Rose Bengal Decorated NaYF₄:Tb Nanoparticles for Low Dose X-ray-Induced Photodynamic Therapy in Cancer Cells

The use of scintillating nanoparticles (ScNPs) in X-ray-induced photodynamic therapy (X-PDT) is a technique for deep tissue-localized tumor therapy with few side effects. ScNPs transfer X-ray-induced energy to photosensitizers, which generate massive amounts of reactive oxygen species (ROS) and kill cancer cells. Here we fabricated rose bengal (RB)-installed, Tb³⁺-rich NaYF₄ nanocrystals (NaYF₄:Tb@RB), in which optically inert Y³⁺ enables highly efficient energy transfer via high amounts of Tb³⁺ doping. NaYF₄:Tb was prepared via solvothermal synthesis to have an average size of 7.6 nm, followed by coating with poly(maleic anhydride-alt-1-octedecene)-poly(ethylene glycol) with a molecular weight of 2000 (C₁₈PMH-PEG_2k). Further, RB was covalently conjugated to carboxyl groups generated from PMH on NaYF₄:Tb using an ethylenediamine linker. NaYF₄:Tb@RB exhibited a hydrodynamic diameter of ∼75 nm with a ζ-potential of -12 mV. NaYF₄:Tb@RB efficiently generated ROS in cultured luciferase-expressing murine epithelial breast cancer (4T1-luc) cells under low dose X-ray irradiation (0.5 Gy). The ROS generation amounts of NaYF₄:Tb@RB were 1.5-2-fold higher than those of NaGdF₄:Tb@RB, in which host nanocrystals were prepared with optically active Gd³⁺. Flow cytometric and confocal microscopic analyses showed higher intracellular ROS production of NaYF₄:Tb@RB, compared to NaYF₄:Tb and RB, resulting in higher X-ray-induced DNA damage in cultured 4T1-luc cells. Ultimately, NaYF₄:Tb@RB elicited significant cytotoxicity after X-ray irradiation (0.5 Gy), while inducing marginal cytotoxicity without X-ray irradiation. Altogether, this research proposes a promising ScNP design for efficient X-PDT agents that make the better use of incident X-ray energy while causing the fewest side effects.