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.

Full-text

Available from: Guiyang Hao, May 02, 2014
0 Followers
 · 
93 Views
  • [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
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hypoxia plays an important role in tumour recurrence among head and neck cancer patients. The identification and quantification of hypoxic regions are therefore an essential aspect of disease management. Several predictive assays for tumour oxygenation status have been developed in the past with varying degrees of success. To date, functional imaging techniques employing positron emission tomography (PET) have been shown to be an important tool for both pretreatment assessment and tumour response evaluation during therapy. Hypoxia-specific PET markers have been implemented in several clinics to quantify hypoxic tumour subvolumes for dose painting and personalized treatment planning and delivery. Several new radiotracers are under investigation. PET-derived functional parameters and tracer pharmacokinetics serve as valuable input data for computational models aiming at simulating or interpreting PET acquired data, for the purposes of input into treatment planning or radio/chemotherapy response prediction programs. The present paper aims to cover the current status of hypoxia imaging in head and neck cancer together with the justification for the need and the role of computer models based on PET parameters in understanding patient-specific tumour behaviour.
    Computational and Mathematical Methods in Medicine 08/2014; 2014:624642. DOI:10.1155/2014/624642 · 1.02 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Targeted MRI contrast agents have proven useful in research and clinical studies for highlighting specific metabolites and biomarkers [Davies GL, et al. (2013) Chem Commun (Camb) 49(84):9704-9721] but their applicability in serial imaging is limited owing to a changing concentration postinjection. Solid enclosures have previously been used to keep the local concentration of contrast agent constant, but the need to surgically implant these devices limits their use [Daniel K, et al. (2009) Biosens Bioelectron 24(11):3252-3257]. This paper describes a novel class of contrast agent that comprises a responsive material for contrast generation and an injectable polymeric matrix for structural support. Using this principle, we have designed a contrast agent sensitive to oxygen, which is composed of dodecamethylpentasiloxane as the responsive material and polydimethylsiloxane as the matrix material. A rodent inspired-gas model demonstrated that these materials are functionally stable in vivo for at least 1 mo, which represents an order of magnitude improvement over an injection of liquid siloxane [Kodibagkar VD, et al. (2006) Magn Reson Med 55(4):743-748]. We also observed minimal adverse tissue reactions or migration of contrast agents from the initial injection site. This class of contrast agents, thus, represented a new and complementary method to monitor chronic diseases by MRI.
    Proceedings of the National Academy of Sciences 04/2014; 111(18). DOI:10.1073/pnas.1400015111 · 9.81 Impact Factor