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Title: SU-F-T-684: Analysis of Cherenkov Excitation in Tissue and the Feasibility of Cherenkov Excited Photodynamic Therapy

Abstract

Purpose: The irradiation of photodynamic agents with radiotherapy beams has been demonstrated to enhance tumor killing in various studies, and one proposed mechanism is the optical fluence of Cherenkov emission activating the photosensitizer. This mechanism is explored in Monte Carlo simulations of fluence as well as laboratory measurements of fluence and radical oxygen species. Methods: Simulations were completed using GAMOS/GEANT4 with a 6 MV photon beam in tissue. The effects of blood vessel diameter, blood oxygen saturation, and beam size were examined, recording spectral fluence. Experiments were carried out in solutions of photosensitizer and phantoms. Results: Cherenkov produced by a 100×100um{sup 2} 6 MV beam resulted in fluence of less than 1 nJ/cm{sup 2}/Gy per 1 nm wavelength. At this microscopic level, differences in absorption of blood and water in the tissue affected the fluence spectrum, but variation in blood oxygenation had little effect. Light in tissue resulting from larger (10mm ×10mm) 6 MV beams had greater fluence due to light transport and elastic scattering of optical photons, but this transport process also resulted in higher absorption shifts. Therefore, the spectrum produced by a microscopic beam was weighted more heavily in UV/blue wavelengths than the spectrum at the macroscopic level.more » At the macroscopic level, the total fluence available for absorption by Verteporfin (BPD) in tissue approached uJ/cm{sup 2} for a high radiation dose, indicating that photodynamic activation seems unlikely. Tissue phantom confirmation of these light levels supported this observation, and photosensitization measurements with a radical oxygen species reporter are ongoing. Conclusion: Simulations demonstrated that fluence produced by Cherenkov in tissue by 6 MV photon beams at typical radiotherapy doses appears insufficient to activate photosensitizers to the level required for threshold effects, yet this disagrees with published biological experiments. Experimental validation in tissue phantoms and cell studies are ongoing to clarify this discrepancy. Funding from NIH grant R01CA109558.« less

Authors:
; ;  [1];  [2]
  1. Dartmouth College, Hanover, NH (United States)
  2. University of Washington, Seattle, WA (United States)
Publication Date:
OSTI Identifier:
22649239
Resource Type:
Journal Article
Resource Relation:
Journal Name: Medical Physics; Journal Volume: 43; Journal Issue: 6; Other Information: (c) 2016 American Association of Physicists in Medicine; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 61 RADIATION PROTECTION AND DOSIMETRY; ABSORPTION; ANIMAL TISSUES; BLOOD VESSELS; COMPUTERIZED SIMULATION; EXCITATION; MONTE CARLO METHOD; OXYGEN; PHANTOMS; PHOTON BEAMS; RADIATION DOSES; SPECTRA; VISIBLE RADIATION

Citation Formats

Saunders, Sara L, Andreozzi, Jacqueline M, Pogue, Brian W, and Glaser, Adam K. SU-F-T-684: Analysis of Cherenkov Excitation in Tissue and the Feasibility of Cherenkov Excited Photodynamic Therapy. United States: N. p., 2016. Web. doi:10.1118/1.4956870.
Saunders, Sara L, Andreozzi, Jacqueline M, Pogue, Brian W, & Glaser, Adam K. SU-F-T-684: Analysis of Cherenkov Excitation in Tissue and the Feasibility of Cherenkov Excited Photodynamic Therapy. United States. doi:10.1118/1.4956870.
Saunders, Sara L, Andreozzi, Jacqueline M, Pogue, Brian W, and Glaser, Adam K. 2016. "SU-F-T-684: Analysis of Cherenkov Excitation in Tissue and the Feasibility of Cherenkov Excited Photodynamic Therapy". United States. doi:10.1118/1.4956870.
@article{osti_22649239,
title = {SU-F-T-684: Analysis of Cherenkov Excitation in Tissue and the Feasibility of Cherenkov Excited Photodynamic Therapy},
author = {Saunders, Sara L and Andreozzi, Jacqueline M and Pogue, Brian W and Glaser, Adam K},
abstractNote = {Purpose: The irradiation of photodynamic agents with radiotherapy beams has been demonstrated to enhance tumor killing in various studies, and one proposed mechanism is the optical fluence of Cherenkov emission activating the photosensitizer. This mechanism is explored in Monte Carlo simulations of fluence as well as laboratory measurements of fluence and radical oxygen species. Methods: Simulations were completed using GAMOS/GEANT4 with a 6 MV photon beam in tissue. The effects of blood vessel diameter, blood oxygen saturation, and beam size were examined, recording spectral fluence. Experiments were carried out in solutions of photosensitizer and phantoms. Results: Cherenkov produced by a 100×100um{sup 2} 6 MV beam resulted in fluence of less than 1 nJ/cm{sup 2}/Gy per 1 nm wavelength. At this microscopic level, differences in absorption of blood and water in the tissue affected the fluence spectrum, but variation in blood oxygenation had little effect. Light in tissue resulting from larger (10mm ×10mm) 6 MV beams had greater fluence due to light transport and elastic scattering of optical photons, but this transport process also resulted in higher absorption shifts. Therefore, the spectrum produced by a microscopic beam was weighted more heavily in UV/blue wavelengths than the spectrum at the macroscopic level. At the macroscopic level, the total fluence available for absorption by Verteporfin (BPD) in tissue approached uJ/cm{sup 2} for a high radiation dose, indicating that photodynamic activation seems unlikely. Tissue phantom confirmation of these light levels supported this observation, and photosensitization measurements with a radical oxygen species reporter are ongoing. Conclusion: Simulations demonstrated that fluence produced by Cherenkov in tissue by 6 MV photon beams at typical radiotherapy doses appears insufficient to activate photosensitizers to the level required for threshold effects, yet this disagrees with published biological experiments. Experimental validation in tissue phantoms and cell studies are ongoing to clarify this discrepancy. Funding from NIH grant R01CA109558.},
doi = {10.1118/1.4956870},
journal = {Medical Physics},
number = 6,
volume = 43,
place = {United States},
year = 2016,
month = 6
}
  • We have solved the problem of layer-by-layer laser-light dosimetry in biological tissues and of selecting an individual therapeutic dose in laser therapy. A method is proposed for real-time monitoring of the radiation density in tissue layers in vivo, concentrations of its endogenous (natural) and exogenous (specially administered) chromophores, as well as in-depth distributions of the spectrum of light action on these chromophores. As the background information use is made of the spectrum of diffuse light reflected from a patient's tissue, measured by a fibre-optic spectrophotometer. The measured spectrum is quantitatively analysed by the method of approximating functions for fluxes ofmore » light multiply scattered in tissue and by a semi-analytical method for calculating the in-depth distribution of the light flux in a multi-layered medium. We have shown the possibility of employing the developed method for monitoring photosensitizer and oxyhaemoglobin concentrations in tissue, light power absorbed by chromophores in tissue layers at different depths and laser-induced changes in the tissue morphology (vascular volume content and ratios of various forms of haemoglobin) during photodynamic therapy. (biophotonics)« less
  • Purpose: Optical properties of terbium (Tb3+)-doped gadolinium trifluoride (GdF3) nanoplates irradiated by electron and photon beams were investigated for their potential as optical probes. The contribution of induced Cerenkov radiation in exciting the nanophosphors was investigated as well. Methods: The emission spectra of Terbium-doped GdF3 dispersed in hexane, embedded in tissue mimicking phantoms were collected by an optical fiber connected to a CCD-coupled spectrograph, while the samples were irradiated by a medical linear accelerator with electron beams of energies 6, 9, 12, 16, and 20 MeV or X-ray beams of energies of 6, and 15 MV. The contribution of inducedmore » Cerenkov radiation in exciting the nanophosphores was investigated in a dedicated experimental apparatus through optical isolation of the samples and also by using 125 kVp X-ray beams whose energy is below the threshold for generating Cerenkov radiation in that medium. Results: Terbium-doped GdF3 nanoplates show characteristic cathodoluminescence emission peaks at 488, 543, 586, and 619 nm, which are responsible for the characteristic f-f transition of terbium ion. In a series of experiments, the contribution of Cerenkov radiation in the luminescence of such nanophosphors was ruled out. Conclusion: We have characterized the optical properties of Terbium-doped GdF3 nanoplates. Such nanocrystals with emission tunability and high surface area that facilitates attachment with targeting reagents are promising in situ light source candidates for molecular imaging or exciting a photosensitizer for ultralow fluence photodynamic therapy. This work is supported by the Department of Radiation Oncology at the University of Pennsylvania, the American Cancer Society through IRG-78-002-28, and the University of Pennsylvania's Nano/Bio Interface Center through NSEC DMR08-32802.« less
  • Purpose: To simulate a Cherenkov glass detector system utilizing prompt gamma (PG) technique to quantify range uncertainties in proton radiation therapy. Methods: A simulation of high energy photons typically produced in proton interactions with materials incident onto a block of Cherenkov glass was performed with the Geant4 toolkit. The standard electromagnetic package was used along with several decay modules (G4Decay, G4DecayPhysics, and G4RadioactiveDecayPhysics) and the optical photon components (G4OpticalPhysics). Our setup included a pencil beam consisting of a hundred thousand 6 MeV photons (approximately the deexcitation energy released from 16O) incident onto a 2.5 ⊗ 2.5 ⊗ 1.5 cm3 ofmore » a Cherenkov glass (7.2 g of In2O3 + 90 g cladding, density of 2.82 g/cm3, Zeff = 33.7, index of refraction 1.56). The energy deposited from incident 6 MeV photons as well as secondary electrons and resulting optical photons were recorded. Results: The energy deposited by 6 MeV photons in glass material showed several peaks that included the photoelectric, the single and double escape peaks. About 11% of incident photons interacted with glass material to deposit energy. Most of the photons collected were in the region of double escape peak (approximately 4.98 MeV). The secondary electron spectrum produced from incident photons showed a high energy peak located near 6 MeV and a sharp peak located ∼120 keV with a continuous distribution between these two points. The resulting Cherenkov photons produced showed a continuous energy distribution between 2 and 5 eV with a slight increase in yield beginning about 3 eV. The amount of Cherenkov photons produced per interacting incident 6 MeV photon was ∼240.7. Conclusion: This study suggests the viability of utilizing the Cherenkov glass material as a possible prompt gamma photon detection device. Future work will include optimization of the detector system to maximize photon detection efficiency.« less
  • Purpose: To investigate from first principles, corroborated by Monte Carlo simulations and experimental measurements, the feasibility of developing a relative Cherenkov emission (CE) dosimetry protocol for electron beam radiotherapy. Methods: Monte Carlo (MC) simulations of mono-energetic electrons incident on water were carried out in Geant4. Percent depth Cherenkov emission (PDCE) and dose (PDD) distributions were scored for incidence energies of 4, 6, 9, 12, 15, and 18 MeV. PDCE-to-PDD analytical conversion models were developed from least-squares data fits generated for PDD as a function of PDCE at the same depth and at different depths. Experimental techniques for validation of thesemore » models are examined. Results: Same-depth PDD versus PDCE data fits indicate that although the relationship is linear to first order (correlation r > 0.9 for all energies), it is much more accurately approximated by separate linear and quadratic models for the build-up and drop-off regions, respectively (r > 0.999), which is theoretically underpinned. To understand the source of this relationship and its basis for developing robust conversion models, an approximate quadratic first-principles model was derived and found in agreement with MC/measured data (20% deviation at worst). Conversely, data fits of PDD versus different-depth PDCE unveiled a depth-invariant effective point of measurement of 1.5–2.1 mm downstream with 4–18 MeV incidence, respectively (r > 0.999 in the drop-off region). We present an analytical first-principles justification for this shift. This method led to errors of <1% in drop-off region PDD (<2% for PDD<20% with 4 MeV incidence) and <0.2 mm in practical range prediction. Conclusion: We present robust quantitative prediction models, derived from first-principles and supported by simulation and measurement, for relative dose from Cherenkov emission by high-energy electrons. This constitutes a major step towards development of protocols for routine clinical quality assurance as well as real-time in vivo Cherenkov dosimetry in radiotherapy. The authors acknowledge partial support by Fonds de recherche du Quebec - Nature et technologies (FRQNT), CREATE Medical Physics Research Training Network grant of the Natural Sciences and Engineering Research Council of Canada (NSERC), CREATE Integrated Sensor Systems grant of NSERC, the Canadian Institutes of Health Research (CIHR), and NSERC.« less
  • Purpose: To simulate the feasibility of a Cherenkov glass material for the determination of the penetration depth of therapeutic proton beams in water. Methods: Proton pencil beams of various energies incident onto a water phantom with dimensions of 5 x 5 x 30 cm{sup 3} were used for simulation with the Geant4 toolkit. The model used standard electromagnetic packages, packages based on binary-cascade nuclear model, several decay modules (G4Decay, G4DecayPhysics, and G4RadioactiveDecayPhysics), and optical photon components (G4OpticalPhysics). A Cherenkov glass material was modeled as the detector medium (7.2 g of In2O3 + 90 g cladding, density of 2.82 g/cm{sup 3},more » Zeff = 33.7, index of refraction n(600 nm) = 1.56, and energy threshold of production Eth = 156 keV ). The emitted secondary particles are analyzed characterizing their timing, energy, and angular distributions. A feasibility analysis was conducted for a simplistic detector system using this material to locate the position of the Bragg Peak. Results: The escaping neutrons have energies ranging from thermal to the incident proton energy and the escaping photons have energies >10 MeV. Photon peaks between 4 and 6 MeV were attributed to originate from direct proton interactions with {sup 12}C (∼ 4.4 MeV) and {sup 16}O (∼ 6 MeV), respectively. The escaping photons are emitted isotropically, while low (≤10 MeV) and high (>10 MeV) neutrons are isotropic and forward-directional, respectively. The emissions of photons are categorized into prompt (∼ns) and delayed (∼min) where the prompt photons include the 4.4 and 6 MeV. The Cherenkov material had on average <2% of neutron interactions while LYSO and BGO scintillators had a minimum of ∼50%. Our simplistic detector system was capable of discerning Bragg Peak locations using a timing discrimination of ∼50 ns. Conclusion: We investigate the viability of using the Cherenkov material for MeV photon detection medium for the prompt gamma technique.« less