Novel radiation-activated Photodynamic Therapy (radioPDT) Theranostic Nanoparticle for Treatment of Deep-seated Tumors

Abstract

Radiotherapy is used in the treatment of 50% of all cancer patients. It has evolved into a high precision therapy in cancer care. Radiotherapy’s main limitation is the damage incurred on normal tissue. Advances in modern radiotherapy allowed for improved precision in delivery and optimizes its Therapeutic Index (TI). Advances in precision are still pursued, but diminishing returns exist with little additional benefit seen with further precision. Photodynamic therapy (PDT) has evolved in clinical use over the last 30 years. It produces anti-tumor cytotoxicity with limited normal tissue damage. PDT’s dependence on activating light has limited its impact on clinical care in oncology. Attempts to combine radiotherapy’s deep penetration and precise targeting with PDT’s superior TI has led to radiation-induced PDT (radioPDT), which uses scintillators to activate PDT with radiation using Forster Resonant Energy Transfer (FRET). Contemporary radioPDT agents have been limited by biocompatibility, toxicity, practicality, or lack of evaluation in a clinically relevant setting such as in hypoxia. This thesis explores the development of a novel radioPDT nanoparticle consisting of LaF3:Ce3+ nanoscintillator co-encapsulated with PPIX into a PEG-PLGA nanocarrier system. The nanoparticle exhibited a high safety profile, ease of synthesis and scalability, exceptional in vivo compatibility and delivery, superior therapeutic effect to radiation alone in vitro and in vivo, and utility as a CT contrast agent with theranostic potential. The nanoparticle exhibits negligible toxicity in inactive form, but once activated with radiotherapy it converts X-ray energy and molecular oxygen into cytotoxic singlet oxygen. This yields impressive anti-tumor cytotoxicity in normoxic and hypoxic conditions with partial oxygen-dependence characteristics and favourable treatment of potentially deep-seated tumors.