A biotinylated piperazine-rhodol derivative: a ‘turn-on’ probe for nitroreductase triggered hypoxia imaging

Zhou, Ying; Bobba, Kondapa Naidu; Lv, Xue; Yang, Dan; Velusamy, Nithya; Zhang, Jun Feng; Bhuniya, Sankarprasad

doi:10.1039/c6an02107g

Cited by 50 publications

(18 citation statements)

References 30 publications

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“…[1][2][3][4] However,u nlike fluoresceins and rhodamines, the structures of rhodolsa re charge-neutral and unsymmetric. This characteristic featurei mparts rhodols with useful applications as fluorescent probes in the context of, for example, monitoring H + and metal ions, [5,6] biological thiols, [7] reactive oxygen or nitrogen species, [8] enzymatic activity, [9,10] and the cell membrane potential [11] in living cells.…”

mentioning

confidence: 99%

Selective Conversion of P=O‐Bridged Rhodamines into P=O‐Rhodols: Solvatochromic Near‐Infrared Fluorophores

Grzybowski

Taki

Yamaguchi

2017

Chemistry A European J

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The substitution of an oxygen atom in rhodols with a phosphine oxide (P=O) moiety affords P=O-bridged rhodols as a new type of near-infrared (NIR) fluorophore. This compound class can be readily accessed upon exposure of the corresponding rhodamines to aqueous basic conditions. The electron-withdrawing effect of the P=O group facilitates the hydrolytic deamination, and, moreover, prolonged exposure to aqueous basic conditions generates P=O-bridged fluoresceins, that is, a series of three P=O-bridged xanthene dyes is available in one simple operation. The P=O-bridged rhodols show significant bathochromic shifts of the longest-wavelength absorption maximum (Δλ=125 nm; >3600 cm ) upon changing the solvent from toluene to water, whereas the emission is shifted less drastically (Δλ=70 nm; 1600 cm ). The hydrogen bonding between the P=O and C=O groups with protic solvents results in substantial stabilization of the LUMO level, which is responsible for the solvatochromism.

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confidence: 99%

Selective Conversion of P=O‐Bridged Rhodamines into P=O‐Rhodols: Solvatochromic Near‐Infrared Fluorophores

Grzybowski

Taki

Yamaguchi

2017

Chemistry A European J

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“…A range of different acceptor moieties have been employed for tumor hypoxia sensing, including nitro-substituents, azo linkages, boronate esters, and N-oxides. [104][105][106][107] Nitro-Group-Based Designs: Nitro-group-based PeT imaging probes are the most popular reductive moieties used in tumor hypoxia sensing and they include a range of nitroderivatives such as nitrobenzyl, [108][109][110][111] nitrobenzene, [112,113] and nitroimidazole. [114,115] The nitro group in these nitro-derivatives is reduced by NTRs to form electron-donating hydroxyl or amino group.…”

Section: Petmentioning

confidence: 99%

Nano versus Molecular: Optical Imaging Approaches to Detect and Monitor Tumor Hypoxia

Cheng

Zheng

2020

Adv Healthcare Materials

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Hypoxia is a ubiquitous feature of solid tumors, which plays a key role in tumor angiogenesis and resistance development. Conventional hypoxia detection methods lack continuous functional detection and are generally less suitable for dynamic hypoxia measurement. Optical sensors hereby provide a unique opportunity to noninvasively image hypoxia with high spatiotemporal resolution and enable real‐time detection. Therefore, these approaches can provide a valuable tool for personalized treatment planning against this hallmark of aggressive cancers. Many small optical molecular probes can enable analyte triggered response and their photophysical properties can also be fine‐tuned through structural modification. On the other hand, optical nanoprobes can acquire unique intrinsic optical properties through nanoconfinement as well as enable simultaneous multimodal imaging and drug delivery. Furthermore, nanoprobes provide biological advantages such as improving bioavailability and systemic delivery of the sensor to enhance bioavailability. This review provides a comprehensive overview of the physical, chemical, and biological analytes for cancer hypoxia detection and focuses on discussing the latest nano‐ and molecular developments in various optical imaging approaches (fluorescence, phosphorescence, and photoacoustic) in vivo. Finally, this review concludes with a perspective toward the potentials of these optical imaging approaches in hypoxia detection and the challenges with molecular and nanotechnology design strategies.

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“…[10][11][12][13][14] On the other hand, optical imaging techniques, such as fluorescence imaging, is a noninvasive imaging technique that is well-suited for imaging tumor hypoxia particularly because such modality affords high sensitivity, high spatiotemporal resolution, and multiplexing capabilities. [15][16][17][18][19] Other fluorescence optical imaging constructs designed for hypoxia imaging suffer from the drawbacks of photophysical and physicochemical deficiencies that limit their efficacy, such as inherently bearing nonneutral net charges that could prevent cell membrane translocation, and therefore are ill-suited for such purpose. 15,[20][21][22][23][24] To overcome such drawbacks, we recently implemented a rational design strategy to develop a hypoxia-sensitive near-infrared (NIR) fluorescent smart probe (NO 2 -Rosol) that is activatable via bioreductive activation afforded by the nitroreductase (NTR) class of enzymes, whose reductive activity toward the nitro group of nitroaromatic moieties could negatively correlate to oxygenation levels.…”

Section: Introductionmentioning

confidence: 99%

“… 10 , 11 , 12 , 13 , 14 On the other hand, optical imaging techniques, such as fluorescence imaging, is a noninvasive imaging technique that is well‐suited for imaging tumor hypoxia particularly because such modality affords high sensitivity, high spatiotemporal resolution, and multiplexing capabilities. 15 , 16 , 17 , 18 , 19 Other fluorescence optical imaging constructs designed for hypoxia imaging suffer from the drawbacks of photophysical and physicochemical deficiencies that limit their efficacy, such as inherently bearing non‐neutral net charges that could prevent cell membrane translocation, and therefore are ill‐suited for such purpose. 15 , 20 , 21 , 22 , 23 , 24 …”

Section: Introductionmentioning

confidence: 99%

A NIR fluorescent smart probe for imaging tumor hypoxia

et al. 2021

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Background: Tumor hypoxia is a characteristic of paramount importance due to low oxygenation levels in tissue negatively correlating with resistance to traditional therapies. The ability to noninvasively identify such could provide for personalized treatment(s) and enhance survival rates. Accordingly, we recently developed an NIR fluorescent hypoxia-sensitive smart probe (NO 2 -Rosol) for identifying hypoxia via selectively imaging nitroreductase (NTR) activity, which could correlate to oxygen deprivation levels in cells, thereby serving as a proxy. We demonstrated proof of concept by subjecting a glioblastoma (GBM) cell line to extreme stress by evaluating such under radiobiological hypoxic (pO 2 ≤ ~0.5%) conditions, which is a far cry from representative levels for hypoxia for brain glioma (pO 2 = ~1.7%) which fluctuate little from physiological hypoxic (pO 2 = 1.0-3.0%) conditions.Aim: We aimed to evaluate the robustness, suitability, and feasibility of NO 2 -Rosol for imaging hypoxia in vitro and in vivo via assessing NTR activity in diverse GBM models under relevant oxygenation levels (pO 2 = 2.0%) within physiological hypoxic conditions that mimic oxygenation levels in GBM tumor tissue in the brain. Methods:We evaluated multiple GBM cell lines to determine their relative sensitivity to oxygenation levels via measuring carbonic anhydrase IX (CAIX) levels, which is a surrogate marker for indirectly identifying hypoxia by reporting on oxygen deprivation levels and upregulated NTR activity. We evaluated for hypoxia via measuring NTR activity when employing NO 2 -Rosol in in vitro and tumor hypoxia imaging studies in vivo.Results: The GBM39 cell line demonstrated the highest CAIX expression under hypoxic conditions representing that of GBM in the brain. NO 2 -Rosol displayed an 8-fold fluorescence enhancement when evaluated in GBM39 cells (pO 2 = 2.0%), thereby establishing its robustness and suitability for imaging hypoxia under relevant physiological conditions. We demonstrated the feasibility of NO 2 -Rosol to afford tumor hypoxia imaging in vivo via it demonstrating a tumor-to-background of 5 upon (i) diffusion throughout, (ii) bioreductive activation by NTR activity in, and (iii) retention within, GBM39 tumor tissue.

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A biotinylated piperazine-rhodol derivative: a ‘turn-on’ probe for nitroreductase triggered hypoxia imaging

Cited by 50 publications

References 30 publications

Selective Conversion of P=O‐Bridged Rhodamines into P=O‐Rhodols: Solvatochromic Near‐Infrared Fluorophores

Selective Conversion of P=O‐Bridged Rhodamines into P=O‐Rhodols: Solvatochromic Near‐Infrared Fluorophores

Nano versus Molecular: Optical Imaging Approaches to Detect and Monitor Tumor Hypoxia

A NIR fluorescent smart probe for imaging tumor hypoxia

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