Štefančíková Lenka, Lacombe Sandrine, Salado Daniela, Porcel Erika, Pagáčová Eva, Tillement Olivier, Lux François, Depeš Daniel, Kozubek Stanislav, Falk Martin
Department of Cell Biology and Radiobiology, Institute of Biophysics of ASCR, Brno, Czech Republic.
Institute des Sciences Moléculaires d'Orsay (ISMO), Université Paris Sud 11, CNRS, Université Paris Saclay, Bât 351, 91405, Orsay Cedex, France.
J Nanobiotechnology. 2016 Jul 28;14(1):63. doi: 10.1186/s12951-016-0215-8.
Tumor 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).
We 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.
We 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.
Our 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.
放射疗法的肿瘤靶向性是一项巨大挑战。添加多模态纳米颗粒，如3纳米的钆基纳米颗粒（GdBNs），已被提议作为一种有前景的策略，以增强肿瘤中的辐射效应，并使用相同的试剂改善诊断。这种名为诊疗一体化的独特特性是GdBNs的独特优势。已经确定，GdBNs对辐射效应的增强似乎是由于快速电子过程。然而，这些纳米颗粒对细胞的影响尚不清楚。特别是，电离辐射激活的纳米颗粒如何与细胞及其成分相互作用仍不明确。一个关键问题仍然悬而未决，即GdBNs（和其他纳米颗粒）产生的放射增敏作用是否需要对细胞核造成损伤。
我们研究了GdBNs对用γ射线照射的U87肿瘤细胞核DNA中DNA双链断裂（DSBs）诱导和修复的影响。为此，我们目前使用基于高分辨率共聚焦荧光显微镜结合两种独立DSBs标记物免疫检测的最灵敏的DSBs检测方法。
我们表明，在GdBNs增强辐射效应的条件下，它们仍位于细胞质中，即不穿透细胞核。此外，细胞质中GdBNs的存在既不会增加γ射线对核DNA中DSBs的诱导，也不会影响其随后的修复。
我们的结果表明，GdBNs介导的放射增敏是一种细胞质事件，与核DNA断裂无关，而核DNA断裂是通常被认为是生物辐射效应解释的一种现象。考虑到我们早期认识到的GdBNs与溶酶体和内体的共定位，我们在此革命性地假设这些细胞器是（某些）纳米颗粒的潜在靶点。如果得到证实，这种由细胞质决定的放射增敏作用的发现为使用纳米放射增强剂改善放射治疗开辟了新的前景，而不会增加与遗传损伤相关的病理风险。
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