Abstract
To improve the prognosis of glioblastoma, innovative radiotherapy regimens are required to augment the effect of tolerable radiation doses while sparing surrounding tissues. In this context, nanoscintillators are emerging radiotherapeutics that down‐convert X‐rays into photons with energies ranging from UV to near‐infrared. During radiotherapy, these scintillating properties amplify radiation‐induced damage by UV‐C emission or photodynamic effects. Additionally, nanoscintillators that contain high‐Z elements are likely to induce another, currently unexplored effect: radiation dose‐enhancement. This phenomenon stems from a higher photoelectric absorption of orthovoltage X‐rays by high‐Z elements compared to tissues, resulting in increased production of tissue‐damaging photo‐ and Auger electrons. In this study, Geant4 simulations reveal that rare‐earth composite LaF3:Ce nanoscintillators effectively generate photo‐ and Auger‐electrons upon orthovoltage X‐rays. 3D spatially resolved X‐ray fluorescence microtomography shows that LaF3:Ce highly concentrates in microtumors and enhances radiotherapy in an X‐ray energy‐dependent manner. In an aggressive syngeneic model of orthotopic glioblastoma, intracerebral injection of LaF3:Ce is well tolerated and achieves complete tumor remission in 15% of the subjects receiving monochromatic synchrotron radiotherapy. This study provides unequivocal evidence for radiation dose‐enhancement by nanoscintillators, eliciting a prominent radiotherapeutic effect. Altogether, nanoscintillators have invaluable properties for enhancing the focal damage of radiotherapy in glioblastoma and other radioresistant cancers.
Highlights
Glioblastoma multiforme is the most common type of primary brain cancer in adults and has a dismal prognosis
It should be noted that LaF3:Ce does not emit in the UV-C, so radioluminescenceinduced DNA damage by these particles will not occur
As both La (Z = 57) and Ce (Z = 58) are high-Z elements, combined with the lack of UV-C emission, LaF3:Ce particles are ideal candidates to investigate the sole role of a potential radiation dose-enhancement effect induced during radiotherapy
Summary
Glioblastoma multiforme is the most common type of primary brain cancer in adults and has a dismal prognosis. Prior to undertaking further translational studies toward radioluminescence-activated PDT and UV-C radioluminescence induced DNA damage, it is crucial to first determine whether nanoscintillators induce a radiation dose-enhancement effect and unravel the complete therapeutic mechanisms associated to nanoscintillators and their radiotherapeutic properties. This will be critical to optimize the design of nanoconjugates for further studies on radioluminescence-induced PDT, as well as of nanoscintillators developed to potentiate radiotherapy by UV-C radioluminescence. X-rays delivered by a synchrotron radiation source, which offers the unique opportunity to investigate the underlying mechanisms responsible for the therapeutic efficacy and to unequivocally identify the existence of a dose-enhancement effect
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