Photoacoustic imaging (PAI) is an emerging tool that bridges the traditional depth limits of ballistic optical imaging and the resolution limits of diffuse optical imaging. Using the acoustic waves generated in response to the absorption of pulsed laser light, it provides noninvasive images of absorbed optical energy density at depths of several centimeters with a resolution of ∼100 μm. This versatile and scalable imaging modality has now shown potential for molecular imaging, which enables visualization of biological processes with systemically introduced contrast agents. Understanding the relative merits of the vast range of contrast agents available, from small-molecule dyes to gold and carbon nanostructures to liposome encapsulations, is a considerable challenge. Here we critically review the physical, chemical and biochemical characteristics of the existing photoacoustic contrast agents, highlighting key applications and present challenges for molecular PAI.

Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing ‘translational gaps’ through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored ‘roadmap’. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use.

Dynamic nuclear polarization is an emerging technique for increasing the sensitivity of magnetic resonance imaging and spectroscopy, particularly for low-g nuclei. The technique has been applied recently to a number of 13 C-labeled cell metabolites in biological systems: the increase in signal-to-noise allows the spatial distribution of an injected molecule to be imaged as well as its metabolic product or products. This review highlights the most significant molecules investigated to date in preclinical cancer models, either in terms of their demonstrated metabolism in vivo or the biological processes that they can probe. Key words: hyperpolarized carbon-13; dynamic nuclear polarization; imaging; metabolism; tumor; pyruvateThe application of magnetic resonance in medicine has been dominated by imaging of tissue anatomy. However, one of the great strengths of magnetic resonance (MR) is spectroscopy, which allows imaging of tissue biochemistry; this was recognized in the earliest applications of MR to intact biological systems (1). Although magnetic resonance imaging (MRI) has become a routine clinical tool, the use of magnetic resonance spectroscopy (MRS) in patients has lagged far behind; this has been primarily due to a lack of sensitivity, which leads to long measurement times and poor image resolution (2-5). In spite of this, 1 H-MRS measurements of cellular metabolites in a variety of tumor types have been shown to provide a sensitive means to diagnose disease and detect response to treatment (2-4). However, these measurements generally give a static picture of cellular metabolism.In contrast, 13 C-MRS measurements of cellular metabolism in systems incubated with 13 C-labeled cell substrates give a dynamic, and therefore potentially more useful, measurement of tissue metabolism (6-8). For example, dynamic measurements of 13 C-labeled glucose incorporation into muscle glycogen have been used to dissect the relative importance of glucose transport and hexokinase and glycogen synthase activity in controlling muscle glycogen synthesis (9). However, the problem of low sensitivity is even more acute in the case of 13 C-MRS. Dynamic nuclear polarization (DNP or hyperpolarization) of 13 C-labeled cell substrates enhances their sensitivity to detection by >10 4 -fold (10,11). Subsequent spectroscopic imaging of their metabolism following intravenous injection offers a solution to the problem of low sensitivity and has the potential to make dynamic metabolic imaging using MRS a routine clinical application.There have been a number of recent review articles and book chapters on this subject (12-17), and therefore, the purpose of this brief review is to: highlight those DNP substrates that have shown the greatest promise for oncological applications in vivo; summarize the biochemical mechanisms responsible for label transfer from pyruvate to other metabolites in tumors; and finally provide an overview of the main challenges in label detection and imaging and how these may be addressed. PROMISING SUBSTRATES FOR HYPERPOLA...