Enzymatic single-electron reduction and aerobic cytotoxicity of tirapazamine and its 1-oxide and nor-oxide metabolites

Šarlauskas, Jonas; Nemeikaitė-Čėnienė, Aušra; Maroziene, Audroné; Misevičienė, Lina; Lesanavičius, Mindaugas; Čėnas, Narimantas

doi:10.6001/chemija.v29i4.3843

Cited by 6 publications

(5 citation statements)

References 19 publications

(26 reference statements)

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“…For electron transfer to occur, an electron must be transported from the Si-QD conduction band to the available levels (which must be positive with respect to the reduction potential of the QD conduction band) [19] of the nearby NACs. The effectiveness of this process should be greater for DNT than for NB, due to its lower reduction potential [40], consistent with the smaller LoDs observed for DNT in the present work. Depending on the intervening groups, this process can occur over large donor-acceptor separations [41].…”

Section: Mechanismssupporting

confidence: 90%

Detection of nitroaromatics in the solid, solution, and vapor phases using silicon quantum dot sensors

et al. 2016

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Silicon quantum dots (Si-QDs) represent a well-known QD fluorophore that can emit throughout the visible spectrum depending on the interface structure and surface functional group. Detection of nitroaromatic compounds by monitoring the luminescence response of the sensor material (typically fluorescent polymers) currently forms the basis of new explosives sensing technologies. Freestanding silicon QDs may represent a benign alternative with a high degree of chemical and physical versatility. Here, we investigate dodecyl and amine-terminated Si-QD luminescence response to the presence of nitrobenzene and dinitrotoluene (DNT) in various solid, solution, and vapor forms. For dinitrotoluene vapor the 3σ detection limit was 6 ppb for monomer-terminated QDs. For nitroaromatics dissolved in toluene the detection limit was on the order of 400 nM, corresponding to ∼100 pg of material distributed over ∼1 cm(2) on the sensor surface. Solid traces of nitroaromatics were also easily detectable via a simple 'touch test'. The samples showed minimal interference effects from common contaminants such as water, ethanol, and acetonitrile. The sensor can be as simple and inexpensive as a small circle of filter paper dipped into a QD solution, with a single vial of QDs able to make hundreds of these sensors. Additionally, a trial fiber-optic sensor device was tested by applying the QDs to one end of a 2 × 2 fiber coupler and exposing them to controlled DNT vapor. Finally, the quenching mechanism was explored via luminescence dynamics measurements and is different for blue (amine) and red (dodecyl) fluorescent silicon QDs.

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Section: Mechanismssupporting

confidence: 90%

Detection of nitroaromatics in the solid, solution, and vapor phases using silicon quantum dot sensors

et al. 2016

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“…3 a. These results further proved that TPZ can be activated under hypoxic conditions and enter the nucleus more effectively, which may exert drug activity more efficiently to hypoxic tumors [ 34 ]. In addition, the cellular Cu content after incubation with GPPCT and G m PCT nanoplatforms was measured by ICP-OES in Fig.…”

Section: Resultsmentioning

confidence: 81%

A tumor microenvironment-responsive poly(amidoamine) dendrimer nanoplatform for hypoxia-responsive chemo/chemodynamic therapy

et al. 2022

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Background Chemodynamic therapy is a promising cancer treatment with specific therapeutic effect at tumor sites, as toxic hydroxyl radical (·OH) could only be generated by Fenton or Fenton-like reaction in the tumor microenvironment (TME) with low pH and high level of endogenous hydrogen peroxide. However, the low concentration of catalytic metal ions, excessive glutathione (GSH) and aggressive hypoxia at tumor site seriously restrict the curative outcomes of conventional chemodynamic therapy. Results In this study, polyethylene glycol-phenylboronic acid (PEG-PBA)-modified generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers were synthesized as a targeted nanocarrier to chelate Cu(II) and then encapsulate hypoxia-sensitive drug tirapazamine (TPZ) by the formation of hydrophobic Cu(II)/TPZ complex for hypoxia-enhanced chemo/chemodynamic therapy. The formed G5.NHAc-PEG-PBA@Cu(II)/TPZ (GPPCT) nanoplatform has good stability and hemocompatibility, and could release Cu(II) ions and TPZ quickly in weakly acidic tumor sites via pH-sensitive dissociation of Cu(II)/TPZ. In vitro experiments showed that the GPPCT nanoplatforms can efficiently target murine breast cancer cells (4T1) cells overexpressing sialic acid residues, and show a significantly enhanced inhibitory effect on hypoxic cells by the activation of TPZ. The excessive GSH in tumors could be depleted by the reduction of Cu(II) to Cu(I), and abundant of toxic ·OH would be generated in tumor cells by Fenton reaction for chemodynamic therapy. In vivo experiments demonstrated that the GPPCT nanoplatform could specifically accumulate at tumors, effectively inhibit the growth and metastasis of tumors by the combination of CDT and chemotherapy, and be metabolized with no systemic toxicity. Conclusions The targeted GPPCT nanoplatform may represent an effective model for the synergistic inhibition of different tumor types by hypoxia-enhanced chemo/chemodynamic therapy. Graphical Abstract

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“…3a. This should be ascribed to that hypoxia-responsive TPZ can be activated under hypoxic conditions and enter the nucleus more effectively, which may exert drug activity more e ciently to hypoxic tumors [30]. In addition, the cellular Cu content after incubation with GPPCT and GmPCT nanoplatforms were also measured by ICP-OES in Fig.…”

Section: Resultsmentioning

confidence: 99%

A Tumor Microenvironment-Responsive Poly(amidoamine) Dendrimer Nanoplatform for Hypoxia-Responsive Chemo/Chemodynamic Therapy

Hao

Gao

Fan

et al. 2021

Preprint

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Background: Chemodynamic therapy is a promising cancer treatment with specific therapeutic effect at tumor sites, since toxic hydroxyl radical (·OH) could only be generated by Fenton or Fenton-like reaction at the tumor microenvironment (TME) with low pH and high endogenous hydrogen peroxide (H2O2). However, the low concentration of catalytic metal ions, excessive glutathione (GSH) and aggressive hypoxia at tumor site seriously restrict its curative outcomes.Results: In this study, polyethylene glycol-phenylboronic acid (PEG-PBA)-modified generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers were synthesized as a targeted nanocarrier to chelate Cu(II) and then encapsulate hypoxia-sensitive drug tirapazamine (TPZ) by the formation of hydrophobic Cu(II)/TPZ complex for hypoxia-enhanced chemo/chemodynamic therapy. The formed G5.NHAc-PEG-PBA@Cu(II)/TPZ (GPPCT) with good stability could be specifically accumulated at tumors, efficiently taken up by tumor cells overexpressing sialic acid residues, and release Cu(II) ions and TPZ quickly in weakly acidic tumor sites via pH-sensitive dissociation of Cu(II)/TPZ. In vitro and in vivo experiments using murine breast cancer cells (4T1) demonstrated that the GPPCT nanoplatform could efficiently generate toxic ·OH in tumor cells while simultaneously deplete GSH, effectively kill hypoxic tumor cells by activated TPZ radicals, reduce tumor metastasis, and show no significant systemic toxicity.Conclusions: The targeted GPPCT nanoplatform may be developed for the synergistic inhibition of different tumor types by hypoxia-enhanced chemo/chemodynamic therapy.

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Enzymatic single-electron reduction and aerobic cytotoxicity of tirapazamine and its 1-oxide and nor-oxide metabolites

Cited by 6 publications

References 19 publications

Detection of nitroaromatics in the solid, solution, and vapor phases using silicon quantum dot sensors

Detection of nitroaromatics in the solid, solution, and vapor phases using silicon quantum dot sensors

A tumor microenvironment-responsive poly(amidoamine) dendrimer nanoplatform for hypoxia-responsive chemo/chemodynamic therapy

A Tumor Microenvironment-Responsive Poly(amidoamine) Dendrimer Nanoplatform for Hypoxia-Responsive Chemo/Chemodynamic Therapy

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