Abstract
Gold nanoparticles (GNPs) have been shown to be effective contrast agents for imaging and emerge as powerful radiosensitizers, constituting a promising theranostic agent for cancer. Although the radiosensitization effect was initially attributed to a physical mechanism, an increasing number of studies challenge this mechanistic hypothesis and evidence the importance of oxidative stress in this process. This work evidences the central role played by thioredoxin reductase (TrxR) in the GNP-induced radiosensitization. A cell type-dependent reduction in TrxR activity was measured in five different cell lines incubated with GNPs leading to differences in cell response to X-ray irradiation. Correlation analyses demonstrated that GNP uptake and TrxR activity inhibition are associated to a GNP radiosensitization effect. Finally, Kaplan-Meier analyses suggested that high TrxR expression is correlated to low patient survival in four different types of cancer. Altogether, these results enable a better understanding of the GNP radiosensitization mechanism, which remains a mandatory step towards further use in clinic. Moreover, they highlight the potential application of this new treatment in a personalized medicine context.
Highlights
Over the past century, radiotherapy has emerged as the main treatment modality for cancer [1]
The proof-of-concept was demonstrated by Hainfeld et al [7] who evidence that injections of 1.9 nm gold nanoparticles (GNPs) increased the survival of tumor-bearing mice in combination with 250 kVp X-rays compared to X-rays alone
We focused on the effect of homemade 10 nm amino-polyethylene glycol (PEG) functionalized GNPs in five different cell lines (A431 epidermoid carcinoma, A549 lung adenocarcinoma, MDA-MB-231 breast adenocarcinoma, PANC-1 pancreatic epithelioid carcinoma and T98G glioblastoma cell lines)
Summary
Radiotherapy has emerged as the main treatment modality for cancer [1]. The proof-of-concept was demonstrated by Hainfeld et al [7] who evidence that injections of 1.9 nm gold nanoparticles (GNPs) increased the survival of tumor-bearing mice in combination with 250 kVp X-rays compared to X-rays alone Since this pioneering work, the development of new high-Z radiosensitizers (including silver [8,9], gadolinium [10,11,12], hafnium [13,14], platinum [15,16], gold [6,17,18] or bismuth [19,20] nanoparticles) has accelerated and many studies have shown their ability, when injected into the tumor, to amplify the X-ray radiation treatment efficacy. Other groups demonstrated the influence of coating agent and GNP shape in the cell uptake process and so, in their involvement in the radiosensitization effect [22,23]
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