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Cherenkov-excited luminescence has previously been demonstrated as a method to improve the depth sensitivity of in vivo optical imaging1–4 and could be an alternative to optical imaging with fluorescence in deeper penetrance. An example application of Cherenkov-excited luminescence is to excite an oxygen-sensitive luminescent compound during radiation therapy utilizing only the radiation as an excitation source and a sensitive camera for detection, as shown in Fig. 1(a). In conventional in vivo fluorescence imaging, utilizing an excitation laser or LED light, there is an exponential decay of the source as it propagates into tissue dictated approximately by the effective attenuation coefficient, μeff, defined by diffusion theory as μeff=3μa(μa+μs′) where the latter coefficients are for absorption and transport reduced scattering, respectively.6 In Cherenkov excitation, the excitation light is produced throughout the volume directly proportional to the dose of the radiation beam for electrons above the 220 keV threshold, following the same build up and fall off with depth, as shown in Fig. 1(c). While in both cases, laser or Cherenkov excitation, the light still has to escape the tissue and is therefore attenuated exponentially by μeff on the way out at the emission wavelength bands, there is still a major benefit from having the exciting light within the volume of tissue. Yet, in comparing optical excitation to radiation beam excitation, it is hard to clearly quantify the benefits for Cherenkov, and so in this study, the (i) spatial resolution, (ii) depth sensitivity, and (iii) optimal fluorophores for Cherenkov excitation, are each examined computationally with Monte Carlo simulations. Open in a separate window Fig. 1 Schematic illustration (a) of an in vivo application of Cherenkov-excited luminescence where Cherenkov light is generated at depths into tissue. In this illustration, a mouse with a hypoxic flank tumor and normal muscle tissue are injected with an oxygen-sensitive phosphorescent compound. As the x-ray beam passes through the tissue, Cherenkov emissions occur and excite the luminescent compound. In vivo imaging can resolve the depth-integrated voxels, and the resulting estimates can be tabulated into a histogram to describe the heterogeneous extracellular oxygen concentration.5 The photon energy distribution used in subsequent Monte Carlo simulations is shown in (b) which determine the characteristics of the Cherenkov intensity and depth within the tissue. The percentage depth-dose (PDD) curves for 10 cm×10 cm photon (6 and 18 MV) and electron (6 and 18 MeV) beams in water are shown in (c) where electrons have a higher chance of interaction and deposit dose more superficially, whereas photon beams must first generate a high-energy electron through Compton scattering before Cherenkov emissions can occur. Cherenkov emissions are correlated with dose, so the PDD can be used as an estimate of the depth distribution of the optical emissions.