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Cite This: ACS Omega 2019, 4, 11981−11987 http://pubs.acs.org/journal/acsodf

Fluorescent Supramolecular Assembly with Coronene Centers for

Controlled DNA Condensation and Drug Delivery
Yu-Hui Zhang,†,∥ Jie Yu,‡,∥ Jie Wang,† Li-Juan Wang,§ Wen-Han Yao,† Siqintana Xin,†
Xianliang Sheng,*,† and Zeyu Guo*,§
†
College of Science and §College of Material Science and Art Design, Inner Mongolia Agricultural University, Hohhot 010018, P. R.
China
‡
School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan 411201, P. R. China
*
S Supporting Information
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ABSTRACT: A multifunctional supramolecular assembly

was successfully constructed by the host−guest complexation
of doubly positively charged adamantane (ADA) with β-CD-
modified hexabenzocoronene and the π-stacking of coronene
with mitoxantrone, which was characterized by transmission
electron microscopy, scanning electron microscopy, dynamic
light-scattering, and zeta potential experiments. Possessing a
small size and rigid backbone coronene center, the water-
soluble biocompatible supramolecular assembly has intra-
cellular imaging abilities. Moreover, after the ester group of
ADA was hydrolyzed into a carboxyl group, the positively
charged quaternary amine strand converted into a zwitterion
structure, which realized the controlled plasmid DNA binding and release. Besides, the cytotoxicity experiments showed that the
supramolecular assembly possesses slightly lower toxicity and a slightly higher anticancer activity than free drug. We believe that
this work might present a convenient method for synergetic cancer treatment.

1. INTRODUCTION stability in physiological environments still deserve our careful

The construction of multifunctional nanocarriers incorporating
two or more different therapeutic strategies with synergistic
effects has recently emerged as a promising approach for
improving cancer therapy.1−3 To this end, a number of
multifunctional carriers based on inorganic nanoparticles,4
carbon nanomaterials,5 liposomes,6 and vesicles7 were
constructed and exhibited effective therapeutic activities to
cancer cells. Nevertheless, the synthetic procedure is
complicated and time-consuming to construct multifunctional
integrated diagnosis, imaging, and drug delivery systems with
multifarious therapeutic approaches, which hinder the further
advance. In this regard, supramolecular host−guest complex-
ation provides a facile and rapid procedure to construct
complicated molecular assemblies through noncovalent inter-
actions, because the representative macrocycles, such as
cyclodextrin (CD), is water-soluble, nontoxic, and possessing
a hydrophobic cavity, which can construct biocompatible
supramolecular assemblies with various substrates in bio-
medical science.8−17 For instance, Liu and co-workers
developed a new type of magnetism and photo dual-controlled
supramolecular nanofiber that integrates targeting peptide-
coated magnetic nanoparticles with β-CD-bearing polysacchar-
ides for suppression of tumor invasion and metastasis,
demonstrating that the nanofibers provide a convenient tool
for tumor therapy.18 Besides, the effective macrocycle-based
delivery systems with suitable size, good water solubility, and
attention.19−23
It is significant to note that multifunctional nanocarriers
simultaneously loading imaging and therapeutic agents have
appeared as a potential candidate in imaging-guided therapy to
realize early detection and prompt treatment of cancer.24,25
Among various imaging agents, nanographenes (coronene
derivatives) have attracted considerable attention because of
their intrinsic properties including superior fluorescence
emission, anti-photobleaching ability, and intermolecular π−π
stacking behaviors.26−28 In this work, a conjugated supra-
molecular assembly was constructed by the noncovalent
multiple interactions with β-CD-modified hexabenzocoronene
(HBCCD) as scaffold centers, which could simultaneous
intracellular imaging and plasmid DNA (pDNA) binding and
anticancer drug loading. The chemical structure and con-
struction route for the preparation of HBCCD−ADA
fluorescent supramolecular assembly are shown in Scheme 1.
There are some unique characteristics of such a system: (1) a
small size coronene derivative was chosen as scaffold because of
its inherent fluorescence properties, which could act as a
fluorescence probe to real-time monitor the drug release,
distribution, and accumulation of the supramolecular assembly;
Received: May 17, 2019
Accepted: June 28, 2019
Published: July 10, 2019

© 2019 American Chemical Society 11981 DOI: 10.1021/acsomega.9b01436

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Scheme 1. Construction of HBCCD−ADA Supramolecular Assembly
Figure 1. Typical (a) TEM and (b) SEM images of HBCCD−ADA supramolecular assembly. (c) DLS and (d) zeta potential experiment results of
HBCCD−ADA supramolecular assembly in deionized aqueous solution.
(2) the controlled binding and release of pDNA was easily
achieved via ester hydrolyze into “zwitterionic” structure;29−31
and (3) anticancer drugs, such as mitoxantrone (MTZ), could
be readily integrated into the water-soluble supramolecular
assembly of HBCCD−adamantane (ADA) by the π−π stacking
interaction between the coronene surface and the aromatic ring
of drug molecule MTZ. Therefore, this water-soluble and
biocompatibility multifunctional nanostructure is taken into
account as a novel strategy for improving cancer treatment.
2. RESULTS AND DISCUSSION
Benefiting from the strong host−guest inclusion complexation
between ADA and β-CD,32 the fluorescent supramolecular
assembly was prepared by simply mixing the aqueous solutions
of ADA and HBCCD together. The structural and morpho-
logical features of the HBCCD−ADA supramolecular assembly
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were characterized by transmission electron microscopy
(TEM), scanning electron microscopy (SEM), dynamic light-
scattering (DLS), and zeta potential measurements. The TEM
image in Figure 1a showed that HBCCD−ADA supra-
molecular assembly have a spherical morphology with a
diameter of ca. 300 nm. The SEM image (Figure 1b) also
showed the 280−310 nm homogeneous spherical nano-
particles. Moreover, DLS measurement indicated that the
hydrodynamic diameter of HBCCD−ADA assembly was ca.
465 nm with a narrow distribution (Figure 1c), which was in
accordance with the results in microscopic images. The zeta
potential of HBCCD−ADA was measured as ca. +14.8 mV
(Figure 1d), suggesting that the surface charge of assembly was
positive charged, which is beneficial to promote the electro-
static interaction between HBCCD−ADA supramolecular
assembly and pDNA.
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Considering that the quaternary amine strands of ADA were
positively charged in aqueous solution, the HBCCD−ADA
supramolecular assembly could be used to bind nucleic acid via
electrostatic interaction. The pDNA binding behavior was
examined by evaluating the electrophoretic mobility at different
N/P ratios in agarose gel. As shown in Figure 2a,b, pDNA was
Figure 2. Agarose gel electrophoresis experiments of (a) ADA, (b)
HBCCD−ADA supramolecular assembly with pDNA at N/P ratios of
5, 10, 20, 30, 40, 50, and 60 from lane 1 to lane 7, respectively, (c)
ADA with pDNA before (lane1) and after (lane 2) esterolysis at the
N/P ratio of 50, (d) HBCCD−ADA supramolecular assembly with
pDNA before (lane 3) and after (lane 4) esterolysis at the N/P ratio of
20.
completely retarded by HBCCD−ADA supramolecular
assembly at an N/P ratio of 10, which was much lower than
that for ADA alone (N/P = 50). This phenomenon might be
that the assembly enriches the quaternary ammonium chains of
ADA together and facilitates the pDNA binding, thus leading to
the enhanced DNA condensation capability. Meanwhile, other
information about the pDNA condensation by the HBCCD−
ADA supramolecular assembly comes from TEM and DLS
experiments. The TEM image (Figure S1a) revealed that
pDNA was condensed into even tighter spherical particles with
an average diameter of 270 nm at the N/P ratio of 20. The DLS
result further indicated that the HBCCD−ADA supramolecular
assembly could effectively bind pDNA into uniform nano-
particles with a hydrodynamic diameter centered at 414 nm
(Figure S1b).
Subsequently, the controlled pDNA release behavior was
investigated by analyzing electrophoretic mobility of supra-
molecular assembly before and after hydrolysis of ester group in
ADA under aqueous NaOH solution. As shown in Figure 2c,d,
pDNA could be released from ADA and HBCCD−ADA
supramolecular assembly (lane 2 and lane 4) after hydrolysis.
This indicated that ADA and HBCCD−ADA supramolecular
assembly could bind pDNA through electrostatic interaction
before esterolysis (lane 1 and lane 3). Nevertheless, when the
neutral ester group in ADA was hydrolyzed to a negatively
charged carboxyl group, the quaternary amine strand in ADA
changed to a zwitterion structure, which realize pDNA-
controlled binding and release (Scheme S1).
As a consequence of the satisfactory π-stacking interaction,
MTZ was chosen as a model anticancer drug and loaded onto
the surface of coronene (Scheme S2).33 As expected, a new
shoulder band at 609 and 660 nm was observed in the UV/vis
spectrum of MTZ@HBCCD−ADA (Figure 3), which was
assigned to the characteristic absorption of MTZ.34 Meanwhile,
the MTZ-loaded solution (MTZ@HBCCD−ADA) turns to
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Figure 3. UV/vis absorption of HBCCD−ADA and MTZ@
HBCCD−ADA, respectively. Inset: Color change of unloaded
HBCCD−ADA assembly (left) compared with MTZ-loaded
HBCCD−ADA assembly (right).
light blue compared with the pale yellow MTZ-unloaded
solution (Figure 3, inset). By monitoring the UV/vis spectrum
of MTZ at 609 nm, the photometric standard curve of MTZ
was measured (Figure S2). Therefore, the encapsulation and
loading efficiency of MTZ by HBCCD−ADA supramolecular
assembly was calculated to be 32.74 and 4.76%, respectively. In
addition, with the gradual addition of MTZ, the fluorescence
intensity of HBCCD−ADA assembly gradually decreased
(Figure S3). The efficiency of fluorescence quenching was
calculated to be 36.3%, which may originate from π-stacking
between MTZ and HBCCD, and then result in the photo-
induced electron transfer process. Moreover, the TEM image in
Figure S4a indicated that the MTZ@HBCCD−ADA assembly
still exists in the spherical morphology with a diameter of 260
nm, and the DLS results revealed a narrow size distribution of
ca. 380 nm accordingly (Figure S4b). These results
demonstrated that the anticancer drug MTZ was loaded on
the HBCCD−ADA supramolecular assembly efficiently.
Subsequently, the releasing behavior of MTZ from
HBCCD−ADA supramolecular assembly was investigated in
physiological environments (0.01 M PBS, 37 °C) at pH 5.7
(the endosomal pH of a cancer cell) and pH 7.2 (physiological
pH). As shown in Figure S5, the MTZ@HBCCD−ADA
displayed a controlled and sustained release of MTZ, and the
release efficiency of MTZ from MTZ@HBCCD−ADA was
much faster at pH 5.7. The low cumulative release of MTZ
probably because the release process is a dynamic equilibrium
process, which results in the drug not being released
completely. This pH responsive releasing behavior could
definitely improve the cytotoxic efficiency to cancer cells and
reduce the toxicity to normal tissues. It is reported that MTZ
hydrochloride is hydrophilic because of the two positively
charged nitrogen atoms, the acidity of protonated MTZ is
reduced in the hydrophobic environment of assembly and pack
more closely, which would prolong the circulation time and
favor its stability and biocompatibility of the drug under the
cellular environment.35 In addition, free MTZ is too hydro-
philic to penetrate into the lipid bilayer of the cell membrane,
while the assembly can carry drug into cells through
endocytosis. These advantages jointly demonstrate that the
assembly could be used as a safe and promising candidate for
drug delivery systems.
Next, cytotoxicity experiments were performed to evaluate
the anticancer activity of MTZ@HBCCD−ADA supramolec-
ular assembly in vitro. As shown in Figure S6, the half-maximal
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inhibitory concentrations (IC50) of MTZ and MTZ@
HBCCD−ADA toward HCT-116 human colon cancer cells
were measured as 2.2236 and 2.04 μM by the MTT assay,
which indicated the enhanced anticancer activity of MTZ@
HBCCD−ADA assembly. In addition, after a 24 h incubation,
the MTZ@HBCCD−ADA assembly exhibited satisfactory
malignant cell inhibition effect toward the HCT-116 cell line
with a relative cellular viability of 43.7% (Figure S7a), which
was slightly lower than that of commercial anticancer drug
MTZ (49.1%); this might be attributed to the assembly that
was preferably internalized in HCT-116 cells through the
endocytosis. The side effects of MTZ@HBCCD−ADA
assembly were also tested by using NIH3T3 mouse embryonic
fibroblast cells. As shown in Figure S7b, MTZ@HBCCD−
ADA assembly gave a relative cellular viability as 56.5%, which
was slightly higher than that with free MTZ. Moreover, it is also
noteworthy that HBCCD−ADA assembly was nontoxic to all
the examined cell lines because of its good biocompatibility.
These results indicated that the supramolecular assembly could
facilitate the selective and accumulation of MTZ in cancer cells,
which holds great promise to present a safe and effective tool
for cancer therapy. Similar results were also observed at 48 h of
incubation (Figure S8). Afterward, we investigated the
intracellular fluorescence imaging ability of the conjugated
supramolecular assembly. As shown in Figure 4, HCT-116 cells
Figure 4. Confocal fluorescence images of HCT-116 cells incubated
with HBCCD−ADA for 24 h. The nucleus was stained by 4′,6-
diamidino-2-phenylindole dihydrochloride hydrate (DAPI).
gave a green fluorescence in cytoplasm after a 24 h incubation
with HBCCD−ADA fluorescence supramolecular assembly.
Besides, late endosomes and lysosomes were stained with
Lysotracker Red for colocalizing assembly.37 As shown in
Figure S9, high colocalization was observed for HBCCD−ADA
assembly, suggesting that the assembly was successfully
internalized into cells, which might have a potential application
value in cancer diagnosis.
Moreover, the real-time cellular uptake of assembly was
evaluated by confocal laser scanning microscopy during the
incubation from 2 to 6 h. As shown in Figure S10, green
fluorescence can be observed at 2 h, and the green fluorescent
intensities increased with time, indicating that the assembly has
entered the cells. This phenomenon validated that the assembly
could act as a fluorescence probe to monitor the distribution,
accumulation, and real-time drug release. After verifying the
internalization of HBCCD−ADA assembly, we continued to
investigate the pathway of cellular internalization with confocal
laser scanning microscopy. First, we examined the cellular
uptake of assembly at 4 and 37 °C (Figure S11). At the lower
temperature, the cellular uptake ability weakened, indicating an
energy-dependent process in the cellular internalization. In
order to further understand which of the energy-dependent
processes involved in the internalization of assembly, we
performed the cellular uptake treated with two types of
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biochemical inhibitors, that is, NaN3/2-deoxyglucose (NaN3/
DOG) was utilized to inhibit the energy-dependent pathway
and sucrose was used to perturb clathrin-mediated endocy-
tosis.37,38 As shown in Figure S11, compared with control, the
cells treated with inhibitors exhibited dramatic decrease in the
cellular uptake of assembly. Thus, we deduced that the
internalization of assembly might be via multiple endocytic
pathways.
3. CONCLUSIONS
In conclusion, we successfully constructed a fluorescent
supramolecular assembly composed of doubly positively
charged ADA with β-CD modified HBCCD as a multifunc-
tional supramolecular platform for controlled DNA condensa-
tion, cell imaging, and drug delivery via host−guest inclusion
complexation of ADA with β-CD and further π-stacking of
coronene with anticancer drug MTZ. After the ester group in
ADA was hydrolyzed to a negative carboxyl, the positively
charged quaternary ammine strand converted into a zwitterion
structure, which realized the controlled binding and release of
pDNA. Moreover, cytotoxicity experiments indicated that the
assembly displayed a slightly higher inhibition effect and a
lower toxicity than free drug. Besides, because of the coronene
intrinsic fluorescence properties, it has potential application as
cell imaging agent. Considering the facile synergetic interaction
in the design of macrocycle-based assembly, we envision that
the constructed multifunctional assembly can be further
functionalized easily by chemical modification of other guest
molecules, thus providing us a facile modular approach for
supramolecular cancer therapy.
4. EXPERIMENTAL SECTION
4.1. General Methods. All chemicals were of reagent grade
unless noted. HBCCD was synthesized according to our
reported method,25 and ADA was synthesized according to the
reported method.30 NIH3T3 mouse embryonic fibroblast cell
line and HCT-116 human colon cancer cell line were obtained
from China Infrastructure of Cell Line Resource. The
absorbance spectra were recorded in a conventional quartz
cell (light path 10 mm) by using a UV/vis spectrophotometer
(U-2900, Hitachi). Steady-state fluorescence emission spectra
were recorded in a conventional quartz cell (10 × 10 × 45 mm)
on a fluorescence spectrometer (Fluorolog-MAX 4, Horiba).
TEM images were acquired by an FEI Tecnai G2 F20
transmission electron microscope. The samples were prepared
by placing a drop of solution onto a carbon-coated copper grid
and air-dried. The SEM images were recorded on a JSM-6700F
scanning electronic microscope. The DLS and zeta potentials
were recorded on Malvern Zetasizer Nano ZS90 (Malvern
Instruments Ltd., Worcestershire, UK). Gel electrophoresis
experiments were measured on a 1% (w/v) agarose gel at 60 V
for 45 min and photographed using a UV transilluminator and
a WD-9415B gel documentation system (Beijing Liuyi
Instrument Factory, P. R. China). Confocal laser scanning
microscopy was performed on a fluorescence inverted micro-
scope (Zeiss LSM 800).
4.2. Preparation of HBCCD−ADA Supramolecular
Assemblies. ADA was dissolved in 10 mL of deionized
water to prepare a stock solution with the concentration of 2
mM, and HBCCD was dissolved in 5 mL of dimethyl sulfoxide
to obtain a stock solution with the [CD] concentration of 4
mM. The stock solution ADA was diluted 20 folds to 0.1 mM.
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Upon sonication, the HBCCD solution (0.5 mL) was slowly
added into the diluted ADA solution (19.5 mL) over 5 min.
The resulting HBCCD−ADA solution was stored at 4 °C.
4.3. Agarose Gel Electrophoresis Experiments. The
controlled condensation ability of assembly to pDNA was
measured by evaluating the electrophoretic mobility on the
agarose gel at different N/P ratios. The gel electrophoresis
experiments were performed in TAE (0.04 M Tris, 0.02 M
acetic acid, and 2.0 mM EDTA) buffer at 25 °C. After samples
loading and electrophoresis process, pDNA bands were stained
in Gen Green solution and were photographed using UV light
at 302 nm.
4.4. MTZ Loading on the HBCCD−ADA Supra-
molecular Assembly. The solution of MTZ (0.65 mg) in
0.5 mL of deionized water was dropwise added to 10 mL of
above prepared aqueous solution of HBCCD−ADA assembly,
and the obtained mixture was stirred overnight at room
temperature in dark for 12 h. The resulting solution was
dialyzed against deionized water for 2 h, and the deionized
water was replaced every 0.5 h. Then, the mixture was freeze-
dried. The drug loading efficiency and encapsulation of MTZ
onto HBCCD−ADA were estimated by the following
equations
Drug loading efficiency (%)
= 100 mMTZ in HBCCD − ADA /mHBCCD − ADA
Drug encapsulation efficiency (%)
= 100 mMTZ in HBCCD − ADA /mtotal MTZ
4.5. MTZ Releasing in Vitro. The release of MTZ from
HBCCD−ADA in vitro was investigated using the dialysis
method in PBS buffer (pH 5.7 and 7.2, I = 0.01 M) at 37 °C.
The solution of 2 mL MTZ@HBCCD−ADA was placed into a
dialysis membrane with a molecular weight cut off 500 and
dialyzed against 30 mL PBS buffer with stirring. At certain
intervals, 2 mL of dialysate was taken out and an equal volume
of PBS buffer was added. The amount of released MTZ was
analyzed by the absorbance of MTZ at 609 nm. This
experiment was performed in three groups, and the data were
presented as the mean ± standard deviation.
4.6. Cytotoxicity Experiments. The NIH3T3 mouse
embryonic fibroblast cell line was cultured in Dulbecco’s
modified Eagle’s medium, the HCT-116 human colon cancer
cell line was cultured in the McCoy’s 5A medium, and both of
the medium were supplemented with 10% fetal bovine serum.
NIH3T3 cells and HCT-116 cells were seeded in 96-well plates
(5 × 104 cells/mL, 100 μL per well) for 24 h; then, the cells
were incubated with MTZ, MTZ@HBCCD−ADA, HBCCD−
ADA, HBCCD, and ADA for 24 and 48 h, respectively. The
relative cellular viability of the cells was determined by the
MTT assay.
Furthermore, the IC50 values of MTZ and MTZ@
HBCCD−ADA toward HCT-116 cell line were evaluated by
MTT assay. HCT-116 cells were seeded in 96-well plates (5 ×
104 cells/mL, 100 μL per well) for 24 h, and then the cells were
incubated with MTZ and MTZ@HBCCD−ADA at different
concentrations for 48 h. The anticancer activities were
determined with MTT assay. All the data were presented as
the mean ± standard deviation.
4.7. Fluorescent Confocal Imaging. HCT-116 cells were
cultured in confocal dish (5 × 104 cells/mL, 1.5 mL per well)
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for 24 h. The cells incubated with HBCCD−ADA for 24 h and
washed with PBS buffer for three times. Then, the cells were
fixed with 4% paraformaldehyde for 15 min. After that, the cell
nuclei were stained with DAPI (1 μg/mL) for 5 min and
observed by a confocal laser scanning microscope. In order to
evaluate the location of assembly in cells, late endosomes and
lysosomes were stained with Lysotracker Red at 200 nM for 30
min after incubation with cells.
4.8. Cellular Uptake of the HBCCD−ADA Supra-
molecular Assembly. HCT-116 cells were cultured in
confocal dish (5 × 104 cells/mL, 1.5 mL per well) for 24 h.
The cells incubated with HBCCD−ADA for 2, 4, and 6 h.
Then, the cells were washed with PBS buffer for three times
and fixed with 4% paraformaldehyde for 15 min. After that, the
cell nuclei were stained with DAPI (1 μg/mL) for 5 min and
observed by a confocal laser scanning microscope.
4.9. Inhibition Studies of Endocytosis. HCT-116 cells
were cultured in confocal dish (5 × 104 cells/mL, 1.5 mL per
well) for 24 h. The cells were separately incubated with 0.1%
NaN3/50 mM 2-deoxy-glucose for 1 h and 225 mM sucrose for
30 min or 4 °C for 1 h. Then, they are washed with PBS buffer
for three times and further incubated with HBCCD−ADA
assembly for 2 h at 37 °C. The cells were washed with PBS
buffer for three times and fixed with 4% paraformaldehyde for
15 min. After that, the cell nuclei were stained with DAPI (1
μg/mL) for 5 min and observed by a confocal laser scanning
microscope.
■ ASSOCIATED CONTENT
* Supporting Information
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsome-
ga.9b01436.
Process of pDNA binding and release; construction
route of MTZ@HBCCD−ADA assembly; TEM and
DLS results of pDNA@HBCCD−ADA assembly at N/P
ratio of 20; UV/vis absorption of MTZ; fluorescence
spectral changes of HBCCD−ADA assembly; TEM and
DLS results of MTZ@HBCCD−ADA assembly; release
profiles of MTZ from MTZ@HBCCD−ADA assembly
in PBS at pH 5.7 and 7.2; curves of HCT-116 cell
inhibitory rate at different concentrations of MTZ and
MTZ@HBCCD−ADA assembly; relative cellular viabil-
ity in 24 and 48 h; confocal fluorescence images of
cellular internalization; real-time cellular uptake; and
inhibition studies of endocytosis (PDF)
■
AUTHOR INFORMATION
Corresponding Authors
*E-mail: shengxl@iccas.ac.cn (X.S.).
*E-mail: guozeyu2010@imau.edu.cn (Z.G.).
ORCID
Xianliang Sheng: 0000-0003-2055-672X
Author Contributions
∥
Y.-H.Z. and J.Y. are equal contributors.
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
We thank the Inner Mongolia Autonomous Region Natural
Science Fund Project (2017BS0206), the Program for Young
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Talents of Science and Technology in Universities of Inner
Mongolia Autonomous Region (NJYT-19-B26), the Programs
of Higher-level Talents of Inner Mongolia Agricultural
University (NDGCC2016-21), and NNSFC (51602162) for
financial support.
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DOI: 10.1021/acsomega.9b01436
ACS Omega 2019, 4, 11981−11987