FLUORO/NO: A Nitric Oxide Donor with a Fluorescence Reporter

Ravikumar, Govindan; Bagheri, Meisam; Saini, Deepak Kumar; Chakrapani, Harinath

doi:10.1002/cbic.201700155

Cited by 15 publications

(6 citation statements)

References 39 publications

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“…Therefore, it is desirable to attach a longer wavelength fluorescence reporter. Here, we used the coumarin-based fluorophore strategy that has been previously used to report delivery of a drug or bioactive molecule. , Imaging in the green channel is possible and this fluorophore is also compatible with two-photon imaging . The phenol-based fluorophore needs to be attached to the trigger.…”

Section: Introductionmentioning

confidence: 99%

Targeted Antibacterial Activity Guided by Bacteria-Specific Nitroreductase Catalytic Activation to Produce Ciprofloxacin

et al. 2019

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Fluoroquinolones (FQs) are among the front-line antibiotics used to treat severe infections caused by Gram-negative bacteria. However, recently, due to toxicity concerns, their use has been severely restricted. Hence, efforts to direct delivery of this antibiotic specifically to bacteria/site of infection are underway. Here, we report a strategy that uses a bacterial enzyme for activation of a prodrug to generate the active antibiotic. The ciprofloxacin-latent fluorophore conjugate 1, which is designed as a substrate for nitroreductase (NTR), a bacterial enzyme, was synthesized. Upon activation by NTR, release of Ciprofloxacin (CIP) as well as a fluorescence reporter was observed. We provide evidence for the prodrug permeating bacteria to generate a fluorescent signal and we found no evidence for activation in mammalian cells supporting selectivity of activation within bacteria. As a testament to its efficacy, 1 was found to have potent bactericidal activity nearly identical to CIP and significantly reduced the bacterial burden in a neutropenic mouse thigh infection model, again, at comparable potency with CIP, a clinically used FQ. Thus, together, we have developed a small molecule that facilitates bacteria-specific fluoroquinolone delivery.

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Section: Introductionmentioning

confidence: 99%

Targeted Antibacterial Activity Guided by Bacteria-Specific Nitroreductase Catalytic Activation to Produce Ciprofloxacin

et al. 2019

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“…To overcome this defect, many NO donors have been developed. − It is also difficult to monitor the delivery of NO directly, owing to its high reactivity and short lifetime (usually less than 1 s under physiological conditions). Thus, novel NO donors with a convenient readout signal for monitoring NO release have attracted great attention. − To take advantage of the BH adduct 5 in constructing prodrugs with off–on fluorescence signal upon activation, we further prepared the fluorogenic NO prodrug, AH-NO (Figure A), and evaluated its release and therapeutic potentials.…”

Section: Resultsmentioning

confidence: 99%

Baylis–Hillman Adducts as a Versatile Module for Constructing Fluorogenic Release System

Zhao

Zhang

et al. 2022

J. Med. Chem.

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The controlled release of a molecule of interest (MOI) is useful in probe design, prodrug construction, and drug delivery. We report herein a versatile thiol-triggered fluorogenic release system using the Baylis–Hillman (BH) adducts as a module. Common functional groups (e.g., amino, hydroxyl, carboxylic, and sulfhydryl groups) in a MOI are readily integrated into the module. The MOI release is fast (∼10 min) with a nearly quantitative yield and a >250-fold fluorescence increment. We further prepared two prodrugs to release camptothecin and nitric oxide (NO) using the two-photon excitable template, and the activation of prodrugs was visualized in live cells and mouse tissues. The therapeutic potential of the NO prodrug was also validated in a stroke model. This BH adduct-based fluorogenic release features multiple advantages, such as easy preparation, compatibility of various functional groups, fast response, high release yield, and tunable emission spectra, and is expected to have broad applications.

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“…The concentration of MPND was prepared as 1 mg/mL, and esterase extracted from porcine liver was prepared as 1.77 μg/mL in 100 mL of PBS (10 mM, pH = 7.4 or 6.5). 38 The release of NO could be monitored by Griess reagent to generate a pinkish compound and quantified by UV−vis absorbance at 540 nm.…”

Section: Methodsmentioning

confidence: 99%

“…In order to quantify the released NO concentration at every time point, NaNO 2 (10, 20, 40, 60, 80, and 100 μM) was used to establish a standard curve first. The concentration of MPND was prepared as 1 mg/mL, and esterase extracted from porcine liver was prepared as 1.77 μg/mL in 100 mL of PBS (10 mM, pH = 7.4 or 6.5) . The release of NO could be monitored by Griess reagent to generate a pinkish compound and quantified by UV–vis absorbance at 540 nm.…”

Section: Experimental Sectionmentioning

confidence: 99%

Glutathione-Responsive Biodegradable Nanoplatform with Endogenous Esterase-Triggered Nitric Oxide Release for Gas Therapy and Enhanced Chemotherapy

Zhang

Meng

Gong

et al. 2021

ACS Appl. Bio Mater.

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The potential therapeutic effect of nitric oxide (NO) for cancers has received considerable attention as a "killer" that causes damage to mitochondria and DNA by oxidation or nitrosation. However, the fabrication of an intelligent and controllable NO release system has remained elusive in the desired location to realize selective cancer therapy. Herein, an intelligent endogenous esterase-triggered nitric oxide (NO) generator for synergetic cancer therapy is fabricated by integrating NO prodrug and doxorubicin (DOX) into a single glutathione (GSH)responsive mesoporous silica nanoparticle (MPND). When the MPND is internalized into the cancer cell, the rupture of −S−S− bridges and the degradation of MPND occur in the tumor microenvironment with a high level of GSH, inducing the on-demand release of DOX. Importantly, the high endogenic esterase concentration can activate the prodrug to generate abundant NO, which further enhances the release performance of DOX. In vitro results verify that the release profiles of NO and DOX show the stimuli-responsive dependence of endogenic esterase and GSH, respectively, demonstrating the potential for ondemand release in the cancer cells. Consequently, MPND shows a high antitumor efficiency in MCF-7 cancer cells. Furthermore, using multicellular tumor spheroids to mimic in vivo experiment, MPND can enhance the tumor penetration and therapeutic effect for killing the deep tumor tissue at the central location. Therefore, the endogenous esterase-triggered NO nanogenerators may provide a potential alternative strategy to develop NO-relevant platforms for synergistic cancer therapy.

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FLUORO/NO: A Nitric Oxide Donor with a Fluorescence Reporter

Cited by 15 publications

References 39 publications

Targeted Antibacterial Activity Guided by Bacteria-Specific Nitroreductase Catalytic Activation to Produce Ciprofloxacin

Targeted Antibacterial Activity Guided by Bacteria-Specific Nitroreductase Catalytic Activation to Produce Ciprofloxacin

Baylis–Hillman Adducts as a Versatile Module for Constructing Fluorogenic Release System

Glutathione-Responsive Biodegradable Nanoplatform with Endogenous Esterase-Triggered Nitric Oxide Release for Gas Therapy and Enhanced Chemotherapy

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