Research

Oncology Applications

Quantitative oximetry

The importance of tumor oxygenation has been reported for many disease sites based on quantitative polarographic oximetry using invasive needle electrodes; notably in patients with cervical, head an neck, lung, prostate and breast cancer (Tatum review). Thus our goal has been to establish robust minimally invasive methods to map tumor heterogeneity and dynamic response to interventions designed to manipulate tumor hypoxia. Our most extensive research has examined the use of perfluorocarbon (PFC) reporter molecules detected by 19F NMR.

Oximetry Figure
Oximetry Figure

19F

Quantitative in vivo MR oximetry has been demonstrated based on the spin lattice relaxation rates of perfluorocarbons (PFCs) using 19F MRI (Zhao et al., 2004). PFCs exhibit very high gas solubility, are essentially inert, and non-toxic. For oximetry the most crucial property is the ideal liquid-gas interaction with oxygen, obeying Henry’s law and providing a linear dependence of the 19F spin lattice relaxation rate R1 = A + B pO2, as reviewed previously (Mason 1994, Zhao et al. 2004).

We have found that hexafluorobenzene offers exceptionally high sensitivity to changes in oxygenation, while being relatively insensitive to temperature. It has a single 19F NMR signal and is readily available commercially. In early studies we demonstrated the sensitivity to pO2 and performed oximetry using 19F NMR spectroscopy (ref). We then developed a rudimentary imaging a method (ref) followed by accelerated approaches so that currently we can achieve maps of 50 to 150 individual locations simultaneously in a tumor at 4.7 T with a precision of 1 to 3 torr in relatively hypoxic regions in 6.5 minutes (ref). The so-called FREDOM (Fluorocarbon Relaxometry using Echo planar imaging for Dynamic Oxygen Mapping) approach has been applied prostate (refs), breast (refs) and lung tumors (refs) in rats with respect to various interventions such as hyperoxic gas challenges (refs) and vascular disrupting agents (refs).

Technique development

"Measuring changes in tumor oxygenation." Zhao D., Jiang L., Mason, R.P., Meth. Enzymol. 2004 386 378-418.

 

Early investigations with perfluorocarbon emulsion:

"Tissue oxygen tension: a novel determination using 19F surface coil NMR spectroscopy of sequestered perfluorocarbon emulsion." R.P. Mason, R. L. Nunnally, and P. P. Antich, Magn. Reson. Med., 18, 71-79 (1991).

"Oxygent: a novel probe of tissue oxygen tension." R.P. Mason, H. Shukla, and P. P. Antich, Biomater. Artif. Cells Immob. Biotechnol., 20, 929-932 (1992).

"In vivo oxygen tension and temperature: simultaneous determination using 19F NMR spectroscopy of perfluorocarbon." R.P. Mason, H. Shukla and P. P. Antich, Magn. Reson. Med., 29, 296-302 (1993).

"Non-invasive determination of tumor oxygen tension and local variation with growth." R.P. Mason, P. P. Antich, E. E. Babcock, A. Constantinescu, P. Peschke and E. W. Hahn, Int. J. Radiat. Oncol. Biol. Phys. 29 (1), 95-103 (1994).

"Oxygen tension mapping by 19F echo planar nmr imaging of sequestered perfluorocarbon." B. R. Barker, R.P. Mason, N. Bansal, and R. M. Peshock, JMRI 4, 595-602 (1994).

Development of hexafluorobenzene as optimal pO2 reporter

"Hexafluorobenzene: a sensitive 19F NMR indicator of tumor oxygenation." R.P. Mason, W. Rodbumrung, and P. P. Antich, NMR in Biomed. 9, 125-134 (1996).

"Regional tumor oxygen dynamics: 19F PBSR EPI of hexafluorobenzene." D. Le, R.P. Mason, S. Hunjan, A. Constantinescu, B. R. Barker and P.P. Antich. Magn. Reson. Imaging, 15 (8) 971-81 (1997).

"Regional tumor oxygen tension: Fluorine echo planar imaging of hexafluorobenzene reveals heterogeneity of dynamics." R.P. Mason, S. Hunjan, D. Le, A. Constantinescu, B. R. Barker, P. S. Wong, P. Peschke, E. W. Hahn, and P. P. Antich, Int. J. Radiat. Oncol. Biol. Phys. 42 (4), 747-50 (1998).

"Regional tumor oxygenation and measurement of dynamic changes." R.P. Mason, A. Constantinescu, S. Hunjan, D. Le, E. W. Hahn, P.P. Antich, C. Blum and P. Peschke, Radiat Res. 152, 239-249 (1999).

"Tumor Oximetry: demonstration of an enhanced dynamic mapping procedure using fluorine-19 echo planar magnetic resonance imaging in the Dunning prostate R3327-AT1 rat tumor." S. Hunjan, D. Zhao, A. Constantinescu, E. W. Hahn, P. P. Antich, and R.P. Mason, Int. J. Radiat. Oncol. Biol. Phys. 49 (4), 1097-1108 (2001).

Correlative validation

The use of 19F NMR to assess tissue oxygenation has been validated using several traditional techniques.

Tumor oxygen dynamics: correlation of in vivo MRI with histological findings. Zhao D., Ran S., Constantinescu A., Hahn E.W., Mason, R.P. Neoplasia 2003 Jul-Aug 5 4 308-18

Dynamic response of breast tumor oxygenation to hyperoxic respiratory challenge monitored with three oxygen-sensitive parameters. Gu Y., Bourke V.A., Kim J.G., Constantinescu A., Mason, R.P., Liu H. Appl Opt 2003 Jun 42 16 2960-7.

Interplay of tumor vascular oxygenation and tumor pO2 observed using near-infrared spectroscopy, an oxygen needle electrode, and 19F MR pO2 mapping. Kim J.G., Zhao D., Song Y., Constantinescu A., Mason, R.P., Liu H. J Biomed Opt 2003 Jan 8 1 53-62.

Tumor oxygen dynamics: comparison of 19F MR EPI and frequency domain NIR spectroscopy. Song Y., Worden K.L., Jiang X., Zhao D., Constantinescu A., Liu H., Mason, R.P. Adv. Exp. Med. Biol. 2003 530 225-36.

Tumor oximetry: comparison of 19F MR EPI and electrodes. Mason, R.P., Hunjan S., Constantinescu A., Song Y., Zhao D., Hahn E.W., Antich P.P., Peschke P. Adv. Exp. Med. Biol. 2003 530 19-27.

Application to prostate cancer

"Non-invasive determination of tumor oxygen tension and local variation with growth." R.P. Mason, P. P. Antich, E. E. Babcock, A. Constantinescu, P. Peschke and E. W. Hahn, Int. J. Radiat. Oncol. Biol. Phys. 29 (1), 95-103 (1994).

"Tumor oxygen dynamics with respect to growth and respiratory challenge: investigation of the Dunning prostate R3327-HI tumor," D. Zhao, A. Constantinescu, E. W. Hahn, and R.P. Mason, Radiat. Res., 156 (5) 510-520 (2001).

"Differential oxygen dynamics in two diverse Dunning prostate R3327 rat tumor sublines (MAT-Lu and HI) with respect to growth and respiratory challenge." D. Zhao, A. Constantinescu, E. W. Hahn, R.P. Mason, Int. J. Radiat. Oncol. Biol. Phys., 53 (3), 744-756 (2002).

"Correlation of tumor oxygen dynamics with radiation response of the dunning prostate." R3327-HI Tumor." D. Zhao, A. Constantinescu, C. H. Chang, E. W. Hahn, & R.P. Mason, Radiat. Res, 159, 621-631 (2003).

Breast cancer

"Dynamic breast tumor oximetry: The development of prognostic radiology." Y. Song, A. Constantinescu, and R.P. Mason, Technol. Cancer Res. Treat. 1 (6), 471-8 (2002).

Tumor physiologic response to combretastatin A4 phosphate assessed by MRI. Zhao D., Jiang L., Hahn E.W., Mason, R.P. Int. J. Radiat. Oncol. Biol. Phys. 2005 Jul 62 3 872-80.

Noting that 19F MR oximetry is facilitated by the extreme hydrophobicity and high gas solubility of perfluorocarbons, it occurred to us that a proton MRI analysis should be feasible. Hexamethyldisiloxane (HMDSO) serves this purpose well, being hydrophobic, symmetrical to provide a single NMR resonance, which is also placed maximally form that of water.

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1H

Hexamethyldisiloxane-based nanoprobes for (1) H MRI oximetry. Gulaka P.K., Rastogi U., McKay M.A., Wang X., Mason, R.P., Kodibagkar V.D. NMR in biomedicine 2011 Mar.

Proton imaging of siloxanes to map tissue oxygenation levels (PISTOL): a tool for quantitative tissue oximetry. Kodibagkar V.D., Wang X., Pacheco-Torres J., Gulaka P., Mason, R.P. NMR Biomed 2008 Oct 21 8 899-907.

Physical principles of quantitative nuclear magnetic resonance oximetry. Kodibagkar V.D., Wang X., Mason, R.P. Front. Biosci. 2008 13 1371-84.

"A novel 1H NMR approach to quantitative tissue oximetry using hexamethyldisiloxane." V. D. Kodibagkar, W. Cui, M. E. Merritt and R. P. Mason, Magn. Reson. Med. 55:743–748 (2006).

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Non-tumor applications

Many diseases are characterized by ischemia and hypoxia and we have demonstrated applications of 19F MR oximetry to other tissues, notably with to myocardial ischemia.

Uncoupling hypoxia signaling from oxygen sensing in the liver results in hypoketotic hypoglycemic death. Kucejova B., Sunny N.E., Nguyen A.D., Hallac R., Fu X., Peña-Llopis S., Mason, R.P., Deberardinis R.J., Xie X.J., Debose-Boyd R., Kodibagkar V.D., Burgess S.C., Brugarolas J. Oncogene 2011 May 30 18 2147-60

Quantitative tissue oxygen measurement in multiple organs using (19) F MRI in a rat model. Liu S., Shah S.J., Wilmes L.J., Feiner J, Kodibagkar V.D., Wendland M.F., Mason, R.P., Hylton N., Hopf H.W., Rollins M.D,. Magnetic resonance in medicine: official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine 2011 Jun.

"A non-invasive assessment of myocardial oxygen tension: 19F NMR spectroscopy of sequestered perfluorocarbon emulsion." R.P. Mason, F. M. H. Jeffrey, C. R. Malloy, E. E. Babcock and P. P. Antich, Magn. Reson. Med., 27, 310-317 (1992)

"Regional Myocardial Oxygen Tension: 19F MRI of Sequestered Perfluorocarbon." H. P. Shukla, R.P. Mason, N. Bansal and P. P. Antich, Magn. Reson. Med., 35, 827-833 (1996)

Non-invasive methods: oxygen enhanced MRI

Strategic reporter molecules can provide quantitative oximetry, but the ability to achieve oxygen sensitive measurements based on endogenous signals is very attractive. As such we have investigated BOLD (blood oxygen level dependent) and TOLD (tissue oxygen level Dependent) MRI approaches. Significantly, we found correlations between tumor growth delay following a single high dose irradiation and magnitude of TOLD response to oxygen challenge prior to irradiation.

Pre-clinical

Dynamic oxygen challenge evaluated by NMR T1 and T2 * - insights into tumor oxygenation.  Zhao D, Pacheco-Torres J, Hallac RR, White D, Peschke P, Cerdán S, Mason RP NMR Biomed 2015 Jun

 A noninvasive tumor oxygenation imaging strategy using magnetic resonance imaging of endogenous blood and tissue water. Z. Zhang, R. R. Hallac, P. Peschke, R.P. Mason, Magn. Reson. Med., online DOI 10.1002/mrm.24691 Feb. 2013.

"Correlations of noninvasive BOLD and TOLD MRI with pO2 and relevance to tumor radiation response." R. R. Hallac, H. Zhou, R. Pidikiti, K. Song, S. Stojadinovic, D. Zhao, T. Solberg, P. Peschke, and R.P. Mason, Magn. Reson. Med., accepted (2013) DOI 10.1002/mrm.24846.

Comparison of 1H blood oxygen level-dependent (BOLD) and 19F MRI to investigate tumor oxygenation. Zhao D., Jiang L., Hahn E.W., Mason, R.P. Magn Reson Med 2009 Aug 62 2 357-64

Comparison of BOLD contrast and Gd-DTPA dynamic contrast-enhanced imaging in rat prostate tumor. Jiang L., Zhao D., Constantinescu A., Mason, R.P. Magn Reson Med 2004 May 51 5 953-60.

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Human

Since BOLD and TOLD approaches require no intervention beyond a simple oxygen breathing challenge, they are readily implemented in patients.

Oxygenation in cervical cancer and normal uterine cervix assessed using blood oxygenation level-dependent (BOLD) MRI at 3T. Hallac R.R, Ding Y., Yuan Q., McColl R.W.,Lea J., Sims R.D., Weatherall P.T., Mason, R.P. NMR Biomed 2012 Dec 25 12 1321-30.

Blood oxygenation level-dependent (BOLD) contrast magnetic resonance imaging (MRI) for prediction of breast cancer chemotherapy response: A pilot study. Jiang L., Weatherall P.T., McColl R.W., Tripathy D, Mason, R.P. J Magn Reson Imaging 2012 Nov.

"Simultaneous measurement of TOLD and BOLD effects in abdominal tissue oxygenation level studies." Y. Ding, R.P. Mason, R. W. McColl, Q. Yuan, R. R. Hallac, R. D. Sims, P. T. Weatherall, J. Magn. Reson. Imaging (JMRI) 2013 Jun 7. doi: 10.1002/jmri.24006.

Therapeutic correlations

"Correlations of noninvasive BOLD and TOLD MRI with pO2 and relevance to tumor radiation response." R. R. Hallac, H. Zhou, R. Pidikiti, K. Song, S. Stojadinovic, D. Zhao, T. Solberg, P. Peschke, and R.P. Mason, Magn. Reson. Med., accepted (2013) DOI 10.1002/mrm.24846.

Correlation of tumor oxygen dynamics with radiation response of the dunning prostate R3327-HI tumor. Zhao D., Constantinescu A., Chang CH, Hahn E.W., Mason, R.P., Radiat. Res. 2003 May 159 5 621-31.

Correlation of radiation response with tumor oxygenation in the Dunning prostate R3327-AT1 tumor. Bourke V.A., Zhao D., Gilio J., Chang C.H., Jiang L., Hahn E.W., Mason, R.P. Int. J. Radiat. Oncol. Biol. Phys. 2007 Mar 67 4 1179-86.

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