Abstract

Despite decades of research, few advancements have been made toward improving the prognosis of patients with glioblastoma, a lethal and invasive form of brain cancer. The current standard of care is fluorescence-guided surgical resection followed by radiotherapy and chemotherapy. Fluorescence guided surgery is performed using 5-aminolevulinic acid (5-ALA), a prodrug that induces the accumulation of fluorescent protoporphyrin IX (PPIX) in malignant cells. Conveniently, 5-ALA mediated production of PPIX is also renowned as the most popular photodynamic therapy (PDT) agent in the world. PDT is a treatment that uses visible light to stimulate a photosensitizer to produce reactive oxygen species, which can damage and kill cells. However, the technique is limited by the tissue depth penetration of light. The advent of nanomedicine has enabled the possibility to achieve PDT by using luminescent nanoparticles to alter the incident excitation source. When X-rays are used to excite the nanoparticles, the process is called X-ray mediated photodynamic therapy (X-PDT).
Herein, we have developed NaLuF4:Pr3+ radioluminescent nanoparticles to achieve X-PDT. The emission spectrum of Pr3+ exhibits strong spectral overlap with the absorption spectrum of PPIX, an endogenous photosensitizer. A reproducible route to synthesizing uniform NaLuF4:Pr3+ nanoparticles at sizes relevant for cell uptake was developed, and the spectroscopic properties of the nanoparticles were evaluated prior to in vitro studies. The nanoparticles were found to exhibit persistent luminescence, and a mechanism was developed to explain the charge (de-)trapping process. The nanoparticle composition was optimized for excitation of PPIX and studied in the human glioblastoma cell line called U251. We evaluated the therapeutic effect of the nanoparticles with and without 5-ALA to establish the radiosensitization capability as well as the X-PDT effect. Three nanoparticle concentrations were studied using 4 radiation doses, including those relevant for intraoperative radiotherapy which is performed on the tumor cavity immediately after resection. The effects on stress, death, damage, senescence and proliferation were studied. and demonstrate promising results at a proof-of-concept level. Throughout this work, current clinical practice guided our experimental design, providing a strong foundation toward using Pr3+-doped nanoparticles for X-PDT in an intraoperative setting using endogenous PPIX as the photosensitizer.