Abstract
Hypoxia has been identified as one of the hallmarks of tumor environments and a prognosis factor in many cancers. The development of ideal chemical probes for imaging and sensing of hypoxia remains elusive. Crucial characteristics would include a measurable response to subtle variations of pO2 in living systems and an ability to accumulate only in the areas of interest (e.g., targeting hypoxia tissues) whilst exhibiting kinetic stabilities in vitro and in vivo. A sensitive probe would comprise platforms for applications in imaging and therapy for non-communicable diseases (NCDs) relying on sensitive detection of pO2. Just a handful of probes for the in vivo imaging of hypoxia [mainly using positron emission tomography (PET)] have reached the clinical research stage. Many chemical compounds, whilst presenting promising in vitro results as oxygen-sensing probes, are facing considerable disadvantages regarding their general application in vivo. The mechanisms of action of many hypoxia tracers have not been entirely rationalized, especially in the case of metallo-probes. An insight into the hypoxia selectivity mechanisms can allow an optimization of current imaging probes candidates and this will be explored hereby. The mechanistic understanding of the modes of action of coordination compounds under oxygen concentration gradients in living cells allows an expansion of the scope of compounds toward in vivo applications which, in turn, would help translate these into clinical applications. We summarize hereby some of the recent research efforts made toward the discovery of new oxygen sensing molecules having a metal-ligand core. We discuss their applications in vitro and/or in vivo, with an appreciation of a plethora of molecular imaging techniques (mainly reliant on nuclear medicine techniques) currently applied in the detection and tracing of hypoxia in the preclinical and clinical setups. The design of imaging/sensing probe for early-stage diagnosis would longer term avoid invasive procedures providing platforms for therapy monitoring in a variety of NCDs and, particularly, in cancers.
Highlights
Non-communicable diseases (NCDs) account for over two thirds of annual deaths worldwide, reaching epidemic proportions and imposing a significant burden to all public health systems and economies
International efforts and collaboration between countries and organizations were deemed necessary in the development of efficient detection, screening and treatment strategies to address NCDs according to the World Health Organization (WHO)1 (Daar et al, 2007)
In the mid-term global action plan to reduce the occurrence of these diseases, the WHO identified several action points which include engaging with leaders, strengthening health systems, modifying unhealthy behaviors, encouraging research and monitoring progress to prevent and control the proliferation of NCDs (Daar et al, 2007
Summary
Non-communicable diseases (NCDs) account for over two thirds of annual deaths worldwide, reaching epidemic proportions and imposing a significant burden to all public health systems and economies. We summarize the current research efforts available in the public domain toward designing and testing oxygen responsive molecules and the application of fluorescence detection for characterization in vitro or in vivo thanks to near-infrared (NIR) emission This is followed by a summary of the molecular imaging techniques applied in the detection and measurement of hypoxia in the preclinical and clinical setup and which rely frequently on nuclear medicine techniques such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). The reduction of the quinone units leads to the formation of the hydroquinones, which are, in comparison, deemed to be electron donor species and unable to quench the emission of the fluorophore (Nohl et al, 1986) By using this strategy, Komatsu and Agira designed a fluorescent ubiquinonerhodol derivative (UQ-Rh) as a probe for NAD(P)H (Figure 6). Several aspects on the use of FRET biosensors for optical signaling of biological processes have been extensively reviewed (Müller et al, 2013; Kaestner et al, 2015; Stumpf and Hoffmann, 2016; Alam et al, 2017; Bohórquez-Hernández et al, 2017; Zheng et al, 2017; Ujlaky-Nagy et al, 2018)
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