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Multimodality imaging of hypoxia in preclinical settings. Q

ABSTRACT Hypoxia has long been recognized to influence solid tumor response to therapy. Increasingly, hypoxia has also been implicated in tumor aggressiveness, including growth, development and metastatic potential. Thus, there is a fundamental, as well as a clinical interest, in assessing in situ tumor hypoxia. This review will examine diverse approaches focusing on the preclinical setting, particularly, in rodents. The strategies are inevitably a compromise in terms of sensitivity, precision, temporal and spatial resolution, as well as cost, feasibility, ease and robustness of implementation. We will review capabilities of multiple modalities and examine what makes them particularly suitable for investigating specific aspects of tumor pathophysiology. Current approaches range from nuclear imaging to magnetic resonance and optical, with varying degrees of invasiveness and ability to examine spatial heterogeneity, as well as dynamic response to interventions. Ideally, measurements would be non-invasive, exploiting endogenous reporters to reveal quantitatively local oxygen tension dynamics. A primary focus of this review is magnetic resonance imaging (MRI) based techniques, such as ¹⁹F MRI oximetry, which reveals not only hypoxia in vivo, but more significantly, spatial distribution of pO₂ quantitatively, with a precision relevant to radiobiology. It should be noted that preclinical methods may have very different criteria for acceptance, as compared with potential investigations for prognostic radiology or predictive biomarkers suitable for use in patients.

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Available from: Guiyang Hao, May 02, 2014
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    • "Magnetic resonance spectroscopy and/or imaging (MRS/MRSI/ MRI) methods include oxygen-enhanced MRI, 19 F oximetry using perfluorocarbons and 1 H MRI-based blood oxygen-level dependent (BOLD) imaging [3] [5]. Pre-clinical developments have been reviewed by Mason et al. [6]. Dissolution dynamic nuclear polarisation (dDNP) of metabolic substrates combined with MRS/MRSI is established pre-clinically for monitoring in vivo metabolism [7] and its first clinical use has now been published [8]. "
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    ABSTRACT: To estimate the rate constant for pyruvate to lactate conversion in tumours in response to a hypoxic challenge, using hyperpolarised (13)C1-pyruvate and magnetic resonance spectroscopy. Hypoxic inspired gas was used to manipulate rat P22 fibrosarcoma oxygen tension (pO2), confirmed by luminescence decay of oxygen-sensitive probes. Hyperpolarised (13)C1-pyruvate was injected into the femoral vein of anaesthetised rats and slice-localised (13)C magnetic resonance (MR) spectra acquired. Spectral integral versus time curves for pyruvate and lactate were fitted to a precursor-product model to estimate the rate constant for tumour conversion of pyruvate to lactate (kpl). Mean arterial blood pressure (MABP) and oxygen tension (ArtpO2) were monitored. Pyruvate and lactate concentrations were measured in freeze-clamped tumours. MABP, ArtpO2 and tumour pO2 decreased significantly during hypoxia. kpl increased significantly (p<0.01) from 0.029±0.002s(-1) to 0.049±0.006s(-1) (mean±SEM) when animals breathing air were switched to hypoxic conditions, whereas pyruvate and lactate concentrations were minimally affected by hypoxia. Both ArtpO2 and MABP influenced the estimate of kpl, with a strong negative correlation between kpl and the product of ArtpO2 and MABP under hypoxia. The rate constant for pyruvate to lactate conversion, kpl, responds significantly to a rapid reduction in tumour oxygenation. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.
    Radiotherapy and Oncology 03/2015; 11. DOI:10.1016/j.radonc.2015.03.011 · 4.86 Impact Factor
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    • "However, these methods are single time-point measurements and are dependent on a biochemical reaction. Direct pO 2 measurements can be achieved by several techniques that each face individual limitations: polarographic electrodes invasively measure oxygenation in the local tissue around the electrode; optical measurements are severely limited by penetration depth; Overhauser imaging and electron paramagnetic resonance imaging are not as readily available to most research groups as alternative imaging approaches, such as magnetic resonance imaging (MRI) [3]. 19 F-MRI oximetry [4] [5] [6] [7], which uses perfluorocarbon (PFC) emulsions as an imaging contrast agent, is a noninvasive method that can map tumor pO 2 in vivo. "
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    ABSTRACT: Quantifying oxygenation in viable tumor remains a major obstacle toward a better understanding of the tumor micro-environment and improving treatment strategies. Current techniques are often complicated by tumor heterogeneity. Herein, a novel in vivo approach that combines (19)F magnetic resonance imaging ((19)F-MRI) R 1 mapping with diffusion-based multispectral (MS) analysis is introduced. This approach restricts the partial pressure of oxygen (pO2) measurements to viable tumor, the tissue of therapeutic interest. The technique exhibited sufficient sensitivity to detect a breathing gas challenge in a xenograft tumor model, and the hypoxic region measured by MS (19)F-MRI was strongly correlated with histologic estimates of hypoxia. This approach was then applied to address the effects of antivascular agents on tumor oxygenation, which is a research question that is still under debate. The technique was used to monitor longitudinal pO2 changes in response to an antibody to vascular endothelial growth factor (B20.4.1.1) and a selective dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor (GDC-0980). GDC-0980 reduced viable tumor pO2 during a 3-day treatment period, and a significant reduction was also produced by B20.4.1.1. Overall, this method provides an unprecedented view of viable tumor pO2 and contributes to a greater understanding of the effects of antivascular therapies on the tumor's microenvironment.
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    • "Several fluorescence as well as magnetic resonance (MR) techniques are currently in use to measure oxygenation in tissues [17] [18]. As an alternative approach , our lab recently demonstrated that hexamethyldisiloxane (HMDSO) could be used to quantitatively measure oxygen tension (pO2) in tissues using 1 H MR [19] [20] and we have developed HMDSO-based nanoemulsions as pO2 nanoprobes [21] . "
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    ABSTRACT: An emerging need for evaluation of promising cellular therapies is a non-invasive method to image the movement and health of cells following transplantation. However, the use of a single modality to serve this purpose may not be advantageous as it may convey inaccurate or insufficient information. Multi-modal imaging strategies are becoming more popular for in vivo cellular and molecular imaging because of their improved sensitivity, higher resolution and structural/functional visualization. This study aims at formulating Nile Red doped hexamethyldisiloxane (HMDSO) nanoemulsions as dual modality (Magnetic Resonance Imaging/Fluorescence), dual-functional (oximetry/detection) nanoprobes for cellular and molecular imaging. HMDSO nanoprobes were prepared using a HS15-lecithin combination as surfactant and showed an average radius of 71±39 nm by dynamic light scattering and in vitro particle stability in human plasma over 24 hrs. They were found to readily localize in the cytosol of MCF7-GFP cells within 18 minutes of incubation. As proof of principle, these nanoprobes were successfully used for fluorescence imaging and for measuring pO(2) changes in cells by magnetic resonance imaging, in vitro, thus showing potential for in vivo applications.
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