Engineered nanoceria cytoprotection in vivo: mitigation of reactive oxygen species and double-stranded DNA breakage due to radiation exposure

Abstract

Cerium oxide nanomaterials are known to absorb ionizing radiation energy, as well as to neutralize free radicals in solution, by undergoing redox changes. We, therefore, proposed that ceria nanoparticles could be used in biomedical applications as an injectable, radio-protectant material. In this study, we examine the effectiveness of engineered nanoparticles in protecting germ cells from the damaging effects of irradiation-induced cell death, in vivo. C57BL/6J male mice were used as a model and irradiation was localized to the scrotal region at 2.5, 5, and/or 10 Gy intensities. Ceria nanoparticles were introduced as 100 μL injections at 100 nM and 100 μM via tail vein injections, weekly, for one month. Following this, the animals were sacrificed and their organs (heart, brain, kidneys) were harvested. Tissues were fixed, sectioned, and stained for instances of cell death, DNA damage (TUNEL assay), and ROS (nitro-tyrosine evolution). Tissues from mice treated with ceria nanoparticles showed significantly less (∼13% decrease; *P < 0.05) tissue damage (per immunohistochemistry) over controls at up to 5 Gy radiation. DNA damage and ROS also decrease substantially with ceria treatment, confirming ceria's capacity as an injectable, radio-protectant material. The study also highlights the ability of ceria nanoparticles to protect cells/tissues from both direct and indirect effects of ionizing radiation.

Ceria Nanoparticles Decrease UVA-Induced Fibroblast Death Through Cell Redox Regulation Leading to Cell Survival, Migration and Proliferation

“…Other studies have demonstrated the value of CNP pre-incubation in conferring optimal cyto-protection. Such studies ascribe the prophylactic treatment's benefits largely to potentiated antioxidant transcription, similar to observation in the current study even following radiation insult, and the kinetics of cellular uptake (Colon et al, 2010;Hirst et al, 2013;Das et al, 2018). Uptake efficiency is affected by particle properties (size, morphology, surface charging, bio-corona character), experimental conditions and cell type (Kettler et al, 2014;Singh et al, 2018).…”

“…The demonstrated wound healing activity and increased proliferation following radiation insult further confirms the improved performance of high Ce 3+ /Ce 4+ formulations in conferring cytoprotection, across biological model systems (esp. as anti-flammation, diabetic wound healing, tumor-stroma interactions) relative to formulations evidencing fewer Ce 3+ evolving defects ( Chen et al, 2006 ; Chigurupati et al, 2012 ; Singh et al, 2016 ; Das et al, 2018 ; Shekunova et al, 2019 ). Findings such as these will further mediate the optimization or “nanoengineering” of CNPs toward optimal therapeutic activity in future studies.…”

“…These surface reactions are catalytic and, thereby, remain active for an extended time protecting cells against the harmful effects of excess ROS production (Celardo et al, 2011;Singh et al, 2011;Das et al, 2014). Further, other studies have demonstrated indirect effects of nanoceria treatment on ROS levels as modulations in native antioxidant enzyme concentrations (e.g., SOD2, glutathione) (Das et al, 2018) as well as expression of proteins related to cellular oxygen metabolism (e.g., HIF1α) (Das et al, 2012).…”

Sonodynamic therapy induces oxidative stress, DNA damage and apoptosis in glioma cells

“…[23][24][25] Excessive amounts of ROS will initiate oxidative stress in many cellular biomacromolecules, which then culminates in subcellular organelle dysfunction and cell death. 26 Dizdaroglu et al reported that DNA base modications could be induced by ROS, especially $OH. 27 ROS-induced DNA damage can occur through oxidative modication of DNA bases or by spontaneous hydrolysis of nucleosides.…”

Radiosensitizing Effect of Gadolinium Oxide Nanocrystals in NSCLC Cells Under Carbon Ion Irradiation

“…As mentioned above, many nanomaterials can serve as radiation enhancers because of the increased production of ROS [22, 23]. Therefore, the influence of GONs on the survival fraction of the studied NSCLC cells could be related to the level of reactive oxygen species in vitro.…”