Physical mechanisms of deep tissue photodynamic therapy using nanoscintillators: A roadmap for designing efficient platforms

Photodynamic therapy (PDT) is a therapeutic modality that combines a photosenzitizer, molecular oxygen and light, to generate reactive oxygen species (ROS), such as singlet oxygen. These ROS induce local cytotoxic damage, vascular shutdown and trigger an immune response, ultimately culminating in an anti-tumor reaction. PDT is currently in the clinic for various indications, including some cancers. However, because of the shallow penetration of light in tissues, PDT remains restricted to superficial lesions or to tumors that can be illuminated using optical fibers. This limitation is a major hurdle in the clinical implementation of this otherwise very promising treatment modality. Nanoscintillators are luminescent nanoparticles able to emit light when exposed to ionizing radiations, such as the X-rays used in radiotherapy. When combined with photosensitizers, they become a promising platform to excite the photosensitizers and induce PDT during radiotherapy, thereby enhancing the overall treatment efficacy. While promising results have been obtained in vitro and in vivo , the origin of such a strong efficacy remains unclear and the overall mechanism under-explored. This contribution aims at providing a comprehensive description of the complex physical sequence that starts when X-ray photons interact with nanoscintillators. During the primary interaction, energy is deposited in the nanoscintillators and part of it can be transferred to excite the photosensitizers. In addition to provide a detailed physical description of this whole sequence, we identified key parameters that will guide the reader for future development of innovative nanoscintillators-based platform for X-ray induced PDT. • No single nanoscintillator-photosensitizer suits all X-ray PDT needs, but optimal combos emerge from key physical parameters. • Systematical analyzes the physical mechanisms and parameters influencing NS/PS performance. • Optimal NS/PS combinations are identified for different photosensitizers. • Findings provide a strong foundation from both physical and chemical perspectives. • Secondary electrons escaping the nanoscintillator can induce the formation of reactive oxygen species.