Combining Pr3+-Doped Nanoradiosensitizers and Endogenous Protoporphyrin IX for X-ray-Mediated Photodynamic Therapy of Glioblastoma Cells

Glioblastomamultiforme is an aggressive type of brain cancer withhigh recurrence rates due to the presence of radioresistant cellsremaining after tumor resection. Here, we report the development ofan X-ray-mediated photodynamic therapy (X-PDT) system using NaLuF4:25% Pr3+ radioluminescent nanoparticles in conjunctionwith protoporphyrin IX (PPIX), an endogenous photosensitizer thataccumulates selectively in cancer cells. Conveniently, 5-aminolevulinicacid (5-ALA), the prodrug that is administered for PDT, is the onlydrug approved for fluorescence-guided resection of glioblastoma, enablingdual detection and treatment of malignant cells. NaLuF4:Pr3+ nanoparticles were synthesized and spectroscopicallyevaluated at a range of Pr3+ concentrations. This generatedradioluminescent nanoparticles with strong emissions from the S-1(0) excited state of Pr3+, which overlapswith the Soret band of PPIX to perform photodynamic therapy. The spectraloverlap between the nanoparticles and PPIX improved treatment outcomesfor U251 cells, which were used as a model for the thin tumor margin.In addition to sensitizing PPIX to induce X-PDT, our nanoparticlesexhibit strong radiosensitizing properties through a radiation dose-enhancementeffect. We evaluate the effects of the nanoparticles alone and incombination with PPIX on viability, death, stress, senescence, andproliferation. Collectively, our results demonstrate this as a strongproof of concept for nanomedicine.