An effective biocompatible fluorescent probe for bisulfite detection in aqueous solution, living cells, and mice

Article abstract of DOI:10.1039/d0ra03329d

Sulfur dioxide, an air pollutant, is easily hydrated to sulfites and bisulfites and extremely harmful to human health. On the other hand, endogenous sulfur dioxide is the fourth gasotransmitter. In view of the above, it is worth developing an effective method for the detection of these compounds. In this paper, a novel colorimetric fluorescent probe (Hcy-Mo), based on hemi-cyanine, for bisulfites is reported. Hcy-Mo shows excellent selectivity for bisulfites over various other species including cysteine, glutathione, CN-, and HS-, and undergoes 1,4-addition reactions at the C-4 atom of the ethylene group. The reaction can be completed in 30 s in a PBS buffer solution and displays high sensitivity (limit of detection is 80 nM) for bisulfites. Test paper experiments show that the probe can be used for bisulfite detection in aqueous solutions. In addition, Hcy-Mo exhibits excellent cell permeability and low cytotoxicity for the successful detection of bisulfites in living MDA-MB-231 cells and in living mice, implying that this probe would be of great benefit to biological researchers for investigating the detailed biological and pharmacological functions of bisulfites in biological systems. This journal is

Full text of DOI:10.1039/d0ra03329d

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An effective biocompatible fluorescent probe for
bisulfite detection in aqueous solution, living cells,
and mice†
Cite this: RSC Adv., 2020, 10, 25352
a
c
Ruqiao Zhou,
Guiling Cui,b Yuefu Hu,b Qingrong Qi,b Wencai Huang
a
*
and Li Yang
Sulfur dioxide, an air pollutant, is easily hydrated to sulfites and bisulfites and extremely harmful to human
health. On the other hand, endogenous sulfur dioxide is the fourth gasotransmitter. In view of the above, it is
worth developing an effective method for the detection of these compounds. In this paper, a novel
colorimetric fluorescent probe (Hcy-Mo), based on hemi-cyanine, for bisulfites is reported. Hcy-Mo
shows excellent selectivity for bisulfites over various other species including cysteine, glutathione, CNꢀ,
and HSꢀ, and undergoes 1,4-addition reactions at the C-4 atom of the ethylene group. The reaction can
be completed in 30 s in a PBS buffer solution and displays high sensitivity (limit of detection is 80 nM) for
bisulfites. Test paper experiments show that the probe can be used for bisulfite detection in aqueous
solutions. In addition, Hcy-Mo exhibits excellent cell permeability and low cytotoxicity for the successful
detection of bisulfites in living MDA-MB-231 cells and in living mice, implying that this probe would be of
great benefit to biological researchers for investigating the detailed biological and pharmacological
functions of bisulfites in biological systems.
Received 14th April 2020
Accepted 5th June 2020
DOI: 10.1039/d0ra03329d
rsc.li/rsc-advances
Therefore, it is vital to nd a fast and efficient method for in vivo
bisulte detection.
Introduction
There are some conventional detection methods for bisul-
tes, such as colorimetry, titrimetry, chromatography, and
electrochemical analysis.19–24 Unfortunately, it is difficult to
apply these methods to endogenous bisulte detection in real
time due to the limitations of the methods and equipment.
Recently, carbon dots,25,26 quantum dots,27,28 and uorescence-
based probes have emerged as uorescent materials for bio-
sensing. Among them, uorescence-based probes are a prom-
ising class due to their non-invasiveness, high sensitivity, and
high temporal and spatial resolution.29–33 At present, bisulte
uorescent probes mainly include dinitrile alkenyl,34,35 dinitrile
alkenyl analogs,36–38 aldehyde derivatives,39–41 and nitro-
containing compounds.42 However, these types of probes have
some disadvantages, including a long response time, unsatis-
factory limits of detection, and interference from biothiols,
which limit their application. In contrast, hemi-cyanine has
many advantages such as simple preparation, low cost,
membrane permeability, organelle targeting and so on.43–45
Therefore, it is highly desirable to develop a novel uorescent
probe for biological samples. Many uorescent probes have
previously been reported in the literature,43,44,46–50 however,
improvements are required for some properties. Therefore, an
ideal uorescent probe for in vivo bisulte detection is still
needed.
Bisultes are widely used in the food, beverage, and pharma-
ceutical industries as essential preservatives due to their anti-
oxidation properties and ability to inhibit microbial growth
and prevent discoloration.1,2 However, pathological studies have
found that high concentrations of bisultes are associated with
inammation,3–6 respiratory diseases,7 chromosomal aberra-
tions,8,9 system diseases,10–13 and even cancer.14 On the other
hand, sulfur dioxide, one of the most well-known air pollut-
ants,15,16 can dissolve in water and form an equilibrium state
between the sultes and bisultes. However, recently
researchers have found that endogenous sulfur dioxide, which
is present as bisultes in vivo, is the fourth gasotransmitter
similar to carbon monoxide (CO), nitrogen monoxide (NO), and
hydrogen sulde (H2S).17,18 Thus, in view of the effects of the
sultes mentioned above and the signicance of bisultes in
vivo, the intake of bisultes by the human body must be limited.
aState Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan
University, Chengdu, Sichuan 610041, P. R. China. E-mail: yangli@scu.edu.cn; Fax:
+86-159-2818-5249; Tel: +86-159-2818-5249
bWest China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 610041,
China
cSchool of Chemical Engineering, Sichuan University, Chengdu, Sichuan, 610065,
China
Herein, a uorescent Hcy-Mo probe with naked eye recog-
nition of bisultes was designed and synthesized. Based on
† Electronic supplementary information (ESI) available: Detailed synthesis,
characterization (NMR, MS, etc.) of the probe. See DOI: 10.1039/d0ra03329d
25352 | RSC Adv., 2020, 10, 25352–25357
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a biologically active hemi-cyanine and featuring a morpholine product was extracted with dichloromethane 3 times. The
group, Hcy-Mo possessed good cell membrane permeability. combined organic phases were concentrated in vacuo. Then,
The response mechanism can be veried by nuclear magnetic 30 mL of isopropyl ether was added to the solution and the
resonance spectroscopy (NMR), that is, the change in molec- solution was ltered. The lter cake was washed 3–4 times with
ular conjugation due to the 1,4-addition reaction of the probe isopropyl ether. Aer that, the product was dried in vacuo to give
and bisultes. Moreover, Hcy-Mo can be used to rapidly and a purple solid product 320 mg, yield 46.9%. 1H NMR (400 MHz,
specically detect bisultes in breast cancer cells and living DMSO-d6) d 8.37 (d, J ¼ 15.8 Hz, 1H), 8.13 (d, J ¼ 8.7 Hz, 2H),
mice.
7.81 (t, J ¼ 7.8 Hz, 2H), 7.57 (t, J ¼ 7.2 Hz, 1H), 7.52 (t, J ¼ 7.3 Hz,
1H), 7.39 (d, J ¼ 15.8 Hz, 1H), 7.11 (d, J ¼ 8.7 Hz, 2H), 4.55 (t, J ¼
7.2 Hz, 2H), 3.75 (t, J ¼ 4.7 Hz, 4H), 3.51 (t, J ¼ 4.8 Hz, 4H), 1.85
Experimental
Materials and instruments
(q, J ¼ 7.3 Hz, 2H), 1.77 (s, 6H), 1.00 ppm (q, J ¼ 7.5 Hz, 3H). 13
C
NMR (100 MHz, DMSO-d6) d 180.85, 155.10, 154.88, 143.51,
141.51, 134.45, 129.35, 128.51, 124.43, 123.37, 114.65, 113.89,
106.94, 66.27, 51.78, 47.10, 46.87, 26.89, 21.92, 11.27 ppm. ESI-
MS m/z calcd for chemical formula: C25H31N2O [M]+: 375.2191;
found: 375.2184.
All of the chemical reagents and solvents were obtained
commercially (Adamas Reagents or Cologne Reagents) and used
as received without further purication unless otherwise stated.
Ultrapure water was puried using a Millipore water purica-
tion system. Silica gel P60 (Qingdao, mesh number 200–300)
was used for column chromatography. H NMR and 13C NMR
1
Spectral experiment
spectra were recorded on a Bruker 400 M instrument and
chemical shis are given in ppm using the peak of residual
proton signals of DMSO-d6 or CDCl3-d6 as the internal standard.
The mass spectra (ESI) were recorded on a Finnigan LCQDECA
spectrometer with ESI mode. UV-Vis and uorescence spectra
were recorded on a SHIMADZU UV-2450 spectrophotometer and
a VARIAN Cary Eclipse FL1003 M013 spectrometer, respectively.
The uorescence images of the MDA-MB-231 cells were recor-
ded on an inverted uorescence microscope (Olympus, Japan).
The uorescence images of the living mice were recorded on
a Night OWL LB983 living imager.
0.91 mg of the Hcy-Mo probe was dissolved in 2 mL of PBS
solution to prepare a 1 mM stock solution. The stock solution
was then diluted to obtain a test concentration (10 mM). 2.08 mg
of sodium bisulte was dissolved in 2 mL of distilled water to
prepare a 10 mM stock solution, which was diluted to prepare
the required test concentrations. Interfering ions were selected
from different sodium salts (NaF, NaCl, NaBr, NaI, NaHCO3,
Na2CO3, CH3COONa, Na2S2O3, Na2SO4, NaNO2, NaN3, NaSCN,
cysteine, glutathione, tetrabutyl cyanamide, and NaHS) for the
preparation of 20 mM stock solutions. The stock solutions were
diluted to the desired test concentration.
All of the animal procedures were performed in accordance
with the Guidelines for Care and Use of Laboratory Animals of
Sichuan University and approved by the Animal Ethics
Committee of Sichuan University.
Cytotoxicity and cell imaging
A 96-well culture plate was inoculated with logarithmic growth
phase cells. The cell suspension concentration in the culture
dish was adjusted and the edge plate was lled with sterile PBS
buffer and placed in an incubator (5% CO2, temperature 37 ꢁC).
The culture was continued until the cell monolayer was spread
over the bottom of the plate. The cells were divided into
experimental groups and a control group. Hcy-Mo was not
added to the control group. Different gradients of the probe
Hcy-Mo solution were added to the experimental groups. Aer
completion, theꢁculture was placed in the incubator (5% CO2,
temperature 37 C). Aer 2 h, 10 mL of the MTT solution was
added to each well and the cells were incubated for 24 hours.
The absorbance of each well was measured using a microplate
reader and the cell survival rate was calculated.
Synthesis of the probe Hcy-Mo
As shown in Scheme 1, Hcy-Mo was prepared over three steps
using 2,3,3-trimethylindolenine as the starting material. Struc-
tural identication of the products was conrmed by NMR and
HRMS spectrometry.
A mixture of 4-morpholinebenzaldehyde (306 mg, 1.6 mmol),
2,2,3-trimethylsulfonium bromide (421 mg, 1.5 mmol), and
anhydrous sodium acetate (120 mg, 1.5 mmol) in 6 mL of
anhydrous acetic anhydride was reuxed at 85 ꢁC for 1–2 h
under a nitrogen atmosphere. The reaction was monitored by
TLC. Aer completion, the mixture was cooled to room
temperature and poured into a saturated brine solution. The
Then, the medium in the well was replaced with a medium
containing the probe (probe concentration: 10 mM). Aer
incubation for 1 h, the medium containing the probe solution
was discarded and the cells were washed with sterile PBS 2–3
times to remove the non-incorporated cells. Aer that, the
sodium bisulte solution was added to each well and incuba-
tion was continued for 30 min. Then, the sample was inverted
under a microscope to observe and collect imaging data using
the red uorescent channel.
Scheme 1 Synthetic route to probe Hcy-Mo.
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Mice imaging
The Hcy-Mo probe (50 mM) and the test substance sodium
bisulte (500 mM) were prepared in PBS. The 24 hour fasting
Kunming mice were divided into a blank group, control group
and experimental group. The blank group was injected with
PBS, the control group was injected with the probe, and the
experimental group was injected with the probe and the test
substance. Tail vein injection was adopted as the injection
method in this study.
Fig. 2 (a) Fluorescence spectra of Hcy-Mo (10 mM) upon the addition
of increasing concentrations of sodium bisulfite (0, 10, 20, 30, 40, 50,
60, 70, 80, 90, and 100 mM) when excited at 510 nm at 25 ꢁC. (b)
Fluorescence intensity changes of Hcy-Mo at 596 nm as a function of
sodium bisulfite concentration.
Results and discussion
Design of Hcy-Mo
3d/k. It is worth mentioning that Hcy-Mo exhibited a high
quantum yield (FF ¼ 0.22) in aqueous medium when excited at
the lmax (510 nm) of Hcy-Mo.
A uorophore is needed for the design of uorescent probes.
Hemi-cyanine has attracted attention for its mitochondrial
targeting.51–55 In addition, morpholine is a good electron donor
and exhibits lysosome-targeting.56,57 Thus, a mitochondrial
targeting group is linked to a lysosome-targeting group by a “p”
bridge. We expect that the Hcy-Mo probe will show excellent
biocompatibility and uorescence response performances.
Selectivity tests
Among all the factors, the selectivity of a probe is the most
important one because of the complexity of biological samples.
For this reason and on the basis of the above results, we further
evaluated the selectivity of Hcy-Mo probe toward bisulte over
other relevant ions and amino acids including NaF, NaCl, NaBr,
NaI, NaHCO3, Na2CO3, CH3COONa, Na2S2O3, Na2SO4, NaNO2,
NaN3, NaSCN, cysteine, glutathione, tetrabutyl cyanide ammo-
nium, and NaHS. As shown in Fig. 3, compared with many ions,
only HSꢀ exhibited a little decrease in the uorescence intensity
of Hcy-Mo. Furthermore, sodium bisulte (100 mM) caused
a reduction in the Hcy-Mo (10 mM) peak intensity at 596 nm,
which is a 5-fold decrease compared with sodium hydrosulde.
Thus, the Hcy-Mo probe showed good selectivity towards
bisulte.
Time response
The absorption spectral properties of Hcy-Mo in the absence
and presence of bisulte in the buffer are shown in Fig. 1. When
10 equiv. of bisulte was added, the maximum absorption of
Hcy-Mo at 503 nm decreased remarkably and a new absorption
peak at 280 nm increased gradually, with a well-dened iso-
sbestic point at 320 nm. At the same time, the color of the
solution changed from brown to colorless, which could be seen
by the naked eye. Moreover, the addition of sodium bisulte
also resulted in a remarkable decline in uorescence at 596 nm
upon excitation at 510 nm.
Sensitivity research
The emission behavior of the Hcy-Mo probe (10 mM) in the
presence of bisulte (0, 10, 20, 30, 40, 50, 60, 70, 80, 90, and 100
mM) was investigated, as shown in Fig. 2. The uorescence
intensity at 596 nm decreased with increasing bisulte
concentration. By plotting the uorescence intensity of the Hcy-
Mo probe at 596 nm versus the concentration of bisulte, a good
linear relationship (R2 ¼ 0.994) was obtained with concentra-
tions ranging from 0 to 100 mM. The detection limit was
calculated to be 80 nM using the detection limit formula LOD ¼
pH stability
In order to explore in vivo imaging potential, Hcy-Mo was placed
under different pH conditions and the changes in uorescence
intensity at 596 nm with the absence and presence of bisulte
were measured. As shown in Fig. S1,† pH did not exert much
inuence on the uorescence intensity of Hcy-Mo over the
range of 7–9.
Fig. 3 (a) Fluorescence responses and (b) fluorescence enhance-
Fig. 1 Absorption (a) and fluorescence spectral (b) changes with the ments at 596 nm of Hcy-Mo (10 mM) to 10 equiv. of sodium bisulfite
addition of the Hcy-Mo probe (10 mM) in the absence and presence of and 20 equiv. of interfering analytes (0: Hcy-Mo, 1: Fꢀ, 2: Clꢀ, 3: Brꢀ, 4:
sodium bisulfite (10 equiv.) in buffer solution (10 mM PBS, pH ¼ 7.4) Iꢀ, 5: HCO3ꢀ, 6: CO32ꢀ, 7: CH3COOꢀ, 8: S2O32ꢀ, 9: SO42ꢀ, 10: NO2
,
ꢀ
with lex of 510 nm at 25 ꢁC.
11: N3ꢀ, 12: SCNꢀ, 13: CNꢀ, 14: Cys, 15: GSH, 16: HSꢀ, 17: HSO3ꢀ).
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Mechanism verication
The detection mechanism of the Hcy-Mo probe toward bisulte
was speculated using data collected from 1H NMR spectroscopy.
As shown in Fig. 4, the quaternary ammonium changed to
a tertiary amine due to a 1,4-addition reaction between the
bisulte and the quaternary ammonium salt. Thus, the chem-
ical shi value of Hb changed from 4.5 ppm to 3.0 ppm.
Meanwhile, the chemical shi value of Hd moved from 8.2 ppm
to 5.0 ppm because the conjugated bridge was broken. More-
over, due to the strong electron-withdrawing effect of bisulte,
Fig.
5
Hcy-Mo (1 mM) with different concentrations of sodium
bisulfite (0, 0.5, 1, 2.5, 5, 10, 15, and 20 mM) in sunlight and 365 nm
fluorescent light.
0
a new signal peak at 4.7 ppm (Hc ) appeared. Thereby, the ow
Moreover, as shown in Fig. 5, the color of the round test strips
changed from brown to white with increasing concentration of
bisulte. Meanwhile, the color changed from purple to blue
under a UV lamp (365 nm). Thus, the results showed that Hcy-
Mo possessed detection potential for bisulte in aqueous
solution.
of electrons in the entire molecule was destroyed and the
molecular uorescence was quenched.
To further conrm the detection mechanism, Gaussian 09W
soware was used for theoretical calculations. As shown in
Fig. S3 and S4,† the optimal conguration of Hcy-Mo and Hcy-
Mo + HSO3ꢀ was obtained using density functional theory with
6-31G as the basis set. Signicant optimal conguration
Cytotoxicity and cell imaging
ꢀ
differences appeared for Hcy-Mo aer the addition of HSO3
,
As mentioned above, to further explore the cytotoxicity and in
vivo uorescence imaging of the Hcy-Mo probe, cell imaging
experiments were carried out. As shown in Fig. 6, strong red
uorescence was observed when the cells were incubated with
a medium containing Hcy-Mo (10 mM) for 30 min. The red
uorescence disappeared aer treatment with sodium bisulte
(100 mM) for 5 min. The results showed that Hcy-Mo has
potential for in vivo experiments.
As shown in the MTT assay in Fig. S4,† cell viability was
reduced to less than 10% aer 24 h of incubation at a concen-
tration of 10 mM, which indicated that Hcy-Mo had low cyto-
toxicity towards MDA-MB-231 cells. Hence, Hcy-Mo shows
potential for biological imaging.
including the breakage of the conjugated bridge, changes to
bond angles, and removal of co-planarity between the electron
donor and acceptor. Moreover, the results of LUMO and HOMO
were visualized, as shown in Fig. S2.† The p electrons in the
HOMO of the probe were mainly located on the benzene ring
and N atom of morpholine, while the electrons in the LUMO
were situated on indolizidine. Thus, ICT occurred between the
donor and acceptor units resulting in strong uorescence.
However, aer treatment with bisulte, the p electrons in the
HOMO of Hcy-Mo + HSO3ꢀ were located on bisulte, while the
electrons in the LUMO were positioned on the benzene ring.
Therefore, the strong uorescence emission disappeared
because of the suppression of electron transfer.
In vivo imaging experiments
In vitro paper test
Encouraged by the promising proles described above, in vivo
imaging was carried out. Kunming mice, a typical experimental
model, were divided into three groups as experimental subjects
to explore the in vivo imaging effect of Hcy-Mo. The blank,
control, and experimental group were injected with PBS, Hcy-
Encouraged by the high sensitivity and selectivity of the Hcy-Mo
probe, we evaluated its potential for the on-site visual detection
of an aqueous solution using a colorimetric tube and probe-
coated test papers. As shown in Fig. S3,† the color changed
from brown to colorless with the addition of bisulte but no
color change was observed with the addition of other ions.
ꢀ
Mo (50 mM), and Hcy-Mo (50 mM) + HSO3 (500 mM), respec-
tively. Tail vein injection was adopted as the injection method.
As shown in Fig. 7, compared to the blank group, the control
group showed strong uorescence emission. At the same time,
the uorescence emission of the experimental group dis-
appeared aer treatment with bisulte. In conclusion, the
Fig. 6 Cell imaging of MDA-MB-231 cells treated with Hcy-Mo (10
mM) in bright filed (a), absence (b) and presence (c) of sodium bisulfite
(100 mM) in the red channel (lex ¼ 510 nm, lem ¼ 580–660 nm) scale
bar: 50 mm.
Fig. 4 1H NMR titration of Hcy-Mo probe with sodium bisulfite.
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Conclusions
In conclusion, based on a hemi-cyanine scaffold and morpho-
line group, a bisulte uorescent probe (Hcy-Mo) was designed
and synthesized. Hcy-Mo shows promising proles including
a fast response (within 30 s), good water solubility (in pure PBS),
pH stability (7–9), and high sensitivity (LOD ¼ 80 nM) and
selectivity. In addition, low cytotoxicity and biological imaging
potential are exhibited in MDA-MB-231 cells. Moreover, the
detection of bisulte in living mice was performed. The results
of the experiments indicated that Hcy-Mo possessed live
imaging potential, which provides a valuable tool for tracing the
distribution and metabolism of bisulte in biological systems.
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Conflicts of interest
There are no conicts to declare.
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