Radiation Dose‐Enhancement Is a Potent Radiotherapeutic Effect of Rare‐Earth Composite Nanoscintillators in Preclinical Models of Glioblastoma

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 LaF 3 :Ce nanoscintillators effectively generate photo-and Auger-electrons upon orthovoltage X-rays. 3D spatially resolved X-ray fluorescence microtomography shows that LaF 3 :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 LaF 3 :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.

Cytotoxic lanthanum oxide nanoparticles sensitize glioblastoma cells to radiation therapy and temozolomide: an in vitro rationale for translational studies

“…Although colony formation assay is vulnerable to observation bias due to possible colony overlap, we note that trends we report would still persist, albeit it at higher absolute proportions. Nevertheless, the trends we report are consistent with what one would expect regarding the Auger effect 12 , where REEs emit greater energy than incoming radiation energy due to an electron cascade across their large number of orbitals 38 . Additionally, the maximum mass absorption coefficient of lanthanum to water ratio was 40 keV per National Institute of Standards and Technology (NIST) data 39 , which is comparable to other radiosensitizing metal nanoparticles 40 .…”

“…This ability to increase potency of incoming radiation is pivotal to translational efforts in the future given radiation therapy remains a staple of GBM treatment, and currently, efforts to reduce administered dose are also a competing priority in clinical studies 41 . To elucidate the exact nature of the interaction between RT and lanthanum-based NPs, intensive investigation across time and dose will be required, as whether or not these NPs have a specific synergistic radiation threshold to exert an Auger effect is beyond the scope of this study 12 . It is foreseeable however that if a small NP dose can augment incoming radiation, its use in the clinic may possibly be to reduce radiation exposure to the GBM patient rather than increase toxicity to the cancer and the patient.…”

“…Despite the name, these elements are not particularly rare, and readily found in the human body, at intravenous levels in the order of 1 ng/kg which remain > 1000 fold below the toxicity threshold 9 , 10 . Studies into these REEs have previously described cytotoxic and anti-cancer effects due to its unique electronic configuration—this includes radiosensitization via the Auger effect, and chemotherapeutic synergy via increased apoptotic activity 11 , 12 . Despite this, lanthanum-based compounds have not been thoroughly investigated in the setting of GBM, but has two specific advantages that render it an element of interest to treat GBM.…”

“…To date, lanthanum-based NP therapies have not been widely investigated in vitro for their potential to target specifically GBM and enhance RT and TMZ 12 . Correspondingly, the aim of this study was to elucidate the preliminary molecular rationale and mechanism of utilizing La 2 O 3 NPs as a therapeutic adjunct in the treatment of GBM cells.…”

The Phospholipid Research Center: Current Research in Phospholipids and Their Use in Drug Delivery

“…To improve the management of treatment-resistant cancers, there is a continued need for new strategies to augment radiotherapy outcomes. The use of ultra-small gold particles (nanoclusters) is a promising way to improve radiation absorption by cancer tissues [ 62 , 63 ], yet their therapeutic potential is limited because of poor tumor accumulation and permeation [ 64 , 65 , 66 ]. Here, the group of Mans Broekgaarden (University Grenoble, Grenoble, France) aims to engineer liposomes to overcome these limitations, thereby enabling the gold nanoclusters to hyper-sensitize cancer tissues to radiotherapy [ 66 ].…”