Article

Multimodality imaging of hypoxia in preclinical settings.

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.

Download full-text

Full-text

Available from: Guiyang Hao, May 02, 2014
0 Followers
 · 
94 Views
  • Source
    [Show abstract] [Hide abstract]
    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.
    Theranostics 12/2012; 2(12):1199-207. DOI:10.7150/thno.4812 · 7.83 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Vascular disrupting agents (VDAs) have been proposed as an effective broad spectrum approach to cancer therapy, by inducing ischemia leading to hypoxia and cell death. A novel VDA (OXi8007) was recently reported to show rapid acute selective shutdown of tumor vasculature based on color-Doppler ultrasound. We have now expanded investigations to noninvasively assess perfusion and hypoxiation of orthotopic human MDA-MB-231/luc breast tumor xenografts following the administration of OXi8007 based on dynamic bioluminescence imaging (BLI) and magnetic resonance imaging (MRI). BLI showed significantly lower signal four hours after the administration of OXi8007, which was very similar to the response to combretastatin A-4P (CA4P), but the effect lasted considerably longer, with the BLI signal remaining depressed at 72 hrs. Meanwhile, control tumors exhibited minimal change. Oximetry used (19)F MRI of the reporter molecule hexafluorobenzene and FREDOM (Fluorocarbon Relaxometry using Echo Planar Imaging for Dynamic Oxygen Mapping) to assess pO2 distributions during air and oxygen breathing. pO2 decreased significantly upon the administration of OXi8007 during oxygen breathing (from 122 ± 64 to 34 ± 20 Torr), with further decrease upon switching the gas to air (pO2 = 17 ± 9 Torr). pO2 maps indicated intra-tumor heterogeneity in response to OXi8007, though ultimately all tumor regions became hypoxic. Both BLI and FREDOM showed the efficacy of OXi8007. The pO2 changes measured by FREDOM may be crucial for future study of combined therapy.
    American Journal of Nuclear Medicine and Molecular Imaging 01/2015; 5(2):143-53. · 3.25 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Combretastatin A-4 (CA4) is a natural product isolated from Combretum caffrum that inhibits tubulin polymerization by binding to the colchicine-binding site. A corresponding water soluble pro-drug (referred to as CA4P), has undergone extensive clinical trials and has been evaluated in pre-clinical studies using multiple modalities. We previously reported a novel assay based on dynamic bioluminescent imaging to assess tumor vascular disruption and now present its application to assessing multiple tumors simultaneously. The current study evaluated the vascular-disrupting activity of CA4P on subcutaneous 9L rat brain tumor xenografts in mice using dynamic bioluminescence imaging. A single dose of CA4P (120 mg/kg, intraperitoneally) induced rapid, temporary tumor vascular shutdown revealed by a rapid and reproducible decrease of light emission from luciferase-expressing 9L tumors following administration of luciferin as a substrate. A time-dependent reduction of tumor perfusion after CA4P treatment was confirmed by immunohistological assessment of the perfusion marker Hoechst 33342 and the tumor vasculature marker CD31. The vasculature showed distinct recovery within 24 hours post therapy. Multiple tumors behaved similarly, although a size dependent vascular inhibition was observed. In conclusion, CA4P caused rapid, temporary tumor vascular shutdown and led to reduction of tumor perfusion in rat brain tumor xenografts and the multiple tumor approach should lead to more efficient studies requiring fewer animals and greater consistency.
    Cancer Letters 10/2014; 356(2). DOI:10.1016/j.canlet.2014.09.038 · 5.02 Impact Factor