Abstract
BackgroundTumor targeting of radiotherapy represents a great challenge. The addition of multimodal nanoparticles, such as 3 nm gadolinium-based nanoparticles (GdBNs), has been proposed as a promising strategy to amplify the effects of radiation in tumors and improve diagnostics using the same agents. This singular property named theranostic is a unique advantage of GdBNs. It has been established that the amplification of radiation effects by GdBNs appears due to fast electronic processes. However, the influence of these nanoparticles on cells is not yet understood. In particular, it remains dubious how nanoparticles activated by ionizing radiation interact with cells and their constituents. A crucial question remains open of whether damage to the nucleus is necessary for the radiosensitization exerted by GdBNs (and other nanoparticles).MethodsWe studied the effect of GdBNs on the induction and repair of DNA double-strand breaks (DSBs) in the nuclear DNA of U87 tumor cells irradiated with γ-rays. For this purpose, we used currently the most sensitive method of DSBs detection based on high-resolution confocal fluorescence microscopy coupled with immunodetection of two independent DSBs markers.ResultsWe show that, in the conditions where GdBNs amplify radiation effects, they remain localized in the cytoplasm, i.e. do not penetrate into the nucleus. In addition, the presence of GdBNs in the cytoplasm neither increases induction of DSBs by γ-rays in the nuclear DNA nor affects their consequent repair.ConclusionsOur results suggest that the radiosensitization mediated by GdBNs is a cytoplasmic event that is independent of the nuclear DNA breakage, a phenomenon commonly accepted as the explanation of biological radiation effects. Considering our earlier recognized colocalization of GdBNs with the lysosomes and endosomes, we revolutionary hypothesize here about these organelles as potential targets for (some) nanoparticles. If confirmed, this finding of cytoplasmically determined radiosensitization opens new perspectives of using nano-radioenhancers to improve radiotherapy without escalating the risk of pathologies related to genetic damage.
Highlights
Tumor targeting of radiotherapy represents a great challenge
Together with providing a detailed information on the intracellular localization of gadolinium-based nanoparticles (GdBNs), we evaluated by currently the most sensitive method to detect double-strand breaks (DSBs) how these nanoparticles influence the radiation damage introduced to the genomic DNA and how these lesions are repaired during a long period of time post-irradiation (PI) in radioresistant U87 human glioblastoma cells
Effect of GdBNs on nuclear DNA DSBs induction and repair in irradiated U87 cells In the step, we studied how cytoplasmic GdBNs influence the extent and reparability of DSBs introduced to the nuclear DNA by irradiation with two Average numbers of DSBs foci per nucleus at indicated periods of time PI are compared for U87 cells irradiated with 1 Gy of γ-rays in absence or presence of 1 mM GdBNs (1 h incubation)
Summary
The addition of multimodal nanoparticles, such as 3 nm gadolinium-based nanoparticles (GdBNs), has been proposed as a promising strategy to amplify the effects of radiation in tumors and improve diagnostics using the same agents. This singular property named theranostic is a unique advantage of GdBNs. It has been established that the amplification of radiation effects by GdBNs appears due to fast electronic processes. The influence of these nanoparticles on cells is not yet understood It remains dubious how nanoparticles activated by ionizing radiation interact with cells and their constituents. A simultaneous enhancement of tumor selectivity and biological effectiveness of radiations is a longlasting objective of cancer radiotherapy
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