Tissue pO2 distributions in xenograft tumors dynamically imaged by Cherenkov-excited phosphorescence during fractionated radiation therapy

Abstract

Hypoxia in solid tumors is thought to be an important factor in resistance to therapy, but the extreme microscopic heterogeneity of the partial pressures of oxygen (pO 2) between the capillaries makes it difficult to characterize the scope of this phenomenon without invasive sampling of oxygen distributions throughout the tissue. Here we develop a noninvasive method to track spatial oxygen distributions in tumors during fractionated radiotherapy, using oxygen-dependent quenching of phosphorescence, oxygen probe Oxyphor PtG4 and the radiotherapy-induced Cherenkov light to excite and image the phosphorescence lifetimes within the tissue. Mice bearing MDA-MB-231 breast cancer and FaDu head neck cancer xenografts show different pO 2 responses during each of the 5 fractions (5 Gy per fraction), delivered from a clinical linear accelerator. This study demonstrates subsurface in vivo mapping of tumor pO 2 distributions with submillimeter spatial resolution, thus providing a methodology to track response of tumors to fractionated radiotherapy.

Theoretical lateral and axial sensitivity limits and choices of molecular reporters for Cherenkov-excited luminescence in tissue during x-ray beam scanning

“…30 In addition, if this functionality could be expanded to include triplet quantum yields in addition to fluorescence quantum yields, this computational search could be expanded to identify potential Cherenkov-excited or x-ray-excited photosensitizers. While many of the compounds identified by this work would not be appropriate for the timedelayed phosphorescent imaging as those used for oxygen estimations, 4,5 the basis demonstrates a method to quickly identify potential compounds based on empirical data. From the given data, a number of coumarins appear to be suitable for detection by Cherenkov-excitation.…”

“…Experimental comparison of the luminescent tumor geometry was not performed, but in vivo applications have been considered previously. [3][4][5] The spectral characteristics of the Cherenkov emissions in the tumor inclusion ( Fig. 2) were compared to the absorption spectrum of compounds in the PhotoChemCAD database.…”

“…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.…”

Dosimetry for FLASH Radiotherapy: A Review of Tools and the Role of Radioluminescence and Cherenkov Emission

“…Electron paramagnetic resonance spectroscopy and imaging with oxygen sensitive particulate or water-soluble probes can also provide direct measurement of pO2 or [O2] with sub-millimeter spatial resolution and temporal resolution <<1 s [124,125]. More recently, Cherenkov excited luminescent imaging (CELI) provided in vivo oxygen pressure maps based on lifetime imaging of fluorophore platinum(II)-G4 (PtG4) [126,127]. The Stern-Volmer equation was used to relate the decay of PtG4 to oxygen tension in tumors and normal tissue (pre and post euthanasia) (Figure 13).…”

Review of in vivo optical molecular imaging and sensing from x-ray excitation

“…33 Full field imaging can work as well, albeit without significant axial resolution because of optical scatter in the tissue, but providing apparent high resolution in lateral imaging of the tissue surface. 34…”