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.