Bilirubin-Coated Radioluminescent Particles for Radiation-Induced Photodynamic Therapy

Photodynamic therapy (PDT) has shown potential as a cancer treatment modality, but its clinical application is limited due to its visible-light activation since visible wavelengths of light cannot penetrate tissues well. Additionally, combination therapies utilizing PDT and radiotherapy have shown clinical promise in several cancers but are limited again by light penetration and the need for selective photosensitization of the treatment area. Herein, we report the development of bilirubin-photodynamic nanoparticles (PEGylated bilirubin-encapsulated CaWO₄ nanoparticles or "PEG-BR/CWO NPs"). PEG-BR/CWO NPs are a formulation of PEGylated bilirubin micelles encapsulating CaWO₄ nanoparticles. These particles are capable of activating PDT via X-ray irradiation within deep tissues due to the radioluminescence properties of their CaWO₄ nanoparticle cores. PEG-BR/CWO NPs facilitate a combination of photodynamic and radiation therapy and represent a previously unexplored application of PEG-bilirubin conjugates as photosensitizing agents. When irradiated by X-rays, PEG-BR/CWO NPs emit UV-A and visible light from their CaWO₄ cores, which excites bilirubin and leads to the production of singlet oxygen. PEG-BR/CWO NPs exhibit improvements over X-ray therapy alone in vitro and in murine xenograft models of head and neck cancer. The data presented in this study indicate that PEG-BR/CWO NPs are promising agents for facilitating combined radio-photodynamic therapy in deep tissue tumors.