An activatable NIR fluorescent rosol for selectively imaging nitroreductase activity

Klockow, Jessica; Hettie, Kenneth S.; LaGory, Edward L.; Moon, Eui Jung; Giaccia, Amato J.; Graves, Edward E.; Chin, Frederick T.

doi:10.1016/j.snb.2019.127446

Cited by 31 publications

(19 citation statements)

References 43 publications

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“…A number of activatable NIR FL probes (e.g., 7 ‒ 9 ) have been successfully obtained by means of the nitro‐to‐amino transformation strategy, demonstrating the feasibility of this means. [ 44–49 ]…”

Section: Advances Of Enzyme‐activatable Optical Probesmentioning

confidence: 99%

“…Recently, quite a few NTR-activatable optical probes or theranostic systems have been reported. [38][39][40][41][42][43][44][45][46][47][48][49] The general working mechanisms are summarized in Figure 4.…”

Section: Reductasementioning

confidence: 99%

“…A number of activatable NIR FL probes (e.g., 7-9) have been successfully obtained by means of the nitro-to-amino transformation strategy, demonstrating the feasibility of this means. [44][45][46][47][48][49] The work shown in Figure 5 is a good example to the strategy I. The nanoprobe developed by Zeng and Wu et al through the self-assembly of Q-NO 2 (i.e., compound 10) is NTR-activatable for the imaging of breast cancer metastases via NIR-I/NIR-II FL imaging and MSOT imaging.…”

Section: Reductasementioning

confidence: 99%

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Most recent advances on enzyme‐activatable optical probes for bioimaging

Mei

Tian

2021

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Enzymes are essential biological elements that play vital roles in many key cellular events and physiological processes. The dysregulation of enzyme activity broadly occurs in a large number of diseases ranging from inflammation to neurodegenerative disorders to tumors. Molecular imaging allows accurate and noninvasive visualization of biological analytes/physiological processes of interest closely linked to human health at different levels. Among various imaging modalities, optical imaging stands out benefited from its high sensitivity, excellent spatiotemporal resolution, real‐time mode, and facile accessibility. Diverse optical probes specifically activatable by disease‐relevant enzymes have sprung up. In comparison to the “always‐on” counterparts, the “off‐on” imaging probes activated by enzymes hold great promise for precise diagnosis of diseases at early stage with high target‐to‐background ratio, dramatically improved specificity, and significantly enhanced sensitivity. Herein, the most recent advances in optical probes activatable by enzymes for biosensing and bioimaging are briefly reviewed emphasizing their molecular design, working mechanism, and biomedical applications. Besides, some important prospects and the current challenges to fully implement the potential of enzyme‐activatable probes for precise and efficient theranostics in life science are also pointed out to hopefully arouse new insights into the development of new generation of theranostics.

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Section: Advances Of Enzyme‐activatable Optical Probesmentioning

confidence: 99%

Section: Reductasementioning

confidence: 99%

Section: Reductasementioning

confidence: 99%

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Most recent advances on enzyme‐activatable optical probes for bioimaging

Mei

Tian

2021

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“…NTR activity is important as a therapeutic target for biological detoxification of nitroaromatic compounds and related diseases [ 3 ]. NTR activity is especially significantly increased in hypoxic tumors and various cancers such as cervical, breast, liver, and lung cancers [ 4 ], indicating that NTR is a potential theranostic target for cancer [ 5 , 6 ]. Indeed, a method capable of the accurate and spatiotemporal detection of NTR-mediated enzyme reaction in the human live cells is an important key technology for the development of theranostics.…”

Section: Introductionmentioning

confidence: 99%

Ratiometric Fluorescence Assay for Nitroreductase Activity: Locked-Flavylium Fluorophore as a NTR-Sensitive Molecular Probe

Kim

Yoon

et al. 2021

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Nitroreductases belong to a member of flavin-containing enzymes that can reduce nitroaromatic compounds to amino derivatives with NADH as an electron donor. NTR activity is known to be elevated in the cancerous environment and is considered an advantageous target in therapeutic prodrugs for the treatment of cancer. Here, we developed a ratiometric fluorescent molecule for observing NTR activity in living cells. This can provide a selective and sensitive response to NTR with a distinct increase in fluorescence ratio (FI530/FI630) as well as color changes. We also found a significant increase in NTR activity in cervical cancer HeLa and lung cancer A549 cells compared to non-cancerous NIH3T3. We proposed that this new ratiometric fluorescent molecule could potentially be used as a NTR-sensitive molecular probe in the field of cancer diagnosis and treatment development related to NTR activity.

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“…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. 25 NO 2 -Rosol is a nitrated congener of THQ-Rosol, which itself derives from the rosol molecular platform. 26 As such, NO 2 -Rosol contains a xanthene core-based scaffold that is synthesized from the methyoxybenzene-based tetrahydroquinoxaline (THQ) moiety beginning with a Friedel-Crafts acylation using the acyl chloride of 3-nitrobenzene followed by an intermolecular condensation with resorcinol.…”

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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An activatable NIR fluorescent rosol for selectively imaging nitroreductase activity

Cited by 31 publications

References 43 publications

Most recent advances on enzyme‐activatable optical probes for bioimaging

Most recent advances on enzyme‐activatable optical probes for bioimaging

Ratiometric Fluorescence Assay for Nitroreductase Activity: Locked-Flavylium Fluorophore as a NTR-Sensitive Molecular Probe

A NIR fluorescent smart probe for imaging tumor hypoxia

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