A highly sensitive and selective ratiometric fluorescent sensor for Zn 2+ ion based on ICT and FRET

Article abstract of DOI:10.1016/j.dyepig.2013.11.011

A ratiometric sensor (QA) for detecting Zn²⁺ with high sensitivity and selectivity was reported. The fluorescence changes of sensor upon the addition of Zn²⁺ were attributed to the conjugation of internal charge transfer and fluorescence resonance energy transfer mechanisms. There is a good linear relationship between the fluorescence ratio I _497nm/I_420nm and the concentrations of Zn²⁺ ranging from 0 μM to 40 μM, which makes an effective ratiometric detection of Zn²⁺ ion. The limit of detection (LOD) was evaluated to be 33.6 nM. The imaging experiments indicated that QA is cell-permeable and can be used to detect Zn²⁺ within living cells with good selectivity over Cd²⁺.

Full text of DOI:10.1016/j.dyepig.2013.11.011

Dyes and Pigments 102 (2014) 301e307
Contents lists available at ScienceDirect
Dyes and Pigments
journal homepage: www.elsevier.com/locate/dyepig
A highly sensitive and selective ratiometric fluorescent sensor for Zn2þ
ion based on ICT and FRET
Yang Ma a , Haiyan Chen , Fang Wang , Srinivasulu Kambam , Yong Wang ,
,
1
b
,
1
a
a
a
c
,
a,
*
*
*
Chun Mao
, Xiaoqiang Chen
a
State Key Laboratory of Materials-Oriented Chemical Engineering, College of Chemistry and Chemical Engineering, Nanjing University of Technology,
Nanjing 210009, China
Department of Biomedical Engineering, School of Life Science and Technology, State Key Laboratory of Natural Medicines, China Pharmaceutical University,
b
Nanjing 210009, China
c
Jiangsu Key Laboratory of Biofunctional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China
a r t i c l e i n f o
a b s t r a c t
A ratiometric sensor (QA) for detecting Zn2 with high sensitivity and selectivity was reported. The
þ
Article history:
Received 20 May 2013
Received in revised form
2þ
fluorescence changes of sensor upon the addition of Zn were attributed to the conjugation of internal
charge transfer and fluorescence resonance energy transfer mechanisms. There is a good linear rela-
tionship between the fluorescence ratio I497 nm/I420 nm and the concentrations of Zn ranging from 0
7
November 2013
2þ
m
M
Accepted 10 November 2013
Available online 20 November 2013
2þ
to 40
evaluated to be 33.6 nM. The imaging experiments indicated that QA is cell-permeable and can be used
mM, which makes an effective ratiometric detection of Zn ion. The limit of detection (LOD) was
to detect Zn2 within living cells with good selectivity over Cd
þ
2þ
.
Keywords:
Crown Copyright Ó 2013 Published by Elsevier Ltd. All rights reserved.
Ratiometric sensor
Fluorescence
2
þ
Zn
Internal charge transfer
Fluorescence resonance energy transfer
Quinoline-based sensor
1. Introduction
times. Fluorogenic methods in conjunction with suitable probes are
preferable approaches for the measurement of Zn2 with high
þ
Zinc is the second most abundant transition-metal ion and plays
very important role in variety of physiological and pathological pro-
cesses such as enzyme regulation, gene expression, catalytic function
ofprotein, apoptosisand so on [1e7]. The disorderofzincmetabolism
in biological systems may lead to a variety of diseases such as Alz-
heimer’s disease, diabetes, epilepsy [8e14]. Therefore, developing
effective methods for monitoring Zn in living systems are very
important for understanding the physiological and pathological role
of zinc in nature. A variety of methods including electrochemical,
photometric determination and electro-thermal atomic absorption
spectrophotometry have been developed for analysis of zinc in
environmental samples and for diagnosis of deficiencies in body
tissue [15e17]. However, these methods have basic limitations in
terms of equipment cost, complexity, sample processing and run
sensitivity, simplicity and real-time detection [18e21].
Although a number of fluorescent sensors based on various
fluorophores including quinoline [22e31], fluorescein [32,33],
coumarin [34,35], naphthalimide [36,37], BODIPY [38,39] and
others [40,41] were developed for detection of zinc ions, it is still
2
þ
desirable to develop new Zn -selective fluorescent sensors with
extremely high affinity and good selectivity over other relevant
metal ions. Since Frederickson et al. reported the first quinoline-
2þ
2
þ
sensor [22], many fluorescent sensors based on 8-
based Zn
aminoquinoline structure have been developed for imaging Zn
2
þ
in aqueous solution and in biological samples [26,29,42e50].
Because cadmium and zinc are in the same group of the periodic
table and have similar properties, sensors based on aminoquinoline
fluorophore usually suffered from the limitation in the effective
2þ
2þ
distinguish between Zn and Cd [29,44,45,48]. Therefore, it is
challenge to design a small molecular sensor based on amino-
quinoline fluorophore which can selectively and sensitively detect
*
Corresponding author. Tel./fax: þ86 025 83587856.
*
* Corresponding author. Tel.: þ86 025 85891536.
2þ
2þ
Zn in the presence of other cations, particularly Cd .
E-mail addresses: maochun127@yahoo.com.cn (C. Mao), chenxq@njut.edu.cn
Herein, based on internal charge transfer (ICT) and fluorescence
resonance energy transfer (FRET) mechanisms, we report a new
(
X. Chen).
1
These authors contributed equally to this work.
0143-7208/$ e see front matter Crown Copyright Ó 2013 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.dyepig.2013.11.011

302
Y. Ma et al. / Dyes and Pigments 102 (2014) 301e307
sensor (QA) bearing quinoline and anthracene fluorophores for the
3 2
KI (0.32 g) in anhydrous CH CN at room temperature under N .
selective detection of Zn2 . The fluorescent sensor based on ICT and
FRET mechanisms has two advantages: one is the large shift be-
tween donor excitation and acceptor emission, which exclude any
influence of excitation backscattering effects; the other is the pres-
ence of two well-separated emission bands with comparable in-
tensities, which ensures accuracy in determining their intensities
and ratios.
þ
The mixture was refluxed overnight, then the resulting mixture
was cooled to room temperature, filtered over gravity and the
solvent was removed in vacuo. The residue was purified by col-
umn chromatography using CH
to get yellow solid (0.66 g) in 69% yield. H NMR (CDCl
(ppm): 8.92 (1H, dd, J ¼ 1.65 Hz), 8.65 (1H, dd,
¼ 4.17 Hz, J
¼ 5.73 Hz, J ¼ 3.30 Hz), 8.58 (1H, d, J ¼ 4.26 Hz), 8.48 (2H, d,
J ¼ 8.76 Hz), 8.38 (1H, s), 8.15 (2H, m), 7.96e7.93 (2H, m), 7.73
(1H, td, J ¼ 1.74 Hz), 7.54 (1H, q, J ¼ 4.20 Hz), 7.47e
¼ 7.65 Hz, J
.37 (6H, m), 7.25e7.24 (1H, m), 4.80 (2H, s), 4.19 (2H, s), 4.52 (2H,
2 2 3
Cl :CH OH (100:1) as the eluent
1
3
, 300 MHz)
d
1
2
J
1
2
2
. Experimental
1
2
7
13
2.1. Materials and equipments
s); C NMR (CDCl
3
, 300 MHz) d (ppm): 169.76, 158.13, 148.80,
138.77, 136.48, 134.33, 131.52, 131.37, 128.98, 128.32, 127.98,
Unless otherwise noted, materials were obtained from com-
127.31, 126.11, 124.82, 124.72, 124.54, 122.54, 121.49, 121.44,
þ
mercial suppliers and were used without further purification.
Chromatography was carried out on silica gel 60 (230e400 mesh
116.42, 58.96, 53.39, 50.77. TOF MS m/z ¼ 483.2181 [M þ H] , calc.
for C32
H
27
N
4
O ¼ 483.2185.
1
13
ASTM). H and C NMR spectra were recorded using Bruker 300/
00. Mass spectra were obtained using a Waters Micromass Q-Tof
5
2.3. Cell culture and fluorescence imaging
mass spectrometer (Agilent 6530). Fluorescence emission spectra
were obtained using RF-5301/PC spectrofluorophotometer. The
imaging experiments were carried out using confocal laser scan-
ning microscopy (Olympus FV-1000).
MCF-7 cells were purchased from American Type Culture
Collection (ATCC, USA), and were seeded in Laser scanning
confocal microscope (LSCM) culture dishes with a density of
5
5
ꢁ 10 cells/well. The cell lines were cultured in RPMI-1640
2
2
0
.2. Synthesis
medium supplemented with 10% (v/v) calf serum, penicillin
100 U mL ) and streptomycin (100 mg mL ). Cells were
maintained at 37 C in a humidified atmosphere containing 5%
ꢂ1
ꢂ1
(
.2.1. 2-Chloro-N-(quinolin-8-yl)acetamide (1)
Chloroacetyl chloride (0.15 mL) was dissolved in dry CH Cl at
2 2
ꢀ
2
CO . When the whole cells took up 70%e80% space of culture
ꢀ
C, and was added slowly to a stirred mixture of quinoline-8-
Cl un-
, the reaction mixture was stirred overnight at room tem-
perature. The reaction mixture was quenched with distilled water
and then was extracted with CH Cl . The combined organic layer
was washed with 10% aqueous HCl solution and dried over anhy-
drous Na SO , and evaporated to afford solid product. The product
was purified by recrystallization from ethanol to give analytically
dishes, the cells were first incubated with 10
mM QA in culture
amine (0.58 g, 4 mmol) and triethylamine (0.3 mL) in CH
der N
2
2
ꢀ
media for 1 h at 37 C. Then the cells were further treated with
2
2þ
2þ
1
1
(
00
m
M Zn or Cd in culture media containing 2% DMSO for
ꢀ
5 min at 37 C. After washing with phosphate buffered saline
PBS) to remove the remaining Zn
2
2
2þ 2þ
or Cd , the cells were
imaged by confocal laser scanning microscopy (Olympus FV-1000).
2
4
2þ
2þ
Zn imaging experiment after removal the intracellular Zn was
carried out by incubation with TPEN for 15 min. The band paths
for green channel and blue channel are 500e600 nm and 425e
1
pure compound (0.82 g) in 93% yield. H NMR (CDCl
3
, 500 MHz)
d
(ppm):10.90 (1H, s), 8.87e8.85 (1H, m), 8.77e8.74 (1H, m), 8.19e
475 nm respectively. The excitation wavelength is 488 nm for
13
8
.16 (1H, m), 7.58e7.53 (2H, m), 7.49e7.46 (1H, m), 4.31 (2H, s);
C
green channel and 405 nm for blue channel.
NMR (CDCl
3
, 75 MHz) (ppm):148.66, 136.27, 133.58,127.95, 127.16,
d
122.52, 121.78, 116.64, 43.34.
2.4. Detection limit
2
.2.2. 2-[(Pyridin-2-ylmethyl)-amino]-N-quinolin-8-yl-acetamide
(R-1)
Fluorescence titration was carried out in HEPES-buffered solu-
1
(0.88 g, 4 mmol) was dissolved in anhydrous CH
stirred mixture of 2-
aminomethylpyridine (0.86 g, 8 mmol), NaHCO (0.69 g) and KI
0.66 g) at room temperature under N . The mixture was refluxed
3
CN and the
tion (10 mM HEPES, 50% (v/v) DMSO, pH ¼ 7.4) to calculate the
detection limit, the detection limit is then calculated with the
equation:
solution was added dropwise to
a
3
(
2
overnight. Then the resulting mixture was cooled to room tem-
perature, filtered over gravity and the solvent was removed in
vacuo. The residue was purified by column chromatography using
detection limit ¼ 3sbi/m
where bi is the standard deviation of blank measurements, m is the
s
CH
in 86% yield. H NMR (CDCl
.83 (2H, m), 8.60 (1H, d, J ¼ 1.44 Hz), 8.19 (1H, d, J ¼ 8.28 Hz), 7.70
1H, t, J ¼ 7.62 Hz), 7.56 (3H, d, J ¼ 5.79 Hz), 7.48 (1H, q, J ¼ 4.11 Hz),
2
Cl
2
:CH
3
OH (100:1) as the eluent to get pale orange solid (1.0 g)
slope between intensity versus sample concentration.
.5. The calculation of K
The fluorescent intensity data were fit to the following equation
1
3
, 300 MHz) d (ppm): 11.43 (1H, s), 8.85e
8
(
7
2
d
13
.27e7.19 (1H, m), 4.09 (2H, s), 3.63 (2H, s), 2.48 (1H, s); C NMR
(
CDCl , 300 MHz) (ppm): 170.23, 158.90, 149.38, 148.40, 136.54,
3
d
d
to calculate K [51]:
1
5
C
36.20, 134.34, 128.09, 127.34, 122.65, 122.26, 121.72, 121.50, 116.65,
þ þ
5.17, 53.31. TOF MS m/z ¼ 293.1404 [M þ H ] , calc. for
ꢀ
hZn2þiꢁ
ꢀh 2þi
ꢁ
H
17
N
4
O ¼ 293.1402.
F ¼
a
1
Kd þ
a
2
½QAꢃtotal
=
Zn
þ Kd
:
17
2.2.3. 2-(Anthracen-9-ylmethyl-pridin-2-ylmethyl-amino)-N-
quinolin-8-yl-acetamide (QA)
1 2
where F is the fluorescence intensity, a , a represent a propor-
R-1 (0.58 g, 2 mmol) was dissolved in anhydrous CH
3
CN and
tionality parameter of fluorescent species, [QA]total means the total
concentration of the QA. Finally, Origin 8.0 software was used to fit
above nonlinear plot to give the K value.
d
the solution was added dropwise to a stirred mixture of 9-
chloromethyl)anthracene (0.46 g, 2 mmol), NaHCO (0.34 g) and
(
3

Y. Ma et al. / Dyes and Pigments 102 (2014) 301e307
303
3
. Results and discussion
3.1. Synthesis of compound QA
The synthetic route of compound QA was shown in Scheme 1.
Firstly, R-1 was synthesized. Then, the reaction of R-1 and 9-
chloromethyl)anthracene in the presence of NaHCO and KI in
CH CN afford the final product QA with the yield of 69%. The syn-
(
3
3
1
13
thesized compound QA was fully characterized by H, C NMR and
Q-Tof mass spectrometer (see Supplementary Data). These char-
acterizations confirmed the formation of compound QA.
3.2. Fluorescence studies with various metal ions
After obtained the sensor, the selectivities of QA to various metal
ions were first examined in DMSO-HEPES buffer (pH ¼ 7.4, 10 mM,
1
3
:1 v/v). The fluorescence spectra were obtained by excitation at
Fig. 1. Fluorescence responses (
metal ions in DMSO-HEPES buffer (pH ¼ 7.4, 10 mM, 1:1 v/v).
l
ex ¼ 330 nm) of 10
m
M probe QA towards various
2
þ
þ
2þ
2þ
30 nm, and various metal ions including Hg , Na , Mg , Cs
,
3
þ
2þ
2þ
2þ
2þ
2þ
þ
3þ
2þ
þ
3þ
2þ
Cr , Ni ,Ca , Zn , Cd , Pb , Ag , Fe , Fe , Li , Al , Mn
2þ
and Cu were used to evaluate the selectivity of QA. As shown in
Fig. 1, when no metal ions were added, QA showed the structured
emission band at 400 nm, 420 nm and 445 nm typical of the
anthracene moiety. Upon the addition of 10 equiv. of various metal
(Fig. 3b) is also observed. The intensity ratios at 497 and 420 nm (I497
2þ
nm/I420 nm) increase until the addition of 8 equiv. Zn . Besides, a good
linearity between the fluorescence intensity ratios and the concen-
ions, Zn2þ caused dramatic fluorescent enhancement at 497 nm
2þ
trations of Zn is obtained in the range of 0
mMe40 mM (Fig. S1).
along with a decrease of emission intensity of the structured
emission band. In contrast, other metal ions such as Na , Mg
Cs , Cr , Ni , Ca , Cd , Pb , Ag , Fe , Fe , Li , Al , Mn
produced the negligible changes at 497 nm while Cu and Hg
þ
3þ
2þ
2þ
2þ
According to fluorescence titration data under the concentration of
,
2þ
3þ
2þ
2þ
2þ
2þ
þ
3þ
2þ
þ
2
þ
led to the entire quenching of fluorescence. It is noteworthy that
the addition of Cd2 did not induce the increase of fluorescent in-
tensity at 497 nm, even though cadmium and zinc are in the same
group of the periodic table and have similar properties. Indeed,
compared with the quinoline-based sensors reported previously
þ
[
24,44,48e50,52e54], the present sensor provided better selec-
2
þ
2þ
tivity towards Zn over Cd . It is proposed that the introduction
of anthracene fluorophore disable the binding between Cd with
2
þ
aminoquinoline moiety. Further, a competition experiment was
2
þ
also performed by adding Zn (10 equiv) to the sensor in the
presence of other metal ions (10 equiv.), which showed that no
obvious interference was observed in its fluorescence except for
2
þ
2þ
Cu
and Hg , which caused the emission ratio of 497 nme
4
20 nm quenched (Fig. 2).
The concentration-dependent fluorescence spectra were further
examined in DMSO-HEPES buffer (pH ¼ 7.4,1:1 v/v). As shown in the
2þ
Fig. 3a, in the absence of Zn , the emission spectrum of QA exhibits a
structured emission band with maxima at 400 nm, 420 nm and
4
45 nm typical of the anthracene moiety. Upon addition of increasing
2þ
Zn , the structured emission band of the anthracene unit gradually
decreases along with a new red-shift emission band at 497 nm and a
well-defined isoemission point at 460 nm. An obvious increase in
fluorescence intensity ratio (I497 nm/I420 nm) changed from 0.6 to 7.5
Fig. 2. The ratio fluorescence responses (I497 nm/I420 nm) of QA (10
mM) containing
2
þ 2þ 2þ þ 2þ 2þ þ
1
00 mM Zn to the selected metal ions: 10 equiv of Pb , Ni , Na , Mn , Mg , Li ,
2þ
2þ
2þ
3þ
2þ
3þ
þ
3þ
2þ
Hg , Cu , Cs , Cr , Ca , Al , Ag , Fe , Fe in DMSO-HEPES buffer (pH ¼ 7.4,
10 mM, 1:1 v/v).
Scheme 1. The synthesis of QA.

304
Y. Ma et al. / Dyes and Pigments 102 (2014) 301e307
M) in DMSO-HEPES buffer (pH ¼ 7.4, 10 mM, 1:1 v/v); b) The plot of fluorescence ratios (I497 nm/I420 nm) versus the concentration of Zn2
þ
.
Fig. 3. a) Fluorescence titration of QA (10
m
Zn2 in the range from 0 to 40
þ
m
M, the limit of detection (LOD) was
when the fluorescent intensity ratio I497 nm/I420 nm was plotted
2
þ
calculated to be 33.6 nM.
against molar factions of QA and Zn under the constant total
concentration (100 M), the maximum point was observed at a
mole fraction of 0.5, which means QA binds Zn
m
2
þ
with a 1:1
.3. The binding between sensor QA and Zn2þ
3
2
þ
stoichiometry. The binding between QA and Zn was identified
further by the high-resolution ESI-MS spectrum. In Fig. 5, the m/z
peak at 545.1345 appeared, which corresponds to the molecular
A Job’s plot analysis was carried out for quantifying the
stoichiometry of the complex of QA and Zn . As shown in Fig. 4,
2
þ
þ
2þ þ
2þ
ion peak of [QA-H þZn ] . The QA and Zn binding affinity
was evaluated by fluorescence titration experiment (Fig. S2), and
2
þ
the dissociation constant (K
d
) for Zn binding to QA is calcu-
lated to be 52 ꢄ 8 M, which is relatively high compared to
m
previously reported Zn ion sensor with the dissociation constant
at pM level [34]. The reason should be attributed to that the
binding affinity of the sensor with mono pyridine moiety is
much weaker than that with double pyridine moieties. The low-
2
þ
2þ
con-
affinity Zn
sensor is potential in monitoring the Zn
centration in synaptic vesicles of many excitatory forebrain
2
þ
neurons where the concentration of Zn was reported to be in
the micro- to millimolar range [55,56].
2
þ
On the mechanism of fluorescence changes induced by Zn
,
2
þ
we proposed that the complexation between Zn and N atoms
in QA provided the “offeon” response for quinoline fluorophore
via internal charge transfer effect, which is similar to the pre-
vious sensors containing 8-aminoquinoline moiety [26,31,44].
Owing to the emission band of anthracene fluorophore overlaps
the excitation band of quinoline fluorophore (Fig. S3), then FRET
effect from donor (anthracene) to acceptor (quinoline) occurred,
leading to the decrease of the emission intensity at 420 nm
accompanied by the increase of the emission intensity at 497 nm
(Fig. 6).
Fig. 4. Job’s plot for determining the stoichiometry of probe QA and Zn2þ in the
HEPES-buffered solution (10 mM HEPES, 50% (v/v) DMSO, pH ¼ 7.4). The total con-
2þ
2þ
2þ
centration of probe and Zn is 100
97 nm.
m
M, XZn ¼ [Zn ]/([Zn ] þ [QA]), monitored at
4
Fig. 5. TOF-mass of the complex of QA with Zn2
þ
.

Y. Ma et al. / Dyes and Pigments 102 (2014) 301e307
305
Fig. 6. The mechanism for detecting Zn2
þ
.
3.4. The bio-imaging of sensor QA in living cells
picture of blue and green channels exhibited the fluorescence of
cells changed into bluish green from blue (Fig. S4). Addition of
0
0
The ability of QA to image zinc ions in living cells was also
the cell-permeable chelator TPEN (N,N,N ,N -tetrakis(ꢂ)[2-
pyridylmethyl]-ethylenediamine) recovered the blue fluores-
cence and faded the green fluorescence, which confirms that the
fluorescence changes result from Zn(II) coordination (Fig. 7j and
evaluated (Fig. 7). After MCF-7 cells incubated with 10
h at 37 C, a blue fluorescence was observed by confocal laser
m
M QA for
ꢀ
1
scanning microscopy (Fig. 7b) while green channel showed
2
þ
2þ
negligible fluorescence (Fig. 7c). However, when 100
m
M of Zn
k). The further imaging with the treatment of Cd indicated that
QA can be used to image Zn without the interference of Cd
2
þ
2þ
was added and incubated for 15 min, the intense green fluores-
cence appeared from the green channel (Fig. 7g) and the overlay
within living cells (Fig. S4).
2
þ
ꢀ
Fig. 7. Confocal fluorescence images of intracellular Zn in MCF-7 cells. MCF-7 cells incubated with probe QA (10
m
M) (in 2% DMSO v:v) at 37 C for 1 h (top); QA stained cells were
2
þ
ꢀ
2
þ
exposed to 100
j) Fluorescence images with emission collected at 425e475 nm. (c), (g), (k) Fluorescence images with emission collected at 500e600 nm. (d), (h), (l) Ratio images F500e600 nm/F425e
75 nm. The blue channel images were collected upon excitation at 405 nm and the green ones were collected upon excitation at 488 nm. Scale bar: 60 m, ratio bar: 0e4.
mM Zn at 37 C for 15 min (middle); and sequestration of intracellular Zn by addition of 200 mM TPEN for 15 min (bottom). (a), (e), (i) Bright-field images. (b), (f),
(
4
m

306
Y. Ma et al. / Dyes and Pigments 102 (2014) 301e307
4
. Conclusions
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concentration of Zn2 ranging from 0
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This work was supported by grants from NSF of China
21002049, 81371684 and 21376117), the Natural Science Founda-
tion of the Jiangsu Higher Education Institutions of China (Grant
No. 10KJB150005), and the Scientific Research Foundation for the
Returned Overseas Chinese Scholars of State Education Ministry.
2011;50:4229e31.
(
[
[
[
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