Near-Infrared Fluorescent Nanoprobe for Detecting Hydrogen Peroxide in Inflammation and Ischemic Kidney Injury

Article abstract of DOI:10.1002/cjoc.202000166

In-situ overexpressed hydrogen peroxide could serve as a biomarker for inflammation and ischemic kidney injury. Herein, a nanoprobe was developed for assay of hydrogen peroxide. The nanoprobe (TA-TPABQ) was formed via the boronate ester groups between the

Full text of DOI:10.1002/cjoc.202000166

Chinese Journal
of Chemistry
CJC 中 国 化 学 - An International Journal
Accepted Article
Title: Near-infrared fluorescent nanoprobe for detecting hydrogen peroxide in
inflammation and ischemic kidney injury
Authors: Lingfeng Xu, Lihe Sun, Fang Zeng,* and Shuizhu Wu*
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Near-infrared fluorescent nanoprobe for detecting hydrogen peroxide in
inflammation and ischemic kidney injury
a
a
,a
,a
Lingfeng Xu, Lihe Sun, Fang Zeng,* and Shuizhu Wu*
a
State Key Laboratory of Luminescent Materials & Devices, Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates, College of
Materials Science & Engineering, South China University of Technology, Guangzhou 510640, China
Cite this paper: Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
Summary of main observation and conclusion In-situ overexpressed hydrogen peroxide could serve as a biomarker for inflammation and ischemic kidney
injury. Herein a nanoprobe was developed for assaying of hydrogen peroxide. The nanoprobe (TA-TPABQ) was formed via the boronate ester groups
between the hydrophilic tannic acid and the boric-acid-containing compound (TPABQ) as well as the hydrophobic interactions. The probe with good
photostability shows good sensitivity and selectivity towards H
2
O
2
. The probe was adopted for identifying endogenous and exogenous H
2
O in living cells.
2
Moreover, the probe was utilized for in vivo imaging experiments in acute abdomina and ankle inflammation mouse models as well as acute renal ischemia
mouse model.
Background and Originality Content
As redox homeostasis is crucial for various cellular functions,
many disordered physiological processes are usually associated
with the abnormal level of oxidative stress (elevated intracellular
the TA-TPABQ nanoprobe, as shown in Figure 1. The hydrophobic
compound TPABQ forms the boronate ester bonds (dynamic-
[45-47]
covalent bonding linkage)
with the hydrophilic natural
polyphenol tannic acid (TA), and then the nanoparticle (nanoprobe)
readily forms owing to the boronate ester bonds and the
hydrophobic interactions. The boronate ester bonds can serve as
[
1-
level of reactive oxygen species (hereinafter referred to as ROS).
4
]
2 2
H O is one of the important members of ROS and is
the recognition moiety for H
cleave boronate ester.
2
O
2
, as hydrogen peroxide can readily
In the absence of H , the
[
5-8]
overexpressed in a variety of diseases,
including the acute
[48-50]
2 2
O
[
9]
[10]
abdominal inflammation and renal ischemia injury. Thus, the
in-situ hydrogen peroxide level in the foci of these diseases could
serve as a biomarker for them, and therefore the sensitive in-situ
fluorescence intensity of the probe was very weak at 725 nm,
whereas strong fluorescence signals occurred when the probe was
exposed to H O . Upon the probe’s reaction with H O , the
2 2 2 2
activated probe namely the resultant product (theoretically the
product is TPAQ-OH) exhibited remarkable fluorescence in the
aggregated state because of its hydrophobicity and AIE feature. The
probe was adopted for identifying endogenous and exogenous
2 2
detection for H O level in the diseases’ site is of great importance
in terms of possible early diagnosis for these diseases.
[
8-10]
Fluorescence detection technique is one of the effective and
convenient imaging tools to identify the target biomarkers in bio-
[
11-20]
system.
Compared to other methods, fluorescence technique
2 2
H O in living cells (RAW264.7, HepG2 and HeLa). Moreover, the
shows higher sensitivity, simple operation process and non-
probe was utilized for in vivo imaging experiments in acute
abdomina and ankle inflammation mouse models as well as acute
renal ischemia mouse model.
[
21-24]
destructive imaging capability.
probes especially those with long-wavelength emission have been
synthesized for H detection, as summarized in Table S1.
To date, various fluorescent
2 2
O
However, most of the reported probes display short Stokes shift,
and are hydrophobic and tend to aggregate in aqueous biological
system, their fluorescence may be quenched due to the π-π
stacking and thus be deleterious for fluorescence response.
Nevertheless, the fluorophores with aggregation-induced emission
Results and Discussion
Synthesis and spectral properties of the nanoprobe TA-
TPABQ
The compound TPABQ was synthesized according to Scheme S1.
Then the nanoprobe TA-TPABQ was obtained with TPABQ and
tannic acid (TA) through the boronate ester bonds and hydrophobic
interaction. Moreover, the TPAQ-OH (theoretical product of the
[
25-27]
(
AIE) can readily avoid the aggregation-caused quenching, this
[
28-39]
feature is beneficial for fluorescence imaging in bio-system.
However, only a few organic probes have been developed for H
2 2
O
detection with AIE characteristic, and most of them still suffered
2 2
reaction between the nanoprobe TA-TPABQ and H O ) was
synthesized as well, as shown in Scheme S2. The intermediate
products and TPAQ-OH were characterized by 1H NMR and MS
[
40-44]
from short wavelength emission (< 650 nm).
In order to construct an activatable near-infrared nanoprobe
for detecting H overexpression in diseases, herein we developed
2 2
O
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spectrometry (Figure S1-Figure S8). The final nanoprobe TA-TPABQ
was investigated by X-ray photoelectron spectroscopy (XPS) as well
Also, as shown in Figure 2e and Figure 2f, the fluorescence intensity
increased gradually with the increasing concentration of H
linear correlation between the fluorescence intensities (at 725 nm)
and H concentrations in the range of 0-40 μM was obtained, and
2 2
O . A
(
Figure S9). The particle size of TA-TPABQ was approximately 100
nm, and that of the TPAQ-OH aggregates was around 120 nm based
on the dynamic light scattering (DLS) method (Figure S10). The
content of TPABQ in the nanoprobe was determined as 29.7 wt%,
through the absorption spectrometry by referring to the
predetermined calibration curve.
Figure 1c, in the absence of H the nanoprobe TA-TPABQ showed
only weak fluorescence at 725 nm; whereas strong fluorescence
appeared at around 725 nm in the presence of H . The electron-
2 2
O
the limit of detection (LOD) was calculated to be 117 nM (Figure
S15).
2 2
Then the selectivity of the nanoprobe TA-TPABQ for H O
[
51]
As shown in Figure 1b and
detection was tested; various anionic ions, cationic ions and bio-
molecules were incubated with the nanoprobe TA-TPABQ, and the
fluorescence intensities were recorded as displayed in Figure S16.
The various substances showed negligible fluorescent changes
compared with the control group (the nanoprobe TA-TPABQ
solution). Whereas, significant fluorescence enhancement was
2 2
O
2 2
O
withdrawing boronate ester groups quench the fluorescence of
TPABQ; while when hydrogen peroxide reacts with the nanoprobe,
the boronate ester bonds are cleaved, and the electron-donating
hydroxyl group is generated on the fluorophore TPAQ-OH, thus the
fluorescence is restored. As for the absorption spectra, the
nanoprobe TA-TPABQ displayed the maximal absorption at 527 nm
observed after the nanoprobe’s incubation with H
2
O
2
-
. Moreover,
, etc.)
-
several kinds of reactive oxygen species (ONOO , ClO , H
2
O
2
-
-
3 2
and nitrogen species (NO , NO , NO) were incubated with the TA-
TPABQ as well, and negligible fluorescence enhancement was
induced under the same conditions. The results show that the
nanoprobe TA-TPABQ possesses high selectivity toward H O , and
2 2
the fluorescence signal won’t be interfered by these substances,
hence the nanoprobe may be suitable for application in complex
biological system. Also, the fluorescence intensities were measured
in the solutions under various pH values (6.5-8.0). As presented in
Figure S17, the fluorescence intensity of the TA-TPABQ remained
relatively stable in the physiological pH range. In the meantime, for
in the absence of H
TPABQ is suitable to serve as a turn-on reporter for H
The AIE feature of TPAQ-OH (the theoretical product from the
reaction between TA-TPABQ and H ) in the good solvent of THF
and the poor solvent PBS mixture was investigated according to the
2 2
O . These data indicate that the nanoprobe TA-
2
O
2
.
2 2
O
[
52,53]
reported method.
the PBS/THF mixture with various PBS volume fractions (f
from 0%-90%. As displayed in Figure 2a and Figure 2b, there was
negligible emission when f was below 30%, and fluorescence
intensities gradually increased with the increasing fraction of PBS.
Especially, when f reached 90%, the fluorescence intensity
The fluorescence spectra were obtained in
p
) ranging
p
2 2
the TA-TPABQ, with the treatment of H O in the same pH range,
an obvious enhancement of fluorescence signal occurred, and the
corresponding fluorescence intensity varied slightly in this pH
range. In addition, the photo-stability of the nanoprobe TA-TPABQ
was investigated under the continuous irradiation by the xenon
p
increased dramatically with about 46.7-fold enhancement
compared with that in good solvent of THF.
2 2
lamp with or without the existence of H O . As displayed in Figure
Detection mechanism and fluorescent response of the
S18, the fluorescence intensity in the time range of 0-120 min were
measured, and results showed that the nanoprobe TA-TPABQ and
the reaction product displayed good photo-stability. The
nanoprobe TA-TPABQ exhibited high stability after 4 days’
incubation in saline, as confirmed by DLS results (as shown in Figure
S19). The good stability of the nanoprobe indicates that it is
suitable for imaging in biological system.
nanoprobe TA-TPABQ towards H
As boronate ester bonds can be cleaved by H
nanoprobe TA-TPABQ being reacted with H , the fluorophore
2
O
2
2 2
O
,[3] upon the
2 2
O
TPAQ-OH is generated, and thus the TPAQ-OH molecules aggregate
and give out strong fluorescence. To confirm the detection
mechanism, the absorption and emission spectra for the
2 2
nanoprobe TA-TPABQ upon being reacted with H O and those of
the synthesized TPAQ-OH (theoretical reaction product) were
compared (Figure S11 and Figure S12). It could be observed that
the absorption and emission spectra of the product after the
2 2
nanoprobe being reacted with H O were quite similar to those of
the synthesized theoretical reaction product TPAQ-OH.
1
Furthermore, the H NMR spectrum of the reaction product
2 2
obtained from the reaction between the nanoprobe and H O and
that of the synthesized theoretical reaction product TPAQ-OH were
found to be similar (Figure S13). These results confirm that TPAQ-
OH is indeed generated after the reaction between the TA-TPABQ
2 2
and H O . Moreover, a large Stokes shift (198 nm) was found in the
resultant product TPAQ-OH, as shown in Figure S14. This feature is
beneficial for bio-detection and imaging, since large Stokes shift
can avoid the interfaces of molecular self-absorption effectively.
Next, the fluorescence response of the nanoprobe TA-TPABQ
towards H O as function of incubation time is shown in Figure 2c
2 2
and Figure 2d. Obviously, the fluorescence intensity increased with
the extended incubation time, and reached a plateau within 15 min.
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Figure 2 (a) Fluorescence spectra of TPAQ-OH (10 μM) in PBS/THF
mixture with different PBS volume ratios (from 0%-90%), λex = 580 nm. (b)
Fluorecence intensity at 725 nm of TPAQ-OH (10 μM) in PBS/THF mixture
with different PBS volume ratios (from 0%-90%). (c) Fluorescence spectra
of the nanoprobe TA-TPABQ (TPABQ 10 μM) exposed to the H
2
O (60 μM)
2
for different incubation time (0-30 min) in PBS (10 mM, pH 7.4). (d)
Fluorescence intensities at 725 nm of the nanoprobe TA-TPABQ (TPABQ 10
μM) after being exposed to the H
0-30 min) in PBS (10 mM, pH 7.4). (e) Fluorescence spectra the nanoprobe
TA-TPABQ (TPABQ 10 μM) upon incubation with various concentrations of
(0-120 μM) for 30 min in PBS (10 mM, pH 7.4). (f) Fluorescence
intensities at 725 nm of the TA-TPABQ (TPABQ 10 μM) after being reacted
O
2 2
(60 μM) for different incubation time
(
H
O
2 2
with various concentrations of H
pH 7.4).
2
O (0-120 μM) for 30 min in PBS (10 mM,
2
Figure 1 (a) Schematic illustration of the nanoprobe TA-TPABQ for H
2
O
2
Fluorescence imaging of H
2
O
2
in living cells
detection. (b) Fluoescence spectra of the nanoprobe TA-TPABQ (TPABQ 10
μM) before or after the incubation of H (60 μM) in PBS (10 mM, pH 7.4).
c) Absorption spectra of the nanoprobe TA-TPABQ (TPABQ 10 μM) before
or after the incubation of H (60 μM) in PBS (10 mM, pH 7.4).
O
2 2
The nanoprobe’s capability of detecting H O in living cells was
2
2
(
evaluated. Prior to the imaging experiments, the cytotoxicities of
the nanoprobe TA-TPABQ against the RAW264.7 (mouse monocyte
macrophage cell line), HepG2 (human hepatoma cell line), HeLa
O
2 2
(
human cervical cancer cell line) and L929 (mouse fibroblast cell
line) were estimated. As displayed in Figure S20, high cell viabilities
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remained after incubation with the TA-TPABQ, even when the
nanoprobe’s concentration reached 60 μM. The results indicate
that the nanoprobe TA-TPABQ presents little cytotoxicity towards
these kinds of cell lines. After that, the nanoprobe TA-TPABQ was
2 2
utilized to image H O in RAW264.7, HepG2 and HeLa cell lines. As
shown in Figure 3a, Figure S21a and Figure S22a, when the living
cells were only treated with the TA-TPABQ, weak fluorescence
signals could be observed. Whereas, when phorbol myristate
acetate (PMA) was employed as a stimulator to trigger the up-
[
54]
regulation of intracellular H
2
O
2
,
the fluorescence signals
increased obviously in the three cell lines. By contrast, it could be
found that fluorescence decreased apparently in the presence of
[
55]
N-acetylcysteine (NAC),
elimination. The results confirm that the nanoprobe TA-TPABQ is
capable of detecting endogenous H in these three cell lines.
Then the nanoprobe TA-TPABQ was applied to image the
2 2
exogenous H in these three living cell lines. The exogenous H O
2 2
a widely used antioxidants for H O
2 2
O
2
O
2
was added into these three living cells lines during the culturing
process, and obvious fluorescence signal could be observed,
suggesting that the fluorescence was triggered by the exogenous
2 2
H O .
Figure 3 (a) Fluorescence images of RAW264.7 cells incubated with the
TA-TPABQ (TPABQ 10 μM) for 30 min; fluorescence images of RAW264.7
pretreated with PMA (1.0 μg/mL, 30 min) and then incubated with the TA-
TPABQ (TPABQ 10 μM) for 30 min; fluorescence images of RAW264.7
pretreated with PMA (1.0 μg/mL, 30 min) and followed with treatment of
NAC (2 mM, 1 h) and incubated with the TA-TPABQ (TPABQ 10 μM) for 30
min afterwards; fluorescence images of RAW264.7 incubated with the TA-
TPABQ (TPABQ 10 μM) for 30 min and then treated with H
min). (b) Fluorescence images of RAW264.7 cells incubated with the TA-
TPABQ (TPABQ 10 μM) for 30 min, and then treated with H (60 μM) for
O
2 2
(60 μM, 30
O
2 2
different time (0-30 min). (c) Fluorescence images of RAW264.7 cells
incubated with the TA-TPABQ (TPABQ 10 μM) for 30 min, and then
incubated with different concentrations of H
2
O (0-60 μM) for 30 min. Scale
2
bar: 20 μm.
Next, we further investigated the response time of the
nanoprobe TA-TPABQ towards H in these three living cell lines
by incubating the cells with H for different time range (0-30 min).
As displayed in Figure 3b, Figure S21b and Figure S22b, the
2 2
O
2 2
O
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fluorescence signals enhanced gradually along with the extended
incubation time. The flow cytometry experiments were also
conducted to assess the nanoprobe’s response time toward H O .
2 2
As shown in Figure S23a, Figure S23c and Figure S23e, with the
prolonged incubation time, the intracellular fluorescence became
stronger gradually, indicating that TA-TPABQ was activated in these
three cell lines, which were consistent with the above fluorescence
imaging results.
the inhibited group weakened because of the inhibitory action of
NAC, since NAC is a common reductant to scavenge the oxygen
species. The quantified mean fluorescence intensities for the three
groups are shown in Figure 4b. The results indicate that the TA-
2 2
TPABQ is capable of detecting the elevated H O in abdominal
inflammation.
After that, the response of the nanoprobe TA-TPABQ towards
different concentrations of H O (0-60 μM) in these three living cell
2 2
lines were investigated as well. As shown in Figure 3c, Figure S21c
and Figure S22c, the fluorescence signals increased when higher
concentrations of H
these three cell lines. The flow cytometry analysis with different
concentrations (0-60 μM) are shown in Figure S23b, Figure
S23d and Figure S23f, with more exogenous H added,
2 2
O were added into the culture medium of
2 2
H O
2 2
O
intracellular fluorescence signals became stronger. The results of
the flow cytometry analysis were consistent with the fluorescence
imaging results. The experimental results indicate that the
nanoprobe TA-TPABQ is able to detect the endogenous and
2 2
exogenous H O effectively.
In vivo fluorescence imaging of overexpressed H
2
2
O in
mouse models
To evaluate the applicability of the nanoprobe TA-TPABQ in
2 2
H O detection in vivo, the biosafety of the TA-TPABQ was
investigated. The ICR mice were divided into two groups randomly.
For one group, the mice were intravenously (i.v.) injected with the
TA-TPABQ (2.8 mg nanoprobe/kg body weight) via the tail vein as
the probe-treated group. For another group, the mice were
injected with the same volume of saline as the control group. The
experiments including the mice body weight tracking, hematoxylin
and eosin (H&E) staining of main organs’ sections (such as the heart,
liver, spleen, lung and kidney) were performed. As shown in Figure
S24, no abnormal changes in mice body weight in both groups were
found. As displayed in Figure S25, histological analysis of the main
organs staining with H&E displayed that, there were no obvious
damages in the main organs of the probe-treated group, and no
obvious differences between the control group and the probe-
treated group could be found. The results show that the nanoprobe
TA-TPABQ has good biosafety and is suitable to be utilized in vivo.
Next, we established the acute abdominal inflammation mouse
model to examine the capability of the nanoprobe for imaging the
Figure 4 (a) Fluorescence imaging of H
2
O in the mouse model with acute
2
abdominal inflammation. The mouse only injected with the nanoprobe TA-
TPABQ was used as the control; the mouse pretreated with rotenone for 1
h and followed with the injection of the nanoprobe TA-TPABQ; the mouse
successively injected with rotenone, NAC and followedwith the injection of
the nanoprobe TA-TPABQ. (b) Mean fluorescence intensities for the region
of interest (ROI, in red circle) in the mouse models in (a). (c) Fluorescence
imaging of H
2
O in the mouse model with acute ankle inflammation. The
2
nanoprobe TA-TPABQ was injected into the left hind ankle; and LPS and the
nanoprobe TA-TPABQ were successively injected into the right hind ankle.
(d) Mean fluorescence intensities for the ROI (red circles) in mouse model
elevated H
2 2
O concentration. The ICR mice were divided into three
in (c). (e) Fluorescence images of the isolated left kidney (control) and right
kidney (ischemic kidney model) of ICR mouse. (f) Mean fluorescence
intensities of the isolated left kidney (control) and right kidney (suffered
from acute ischemia) in (e). Columns represent mean ± SD. ***p <0.001.
groups randomly. The first group were injected with the nanoprobe
TA-TPABQ into the peritoneal cavity (as the control group); the
[56]
second group of mice were injected with the stimulator rotenone
and followed with the injection of the TA-TPABQ intraperitoneally
as the stimulated group); and the third group of mice were
(
Afterwards the acute ankle inflammation mouse model was
established to further evaluate the nanoprobe’s capability to image
the elevated endogenous H O in vivo. The ICR mice’ right hind
2 2
ankles were injected with the TA-TPABQ as the control side, while
their left hind ankles were successively injected with the
lipopolysaccharide (LPS, 2.0 μg/mL in saline) and the TA-TPABQ as
the LPS-treated side. The fluorescence images are shown in Figure
intraperitoneally injected with the rotenone and then successively
with NAC and the TA-TPABQ (as the inhibited group). The mice were
then submitted to imaging, and the results are shown in Figure 4a.
The mouse in control group displayed relatively weak fluorescence
intensity in the abdominal region, and the fluorescence intensity
increased obviously in the stimulated group, which may be
attributed to the enhanced level of endogenous H
2 2
O induced by
4
c; the fluorescence intensity in the left ankle was stronger than
the stimulator rotenone. By contrast, the fluorescence intensity in
that in the right ankle (control), since the LPS is a widely used
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inflammation inducer, which may leads to the up-regulation of
TA-TPABQ was prepared by dispersing it into the PBS (10 mM, pH
7.4). For response performance test, the test solution was prepared
with addition of the stock solution of the nanoprobe TA-TPABQ,
[
57]
H
2
O
2
.
And the quantified mean fluorescence intensities for the
LPS-treated side and the control side are shown in Figure 4d. The
results confirm that the nanoprobe TA-TPABQ can be used to image
different concentrations of H
in total. For selectivity experiments, the nanoprobe solutions were
incubated with H or other analytes, such as the reactive sulfur
2 2
O was added with final 3 mL volume
2 2
the elevated H O concentration in acute inflammation diseases.
To further explore the nanoprobe’s capability to be applied in
other disease models, the acute ischemic kidney injury mouse
model was established. Ischemia of organs usually occurs with the
insufficient supply of blood to the organs, which can disrupt the
2 2
O
species, amino acids, cations and anions for 30 min (in PBS, 10 mM
pH 7.4).
[
58]
Cell imaging experiment
normal functions of organs. Excessive production of ROS may be
accompanied with the aberrant immune responses in the ischemic
For cell imaging experiments, the procedures were proceeded
[
59]
[61,62]
organs. In this experiment, the mice were anesthetized, and the
ischemia in the right kidneys was induced through the vessel
ligation (as the ischemia side), while the left kidneys without vessel
ligation acted as the control side. Then the nanoprobe TA-TPABQ
was injected via tail vein after the removal of ligation, and then
both the kidneys were harvested from the mice. As displayed in
Figure 4e, the fluorescence signal of the right kidney increased
significantly, while for the control side of the left kidney, the
fluorescence signal was relatively lower. The corresponding
quantitative fluorescence data are displayed in Figure 4f. The above
experimental results demonstrate that the nanoprobe TA-TPABQ
according to the previous studies
with necessary
modifications herein. In detail, three cell lines such as HeLa cell line
(human cervical cancer cell line), HepG2 cell line (human hepatoma
cell line) and RAW264.7 cell line (mouse macrophage cell line) were
seeded inside 35 mm glass culture dishes in the corresponding
complete medium for adherence. After incubation for over 12 h,
the culture dishes were washed with PBS, then filled with the
corresponding fresh medium. In one experiment, one group of cells
in the 6-well culture dishes were cultured with the nanoprobe TA-
TPABQ (TPABQ 10 μM); another group was pre-treated with
phorbol myristate acetate (PMA, 1.0 μg/mL, 30 min), then
incubated with the nanoprobe TA-TPABQ (TPABQ 10 μM); the third
group was pre-treated with PMA, then treated with N-
acetylcysteine (NAC), and then with the nanoprobe TA-TPABQ
can detect the elevated H
2 2
O in acute inflammations and ischemic
kidney injury in vivo.
(
TPABQ 10 μM); the last group was pre-treated with the nanoprobe
Conclusions
TA-TPABQ (TPABQ 10 μM) and incubated with the exogenous H
2 2
O
The near-infrared fluorescent nanoprobe TA-TPABQ was
developed successfully, which was prepared through the boronate
ester bonds (dynamic covalent bonding) between the compound
TPABQ and tannic acid as well as the aggregation induced by
(60 μM) for 30 min. In another experiment, the three cell lines were
cultured with the nanoprobe TA-TPABQ, and followed with
incubation with H O (60 μM) for different culture time (0 min, 10
2
2
min, 20 min, 30 min). In another experiment, three cell lines were
incubated with the nanoprobe TA-TPABQ (TPABQ 10 μM) for 30 min,
subsequently incubated with different concentrations of H O (0
2 2
hydrophobic interaction. Upon the nanoprobe’s reaction with H O
the fluorophore TPAQ-OH is released, which shows an obvious
turn-on fluorescence signal with AIE feature and a large Stokes shift
of 198 nm. Moreover, the nanoprobe has been successfully utilized
2
2
μM, 20 μM, 40 μM and 60 μM) for 30 min. All the culture dishes
were placed in the humidified incubator Forma™ Steri-Cult™
to image the endogenous and exogenous H
RAW264.7, HepG2 and HeLa). Furthermore, this nanoprobe has
been applied to detect the over-expressed H in the acute
2
O
2
in three cell lines
(ThermoFisher, USA) at 37 °C, containing 5% CO . Prior to the cell
2
imaging experiment, cells were rinsed with PBS three times to
remove the culture medium, then subjected to fluorescence
microscope imaging. An Olympus IX71 inverted fluorescence
microscope with DP72 color CCD was employed for fluorescence
imaging.
(
2 2
O
abdominal inflammation mouse model, the acute ankle
inflammation mouse model and the ischemic kidney injury mouse
model. Hence, this nanoprobe holds promise for serving as an
2 2
effective tool for detecting H O overexpression in related
Fluorescent imaging in animal models
diseases.)
The animal experiments were performed in the Laboratory
Animal Center of South China Agricultural University (SCAU), and
the animals were maintained under Specific Pathogen-Free (SPF)
conditions. All the experimental protocols have been approved and
conducted according to the guidelines and regulations of Animal
Ethics Committee of SCAU for the care and use of laboratory
animals, and the experiments were conducted in compliance with
the regulations on the management of laboratory animals of China.
Herein, ICR mice (5-6 weeks old) for in vivo imaging were provided
by Guangdong Medical Laboratory Animal Center (GDMLAC).
The acute abdominal inflammation model experiments were
conducted as follows: In detail, the mice were fasted for 12 h. The
mice were divided into the control group, the stimulated group and
the inhibited group. Then the mice were anesthetized with 2.0%
isoflurane by inhalation during the operation procedure. The mice
Experimental
Preparation process and characterization of TA-TPABQ
Detailed synthetic routes were illustrated in the Supporting
Information, as shown in Scheme S1 and Scheme S2, and the
corresponding characterizations of intermediate products and the
final nanoprobe TA-TPABQ were provided in Figure S1-Figure S9.
General spectra analysis procedure
The spectra analysis procedures were according to the previous
[
60]
literatures with slight modifications. In detail, the fluorescence
spectra were recorded at the excitation of 580 nm and the emission
range from 650 nm to 900 nm. The stock solution of the nanoprobe
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Running title
Chin. J. Chem.
in the control group were given with an injection of TA-TPABQ (2.8
mg probe/kg body weight) into the peritoneal cavity. The mice in
the stimulated group was pre-treated with the rotentone (2 mM)
into the peritoneal cavity, followed with intraperitoneal (i.p.)
injection of the nanoprobe TA-TPABQ (2.8 mg probe/kg body
weight) in the same region 2 h later. The mice in the inhibited group
was successively treated with the rotentone (2 mM) for 1 h, then
followed with i.p. injection of NAC (20 mM) for 1 h, then the
nanoprobe TA-TPABQ (2.8 mg probe/kg body weight) was i.p.
injected into the same region. 15 min after the probe injection,
fluorescence imaging was then acquired by using Ami small animal-
imaging system (SI Imaging Company), with excitation filter 560 nm
and emission filter of 730 nm.
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The ankle inflammation mouse model experiment was
conducted as follows. Prior to the experiment, the ICR mice were
anesthetized with 2.0% isoflurane by inhalation. In detail, the left
hind ankles of ICR mice were injected with LPS (2.0 μg/mL in saline)
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2.0 mg probe/kg body weight) was injected into the same region
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of the ankles with inflammation after the LPS treatment for 24 h.
And the right hind ankles were acted as the control side without
any treatment with the stimulators. 15 min after the probe
injection, fluorescent images were taken through an Ami small
animal-imaging system (SI imaging Company) with an excitation
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60 nm filter and an emission 730 nm filter.
The acute ischemic kidney injury mouse model experiment was
conducted as follows: Before the imaging procedure, the ICR mice
were fasted for 12 h. The mice were anesthetized with 2.0%
isoflurane inhalation and the simple laparotomy operation was
performed to induce the inflammation of renal ischemia. In detail,
the abdominal cavity was exposed, and the corresponding right
renal artery was clamped, the acute renal ischemia was induced. In
the control group, the left kidney was exposed without any
operation. After one hour, the ligation of the right kidney was
removed. Then the mice were injected with the nanoprobe TA-
TPABQ (2.8 mg probe/kg body weight) via the tail vein. At 15 min
2
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Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
Acknowledgement
This work was supported by NSFC (51673066, 21875069 and
2019, 9, 77-89.
2
(
1574044), the Natural Science Foundation of Guangdong Province
2016A030312002) and the Fund of Guangdong Provincial Key
Laboratory of Luminescence from Molecular Aggregates
2019B030301003).
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(
The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2019
Manuscript revised: XXXX, 2019
Manuscript accepted: XXXX, 2019
Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
Zhao, W. J.; Li, Y. H.; Yang, S.; Chen, Y.; Zheng, J.; Liu, C. H.; Qing, Z. H.;
Li, J. S.; Yang, R. H. Target-activated modulation of dual-color and two-
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Entry for the Table of Contents
Page No.
Near-infrared fluorescent nanoprobe for
detecting hydrogen peroxide in inflammation
and ischemic kidney injury
,
a
Lingfeng Xu, Lihe Sun, Fang Zeng,* Shuizhu
Wu,*
A nanoprobe with activated AIE feature was developed for monitoring the overexpression of
hydrogen peroxide in inflammation and ischemic kidney injury.
,
a
a
State Key Laboratory of Luminescent Materials & Devices, Guangdong
Provincial Key Laboratory of Luminescence from Molecular Aggregates,
College of Materials Science & Engineering, South China University of
Technology, Guangzhou 510640, China
E-mail: mcfzeng@scut.edu.cn; shzhwu@scut.edu.cn.
Chin. J. Chem. 2018, template© 2018 SIOC, CAS, Shanghai,
&
WILEY-VCH Verlag GmbH
&
Co. KGaA,
Weinheim
This article is protected by copyright. All rights reserved.