Synthesis and Characterization of Amphiphilic Gd(III) Complexes: Gd-DTPA-BA

Article abstract of DOI:10.1002/jsde.12155

Magnetic resonance imaging (MRI) is widely used to identify different diseases. MRI contrast agents, used to enhance the MRI signal, have been studied extensively for precise diagnosis. Based on the advantages of macromolecular MRI contrast agents of higher contrast imaging ability and a longer cycle time, this article modified the most common micromolecular contrast agent (Gd-diethylene triamine pentaacetic acid [DTPA]). 2 long saturated aliphatic chains were attached to both sides of DTPA. DTPA derivatives with 12, 14, and 16 carbon lengths were synthesized and chelated to Gd³⁺. 3 amphiphilic MRI contrast agents were obtained and their structures were characterized using mass spectrometry, ¹H NMR, and Fourier transform infrared. Furthermore, the surface tension of the compounds was measured, and liposomes were prepared by mixing the synthesized amphiphilic molecules with egg lecithin and cholesterol. The assembly behavior of the liposomes was studied using transmission electron microscopy (TEM), dynamic light scattering (DLS), and zeta potential measurements. TEM showed that the liposomes possessed bilayer vesicle structures. The liposome size distribution determined by DLS was from 10 to 1000 nm, and as the aliphatic chain length increased, the polydispersity index (PDI) and zeta potential increased. No obvious changes in the PDI and zeta potential of the liposomes were observed after 5 days at room temperature, suggesting that they possess good stability.

Full text of DOI:10.1002/jsde.12155

J Surfact Deterg (2018) 21: 601–607
DOI 10.1002/jsde.12155
ORIGINAL ARTICLE
Synthesis and Characterization of Amphiphilic Gd(III)
Complexes: Gd-DTPA-BA
Zheng Zhao1 · Hui Fang1 · Weihong Qiao1
Received: 27 July 2017 / Revised: 5 March 2018 / Accepted: 6 March 2018
© 2018 AOCS
Abstract Magnetic resonance imaging (MRI) is widely
used to identify different diseases. MRI contrast agents,
used to enhance the MRI signal, have been studied exten-
sively for precise diagnosis. Based on the advantages of
macromolecular MRI contrast agents of higher contrast
imaging ability and a longer cycle time, this article modi-
fied the most common micromolecular contrast agent (Gd-
diethylene triamine pentaacetic acid [DTPA]). 2 long satu-
rated aliphatic chains were attached to both sides of DTPA.
DTPA derivatives with 12, 14, and 16 carbon lengths were
synthesized and chelated to Gd3+. 3 amphiphilic MRI con-
trast agents were obtained and their structures were charac-
terized using mass spectrometry, 1H NMR, and Fourier
transform infrared. Furthermore, the surface tension of the
compounds was measured, and liposomes were prepared
by mixing the synthesized amphiphilic molecules with egg
lecithin and cholesterol. The assembly behavior of the lipo-
somes was studied using transmission electron microscopy
(TEM), dynamic light scattering (DLS), and zeta potential
measurements. TEM showed that the liposomes possessed
bilayer vesicle structures. The liposome size distribution
determined by DLS was from 10 to 1000 nm, and as the
aliphatic chain length increased, the polydispersity index
(PDI) and zeta potential increased. No obvious changes in
the PDI and zeta potential of the liposomes were observed
after 5 days at room temperature, suggesting that they pos-
sess good stability.
Keywords Gd-DTPA Á Synthesis Á Amphiphilic Á
Liposome Á Stability
J Surfact Deterg (2018) 21: 601–607.
Introduction
Magnetic resonance imaging (MRI) is an imaging tech-
nique based on the nuclear magnetic resonance (NMR)
principle. Compared with computerized tomography, MRI
has advantages such as better soft-tissue resolution and
avoids the use of radiation. For these reasons, MRI is
widely used in clinical lesion diagnosis (Mulder, Strijkers,
van Tilborg, Griffioen, & Nicolay, 2006).
As ancillary tools of MRI, MRI contrast agents enhance
the contrast of the magnetic resonance image between focal
lesions and normal tissues. Magnevist (Fig. 1) is a widely
used MRI contrast agent, which is a complex of Gd3+ and
diethylene triamine pentaacetic acid (DTPA). However, it
still has shortcomings such as a short cycle time in the
body, large dosage requirements, and an unsatisfactory
contrast effect (Mi et al., 2013). These deficiencies are
addressed using the Solomon−Bloembergen−Morgan
(SBM) theory (Lauffer, 1987). The SBM theory states that
increasing the molecular weight can increase the cycle time
in the body and enhance the imaging contrast by increasing
the rotation time of the molecules. The molecular weight
relationship is supported by previous research (Caravan,
Ellison, McMurry, & Lauffer, 1999; Ranganathan et al.,
Electronic supplementary material The online version of this article
(doi:10.1002/jsde.12155) contains supplementary material, which is
available to authorized users.
* Weihong Qiao
qiaoweihong@dlut.edu.cn
1
State Key Laboratory of Fine Chemicals, School of Chemical
Engineering, Dalian University of Technology, Dalian 116024,
China
Published online: 28 May 2018
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spectroscopy (MPA; Bruker, Karlsruhe, Germany), NMR
spectroscopy (Avance II 400; Bruker, Germany), elemental
analysis (Vario EL; Elementar, Hanau, Germany), tensiom-
etry (K100C; Krüss Co., Hamburg, Germany), particle size
analysis (Nano ZS-90; Malvern, Malvern, UK), and trans-
mission electron microscopy (TEM) (JEM-2000EX; Tokyo
JEOL, Tokyo, Japan).
Fig. 1 The structure of Magnevist
1998). Based on this theory, researchers have synthesized
some large molecular structures (Ai, 2011; Bunschoten
et al., 2016; Clear et al., 2016; Kimpe et al., 2003; Zhang
et al., 2014). For example, Moghaddam et al. (2014) con-
nected oleyl chains to Gd-DTPA; Parac-Vogt et al. (2004)
synthesized Gd-DTPA derivatives with aromatic groups.
However, studies about macromolecular MRI contrast
agents still need to be extended.
To increase the weight of MRI contrast agents, a series
of amphiphilic MRI contrast agents based on a commercial
MRI contrast agent (Gd-DTPA) were designed. Two long
saturated aliphatic chains were attached to both sides of
DTPA and then Gd3+ was chelated to the DTPA deriva-
tives, as shown in Fig. 2. Gd-DTPA derivatives with
12, 14, and 16 carbon lengths were synthesized and charac-
terized. The higher molecular weight contrast agents show
the ability to form vesicles. In addition, liposomes with sta-
ble bilayer structures were prepared with the synthesized
amphiphilic Gd-DTPA derivatives, egg lecithin, and
cholesterol.
Synthesis of 2-[Bis[2-(2,6-dioxomorpholino)ethyl]
amino]acetic acid (2)
DTPA (1) (2.00 g, 5.08 mmol) in anhydrous acetic anhy-
dride (2.5 mL, 26.4 mmol) and anhydrous pyridine
(3.5 mL, 43.4 mmol) was stirred under a N2 atmosphere at
65 ꢀC for 24 h. After cooling to room temperature, the
reaction mixture was washed with anhydrous acetic anhy-
dride and anhydrous diethyl ether repeatedly. The solvents
were removed under vacuum to yield a light yellow solid.
Yield (1.56 g, 85.9%), m.p. 178–188 ꢀC.
Synthesis of DTPA-BA (3a–c)
Under a N2 atmosphere, 2 (0.50 g, 1.40 mmol) in anhy-
drous dimethyl formamide (DMF) was heated to 85 C.
ꢀ
After the solid was entirely dissolved, the system tempera-
ꢀ
ture was cooled to 40 C and then dodecanamine (0.57 g,
3.08 mmol) dissolved in trichloromethane was added to the
solution dropwise. The mixture was stirred for 2 h. After
cooling and filtering, the residue was dissolved in 1 M
NaOH, and then filtered again. The filtrate was adjusted to
pH 2–3 by adding 1 M HCl, filtered, and then the residue
was dried in vacuo overnight. The solid was recrystallized
from anhydrous EtOH and then dried in vacuo overnight.
3b was recrystallized from a mixture of MeOH and chloro-
form, and 3c from n-butylalcohol.
Experimental
Materials
DTPA was purchased from Tianjin Guangfu Fine Chemi-
cals Institute (Tianjin, China). Dodecylamine, tetradecyla-
mine, and hexadecylamine were purchased from J & K
Chemical, Ltd (Beijing, China). GdCl3Á6H2O was pur-
chased from Shanghai Diyang Chemical Co., Ltd
(Shanghai, China).
3a: White solid. Yield (0.60 g, 58.9%). 1H NMR
(300 MHz, CD3COOD,
δ = 11.62 ppm) δ (ppm):
1.29–1.31 (6H, CH3), 1.74 (36H, CH2), 2.03–2.04 (4H,
CH2), 3.79–3.82 (4H, CH2), 4.16–4.17 (4H, CH2),
4.46–4.50 (6H, CH2), and 4.91–4.95 (8H, CH2). FTIR
(KBr) ʋ (cm−1): 3358 (ʋN H, ʋCOO H), 2958, 2922, and
2852 (ʋC H, aliph), 1667 and 1629 (amide I), 1558 (amide
II), 1241 (ʋC O), 722 (ʋC H, aliph). electrospray-atmo-
spheric pressure ionization (ES-API) MS: [M − H]− m/z
726.5; [M − 2H]2− m/z 362.8.
Instruments
Complexes were characterized using electrospray ioniza-
tion mass spectrometry (ESI–MS, 6130MSD; Agilent,
Santa Clara, USA), Fourier transform infrared (FTIR)
3b: White solid. Yield (0.69 g, 62.9%). 1H NMR
(300 MHz, CD3COOD,
δ = 11.62 ppm) δ (ppm):
1.33–1.34 (6H, CH3), 1.77 (44H, CH2), 2.07–2.08 (4H,
CH2), 3.84–3.85 (4H, CH2), 4.22 (4H, CH2), 4.52–4.57
(6H, CH2), and 4.95–4.99 (8H, CH2). FTIR (KBr) ʋ
(cm−1): 3288 (ʋN H, ʋCOO H), 2940, 2922, and 2852 (ʋC
,
H
aliph), 1715 (ʋC O), 1660 and 1629 (amide I band), 1558
(amide II band), 1222 (ʋC O), and 722 (ʋC H, aliph). ES-
Fig. 2 The structure of the objective molecules
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603
API MS: [M − H]− m/z 782.5; [M − 2H]2− m/z 390.5; and
[M − 2H + K]− m/z 820.5.
3c: Light yellow solid. Yield (0.72 g, 61.2%). H NMR
Preparation of Liposomes (Lip1–3)
1
A mixture of 4a (0.0040 g), egg lecithin (0.0120 g), and
cholesterol (0.0040 g) was dissolved in anhydrous EtOH
(3 mL) in a round-bottom flask, and then the solvent was
slowly removed by rotary evaporation to form a thin lipid
film. The film in the flask was dried in vacuo for 5 h. Milli-
(300 MHz, CD3COOD,
δ = 11.62 ppm) δ (ppm):
1.34–1.35 (6H, CH3), 1.78 (48H, CH2), 2.08–2.09 (4H,
CH2), 3.85–3.86 (4H, CH2), 4.19–4.20 (4H, CH2),
4.50–4.54 (6H, CH2), and 4.96–4.98 (8H, CH2). FTIR
(KBr) ʋ (cm−1): 3429 (ʋN H, ʋCOO H), 2922 and 2853
ꢀ
Q water (15 mL, 35 C) was added to the flask. The film
(ʋC
aliph), 1715 (ʋC O), 1660 and 1630 (amide I band),
was rehydrated at 35 ꢀC. Rehydrated liquid (5 mL) was then
treated under ultrasound to obtain Lip1 (ultrasonic operating
parameters: work 2 s, pause 5 s, power 40%, temperature 40
ꢀC, and total time 20 min). Lip2 and Lip3 were obtained in
a similar manner to Lip1 (ultrasound parameters: 45 ꢀC and
40 min for Lip2; 48 ꢀC and 60 min for Lip3).
H,
1564 (amide II band), 1221 (ʋC O), and 722 (ʋC H, aliph).
ES-API MS: [M − H]− m/z 838.7; [M − 2H]2− m/z 418.9;
[M − 2H + K]−− m/z 876.7; and [M + NO]− m/z 900.6.
Synthesis of Gd-DTPA-BA (4a–c)
3a (0.5 g, 0.687 mmol) was dissolved in anhydrous pyri-
dine, then GdCl3Á6H2O (0.280 g, 0.755 mmol) in H2O
Dynamic Light Scattering and Zeta Potential
Experiments
ꢀ
(1 mL) was added. The mixture was stirred at 70 C for
4 h. The solvent was removed by rotary evaporation to
leave a transparent solid in the flask. The transparent solid
was extracted with anhydrous EtOH. The upper clear liquid
was separated, removed by rotary evaporation, and then the
resulting solid was washed with cold water. The residue
was filtered and dried in vacuo overnight.
The average hydrodynamic diameter, polydispersity index
(PDI), and zeta potential of the liposomes were measured
by dynamic light scattering (DLS) using a Malvern autosi-
zer at a scattering angle of 90ꢀ. The data were collected and
fit by intensity-weighted cumulative analysis software.
4a: White solid. Yield (0.42 g, 69.3%). FTIR (KBr) ʋ
(cm−1): 3430 and 3246 (ʋN H, ʋHO H), 2925 and 2854
(ʋC H, aliph), 1630 (ʋC O), and 722 (ʋC H, aliph). ES-API
TEM Measurements
The prepared Lip1 in Milli-Q water was negatively stained
with phosphotungstic acid acetate solution (2%) and dis-
persed on a carbon-coated copper TEM grid (300 mesh).
TEM micrographs were measured at a voltage of 120 kV.
MS: [M
+
H]+ m/z 883.5. Anal. Calcd for
C38H70N5GdO8Á4.5H2O (754.49): C, 47.38; H, 8.27;
and N, 7.27. Found: C, 47.50; H, 7.99; and N, 7.14.
4b: White solid. Yield (0.42 g, 69.3%). FTIR (KBr) ʋ
(cm−−1): 3288 (ʋN H, ʋO H), 2925 and 2854 (ʋC H, aliph),
1627 (ʋC O), and 720 (ʋC H, aliph). ES-API MS: [M + H]+
m/z 939.5. Anal. Calcd for C42H78N5GdO8Á5H2O
(762.55): C, 49.05; H, 8.62; and N, 6.81. Found: C,
49.83; H, 8.31; and N, 6.78.
Results and Discussion
Synthesis
4c: Light yellow solid. Yield (0.42 g, 69.3%). FTIR
(KBr) ʋ (cm−1): 3429 (ʋN H, ʋO H), 2922 and 2853 (ʋC
aliph), 1715 (ʋC O), 1660 and 1630 (amide I band), 1564
Molecular structure design was used to conveniently synthe-
size the target compounds Gd-DTPA-BA (4a–c) in three steps
as shown in Fig. 3. The reactions produced a few impurities,
which avoided column chromatography separation.
H,
(amide II band), 1221 (ʋC O), and 722 (ʋC
aliph). ES-
H,
API MS: [M + H]+ m/z 995.5. Anal. Calcd for
C46H86GdN5O8Á6H2O (770.61): C, 50.11; H, 8.96; and N,
6.35. Found: C, 50.43; H, 8.53; and N, 6.29.
Because of the low reactivity and low selectivity of the
five carboxyl groups of DTPA to amidation, the anhydride
of DTPA (DTPAA) was used to improve the reactivity by
activating the carboxyl groups at both ends of the molecule.
In addition, using DTPAA to synthesize amides provided
higher selectivity compared with using a carbodiimide cata-
lyst. We can attach one or two groups to the ends of the
activated DTPAA, some related compounds have been
reported (Periasamy et al., 1991). Acetic anhydride
(a dehydrating agent) and pyridine (an acid-binding agent)
have been used to synthesize DTPAA (Hnatowich, 1985).
Furthermore, researchers found that the optimal molar ratio
Surface Tension Measurements
Before surface tension measurements, ultrasound (UP-250,
Ningbo Haishu Heng Instruments Co., Ningbo, China) was
ꢀ
used to dissolve compounds at 25 C. The surface tension
of 4a–c was measured at 25 ꢀC using a surface tensiometer.
The critical micelle concentration (CMC) of each complex
was found by plotting the surface tension against the loga-
rithm of concentration.
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Fig. 3 Synthesis of 4a–c
1
of DTPA:acetic anhydride:pyridine is 1:3:5. In this paper,
we used a DTPA:acetic anhydride:pyridine ratio of 1:5:8,
and obtained a reasonable yield of 85.9%.
shape and integral area of the H NMR spectra, making
1
them unclear (Daman & Dill, 1984). The H NMR spectra
of complexes 4a–c contained broad peaks that were diffi-
cult to integrate. However, the 1H NMR spectra of interme-
diate compounds 3a–c were of value to elucidate the
structure of 4a–c, because the final chelation reaction of
gadolinium should not change the basic structure of 3a–c.
The synthesis of compounds 3a–c is efficient under rela-
tively mild reaction conditions. Base solution and acid
solution were used alternately in purification to remove
DTPA and amine, target molecules were obtained after
recrystallization. We tried different solvents for recrystalli-
zation. Ethanol, chloroform/methanol, and n-butyl alcohol
were selected as suitable recrystallization solvents for 3a,
3b, and 3c, respectively. The synthesis of 3c was reported,
for which a large amount of chloroform was used (500 mL
to 0.874 g of 3c) for recrystallization (Jasanada & Nepveu,
1992). But in this paper, the amount of solvent (about
25 mL of n-butyl alcohol to 0.72 g of 3c) was decreased
greatly (by about 20 times) compared with the amount of
chloroform aforementioned.
1
We highlighted ligand a as an example. In the H NMR
spectrum of 3a, the terminal methyl protons of
[(CH2)n CH3] appeared at δ = 1.29–1.31 ppm, the methy-
lene protons [(CH2)n CH3] of the long carbon chains were
at δ = 1.74 ppm, the first and the second methylene from
the N-atom [N CH2 CH2 (CH2)n CH3] were at
δ = 3.79–3.82 and 2.03–2.04 ppm, respectively, the methy-
lene
[N CH2 C ONH] appeared at δ = 4.16–4.17 ppm, the
methylene protons attached to carboxyl group
protons
attached
to
the
acid
amide
a
Pyridine and EtOH were used as solvents in the synthesis
of compounds 4a–c. As a Lewis base, pyridine showed a
higher reaction efficiency than EtOH because it could absorb
the H+ produced from the chelation reaction, facilitating the
complexation reaction. The target compounds 4a–c have
lower water solubility than 3a–c, which means that the solu-
bility decreases after the complex reaction. We speculated that
most electrons of the hydrophilic group (DTPA) have coordi-
nated with the unoccupied orbital of Gd3+ forming stable
covalent bonds. Therefore, these electrons lose the chance to
form a hydrogen bond to H2O, which leads to limited solubil-
ity of 4a–c in water. The solubility of 4a–c decreases as the
carbon length increases. Even so, this bad solubility can be
used to remove poisonous Gd3+ by washing in cold water.
[CH2 C OOH] lie at δ = 4.46–4.50 ppm, and the methy-
lene protons attached to an amine [N CH2 CH2 N] were
at δ = 4.91–4.95 ppm. Also, the FTIR spectrum of 3a con-
tained peaks at 722, 2958, 2922, and 2852 cm−1 consistent
with the presence of an aliphatic chain, along with amide I
bands at 1667 and 1629 cm−1 and an amide II band at
1558 cm−1. Overall, the ESI–API MS, FTIR, and 1H NMR
data confirmed the structure of 3a.
Furthermore, the thermogravimetric analysis (TGA), ele-
mental analysis, and FTIR contrast data of 4a were ana-
lyzed. Gadolinium has nine coordination orbitals, so it can
readily coordinate with extra H2O molecules. The number
of H2O molecules is difficult to confirm by FTIR and MS
measurements, but can be determined using TGA and ele-
mental analysis. According to the TGA curve of 4a (shown
in Fig. 4), from 25 to 300 ꢀC, it loses weight slowly; about
8.50% of its weight was lost at this stage, which suggests
that the coordinate bonds between water and gadolinium
were destroyed. The TGA curve of 4a declines sharply
after 300 ꢀC, meaning that the compound decomposes. The
Characterization
It was difficult to characterize compound 4a–c containing a
1
paramagnetic metal using H NMR spectroscopy. This is
because paramagnetic metal elements influence the peak
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one peak at about 1630 cm−1, consistent with the change of
carbonyl COO−, and both the peaks at 1547 cm−1 (N H)
and 1241 cm−1 (C O) disappear, suggesting that 3a has
coordinated with Gd3+.
Surface Tension
Figure 6 shows the surface tension of 4a–c at different con-
centrations. CMC and γcmc of 4a were 1.5 × 10−4 mol L−1
and 35.9 mN m−1, respectively, which showed good sur-
face activity of the chelates. Because of the poor solubility
of 4b and 4c, surface tension (>10−5 mol L−1) cannot be
measured accurately. We speculated that 4b and 4c reach
their saturation concentration at around 10−5 mol L−1.
Fig. 4 TGA curves of 4a–c
Self-Assembly Behavior
number of coordinated water molecules per complex was
calculated from the weight loss in the TGA curve. The
results show that each 4a molecule has 4.5 water molecules
on average, which is consistent with the elemental analysis
results. Because of the low binding energy between H2O
and gadolinium and the quick molecular exchange with the
solvent, most mass spectrometers cannot track the coordi-
nated water molecules, including ESI–MS and atmospheric
pressure chemical ionization (APCI)–MS. Although some
researchers have reported that combined water has been
observed through APCI-MS (Chung et al., 1998; Loo et al.,
2015); unfortunately, the coordinated water in the com-
plexes could not be seen through ESI–API MS here. How-
ever, ESI–API MS of 4a (Fig. S1) shows the isotope peak
of gadolinium, which confirms the formation of the desired
coordination compound. Comparison of the FTIR spectra
of 4a and 3a (Fig. 5) reveals that the peak at about
3300 cm−1 widens and weakens, which suggests the pres-
ence of combined water. Meanwhile, the peaks merge into
Liposome carriers have commercial potential because they
possess advantages of safety and a large loading space for
drugs. Liposomes Lip1–3 were prepared by using the Gd-
DTPA derivatives mixed with egg lecithin and cholesterol.
The dispersion and stability of the liposomes in water were
tested after 1 and 5 days at room temperature, and the
results are listed in Table 1. Figure 7 shows the size disper-
sion of Lip1–3 after 5 days. The three types of liposomes
ranged from 10 to 1000 nm in size. Lip1 was monodis-
perse, while Lip2 and Lip3 were polydisperse. The average
sizes of Lip1, Lip2, and Lip3 were 110.5, 110.8, and
194.5 nm, respectively. TEM showed that the assembled
structures of Lip1 were 78 and 120 nm in diameter
(Fig. 8). As expected, the vesicle displayed a light margin,
implying a bilayer structure, and the dark center of the vesi-
cle was hollow. Most of the amphiphilic 4a–c molecules
were embedded in the bilayer through the intermolecular
interactions of their amphiphilic structures. Regarding the
Fig. 6 Surface tension versus concentration of 4a–c
Fig. 5 FTIR comparison spectra of 3a and 4a
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Table 1 Average size, PDI, and zeta potential of Lip1–3
solubility of the complexes affects liposome formation and
aggregation. Still, after 5 days at room temperature, no
obvious changes in the zeta potential and PDI were
observed, and the good stability of these liposomes was
further confirmed.
D-Average (nm)
PDI
Zeta (mV)
(1 day/5 days)
(1 day/5 days)
(1 day/5 days)
Lip1
Lip2
Lip3
111.5/114.2
110.8/111.7
194.5/196.3
0.220/0.244
0.276/0.294
0.302/0.323
−42.5/−39.0
−27.1/−28.9
−20.9/−19.3
Conclusions
Three Gd-DTPA-based imaging amphipathic complexes
4a–c were synthesized in three steps. Precursors 3a–c were
characterized using ESI–API MS, FTIR, and 1H NMR,
while 4a–c were characterized using ESI–API MS, elemen-
tal analysis, FTIR, and TGA. The surface tension of 4a–c
was measured at 25 ꢀC, CMC and γcmc of 4a are
1.5 × 10−4 mol L−1 and 35.9 mN m−1. Liposomes Lip1–3
were prepared from the Gd-DTPA derivatives mixed with
egg lecithin and cholesterol. DLS, zeta potential, and TEM
analyses showed that stable bilayer vesicle structures with a
size of 10–1000 nm were formed. As the carbon chain
length increased, the stability of the liposomes decreased.
No obvious changes in the PDI and zeta potential of the
liposomes were observed after 5 days at room temperature,
suggesting that they have good stability.
Fig. 7 Size distribution of Lip1–3
Acknowledgements We acknowledge the financial support received
from the International Science & Technology Cooperation Program of
China (no. 2015DFA41670).
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