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Second near-infrared (NIR-II) fluorescence imaging is the most advanced imaging fidelity method with extraordinary penetration depth, signal-to-background ratio, biocompatibility, and targeting ability. It is currently booming in the medical realm to diagnose tumors and is being widely applied for fluorescence-imaging-guided tumor surgery. To efficiently execute this modern imaging modality, scientists have designed various probes capable of showing fluorescence in the NIR-II window. Here, we update the state-of-the-art NIR-II fluorescent probes in the most recent literature, including indocyanine green, NIR-II emissive cyanine dyes, BODIPY probes, aggregation-induced emission fluorophores, conjugated polymers, donor–acceptor–donor dyes, carbon nanotubes, and quantum dots for imaging-guided tumor surgery. Furthermore, we point out that the new materials with fluorescence in NIR-III and higher wavelength range to further optimize the imaging results in the medical realm are a new challenge for the scientific world. In general, we hope this review will serve as a handbook for researchers and students who have an interest in developing and applying fluorescent probes for NIR-II fluorescence-imaging-guided surgery and that it will expedite the clinical translation of the probes from bench to bedside.

Sigma receptor (σR) ligands have proven to be useful as cancer diagnostics and anticancer therapeutics and their ligands have been developed as molecular probes in oncology. Moreover, various σR ligands generate cancer cell death in vitro and in vivo. These σR ligands have exhibited promising results against numerous human and rodent cancers and are investigated under preclinical and clinical study trials, indicating a new category of drugs in cancer therapy.

Hydrogen peroxide (H₂O₂) is an incompletely reduced metabolite of oxygen that has a diverse array of physiological and pathological effects within living cells depending on the extent, timing, and location of its production. Characterization of the cellular functions of H₂O₂ requires measurement of its concentration selectively in the presence of other oxygen metabolites and with spatial and temporal fidelity in live cells. For the measurement of H₂O₂ in biological fluids, several sensitive methods based on horseradish peroxidase and artificial substrates (such as Amplex Red and 3,5,3'5'-tetramethylbenzidine) or on ferrous oxidation in the presence of xylenol orange (FOX) have been developed. For measurement of intracellular H₂O₂, methods based on dihydro compounds such as 2',7'-dichlorodihydrofluorescein that fluoresce on oxidation are used widely because of their sensitivity and simplicity. However, such probes react with a variety of cellular oxidants including nitric oxide, peroxynitrite, and hypochloride in addition to H₂O₂. Deprotection reaction-based probes (PG1 and PC1) that fluoresce on H₂O₂-specific removal of a boronate group rather than on nonspecific oxidation have recently been developed for selective measurement of H₂O₂ in cells. Furthermore, a new class of organelle-targetable fluorescent probes has been devised by joining PG1 to a substrate of SNAP-tag. Given that SNAP-tag can be genetically targeted to various subcellular organelles, localized accumulation of H₂O₂ can be monitored with the use of SNAP-tag bioconjugation chemistry. However, given that both dihydro- and deprotection-based probes react irreversibly with H₂O₂, they cannot be used to monitor transient changes in H₂O₂ concentration. This drawback has been overcome with the development of redox-sensitive green fluorescent protein (roGFP) probes, which are prepared by the introduction of two redox-sensitive cysteine residues into green fluorescent protein; the oxidation of these residues to form a disulfide results in a conformational change of the protein and altered fluorogenic properties. Such genetically encoded probes react reversibly with H₂O₂ and can be targeted to various compartments of the cell, but they are not selective for H₂O₂ because disulfide formation in roGFP is promoted by various cellular oxidants. A new type of H₂O₂-selective, genetically encoded, and reversible fluorescent probe, named HyPer, was recently prepared by insertion of a circularly permuted yellow fluorescent protein (cpYFP) into the bacterial peroxide sensor protein OxyR.

Curcumin, the most important secondary metabolite isolated from Curcuma longa, is known for its numerous purported therapeutic properties and as a natural dye. Herein, based on curcumin’s intrinsic fluorescence, a search for improved curcumin-based fluorophores was conducted. Within the set of semi-synthetic curcumin derivatives i.e. mono (1), di (2), tri (3), tetra (4) benzylated and dibenzyl-fluoroborate (5), the fluorescence properties of 2 and 5 in solution outstood with a two-fold quantum yield compared to curcumin. Furthermore, all benzylated derivatives showed a favorable minimal cytotoxic activity upon screening at 25 μM against human cancer and non-tumoral COS-7 cell lines, with a reduction of its cytotoxic effect related to the degree of substitution. Fluorophores 2 and 5 are versatile bioimaging tools, as revealed by Confocal Fluorescence Microscopy (CFM), and showed permeation of living cell membranes of astrocytes and astrocytomas. When 2 is excited with a 405- (blue) or 543-nm (green) laser, it is possible to exclusively and intensively visualize the nucleus. However, the fluorescence emission fades as the laser wavelength moves towards the red region. In comparison, 5 allows selective visualization of cytoplasm when a 560-nm laser is used, showing emission in the NIR region, while it is possible to exclusively observe the nucleus at the blue region with a 405-nm laser.

A clear identification of the etiology of glomerular disease is essential in patients with diabetes. Renal biopsy is the gold standard for assessing the underlying nephrotic pathology; however, it has the risk for potential complications. Here, we aimed to investigate the feasibility of urinary fluorescence imaging using an enzyme-activatable probe for differentiating diabetic kidney disease and the other glomerular diseases. Hydroxymethyl rhodamine green (HMRG)-based fluorescent probes targeting gamma-glutamyl transpeptidase (GGT) and dipeptidyl-peptidase (DPP) were used. Urinary fluorescence was compared between groups which were classified by their histopathological diagnoses (diabetic kidney disease, glomerulonephritis, and nephrosclerosis) as obtained by ultrasound-guided renal biopsy. Urinary fluorescence was significantly stronger in patients with diabetic kidney disease compared to those with glomerulonephritis/nephrosclerosis after DPP-HMRG, whereas it was stronger in patients with nephrosclerosis than in patients with glomerulonephritis after GGT-HMRG. Subgroup analyses of the fluorescence performed for patients with diabetes showed consistent results. Urinary fluorescence imaging using enzyme-activatable fluorescence probes thus represents a potential noninvasive assessment technique for kidney diseases in patients with diabetes.

The hypothesis was tested that flavonoids may scavenge singlet oxygen (¹O₂) in mesophyll cells of Phillyrea latifolia exposed to excess-light stress. In cross-sections taken from leaves developed at 10% (shade) or 100% (sun) solar irradiance, we evaluated the excess photosynthetically active radiation (PAR)-induced accumulation of ¹O₂ in mesophyll cells by imaging the fluorescence quenching of the specific ¹O₂ probe N-[2-(diethylamino)ethyl]-N-[(2,5-dihydro-2,2,5,5-tetramethyl-1H-pyrrol-3-yl)methyl]-5-(dimethylamino)-1-naphthalenesulfonamide (DanePy). The intracellular location of flavonoids was also analyzed using three-dimensional deconvolution microscopy. Photo-induced quenching of DanePy fluorescence was markedly greater in the mesophyll of shade leaves than in that of sun leaves, the former showing a negligible accumulation of mesophyll flavonoids. The photo-induced generation of ¹O₂ was inversely related to the content of flavonoids in the mesophyll cells of sun leaves. Flavonoids were located in the chloroplasts, and were likely associated with the chloroplast envelope. Here we provide relevant evidence for the potential scavenger activity of chloroplast-located flavonoids against ¹O₂ and new insights into the photo-protective role of flavonoids in higher plants.

Voltage-gated Na+ (NaV) channels are significant therapeutic targets for the treatment of cardiac and neurological disorders, thus promoting the search for novel NaV channel ligands. With the objective of discovering new blockers of NaV channel ligands, we screened an In-House vegetal alkaloid library using fluorescence cell-based assays. We screened 62 isoquinoline alkaloids (IA) for their ability to decrease the FRET signal of voltage sensor probes (VSP), which were induced by the activation of NaV channels with batrachotoxin (BTX) in GH3b6 cells. This led to the selection of five IA: liriodenine, oxostephanine, thalmiculine, protopine, and bebeerine, inhibiting the BTX-induced VSP signal with micromolar IC50. These five alkaloids were then assayed using the Na+ fluorescent probe ANG-2 and the patch-clamp technique. Only oxostephanine and liriodenine were able to inhibit the BTX-induced ANG-2 signal in HEK293-hNaV1.3 cells. Indeed, liriodenine and oxostephanine decreased the effects of BTX on Na+ currents elicited by the hNaV1.3 channel, suggesting that conformation change induced by BTX binding could induce a bias in fluorescent assays. However, among the five IA selected in the VSP assay, only bebeerine exhibited strong inhibitory effects against Na+ currents elicited by the hNav1.2 and hNav1.6 channels, with IC50 values below 10 µM. So far, bebeerine is the first BBIQ to have been reported to block NaV channels, with promising therapeutical applications.

Near-infrared photoluminescence is intrinsic only to a minority of carbonaceous nanomaterials. Longwave fluorescence is, however, well suited for bio-sensing and bio-imaging owing to the low autofluorescence and low absorbance by biomatter. The authors describe here sulfur doped carbon quantum dots (S-CQDs) and their derivatives (referred to as 3D carbon nanoflowers; S-CNFs). Their average diameters are 2 and 28.5 nm, respectively. They display two emission peaks, one being purple and peaking at 407 nm, the other in the near-infrared and peaking at 780 nm. Quantum yields are 4% for S-CQDs and 6.4% for S-CNFs. The nanoparticles are shown to be viable fluorescent probes for hydrogen peroxide which acts as a quencher. The 3D structure of the S-CNFs and near-infrared detection result in a better linear relationship and lower detection limits. The detection limits for H 2 O 2 are 1.1 μM for S-CQDs, and 0.6 μM for S-CNFs. The results presented here contribute to an improved understanding on how the nanostructure and selection of wavelengths affect the sensitivity and detection limits of such probes. Graphical abstract “Button-up” - synthesized sulfur-doped carbon quantum dots and carbon nanoflowers display two emission peaks, one being purple, the other in the near-infrared. The nanoparticles are shown to be viable fluorescent probes for hydrogen peroxide which acts as a quencher.

Amantadine (AMA) and its derivatives are illicit veterinary drugs that are hard to detect at very low concentrations. Developing a fast, simple and highly sensitive method for the detection of AMA is highly in demand. Here, we designed an anthracyclic compound (ABAM) that binds to a cucurbit[7]uril (CB[7]) host with a high association constant of up to 8.7 × 108 M−1. The host-guest complex was then used as a fluorescent probe for the detection of AMA. Competition by AMA for occupying the cavity of CB[7] allows ABAM to release from the CB[7]-ABAM complex, causing significant fluorescence quenching of ABAM (indicator displacement assay, IDA). The linear range of the method is from 0.000188 to 0.375 μg/mL, and the detection limit can be as low as 6.5 × 10−5 μg/mL (0.35 nM). Most importantly, due to the high binding affinity between CB[7] and ABAM, this fluorescence host-guest system shows great anti-interference capacity. Thus, we are able to accurately determine the concentration of AMA in various samples, including pharmaceutical formulations.

Marine organisms are a rich source of bioactive secondary metabolites. Although many marine natural products with bioactivities have been isolated, successful elucidation of their mechanisms of action remains limited. In this study, we prepared a probe molecule based on the marine cyclic peptide kapakahine A (1) by introducing a linker with an azide terminal group, which enables the introduction of fluorescent groups for the effective monitoring of subcellular localization, or coupling to affinity beads for the pull-down of target proteins. The results of LC/MS/MS measurements, ProteinPilot analysis, and Western blotting suggest that kapakahine A interacts with the mitochondrial inner membrane proteins PHB1, PHB2, and ANT2, which is consistent with the results of the subcellular localization analysis using a fluorescent probe.