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Surname et al. Chem Synth Year;Volume:NumberDOI: 10.20517/cs.2021.04
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Chemical SynthesisReview1
2
Gas probes and their application in gas therapy3
4
Wan-Jun Gong1,2, Zhi-Qiang Yu3, Qian-Jun He1,4#5
61School of Biomedical Engineering, Health Science Center, Shenzhen University,7
Shenzhen 518060, Guangdong, China.82Shenzhen Hospital of Southern Medical University, Shenzhen 518052, Guangdong,9
China.103Guangdong Provincial Key Laboratory of New Drug Screening, School of11
Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515,12
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technology is required to monitor the gas amount in vivo. Besides, the transportation of31
gas into human body and in vivo biodistribution of gas are also needed to be evaluated.32
Among the technologies adopted in gas therapy, fluorescence imaging technology is the33
first choice due to its high specificity, high sensitivity, and non-invasion. And as the34
core of fluorescence imaging, the properties of fluorescent dyes directly determine the35
quality of imaging. So, it is critical to choose suitable gas probes for different purposes.36
Here, we review common gas detection methods, including a brief introduction of37
fluorescence, the distinctive properties of five fluorophore cores, and the detection38
mechanisms of common gas probes. Then, the applications of gas probes in gas39
delivery, gas release, and gas therapy are summarized. At last, we discuss the potential40
of developing further intelligent gas probes and fluorescence imaging technologies for41
gas therapy.42
43
Keywords: Gas therapy, fluorescence imaging, gioprobe, gas detection, gas delivery44
45
Graphical Abstract46
4748
49
INTRODUCTION50
In the past decades, there are several small gas molecules including NO (nitric oxide),51
CO (carbon monoxide), CO2 (carbon dioxide), H2S (hydrogen sulfide), O2 (oxygen),52
NO2 (nitrogen dioxide), and H2 (hydrogen), which can exhibit biological effects in the53
human body. NO, for example, has been regarded as a serious air pollutant and54
poisonous to human health for a long time. But a more comprehensive understanding of55
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NO was achieved when NO was uncovered to be a signal molecule generated by56
endothelial cells in the presence of acetylcholine responsible for the relaxation effect.57
Along with relaxation function, NO also regulates cellular processes, such as58
angiogenesis, immune response, apoptosis, and synaptic communication. Moreover,59
NO radical has been proven to be involved in the etiology and progression of many60
diseases including various cancers.61
62
In contrast to compounds of structural complexity, gas molecules are easier to obtain63
and more stable under physical conditions. In addition, their transport into the human64
body could be achieved through several means such as direct inhalation or consumption65
of gas-rich water. Due to these advantages, a newly burgeoning field, gas therapy, has66
emerged. Gas therapy has distinct advantages over pharmaceutical drugs. First, gas67
molecules are extremely small so that they can easily cross biomembranes and diffuse68
into varied subcellular organelles. With these advantages, the gases may be effective in69
treating clinically many diseases. Moreover, gas molecules such as hydrogen are much70
biosafer and have fewer toxic side effects than traditional drugs and multidrug71
resistance could be overcome to a certain extent when gases are integrated with drugs.72
73
Only at the right location and proper concentration, therapeutic gases can play their74
therapeutic effects and biological roles. Thus, it is of significant importance to monitor75
the biodistribution and concentration of therapeutic gases during treatment. As having76
been developed for years, imaging systems like CT (computed tomography) in clinical77
research could allow us to get the details of attractive targets, but in terms of small78
molecules, particularly in vivo imaging, fluorescence imaging is frequently the first79
choice. With a suitable fluorescent probe, a fluorescence microscope could provide us80
the detailed structure of an interesting target, and because of non-invasiveness,81
fluorescence imaging has become one of the most popular methods to study the82
dynamic behavior of drugs in live cells and animal models. Recently, NIR fluorophores83
have greatly improved imaging quality in deep-tissue imaging. Combined with the84
importance of gas therapy, a big challenge in achieving in vivo gas monitoring is to85
design appropriate fluorescent probes. Thus, we here provide a review concentrated on86
the fluorophores used in gas therapy involving the fluorescent properties, the87
mechanisms of turn-on or turn-off when reacting with therapeutic gases, and their88
applications in gas therapy.89
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90
FLUORESCENT PROBES FOR GAS DETECTION91
As illustrated by the Jablonski diagram in Figure 1a, a molecule in the S0 state could92
absorb certain energy to jump up to the S1 stage, then returns to the S0 stage by emitting93
a photon normally. These molecules could be termed fluorophores, and this94
phenomenon is fluorescence. The fluorescence was discovered for the first time in 184595
by Fredrick W. Herschel when a quinine solution was illuminated by a UV light, the96
blue light was observed. Following this, the growing fluorescence foundation was97
reported and numerous fluorophores were discovered or synthesized. Fluorophores98
refer to small organic molecules (20-100 atoms) which are most widely used and99
explored. However, fluorescent proteins such as green fluorescent protein and100
fluorescent particles such as quantum dots widen fluorophore family. But as a kind of101
specific probes or sensors, organic fluorophores are often the first choice because of102
their broad spectral range, small size, high photostability, and high brightness.103
104
105
Figure 1. Jablonski diagram (a) and several commonly used fluorophore cores (b).106
After decades’ development, many organic fluorophores with excellent photophysical107
properties have been designed and synthesized. These organic fluorescent molecules108
have not only enriched the family of fluorescent dyes but also help researchers to solve109
a wide range of problems. Though the structures of fluorescent molecules vary across110
molecules, the core structure that is responsible for absorbing and emitting light111
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remains the same. Generally, synthesized organic dyes are based on several basic112
structures, such as coumarin, 1,8-naphthalimide, BODIPY (boron-dipyrromethene),113
xanthene, pyrene, and cyanine (Figure 1b). These basic structures own their distinct114
advantages. For example, regarding fluorophores based on xanthene, including115
fluoresceins and rhodamines, their high photostability and high fluorescence quantum116
yields make them suitable for long-duration imaging. And the absorbance and emission117
wavelength could be adjusted by modifying their structures to extend their applications.118
But due to the existence of hydroxyl and amine groups, most of them are sensitive to119
pH. So, environmental acidity must therefore be taken into consideration when they are120
used for molecular recognition. But this problem does not exist in most BODIPY-based121
probes. In this section, we summarized a variety of gas probes based on different122
fluorophore cores including their structural characteristics (Figure 2), photophysical123
properties (Table 1), and gas detection mechanisms.124
125
126
Figure 2. Typical fluorescent probes for detection of varied gas molecules.127
128
Coumarin-based gas probes129
Coumarin compounds are a class of important heterocyclic chemicals that widely exist130
in nature, and the coumarin core itself owns excellent optical properties. Moreover, the131
introduction of an electron acceptor group in the 3/4 position and an electron donor132
group in the 6/7 position could form a pull-push electron system, leading to an increase133
of fluorescence quantum yield. And this pull-push electron system could be further134
modified to control fluorescence behaviors. Taking advantage of easy modification,135
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high fluorescence quantum yield, large Stokes’s shift, good stability, and high cell136
penetration ability, coumarin derivatives are utilized for ion and small molecule137
detection. And in the field of gas molecule recognition, coumarin-based probes are138
typically used for intracellular detection of H2S and SO2.139
The coumarin core structure is rigid and stable, and hard to be chemically attacked. But140
a π-conjunction system with expanding modification could not only change its141
photophysical properties but also give rise to chemical reactivity. For instance, inspired142
by Salicylaldehyde, the aldehyde group on coumarin was found to be reactive [1–3], and143
this structure could be used for SO2 detection. Another way to endow coumarin with144
gas detection performance is also to introduce unsaturated bonds [4–7]. The conjugated145
system would be broken if these bonds reacted with analytes, and the fluorescence146
signal changed consequently. Coumarin-based fluorescent probes are also useful for147
sensing H2S. Hatai Joydev[8] prepared coumarin-based spherical nanoparticles, in which148
the fluorescence was quenched by Pd2+. And after reacting with H2S, the polymer149
decomposed and fluorescence recovered. Another strategy used for detecting H2S is the150
reducing reaction of NO3 into NH2[9]. Once the reaction was triggered by H2S,151
coumarin analogues would shed high fluorescence because of the distinction of152
electronegativity between azido and amino groups.153
154
After a credible method for gas detection was established, fluorescent probes began to155
be used for varied purposes in gas therapy. W. Shen[10] and coworkers designed and156
synthesized a kind of glutathione (GSH)-responsive polymer prodrug of SO2. To157
investigate intracellular release of SO2 triggered by thiol, DEACAwas adopted as a158
fluorescent probe, and after reacting with released SO2, fluorescence intensity of the159
probe increased by three folds. S. Li[11] also used DEACA to study the photo-induced160
release of SO2 from NIR-sensitive nanoparticles. By comparing the fluorescence161
change at 483 nm of different samples, they proved that SO2 was controllably produced162
by applying 980 nm laser stimuli.163
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164
Figure 3. Typical gas probes based on the coumarin core. a, Coumarin-based probe for165
SO2 detection; b, NDI-based probe for NO detection; c, Rhodamine-based probe for166
H2S detection; d, BODIPY-based probe for CO detection; e, Fluorescein-based NO167
detection; f, Methylene blue-based probe for H2 detection; g, Cy7-based probe for H2S168
detection.169
170
BODIPY-based gas probes171
BODIPY dyes are a widely used fluorophore family because their core is highly172
tolerant to substitutions for varied applications. And a small addition to the core173
structure could cause a change in fluorescence properties. In addition to this advantage,174
BODIPY-based fluorophores generally have a high molar extinction coefficient and175
high fluorescence quantum yield, and these properties are solvent-independent.176
Otherwise, the small FWHM (full width at half maximum) of emission spectra benefits177
them in the collection of fluorescence signals to avoid the interruption of other178
fluorescent materials. Moreover, BODIPY-based fluorophores commonly have high179
photostability, making them suitable for long-time observation applications. Owing to180
these excellent properties, BODIPY-based fluorophores have been widely utilized in181
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various fields.182
183
As the structure illustrates, BODIPY fluorophores own up to 7 sites to modify. As a184
result, their fluorescence could be quenched by several methods. So, different gas185
detection strategies have been designed based on the cleavage of quenching fraction.186
For example, as known to all, heavy metals could efficiently quench fluorescence. So, a187
palladium-mediated carbonylation reactivity-based CO probe (COP-1) was reported by188
B. W. Michel [12]. The fluorophore of probe was based on BODIPY whose fluorescence189
was quenched by the Pd atom via heavy-atom electronic effect. Upon reacting with CO,190
Pd was released and its fluorescence recovered. Using this method, the as-prepared191
probe could selectively react with CO over a variety of reactive nitrogen, oxygen, and192
sulfur species and can be used to image CO in living cells[13,14]. A similar strategy was193
also used for the detection of H2S in the presence of Co[15]. Another quenching method194
involves levulinate[16] and aromatic diamine[17] which are easily and selectively reacted195
with sulfite[16] and NO[17], respectively.196
197
Besides the quenching moiety, the photophysical property of fluorophore could also be198
regulated by other methods. In some cases, reaction or environment change could199
interrupt the photo-induced electron transfer (PET) or the intramolecular electron200
transfer (ICT)[18]. For example, when the adjacent hydrogen atoms in an aromatic201
structure are replaced by aldehyde and α, β-unsaturated moiety, the CHO group is ready202
to react with free sulfide and the formed intermediate could further react with the203
unsaturated bond by the Michael addition to generate a thioacetal. Based on the tandem204
reaction, a BODIPY-based H2S probe was synthesized by Y. Qian[19] and used to205
monitor enzymatic H2S biogenesis and image-free sulphide in living cells.206
207
It is common sense that the environmental pH value should be taken into consideration208
in probe designing because photophysical properties are easily influenced by the pH209
change, especially when they own pH-sensitive groups. But on the other side, this kind210
of probes could be utilized since the dissolving process of CO2 is usually accompanied211
by pH change. Based on this strategy, I. Klimant[20] synthesized a set of BODIPY-based212
NIR molecules with hydroxyl groups for CO2 detection.213
214
Xanthene-based gas probes215
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Xanthene fluorescent dyes are mainly divided into two types according to the216
substituents on the 3 and 6 sites, which were substituted by amino and hydroxyl217
compounds for construction of rhodamine[22] and fluoresceins[21], respectively. With218
similar structures, two types shared the similar features such as good photo-resistance,219
high absorption coefficient, high fluorescence quantum yield, and relatively long220
emission wavelength. But due to the distinctive properties of nitrogen and oxygen221
atoms, rhodamine commonly owns higher emission intensity and more modification222
sites than fluoresceins. However, compared to rhodamine, fluorescein derivatives223
always are more water-soluble.224
225
There are three typical principles for designing fluorescent probes based on rhodamine226
and fluorescein. First, it should be noticed that carboxylic and hydroxyl groups in the227
structure could react with the double bond to yield spirocyclic derivatives. As a result,228
the fluorescence turns off once the conjunction system of xanthene was broken. Based229
on this strategy, a NO fluorescent probe was designed and synthesized by J.-G. Xu[23],230
Rhodamine NO-2 consisted of two parts, rhodamine B spirolactam, and231
o-phenylenediamine. The spiro ring of rhodamine would open while amino group was232
diazotized and then the intermediates hydrolyzed into rhodamine B and benzotriazole233
with fluorescence enhancement. Using the similar strategy, another fluorescent probe234
based on fluorescein (Fluorescein-H2S-2) was reported by W. Guo[24].235
236
Apart from the ring-opening and closing principle, another design concept is based on237
the introduction of a new recognition moiety. As early as 1998, T. Nagano reported the238
fluorescein-based NO probes[25] whose NO detection was based on the reaction239
between NO and vicinal diamines. They introduced an aromatic structure containing240
two amine groups to the meso position of fluorescein. After the formation of a triazole241
with NO, fluorescence quantum efficiency increased by more than 100 times. Later,242
this diamines approach was further used in designing varied NO detection probes based243
on xanthene[26–28].244
245
Another major design concept is based on the protection of hydroxyl group. K. Koide246[29] reported a fluorescent ozone probe based on fluorescein using butenyl as a247
protection group. The terminal olefin of the probe could react with O3 via cycloaddition,248
and the intermediate then decomposed to give an aldehyde which further underwent a249
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β-elimination reaction. At last, the deprotected fluorescent species were formed with250
the production of acrylaldehyde. Compared to previously reported probes, the251
selectivity of the xanthene-based ozone probe is much better, and the product is252
fluorescent so the reaction is visualized easily. Levulinate, as mentioned above, is253
another protection moiety and readily reacted with H2S. Following the similar concept,254
other fluorescent probes based on xanthene were built for the detection of H2S[30,31] and255
CO[32,33].256
257
Cyanine-based gas probes258
With increasing requirements of fluorescence imaging, common fluorophores emitted259
photons in the UV/Vis window are not suitable for deep tissue imaging. Thus, the260
fluorophores which could emit fluorescence in the NIR window are more attractive.261
Though common fluorophores could be modified to expand their conjunction system,262
their synthesis is complicated and the products are fragile. Cyanine, a commonly used263
fluorophore, could be easily prepared relatively. The photophysical properties rely on264
its methene group number, and thus the emission wavelength could be effortlessly265
tuned to NIR, which makes cyanine dyes suitable for bioimaging and protein-labeling.266
267
B. Tang and coworkers[34] reported a tandem nucleophilic addition/cyclization268