Is Cherenkov luminescence bright enough for photodynamic therapy?

To the Editor — It has recently been proposed that Cherenkov luminescence from radionuclides can be used to activate tumour-localized photosensitizing nanoparticles (TiO₂) and cause enhanced tumour cell death¹. This approach is proposed as a new method for circumventing the depth penetration limits of conventional light-based therapies. While the results of this study leave little doubt that radionuclides and photosensitizers interact in a synergistic manner, they do not prove that this interaction occurs through Cherenkov luminescence.

Cherenkov luminescence is known to be an exceedingly dim phenomenon². Average Cherenkov emission from ¹⁸F is approximately three photons per radioactive decay in water (refractive index n = 1.33) over the 250–800 nm range³. In terms of energy, Cherenkov light represents less than 0.006% of the total energy released during the radioactive decay of ¹⁸F. The vast majority of the energy (>99.99%) is dissipated through molecular excitation, ionization, Bremsstrahlung radiation and heat.

On average, a single ¹⁸F decay (250 keV) yields 6,800 hydroxyl radicals (OH^•) through radiolysis of water⁴. These OH^• radicals play a major role in mediating the biological action of ionizing radiation on DNA. For Cherenkov luminescence to produce a significant biological effect, its action on DNA must be comparable to or greater than that of 6,800 OH^• radicals. However, due to the bandgap of TiO₂ (3.2 eV), it is impossible for three Cherenkov photons to produce more than three OH^• radicals.

An alternative explanation for the observed increase in free radical production and cell death is that ionizing positrons interact directly with TiO₂ nanoparticles to enhance cellular toxicity, without intervention of Cherenkov light. One simple way to test this alternative mechanism would be to irradiate the specimens with X-rays at energies below the Cherenkov threshold, with and without photosensitizer. It is also worth noting that a previous study reporting activation of TiO₂ nanoparticles from radioactive ³²P did not invoke Cherenkov luminescence as the mechanism of action⁵.