Bioreductive fluorescent imaging agents: applications to tumour hypoxia

Abstract

Large tumours contain regions with very low intracellular O2 concentrations. Known as hypoxia, this feature of tumours yields a highly reducing environment owing to the presence of numerous oxygen sensitive reductase enzymes. The development of new optical chemosensors for these various reductases presents an ideal approach to visualise areas of hypoxia or highly reducing environments. Critical to the success of such chemosensors is the design of probes containing a bioreductively activated moiety that either ensures the selective retention of fluorescence within a hypoxic tissue or a probe that irreversibly releases a reporter fluorophore. This Feature Article aims to summarise the fluorescent tools that have been developed to image tumour hypoxia and the various reductase enzymes associated with the bioreduction process.

Hypoxia-activated NIR photosensitizer anchoring in the mitochondria for photodynamic therapy

“…Nitroreductase (NTR) is a well-known specic enzyme overexpressed in solid tumours due to the hypoxic microenvironment which can effectively reduce the nitroaromatic to the corresponding arylamine by using reduced nicotinamide adenine dinucleotide (NADH) as an electron donor. 29,30 Based on this reduction reaction, many nitroaromatic decorated probes have been developed for hypoxia imaging. [31][32][33][34][35] Li's group proved that nitroreductase was over-expressed when the O 2 concentration was below 10% and the para-nitro benzoate group was an ideal substrate for NTR with a fast response, high sensitivity and excellent selectivity because of the strong hydrogen-bonding interaction and spatial match 31 Herein, a hypoxia-activated photosensitizer ICy-N was designed, not only for hypoxic imaging, but also for PDT of cancer cells under hypoxic conditions, by decorating hemicyanine dye Cy-OH with 4-nitrobenzyl bromide as the recognition site and the introduction of iodine into the indole ring was used to improve the intersystem crossing (ISC) process so as to increase singlet oxygen production.…”

Adverse Effect of the Neuronal Cells and the Coronary Artery Endothelium in Extreme Environments- Roles of Advanced Molecular Imaging Bio-Imaging Markers

“…The contemporaneous approach via the enhancement of the fluorescence of organic molecules could signal the intramolecular modification that occurs in the hypoxic environment (41) For instance, the use of hypoxia-sensitive chemical functionalities, such as nitroaromatic, quinone, or azobenzene groups, has been used to develop hypoxia-sensitive ON/OFF FRET molecular probes. Other molecular probes for hypoxia, i.e., intracellular reduction of nitroaryl compounds, are inhibited by molecular oxygen that can be used to assess the level of intracellular oxygen present (42). The myocardial perfusion imaging with 82Rb PET would provide substantial information of the early changes of the myocardial perfusion of the myocardium in coronary artery disease (43).…”

Strategies for Tumor Hypoxia Imaging Based on Aggregation‐Induced Emission Fluorogens

“…Because of NTR, azoreductase, and DT‐diaphorase overexpression in the tumor hypoxic microenvironment, tumor hypoxia imaging fluorescent probes based on conventional fluorophores sensitive to these enzymes have been reported . The main principle to design the hypoxia‐responsive fluorescent probe is to attach a hypoxia‐responsive moiety as a marker to the fluorescent molecule, such as nitro and azo groups.…”

“…Because of NTR, azoreductase, and DT-diaphorase overexpression in the tumor hypoxicm icroenvironment, tumor hypoxia imaging fluorescent probesb ased on conventional fluorophores sensitive to these enzymes have been reported. [26][27][28][29] The main principle to designt he hypoxia-responsive fluorescent probe is to attach ah ypoxia-responsive moiety as a marker to the fluorescent molecule, such as nitro and azo groups.T his sectionf ocuses on typical samples of hypoxia-responsivef luorescent probes based on conventional fluorophores for hypoxia imaging, which can be instructive for the construction of hypoxia-responsive AIE probes.…”