Dual Porphyrin‐Loaded Scintillating Nanoparticles Enhanced Photodynamic Therapy in Hypoxic Cancer Cells under X‐ray Irradiation

Tumor hypoxia represents a major challenge to achieving successful therapy outcomes with photodynamic therapy (PDT). We hypothesized that systemic loading of dual porphyrins, protoporphyrin IX (PPIX) as a photosensitizer (PS) and hemin (Fe3+‐PPIX) as an oxygen generator, onto Eu‐doped NaYF4 scintillator (Sc), collectively terms as Eu‐PPIX@Hemin, could enhance the activity of X‐ray mediated PDT. Catalase‐like property of hemin in the presence of H2O2 facilitated the production of oxygen molecules (3O2) in hypoxic cancer cells. The produced 3O2 reacts with nearby excited PPIX molecules (PPIX*) in the Sc‐PS pairs to produce singlet oxygen (1O2), as cytotoxic reactive oxygen species (ROS) under X‐ray irradiation. Eu‐PPIX@Hemin nanoparticles (NPs) with a diameter of ~60 nm efficiently produced oxygen in the presence of H2O2, which its concentration in tumor cells is higher than that in normal cells. Eu‐PPIX@Hemin generated similar amounts of ROS in hypoxic cultured cancer cells under low dose X‐ray irradiation (0.5 Gy), compared to those in normoxic cancer cells. Notably, Eu‐PPIX@Hemin exhibited similar cytotoxic effects in both hypoxic and normoxic cancer cells under X‐ray irradiation. Overall, the mutual Sc‐PS performance between PPIX and Eu was synergistically enhanced by hemin in Eu‐PPIX@Hemin, which relieved hypoxia in the cancer cells under X‐ray irradiation.