Zhizi Feng1
University of Georgia1
Photodynamic therapy (PDT) is an emerging therapeutic approach to kill tumor cells by using photosensitizer (PS, both singular and plural) molecules that can be activated by light to produce reactive oxygen species (ROS), most important singlet oxygen (<sup>1</sup>O<sub>2</sub>). Only the combination and co-localization of light and PS can cause cell death, which is highly selective. Also PDT may be applied repeatedly without resistance, and can be used with chemotherapeies and immunotherapies for synergistic therapies. But the limited tissue penetration restrains PDT from the mainstream cancer treatment options. X-ray induced photodynamic therapy (X-PDT) combines the advantages of radiotherapy and PDT, potentially solves the challenge of conventional photodynamic therapy for deep-penetrating cancer therapy, and is applied by us and other groups for cancer treatment. Herein, we report a streamlined X-PDT strategy based on CsI(Na)@MgO nanoparticles and 5-aminolevulinic acid (5-ALA). The combination of CsI(Na)@MgO-and-5-ALA can kill cancer cells with the existence of X-ray, because CsI(Na)@MgO nanoparticles produce strong ~410 nm X-ray luminescence, which matches the Soret band of PpIX. While 5-ALA is a photosensitizer approved by FDA, converted to protoporphyrin IX (PpIX) in mitochondria of cancer cells. So after X-ray irradiation, protoporphyrin IX (PpIX) converted from 5-ALA can produce ROS in mitochondria with the ~410 nm X-ray luminescence caused by CsI(Na)@MgO nanoparticles, causing damages to mitochondria, and synergizes with DNA-targeted irradiation. While scintillator nanoparticles and photosensitizer are administered separately, the approach forgoes issues such as self-quenching or uncontrolled release of photosensitizers. When tested with 4T1 cells <i>in vitro</i>, the combination of CsI(Na)@MgO and 5-ALA elevated radiation-induced reactive oxygen species (ROS), which enhance damages to mitochondria, DNA, and lipids, and eventually reduced cell proliferation and clonogenicity. When tested in 4T1 models <i>in vivo</i>, the combination of X-PDT with the CsI(Na)@MgO and 5-ALA significantly improved tumor suppression and animal survival comparing with radiation therapy (RT) alone. After treatment, the scintillator nanoparticles, made of low-toxic alkali and halide elements, were efficiently excreted, causing no detectable harm to the hosts. Overall, separately administering CsI(Na)@MgO nanoparticles and 5-ALA represents a safe and streamlined X-PDT approach with a potential in clinical cancer treatment.