Introduction Oxygenation quantification based on ...

Oxygenation quantification based on Čerenkov radiation excited luminescence (CREL) Rongxiao Zhang1, Adam Glaser2, Tatiana V. Esipova3, Sergei Vinogradov3, David Gladstone4, Brian W. Pogue1,2,4 1Department

of Physics & Astronomy, 2Thayer School of Engineering, Dartmouth College, Hanover NH 03755 3Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA 19104. 4Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon NH 03755

Introduction

Oxygenation tomography

Recovered lifetime compared with reference values

Tissue oxygenation is a major factor influencing the success or failure of radiation therapy. Thus, techniques for measuring tumor partial pressure of oxygen (pO2) during the daily fractions of radiation therapy given to patients could be extremely useful for tuning treatment conditions and monitoring therapeutic outcome. However, most methods to measure pO2 in tissue require invasive instruments and thus are difficult to repeat daily and are sensitive to the high microscopic heterogeneity of pO2 in tumors. Čerenkov emission occurs when charged particles move through a dielectric medium at a phase velocity greater than the speed of light in that medium inelastically losing energy through electrical field interactions with the transiently polarized medium. Radiotherapy generates Čerenkov radiation emission in tissue and can be used to excite an oxygen-sensitive phosphorescent probe, PtG4, whose NIR emission lifetime is directly sensitive to the tissue oxygen partial pressure (pO2). Optical diffuse tomography of the lifetime of Čerenkov radiation excited luminescence will reveal the distribution of pO2 in tissue.

Sampling depth Images of phosphorescence yield from CREL tomography and associated contrast-to-background values for four PtG4 phantom configurations.

4

x 10

 (M-1cm -1)

435nm 10

Emission intensity(normalized)

1

Stern-Volmer model:     kq  pO2 0

The geometry of simulations and optical properties of phantom are shown with (A) a 60x60x100mm cuboid container defined and voxelised into 0.5mm cubes. The coordinate system was as indicated here, and a fiber with diameter 1.2mm and numerical aperture 0.22 was posited right on the surface of the container at position (x=30mm, y=0mm, z=75mm). The external electron beam irradiated the phantom from the top surface. In (B) the intersections of a typical simulation to show how the sensitivity distribution appeared in 3D, and in (C) the optical properties are shown of the tissue mimicking phantom made of water, 1% intralipid, 1% whole blood and PtG4 with a concentration of 5μM.

623nm

5

0

1

Absorption

400

500

1

600 700 Wavelength(nm) 772nm

0.8

800

Emission

0.6 0.4 0.2 700

750

800 850 Wavelength(nm)

900

950

Methods

(A) Recovered lifetime distribution. (B) pO2 distribution converted from the lifetime distribution using the Stern-Volmer model. (C) Phosphorescence decays calculated as the average values in the aerated anomaly and anoxic background.

Conclusions (A) Diagram of the measurement system consisting of a linear accelerator, radiation/optical tissue phantom, and an optical fiber which couples light from the phantom to a spectrometer with a gated ICCD synchronized to the radiation bursts of the LINAC. (B) Top view of the phantom geometry. (C) A 2D cross section of the Cherenkov field modeled using GAMOS and used as the excitation field for phosphorescence yield image reconstruction.

Detective sensitivity distribution of Čerenkov radiation emission and sensitivity vs. depth profiles. In (A) & (C) the Detective sensitivity distribution of Čerenkov radiation emission is shown in y-z plane. In (B) & (D) the sensitivity vs. depth profiles for fiber-beam distances of 0mm and 10mm and wavelength from 300nm to 1000nm with 100nm increment.

• Phantoms were composed of water with 1% v/v intralipid as a scattering standard and 1% v/v porcine whole blood as an absorber. PtG4 was added at a concentration of 5μM • Intensified CCD was synchronized to radiation bursts • For tomography, both the background and anomaly were filled with 1% v/v intralipid. PtG4 was added to the background and anomaly regions of the phantom. • Remove oxygen: oxidase/catalase

In (A) the effective sampling depth vs. wavelength are shown for fiber-beam distances of 0mm, 10mm, 20mm and 30mm. In (B) the normalized intensity of Čerenkov radiation emission vs. wavelength is shown (i.e. simulated spectrum).

Spectra measurement and lifetime fitting 5

CW(pO2=2.31Torr)

(B) x 10

CW(pO2=141.95Torr)

10000

Gated(pO2=141.95Torr)

6000 4000

CREL intensity(A.U)

CREL intensity(A.U)

Gated(pO2=2.31Torr) 8000

CREL intensity(pO2=2.31Torr)

5

Exponential fitting(pO2=2.31Torr) CREL intensity(pO2=141.95Torr)

4

Exponential fitting(pO2=141.95Torr)

3

2

1

2000

700

720

740

760 780 Wavelength(nm)

800

820

0 0

20

40

60

80

100 Time(s)

120

140

160

180

200

(A) A continuous wavelength and gated spectrum measurement of CREL shown from tissue mimicking phantoms with different pO2 levels (pO2=141.95Torr and pO2=2.31Torr). In (B) the lifetime fitting of the fast time gated CREL intensity data is shown.

The ability to image pO2 distribution during radiotherapy, as demonstrated here, would provide unprecedented information about the tumor microenvironment. This may have a significant impact in radiotherapy research programs, such as in the development of adjuvant and synergistic therapies, and in planning and tailoring clinical treatment regimens.

References

glucose/glucose

• Reference value measured by a frequencydomain phosphorometer

(A)

oxygenation could be assessed by lifetime measurement of oxygen sensitive CREL.  CREL could be detected at depths of a few centimeters into tissue.  CREL-based oxygen tomography is feasible and that incorporating time-domain analysis can provide an accurate, robust, and quantitative pO2 imaging paradigm. 

• Varian Clinic 2100CD LINAC

(a)

 Tissue

Calculated sensitivity distribution and sensitivity vs. depth profile of CREL are shown in (A-D) in the y-z plane while x=30mm for fiber-beam distances of 0mm, 10mm, 20mm and 30mm. In (E) the sensitivity vs. depth profiles for the same FBDs are shown.

1. R. Zhang, A. Glaser, T. V. Esipova, S. C. Kanick, S. C. Davis, S. Vinogradov, D. Gladstone, and B. W. Pogue, "Cerenkov radiation emission and excited luminescence (CREL) sensitivity during external beam radiation therapy: Monte Carlo and tissue oxygenation phantom studies," Biomed Opt Express 3, 2381-2394 (2012). 2. A. K. Glaser, R. Zhang, S. C. Davis, D. J. Gladstone, and B. W. Pogue, "Time-gated Cherenkov emission spectroscopy from linear accelerator irradiation of tissue phantoms," Opt Lett 37, 1193-1195 (2012). 3. T. V. Esipova, A. Karagodov, J. Miller, D. F. Wilson, T. M. Busch, and S. A. Vinogradov, "Two new "protected" oxyphors for biological oximetry: properties and application in tumor imaging," Anal Chem 83, 8756-8765 (2011). 4. R. Zhang, S. C. Davis, J. L. Demers, A. K. Glaser, D. J. Gladstone, T. V. Esipova, S. A. Vinogradov, and B. W. Pogue, "Oxygen tomography by Cerenkov-excited phosphorescence during external beam irradiation," Journal of biomedical optics 18, 50503 (2013).

Acknowledgements

This work was supported by NIH grants R01CA120368 (BWP), R01CA109558 (BWP) and Department of Defense award W81XWH09-1-0661 (SCD). SAV acknowledges support of the grant from the Penn Comprehensive Neuroscience Center.