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

Abstract

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.

Radiosensitizing Effect of Gadolinium Oxide Nanocrystals in NSCLC Cells Under Carbon Ion Irradiation

“…Consistent with our findings, AGuIX gadolinium nanoparticles also intensified DSB occurrence in head and neck tumor cells exposed to carbon ion irradiation [13]. In contrast, Gd-, Pt-, and Au-based nanoparticles approximately 2–3 nm in size all made no difference to the DSB occurrence under γ-rays, as newly reported by Pagáčová [41]. In our previous study, we also found that cotreatment with GONs and X-ray irradiation failed to induce more serious DSBs than that observed with irradiation alone [42].…”

Mechanisms of nanoparticle radiosensitization

“…In another study, DSBs did not increase for either kV or MV energies with GNPs (Jain et al, 2011). In a thorough study of DNA damage and repair across multiple cell lines and for three different nanoparticles, Pagáčová et al (2019) found that the nanoparticles generally had no effect on enhancing foci. Increases in cell killing in combining radiation with nanoparticles measured through clonogenicity or proliferative ability can be confirmed, yet this does not always correlate with increased DNA damage.…”

DeepFoci: Deep Learning-Based Algorithm for Fast Automatic Analysis of DNA Double Strand Break Ionizing Radiation-Induced Foci

“…Gy and fixed at different periods of time post-irradiation. given conditions and various cell types [14][15][16]18,20,28,34,40,41,76,88,89].…”

“…Imprecise DSB repair then causes mutagenesis and may lead to cancer [7,12]. DSB damage induction and repair monitoring thus opens the doors to personalized medicine [3,4,[13][14][15], for instance, coupled with direct radiotherapy effect monitoring [13,16], and rational development of new DNA damaging [17][18][19][20] or protecting drugs [21][22][23][24] needed in medicine [25,13,16] and radiation protection [26,27]. Precise and automated DSB damage monitoring is also irreplaceable in biodosimetry [26][27][28][29][30], for instance in situations related to mass radiation accidents (terrorist attacks with radioactive materials) or space exploration where astronauts would be exposed to a mixed field of different radiation types [31][32][33][34][35][36][37].…”