Schäfer Myriam, Hildenbrand Georg, Hausmann Michael
Kirchhoff-Institute for Physics, Heidelberg University, Im Neuenheimer Feld 227, 69120 Heidelberg, Germany.
Faculty of Engineering, University of Applied Sciences Aschaffenburg, Würzburger Str. 45, 63743 Aschaffenburg, Germany.
Int J Mol Sci. 2024 Nov 29;25(23):12843. doi: 10.3390/ijms252312843.
In radiation tumor therapy, irradiation, on one hand, should cause cell death to the tumor. On the other hand, the surrounding non-tumor tissue should be maintained unaffected. Therefore, methods of local dose enhancements are highly interesting. Gold nanoparticles, which are preferentially uptaken by very-fast-proliferating tumor cells, may enhance damaging. However, the results in the literature obtained from cell culture and animal tissue experiments are very contradictory, i.e., only some experiments reveal increased cell killing but others do not. Thus, a better understanding of cellular mechanisms is required. Using the breast cancer cell model SkBr3, the effects of gold nanoparticles in combination with ionizing radiation on chromatin network organization were investigated by Single-Molecule Localization Microscopy (SMLM) and applications of mathematical topology calculations (e.g., Persistent Homology, Principal Component Analysis, etc.). The data reveal a dose and nanoparticle dependent re-organization of chromatin, although colony forming assays do not show a significant reduction of cell survival after the application of gold nanoparticles to the cells. In addition, the spatial organization of γH2AX clusters was elucidated, and characteristic changes were obtained depending on dose and gold nanoparticle application. The results indicate a complex response of ALU-related chromatin and heterochromatin organization correlating to ionizing radiation and gold nanoparticle incorporation. Such complex whole chromatin re-organization is usually associated with changes in genome function and supports the hypothesis that, with the application of gold nanoparticles, not only is DNA damage increasing but also the efficiency of DNA repair may be increased. The understanding of complex chromatin responses might help to improve the gold nanoparticle efficiency in radiation treatment.
在放射肿瘤治疗中，一方面，辐射应导致肿瘤细胞死亡。另一方面，周围的非肿瘤组织应保持不受影响。因此，局部剂量增强方法极具吸引力。金纳米颗粒优先被快速增殖的肿瘤细胞摄取，可能会增强损伤作用。然而，文献中从细胞培养和动物组织实验获得的结果非常矛盾，即只有一些实验显示细胞杀伤增加，而其他实验则没有。因此，需要更好地理解细胞机制。使用乳腺癌细胞模型SkBr3，通过单分子定位显微镜（SMLM）以及数学拓扑计算（如持久同调、主成分分析等）的应用，研究了金纳米颗粒与电离辐射联合作用对染色质网络组织的影响。数据显示染色质存在剂量和纳米颗粒依赖性的重新组织，尽管集落形成试验未显示在细胞中应用金纳米颗粒后细胞存活率有显著降低。此外，阐明了γH2AX簇的空间组织，并根据剂量和金纳米颗粒的应用获得了特征性变化。结果表明，与电离辐射和金纳米颗粒掺入相关的ALU相关染色质和异染色质组织存在复杂反应。这种复杂的整个染色质重新组织通常与基因组功能的变化相关，并支持这样的假设，即随着金纳米颗粒的应用，不仅DNA损伤增加，而且DNA修复效率也可能提高。对复杂染色质反应的理解可能有助于提高金纳米颗粒在放射治疗中的效率。
