirradiated (abscopal) tumors when coupled with immunotherapy, converting an immunologically “cold” tumor to an immunologically “hot” tumor. X-ray–excited photodynamic therapy with immunotherapy stimulates a local antitumor response and a systemic anticancer effect.