Coordination Chemistry Reviews 427 (2021) 213581

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Coordination Chemistry Reviews

journal homepage: www.elsevier.com/locate/ccr

Metal-coordinated fluorescent and luminescent probes for reactive

oxygen species (ROS) and reactive nitrogen species (RNS)
Nahyun Kwon a,1, Dayeh Kim a,1, K.M.K. Swamy a,b, Juyoung Yoon a,⇑
a
Department of Chemistry and Nanoscience, Ewha Womans University, Seoul 03760, South Korea
b
Department of Pharmaceutical Chemistry, V. L. College of Pharmacy, Raichur 584103, India

a r t i c l e i n f o a b s t r a c t

Article history: Reactive oxygen species (ROS) are chemically reactive species containing oxygen, which are produced
Received 8 July 2020 from molecular oxygen (O2) during vital processes occurring in humans and other living organisms.
Received in revised form 31 August 2020 These species include hydrogen peroxide (H2O2), hypochlorous acid/hypochlorite (HOCl/ClO–), hydroxyl
Accepted 31 August 2020
radicals (OH), superoxide anion radicals (O– 1
2 ) and singlet oxygen ( O2). ROS play key roles in various sig-
naling and pathological processes and are essential to human life, but overproduction of ROS by exoge-
nous stimuli is harmful because ROS can induce oxidation of DNA, proteins or lipids, resulting in cell
Keywords:
death. Therefore, unusual ROS levels can indicate ailments such as Parkinson’s and Alzheimer’s diseases,
Reactive oxygen species (ROS)
Reactive nitrogen species (RNS)
inflammation, diabetes and cancer. Reactive nitrogen species (RNS) are another group of important
Fluorescent probes for ROS chemically reactive species, which can damage cells via nitrosative stress. RNS include nitric oxide
Luminescent probes for ROS (NO), nitroxyl (HNO), nitrogen dioxide (NO2) and peroxynitrite (ONOO–). Due to their importance in
Metal coordination human life, research into fluorescent and luminescent sensing and imaging of these ROS and RNS has
been very active over the last couple of decades. Metal ions play key roles in the probes as an on–off redox
switch for photoinduced quenching and as a reaction site with ROS, RNS or luminescent cores. Metal
coordination reports the presence of analyte by changing the fluorescence intensity, lifetime, or excita-
tion/emission maxima. Redox-active metal ions can be trigger switches that control fluorescence quench-
ing effects, which can be used to sense ROS or RNS. In addition, metal ions, especially lanthanide metal
ions, can often be themselves a source of light emission. In this review, we cover ROS- and RNS-selective
fluorescent and luminescent probes based on metal-coordinated systems. This review is organized by the
target ROS or RNS, which are H2O2, HOCl/ClO–, OH, O– 1 –
2 , O2, NO, ONOO , HNO and NO2.
Ó 2020 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. Metal-coordinated fluorescent and luminescent probes for reactive oxygen species (ROS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.1. Fluorescent and luminescent probes for hydrogen peroxide (H2O2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.2. Fluorescent and luminescent probes for hydroxyl radicals (OH). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.3. Fluorescent and luminescent probes for singlet oxygen (1O2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
2.4. Fluorescent and luminescent probes for superoxide anion radical (O2–) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
2.5. Fluorescent and luminescent probes for hypochlorous acid (HOCl) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
3. Metal-coordinated fluorescent and luminescent probes for reactive nitrogen species (RNS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
3.1. Fluorescent and luminescent probes for peroxynitrite (ONOO–) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
3.2. Fluorescent and luminescent probes for nitric oxide (NO) and nitrogen dioxide (NO2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
3.3. Fluorescent and luminescent probes for nitroxyl (HNO) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
4. Summary and outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Declaration of Competing Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

⇑ Corresponding author.
E-mail address: jyoon@ewha.ac.kr (J. Yoon).
1
These authors contributed equally to this work.

https://doi.org/10.1016/j.ccr.2020.213581
0010-8545/Ó 2020 Elsevier B.V. All rights reserved.
N. Kwon et al.
1. Introduction
Chemically reactive oxygen-containing species, or reactive oxy-
gen species (ROS), are produced from molecular oxygen (O2) dur-
ing vital processes occurring in humans and other living
organisms [1]. Mitochondrial respiration is a major endogenous
process for generating these species [2]. The NOX pathway is
another relevant endogenous process, as it generates ROS for
immune cell signaling when stimulated [3].
ROS can also be generated by exposure to infections, UV light
and other deleterious factors. ROS are essential to human life and
play key roles in various signaling and pathological processes,
but overproduced ROS from exogenous stimuli can cause cell death
by inducing oxidation of DNA, proteins or lipids [4]. Therefore, the
amount of ROS can be a sign of various diseases, such as Alzhei-
mer’s disease, Parkinson’s disease, inflammation, diabetes and can-
cer [5]. Cellular redox mechanisms of various ROS and reactive
nitrogen species (RNS) are presented in Fig. 1 [6].
‘Highly reactive oxygen species’ were first reported in 1977 by
Weiss et al. [7]. ROS include hydrogen peroxide (H2O2), hypochlor-
ous acid/hypochlorite (HOCl/ClO–), the hydroxyl radical (OH), the
superoxide anion radical (O– 1
2 ) and singlet oxygen ( O2). The roles
of these ROS and RNS in biology will be briefly explained in the rel-
evant sections. For example, O–2 is the precursor of most ROS and is
formed from O2 by electron reduction by NADPH oxidases or via
the electron transport chain [8]. Disproportionation of O–
2 can form
H2O2, which can decompose to hydroxide and OH [9]. In addition,
myeloperoxidase (MPO) can convert H2O2 to HOCl in the presence
of Cl– [10].
Another important class of chemically reactive species is the set
of reactive nitrogen species (RNS), which can damage cells via
nitrosative stress. RNS include nitric oxide (NO), nitroxyl (HNO),
nitrogen dioxide (NO2) and peroxynitrite (ONOO–) [11]. For exam-
ple, NO can be endogenously generated by nitric oxide synthases,
and failure of NO homeostasis can induce cancer, neurodegenera-
tive diseases and stroke [11]. ONOO–, which is produced from NO
with O–2 , was considered an ROS only after a report by Beckman
in 1990 [12]. Due to its oxidizing and nitrating abilities, ONOO–
also commonly oxidizes DNA, proteins and lipids, which can cause
various cancers, inflammation and neurodegenerative diseases
[13]. Its protonated form (ONOOH, pKa = 6.8) decomposes to NO2
and OH. HNO is both the protonated form of NO and the one-
electron reduced form of NO.
O2
GSSG
GS
GSH
OH GS
O2
GSOO
Fe3+/Cu2+
NO3
ascorbate
OH N 2O 3
Fe2+/Cu+ ONOOH
NO
NO2
NO
HOCl Cl
MPO H O ONOO
2 2
CO2
NO2 NO2 O2 ONOOCO2
2e
e
mitochondria, NADPH oxidases, redox cycling of xenobiotics
Fig. 1. Cellular redox mechanisms of various reactive oxygen species (ROS) and
reactive nitrogen species (RNS). Modified with Copyright 2018 Elsevier B.V.
Coordination Chemistry Reviews 427 (2021) 213581
Fluorescent and luminescent probes are an inevitable solution
to the issue of tracking a specific ROS or RNS to study its key mech-
anisms in living organisms. Detecting and imaging these ROS and
RNS with fluorescent and luminescent compounds has been a
highly active area of research for the last couple of decades due
to the importance of ROS and RNS to human life [14–17]. To suc-
cessfully sense ROS/RNS, several criteria must be considered. It
should have high selectivity and sensitivity for specific ROS or
RNS to limit off-target effects. In order to detect targets in living
cells, it is advantageous to display ’turn-on’ fluorescence, which
is distinct from intracellular auto fluorescence. The reversibility
of the probes is also important, but most probes use a group of trig-
gers that can react with specific ROS and RNS probes, so they are
irreversible. In this regard, probes containing redox metal ion can
be a solution to solve this problem.
Early probes could only detect ROS in solution, but cellular
imaging using confocal microscopy and imaging ROS and RNS in
live animals have become popular within the past decade [18]. Flu-
orescent probes that target specific organelles and fluorescently
label ROS/RNS provide information on various diseases including
cancer and neurodegenerative disorders. The localization of the
probe provided information on oxidative stress specific to the cel-
lular organelles where the probe was accumulated [19]. Probes
using irreversible reactions with specific ROS/RNS are unable to
distinguish between chronically elevated ROS levels as a patholog-
ical feature and transient fluctuations in ROS production in physi-
ological events [20]. A reversible probe was developed to monitor
the redox status in cells in real time [21]. In addition, the develop-
ment of ratiometric probes prevented defects resulting from
changes in fluorescence emission intensity due to differences in
sensor concentration [22]. Owing to the real-time monitoring
enabled by this approach, these probes have been successfully
used for imaging-guided surgery.
Many ROS- and RNS-selective fluorescent and luminescent
probes adopt basic but important organic reactions. Therefore,
most of these probes are self-immolative systems [23] or so-
called chemodosimeters [24]. Probes called chemodosimeters react
with analytes and undergo significant chemical modifications,
including the breaking and formation of covalent bonds. Because
these chemical modifications are irreversible, they cannot act as
a reversible probe. For example, oxidations of arylboronic acids
to phenols were the most popular organic reactions for sensing
H2O2 [25], HOCl [26] and ONOO– [27,28]. More recently, conver-
sion from N-heterocyclic carbene (NHC) boranes to imidazolium
salts has been used to detect HOCl [29,30].
Meanwhile, the metal coordination of the metal complex plays
an essential role in the design of photoluminescent probes. Metal
O2
ions play key roles in the probes as an on–off redox switch for pho-
toinduced quenching and as a reaction site with ROS, RNS or lumi-
nescent cores. For example, H2O2 is cleaved reductively to OH by
Cu+ or Fe2+ in the Fenton reaction, and the heme Fe2+–O2 adducts
can generate O– 2 in vivo [31]. Redox-active metal ions can be trig-
ger switches that control fluorescence quenching effects, which
can be used to sense ROS or RNS. Further, metal ions, especially
lanthanide metal ions, often can be the source of luminescence
themselves [32]. They have been widely used as luminescent
probes because of their large Stokes, narrow emission bands, and
long-lived luminescence, which can reduce the background signal
CO3 [33]. On the other hand, metal nanoparticles have enormous
NO2 potential as sensors because of their unique properties such as high
electrical conductivity and surface reaction activity. Formation of
metal nanostructure is one of the effective approaches for a biosen-
sor platform as it can improve biocompatibility and increase quan-
tum yield [34]. For example, quantum dots, gold clusters, metal
2
N. Kwon et al.
core-shall nanoparticles, etc. are actively investigated to provide
improved fluorescence and increased photostability [35,36]. Espe-
cially, upconversion nanoparticles (UCNPs), a type of lanthanide-
doped luminophore, are particularly suitable for biosensing and
bioimaging applications because they can be excited with NIR
region light [37]. The metal–organic framework (MOF), on the
other hand, has been extensively utilized as an effective method
to form various metal nanostructures in various applications such
as chemical sensing and drug delivery over the past few years due
to its easy-to-adjust structural properties [38]. Metal complexes
can have several advantageous photophysical properties compared
to organic fluorophore. They are generally advantageous for
bioimaging because they have a long emission lifetime, high lumi-
nescence efficiency, and large Stokes shift. In addition, metal ions
can be easily quantified in the bio system through inductively cou-
pled plasma mass spectrometry (ICP-MS) or X-ray fluorescence
(XRF).
The probes discussed in this review are categorized by the tar-
get ROS or RNS, which are H2O2, HOCl/–OCl, OH, O– 1
2 , O2, NO,
–
ONOO , HNO and NO2. In this review, we cover ROS- and RNS-
selective fluorescent and luminescent probes designed from
metal-coordinated systems over the last decade in accordance with
the theme topic of this special issue. We believe that both these
previously reported probes and those that will be developed in
the future will find important applications in clinical diagnosis,
prediction of drug efficacy, imaging-guided surgery and theranos-
tics [16,39].
2. Metal-coordinated fluorescent and luminescent probes for
reactive oxygen species (ROS)
2.1. Fluorescent and luminescent probes for hydrogen peroxide (H2O2)
Of the various ROS, H2O2 is one of the major species of interest,
along with O– 
2 . It is a long-lived ROS, and it is a precursor for OH
and other ROS. A high concentration of H2O2 is a common feature
of cancer cells [40]. Accordingly, many fluorescent probes have
been designed to selectively sense H2O2 [41]. The oxidative inter-
action between iron and H2O2 is used for fluorescence detection
of H2O2. To design H2O2 detection probes, a variety of probes that
mimic the bioredox process between the iron porphyrin center of
the heme enzyme and H2O2 have been developed. In addition,
H2O2 chelation by Eu3+-tetracycline complex, photooxidation of
thioether and H2O2 induced cleavage of boronate has been used
in the design of H2O2 detection probes.
Zhang et al. reported that probe 1 can selectively image H2O2 in
lysosomes when MPO is present (Fig. 2a), which means that probe
1 can image H2O2 in the relatively acidic pH range of 4.5–6 [42]. In
the absence of MPO, probe 1 can selectively react with ClO– over
various other ROS, such as OH, ROO, t-BuOOH, O– –
2 , ONOO and
H2O2. However, the addition of H2O2 and Cl– in the presence of
MPO resulted in a large increase in fluorescence at 610 nm upon
excitation at 380 nm. Thus, probe 1 with MPO showed high selec-
tivity for H2O2 over other ROS, with a reported detection limit of
42 nM. Probe 1 was localized in lysosomes in the cell imaging data
with MPO, which was confirmed by LysoTracker Green with a Pear-
son’s correlation coefficient of 0.92. These results indicate that
probe 1 can successfully image lysosomal H2O2 and lysosomal
H2O2 flux.
The iron-complexed fluorescein derivative 2 was reported as a
H2O2-selective fluorescent probe at pH 7.0 (25 mM PIPES buffer)
[43]. The fluorescence of 2 is quenched when the iron center is
paramagnetic, and the addition of H2O2 induced an enhancement
of fluorescence at 528 nm. Activation of the iron center by H2O2
followed by oxidative dealkylation affords the fluorescein biscar-
3
Coordination Chemistry Reviews 427 (2021) 213581
boxylate shown in Fig. 2b, as confirmed by 1H NMR spectroscopy
and ESI mass spectrometry. Probe 2 displayed excellent selectivity
for H2O2 over various other ROS and metal ions, and the reported
limit of detection was 29 mM. Finally, probe 2 was successfully
used to image lysosomal exogenous H2O2 in HeLa cells.
Hitomo and coworkers reported an Fe3+ complex of a resorufin
derivative (3) at pH 7.2 (20 mM HEPES buffer) [44]. Probe 3 was
designed as a mimetic of nonheme Fe3+ peroxidase bearing a
stable O-alkyl resorufin. The addition of H2O2 induced an enhance-
ment of fluorescence at 590 nm upon excitation at 530 nm, which
was attributed to the release of resorufin after the reaction of the
iron complex with H2O2, as shown in Fig. 2c. Probe 3 was highly
selective for H2O2 over other ROS and RNS, such as ClO–, O– 2 and
NO, and was used to image exogenous H2O2 in living HeLa cells.
Furthermore, probe 3 successfully imaged epidermal growth factor
(EGF)-stimulated H2O2 generation.
Das and coworkers reported the synthesis of carbon dots from
hemoglobin. These so-called blood dots (BD) contain heme groups;
specifically, Fe2+ held in a porphyrin ring. The blue fluorescence of
the BD is quenched by OH and O– 2 generated in situ from H2O2 by
the BD, as shown in Fig. 3 [45]. BD can distinguish cancer cells
(HeLa cells) from noncancer cells (CHO cells) because the H2O2
concentration is higher in cancer cells, and H2O2 can be converted
to OH and O– 2+
2 by the Fe -enriched BD, resulting in fluorescence
quenching. At the same time, the Fe2+-enriched BD activate H2O2,
which acts as a prodrug producing ROS to cause oxidative damage
to DNA. BD can selectively kill cancer cells with 3-fold greater effi-
cacy compared to normal cells.
Chen, Lu and coworkers reported the Fe2+ complex 5,10,15,20-
(4-sulphonatophenyl)porphyrin (TPPS4) (Fig. 4) as a turn-off fluo-
rescent sensor for H2O2 at pH 7.4 (Tris-HCl buffer) [46]. Excitation
at 515 nm promoted fluorescence at 645 and 700 nm, which was
turned off by the addition of H2O2. The oxidation of Fe2+ to Fe3+
by H2O2 was attributed to the formation of a TPPS4-Fe3+ complex;
the electron transfer (ET) process resulted in fluorescence quench-
ing. The calculated detection limit was 1.24 nM, with a linear
response range of 0–42 lM.
Shao and coworkers reported a ratiometric fluorescent probe
for H2O2 composed of silver nanoparticles and denatured lyso-
zymes (dLys-AgNCs), which is shown in Fig. 5 [47]. In the presence
of Fe2+, H2O2 is reduced to OH via the Fenton reaction. This can
cause oxidation of tyrosine in the lysozyme, resulting in enhance-
ment of the dLys-AgNCs emission at 450 nm, along with quenching
of the original emission of dLys-AgNCs at 640 nm by both OH and
Fe3+. Lysozyme acts as a stabilizing ligand for the AgNCs as well as
a blue fluorescent source. The calculated detection limit was
0.2 mM, with a linear response range of 0.8–200 mM. In the presence
of O2, GOx catalyzes glucose to generate H2O2. Accordingly, the
addition of glucose, Fe2+ and GOx induced ratiometric fluorescence
changes in dLys-AgNCs, which means dLys-AgNCs can be used to
sense glucose. Further, dLys-AgNCs were reported to have imaged
endogenous OH in living cells.
Li et al. reported neutral iridium(III) complex 4, which bears a
benzeneboronic acid pinacol ester (bpe) as a reactive moiety to
detect H2O2, as a phosphorescent probe that is selective for H2O2
over other ROS [48]. As shown in Fig. 6a, 3-(benzothiazol-2-yl)-7-
hydroxy-coumarin bearing a bpe moiety was a cyclometalated
ligand of 4-I, which absorbs at 460 nm and phosphoresces at
560 nm. The reaction with H2O2 induced significant intermolecular
aggregation owing to the removal of the steric hindrance caused by
the bulky pinacol ester moiety, resulting in decreased phosphores-
cence. A boronic acid or ester deprotection strategy was nicely
adopted to sense H2O2 in this work.
A Eu3+-coordinated polymer containing a sulfur tag was
reported as a H2O2-selective luminescent probe that had been syn-
thesized from Eu(NO3)3
6H2O and 2,20 -thiodiacetic acid [49]. A
N. Kwon et al. Coordination Chemistry Reviews 427 (2021) 213581

(a)
NC CN NC CN

N N N N
Zn MPO
Zn
O O O O
H2O2, Cl-
N S S N N S O O S N

(b) H 2O H2 O
N N H2O
H2O
Fe Fe
N N N N CHOO- COO-
HO O O
O O O H2O2

Cl Cl
Cl Cl
-
CO2-
CO2

2
(c)
N +
O
O 2+
H
O N HO O O
H2O2 FeIII N
H O H
N N N
N O resorufin
HO FeIII N
N N
O

Fig. 2. Reaction mechanism of (a) probe 1 with H2O2 in the presence of MPO and that of (b) probe 2 and (c) 3 with H2O2.

Fig. 3. Hemoglobin-based blood dot (BD) and its reaction mechanism with H2O2. Copyright 2018 American Chemical Society.

SO3H
conversion from a microcrystal structure to a nanoparticle struc-
ture with retention of fluorescence occurs upon increasing the
temperature. The peaks in its emission spectra were attributed to
the 5D0 ? 7F04 transitions of Eu3+. The addition of H2O2 oxidizes
the thioether moiety to sulfoxide, as shown in Fig. 6b, which leads
to quenching of the Eu3+ emission. A linear correlation range of 5–
N HN
SO3H
150 lM was reported. The microcrystals could detect ROS in aero-
HO3S
N
sols, whereas the nanoparticles could image exogenous H2O2 in
NH
human embryonic kidney 293 T (HEK 293 T) cells.
Xu and Kuang et al. reported chiral upconversion nanoassem-
blies (UCNP@ZIF-NiSx) that detect ROS, especially H2O2 in living
cells [50]. As shown in Fig. 7, upconversion nanoparticles (UCNPs)
were first stabilized by oleic acid (OA) to form hexagonal-plate-like
SO3H
UCNPs-OA. After a reaction with HCl to remove the OA, the UCNPs
Fig. 4. The structure of 5,10,15,20-(4-sulphonatophenyl)porphyrin (TPPS4). were decorated with polyvinylpyrrolidone (PVP) to form UCNP-

4
N. Kwon et al. Coordination Chemistry Reviews 427 (2021) 213581

thesized from 2-boronobenzene-1,4-dicarboxylic acid and ZrOCl2-

8H2O in the presence of formic acid (HCOOH), as shown in Fig. 8
[51]. The Zr-MOF contains the UiO-66 structure, and 2-
boronobenzene-1,4-dicarboxylic acid acts as a linker. Zr-UiO-66-
B(OH)2 displayed a fluorescence enhancement at 428 nm that
was selective for H2O2 over other ROS at pH 7.4 (HEPES buffer).
The addition of H2O2 induced the oxidative breakage of the  B
(OH)2 moiety into an  OH group. The reported detection limit
was 0.015 lM, and the probe was used to image exogenous H2O2
in MDAMB-231 cells.

2.2. Fluorescent and luminescent probes for hydroxyl radicals (OH)

Owing to the physiological significance of OH, fluorescent

Fig. 5. Ratiometric fluorescent sensing of H2O2 and OH using lysozyme–silver
nanoclusters (dLys-AgNCs). Copyright 2016 American Chemical Society.
PVP, which was further coated with zeolitic imidazolate framework-
8 (ZIF) to form UCNP@ZIF. Finally, further reactions with nickel(II)
ions and chiral L-/D-penicillamine (Pen) ligands as a sulfide source
afforded chiral UCNP@ZIF-NiSx. UCNP@ZIF-NiSx displayed strong
circular dichroism (CD) signals at 440 and 530 nm, and upconversion
luminescence (UCL) signals were observed at 540 nm and 660 nm.
So, dual-mode detection of CD and fluorescent signals could be used
to detect ROS
H2O2 was chosen as a representative ROS. Upon the
addition of H2O2, the UCL signal of the UCNPs at 540 nm decreased,
while the UCL signal at 660 nm remained the same. Based on the
UCL intensities (I660/I540 ratio), the reported detection limit was
0.037 lM, with a linear response range of 0.05–20 lM. Using normal
primary uterine fibroblast cells (PCS-460–010), the authors success-
fully demonstrated that these chiral nanoassemblies can quantita-
tively monitor exogenous H2O2 when excited with a 980 nm laser.
The UCL in the green region increased, while the UCL in the red region
was almost the same. Based on the UCL signal, the calculated detec-
tion limit was 0.13 lΜ, with a linear response range of 0.18–10.2 lΜ.
Biswas and coworkers reported a Zr(IV) metal–organic frame-
work (Zr-MOF) bearing a boronic acid moiety (Zr-UiO-66-B(OH)2)
as a H2O2-selective fluorescent probe. Zr-UiO-66-B(OH)2 was syn-
probes to selectively detect and image OH have been attractive
research targets. However, of the various ROS and RNS, OH is par-
ticularly challenging to detect due to its high reactivity and extre-
mely short half-life of 109 s [52]. To designing the OH probe,
aromatic hydroxylation, oxidative dearylation, and upconversion
NPs (UCNPs) are frequently-used mechanisms. First, with aromatic
hydroxylation, OH can easily attack the aromatic rings and make it
hydroxylated. When there are lanthanide ions, the hydroxylated
moiety can be a more efficient sensitizer, which usually give dis-
tinct optical changes [53]. Next, electron rich units like aniline or
phenol groups can mask the hydroxyl or amine in probes, resulting
in quenching through PET. Through OH-triggered oxidative deary-
lation, the fluorescence get recovered. Finally, in UCNPs, lanthanide
metal ions such as Yb3+ are doped in an appropriate host lattice.
Luminescence resonance energy transfer (LRET) is common feature
of UCNPs-based fluorescent probes from an upconversion donor to
an energy acceptor [54].
Time-gated (or time-resolved) luminescence using lanthanide-
based compounds is an active area of investigation for luminescent
probes [55]. Pierre and coworkers reported ternary terbium (Tb)
complex 5 (Fig. 9a) as a selective probe for OH via time-gated
luminescence [53]. Probe 5 can detect OH at concentrations as
low as 0.75 fM. Hydroxylation of trimesate to hydroxytrimesate
was followed by coordination to form Tb complex 5 (Fig. 9a), which

(a)
O
B OH
O
+
S N S N
O O
O
Ir Ir
O O
O O
O O
O
H2O 2
O B
O OH 2
2

4-I
4

(b) UV Emission Quenched

UV

O O
+

S
HO OH O R
H2 O 2
+ Eu S
R'
Eu(NO3)3¡¤6H2O

Fig. 6. Proposed mechanism of (a) luminescent probe 4 and (b) a Eu(III)-coordinated polymer with H2O2.

5
N. Kwon et al.
Fig. 7. Proposed scheme for UCNP@MOF-NiSx system to detect ROS. Copyright 2019 American Chemical Society.
Fig. 8. The synthetic route for Zr-UiO-66-B(OH)2 and its fluorescence enhancement
at pH 7.4 (10 mM HEPES). Copyright 2018 American Chemical Society.
induced fluorescence at 545 nm. This approach was highly selec-
tive for OH over other ROS and RNS, such as O 1  
2 , O2, t-BuO , ClO ,
H2O2 and NO. With the aid of a long time-gate (0.2 ms), selective
luminescence of Tb was observed without interference from back-
ground luminescence.
The self-immolative, luminescent terbium(III) complex 6 was
reported as a probe for the selective detection of OH (Fig. 9b)
[56]. The probe had an emission maximum at 514 nm upon excita-
tion at 315 nm. The electron-rich p-nitrophenoxy moiety can effi-
ciently quench the luminescence by PET. 49-fold enhancement of
luminescence was observed upon the addition of OH at pH 7.0
(0.05 M HEPES), which was attributed to the elimination of the
p-aminophenyl group, as shown in Fig. 9b. The reported detection
limit was 270 nM, with a long time-resolved lifetime (2.76 ms). Tb
complex 6 was successfully used to detect exogenous OH in HeLa
cells with background-free luminescence.
6
Coordination Chemistry Reviews 427 (2021) 213581
Tian and coworkers reported AuNC@HPF, which is a gold nan-
ocluster (AuNC) decorated with bovine serum albumin (BSA) and
2-[6-(40 -hydroxy)phenoxy-3H-xanthen-3-on-9-yl]benzoic acid
(HPF), as a ratiometric fluorescent sensor for OH (Fig. 10) [57].
As shown in Fig. 10, only the emission at 632 nm from AuNCs
was observed upon excitation at 488 nm because HPF is weakly
fluorescent. The addition of OH induced additional emission at
515 nm from the reaction product, fluorescein, which results in
ratiometric fluorescence changes. The reported detection limit
was 0.68 lM, with a linear response range of 1  106 to
1.5  104 M. AuNC@HPF was then used to image endogenous

OH in HeLa cells stimulated by lipopolysaccharides (LPS).
AgNCs were stabilized by cytosine-rich oligonucleotides to
detect OH from among various ROS and RNS by Tian and cowork-
ers [58]. Rolling circle amplification (RCA) was employed to pre-
pare a DNA hydrogel, which is cross-linked with cytosine-rich
sequences in the presence of Ag+ via cytosine–Ag+–cytosine
(Fig. 11). After the reduction of Ag+, the resulting RCA-stabilized
AgNCs (RCA-AgNCs) displayed improved photostability. The green
channel detected emissions between 500 and 560 nm upon excita-
tion at 448 nm, and the red channel detected emissions between
610 and 700 nm upon excitation at 552 nm. The addition of OH
induced a decrease in red fluorescence and an increase in green flu-
orescence. The reported detection limit was 58 nM, with a linear
response range between 0.2 and 80 lM. RCA-AgNCs were subse-
quently used to dynamically and ratiometrically monitor endoge-
nous ROS/RNS in LPS-stimulated A549 cells.
AgNCs were reacted with a DNA template to form DNA-AgNCs
(Fig. 12) and were reported as a OH-selective fluorescent probe
by Lei and coworkers [59]. The DNA-AgNCs showed a strong green
emission at 550 nm upon excitation at 440 nm. The addition of OH
cleaved the DNA template and induced aggregation of the AgNCs,
resulting in fluorescence quenching. A linear response to OH was
observed in the range of 50 nM to 5.0 mM, and the DNA-AgNCs
were successfully used to image endogenous OH in SK-N-SH cells.
The corresponding OH concentration in cell extracts stimulated by
PMA was 0.35 lM, which was very close to the value obtained by
HPLC (0.31 lM).
N. Kwon et al. Coordination Chemistry Reviews 427 (2021) 213581

(a) O
O
OH2
N HN O O
OH2 O O
O Tb
O O N N O
O HO O O N HN O
O O
O OH O O
Tb
O
N N O
O O O
O
O O
O O O 5
O

(b)
O
CH2OH

NH2

N N OH N N
N N N N N N

N N NH - N
CO2- -O2C N O 2C
CO2-
- - -
CO2 O 2C O2C
Tb3+ O CO2- Tb3+
6

Fig. 9. Reaction mechanism of (a) a terbium-based luminescent probe (5) via hydroxylation of trimesate and (b) Tb-based luminescent probe 6 with OH.

Fig. 10. Strategy for the preparation of AuNC@HPF and its reaction scheme with OH. Copyright 2014 American Chemical Society.

7
N. Kwon et al.
Fig. 11. Scheme for the synthesis of RCA-AgNCs. Copyright 2018 American
Chemical Society.
Liu and coworkers reported a luminescence resonance energy
transfer (LRET)-based upconversion nanoprobe as a OH-selective
sensor [60]. The upconversion nanoprobe was prepared by intro-
ducing an azo dye, which can be oxidized by OH, onto the surface
of the NaYF4@NaYF4:Yb,Tm@NaYF4 nanoprobe via interactions
between the carboxylic acid moieties and lanthanide ions. The
nanoprobe emits at 487 nm upon excitation at 980 nm. When
 was 37 nM, with a linear response range of 50 nM to 1 M.
OH was added, the luminescence quenching due to LRET from
the upconversion nanoparticles to the azo dyes (Fig. 13) was
revived owing to the oxidative decomposition of the azo dye with

OH. An excellent detection limit of 1.2 fM was reported, with a lin-
ear range of 1.2–194.6 fM. The probe was used to detect endoge-
nous OH in HeLa cells and mouse tissues stimulated by LPS, as
shown in Fig. 13.
2.3. Fluorescent and luminescent probes for singlet oxygen (1O2)
1
O2 is cytotoxic due to its oxidation of proteins, DNA and lipids.
1
O2 is generated via enzymatic and nonenzymatic reactions, but
photosensitizers in photodynamic therapy also may generate 1O2
to kill cancer cells [61,62].
(2 + 4) cycloaddition of 1O2 to anthracene to form an endoper-
oxide was used as a delivery system for 1O2 to induce antitumor
efficacy [63,64]. The opposite path of receiving 1O2 instead of deliv-
ering it has been a popular strategy for designing a selective lumi-
nescent probe for 1O2. Endoperoxide adducts are generated from
europium complex 7, as shown in Fig. 14 [65]. Upon the addition
of 1O2 to form the endoperoxide product, the fluorescence quench-
ing due to PET was eliminated, resulting in strong fluorescence at
794 nm at pH 7.4 (0.05 M Tris-HCl buffer). The calculated detection
limit was 3.7 nM. When probe 7 was treated with PDT drugs, such
as hematoporphyrin monomethyl ether (HMME), in HeLa cells, the
generation of 1O2 was successfully monitored by time-gated
luminescence.
AgNO3
NaBH4 DNA-AgNCs
: DNA : Ag nanocluster
Fig. 12. Synthesis of DNA-AgNCs and the reaction of DNA-AgNCs with OH.
8
Coordination Chemistry Reviews 427 (2021) 213581
Zeolitic imidazolate framework-8 (ZIF-8) was employed as a
host for fluorescent sources to afford EuPS@AnC/ZIF-8, a ratiomet-
ric fluorescent sensor for 1O2, as illustrated in Fig. 15 [66]. 9-
Anthracenecarboxylic acid (AnC), 2-methylimidazole and zinc
nitrate were treated with a polystyrene core decorated with a
europium chelate (EuPS) to afford EuPS@AnC/ZIF-8. In this ratio-
metric system, the emission at 615 nm from Eu3+ acts as a refer-
ence signal and the emission at 410 nm from AnC displays
distinct fluorescence quenching after the reaction with 1O2. In
addition, a colorimetric change from blue-violet to red was
observed after the reaction with 1O2. The reported detection limit
was 43 nM, with a linear response range of 0.5–200 lM.
Wang and coworkers reported a dinuclear Ru2+ complex con-
taining an anthryl moiety (8) as a 1O2-selective luminescent probe
(Fig. 16) [67]. Probe 8 reacts with 1O2 to form its endoperoxide at
pH 7.0 (50 mM Tris-HCl buffer) and pH 10.5 (0.1 M carbonate buf-
fer), resulting in a large enhancement of emission at 609 nm upon
excitation at 458 nm. The reported detection limits were 3.1 nM at
pH 7 and 2.7 nM at pH 10.5.
Voelcker and coworkers reported MC-EuA, which was synthe-
sized from a porous silicon microcavity (pSiMC) with a
europium-anthracene (EuA) moiety as a luminescent probe for
1
O2 [68]. On a porous silicon thin film, anthracenes linked by Si–
O bonds react with 1O2 to form the corresponding endoperoxide
adducts. Fig. 17 shows that the MC-EuA emission at 615 nm was
quenched with the addition of ClO– and was dramatically
enhanced upon the addition of 1O2. The reported detection limit
2.4. Fluorescent and luminescent probes for superoxide anion radical
(O–
2)
The primary ROS is O–2 , which is the one-electron reduced form
of O2 and a precursor of several other ROS and RNS. For example,
O– –
2 can generate ONOO by a nonenzymatic reaction with NO. In
addition, O–
2 plays key roles in both physiological and pathological
processes [69].
Tang and coworkers reported DBZTC/Ag@SiO2 as a nanoprobe
for O– 2 [70]. The 2-chloro-1,3-dibenzothiazoline-cyclohexene
(DBZTC) group on the surface of Ag@SiO2 is oxidized in the pres-
ence of O–
2 (Fig. 18), which can induce fluorescence enhancement
at 520 nm upon excitation at 485 nm at pH 7.4 (20 mM HEPES).
The calculated detection limit was 0.73 nM, with a linear response
range of 0.02–3.33 mM. DBZTC/Ag@SiO2 was successfully used to
image endogenous O– 2 upon stimulation by PMA in RAW264.7
cells.
Li and Xiao reported gold nanodots (Au NDs) as a selective flu-
orescent probe for O–
2 in which 2-mercaptobenzothiazole was used
as a stabilizing agent and D-(+)-mannose was used as a reducing
agent via a one-pot sonochemical method, as illustrated in
Fig. 19 [71]. The Au NDs displayed a strong orange emission at
532 nm upon excitation at 346 nm, which was efficiently
quenched by the addition of O– 2 . The reported detection limit
was 445 nM, with a linear response range of 0.6–78 lM. The addi-
OH
Fluorescence quenching
N. Kwon et al. Coordination Chemistry Reviews 427 (2021) 213581

COOH

N COOH
N
= N = oxidized azo dye
OH

Azo dye

Fig. 13. Luminescence resonance energy transfer (LRET)-based upconversion nanoprobe, in which oxidative decomposition of an azo dye with OH induced the recovery of
luminescence, and its application to the imaging of endogenous OH in HeLa cells and tissues. Modified with permission from Copyright 2015 American Chemical Society.

O
O

PET 1 PET
N
O2
N +
N N N N
Eu3+ Eu3+
CO2 O 2C CO2 CO O 2C
CO2 N 2
N
N N N
N
7

Fig. 14. Reaction mechanism of probe 7 containing an anthracene moiety with 1O2.

Fig. 15. Preparation of EuPS@AnC/ZIF-8 and its reaction mechanism with 1O2. Copyright 2017 Royal Society of Chemistry.

tion of vitamin C revived the emission at 532 nm. The Au NDs were In the same paper, the authors also reported the application of this
then used to image exogenous O– 2 in HepG2 cells. system as a MOF-based catalyst for Knoevenagel condensation.
Zr-UiO-66-NH-CH2-Py was reported as a new MOF-based fluo-
rescent sensor for O–2 that had been synthesized from Zr
4+
ions 2.5. Fluorescent and luminescent probes for hypochlorous acid (HOCl)
and 2-[(pyridin-4-ylmethyl)amino]terephthalic acid (Fig. 20, left)
[72]. There was a distinct enhancement of fluorescence at HOCl (pKa = 7.6), which often exists as ClO–, is a strong oxidant
430 nm upon excitation at 330 nm when O– 2 was added to the and is produced from H2O2 in the presence of chloride and
aqueous solution of Zr-UiO-66-NH-CH2-Py (Fig. 20). The reported myeloperoxidase (MPO) [73]. HOCl plays an important role in innate
detection limit was 0.21 lM with a fast response time of 240 s. immune systems to destroy invasive bacteria, but excessive amounts
9
N. Kwon et al. Coordination Chemistry Reviews 427 (2021) 213581

4+ occurred at 587 nm with an emission lifetime of 155 ns, which

was attributed to 3[p(ppy) ? p*(L1/L2)] 3LLCT and 3[5d(Ir) ? p*
N N (L1/L2)] 3MLCT. As shown in Fig. 21a, ClO converts probe 9 to
N H H N
N N N N its carboxylic acid product. In addition, luminescent probe 9
Ru Ru showed excellent selectivity towards ClO over other ROS and
N N N N N N
metal ions.
N N
Yuan and coworkers reported ruthenium(II) complex 10 for
HOCl detection at pH 7.4 (50 mM borate buffer) [80]. Very weak
8 emission was observed for Ru(II) complex 10 due to PET, but after
1
O2 it reacted with HOCl, strong luminescence was observed at 612 nm
upon excitation at 456 nm The detailed proposed mechanism is
4+ presented in Fig. 21b. The addition of HOCl induced the formation
of the unstable intermediate of benzoxazolone N-oxide 10 I, which
N N was converted to the strongly emissive product 10-II. The reported
N H H N
N N N N detection limit was 33 nM, with a linear response range of 2.5–
O
Ru
N
O
N
Ru 40 lM. Probe 10 was successfully used to image exogenous and
N N N N
endogenous HOCl in HeLa cells and porcine neutrophils.
N N
The Ru(II) complex 11 was reported as a HOCl-selective lumi-
nescent probe (Fig. 21c) in which the 2,4-dinitrophenyl (DNP)
group acts as an electron acceptor and fluorescence quencher
Fig. 16. The reaction mechanism of a dinuclear Ru2+ complex containing an anthryl [81]. Weak luminescence was observed for probe 11 due to the
moiety (8) with 1O2. DNP moiety, but HOCl selectively ‘‘turned on” the probe
by  190-fold at 626 nm upon excitation at 456 nm at pH 7.4
(0.1 M phosphate buffer). The addition of HOCl cleaves the DNP
of HOCl cause rheumatoid arthritis, atherosclerosis, cardiovascular group, followed by oxidation to a carboxylic acid moiety
diseases and other chronic diseases [74]. Accordingly, a great many (Fig. 21c). The reported detection limit was 53.5 nM, with a linear
probes have been developed to selectively sense HOCl among vari- response range of 2.5–50 mM. Ru(II) complex 11 could image
ous ROS and RNS [75,76]. For detecting HOCl/OCl, the well- endogenous HOCl in RAW264.7 cells.
known recognition sites are reactive groups like rich electron groups An iridium(III) complex (12) was reported as a ClO–-selective
such as S, Se, double bond, hydroximic acid, and hydrazine. Partially- luminescent probe at pH 7.4 (10 mM PBS buffer) [82]. Probe 12
positive-charged Cl atom in HOCl can easily react with recognition exhibited strong fluorescence at 615 nm upon excitation at
group containing partial negative charge to produce chloride. After 370 nm, which was quenched by the addition of ClO. The fluores-
that, the chloride sometimes undergoes b-elimination or hydrolysis cence of probe 12 was selectively quenched by ClO– with a rapid
to cause changes of fluorescence [77]. Recently, DUOX-dependent response time (<30 s) and a reported detection limit of 0.41 lM.
HOCl production was visualized in the intestine following gut infec- As shown in Fig. 21d, the methacrylate group is converted to its
tion using a rhodamine-based fluorescent probe, which demon- phenol product via oxidation by ClO–, which was confirmed by
strates the role of specific ROS- or RNS-selective fluorescent probes NMR and mass spectroscopy. Probe 12 was subsequently used to
[78]. image ClO– in HepG2 cells.
Chen and coworkers presented iridium complex 9 as a ClO- b-Diketonate–europium complexes 13-I and 13-II were
selective luminescent probe. Iridium complex 9 displayed very reported as mitochondria- and lysosome-selective HOCl probes,
weak emission at pH 7.2 (DMF–HEPES 4:1 v/v), which was attrib- respectively [83]. Both probes displayed strong red emission at
uted to isomerization of the C = N–OH bond; strong luminescence 607 nm upon excitation at 330 nm at pH 7.4 (PBS buffer). The addi-
was observed at 77 K in frozen DMF due to inhibition of this rota- tion of HOCl induced efficient fluorescence quenching (Fig. 21e).
tion (Fig. 21a) [79]. Upon the addition of ClO, strong emission The calculated detection limit was less than 15 nM. Due to the

Fig. 17. (a) Emission spectra of MC-EuA with ClO– and MC-EuA+1O2 (solid red curve) upon excitation at 348 nm. (b) Proposed scheme of MC-EuA interacting with 1O2.
Reproduced with permission. Copyright 2017 American Chemical Society.

10
N. Kwon et al. Coordination Chemistry Reviews 427 (2021) 213581

Ag@SiO2 DBZTC/Ag@SiO2 time-gated luminescence microscopy was successfully used to

image the uptake of HOCl by Daphnia magna using these probes.
Probe 14 was reported as a time-gated luminescence (TGL)
DBZTC O2
Ag Ag Ag probe for HOCl in lysosomes, in which luminescent Tb3+ is a fluo-
rescence resonance energy transfer (FRET) donor and a rhodamine
moiety bearing a HOCl trigger group is a FRET acceptor (Fig. 22a)
[84]. The addition of HOCl induced a decrease of the Tb3+ emission
at 540 nm and an increase of the rhodamine emission at 580 nm at
Oxidized DBZTC
DBZTC H pH 7.4 (50 mM PBS). In addition, the lifetime of the Tb3+ emission
N S N S
= = decreased from 588 ls to 254 ls, along with the FRET process. The
S Cl HN S Cl N reported HOCl detection limit was 0.34 lM, with a linear response
range of 0.5–45 lM. Ultimately, probe 14 was successfully used to
Fig. 18. Proposed mechanism of DBZTC/Ag@SiO2 with O
2 .
image lysosomal endogenous HOCl in HepG2 cells, which was con-
firmed with LysoSensor Green.
Pt pincer complexes containing 4,5-bis(diphenylphosphino)acri
dine and either benzenethiolate (15) or 4-thiolatobenzoic acid (16)
were reported as HOCl-selective fluorescent probes [85]. Probe 15
displayed selective fluorescence enhancements with HOCl and
ONOO–. Probe 16, which has the less electron-rich 4-
thiolatobenzoic acid, shows a highly selective fluorescence
enhancement at  490 nm only with HOCl. The oxidation mecha-
nisms of probes 15 and 16 with HOCl are shown in Fig. 22b. The
reported HOCl detection limit of 16 was 33 nM and the reported
HOCl and ONOO– detection limits of 15 were 26 and 33 nM,
respectively.
The nanoscale metal–organic framework (NMOF) UiO-68-ol
was reported as a HOCl-selective fluorescent sensor [86]. The p-
methoxyphenol ligand was first studied as a redox-switchable
ligand, in which the conversion from p-methoxyphenol to quinone
followed by the formation of hydroquinone was confirmed. The p-
methoxyphenol ligand then reacted with ZrCl4 to form the Zr-MOF
UiO-68-ol. A colorimetric change from colorless to yellow was
observed selectively with HOCl over other ROS and RNS with the
naked eye, as shown in Fig. 23. In addition, the original fluores-
cence at 475 nm upon excitation at 405 nm was efficiently
quenched, with a detection limit of 0.1 lM in PBS buffer. UiO-68-
Fig. 19. Synthesis of gold nanodots (Au NDs) and reaction mechanism with O–
2.
ol was subsequently used to image both exogenous and endoge-
Copyright 2017 Royal Society of Chemistry. nous HOCl production in RAW264.7 cells.
The metal–organic framework (MOF) {[Eu2Cu(IN)5(CO3)(H2O)]},
which was prepared from CuI and the lanthanide duplex chain
triphenylphosphonium group in 13-I and the morpholine moiety shown in Fig. 24, was reported as a ClO-selective sensor [87].
in 13-II, 13-I could be selectively located in mitochondria and The MOF complex fluoresces at 486 nm, which is a characteristic
could image exogenous and endogenous HOCl in the organelle, emission of CuI. The MOF sensor showed selective fluorescence
whereas 13-II could selectively image HOCl in lysosomes. Notably, quenching upon the addition of ClO , with a distinct colorimetric

Fig. 20. Zr-UiO-66-NH-CH2-Py as a fluorescent sensor for O–

2 and Zr-UiO-66-NH-CH2-Py as a MOF-based catalyst for Knoevenagel condensation (left) and fluorescent changes
of Zr-UiO-66-NH-CH2-Py at 430 nm with various amounts of O– 2 upon excitation at 330 nm (right). Inset: Photos of cuvettes containing Zr-UiO-66-NH-CH2-Py before and
–
after the addition of O2 under a UV–Vis lamp. Copyright 2019 Royal Society of Chemistry.

11
N. Kwon et al. Coordination Chemistry Reviews 427 (2021) 213581

(a) PF6-
OH
N COOH
N N
N N
ClO-
Ir Ir
N N
N N

(b) NH2 N
+ O
O N OH
O NO2
O-
N N N
N N N
N N N
HOCl HOCl
Ru II RuII RuII
N N N N N
N
N N N

10 10-I 10-II

(c) NO2 NO2

T
PE
S
COOH
N N
N N HOCl N N
Ru2+ Ru2+
N N N N
N N

11

(d)
N N
N N N N
ClO-
Ir Ir
N N
N N

O OH
2
O 2 12 non-fluorescent
fluorescent

(e) R
R

HOCl

O O
Eu3+
O O HO O O OH
C3F7 1/2 C3F7
Non-fluorescent
Fluorescent at 607 nm
Br
13-I: SO2-NH(CH2)6P(Ph)3 13-II: SO2-NH(CH2)6N O

Fig. 21. Proposed reaction mechanism of (a) iridium complex 9 with ClO, (b) ruthenium(II) complex 10, (c) complex 11, (d) iridium complex 12 and (e) europium complex
probes with HOCl.

change from yellow to blue that is readily observed with the naked to the naked eye, which were attributed to a reversible redox pro-
eye. The calculated detection limit was 10 lM. cess with vitamin C (VC). The calculated detection limit was
Dong and coworkers reported the MOF-based UiO-68-PT as a 0.28 lM, with a linear response range of 0–80 lM. UiO-68-PT
selective fluorescent probe for HOCl. UiO-68-PT was synthesized and poly(vinyl alcohol) could form mixed membrane material
from ZrCl4 and a phenothiazine–benzimidazole–dicarboxylate (MMM), which appeared as a deep red color with an absorption
bridge as a ligand (Fig. 25) [88]. The addition of HOCl induced a band at 533 nm upon the addition of HOCl, as shown in Fig. 25.
large fluorescence enhancement at 392 nm upon excitation at A luminescent metal–organic framework (AF@MOF-801) was
323 nm and a highly selective colorimetric change that is distinct reported to selectively detect HOCl by a size-selective effect in
12
N. Kwon et al. Coordination Chemistry Reviews 427 (2021) 213581

NO2
(a)
O 2N
O O O
HN CO2H
N N
N N
N
N N

O O

N N HOCl N N
3+ N pH 7.4 N
Tb Tb3+
CO2 CO2 CO2 CO2 CO2 CO2 CO2 CO2
14 14-I FRET

(b)

PPh2 PPh2

N Pt S HOCl or ONOO-
N Pt S O
O
PHPh2 PPh2
ClO4- ClO4-
15 15-I

CO2H CO2H
PPh2 PPh2

N Pt S HOCl
N Pt S O
O
PPh2 PPh2
ClO4- ClO4-
16 16-I

Fig. 22. The reaction mechanisms of (a) luminescent Tb3+ complex 14 with HOCl and (b) platinum–acridine-based probes 15 and 16 with ONOO–.

Fig. 23. The Proposed structure of UiO-68-ol and its color changes with various ROS and RNS, including HOCl, and confocal fluorescence images of RAW264.7 cells with HOCl.
Copyright 2017 American Chemical Society.

which large interferents can be effectively inhibited from entering
the cage [89]. The authors described a ‘‘ship in a bottle” strategy to
prepare the luminescent metal–organic framework MOF-801 using
Zr6 clusters as inorganic nodes and fumaric acid as organic ligands
(Fig. 26). The luminescent marker 5-aminofluorescein (AF) was
encapsulated during the formation of the MOF to afford
AF@MOF-801. The addition of HOCl induced about 80% quenching
of AF@MOF-801 emission at pH 7.4 (60 mM HEPES). The size selec-
tivity for ClO– was attributed to the small pores of the entrance.
The calculated detection limit was 0.052 lM, with a linear
response range of 0–7 lM. AF@MOF-801 was subsequently used
to monitor intracellular exogenous ClO in SMMC-7721 and HeLa
cells.
Tan and coworkers reported the MOF CD/CCM@ZIF-8 as a FRET
sensor for HOCl that exhibits ratiometric fluorescence [90]. As
shown in Fig. 27, ZIF-8 was selected as a frame for the MOF, which
can accommodate curcumin (CCM) and carbon dots (CD) during
the assembly. The addition of HOCl induced an increase of the
CD emission at 410 nm and a decrease of the CCM fluorescence
at 585 nm. The reported detection limit was 67 nM, with a linear
response range of 0.1–50 lM. CD/CCM@ZIF-8 was then used to
detect HOCl in serum. The serum was treated with N-ethyl malei-
mide to remove biothiols, such as GSH, before the HOCl was added.
The amount of HOCl spiked in the serum was determined from the
ratiometric fluorescence of CD/CCM@ZIF-8, which was in good
agreement with the results determined by kit assay.

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N. Kwon et al. Coordination Chemistry Reviews 427 (2021) 213581

PVP-capped copper nanoclusters (CuNCs) prepared from Cu2+

with PVP as the scaffold material and ascorbic acid (AA) as the
reducing agent showed sensitive, HOCl-selective fluorescence
quenching (Fig. 28) [91]. PVP-capped CuNCs exhibited strong emis-
sion at 416 nm upon excitation at 340 nm, which was selectively
quenched with HOCl. The fluorescence quenching was attributed
to the oxidation of copper on the surface of the nanocluster by
HOCl. The reported detection limit was 55 nM, which decreased
to 19 nM in the presence of excess iodide (I–). HOCl oxidizes iodide
to iodine (I2), which can react with copper on the surface of the
nanocluster to afford cuprous iodide (CuI) as a precipitate.
As shown in Fig. 29, GSH-decorated AuNCs (GSH-AuNCs) were
encapsulated in NMOFs made of 2-methylimidazole (2-HIm) and
Zn2+ to form AuNCs@NMOFs [92]. The fluorescence of the
AuNCs@NMOFs was about 10 times stronger than that of the
GSH-AuNCs, and it was efficiently quenched by highly reactive
oxygen species (hROS). The calculated detection limit was 30 nM,
with a linear response between 80 nM and 1.0 mM. The AuNCs@N-
MOFs could also be used to image exogenous and endogenous ROS
in living cells.

3. Metal-coordinated fluorescent and luminescent probes for

reactive nitrogen species (RNS)

Fig. 24. (a) Structure of Cu(I) complex, (b) a lanthanide duplex chain, (c) 3D
framework of {[Eu2Cu(IN)5(CO3)(H2O)]}. Reproduced with permission. Copyright
2018, Wiley-VCH Verlag GmbH & Co. KGaA.
3.1. Fluorescent and luminescent probes for peroxynitrite (ONOO–)
Like HOCl, ONOO– displays antibacterial efficacy, but it can also
damage DNA and proteins due to its oxidizing power [93]. In recent

Fig. 25. The reaction mechanism of UiO-68-PT with HOCl and its reversible colorimetric change with HOCl and vitamin C (VC) (left) (a) Emission spectra of UiO-68-PT upon
addition of HOCl. (b) Colorimetric changes of UiO-68-PT in the presence of various analytes. (c) Fluorescence changes of UiO-68-PT for various analytes, including HOCl.
Copyright 2019 American Chemical Society.

14
N. Kwon et al. Coordination Chemistry Reviews 427 (2021) 213581

Fig. 26. A ‘‘ship in a bottle” strategy from Zr6 clusters (inorganic node) and fumaric acid (organic ligand) to prepare LMOF-801 NPs and size-selective sensing of ClO.
Copyright 2019 The Royal Society of Chemistry.

Fig. 27. Proposed scheme for the assembly of CD/CCM@ZIF-8 and its ratiometric sensing of HOCl. Copyright 2020 American Chemical Society.

Fig. 28. Proposed mechanism of PVP-Capped CuNCs with HOCl. Copyright 2020 American Chemical Society.

decades, a variety of ONOO–-selective fluorescent and luminescent
imaging probes have been actively investigated [28,94,95]. For
sensing ONOO-, the nucleophilicity and oxidizability of ONOO
are utilized to design the probes. Oxidation of boronates or boronic
acids and oxidative N-dearylation are widely used. Boronic acids or
esters go through the nucleophilic addition with strong nucle-
ophile, ONOO–, and at the end, it undergoes the subsequent hydrol-
ysis resulting in different photophysical properties. For oxidative
N-dearylation, PET-based fluorescence quenched group is oxidized
to produce an iminium ion in the presence of ONOO–, followed by
the subsequent hydrolysis to induce the release of the amino fluo-
rophore [94].
Zhang and coworkers reported two nanoprobes, NMOF-PVA-
Abt (MA) and NMOF-PVA-BDY (MB), as ratiometric fluorescent
sensors for ONOO– in which the Zr4+-encapsulated MOF was coated
with poly(vinyl alcohol) (PVA) and the boronic acid derivatives,
ABt and BDP, were attached through the formation of boronate
esters (Fig. 30) [96]. When excited at 340 nm in PBS buffer at pH
7.4, MA displayed fluorescence at 530 nm, whereas MB emitted
at 610 nm via FRET. The addition of ONOO– induced a distinct
ratiometric change in the emissions and a hypsochromic shift at
403 nm, which corresponds to the MOFs. As shown in Fig. 30,
ONOO– quickly converts arylboronates to hydroxyl derivatives.
Both MA and MB showed linear relationships with ONOO– in the
range of 0.0–0.1 lM. Finally, both MA and MB could image exoge-
nous ONOO– in HeLa cells via ratiometric fluorescence changes.
TD-DC was reported as a ratiometric, time-resolved lumines-
cent nanoprobe for ONOO– [97]. TD-DC is composed of Tb(DPA)3
and DC; the reaction mechanism of the DC moiety is detailed in
Fig. 31. TD-DC displays emissions at 547 nm and 620 nm upon
excitation at 330 nm. The addition of ONOO– induced a decrease
at 620 nm and an increase at 547 nm, resulting in a 48.7-fold ratio-
metric enhancement (I547/I620). The reported detection limit was
39 nM, with a fast response time (29 s). The addition of ONOO– also
enhanced the lifetime from 100 ns at 620 nm to 1 ms at 547 nm.
TD-DC was subsequently used to image endogenous ONOO– in
A375 cells. Imaging with Mito-Tracker Green showed that TD-DC
was mainly localized in mitochondria, with a Pearson’s colocaliza-
tion coefficient of 0.85.
An iridium(III) based nanoprobe (MSN-ONOO) was reported as
a ONOO–-selective phosphorescent probe, in which a ONOO–-
triggered boronate-bearing Ir(III) derivative (Ir1) was embedded

15
N. Kwon et al. Coordination Chemistry Reviews 427 (2021) 213581

N
N

O
HO
HOOC
O
H 2N O
NH
NH

ONOO-
TD TD

TD-DC

Fig. 31. Reaction mechanism of TD-DC with ONOO–.

Fig. 29. Synthesis of AuNCs@NMOFs and hROS detection in living cells. Copyright
2019 Elsevier B.V.
10% CH3CN). The N-dearylation reaction by ONOO– [99] was also
within mesoporous silica nanoparticles (MSN-Ir3*) (Fig. 32) [98].
used in P-ONOO, as shown in Fig. 33a. The addition of ONOO–
At pH 7.4 (0.01 M PBS buffer containing 10% CH3CN), MSN-ONOO
induced a large increase in phosphorescence at 680 nm, but there
shows a strong emission at 474 nm and a moderate emission at
was no significant change in the emission at 600 nm. The calcu-
605 nm, which were attributed to the emissions from Ir1 and
lated detection limit was 0.018 lM, with a linear response range
Ir3*, respectively. The addition of ONOO– induced a large decrease
of 2–8 lM. When 3-morpholinosydnonimine hydrochloride (SIN-
of the emission at 474 nm but barely affected the emission at
1) was used to release endogenous ONOO– in RAW264.7 cells,
605 nm, which was accompanied by the color of the phosphores-
the green emission (575–625 nm) remained constant and the red
cence changing from white-pink to red. A linear relationship was
emission (655–705 nm) increased dramatically. ONOO– can be an
observed between 0 and 10 lM, with a detection limit of
early biomarker for drug-induced liver injury (DILI). A
11.3 nM. Upon the addition of ONOO– in RAW264.7 cells, a
ketoconazole-induced liver injury was successfully detected from
decrease in the green channel emission was observed, while the
the elevated ONOO– concentration using P-ONOO.
red emission remained nearly constant. MSN-ONOO was used to
A water-soluble luminescent Eu(III) probe bearing a quinoline
image endogenous ONOO– in zebrafish and living mice stimulated
moiety (17) (Fig. 34) was reported as a ONOO– selective probe that
with LPS and interferon gamma (IFN-c).
can show time-resolved luminescence at pH 7.4 (0.1 M PBS buffer)
The same group extended their work to a polymeric probe con-
[100]. Emission in the range of 605–720 nm was observed upon
taining the N-(4-hydroxylphenyl)-rhodol group (P-ONOO), which
excitation at 355 nm. The benzyl boronic moiety, which is the trig-
displayed dual emissions at 680 nm and 600 nm in PBS (pH 7.4,
ger group, was cleaved via oxidative cleavage by ONOO– to afford

Fig. 30. Proposed sensing mechanism of MOF-based sensors for ONOO– (MA and MB). Reproduced with permission. Copyright 2017 The Royal Society of Chemistry.

16
N. Kwon et al.
Fig. 32. (a) Structures of iridium(III) complexes and reaction mechanism with ONOO–. (b) Synthesis of nanoprobe MSN-ONOO. (c) Reaction mechanism of MSN-ONOO with
ONOO–. Copyright 2018 American Chemical Society.
the 8-hydroxyquinoline moiety, as shown in Fig. 34. This can pro-
hibit the energy transfer to Eu(III), resulting in a decrease in the
time-resolved luminescence. A linear correlation was observed in
the range of 1 nM to 1 lM and a nanomolar range of endogenous
ONOO– was successfully detected in living cells. Eu(III) probe 17
was mainly located in the mitochondria of HeLa cells, with a
reported Pearson’s coefficient of 0.8.
3.2. Fluorescent and luminescent probes for nitric oxide (NO) and
nitrogen dioxide (NO2)
NO, which is endogenously generated by nitric oxide synthases,
can induce ailments such as cancer, neurodegenerative diseases
and stroke [16]. NO was selected as the molecule of the year in
1992 [101]. Among the various approaches to design a NO-
selective probe [102,103], the Lippard group reported pioneering
work in which the manipulation of fluorescence was achieved via
17
Coordination Chemistry Reviews 427 (2021) 213581
NO-induced reduction of paramagnetic Cu(II) to diamagnetic Cu
(I) [104]. The reaction with the addition of NO undergoes through
the metal reduction without fluorophore displacement to form
RONO and H+ [104]. Paramagenetic or heavy metal ion get dis-
placement or coordination upon the interaction with NO. As
another method, o-diamine can be used and transformed into a flu-
orescent triazole derivative, which is electron-poor by the reacting
with NO. The PET get interfered by this chemical change and makes
the probe show different photophysical properties [105].
Lippard and coworkers reported seminaphthofluorescein
derivatives 18a–d as NO-selective fluorescent probes (Fig. 35)
[106]. When NO was introduced to these probes, large fluorescence
enhancements (20–45-fold) occurred within the range of 550–
625 nm upon excitation at 535–575 nm. The proposed explanation
for the fluorescence changes was Cu2+ to Cu+ reduction by NO fol-
lowed by the elimination of Cu+ from the ligand and nitrosation of
the secondary amine. Other RONS or ROS, such as HNO, NO 
2 , NO3 ,
N. Kwon et al. Coordination Chemistry Reviews 427 (2021) 213581

Fig. 33. (a) N-Dearylation reaction by ONOO–. (b) Structures of Ir(III) complexes (Ir1, Ir2, Ir3, and Ir4) and their N-dearylation sensing mechanisms with ONOO–. (c) Structures
of P-ONOO and its sensing mechanism with ONOO–. Copyright 2020 American Chemical Society.

HO
B OH

O N O O N O O N O
O O O
O O O O O O O
N ONOO- N Cu2+ NO
N N N N
Eu O O Eu O NH2 NH2 NH2
N N N N NH N N
O O Cu2+ Cu+ N
17 17-I X O
N N N
Emission ON Emission OFF X
19 X = anion
–
Fig. 34. Reaction mechanism of Eu(III) probe 17 with ONOO . Weak fluorescence Weak fluorescence

N
N N
O
R +
N
R -Cu
N
NO
N N
H N O O
Cu N O ON 19-I
Cl
O O HO O Strong fluorescence

X X Fig. 36. Reaction mechanism of 19 with Cu2+ and NO.

Cu(I) CO2H
CO2H

18a 18b 18c 18d

Ex: 340 nm Ex: 340 nm
X=H Br H Br
R=H H OCH2CO2Et OCH2CO2Et
HN N
Cu2+
Fig. 35. Reaction mechanisms of 18a–d with NO. O O
N N
N N Em: 481 nm
2+
Cu FRET
ONOO, ClO and H2O2, did not induce any significant fluorescence HO O
HO O OH O
change. The endogenous NO in RAW264.7 cells could be success-
fully imaged by these probes upon stimulation by LPS and INF-c. 20
NO Em: 518 nm
Qian and coworkers reported the o-phenylenediamine-bearing 20-Cu+-NO
. 2+
20 Cu
naphthalimide derivative 19 as a NO-selective fluorescent probe Fluorescence OFF
[107]. Probe 19 showed relatively weak fluorescence due to the
electron-withdrawing effect of the quinolone moiety. The addition Fig. 37. Reaction mechanism of 20 with Cu2+ and NO.

18
N. Kwon et al.
of Cu2+ to probe 19 resulted in weak emission at 440 nm at pH 7.3
(Tris buffer containing 40% ethanol) and a distinct colorimetric
change from yellow to pink. The addition of NO induced the
removal of paramagnetic Cu2+ to afford the benzotriazole product,
as shown in Fig. 36, which induced a dramatic enhancement of flu-
orescence at 425 nm upon excitation at 350 nm and a color change
from pink to colorless. The reported detection limit was 30 nM,
with a linear response range of 0–80 mM.
Iyer and coworkers reported a Cu2+ complex of a fluorescein
hydrazone derivative (20) as a NO-selective fluorescent probe
(Fig. 37) [108]. The spirolactam-ring-closed form of 20 showed
very weak fluorescence from the indole moiety at 481 nm upon
excitation at 340 nm. The addition of Cu2+ induced a spiro-ring-
opening process, resulting in strong green fluorescence at
518 nm attributed to FRET from indole to fluorescein. When NO
was added, fluorescence quenching was observed and attributed
to fluorophore displacement or nitrosation. The reported detection
limit was 13.8 lL. 20 fluoresced strongly in RAW264.7 cells upon
the addition of Cu2+, which was quenched by the endogenous NO.
A Cu2+ complex of a dansyl derivative (21) was reported as a
NO-selective fluorescent probe by Mondal and coworkers [109].
Upon excitation at 342 nm, fluorescent emission at 550 nm was
revived due to the conversion of paramagnetic Cu2+ to diamagnetic
Cu+ by NO (Fig. 38). The calculated detection limit was  10 nM.
Another Cu2+ complex of a dansyl derivative (22) was reported
as a NO-selective fluorescent probe at pH 7.20 (HEPES buffer, CH3-
CN–H2O 9:1 v/v) by Ali and coworkers [110]. The addition of NO
reduces Cu2+ to Cu+, which can block PET and revive the fluores-
cence at 532 nm upon excitation at 345 nm (Fig. 39a). The reported
detection limit was 1.6 nM. Probe 22 was subsequently used to
detect NO by addition of Angeli’s salt (Na2N2O3) in HeLa cells.
N reported as a luminescent probe for NO (Fig. 42) [116]. Probe 25
O S O
N NO
N N
N N
Cu2+
21
CH3OH
Fluorescent
Fig. 38. Reaction mechanism of probe 21 with NO.
(a) N N
NO
O S O O S O
N N
N N N N
N N N Cu+
Cu2+
Cl Cl
22
(b) NH2
O NO
Cu2+ Cl
N N
N
NH2 NO
N O N N
23
Fig. 39. Reaction mechanism of (a) probe 22 and (b) 23 with NO.
Coordination Chemistry Reviews 427 (2021) 213581
The unique ring-opening processes of rhodamines, which can
induce the dramatic enhancement of fluorescence as well as dis-
tinct color changes, have been used to design various rhodamine-
based fluorescent probes [111,112]. Duan and coworkers reported
rhodamine-Cu2+ 23 as a NO-selective fluorescent probe in which a
rhodamine ring-opening process [113] and NO-induced reduction
from Cu2+ to Cu+ was followed by a reaction with NO to form the
ring-opened product (Fig. 39b). Upon the addition of NO, strong
fluorescence at 580 nm was observed upon excitation at 510 nm
at pH 7.4 (0.1 M PBS buffer). The reported detection limit was
1 nM, with a linear response range of 1–10 nM. 23 was also used
to detect exogenous NO in MCF-7 cells.
Nagano and coworkers reported Yb(2,7-dichlorocalcein) com-
plex 24 as a NO-selective near-infrared luminescent probe [114].
Probe 24 is non-fluorescent due to PET from 2,7-dichlorocalcein
to Yb3+. The addition of NO induced the conversion of the o-
diaminophenyl moiety to triazole (Fig. 40), and the corresponding
triazole product showed a strong emission at 980 nm upon excita-
tion at 500 nm at pH 7.2 (50 mM HEPES buffer). The reported
detection limit was 90 nM.
Duan and coworkers reported Ce4(H2TTS)4, a metal–organic
polyhedra (MOPs)-based fluorescent probe, as a selective fluores-
cent probe for NO [115]. The amide-containing tridentate chelating
ligand was synthesized from salicylaldehyde and 4,40 ,400 -nitrilotri
benzocarbohydrazide, which reacted with Ce(NO3)3
6H2O to afford
Ce4(H2TTS)4. As shown in Fig. 41, the resulting MOPs complex
accommodates 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3
-oxide (PTIO), a known NO trapper, in its cavity to detect NO.
The fluorescence of Ce4(H2TTS)4 at 470 nm upon excitation at
350 nm was quenched upon complexation with PTIO and revived
upon the addition of NO. Other ROS and RNS did not induce any
significant fluorescence change. Ce4(H2TTS)4 successfully imaged
endogenous NO in MCF-7 cells with a detection limit of 5 nM.
The iridium(III) complex 25 bearing an o-diamino moiety was
N
showed a large enhancement of the emission at 580 nm at pH
7.4 (50 mM PBS buffer containing 10% DMSO) in the presence of
O S O sodium nitroprusside (SNP), which can controllably release NO.
N The reported detection limit was 0.18 lM, with a linear response
range of 5–25 lM. Probe 25 was also successfully used to image
N N endogenous NO in HeLa cells.
Cu+ UCNPs were investigated as a ratiometric fluorescent probe for
NO
NO [117]. As shown in Fig. 43, the UCNP core, which emits at
540 nm and 656 nm, and a NO-selective rhodamine B derivative
were encapsulated within mesoporous SiO2, which was further
decorated with a b-cyclodextrin (bCD) layer. The o-
phenylenediamine moiety of the rhodamine B derivative reacted
with NO to induce ring-opening followed by hydrolysis to rho-
damine B, the absorption bands of which (500–600 nm) overlap
with the green emission (540 nm) of UCNPs via LRET. The addition
of NO induced an increase of ratiometric change (I656/I540 ratio) in
N
NH2 HN N
NH2 N
COOH COOH
Cl Cl Cl Cl
NO
NH2
N -
-
O O O O O O
O
NH2 COO- -OOC COO- -OOC
3+
O N
COO- Yb
3+
-
OOC COO- Yb -OOC
24
Fig. 40. Proposed reaction mechanism of luminescent probe 24 with NO.
19
N. Kwon et al. Coordination Chemistry Reviews 427 (2021) 213581

Fig. 41. Structure of metal–organic polyhedra (MOPs)-based fluorescent probe Ce4(H2TTS)4 and its fluorescence change upon the addition of NO and 2-phenyl-4,4,5,5-
tetramethylimidazoline-1-oxyl-3-oxide (PTIO). Copyright 2011 American Chemical Society.

PET

N N
N NH2 N N
H 3C NO H3C
Ir Ir N
H 3C H 3C N
N NH2 N
H
N N

25
Fluorescent

Fig. 42. Reaction mechanism of Ir-based probe 25 with NO.

PBS (10 mM, pH 7.4). The reported detection limit was 73 nM, with
a linear response range of 7.4–110 lM. This probe system was suc-
cessfully used to detect exogenous NO in living HeLa cells, serum
and liver tissues of mouse models.
A sulforhodamine B fluorophore was linked to dithiocarbamate
bound to Ni2+, which was reported as a NO2-selective fluorescent
probe in 10 mM PBS (pH 7.4). As shown in Fig. 44, a PET quenching
effect due to Ni2+ was observed for 26 [118]. The fluorescence was
revived by the oxidation of the dithiocarbamate ligand upon the
addition of NO2 to afford the decomplexed forms 26-I or 26-II.
Strong fluorescence at 590 nm was observed upon excitation at
540 nm when diethylamine NONOate was used as the NO donor.
The reported detection limit was 1 ppm for gaseous exogenous
NO2 with the naked eye when 26 was deposited on filter paper.
Finally, the probe system was used to image NO2 in RAW264.7
cells.
Wang and coworkers reported a CdTe quantum dot (QD) and
carbon dot (CD) hybrid system as a ratiometric fluorescent probe
20
for NO2 (Fig. 45) [119]. The hybrid nanoprobe 27 showed emissions
at 665 nm from the CdTe-QDs and 460 nm from the CDs upon exci-
tation at 365 nm. Upon the addition of NO2, the emission at
665 nm was quenched and the emission at 460 nm was almost
unchanged, producing a clear ratiometric change. A distinct fluo-
rescent color change from orange-red to blue was easily observed
with the naked eye. The reported detection limit was 19 nM, with a
linear response range of 0.2–1.2 lM.
3.3. Fluorescent and luminescent probes for nitroxyl (HNO)
HNO, which is the one-electron reduced form of NO, mostly
exists as the protonated form (pKa = 11.4) [120], which displays
different biochemistry than NO does [121]. Recently, the most
common design strategy of fluorescent HNO probes is to use the
Cu2+/Cu+ redox couple, which is also commonly used for NO
probes. However, in the presence of HNO, paramagnetic Cu2+ is
reduced to diamagnetic Cu+ and fluorescence is restored with the
N. Kwon et al. Coordination Chemistry Reviews 427 (2021) 213581

Fig. 43. Ratiometric upconversion nanoprobe for NO and its optical responses with NO.

S
SO3- R2N Ni NO2
NO2 S
S N N
NO2 S S HS
N Ni R2N Ni NR2 NR2 HN N
O 2S N S S S Br Cu2+ Cu2+ H Br
S
2 HO O O O O O
26
PET
N N
Cu+ HNO
S S O S
CH3OH S NR2 O
S NR2
28 28-Cu2+
OMe R2N S R2N
R2 N S S
S S
O
26-I Fig. 46. A reversible mechanism between 28 and 28-Cu2+ in the presence of HNO.
26-II
-
SO3

= R2N =
N
emission at 623 nm upon excitation at 570 nm, which can induce
Et2N O NEt2 O 2S N the reduction of Cu2+ to Cu+. Interestingly, the reduced Cu+ dissoci-
+
ated from the binding site and regenerated 131, which can provide
Fig. 44. The reaction mechanism of sulforhodamine B-dithiocarbamate-Ni2+ (26), a reversible sensing system. 131 was also reported to image exoge-
with NO2. nous HNO in RAW264.7 and HeLa cells.
Lippard and coworkers reinvestigated their previously reported
[124] fluorescent probe 29, [Cu(BOT1)Cl]Cl, for HNO. Probe 29 was
Ex = 365 nm Ex = 365 nm
prepared using ‘‘click” chemistry to connect BODIPY and tripodal
Cu2+ moieties via a triazole linker in improved yield, and its X-
2

2
2
NH

2
NH

NH

NH

GSH GSH GSH GSH ray crystal structure was newly reported [125]. The addition of
NH2 CDs
O NO2 O
HNO induced a  10-fold fluorescence enhancement at 526 nm.
N C S QDs GSH NH2 CDs N C S QDs GSH
H H As shown in Fig. 47, the fluorescence quenched by Cu2+ was
GSH GSH revived after reduction to Cu+. Probe 29 was used to image HNO
NH

GSH GSH
NH

x
NH

NH
2

2
2

in HeLa cells using 3 mM of Angeli’s salt, which was mostly local-

2

108
460 nm 665 nm
Fig. 45. QD-CD hybrid probe 27 for NO2.
addition of HNO [122]. The fluorescent probes binding with Cu2+
often show weak fluorescence or even no fluorescence, because
Cu2+ can quench the fluorescence by PET. HNO can selectively
reduce Cu2+ to Cu+ which blocks PET and therefore, it recovers
the fluorescence of the fluorophore [120].
A benzoresorufin derivative 28-Cu2+ was reported as a HNO-
selective probe by Lippard et al. (Fig. 46) [123]. When CuCl2 was
added, the fluorescence was quenched by the paramagnetic Cu2+.
The addition of Angeli’s salt induced 4.8-fold enhancement of
460 nm 665 nm
ized in the endoplasmic reticulum (ER) and Golgi with Pearson’s
coefficients of 0.51 and 0.63, respectively.
CuDHX1 was reported as a HNO-selective NIR fluorescent probe
by Lippard and Rivera-Fuentes et al. (Fig. 48) [126]. The addition of
HNO induced the enhancement of fluorescence at 715 nm upon
excitation at 650 nm at pH 7 (50 mM PIPES, 100 mM KCl). HNO
induced the conversion of Cu2+ to Cu+, which dissociated from
the cyclam ligand. CuDHX1 could selectively detect HNO over
other ROS and RNS. CuDHX1 is a good NIR fluorescent probe that
can detect HNO in HeLa cells even in the presence of GSH, Cys or
H2S. Angeli’s salt was used as the HNO precursor for cell imaging,
which is known to decompose to HNO and NaNO2 at pH 7 quickly
(t1/2 = 3 min).

21
N. Kwon et al. Coordination Chemistry Reviews 427 (2021) 213581

Cl
F Cl F Cl
F B N F B N
Cu2+ HNO Cu+
N N N
N N N
N N N
N
N N
2 2
29

Fig. 47. Proposed reaction mechanism of fluorescent probe 29, [Cu(BOT1)Cl]Cl, with HNO.

O OH

N N
CuDHX1 Cu
= 650 nm N N
ex
em = 715 nm

Fig. 48. Structure of CuDHX1 and its fluorescence microscopy images of HeLa cells. (A) Differential interference contrast (DIC) image; (B) blue region showing nuclei, (C) NIR
region, (D) NIR region after treatment with Angeli’s salt (1.5 mM). Scale bar = 25 lm. Copyright 2014 American Chemical Society.

Yao et al. reported coumarin-based probe 30 as a selective flu-
orescent probe for HNO (Fig. 49a) [127]. The addition of HNO to 30
induced 17.2-fold enhancement of fluorescence at 499 nm. The cal-
culated association constant was 7.9  105 M1. HNO selectively
enhanced the fluorescence at 499 nm in HEPES buffer (50 mM,
0.1 M KNO3, pH 7.4), which was attributed to the reduction of
Cu2+ to Cu+. Probe 30 was further applied to image HNO in A375
cells by pretreatment with Angeli’s salt (50 lM).
Lin and Yao et al. extended their study to a Cu2+ complex of a
coumarin derivative (31) as a HNO-selective fluorescent probe
(Fig. 49b) [128]. The addition of Cu2+ induced efficient quenching
of fluorescence intensity at 499 nm in HEPES buffer (50 mM, pH
7.4). The reported binding constant of 31 with Cu2+ was
8.34  105 M1. Of the various ROS and RNS, a 6.9-fold enhance-
ment of fluorescence intensity was observed when HNO was added
to 31-Cu(II), which was explained by the formation of 31-Cu(I).
Exogenous HNO was successfully detected in NIH3T3 cells using
31-Cu(II), which was further used to detect the same in the bacte-
riovorous nematode C. elegans.
A similar paramagnetic Cu2+ to diamagnetic Cu+ conversion
occurred in dansyl derivative DQ468 (Fig. 49c) [129]. PET fluores-
cence quenching of the green emission at 543 nm was observed
when paramagnetic Cu2+ was added. The reported detection limit
of DQ468 for Cu2+ was 0.091 lM, and the reported detection limit
of [CuII(DQ468)Cl]+ for HNO was 0.41 lM. HepG2 cells were used
to prove the utility of this system. Cu2+ efficiently quenched the
green fluorescence of DQ468, which was revived after treatment
with Angeli’s salt at 37 °C; this behavior is attributed to the reduc-
tion of Cu2+ to Cu+.
A new BODIPY derivative bearing a terpyridyl moiety was
reported to selectively sense HNO by utilizing the redox reaction
of Cu(II) [130]. As shown in Fig. 50, the BODIPY-Cu(II) complex
22
Cu(II)-BTPY showed very weak fluorescence. Upon the addition of
HNO, the conversion from Cu2+ into Cu+ induced enhancement of
emission. BTPY displayed a relatively high fluorescent quantum
yield of 34.8% with a stock shift of 62 nm. The efficient quenching
of fluorescence was attributed to the paramagnetism of Cu2+. The
reduction of Cu2+ to Cu+ upon the addition of HNO was confirmed
by EPR. Cu(II)-BTPY displayed high selectivity for HNO over other
ROS and RNS and was successfully used to image HNO in HeLa
cells.
4. Summary and outlook
ROS and RNS play key roles in various signaling and pathologi-
cal processes and are essential to human life, but overproduction of
ROS/RNS by exogenous stimuli is harmful because ROS/RNS can
induce oxidation of DNA, proteins or lipids, resulting in cell death.
Therefore, unusual ROS/RNS levels can indicate ailments such as
Parkinson’s and Alzheimer’s diseases, inflammation, diabetes and
cancer. In this review, we have discussed metal coordination com-
plexes that act as fluorescent or otherwise luminescent probes for
H2O2, HOCl/ClO–, OH, O– 1 –
2 , O2, NO, HNO, NO2 and ONOO . Lumines-
cent detection methods have many advantages over other analyti-
cal methods, such as simplicity and sensitivity. Even more
importantly, these methods could be used for cell, tissue and small
animal in vivo imaging as well as imaging-guided human surgery.
Self-immolative or chemodosimetric approaches have blos-
somed over the last decade, especially with respect to ROS- or
RNS-related organic reactions that could be applied to imaging
ROS and RNS in living organisms, diagnostics or ROS- or RNS-
activated drug delivery systems. So far, the main strategies to
design ROS- or RNS-selective probes have been protecting groups,
N. Kwon et al. Coordination Chemistry Reviews 427 (2021) 213581

(a)

N O O
N O O
N
N 2+ N N N Cu+ N
N N Cu HNO

N
N N
N
30

(b)

N O O

N O
N N O
31 N
N

Cu2+

N O O
N O O
N
N HNO N +O O
N 2+O O N Cu
N Cu N
N N
31-Cu(II) N 31-Cu(I)

(c)

N N N

CuCl2 HNO
O O O O O O
S S S
N N N
N Cu N Cu N
N N Cl N

DQ468
[CuII(DQ468)Cl]+
"ON" "ON"
"OFF"

Fig. 49. Reaction scheme for (a) 30, (b) 31-Cu(II) with HNO and (c) [CuII(DQ468)Cl]+ with HNO.

Fig. 50. The reaction scheme of Cu(II)-BTPY with HNO and its fluorescent change.

selective cleavages or destructive approaches and selective addi- to develop new classes of fluorophores with improved photo-
tions with specific ROS- or RNS-induced fluorescence enhance- properties, such as AIE [39], fluorescent probes for super-
ments or ratiometric changes. Researchers are also endeavoring resolution imaging [131], two-photon probes [132], NIR/NIR-II

23
N. Kwon et al.
[133], TADF-based probes [134], upconversion probes [135] and
MOFs [136].
Metal coordination of the metal complex plays an essential role
in the design of photoluminescent probes. Metal ions play key roles
in the probes as an on–off redox switch for photoinduced quench-
ing and as a reaction site with ROS, RNS or luminescent cores. As
shown in this review, redox-active metal ions can be trigger
switches that control fluorescence quenching effects, which can
be used to sense ROS or RNS. Most common example was NO-
induced reduction of paramagnetic Cu2+ to diamagnetic Cu+. In
addition, metal ions, especially lanthanide metal ions, can often
be themselves a source of light emission. In most cases, metal com-
plexes showed several advantageous photophysical properties
compared to those of organic fluorophore, such as a long emission
lifetime, high luminescence efficiency, and large Stokes shift. In
addition, metal nanoparticles or MOFs are powerful methods to
introduce more than one function or provide a dramatically
improved photophysical properties using a combination of lumi-
nescent sources.
Fluorescent probes that target specific organelles and fluores-
cently label ROS/RNS provide information on various diseases
including cancer and neurodegenerative disorders. The localization
of the probe provided important information on oxidative stress
specific to the cellular organelles where the probe was accumu-
lated. Various probes introduced in this review are already suc-
cessfully applied for disease diagnostics. For example, a
ketoconazole-induced liver injury was successfully detected from
the elevated ONOO– concentration by Chen, et al. [99]. For the
examples to utilize redox-active metal ions, the Lippard group
reported pioneering and important work, in which fluorescent
change was achieved via NO-induced reduction of paramagnetic
Cu2+ to diamagnetic Cu+ [104]. This work especially influenced
the following related works from various other groups.
As probes for tumors or other sites with especially high levels of
ROS or RNS become essential for imaging-guided surgery and
improved therapeutic and theranostic precision, fluorescent probes
that can dynamically monitor the level of ROS or RNS are urgently
needed. The obstacles to overcome in the development of probes
for practical applications include high selectivity with high photo-
stability as well as reversibility. Some key issues such as biocom-
patibility and organ toxicity of metal complexes are still needed
to be improved. It is also necessary to increase the rate of intracel-
lular absorption. We believe researchers will make great contribu-
tions to this field for decades to come.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgement
This work was supported by the National Research Foundation
of Korea (NRF) grant funded by the Korea government (MSIP) (No.
2012R1A3A2048814).
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