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org/ac Article

Intratumoral Glutathione Activatable Nanoprobes for Fluorescence

and 19F Magnetic Resonance Turn-On Imaging
Yangyang Zhang, Qian Ma, Yunhe Yan, Chang Guo, Suying Xu,* and Leyu Wang*
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ABSTRACT: Tumor microenvironment turn-on nanoprobes that

could specifically detect the occurrence of diseases possess great
potential in early diagnosis. Here, a GSH activated nanoprobe was
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designed for fluorescence and 19F magnetic resonance (MR) dual-

modal turn-on imaging of tumors. Specifically, fluorescence AgInS2
quantum dots (QDs for fluorescence imaging) were co-
encapsulated with perfluoro-15-crown-5-ether (P19FCE for19F
MRI) by amphiphilic polymers and further coated with in situ
formed manganese dioxide (MnO2) nanoshells, which served as
efficient fluorescence and 19F MR quenchers due to energy transfer
and paramagnetic relaxation effects, respectively. The over-
expressed GSH in tumors would decompose the MnO2 nanoshells,
resulting in remarkable enhancement of both fluorescence and 19F
MRI signals of the nanoprobes, accordingly lighting up the tumor site.

accommodate for fluorescence imaging and 19F MRI is very

D evelopment of smart activatable nanoprobes with
different imaging modalities for early diagnosis of various
diseases has attracted tremendous attention.1 In particular,
those dual-modal imaging systems such as use high spatial
resolution of fluorescence modality2−4 and deep tissue
penetration of magnetic resonance imaging (MRI)5−9 are
capable of taking advantage of features of each imaging
modality and overcoming the corresponding limitation. 1H
MRI has been widely utilized in clinics, of which the signal was
originated from the protons in biological systems.10 Given that
diagnosis of diseases is based on the slight signal variation
between health and pathological regions, it is particularly
challenging for discriminating areas of interest. Thus, various
1
H MRI contrast agents were explored to adjust the relaxation
rates (longitudinal relaxation time (T1) and transverse
relaxation time (T2)) of naturally occurring water molecules,
so as to increase the MRI image contrast,11 yet, only to a limit
degree. Different from traditional 1H MRI, 19F MRI utilized
exogenous fluorinated contrast agents, thus with negligible
endogenous background noise, which further provides
quantitative information with high specificity.12−14 Therefore,
19
F MRI may become a promising supplementary technique
for 1H MRI because it can provide accurate and intuitive
images in pathological imaging through the anatomical
position of 1H MRI. In addition to combined imaging
modalities, activated nanoprobes could gain information
about dynamic processes and obtain functional information
in real time, which can facilitate more specific diagnosis.15−20
In this regard, exploration of activatable nanoprobes that could
intriguing.
Among various biological stimulus imaging probes such as
pH,20,21 enzyme,17,22 redox, and so on, redox-activated imaging
probes are extremely intriguing because of the important role
of redox processes in organisms.23−26 The reduced glutathione,
a peptide composed of glutamic acid, cysteine, and glycine, is
an essential endogenous antioxidant that plays a vital part in
physiological functions such as defense against toxins and free
radicals.27,28 In addition, the concentration of GSH is
implicated in many diseases typically associated with cancer,28
dementia,29 or neurodegenerative diseases.30 To date, GSH-
responsive 19F MRI probes were mainly constructed by
introducing redox sensitive moieties such as disulfide linkers31
and 4-dinitrobenzenesulfonyl groups32 in fluorinated polymers.
The presence of GSH would either induce assemble or
disassemble of polymers or modulate paramagnetic relaxation
enhancement (PRE) effects toward fluorinated moieties,
resulting in activation or attenuation of 19FMRI signals.33,34
In addition, most of the reported probes can hardly achieve
“one stone for two birds” results, that is, using one single
trigger to induce different signal responses, which would
Received: October 13, 2020
Accepted: October 30, 2020
Published: November 11, 2020

© 2020 American Chemical Society https://dx.doi.org/10.1021/acs.analchem.0c04301

15679 Anal. Chem. 2020, 92, 15679−15684
Analytical Chemistry
improve the diagnosis accuracy. There is only one GSH-
activatable nanoprobe with dual-mode turn-on imaging
properties,15 yet, the 19F MRI signal of which is far from
enough for in vivo imaging. Herein, we synthetized a GSH
activated dual-modal nanoprobe for19 F MRI and fluorescence
imaging of tumors. As shown in Scheme 1, 19F moiety and
Scheme 1. Illustration Scheme of GSH-Activated FAN@
MnO2 Nanoprobes for 19F MRI and Fluorescence Turn-On
Imaging
AgInS2 QD loaded nanoparticles (FANs) were successfully
prepared by encapsulating AgInS2 and perfluoro-15-crown-5-
ether (P19FCE) with amphiphilic polymers (oleylamine and 1-
(3-aminopropyl) imidazole functionalized polysuccinimide),
which were further coated with manganese dioxide (MnO2)
nanoshells through in situ reduction of KMnO4 with 2-(N-
morpholino) ethanesulfonic acid (MES) to afford FAN@
MnO2 nanoprobes. The MnO2 coating could effectively
quench the fluorescence and 19F NMR signals through the
energy transfer process and PRE effect, respectively, yet the
elevated GSH level in tumors would induce the decomposition
of MnO2 into Mn2+, accordingly achieving recovery of both
fluorescence and 19F NMR signals.
■ EXPERIMENTAL SECTION
Reagents and Chemicals. NaOH, NaH2PO4·2H2O,
Na2HPO4·12H2O, KMnO4, cyclohexane, 1-dodecanethiol
(DDT), chloroform, ethanol, methanol, N, N-dimethylforma-
mide (DMF), and dimethyl sulfoxide (DMSO) were supplied
by Beijing Chemical Factory. 1-(3-Aminopropyl) imidazole
and N-methylmaleimide (NMM) were purchased from Alfa
Aesar Chemical Company. Polysuccinimide (PSI, MW ∼7000
Da) was obtained from Shijiazhuang Desai Chemical
Company (China). Oleylamine (OAm) and 1-octadecene
(ODE) were obtained from Sigma-Aldrich. The PSI was
functionalized with both OAm and 1-(3-aminopropyl)
imidazole to get the amphiphilic polymer for the surface
coating of hydrophobic AgInS2 QDs. Indium nitrate hydrate
and glutathione (GSH) were purchased from Aladdin. Stearic
acid was supplied by TCI. AgNO3 was purchased from
Innochem company. 2-(N-morpholino) ethanesulfonic acid
(MES) was obtained from Amethyst company. Sublimed sulfur
and PEG-2000 were purchased from Xilong Chemical
Industrial Company (China). Perfluoro-15-crown-5-ether
(P19FCE) was supplied by Matrix scientific company. NO
was prepared from diethylamine NONOate sodium salt
hydrate (DEA NONOate). For the cell culture, phosphate-
buffered solution and methyl thiazolyltetrazolium were
obtained from Amresco Inc. Dulbecco’s modified eagle
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medium (DMEM) and trypsin were purchased from M&C
Gene Technology. Fetal calf serum (FBS) was obtained from
Hangzhou Sijiqing Bioengineer Materials Ltd. All of the above
chemicals were used directly without further purification.
Deionized (DI) water was used throughout all experiments.
Instrumentation. Transmission electron microscope
(TEM) images were acquired by using a JEOL JEM-1200EX
(100 kV), and high-resolution transmission electron micros-
copy (HRTEM) images were obtained via a JEOL JEM-2100F
transmission electron microscope (200 kV). Dynamic light
scattering (DLS) particle size analysis and zeta potentials were
measured by using a Zeta sizer Nano-ZS90 zeta and size
analyzer from Malvern. Fluorescence spectra were recorded on
an F-4600 fluorescence spectrophotometer (Hitachi, Japan).
19
F NMR spectra were obtained from a Bruker Avance-III 400
MHz spectrometer. The cytotoxicity experiment was tested
using an ELISA plate reader (F50, TECAN). Cell imaging was
carried out using a laser scanning confocal microscope (Leica
SP8). Energy-dispersive spectroscopy (EDS) was acquired by
using a scanning electron microscope (SEM, SU-8010). X-ray
diffraction (XRD) patterns were recorded on a Shimadzu
XRD-7000 X-ray diffractometer using Cu Kα radiation (λ =
1.5418 Å). X-ray photoelectron spectroscopy (XPS) was
measured on an X-ray photoelectron spectrometer from
ThermoFisher Scientific USA. All MRI experiments were
performed using a 7.0 T Bruker Bio-Spec70/20USR MRI
system. Fluorescence imaging was performed on a small animal
live imaging system from PE company (IVIS Spectrum). The
Mn2+ concentration tests were carried out on an inductively
coupled plasma optical emission spectroscopy (ICP-OES,
Thermo Scientific iCAP 6000 series).
Preparation of Both 19F Moiety and AgInS2 QD
Loaded Nanoparticles (FANs). In brief, the as-synthesized
AgInS2 QDs (2 mg) (details in the Supporting Information),
amphiphilic polymer (25 mg), and P19FCE (5 μL) were
dissolved in 1.0 mL of CHCl3. Then, the mixture was added
into 10 mL of DI water (containing 0.32 mg of NaOH) with
ultrasonication treatment and magnetic stirring (600 W for 6
min, pulsed working as 3 s “on” and 3 s “off”). Once the
resultant mixture solution changed into an emulsion, the
CHCl3 was evaporated at 38 °C. After being centrifuged at a
speed of 18,000 rpm for 20 min, the precipitation was
dispersed into DI water (1.0 mL) and stored for later use.
Preparation of Water-Dispersible FAN@MnO2. In situ
formation of MnO2 nanoshells on FANs was carried out by
adding 500 μL of KMnO4 aqueous solution (10 mM) into the
as-prepared FAN colloid solution (1.0 mL) in the presence of
MES buffer (4.0 mL, 0.1 M, pH = 6.0). It was observed that
the color of solution immediately became dark brown. Then,
the solution was vigorously stirred for 30 min at room
temperature before centrifugation at 15,000 rpm for 10 min.
The as-obtained precipitate was washed with DI water twice
and then redispersed in DI water. Finally, PEG-2000 (10 mg)
was added. The colloidal solution was stirred at room
temperature for 30 min. FAN@MnO2 was collected by
centrifugation at 1000 rpm for 6 min to remove large
nanoparticles. The obtained supernatant solution was centri-
fuged at 15,000 rpm for 10 min. The precipitate was dispersed
in 1.0 mL of DI water and stored in the dark at 4 °C.
In Vivo Experiments. All animal experiments and
treatments were approved by the local ethics review committee
and conducted in accordance with the guidelines of the Animal
Care and Use Committee of Beijing University of Chemical
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Anal. Chem. 2020, 92, 15679−15684
Analytical Chemistry
Technology. Four-week old female nude mice (Balb/c) were
used for animal experiments. The 4T1 cells (∼107) were
injected subcutaneously into the right hind limb of mice. When
the tumor size grew to a size of about 900 mm3, FAN@MnO2
nanoprobe colloidal solution (200 μL, 12 mg/mL) was
injected into the tumor, and as a control, an equal amount
of FAN@MnO2 nanoprobe colloidal solution was injected
subcutaneously into the healthy tissues in the left hind limb of
the same mouse. Those mice were anesthetized by using
isoflurane prior to MRI measurements. The T1 RARE
sequence was applied for 19F MRI (FOV = 50 mm × 50
mm, slice thickness = 5 mm, TR = 3000 ms, effective TE =
4.24 ms, echo spacing = 4.24 ms, RARE factor = 4, NEX = 20,
matrix size = 100 × 100, acquisition time = 19 min).
■ RESULTS AND DISCUSSION
AgInS2 QDs were prepared through a previously published
method with slight modification.35 As shown in Figure 1a, the
Figure 1. (a) TEM and HRTEM (inset of 1a) images of AgInS2 QDs;
(b) excitation (black line, λex = 500 nm) and emission (red line, λem =
654 nm) spectra of AgInS2 QDs; the inset photo was hydrophobic
AgInS2 QDs dispersed in chloroform under daylight (left) and 365
nm light (right); (c) TEM image and (d) DLS size distribution of
FAN@MnO2 nanoprobes, respectively.
TEM and HRTEM images showed that the average size of
AgInS2 QDs was around 4.0 nm, with a clear lattice spacing of
0.33 nm, well consistent with the (112) facet of the tetragonal
AgInS2 phase observed by XRD patterns (Figure S1).36 The
acquired hydrophobic AgInS2 QD suspension displayed
intense fluorescence with maximal emission at 654 nm (Figure
1b). Under ultrasonication treatment, the FAN with a particle
size of 78.3 ± 25.8 nm was successfully fabricated by
encapsulating AgInS2 QDs and P19FCE with the as-synthesized
amphiphilic polymer (Figure S2a). The fluorescence of the
FAN dispersed in water shows a slight decrease, compared to
that of AgInS2 QDs dispersed in chloroform (Figure S2b).
Moreover, the FAN was further coated with MnO2 nanoshells.
The TEM image (Figure 1c) indicated that FAN@MnO2
nanoprobes were successfully synthesized by in situ coating
MnO2 nanoshells. Meanwhile, the DLS size of FAN@MnO2
nanoprobes (114.8 ± 37.7 nm) was larger than that of the
FAN (78.3 ± 25.8 nm) (Figure 1d). Due to the significant
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overlap between the absorption spectrum of MnO2 and the
excitation spectrum of FAN (Figure S3), a dramatic
fluorescence quenching was observed along with the increased
dosages of KMnO4 (Figure S4a). Similar to the trend of
fluorescence, the 19F NMR signal was gradually decreased as
well (Figure 4a), and a final dosage of KMnO4 (10 mM) was
fixed at 0.5 mL for the formation of MnO2 nanoshells. The
formation of MnO2 was further supported by the zeta potential
changes. As shown in Figure S4b, the pristine FAN was
positively charged with the zeta potential of +62 mV. After
coating MnO2 nanoshells, the zeta potential of FAN@MnO2
nanoprobes was gradually decreased. Furthermore, the XRD,
EDS analysis results, and XPS results (Figure S5) demon-
strated the successful construction of FAN@MnO2. The as-
prepared FAN@MnO2 displayed a good stability as no obvious
size changes were observed for at least 20 days both in the DI
water and FBS medium (Figures S6 and S7).
Initially, the 19F NMR signal recovery ability of FAN@
MnO2 nanoprobes was investigated in the presence of GSH
(10 mM) at pH 6.0, as it was assumed that the in situ formed
MnO2 nanoshells could be degraded under tumor micro-
environments.37,38 As for FAN@MnO2 nanoprobes, due to the
intense PRE effect of MnO2, the 19F NMR signal intensities of
nanoprobes would be attenuated. When in the presence of
GSH at pH 6.0, an obvious increase of the 19F NMR signal
intensity, a singlet peak at −91.8 ppm, was observed, as shown
in Figure S8. It was reasoned that the MnO2 nanoshells of
nanoprobes were decomposed to Mn (II) ions by GSH at pH
6.0, and free Mn (II) would be away from nanoprobes to
impair the PRE effect, resulting in recovery of 19F NMR signal
intensities. The impairment of the PRE effect was also
supported by the changes of measured 19F NMR relaxation
time, listed in Table S1, where a clear increase of T2 from 129
to 708 ms was observed after incubation with GSH (10 mM)
at pH 6.0. Inversely proportional to T2 relaxation time, the half
peak widths of nanoprobes decreased from 33.5 to 14.3 Hz,
again demonstrating the proposed mechanism in FAN@MnO2
nanoprobes. Moreover, the decomposition of MnO2 was also
verified by the decreased size and morphology changes of
FAN@MnO2 nanoprobes (Figure S9). At the same time, the
ICP-OES results showed that the Mn2+ ions in the supernatant
had increased from 1.216 to 5.345 μg/mL after adding 10 mM
of GSH. All these observations strongly supported the
assumption that MnO2 would be decomposed under tumor
microenvironments.
Then, we investigated the influence of incubation time by
measuring the 19F NMR signal of a mixed solution containing
FAN@MnO2 nanoprobes after incubation with different
concentrations of GSH for different time intervals. As shown
in Figure 2a, at pH 6.0, the 19F NMR signal was gradually
recovered by adding GSH, and the 19F signal-to-noise ratio
(SNR) reached a plateau at 2 h. Moreover, the 19F NMR signal
of nanoprobes was gradually recovered along with the increase
of GSH in a weak acid buffer solution (pH 6.0). Yet, the signal
was stable, and no significant enhancement was observed
under neutral buffer solution (pH 7.4), as seen in Figure 2b,
which suggested that acidic conditions would facilitate MnO2
decomposition. In addition, in vitro 19F MRI was also
evaluated; as shown in Figure 2c, when the concentration of
GSH increased, the 19F MRI of the nanoprobes enhanced. The
19
F MRI SNR was proportional to the concentration of GSH
(Figure 2d), with a linear regression equation of SNR = 0.710
C + 6.70 (R2 = 0.958). Herein, the C represented the
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Anal. Chem. 2020, 92, 15679−15684
Analytical Chemistry
Figure 2. (a) Time-dependent evolution of 19F NMR signal-to-noise
ratio (SNR) of the FAN@MnO2 nanoprobes in the presence of
different concentrations of GSH at pH = 6.0. (b) SNR recovery of
FAN@MnO2 nanoprobes containing different concentrations of GSH
under different pH values (7.4 and 6.0). (c) 19F MRI of FAN@MnO2
nanoprobes incubated with different concentrations of GSH at pH =
6.0. (d) Corresponding calibration plot of 19F MRI SNR versus the
concentration of GSH. (e) Fluorescence imaging of FAN@MnO2
nanoprobes incubated with different concentrations of GSH at pH =
6.0 (λex = 500 nm; λem = 640 nm).
concentration of GSH (mM). Given that the broad absorption
of MnO2 nanoshells overlaps with the fluorescence excitation
of the FAN, the fluorescence intensities of FAN@MnO2
nanoprobes experienced a clear turn-on response with the
increment of GSH under weakly acidic conditions due to the
decomposition of MnO2 (Figures S10a, S10b and Figure 2e).
Meanwhile, a series of other species that commonly occurred
in biological systems including L-cysteine, H2S, KSCN, NO,
H2O2, and NaNO2 were tested (Figures S11 and S12), which
indicated that FAN@MnO2 displayed high specificity toward
GSH under biological conditions.
Prior to imaging, the cell cytotoxicity of FAN@MnO2
nanoprobes was evaluated. As shown in Figure S13a, FAN@
MnO2 nanoprobes were incubated with HUVEC cells for 24
and 48 h, respectively. When the concentration of the FAN@
MnO2 nanoprobes reached 250 μg/mL, 84% viability was
acquired after 48 h, indicating that nanoprobes had good
biocompatibility. However, the viability of HeLa cells (Figure
S13b) was about 55% after 48 h, and the viability of 4T1 cells
(Figure S13c) was about 50%, which might be attributed to the
elevated GSH level in cancer cells than that in normal cells,39
implying that the FAN@MnO2 nanoprobes may serve as
theranostic platforms for tumors.
In vitro imaging was initially performed by incubating
nanoprobes with HeLa cells for different time periods (0.5, 2,
4, and 6 h, Figure 3 and Figure S14). As shown in Figure S14,
the fluorescence signal was almost undetectable at 0.5 h, and
red fluorescence could be seen on the cell membrane at 4 h.
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Figure 3. Intracellular imaging of HeLa cells with different treatments.
Cells incubated with FAN@MnO2 nanoprobes for (a1−a3) 0.5 h and
(b1−b3) 6 h; (c1−c3) cells pretreated with NMM (500 μM) for 30
min followed by incubation nanoprobes for 6 h. Scale bar was 20 μm.
Then, nanoprobes were taken up by the cells after 6 h. As a
positive control, FAN nanocomposites were incubated with
HeLa cells and an intense emission was observed (Figure S15),
suggesting that MnO2 formation accounts for the initial weak
emission signals of FAN@MnO2 nanoprobe-treated HeLa
cells. To further investigate whether FAN@MnO2 was able to
respond to intracellular GSH in living cells, the cells were
pretreated with the GSH scavenger (N-methylmaleimide,2
NMM) for 30 min and then incubated with the cells for 6 h
before cell imaging. It was worth noting that the fluorescence
of cells treated with NMM was significantly decreased (Figure
3c1−c3) compared with that of untreated cells (Figure 3b1−
b3), suggesting the specificity of FAN@MnO2 toward GSH. In
addition, a 4T1 xenograft tumor model was used to evaluate
the ability of intratumoral glutathione for lighting up FAN@
MnO2. As shown in Figure S16, strong fluorescence intensity
was observed at the tumor site, suggesting the tumor
microenvironment responsiveness of the as-prepared nanop-
robes.
Encouraged by these promising results, we explored the in
vivo utilization possibility of these nanoprobes. As shown in
Figure 4, the same amounts of FAN@MnO2 nanoprobe
colloidal solution were injected into the tumor and the healthy
tissues of the same mouse, respectively. As indicated in Figure
4b,c, the stronger 19F MRI signals were observed at the tumor
site 1 h post injection than those in normal tissues, implying
tumor microenvironment activatable features of FAN@MnO2.
These results demonstrated that the FAN@MnO2 nanoprobes
could indeed be turned on under tumor microenvironments.
Figure 4. (a) In vivo 1H MRI, (b) 19F MRI, and (c) merged images
for tumor-bearing mouse by injecting the same amounts of FAN@
MnO2 nanoprobes at tumor sites and the contralateral site,
respectively.
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Anal. Chem. 2020, 92, 15679−15684
Analytical Chemistry
■
pubs.acs.org/ac
CONCLUSIONS
In conclusion, we designed tumor microenvironment activated
FAN@MnO2 nanoprobes for simultaneous fluorescence and
19
F MRI turn-on imaging. The nanoprobes were fabricated by
coating the 19F moiety and fluorescence AgInS2 QD core with
in situ formed MnO2 nanoshells, where the fluorescence
intensity and the 19F MRI signal were quenched by adjacent
MnO2 shells through the energy transfer process and PRE
effect, respectively. Under slightly acidic conditions with high
GSH levels, the MnO2 shells were decomposed, which resulted
in the shielded signals turn-on. Both the in vitro and in vivo
imaging results demonstrated that these nanoprobes were
sensitive to tumor microenvironments, thus possessing great
potential for precisely lighting up the tumor site without
inducing off-targeting signals.
■
sı
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.analchem.0c04301.
XRD pattern of AgInS2 QDs (Figure S1); DLS, TEM
image, excitation and emission spectra of FAN (Figure
S2); excitation spectrum of FAN and absorption
spectrum of MnO2 (Figure S3); 19F NMR signal
intensities, fluorescence intensities, and zeta potentials
of FAN@MnO2 (Figure S4); XRD, EDS, and XPS of
FAN@MnO2 (Figure S5); stability investigation of
FAN@MnO2 nanoprobes (Figures S6 and S7); proper-
ties of FAN@MnO2 nanoprobes with and without GSH
(Table S1 and Figure S8); DLS and TEM image of
FAN@MnO2 nanoprobes after incubation with GSH
(Figure S9); responses of FAN@MnO2 nanoprobes
toward GSH (Figure S10) and species in biological
systems (Figures S11 and S12); cell viability tests of
nanoprobes (Figure S13); fluorescence imaging of
FAN@MnO2 nanoprobes in HeLa cells (Figure S14
and S15); and in vivo fluorescence imaging (Figure S16)
(PDF)
■
AUTHOR INFORMATION
Corresponding Authors
Suying Xu − State Key Laboratory of Chemical Resource
Engineering, Beijing Advanced Innovation Center for Soft
Matter Science and Engineering, Beijing University of
Chemical Technology, Beijing 100029, P. R. China;
orcid.org/0000-0001-6638-0040; Email: syxu@
mail.buct.edu.cn; Fax: (86)10-64427869
Leyu Wang − State Key Laboratory of Chemical Resource
Engineering, Beijing Advanced Innovation Center for Soft
Matter Science and Engineering, Beijing University of
Chemical Technology, Beijing 100029, P. R. China;
orcid.org/0000-0002-5961-7764; Email: lywang@
mail.buct.edu.cn
Authors
Yangyang Zhang − State Key Laboratory of Chemical
Resource Engineering, Beijing Advanced Innovation Center
for Soft Matter Science and Engineering, Beijing University of
Chemical Technology, Beijing 100029, P. R. China
Qian Ma − State Key Laboratory of Chemical Resource
Engineering, Beijing Advanced Innovation Center for Soft
15683
Article
Matter Science and Engineering, Beijing University of
Chemical Technology, Beijing 100029, P. R. China
Yunhe Yan − State Key Laboratory of Chemical Resource
Engineering, Beijing Advanced Innovation Center for Soft
Matter Science and Engineering, Beijing University of
Chemical Technology, Beijing 100029, P. R. China
Chang Guo − State Key Laboratory of Chemical Resource
Engineering, Beijing Advanced Innovation Center for Soft
Matter Science and Engineering, Beijing University of
Chemical Technology, Beijing 100029, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.analchem.0c04301
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
The authors gratefully acknowledge the financial support from
the National Natural Science Foundation of China (21675009,
21725501, and 21874007) and the Fundamental Research
Funds for the Central Universities (XK1901).
■
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