Co-imaging of the tumor oxygenation and metabolism using electron paramagnetic resonance imaging and 13-C hyperpolarized magnetic resonance imaging before and after irradiation.

Masayuki Matsuo,Jeeva Munasinghe,Keita Saito,Shun Kishimoto,Murali C Krishna,Nallathamby Devasahayam,Tatsuya Kawai,James B Mitchell

doi:10.18632/oncotarget.25317

Abstract

To examine the relationship between local oxygen partial pressure and energy metabolism in the tumor, electron paramagnetic resonance imaging (EPRI) and magnetic resonance imaging (MRI) with hyperpolarized [1-13C] pyruvate were performed.SCCVII and HT29 solid tumors implanted in the mouse leg were imaged by EPRI using OX063, a paramagnetic probe and 13C-MRI using hyperpolarized [1-13C] pyruvate. Local partial oxygen pressure and pyruvate metabolism in the two tumor implants were examined. The effect of a single dose of 5-Gy irradiation on the pO2 and metabolism was also investigated by sequential imaging of EPRI and 13C-MRI in HT29 tumors.A phantom study using tubes filled with different concentration of [1-13C] pyruvate, [1-13C] lactate, and OX063 at different levels of oxygen confirmed the validity of this sequential imaging of EPRI and hyperpolarized 13C-MRI. In vivo studies revealed SCCVII tumor had a significantly larger hypoxic fraction (pO2 < 8 mmHg) compared to HT29 tumor. The flux of pyruvate-to-lactate conversion was also higher in SCCVII than HT29. The lactate-to-pyruvate ratio in hypoxic regions (pO2 < 8 mmHg) 24 hours after 5-Gy irradiation was significantly higher than those without irradiation (0.76 vs. 0.36) in HT29 tumor. The in vitro study showed an increase in extracellular acidification rate after irradiation.In conclusion, co-imaging of pO2 and pyruvate-to-lactate conversion kinetics successfully showed the local metabolic changes especially in hypoxic area induced by radiation therapy.

Highlights

Tissue partial pressure of oxygen is linked to many pathophysiological conditions
To take full advantage of the curative potential of modern and modern radiotherapy techniques such as stereotactic radiotherapy, radiosurgery, and intensity-modulated radiotherapy (IMRT), molecular imaging to profile the microenvironment is needed for identification of target volumes [24,25,26,27,28]
The higher lactate-to-pyruvate ratio observed in SCCVII than HT29 as shown in Figure 3D was consistent with higher hypoxic fraction in SCCVII presumably due to higher lactate dehydrogenase (LDH) activity under anaerobic glycolytic state (Figure 3A)

Summary

Introduction

Tissue partial pressure of oxygen (pO2) is linked to many pathophysiological conditions (e.g., ischemic diseases, reperfusion injury, and oxygen toxicity). Oxygen deficiency or hypoxia can increase the tumor’s resistance toward cancer treatments, including radiation therapy and chemotherapy [1, 2]. There is a clear oxygen dependent relationship between the radiation dose delivered locally to the tumor and the response to the radiation. This finding was essentially attributed to hypoxic cells being resistant to radiation [6]. Considering the fact that many solid tumors outgrow the blood supply and, have some regions with chronic and intermittent hypoxia [7,8,9], investigation of both tumor oxygenation and energy metabolism simultaneously and non-invasively is required to understand the radiosensitivity in individual tumor and assess the treatment efficacy of radiation therapy

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Conclusion