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Page 1 of 17 Analyst DOI: 10.1039/C4AN01909A

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ARTICLE
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9 Fluorescence Chemosensors for Hydrogen
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11 Cite this: DOI: 10.1039/x0xx00000x

Sulfide Detection in Biological Systems
12
13 Zhi Guoa,b, Guiqiu Chen ,a,b, Guangming Zeng,a,b, Zhongwu Li a,b, Anwei Chenc,
14 Jiajia Wang a,b, Longbo Jiang a,b
15
Received 00th January 2014,
16 Accepted 00th January 2014 Abstract: A comprehensive review of the development of H 2S fluorescence-sensing strategies, including

Analyst Accepted Manuscript

17 sensors based on chemical reactions and fluorescence resonance energy transfer (FRET), is presented.
18 DOI: 10.1039/x0xx00000x
The advantages and disadvantages of fluorescence-sensing strategies are compared with those of
19 traditional methods. Fluorescence chemosensors, especially those used in FRET sensing, are highly
www.rsc.org/
20 promising, because of their low cost, technical simplicity, and use in real -time sulfide imaging in living
21
cells. Potential applications based on sulfate reduction to H 2S, the relationship between sulfate-
22
reducing bacteria activity and H 2S yield, and real-time detection of sulfate-reducing bacteria activity
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using fluorescence sensors are described. The current challenges, such as low sensitivity and poor
24
stability, are discussed.
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a
51 College of Environmental Science and Engineering, Hunan University, Changsha 410082, P.R. China.
b
52 Key Laboratory of Environmental Biology and Pollution Control (Hunan University), Ministry of Education,
53 Changsha 410082, P.R. China.
54 c
College of Resources and Environment, Hunan Agricultural University, Changsha 410128, P.R. China.

55 Corresponding Author. Phone: +86 731 88822829. Fax: +86 731 88823701. E-mail: gqchen@hnu.edu.cn
56 (G.C.); zgming@hnu.edu.cn (G.Z.).
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1 1．Introduction strategies are highly desirable compared with traditional
2 methods, and offer high biocompatibility as well as real-time
3 H2S is a colorless gas; it has a distinct smell of rotten imaging. Fluorescence resonance energy transfer (FRET), a
4 eggs, and is mainly produced by the decomposition of non-radiative energy transfer process, is a widely used
5 organic compounds or as a byproduct of a range of industries, sensing mechanism, because it is particularly promising in
6 including petroleum refining, farming, waste management, biological imaging. To date, many FRET processes are based
7 and natural gas production. 1,2 The toxic effects of H 2S were on QDs and covalently linked dye scaffolds. However, there
8 first documented roughly 300 years ago; since then, much are no FRET processes reported for H 2S detection. Although
9 work has focused on its potential damage to biological several reviews about H 2S sensing in biological systems
10 systems.3–8 H2S is extremely dangerous to the human body, already exist, the field is advancing at a rapid pace and the
11
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because of its reducibility and high lipid solubility, even at current manuscript offers insightful new perspectives on
12 low levels.9 Previous reports have shown that the
13 designs and applications. 44–45 Sulfate reducing bacteria (SRB)
cystathionine β-synthase (CBS) gene, which is one of three are regarded as the main contributor to anaerobic corrosion.
14 enzymes able to produce H 2S, is overexpressed in Down’s
15 It is crucial to determine the activity in the environment
syndrome.10 The secretion level of insulin, a crucial factor in instantaneously, but few fluorescence methods have been
16

Analyst Accepted Manuscript

avoiding the development of diabetes, is reduced by high reported. In this review, we summarize new reaction based
17
concentrations of H 2S.11 It has also been reported that fluorescence molecular sensors with different functional
18
deregulation of H 2S increases the possibility of liver groups. Among them, the fluorescence molecular sensors
19
cirrhosis.12 In addition to biological damage, this odorous suitable for two-photon microscopy (TPM) are taken as a
20
and toxic gas is corrosive, and damages pipelines and separate part due to the particular sensing manner. Other
21
catalysts, and the ceramic membranes used in syngas fluorescence sensors that employ FRET processes are
22
separations.13–15
23 introduced as a promising manner for H 2S recognition. We
24 Recent evidence has shown that H 2S acts as a third also show the potential promise of fluorescence sensors
25 endogenously generated gaseous signaling compound with based on QDs, and at the same time, present the challenges
26 cytoprotective properties; the other two are the well-known on the way. Moreover, the potential application in sulfate
27 gasotransmitters NO and CO. It has diverse functions in reducing bacteria activity detection is proposed and
28 several pathophysiological processes, especially in regulating discussed.
29 vascular contractility and neuronal activity. 16–18 In mammals,
30 H2S production is derived primarily from three enzymes: 2. Reaction-based molecular sensors for H2S
31 cystathionine γ-lyase, CBS, and 3-mercaptopyruvate
detection derived from functional groups
32 sulfurtransferase.19,20 The widespread but differential
33 expression of these enzymes in different tissues suggests that Recently, a large number of reaction-based sensors for
34 H2S has wide importance and significance in the H2S detection have been reported;46 these typically offer
35 cardiovascular, circulatory, respiratory, urinary, and nervous higher spatiotemporal resolution and greater living-cell
36 systems. In addition to the pathophysiological conditions compatibility than traditional detection methods. Such
37 associated with H 2S misregulation, H 2S can also act on reaction-based sensors have been derived from azide or nitro
38 specific cellular targets, including heme proteins, 21 cysteine compounds, an azamacrocyclic Cu(II) ion complex, and H2S-
39 (Cys) residues on ATP-sensitive K+ channels,22 NO,23 and specific Michael acceptors. In these sensors, a fluorophore
40 other emerging targets. that has a high quantum yield, emits a long wavelength, and
41 Regardless of the dangers or benefits of H 2S, it is responds to hydrosulfide by fluorescence changes is required.
42 important to develop efficient methods for the detection of When H2S is present, a known unique reaction, followed by
43 H2S in living systems. The available methods should meet an optical change, is triggered. The corresponding optical
44 the following four criteria. They should 1) act rapidly (within changes are usually either linear or non-linear with respect to
45 seconds) under mild conditions; 2) be sensitive for detection H2S concentration, which is crucial to further H 2S
46 under near physiological conditions; 3) show minimal or no quantification.
47 interference by other anions in blood serum; and 4) be
48 functional in aqueous solutions and blood plasma.24 However, 2.1. Fluorescence molecular sensors derived from azide or
49 traditional methods of H 2S detection, including nitro compounds
50 colorimetry,25,26 gas chromatography, 27,28 electrochemical One important approach to designing sulfide-selective
51 analysis,29,30 and metal-induced sulfide precipitation, 31 are optical sensors relies on the unique interactions that occur
52
often limited by poor compatibility with living cells, low between sulfides and azide or nitro compounds. One
53
temporal resolution, and extensive sample preparation important process in these strategies depends strongly on the
54
requirements. reduction of azide and nitro groups on masked fluorophores
55
Recently, fluorescence imaging has emerged as a hot to generate amines, which resulted in fluorescence emission.
56
topic in the field of H 2S detection, because of its high As shown in Figure 1A, H 2S can reduce the nitro group in
57
sensitivity, real-time spatial imaging, and non-damaging probe 1 and the azide group in probe 2 to amine groups,
58
detection of targets in living cells or tissues. 32–43 These thereby creating off–on fluorescence signaling that can be
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1 used for H2S detection.47 Treatment of a 5 μM solution of
2 probes 1 and 2 with 100 equiv of H 2S resulted in
3 significantly increased fluorescence. For probe 1, a 15-fold
4 turn-on was observed after 90 min, and a 60-fold turn-on was
5
observed after 45 min for probe 2. The detection limits of
6
probes 1 and 2 for H2S after 60 min incubation were 5–10
7
and 1–5 μM, respectively. Human cervical carcinoma cell
8
lines (HeLa cells) were incubated with probe 1 and 2 for 30
9
min, respectively. As shown in the Figure 1B, the HeLa cells 24
10 Figure 2. Proposed reaction of probe 4 with H2S.
images (a and c) were non-fluorescent (or low-fluorescent)
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after the incubation. However, the cells became fluorescent

12 In 2011, Chang et al. developed a pair of new reaction-
13 or showed fluorescence enhancement (b and d) after 250 µM based fluorescent probes, i.e., sulfidefluor-1 (probe 5) and
14 H2S was added to the cells of a and c and incubated for sulfidefluor-2 (probe 6), for selective imaging of H 2S in
15 another 30 min. living cells; these probes exploit the H2S-mediated reduction
16 of azides to fluorescent amines (see Figure 3). 57 Both probes

Analyst Accepted Manuscript

17 displayed good selectivity for H 2S over abundant
18 biologically relevant thiols, including 5 mM glutathione
19 (GSH) and 5 mM Cys. Probe 5 displayed an approximately
20 three-fold increased response for H 2S than for most other
21 species tested, and approximately two-fold increased
22 selectivity versus O 2−. For probe 6, better selectivities versus
23 GSH (ca. five-fold), sulfite (ca. four-fold), and O2− (ca. four-
24 fold) were observed. In addition, a clear increase in
25 intracellular fluorescence intensity was observed for H 2S-
26 treated human embryonic kidney 293T (HEK293T) cells
27 using 5 or 6 as the probe. Probe 5 showed a higher turn-on
28
response than probe 6 for the detection of H 2S in cells,
29
because of increased lipophilicity and cellular retention.
30
Similar sensors, CLSS-1 (probe 7) and CLSS-2 (probe
31
8), were developed, with 128- and 48-fold enhanced
32
luminescence responses toward H2S, with detection limits of
33
0.7 ± 0.3 and 4.6 ± 2.0 μM, respectively (Figure 3).58 They
34
were reaction-based chemiluminescent sulfide sensors.
35
Figure 1. (A) Proposed reaction of probe 1 and 2 with H2S. (B) Fluorescence Because chemiluminescence does not require an excitation
36 microscopic imaging of living HeLa cells incubated with probe (a) 1; (b) 1 with
37 source, there is little chance for photodegredation of the
H2S; (c) 2; (d) 2 with H2S.47
38 sensing platform, which may occur in ordinary fluorescence
39 probes. In addition, these chemiluminescent sensors offered
The potential applications of fluorescence detection of
40 high signal-to-noise ratios because biological materials
H2S have led to many types of fluorophore being combined
41 typically did not spontaneously emit light. This special
with azide or nitro compounds to generate fluorescent probes.
42 characteristic made the sensors more suitable in biological
Dansyl is a commonly used fluorophore, and is well known
43 system application although cysteine derived reductants
for its strong fluorescence and long emission wavelength. 48–
44 56 might interfere the selectivity of probe 7. Compared with
A fluorescent dansyl–azide probe (probe 4) was
45 probe 7, probe 8 displays higher selectivity for H 2S over
synthesized using dansyl 3 as the precursor (see Figure 2). 24
46 Probe 4 itself is non-fluorescent. However, on addition of
other reactive sulfur, nitrogen, and oxygen species, including
47 GSH, Cys, homocysteine (Hcy), S 2O32−, NO2−, HNO,
H2S, a solution of 4 showed strong fluorescence
48 ONOO−, and NO.
enhancement, following reduction of the azido group to an
49 amino group. The addition of 25 μM H2S led to a 40-fold
50
fluorescence enhancement in 20 mM sodium phosphate
51
buffer (pH 7.5) with 0.5% Tween-20 (buffer/Tween). The
52
detection limit was as low as 1 μM in buffer/Tween and 5
53
μM in bovine serum, with a signal-to-noise ratio of 3:1.
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14 Figure 4. Proposed reaction of probe 9 and 10 with H2S.

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16 Figure 3. Structures of 5−8.
57,58

Analyst Accepted Manuscript

17
18 Surfactants such as micelles and other aggregates are
19 widely used in various scientific fields because of their
20 physicochemical properties. Based on the ability of
21 cetyltrimethylammonium bromide (CTAB) micelles to adjust
22 the fluorescence detection sensitivity, two colorimetric and
23 turn-on fluorescent probes (9 and 10) were designed for
24 selective recognition of H 2S (Figure 4).59 The probes were
25 Figure 5. Proposed reaction of 12 with H2S.60
constructed by incorporating an azido group into a
26 naphthalimide fluorophore as a specific group for reactions
27 Fluorescent protein (FP) is widely used in biological
with sulfide, based on its reducing properties. In the presence
28 imaging, because it does not alter the function or localization
of the cationic surfactant CTAB, the azido groups of the
29 of the targeted protein. 61–70 FP can be engineered to self-
probes were reduced to amino groups by H 2S and the
30 assemble into protein particles displaying protein functions
solution changed from colorless to yellow, accompanied by
31 suitable for various applications in diagnostics or detection. 71
strong yellow-green fluorescence within 10 min. Compared
32 Genetically encoded FPs were modified with sulfide-reactive
with the reaction in a buffer, the detection limit in CTAB
33 azide functional groups, by expanding the genetic codes of E.
decreased to 20 nM from 0.5 μM. The linear concentration
34 coli and mammalian cells (probes 13 and 14, Figure 6).72
range for H 2S detection was adjusted using differently
35 These structurally modified chromophores were selectively
36 charged surfactants, and the overall linear range covered five
reduced by H2S, resulting in sensitive fluorescence
37 orders of magnitude, from 0.05 μM to 1 mM. The probes
enhancement, which was detectable using fluorescence
38 were successfully used for rapid and sensitive detection of
microscope techniques (Figure 7). The fluorescence
39 H2S levels in fetal bovine serum, without any sample
enhancement showed a linear relationship with H 2S in the
40 pretreatment.59
range 0–50 μM. Probes 13 and 14 have many advantages
41 7-Amino-4-methylcoumarin (11) is widely used in
such as the addition of cell localization tags to allocate the
42 fluorogenic enzyme assays and can easily be converted to
probe to specific cell subdomains. 73 In addition, the approach
43 non-fluorescent 7-azido-4-methylcoumarin (probe 12; Figure
described relies on recognition of target molecules or
44 5)60 In the presence of NaHS, 12 is converted to 11, with a
enzymatic reactions;74 which is different from the
45 concomitant fluorescence increase that is linear for NaHS
incorporation of unnatural amino acids into FPs based on
46 concentrations from 100 nM to 100 mM. CBS activity assays
selective chemical transformations. However, because of the
47 showed no responses by the sensors to 10 mM Cys or Hcy, 1
reaction of dithiothreitol with these probes, caution must be
48 mM pyridoxal 5'-phosphate, or 1 mM S-adenosyl-l-
exercised to exclude dithiothreitol when measuring H 2S in
49 methionine, the allosteric activator of human CBS. These
vitro. The reaction with probes may be caused by the strong
50 results indicate that the sensors are highly selective.
reductive power of two free thiols of dithiothreitol.
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1 ions (the ratio of final and initial fluorescence intensity (I/Io)
2 at 517 nm = 87). However, further study confirmed that this
3 probe does not have sufficient selectivity for H 2S in the
4 presence of reduced GSH. A clear fluorescence enhancement
5
was observed on addition of 10 mM GSH. 76
6
It is well known that azamacrocyclic rings form stable
7
metal complexes with Cu 2+, and the paramagnetic Cu 2+
8
center has a pronounced quenching effect on fluorophores. 77
9
Based on these observations, Nagano et al. designed and
10
synthesized four sensor probes based on a fluorescein (AF)
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72
Figure 6. Structures of 13, 14.
scaffold conjugated with an azamacrocyclic Cu 2+ complex
12
13 (Figure 9).76 The four macrocyclic fluoresceins, namely
14 1,4,7-triazacyclononane (17), 1,4,7,10-tetraazacyclododecane
15 (cyclen, 18), 1,4,8,11-tetraazacyclotetradecane (19), and
16 N,N,N-trimethylcyclen (20), were used as chelators for

Analyst Accepted Manuscript

17 Cu2+ instead of DPA. Sensitivity and selectivity assays
18 indicated that 18-AF+Cu2+ has excellent selectivity and
19 sensitivity as a fluorescent probe for H 2S detection. As
20 shown in Figure 10, the fluorescence intensity of 18-
21 AF+Cu2+ showed a large and immediate increase with the
22 addition of 10 μM H 2S, whereas almost no increase in
23 Figure 7. Fluorescence microscopic imaging of living HeLa cells before (A) and
fluorescence is observed with the addition of 10 mM GSH.
24 after (B) the addition of buffered NaHS. 72 In the cases of the other three probes, 17-AF+Cu2+ showed
25 high sensitivity and low selectivity, whereas 19-AF+Cu2+
26 2.2. Fluorescence molecular sensors derived from and 20-AF+Cu2+ showed low sensitivities and high
27 azamacrocyclic Cu(II) ion complex selectivities. Reaction-based methods derived from
28 azamacrocyclic Cu(II) ion complexes overcome the
29 disadvantages of some other methods, e.g., being relatively
30 slow reaction and showing poor selectivity for H 2S over
31 reactive oxygen species.57,78
32
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40
41 Figure 9. Structures of four macrocyclic fluorescein–Cu2+ conjugate.76
42
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45
75
46 Figure 8. Signaling of sulfide ions by 15.
47
48 Recently, a new sulfide-selective chemosignaling
49 system was devised based on a dipicolylamine (DPA)–
50 fluorescein complex 16 with Cu2+ (probe 15).75 The Cu2+
51 ions in probe 15 form stable species with the targeted sulfide
52 ions. The higher stability of Cu 2+–sulfide ion species
53 compare with 15 results in the release of free 16.
54 Concomitantly, the fluorescence of 16 is fully restored by the
55 transformation from probe 15 (quenched, off) to free 16, with
Figure 10. (A) Time course of reactions of 18 without addition (red) or with
56 a detection limit of 420 nM in 100% aqueous solution in addition of 10 mM GSH (orange), 100 μM Na 2S (green), or 10 μM Na2S (blue).
57 response to sulfide anions (Figure 8). The probe has selective (B) Fluorescence spectra of 1 μM 18 before (red) and after (blue) reaction
58 fluorescence-enhancing behavior exclusively with sulfide with 100 μM Na2S.76
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1 2.3. Fluorescence molecular sensors derived from H2S-specific The fluorescence signal should therefore be selective only for
2 Michael acceptors H2S.81 The selectivity can be further demonstrated in Figure
3 11B, from which biological thiols such as cysteine and
4 Recent studies have indicated that many nucleophile-
based approaches suffer from irreversible probe deactivation glutathione, would not cause fluorescence enhancement.
5
on reaction with other nucleophiles, thereby greatly However, NaHS addition promotes obvious fluorescence
6
diminishing the H 2S detection capacity. 79 To detect H2S intensity enhancement immediately.
7
selectively, it is important to differentiate H 2S from other In 2012, Xian et al. devised two closely related sensors,
8
biological nucleophiles, especially thiols such as Cys and probes 25 and 26, which are reversible, and are not
9
GSH. One of the current strategies for addressing this consumed during the detection process (see Figure 12). 80 The
10
two probes were stable toward esterases. H 2S can be detected
11 problem is to interdict possible fluorescence change caused
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by fluorescence turn-on using these probes, as a result of

12 by the reaction of nucleophiles with the probes. The other
13 method is to develop fluorescent probes derived from intramolecular cyclization to release the fluorophore, similar
14 reversible Michael acceptors (an electrophilic conjugated to probe 21. When treated with biological thiols, however, no
15 system acting as an electron acceptor in the Michael addition Michael addition products were isolated. The detection limit
16 reaction). These probes allow chemically reversible reactions for H2S using these probes was found to be ∼1 μM, with a

Analyst Accepted Manuscript

17 with thiols prior to reaction with H 2S and therefore the linear NaHS concentration range of 1–100 μM. Probe 26 was
18 probes are not consumed. 80
19
20
21
22
23
24
25
26
27
28 Figure 12. Structures of 25 and 26.80
29
30 identified as being better than probe 25, because of its higher
31 sensitivity for, and faster reaction with, H 2S. In the treatment
32 of 100 μM NaHS for 30 min with 5 μM probes 25 and 26,
33 probe 25 produced an 11-fold turn-on response. The
34 cyanoacrylate probe 26 proved to be more sensitive to H 2S,
35 and gave a 160-fold turn-on response.
36 Many new but more applicable methods have been
37 proposed, based on this strategy. The novel ratiometric
38 fluorescent probe 27 was synthesized based on the selective
39 nucleophilic addition of HS− to a specific merocyanine
40 derivative in a medium of pH 7.4 (Figure 13). 82 The probe
41 Figure 11. (A) Proposed reaction mechanism of 21 with H2S. (B) Fluorescence
response of probe 21 toward H2S and other thiols: 1) 21 only (100 µM), 2) 21 responds rapidly to intracellular H 2S and was successfully
42 (100 µM) + NaHS (50 µM); 3) 21 (100 µM) + cysteine (50 µM); 4) 21 (100 µM) used for imaging of H 2S in mitochondria of living cells. The
43 + glutathione (50 µM), 5) 21 (100 µM) + glutathione (50 µM) + NaHS (50
µM)81
detection limit of the ratiometric fluorescence sensor was
44
approximately 1 μM. On titration with HS −, the absorption
45
As shown in Figure 11A, H2S reacts with the most intensity at 588 nm of free 27 decreased gradually,
46
electrophilic component of a fluorescent probe such as 21 to confirming the transformation of 27 to 28 as a result of HS−
47
form a free-SH-containing intermediate 22. Then the −SH addition. The solution turned from dark blue to very pale
48
49 group undergoes spontaneous cyclization to release the blue, suggesting that HS− can be detected with the naked eye
50 fluorophore and form product 24 if another electrophile, such using probe 27.
51 as the ester group shown in 22, is present at a suitable
52 position. The corresponding fluorescence signal correlates
53 well with the H2S concentration. Based on these principles,
54 H2S can be quantified using a convenient and sensitive
55 fluorescence measurement. This strategy can also be used for
56 imaging H2S in living cells. Although substrate 21 could
57 potentially react with biological thiols such as Cys, product
58 23 would not undergo cyclization to release the fluorophore. Figure 13. Proposed reaction of 27 with sulfide.82
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15 Figure 14. Structures of 29 and 30.83
16

Analyst Accepted Manuscript

17 Probes 29 and 30 were devised based on a chemical
18 strategy for effective in vivo and in vitro detection of H2S
19 (Figure 14).83 The reactions of probe 29 (10 μM) and 30 (5
20 μM), with Na2S (50 μM) as an aqueous sulfide source, at
21 37 °C in phosphate-buffered saline, yielded a time-dependent
22 fluorescence increase. A greater than 10-fold increase in the
23
fluorescence intensity, accompanied by a blue shift in the
24 Figure 15. (A) Proposed reaction of probe 31 with H2S. (B) Fluorescence
emission maximum from 428 to 391 nm, was observed for response with time for the reactions of 31 with Na2S in HEPES buffer.94
25
probe 29 (ε = 2320 M−1 cm−1, Φ = 0.058). For 30, a greater
26
than 13-fold increase in the fluorescence intensity of the
27
emission maximum at 510 nm was observed when the probe
28
was excited at 465 nm (ε = 47 100 M−1 cm−1, Φ = 0.208).
29
Probes 29 and 30 have excellent selectivities for sulfide, with
30
31 linear responses in the Na 2S concentration ranges 10–50 and
32 5–100 μM, respectively. For 30, the fluorescence intensity
33 increased 2.6–16-fold on addition of 5–100 μM Na2S. This
34 probe is ~260-fold more selective for Na 2S than for Cys, and
35 ~150-fold more selective for Na 2S than for GSH. Similarly,
36 the responses of probe 29 to all the tested thiols were very
low, with at least 50–100-fold selectivities for sulfides. These Figure 16. (A) TPM and (B) OPM images of astrocytes colabeled with (A) 31
37
and (B) MitoTracker Red FM. (C) Merged image. 94
38 reactions, using H 2S at concentrations as low as 1 μM,
39 produce a color change that is visible to the naked eye. The
Joe et al. reported a TP probe, 31, which can image H 2S
40 sensor was also used in a reported study of H 2S imaging in
intracellular in mitochondria (Figure 15).94 According to
41 HeLa cells.
their study, 6-(benzo[d]thiazol-2′-yl)-2-
42
3. Fluorescence molecular sensors suitable for TPM (methylamino)naphthalene, 4-azidobenzyl carbamate, and
43
triphenylphosphonium were used as the fluorophore, and
44 Although some H2S-triggered specific reactions have
response sites for H 2S and mitochondria, respectively. As
45 been successfully developed for intracellular H 2S imaging,84–
46 89 shown in Figure 15A, when the reaction with the azide group
most of these probes are based on one-photon dyes. The
47 was triggered by thiolate, the carbamate linkage was cleaved,
use of such probes for bioimaging with one-photon
48 leading to the release of an amino group. As a result, the
microscopy (OPM) requires a short excitation wavelength
49 emission maximum shifted significantly and the TP cross-
(usually <500 nm); which limits their biological applications,
50 section increased, as shown in Figure 15B. The probe had
because of photobleaching, autofluorescence in cells and
51 good selectivity and high sensitivity, with a detection limit of
tissues, and shallow penetration depths (<100 μm). 90 To
52 0.4 μM for Na2S. The probe was also successfully used in
address these shortcomings, TPM, which uses two photons of
53 astrocyte imaging. The TPM image of 31 merged well with
lower energy as the excitation source, has been proposed.
54 the OPM image of MitoTracker Red, and showed a
TPM has a number of advantages compared with other
55 significant TP cross-section, and a marked blue-to-yellow
strategies, including greater penetration depth (>500 μm),
56 localization of excitation, and extended observation times. 91–
emission color change in response to H 2S (Figure 16).
57 93
To date, only a few two-photon (TP) probes have been
Figure 17 shows a similar probe, 32, which was
58 developed by Joe et al.94 This probe also showed excellent
developed for intracellular H 2S imaging.80
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ARTICLE Journal Name
1 selectivity for H 2S, with a detection limit of 0.2 μM.
2 However, the TP action cross-section (Φδmax, where δ is the
3 TP absorption cross-section) values of probe 31 were
4 1.9−2.3-fold larger than that of 32. The TPM images of cells
5
labeled with 31 were much brighter than those labeled with
6
32, although both probes showed high photostability. These
7
results indicate that probe 31 is more suitable for H 2S
8 Figure 19. Structures of 34 and 35.95,96
detection than probe 32.
9
At almost the same time, another new TP bioimaging
10
probe, 6-(benzo[d]thiazol-2′-yl)-2-azidonaphthalene (33),
11 4. Sensors based on FRET for H2S detection
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was developed (Figure 18).90 This probe uses a donor–π-

12
acceptor-structured naphthalene derivative as the TP FRET is a non-radiative energy transfer process in
13
14 fluorophore and an azide group as the recognition unit. The which the excitation energy of the donor is transferred to a
15 probe shows high selectivity and sensitivity to H 2S in the proximal ground state acceptor via long-range dipole−dipole
16 linear response concentration range (0−5 μM), with a interactions and/or short-range multipolar interactions. 97 The

Analyst Accepted Manuscript

17 detection limit of 20 nM. The selective recognition of H 2S by fabrication of fluorescent sensing systems is simple,
18 33 is based on the reducing properties of sulfides. Probe 33 therefore FRET-based probes are widely used for biological
19 alone is non-fluorescent. The addition of NaHS results in applications.98–108 Unlike one-signal sensors, a FRET-based
20 conversion of the electron-withdrawing azido group in 33 to probe is not dependent on the concentration of a single
21 an electron-donating amino group with significant emissive probe, but uses the ratio of two fluorescence
22 enhancement of the characteristic fluorescence emission peak intensities to detect analytes quantitatively. This method can
23 (480 nm). All these features indicate that the probe is suitable eliminate most ambiguities in the detection by self-
24 for directly monitoring H 2S in complex biological samples. calibration of two emission bands.109–111 The efficiency of
25 the FRET-based process is distance dependent, and this
26 provides the basis for the design of FRET probes with
27 analyte-induced donor–acceptor distance changes. 112 The
28 distance scale for detection based on FRET is limited by the
29 nature of the dipole−dipole mechanism, which effectively
30 constrains the scale to distances of the order of <100 Å. 98
31 FRET-based probes are used to detect a wide range of
32 species, including DNA, metal ions, and small molecules.
Figure 17. Proposed reaction of probe 32 with H2S.94
33
34 No FRET FRET
35
36
37
38 H2S（aq）
39
40
41 v

42 Figure 18. Proposed reaction of probe 33 with H2S.90 Label on Label off
43
44 Cho et al. reported a TP probe, 34 (Figure 19), which Figure 20. Schematic of FRET based on fluorescent label of Co-PDF.113
45 showed a 21-fold TP-excited fluorescence enhancement in
46 response to H2S. This probe also selectively detected H 2S in
47 rat hippocampal slices at a depth of 90–190 μm, usingTPM.95
48 Fan et al. synthesized a TP fluorescent probe, 35, with a
49 near-infrared (NIR) emission, for H 2S detection.96 The probe
50 was successfully used for H 2S imaging in bovine serum,
51 living cells, tissue, and live mice. The principle of these
52 probes in H2S detection is based on reduction of the azide
53 group to an amino group; which is similar to the reaction-
54 based methods using azides.
55
56
57 Figure 21. (A) Absorption spectrum of H 2S-free Co-PDF (gray) and the H2S-
bound form (dark gray) and emission spectrum (dotted trace) of Atto620
58
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Journal Name ARTICLE
1 (λmax = 645 nm). (B) Fluorescence emission spectrum (λex = 620 nm) of Using quantum dots (QDs) as a donor in the sensing
113
2 Atto620-labeled H2S-free (black trace) and H 2S-bound (gray trace) Co-PDF.
process, FRET probes based on QDs have received much
3 attention because of their high fluorescence quantum yields,
4 Recently, FRET was successfully used by Strianese et al.
narrow emission bands, high Stokes shifts, and stability
5 in H2S sensing based on fluorescent-labeled cobalt peptide
against photobleaching.116–121. These QDs based FRET
6 deformylase (Co-PDF; Figure 20).113 The absorption
sensing strategies are powerful tools and are promising for
7 spectrum of Co-PDF has a band at 280 nm, and three less
applications in biological imaging. Although they have
8 intense bands, centered at 320, 560, and 660 nm. 114 H2S
potential excellences including high sensitivity, excellent
9 quenches the bands of 560 and 660 nm, and two new bands
biocompatibility, and in vivo detection, little attention has
10 appear, at 625 and 665 nm (Figure 21A). Based on this, the
been paid to endogenous H 2S imaging. In order to further
11
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authors synthesized a probe by covalent attachment to the

understand the pathophysiological effects of endogenous H 2S,
12 protein of a fluorescent dye label (Atto620) with an emission
13 more work should be performed using fluorescence detection,
spectrum that overlaps with either 625 or 665 nm band of the
14 especially FRET sensing based on QDs.
protein in its H 2S-bound state. When the protein is in the
15 Fortunately, a FRET ratiometric fluorescence sensor,
H2S-free state, all the energy absorbed by the label is emitted
16 which employs carbon dots (CDs) as the energy donor and
as fluorescence. However, the label fluorescence is (partly)

Analyst Accepted Manuscript

17 anchoring site, was reported in 2013 (Figure 23).122 In the
quenched when H2S is present, because of FRET to the 625
18 absence of H2S, CD excitation at 340 nm led to emission by
and 665 nm bands (Figure 21B). The detection limit of the
19 the CDs at 425 nm. In the presence of H 2S, the CD emission
proposed system was found to be in the micromolar range.
20 at 425 nm gradually decreased, and a new emission band
The authors also examined the selectivity of the probe in the
21 appeared at 526 nm. This phenomenon was attributed to
presence of biologically relevant and potentially competing
22 reduction of the naphthalimide-azide to naphthalimide-amine
thiols such as L-Cys and GSH. The results indicate that the
23 by H2S, resulting in FRET by the CDs to naphthalimide-
probe was highly selective for H 2S, and little interference
24 amine. The sensor displayed good selectivity for H 2S over a
was observed.
25 number of biologically relevant thiols such as GSH, Cys, and
Combining the advantage of the characteristics of a NIR
26 some other anions. The detection limits were found to be 10
optical response with the sensitivity of a FRET based
27 nM in buffer and 19.5 nM in bovine serum, with a wide pH
fluorophoric response for the construction of a chemosensor
28 range of 4.0–9.0. More importantly, this system achieved
29 probe, another FRET-based sensor for S2- sensing was
H2S imaging in HeLa and L929 cells.
30 reported recently. 115 The receptor, L 1, was used as a
31 resonance-energy-transfer-based sensor for the detection of
32 Cu2+, based on a process involving a donor indole and a
33 Cu2+-bound xanthene fragment acceptor. Formation of the
34 corresponding product, an L 1–Cu complex, is selectively
35 reversible in the presence of sulfide anions (Figure 22). HeLa
36 cells were used as a model to check the imaging ability of the
37 probe. The results showed that the L 1–Cu complex could
38 readily cross the membrane barrier, permeate into HeLa cells,
39 and rapidly sense intracellular S 2−. However, the probe needs
40 a Cu2+-bound xanthene fragment as the acceptor to form the
41 L1–Cu complex. This requirement is an obstacle to further
42 applications in S2− imaging, and Cu2+ can cause
43 environmental pollution and cell damage.
44
45
2- 122
46 Figure 23. Schematic of FRET in S sensing.
47
48
5. Comparsion of fluorescence sensing strategies
49
50 and traditional methods for H2S detection
51 Traditional methods for H2S detection include
52 colorimetry, gas chromatography, electrochemical analysis,
53 and metal induced sulfide precipitation. These methods
54 showed various sensitivities to different samples. Although
55 they seem more sensitive in some aspects compared to
56 fluorescence sensing, fluorescence sensing strategies are
57 L1-Cu complex more appealing and have some other advantages. Table 1
58 Figure 22. Schematic of FRET in S sensing.115
2-
compares traditional methods and new fluorescence-sensing
59
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ARTICLE Journal Name
1 detection methods. In some aspects, the traditional methods, sensing has excellent prospects for applications in sulfide
2 such as gas chromatography, are extremely sensitive to H 2S imaging. However, it is important to note that challenges
3 with the reported detection limits under 0.2 pM. However, such as poor detection limits remain. The intracellular
4 extreme conditions such as high alkalinity (pH = 8.5) are concentration of H 2S has been reported to be nM levels and
5
required to achieve detection. 27 Moreover, traditional would rise to low µM levels in response to physiological
6
methods cannot be used in cell imaging, require large stimuli under extreme cases.11,76,130 Without stimulation, the
7
instruments for quantitative H 2S detection, and cause cell concentration may be lower due to the stimulation increasing
8
damage. These requirements mean that many detection H2S release.131,132 Moreover, some thiol groups may occupy
9
methods can be used for imaging in vitro, but not in vivo. part of the sensors in the detection process. Therefore, it is
10
In contrast, fluorescence sensing requires moderate important to further improve the sensor’ sensitivity in
11
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detection conditions such as neutral pH and room consideration of the low detection limit . And also, the
12
13 temperature.125–129 As the data in Table 1 have shown, fluorescence sensors were mainly derived from chemical
14 fluorescent probes have excellent biocompatibilities with materials. These materials may degrade or react with other
15 HeLa cells, C6 cells, HEK293 cells, and mutant mice. The agents in the environment which limiting their stability at
16 success of fluorescence imaging in living cells has expanded long-term usage.

Analyst Accepted Manuscript

17 their application range, especially in clinical and biomedical
18 sciences. Based on these attractive advantages, fluorescence
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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42
43
44
45
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1
2 Table 1. Comparison of Detection Methods for H2S
3
4 detection methods linear range LOD biological application pH intracellular/ reference
5 extracellular
6
7
8
9 intracellular/
colorimetry a – 1.112 mM b c 9.0 123
extracellular
10
11
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12 gas
a 0.2 pM c 8.5 extracellular 28
chromatography
13
14
15 electrochemical 0.6 nM – 10 nM 0.2 nM c > 7.0 intracellular/ 29
16 analysis a 10 nM c < 6.8 extracellular 30

Analyst Accepted Manuscript

17
18 metal induced
19 sulfide 10 nM – 1 mM 0.31 nM c 6 extracellular 31
precipitation
20
21
22
a – 100 μM 1 μM C57BL6/J mouse model 7.5 24
23 a 5 μM and 1 µM HeLa cells 7.4 47
sensors derived
24 from azide or
a 5 μM – 10 μM HEK293T cells 7.4 intracellular/ 57
25 a – 50 nM 0.7 nM C6 cells 7.4 extracellular 58
nitro
50 nM – 1 mM 20 nM fetal bovine serum 7.4 59
26 10 µM – 50 µM b HeLa cells 7.4 72
27
28
29 sensors derived
30 from an
a 420 nM c 7.0 intracellular/ 75
31 azamacrocyclic
a < 10 µM HeLa and HEK 293 cells 7.4 extracellular 76
Cu(II) ion
32 complex
33
34
35 1 µM – 100 µM ~ 1 µM COS7 cells 7.4 80
sensors derived
36 a – 10 µM a COS7 cells 7.4 intracellular/ 81
from H2S specific
37 a ~ 1 µM MCF-7 cells 7.4 extracellular 82
Michael acceptors
10 µM – 50 µM b HeLa cells 7.4/7.0 83
38
39
40
41 a – 5 µM 20 nM HeLa cells 7.4 90
42 TPM
a 0.2 µM and 0.4 µM HeLa cells 7.4 intracellular/ 94
43 100 µM – 300 µM 5 µM – 10 µM HeLa cells 7.2 extracellular 95
25 µM – 250 µM 3.05 µM MCF-7, HeLa cells and 7.4 96
44 mice tissue
45
46 a 10 nM HeLa and L929 cells 4.0 – 9.0 intracellular/ 122
47 FRET
a b HeLa cells 7.3 extracellular 124
48
49 a
No reported or uncertain results. bNo reported results. cNo or have not reported yet. LOD: limit of detection.
50
51
52
53
54
55
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1
2 Journal Name RSCPublishing
3
4
5
6
ARTICLE
7
8 seas, in flooded soils such as rice paddies, and technical
9 6. Outlook and further application aqueous systems such as sludge digesters and oil tanks. 144–146
10
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These bacteria have been recognized as a major group of

11 6.1. Fluorescence sensors based on QDs for H2S detection
microorganisms linked to anaerobic corrosion. 147–152
12 As mentioned in the section of Introduction, H2S is a toxic Biocorrosion causes energy and efficiency losses and structural
13 gas that causes biological damage and human diseases. The failures, resulting from corrosion of pipes and equipment. 153
14
rotten egg smell of tainted food, water eutrophication, and fecal Recently, SRB have been used in the bioprecipitation of metal
15
contamination is always related to H 2S formation. Although ions, and their potential use in remediation has received a great
16
deal of attention.154–161 Under favorable conditions, i.e., an

Analyst Accepted Manuscript

recent studies have focused on gaseous signaling, it is important
17
to detect kinetic variations of H 2S, to determine its potential acidic environment and the presence of organic compounds
18
effects on the environment, especially in biocorrosion and such as acetate as electron donors, SRB can catalyze oxidation
19
20 human health. reactions and reduce sulfate to H 2S:162–165
21 The use of fluorescence sensing as a H2S detection 2CH3 CH2 OH + 3SO4 2- + 3H+ → 3HCO3 - + 3H2 S + 3H2 O + CO2
22 strategy has several advantages such as moderate conditions, in (1)
23 vivo imaging, and high sensitivity. Much work has been carried Then, Metal ions present in groundwater form stable, insoluble
24 out on the use of these probes in bioimaging, labeling, metal sulfides in the presence of H2S:
25 separation, disease diagnosis, and therapy. However, there are H2 S + Metal2+ → MetalS(s) + 2H+ (2)
26 still several obstacles and limitations such as low sensitivity, Based on this sense, it will be of great significance to
27 low stability, and non-real-time imaging. FRET methods, as a indicate sulfate reducing bacteria activity for anticorrosion and
28 special fluorescence-sensing strategy, are more attractive for heavy metals removal. However, the currently available
29 specific in vivo and in situ imaging. The use of FRET expands characterization methods are inconvenient, because of the need
30 the application range of sulfide fluorescence analysis. for auxiliary equipment. 164−167 In 2011, McMahan et al.
31 Although numerous examples of fluorescence-sensing proposed a method for detecting fecal bacteria via H 2S tests
32 strategies in the detection of H 2S are presented in this review, using culturing and molecular methods. 168 However, no specific
33 these strategies, especially FRET, remain underused and methods have yet been reported for detecting bacterial activity
34 underappreciated as analytical tools. The primary obstacle is via H2S analysis, because many difficulties are encountered. As
35 their relatively low sensitivities compared with traditional shown in Equation 1, the SRB activity is directly related to H 2S
36 methods. QDs, because of their unique optical profiles, have concentration. A simple, sensitive, and real-time method, based
37 been combined with many sensing strategies used in on fluorescence-sensing strategies for H 2S detection, could be
38 bioanalysis.133–142 In the past, many studies have shown that developed for determination of SRB activity via sulfide
39 QDs are excellent donors in FRET and have several advantages detection.
40 in metal ion and compound detection compared with molecular
41 fluorophore donors. However, there is no fluorescence 7. Conclusions
42 detection of sulfide based on QDs reported although some other
43 nanomaterial, such as Au-Ag core-shell nanoparticles, was H2S is of particular interest, because of the important roles
44 designed as probes for sulfide mapping in living cells in it plays in physiological equilibria. Many methods have
45 2013.143 The unique optical properties of QDs and the therefore been developed to assess the levels of sulfide in
46 modulation of those properties via FRET would provide drinking water and wastes, and for H 2S imaging in living cells.
47 researchers with a versatile toolkit for bioanalyses. Multiplex This review provides a comprehensive overview of the
48 detection is possible using new formats that are simple, flexible, development of fluorescence sensors for sulfide detection in
49 and anticipated to enable the future development of novel recent years, including reaction-based strategies and FRET
50 sensing. The design of FRET-based sulfide-selective
diagnostic techniques and intracellular probes. Although
51 chemosensors, especially using QDs as donors, has attracted
significant challenges remain, FRET nanosystems could serve
52 much interest, despite the disadvantage of low sensitivity.
as practical tools for biological studies.
53 Important potential applications in SRB activity determination
54 6.2. Possible application in SRB activity detection during are discussed, and future developments are indicated. Although
55 anaerobic corrosion these new sensors are promising, it is worth noting that much
56 work still has to be done on improving their sensitivities and
57 SRB are widespread in marine and terrestrial aquatic
environments. They can be found in the sediments of lakes and stabilities.
58
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1
Acknowledgments 9. Reiffenstein, R. J.; Hulbert, W. C.; Roth, S. H. Annu. Rev. Pharmacol.
2
This study was financially supported by the National Natural Toxicol. 1992, 32, 109−134.
3
Science Foundation of China (51178171, 51039001, 41271294). 10. Kamoun, P.; Belardinelli, M. C.; Chabli, A.; Lallouchi, K.;
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The authors declare no competing financial interest. 519−531.
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3-MST 3-mercaptopyruvate
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CTAB cetyltrimethyl ammonium bromide

Analyst Accepted Manuscript

17 16. Li, L.; Hsu, A.; Moore, P. K. Pharmacol. Ther. 2009, 123, 386−400.
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32 Fairclough, S. M.; Smith, J. M.; Giovanelli, E.; Lequeux, N.; Pons, T.; Marazioti, A.; Zhou, Z.; Jeschke, M. G.; Branski, L. K.; Herndon, D.
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