Recent work demonstrated the occurrence of Čerenkov emission light during external beam radiotherapy [1
], using linear accelerator (LINAC) irradiation from electrons and photons. The emitted radiation has broad spectrum, and both absorption and emission properties of the medium can be quantified using this radiation [2
]. The generation of the broadband light from within irradiated tissue opens up potential possibility to sample the tissue microenvironment in vivo during therapy. In this study, the particular focus is on determining the potential for sensing oxygenation in vivo and determining the spatial origins of the signal. While a previous study demonstrated that spectroscopy of tissue hemoglobin oxygen saturation (St
) is feasible using Čerenkov emission as an internal light source, the spatial origins of the signal and the detection sensitivity distribution were not examined. The present study considers this, as well as the potential to induce phosphorescence of exogenous oxygen-sensitive probes [3
] in tissue, thereby measuring both tissue St
and oxygen partial pressure (pO2
]. This combined approach may be useful in tumor radiotherapy, as it may allow comprehensive quantification of tissue hypoxia as well as changes in hypoxia during the course of fractionated radiation therapy. The spatial origins of both absorption-based St
and phosphorescent-based pO2
signals have been quantified in our study through experiments and Monte Carlo modeling.
Čerenkov emission occurs when charged particles move through a dielectric medium at a phase velocity greater than the speed of light in that medium [5
], inelastically losing energy through electrical field interactions with the transiently polarized medium. This emission can happen in biological media such as human tissue [6
]. Unlike atomic or molecular luminescence spectra that have characteristic spectral peaks corresponding to quantized energy transitions, Čerenkov emission has continuous spectrum across the entire UV, visible and NIR spectrum with intensity varying as the inverse-square of the wavelength [7
]. Thus, the emission at higher frequencies (shorter wavelengths) is more intense, giving rise to its characteristic blue glow appearance, and it tends to be directionally emitted at an acute angle relative to the path of travel [7
]. The Cerenkov emission originating from several biomedical radiotracers (18F, 64Cu, 68Ga, etc.) has recently been characterized in both phantoms and small animals [8
]. The discovery of optical molecular Čerenkov luminescence imaging (CLI) has been recently reported [10
], and later this approach has been extended on 3D tomography [6
]. Nonetheless, the exploitation of Cerenkov emission in radiation therapy is quite recent, and it is still unexplored as a method of sampling tumor tissue microenvironment.
It is well known that tissue oxygenation is a major factor influencing the outcome of radiation therapy [17
], since oxygenated cells are more effectively killed by radiation than hypoxic cells. Additionally, chronically hypoxic tumor tissues are insensitive to vascularly delivered drugs, e.g. in chemotherapy, due to poor delivery. Thus techniques for measuring tumor pO2
during fractionated therapy may be extremely useful for tuning the treatment conditions and monitoring therapeutic outcome. However, current measurements of pO2
are usually invasive [19
], and the obtained signals are heterogeneous on a microscopic scale, requiring sampling of large volumes to gain information about individual tumor’s oxygenation status [20
]. Optical spectroscopy is a noninvasive technique that has been used to measure oxygen hemoglobin saturation, which is related to tissue pO2
, during the course of fractionated radiation therapy in experimental tumors [22
]. Since Čerenkov light has the spectrum allowing quantification of hemoglobin St
], measuring this spectrum during treatment has the potential for real-time monitoring of blood oxygen saturation during treatments. In the previous work, alterations in the Čerenkov emission spectroscopy (CES) measured during radiation treatment of living tissue have been combined with diffuse optical tomography (DOT) to estimate microvascular St
]. Further exploration of the utility of CES for determination of tumor blood oxygen saturation may prove to be valuable for potential clinical applications. Using simulations, this study takes an in-depth look at the spatial origins of the CR signal induced by an electron beam and sampled by an optical fiber, with varying fiber-to-beam distances.
Čerenkov emission has been shown to be able to serve as an excitation source for secondary luminescence, most recently with quantum dots (Qtracker705) [23
]. The UV-blue-green components of this emission are higher in intensity, but the attenuation of this light is orders of magnitude higher than of the red-near-infrared components due to the hemoglobin absorption. Thus Čerenkov Radiation Excited Luminescence (CREL) can be used to induce emission at wavelengths in the near-infrared (NIR) range, where there is less absorption and light originating from deep tissues reaches the surface. One of the advantages of Čerenkov emission is that it is generated only within the targeted tissue of interest, such as within tumor during targeted radiation therapy. This provides a broadband source within the irradiated tissue with a well-known spatial origin, whereby CREL detection can be optimized by arranging the detection system with respect to the incident electron or photon beam.
Here we explore the possibility of combining Cerenkov emission with the phosphorescence quenching method [4
] for tissue oxygen imaging. CES of hemoglobin and CREL in combination with phosphorescence has been shown to have the potential to reveal spatial distributions of two important tissue parameters: St
. Spatial origins of the two signals have been evaluated in order to evaluate the technique's potential for pre-clinical or clinical radiation therapy. This study was based on tissue phantoms and Monte Carlo simulations to characterize spatial signal distributions for CES and CREL. The experimental CREL lifetime measurements were carried out using a well-characterized oxygen sensitive probe, PtG4 [3
]. Since the lifetime of CREL of PtG4 is sensitive to changes in pO2
, phosphorescence lifetime measurements could be used to obtain information on oxygenation of the sampled region. Simulations were carried out to investigate the influence of spatial arrangements of the radiotherapy beam relative to the sampling optical fiber.