Probing the Intracellular Dynamics of Nitric Oxide and Hydrogen Sulfide Using an Activatable NIR II Fluorescence Reporter

Article abstract of DOI:10.1002/anie.202015650

Understanding the complex interplay among gasotransmitters is of great significance but remains technically challenging. In this study, we present the design and synthesis of a dually responsive BOD-NH-SC reporter for probing the dynamic and alternating existence of NO and H₂S in living cells. This designed reporter can repeatedly cycle S-nitrosation and transnitrosation reactions when successively treated with NO and H₂S, thus affording the interchange of NIR fluorescence at 645 nm (NO) and NIR II fluorescence at 936 nm (H₂S). In light of this unique fluorescence alternation between two colors, we synthesized water-soluble BOD-NH-SC dots to visualize the intracellular dynamics of NO and H₂S. These molecular probes thus provide a toolbox to elucidate the interplaying roles of NO and H₂S in the complex interaction networks of various signal transduction pathways.

Full text of DOI:10.1002/anie.202015650

Angewandte
Communications
Chemie
How to cite: Angew. Chem. Int. Ed. 2021, 60, 8450–8454
International Edition:
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doi.org/10.1002/anie.202015650
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Fluorescence Probes
Probing the Intracellular Dynamics of Nitric Oxide and Hydrogen
Sulfide Using an Activatable NIR II Fluorescence Reporter
Tianli Zhu+, Ning Ren+, Xia Liu, Yan Dong, Rongchen Wang, Jinzhu Gao, Jie Sun, Ying Zhu,
Lihua Wang, Chunhai Fan, He Tian, Jiang Li,* and Chunchang Zhao*
Abstract: Understanding the complex interplay among gaso-
transmitters is of great significance but remains technically
challenging. In this study, we present the design and synthesis
of a dually responsive BOD-NH-SC reporter for probing the
dynamic and alternating existence of NO and H2S in living
cells. This designed reporter can repeatedly cycle S-nitrosation
and transnitrosation reactions when successively treated with
NO and H2S, thus affording the interchange of NIR fluores-
cence at 645 nm (NO) and NIR II fluorescence at 936 nm
(H2S). In light of this unique fluorescence alternation between
two colors, we synthesized water-soluble BOD-NH-SC dots to
visualize the intracellular dynamics of NO and H2S. These
molecular probes thus provide a toolbox to elucidate the
interplaying roles of NO and H2S in the complex interaction
networks of various signal transduction pathways.
rent literatures have also established the importance of the
bidirectional relationship between NO and H2S for modu-
lation of many physiological and pathological processes in
living organisms.[3] However, understanding about the corre-
lation between these two gasotransmitters remains woefully
incomplete.
Fluorescence imaging, a noninvasive imaging technique
with operational simplicity and high spatiotemporal resolu-
tion, provides a powerful tool for biomedical and clinical
applications.[4] In this context, molecular imaging with H2S-
responsive fluorescent probes has been developed and found
widespread applications.[5] Meanwhile, various fluorescent
probes that are capable of NO imaging have been developed
over the years.[6] Despite these great advantages, evaluating
the correlation between NO and H2S remains an immense
challenge. Since HNO is a reactive intermediate generated by
the interaction between NO and H2S, several HNO-respon-
sive fluorescent probes were recently explored for visualizing
the NO/H2S cross-talk in biological systems.[7] However, the
specificity and accuracy may be depressed by such indirection
assays because HNO do not adequately mimic the complex
interplay between NO and H2S.[8] A simple method, con-
jugating H2S-responsive and NO-sensitive fluorophores in
a single molecular probe, has been employed to simultane-
ously measure H2S and NO.[9] Such designed probe can
respond to H2S, NO, and H2S/NO with distinct fluorescence
signal outputs of green, red and red, respectively. Although
the discrimination between NO red and H2S/NO red signals is
realized by independent excitation, high fluorescence back-
ground is inevitably introduced due to their high dependence
on Fçrster resonance energy transfer efficiency. Moreover,
such probe is incapable of monitoring the dynamic and
alternating existence of NO and H2S in the signal transduction
cycles.
To accurately and specifically reporting the interplay
between NO and H2S, we herein report a dual-stimuli
responsive BOD-NH-SC with activatable NIR II fluores-
cence for reporting the dynamic and alternating existence of
NO and H2S. As shown in Figure 1, our molecule features an
N-Methyl-2-methoxyaniline moiety as the NO-responsive
site. In contrast, the response to H2S relies on H2S-initated
nucleophilic substitution of 4-nitrobenzenethiol-substituted
boron dipyrromethene (BODIPY).[10] In light of the rapid
production of N-nitroso product (BOD-NO-SC) upon treat-
ment of BOD-NH-SC with NO, bright NIR emission lighting
up at 655 nm was observed. Further incubation with H2S led
to the generation of bright NIR II fluorescence at 936 nm due
to the formation of sulfhydryl-functionalized BODIPY
(BOD-NO-SH), accompanied by the quenching of the
N
itric oxide (NO) and hydrogen sulfide (H2S) are the
predominant members of gasotransmitters in mammals,
contributing to the regulatory roles in the cardiovascular,
nervous, and immune systems.[1] While NO is endogenously
synthesized by nitric oxide synthases through the oxidation of
L-arginine, H2S is generated enzymatically from L-cysteine
and homocysteine by the action of cystathionine-g-lyase,
cystathionine-b-synthase, and 3-mercaptopyruvate sulfur-
transferase.[2] The crucial role of NO and H2S in many
biological processes have individually been identified. Cur-
[*] T. Zhu,[+] Y. Dong, R. Wang, J. Gao, J. Sun, Prof. H. Tian, Prof. C. Zhao
Key Laboratory for Advanced Materials, Institute of Fine Chemicals,
School of Chemistry and Molecular Engineering, Frontiers Science
Center for Materiobiology and Dynamic Chemistry, East China
University of Science and Technology
Shanghai 200237 (P. R. China)
E-mail: zhaocchang@ecust.edu.cn
Dr. N. Ren,[+] X. Liu, Prof. Y. Zhu, Dr. L. Wang, Prof. J. Li
Bioimaging Center, Shanghai Synchrotron Radiation Facility, Zhang-
jiang Laboratory, Shanghai Advanced Research Institute, Division of
Physical Biology, CAS Key Laboratory of Interfacial Physics and
Technology, Shanghai Institute of Applied Physics, Chinese Academy
of Sciences
Shanghai 201210 (China)
E-mail: lijiang@zjlab.org.cn
Prof. C. Fan
School of Chemistry and Chemical Engineering, Frontiers Science
Center for Transformative Molecules and National Center for Trans-
lational Medicine, Shanghai Jiao Tong University
Shanghai 200240 (China)
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202015650.
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Figure 1. a) Schematic profile of BOD-NH-SC and proposed reaction mechanism with NO and H2S. Time dependent b) absorption and
c) emission changes of BOD-NH-SC (5 mM) in the presence of DEA·NONOate (500 mM). Time dependent d) absorption and e) emission changes
of BOD-NO-SC in the presence of H2S (100 mM).
emission at 655 nm. Notably, the production of sulfhydryl
moiety is crucial for reporting the dynamic and alternating
existence of NO and H2S. As demonstrated, treatment of
BOD-NO-SH with another portion of NO resulted in the new
NIR emission at 645 nm, which can regenerate BOD-NO-SH
with emission at 936 nm upon further incubation with H2S.
Specifically, such process is repeatedly cycled, thus capable of
accurately monitoring the dynamic and alternating existences
of NO and H2S.
Since a good leaving group 4-nitrobenzenethiol in BOD-
NO-SC, H2S-dependent optical changes could be initiated
through aromatic nucleophilic substitution (SNAr). As
expected, the exposure to H2S led to SNAr with BOD-NO-
SC in test solutions to generate BOD-NO-SH. This trans-
formation was supported by HRMS (Figure S5). In contrast,
other reactive sulfur species gave no such SNAr reaction
(Figure S6). Particularly, the SNAr activated a strong absorp-
tion around 806 nm and annihilated the absorption band at
588 nm concomitantly (Figure 1d), affording a distinct red-
shift of 218 nm. Importantly, the H2S-triggered transforma-
tion of BOD-NO-SC into BOD-NO-SH elicited a bright NIR-
II fluorescence (fluorescence quantum yield of 0.06%) at
936 nm (Figure 1e) with a dose-dependent manner (Fig-
ure S7,8), accompanied by quenching of the fluorescence at
655 nm (Figure S9). This lighting up NIR II fluorescence is
especially preferable for in vivo bioimaging due to good
spatial resolution and highly deep tissue penetration.[11]
In light of the known role of NO action for S-nitro-
sation,[12] the sulfhydryl moiety in BOD-NO-SH must exhibit
rapid reactivity with NO to yield a reactive S-nitrosothiol
intermediate (BOD-NO-SNO). Once formed, a transnitrosa-
tion reaction[13] between H2S and BOD-NO-SNO proceeds to
release BOD-NO-SH. Such S-nitrosation and transnitrosa-
tion processes were repeatedly cycled, which was demon-
strated in Figure 2 and Figure S10. Although the NIR II
The synthesis of BOD-NH-SC is depicted in Scheme S1.
As NO contributes to the production of H2S in colonic and
vascular smooth muscle cells,[3a] we were interested to
determine the fluorescence patterns of BOD-NH-SC when
successively treated with NO and H2S. We first verified that
BOD-NH-SC showed NO-activatable photophysical features
in CH3CN/PBS buffers (1:1, v/v, 10 mM, pH 7.4, 378C). Free
BOD-NH-SC displayed a main absorption at 664 nm with
minimal fluorescence (Figure 1), which can attribute to an
efficient photoinduced electron transfer (PET) from the
electron-rich N-Methyl-2-methoxyaniline moiety to the
excited BODIPY core. The introduction of DEA·NONOate
(500 mM, a commonly employed NO donor) activated
a strong absorption at 588 nm, accompanied by a reduction
of the original NIR peak at 664 nm (Figure 1b). Such
a significant 76 nm hypsochromic shift of the lmax upon
treatment with NO could be attributed to the N-nitrosation of
N-Methyl-2-methoxyaniline unit to suppress the electron
donating strength. Interestingly, the N-nitrosation with NO
elicited a fluorescence enhancement of 214-fold at 655 nm
under 570 nm light irradiation (Figure 1c). The effective N-
nitrosation to produce BOD-NO-SC was confirmed by NMR
and HRMS analysis (Figure S1). BOD-NH-SC showed dose-
dependent fluorescence responsiveness to NO with a respon-
sive limit of 31 nM (Figure S2). In particular, there was no
obvious fluorescence enhancement when BOD-NH-SC was
incubated with a variety of reactive species (Figure S3),
demonstrating high selectivity of BOD-NH-SC for NO. In
addition, good responsiveness was observed between pH 5–9
(Figure S4).
Figure 2. The repeatedly cycled S-nitrosation and transnitrosation
processes revealed by optical spectra, a) absorption and b) emission.
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fluorescence at 936 nm was attenuated, reaction between
BOD-NO-SH and NO afforded a fluorescence turn-on
response at 645 nm. The ability of H2S to participate in
transnitrosation reaction led to the regeneration of BOD-
NO-SH with NIR II emission at 936 nm. Due to the labile
nature of S-nitrosothiols, we employed HRMS analysis of
a reductive ligation reaction of BOD-NO-SNO with phenyl 2-
(diphenylphosphanyl) benzoate to support the reaction
mechanism.[12c] This reductive ligation leads to the sulfena-
mide 10 and phosphine oxide 11 (Scheme S2). Under our
reaction conditions, 10 readily underwent reductive fragmen-
(Figure S16). Spherical morphology with an average diameter
of around 6 Æ 1 nm was also revealed by transmission electron
microscopy (TEM) image. The repeatedly reversible respon-
siveness through S-nitrosation and transnitrosation cycles
when successively treated with NO and H2S was then
investigated. It was found that these promising optical
responses to NO and H2S were well maintained within these
water-dispersible nanocomposites in PBS buffer solutions
(Figure S17). Furthermore, the fluorescence quantum yields
of BOD-NH-SC dots in response to NO and NaHS were
determined to be 4.56% (BOD-NO-SC dots), 0.058% (BOD-
NO-SH dots) and 0.04% (BOD-NH-SH dots) in PBS
solutions, respectively.
After identifying the low cytotoxicity of BOD-NH-SC
dots toward living cells, we then applied BOD-NH-SC dots to
evaluate the alternating presence of NO and H2S in living
colonic smooth muscle and HepG2 cells. As described in
Figure 3 and Figure S18, both colonic smooth muscle and
HepG2 cells treated with BOD-NH-SC dots gave negligible
fluorescence signal in red channel (650–660 nm) and NIR II
fluorescence channel (900–1000 nm). However, when the
NO-pretreated living colonic smooth muscle or HepG2 cells
were loaded with the probe dots, there were bright fluores-
cence signals in the red channel but minimal fluorescence in
NIR II channel. These results suggested that BOD-NH-SC
dot was responsive to NO and N-nitrosation of aniline moiety
occurred in the living cells. Interestingly, significant fluores-
cence emergence in NIR II channel concomitant with signal
attenuation in red channel were noted when these cells were
further treated with NaHS, indicative of H2S-initiated SNAr
reaction in living cells. Notably, fluorescence enhancement in
NIR II channel and attenuation in red channel showed a H2S
dose-dependent manner (Figure S19). Subsequently, succes-
sive incubation with another portion of NO and H2S were
performed. As shown in Figure 3 (cycle 2), NO-triggered S-
nitrosation in these cells afforded significantly incremental
fluorescence in red channel while H2S-induced transnitrosa-
tion led to the generation of bright fluorescence in NIR II
channel. These imaging results manifest that BOD-NH-SC is
suitable for visualizing the dynamic and alternating existence
of NO and H2S in living cells.
Next, BOD-NH-SC dots were explored for monitoring
endogenous H2S generation with fluvastatin stimulated
murine raw 264.7 macrophages in the presence of DEA·N-
ONOate (Figure S20). As observed, the presence of NO in
macrophages cells afforded bright red fluorescence but
minimal NIR II fluorescence after incubation with BOD-
NH-SC dots. Interestingly, a distinct 16.2-fold increase from
0.5 to 8.1 in NIR II fluorescence channel was noted in
fluvastatin-stimulated cells when compared with the
untreated cells. These imaging experiments indicated that
BOD-NH-SC dots could be used for visualization of the
existence of endogenous H2S assisted by NO in living cells.
In summary, we designed and synthesized a dual-stimuli
responsive probe BOD-NH-SC for reporting the dynamic and
alternating existence of NO and H2S. This designed probe
generated bright NIR II fluorescence when successively
treated with NO and H2S due to the formation of BOD-
NO-SH. Of particular importance was that BOD-NO-SH
À
tation to cleave the S N bond, leading to the formation of 12
and BOD-NO-SH. Notably, BOD-NO-SH showed a signifi-
cant red-shift in its absorption compared to BOD-NO-SNO
due to the NO action for S-nitrosation greatly reduced the
electron donating nature, which is consistent with the
theoretical calculations (Figure S11). Additionally, the
absorption properties of BOD-NO-SH or BOD-NO-SNO
remained unchanged in buffer solutions for at last 1 h
(Figure S12). However, both BOD-NO-SH and BOD-NO-
SNO seemed to undergo complex chemical reaction upon
drying, and therefore, no pure BOD-NO-SH and BOD-NO-
SNO were obtained for NMR characterizations. Collectively,
the repeatedly cycled S-nitrosation and transnitrosation
processes by successive treatment with NO and H2S demon-
strated that our probe is a promising tool for accurately
monitoring the dynamic and alternating existences of NO and
H2S.
Next, we evaluated the optical changes of BOD-NH-SC
when successively treated with H2S and NO. The presence of
H2S led to an increase in the absorption peak at 840 nm
accompanied by a decrease of that at 664 nm (Figure S13).
However, relatively weak NIR II emission at 997 nm was
triggered with excitation at 840 nm due to the PET from N-
Methyl-2-methoxyaniline moiety to BODIPY. This SNAr
reaction proceeded slowly and reached a plateau within 4
hours. At this time point, NO was further introduced to the
test solution. The decrease of absorption band at 840 nm
along with the emergence of a blue-shifted absorption
centered at 581 nm was observed. Upon excitation at
570 nm, gradual enhancement of bright fluorescence around
645 nm was also noted (Figure S14), which was virtually
consistent with the transformation of BOD-NH-SH to BOD-
NO-SNO. Subsequently, the reversible transnitrosation and
S-nitrosation began to cycle when successive addition of H2S
and NO (Figure S15). It should be noted that the slow SNAr
reaction kinetics between BOD-NH-SC and H2S limited the
practical bioimaging applications.
After demonstrating the promising capability of BOD-
NH-SC for accurately monitoring the dynamic and alternat-
ing existences of NO and H2S, we then explored the potential
for fluorescence mapping in living cells. BOD-NH-SC mol-
ecules were first processed into water-soluble and biocom-
patible BOD-NH-SC dots via direct nanoprecipitation in the
assistance of encapsulation matrix 1,2-distearoyl-snglycero-3-
phosphoethano -lamine-N-[amino(polyethyleneglycol)-2000]
(mPEG-DSPE 2000). The resulting BOD-NH-SC dot was
stable in aqueous solution with the hydrodynamic diameter of
about 9.8 Æ 1 nm as measured by dynamic light scattering
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Figure 3. Evaluation of the alternating presence of NO and H2S in living a) HepG2 and b) colonic smooth muscle cells with BOD-NH-SC dots.
Cycle 1 NO+: cells treated with DEA·NONOate (1 mM) for 40 min, followed by incubation with BOD-NH-SC dots for 2 h. Cycle 1 H2S+: cells of
“Cycle 1 NO+” were further treated with NaHS (1 mM) for 2 h. Cycle 2 NO+: cells of “Cycle 1 H2S+” were further treated with DEA·NONOate
(1 mM) for 2 h. Cycle 2 H2S+: cells of “Cycle 2 NO+” were further treated with NaHS (1 mM) for 2 h. Representative cells (outlined with white
dashes in upper rows) are magnified from the boxed regions in the wide-view images (lower rows). Scale bar: 40 mm. Error bars indicate standard
deviation from at least three independent tests.
Research and Development Program (2016YFA0201200), the
Shanghai Municipal Science and Technology Commission
(19JC1410300) and the Youth Innovation Promotion Associ-
ation of CAS (Grant No. 2016236).
exhibited S-nitrosation reaction in the presence of NO and
subsequent H2S-initiated transnitrosation. Such S-nitrosation
and transnitrosation processes were repeatedly cycled, rever-
sibly switching the fluorescence from NIR II at 936 nm to
NIR at 645 nm and thus alternating fluorescence between two
colors. The formulated BOD-NH-SC dots with good water-
solubility and biocompatibility maintained the aforemen-
tioned promising optical responses to NO and H2S, enabling
the visualization of the dynamic and alternating existence of
NO and H2S in living cells. This is the first time that
monitoring the alternating existence of NO and H2S with
a single fluorescent probe has been realized. We expect that
our studies could facilitate the development of unique
molecular probes to investigate the complex interplay
between NO and H2S in various signal transduction pathways.
Conflict of interest
The authors declare no conflict of interest.
Keywords: activatable probe · H2S · molecular probe ·
NIR II Fluorescence · NO
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Acknowledgements
We gratefully acknowledge financial support by the National
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Manuscript received: November 23, 2020
Revised manuscript received: December 24, 2020
Accepted manuscript online: January 25, 2021
Version of record online: March 3, 2021
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