Scientists have shown that gold and titanium dioxide nanoparticles can help radiation kill cancer cells even when oxygen is scarce. It's a major breakthrough for tackling hypoxia-linked treatment resistance.
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A recent study published in Nano Letters investigated how gold and titanium dioxide nanoparticles can enhance radiotherapy in tumours with low oxygen levels. These regions, common in many solid cancers, are notoriously hard to treat with standard radiation. By examining physical and chemical mechanisms, the researchers investigated how different nanoparticles operate in oxygen-starved environments, finding promising implications for cancer treatment.
The Problem With Oxygen-Poor Tumours
Radiotherapy depends on the presence of oxygen to generate reactive oxygen species, unstable molecules that damage DNA and destroy cancer cells. This process becomes significantly less effective in hypoxic tumours, where the oxygen supply is limited due to abnormal blood vessels and poor diffusion. As a result, these tumours often resist treatment and are more likely to recur.
Researchers have been exploring ways to overcome this challenge using nanotechnology. Nanoparticles can boost the impact of radiation through physical and chemical enhancements. In this study, the scientists attempt to answer the question of whether these enhancements can still work in hypoxic conditions, where oxygen-dependent mechanisms typically fail.
The Study
The researchers focused on two types of nanoparticles that have shown radiosensitizing potential: gold and titanium dioxide. Gold nanoparticles, with their high atomic number, are known to amplify the physical dose of radiation by increasing secondary electron emission. This effect is strongest at kilovoltage X-ray energies, where photoelectric interactions dominate, but tends to weaken at the megavoltage energies used in most clinical treatments.
Titanium dioxide, while having a much lower atomic number, has different strengths. It is catalytically active and capable of producing reactive oxygen species through photocatalytic and radiocatalytic processes. These chemical reactions, which are less reliant on oxygen, could prove especially useful in targeting hypoxic tumours.
The team conducted a series of experiments using fibrosarcoma cancer cells to explore how these nanoparticles perform under different oxygen conditions. The cells were cultured in both normoxic and hypoxic environments and exposed to radiation using X-ray sources representative of preclinical and clinical settings. The nanoparticles were carefully characterized, and their uptake into the cells was confirmed to ensure fair comparisons.
The researchers then measured the effects of the nanoparticles on DNA damage, cell survival, and reactive oxygen species production. They used a combination of DNA damage markers, survival curve analyses, and electron paramagnetic resonance imaging to assess the effects of the nanoparticles. The photocatalytic activity of titanium dioxide was also evaluated using methylene blue degradation, a method that helps identify ROS production through catalytic pathways.
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Results of the Nanoparticle Treatment
Gold and titanium dioxide behaved very differently under hypoxia. Gold nanoparticles mainly improved radiation effectiveness through physical interactions that produce secondary electrons. This enhancement was noticeable at kilovoltage energies but significantly diminished at megavoltage levels, where Compton scattering is more dominant and high-atomic-number materials are less effective.
Under low-oxygen conditions, the physical dose enhancement from gold nanoparticles was slightly reduced. Their chemical effect via oxygen-mediated ROS production persisted but was also somewhat reduced.
In contrast, titanium dioxide nanoparticles showed an unexpected advantage under hypoxia. Rather than declining in efficacy, their ability to generate reactive oxygen species improved in oxygen-poor environments. This was attributed to their catalytic activity, which allows them to produce ROS independently of external oxygen.
Methylene blue degradation assays confirmed increased photocatalytic activity under hypoxic conditions, and this correlated with more significant biological damage in cancer cells after radiation exposure. These results suggest that titanium dioxide could help to fill a gap in radiotherapy, offering a way to sensitize tumours where oxygen-dependent treatments fall short.
Towards Smarter, More Effective Radiotherapy
The study highlights how nanoparticles can be engineered to target cancers under different conditions, and how understanding their mechanisms is essential for clinical application. Gold nanoparticles, while powerful at enhancing dose through physical means, were limited in hypoxia and less effective at the radiation energies typically used in patients. Titanium dioxide, on the other hand, showed a distinct advantage in those same conditions by using a chemical route that doesn’t rely on oxygen.
Combining nanoparticles that work via different mechanisms, such as tackling well-oxygenated and hypoxic regions within the same tumour, like this study, could lead to more comprehensive, effective radiotherapy and better outcomes for patients with hard-to-treat cancers.
Journal Reference
Gerken, L. R. H., et al. (2025). Chemical vs Physical Radioenhancement from TiO2 and Au Nanoparticles to Overcome Hypoxic Radioresistance in X-ray Therapy. Nano Letters, 25, 12806–12815. https://doi.org/10.1021/acs.nanolett.5c02080