Abstract
Owing to its unique redox properties, cerium oxide (nanoceria) nanoparticles have been shown to confer either radiosensitization or radioprotection to human cells. We investigated nanoceria's ability to modify cellular health and reactive oxygen species (ROS) at various absorbed doses (Gray) of ionizing radiation in MDA-MB231 breast carcinoma cells. We used transmission electron microscopy to visualize the uptake and compartmental localization of nanoceria within cells at various treatment concentrations. The effects on apoptosis and other cellular health parameters were assessed using confocal fluorescence imaging and flow cytometry without and with various absorbed doses of ionizing radiation, along with intracellular ROS levels. Our results showed that nanoceria were taken up into cells mainly by macropinocytosis and segregated into concentration-dependent large aggregates in macropinosomes. Confocal imaging and flow cytometry data showed an overall decrease in apoptotic cell populations in proportion to increasing nanoparticle concentrations. This increase in cellular health was observed with a corresponding reduction in ROS at all tested absorbed doses. Moreover, this effect appeared pronounced at lower doses compared to unirradiated or untreated populations. In conclusion, internalized nanoceria confers radioprotection with a corresponding decrease in ROS in MDA-MB231 cells, and this property confers significant perils and opportunities when utilized in the context of radiotherapy.
Highlights
Ionizing radiation has been used quite early on in a variety of clinical areas since the discovery of X-rays and radioactivity in the late 1800s, including physiology, immunology, diagnostic, and therapeutic medicine [1]
We first evaluated the ability of MDA MB231 cells to take up the CeO2 nanoparticles and the precise site of localization within the cellular compartments
We describe a systematic approach to track the uptake, localization, and modulation of the radiosensitivity of MDA MD231 breast carcinoma cells by unmodified cerium oxide nanoparticles
Summary
Ionizing radiation has been used quite early on in a variety of clinical areas since the discovery of X-rays and radioactivity in the late 1800s, including physiology, immunology, diagnostic, and therapeutic medicine [1]. The initial action of ionizing radiation is two-fold: direct ionization of cellular structures, especially DNA, and the radiolysis of water, which accounts for 70% or more of the total cell mass [6] The former results in chromosomal aberrations, DNA damage, mutagenesis, and carcinogenesis, while the latter leads to the production of a variety of reactive oxygen species and the amplification of free radicals, causing structural damage to biomolecules in their vicinity, including proteins, lipids, and nucleic acids [7]. Cells have natural protective mechanisms in place with DNA repair mechanisms and free-radical scavengers to counter the effects of radiation at lower absorbed doses, but this protective apparatus breaks down when overwhelmed by radiation [8] This is significant in the context of nuclear medicine and radiation therapy, and even more so at comparatively lower therapeutic doses, where significant detrimental bystander effects can occur mainly due to the intercellular signaling propagated from the site of irradiation to surrounding healthy tissues [9]. Radiosensitizers, on the other hand, are agents that enhance the therapeutic ratio of radiation therapy by enhancing DNA damage, free-radical production, or both when combined with radiation, while not damaging the normal cells in the process
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