Combined physical and biological contributions to radiotherapy enhancement by Lu-based nanoscintillators in pancreatic cancer models.

Rationale: Pancreatic cancer has a dismal prognosis and requires better treatments. One promising approach aims at improving radiotherapy using nanoscintillators, which down-convert ionizing radiation into visible light, triggering various radiotherapeutic effects upon X-ray irradiation. One such effect is radiation dose-enhancement, driven by high-Z elements present in the nanoscintillator core. These elements efficiently absorb X-rays, releasing secondary electrons that amplify the radiation dose in the surrounding tissue. Methods: In this paper, we study the ability of Lu3Al5O12:Pr@SiO2, a lutetium-based nanoscintillator, to exert a radiation dose-enhancement effect in two human pancreatic cancer cell models, namely PANC-1 and MIA PaCa-2. Results: Lu3Al5O12:Pr@SiO2 nanoparticles showed negligible toxicity up to 1 mg/mL in 2D and 3D models. Using monochromatic synchrotron radiation, we demonstrated that a subtoxic nanoparticle concentration enhances the radiation dose in 3D spheroids in an energy-dependent manner. These results were further supported by Monte Carlo simulations. Beyond this physical contribution, γ-H2AX foci quantification revealed a biological component to the radiosensitization: Lu3Al5O12:Pr@SiO2 nanoparticles not only amplified initial DNA damage, but also impaired its repair. Conclusion: These findings highlight the dual contribution of Lu3Al5O12:Pr@SiO2 nanoparticles to radiotherapy enhancement, combining both physical dose-enhancement and biological modulation of DNA repair.