Effect of gadolinium-based nanoparticles on nuclear DNA damage and repair in glioblastoma tumor cells

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.

Synergistic antitumor effect of the combination of a dual cancer‑specific oncolytic adenovirus and cisplatin on lung cancer cells

“…However, because of the specificity of tumors and the side effects of these methods, treatment is far from satisfactory. With the emergence of, for example, drug resistance ( 3 ) and DNA damage repair ( 29 , 30 ) during the treatment, the therapeutic effect is compromised in cancers when using monotherapy. Therefore, it is necessary to use combinations of two or more therapeutic methods that act via different mechanisms to produce synergistic effects to treat cancers.…”

Modelling direct DNA damage for gold nanoparticle enhanced proton therapy

“…Our work and previous studies 32,33 make clear that the radiosensitization under proton irradiations, unlike photon irradiations where physical interactions can also contribute to the effect, is highly unlikely to originate from direct or indirect damage to the DNA. As a result, the alternative or supplementary mechanisms that have been proposed for photon irradiations, such as increased oxidative stress, mitochondria function disruption, 36,37 and lysosomal rupture, 38 might be more important in the case of proton irradiations, and ultimately the key to understanding radiosensitization with heavy metal nanoparticles bombarded with ions.…”

Preparation, characterization and X-ray attenuation property of Gd2O3-based nanocomposites

“…Kusiak and Zaborski (2012) 50, 30, 20 and 20 phr, respectively, are found to strongly absorb X-rays. Stefancikova et al (2016) have studied the role of gadolinium-based nanoparticles as radiosensitizers and have shown that the radiosensitization mediated by gadolinium-based nanocomposite is a cytoplasmic event, independent of nuclear DNA damage.…”