Challenges and Contradictions of Metal Nano-Particle Applications for Radio-Sensitivity Enhancement in Cancer Therapy

International Journal of Molecular Sciences

Tomáš Vičar¹  Lenka Štefančíková²  Eva Pagáčová²  Iva Falková²  Daniel Depeš²  Martin Falk²  Olga Kopečná²  Frederik Wenz³  Felix Bestvater⁴  Stéphane Roux⁵  Erika Porcel⁶  Sandrine Lacombe⁶  Franz Schmidt-Kaler⁷  Georg Hildenbrand⁷  Michael Hausmann⁷  Jin-Ho Lee⁷ 

[1] Brno University of Technology, Department of Biomedical Engineering, Technická 3082/12, 61600 Brno, Czech Republic;Czech Academy of Sciences, Institute of Biophysics, v.v.i., Kralovopolska 135, 612 65 Brno, Czech Republic;Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany;German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany;Institute UTINAM, UMR CNRS 6213-Université de Bourgogne Franche-Comté, 25020 Besançon Cedex, France;Institute des Sciences Moléculaires d’Orsay (ISMO), Université Paris Saclay, Université Paris Sud, CNRS, 91405 Orsay Cedex, France;Kirchhoff-Institute for Physics, University of Heidelberg, Im Neuenheimer Feld 227, 69120 Heidelberg, Germany;

关键词: metal nanoparticles;    cancer radiotherapy;    tumor cell radiosensitization;    DNA damage;    DNA repair;    DNA double strand breaks (DSBs);    super-resolution microscopy;    single-molecule localization microscopy (SMLM);    DNA repair foci;    damage to lysosomes;   

DOI  :  10.3390/ijms20030588

来源: DOAJ

【 摘 要 】

From the very beginnings of radiotherapy, a crucial question persists with how to target the radiation effectiveness into the tumor while preserving surrounding tissues as undamaged as possible. One promising approach is to selectively pre-sensitize tumor cells by metallic nanoparticles. However, though the “physics„ behind nanoparticle-mediated radio-interaction has been well elaborated, practical applications in medicine remain challenging and often disappointing because of limited knowledge on biological mechanisms leading to cell damage enhancement and eventually cell death. In the present study, we analyzed the influence of different nanoparticle materials (platinum (Pt), and gold (Au)), cancer cell types (HeLa, U87, and SKBr3), and doses (up to 4 Gy) of low-Linear Energy Transfer (LET) ionizing radiation (γ- and X-rays) on the extent, complexity and reparability of radiation-induced γH2AX + 53BP1 foci, the markers of double stand breaks (DSBs). Firstly, we sensitively compared the focus presence in nuclei during a long period of time post-irradiation (24 h) in spatially (three-dimensionally, 3D) fixed cells incubated and non-incubated with Pt nanoparticles by means of high-resolution immunofluorescence confocal microscopy. The data were compared with our preliminary results obtained for Au nanoparticles and recently published results for gadolinium (Gd) nanoparticles of approximately the same size (2⁻3 nm). Next, we introduced a novel super-resolution approach—single molecule localization microscopy (SMLM)—to study the internal structure of the repair foci. In these experiments, 10 nm Au nanoparticles were used that could be also visualized by SMLM. Altogether, the data show that different nanoparticles may or may not enhance radiation damage to DNA, so multi-parameter effects have to be considered to better interpret the radiosensitization. Based on these findings, we discussed on conclusions and contradictions related to the effectiveness and presumptive mechanisms of the cell radiosensitization by nanoparticles. We also demonstrate that SMLM offers new perspectives to study internal structures of repair foci with the goal to better evaluate potential differences in DNA damage patterns.

【 授权许可】

Unknown