Journal of Electroanalytical Chemistry 863 (2020) 114052

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Journal of Electroanalytical Chemistry

journal homepage: www.elsevier.com/locate/jelechem

Au nanoparticles @metal organic framework/polythionine loaded with

molecularly imprinted polymer sensor: Preparation, characterization, and
electrochemical detection of tyrosine
⁎∗
Bangjie Chen a, Yunsong Zhang a, Li Lin a, Hui Chen b, Maojun Zhao a,
a
College of Science, Sichuan Agricultural University, Xin Kang Road, Yucheng District, Ya'an 625014, PR China
b
College of Life Science, Sichuan Agricultural University, Xin Kang Road, Yucheng District, Ya'an 625014, PR China

A R T I C L E I N F O A B S T R A C T

Article history: In this study, a new dual-signal electrochemical sensor using a glassy carbon electrode (GCE) modified with molecu-
Received 21 November 2019 larly imprinted polyaniline/polythionine/gold nanoparticles@zeolitic imidazolate framework-67 composite (MIP/
Received in revised form 19 February 2020 pTH/Au@ZIF-67) is fabricated for the quantitative analysis of tyrosine (Tyr). Au@ZIF-67 is used as a matrix to improve
Accepted 9 March 2020
the surface area and electron-transfer ability of the sensor. The pTH as a built-in probe provides a signal-off response,
Available online 10 March 2020
meanwhile the oxide current of Tyr acts as a signal-on response. The MIP is prepared in the presence of aniline mono-
Keywords:
mer and Tyr template by electro-polymerization for Tyr specific recognition. Under the optimized conditions, the sen-
Molecularly imprinted polymer sor demonstrates a linear range from 1 × 10−8 M to 4 × 10−6 M for Tyr determination and a limit of detection (LOD)
Dual-signal of 7.9 × 10−10 M (S/N = 3). Furthermore, the sensor exhibits excellent selectivity, superior stability and good repro-
ZIF-67 ducibility toward Tyr. More importantly, the sensor is successfully employed to detect Tyr in human serum with sat-
Polythionine isfactory recoveries.
Tyr © 2020 Elsevier B.V. All rights reserved.
Electrochemical sensor

1. Introduction
Tyrosine (Tyr) is one of the essential amino acid for humans. It is an es-
sential component of proteins and is absolutely necessary for the mainte-
nance of positive nitrogen balance [1]. Deficiency of Tyr may induce
depression, dementia and hypothyroidism. Elevation of Tyr can also
cause Parkinson's disease and hyperthyroidism [2,3]. Therefore, it is impor-
tant to monitor Tyr for diagnosis and treatment of the diseases. To date, sev-
eral technologies have been employed for Tyr determination, including
liquid chromatographic-tandem mass spectrometry (LC-MS) [4], high-
performance liquid chromatography (HPLC) [5,6], capillary electrophore-
sis [7] and electrochemical method [8–10]. Among these techniques, the
electrochemical analysis has received extensive attention due to its fast re-
sponse, high sensitivity, excellent accuracy, simplicity and low cost [2,11].
As we know, it is lack of selectivity, high sensitivity and excellent accuracy
by using conventional electrodes for direct detection of Tyr because of the
high overpotential of Tyr and fouling effect [12,13].
With the development of modern analysis technology, molecularly
imprinted polymer (MIP) has been widely combined with electrochemical
measurement method to prepare MIP-based sensors for identification of
⁎ Corresponding author.
E-mail address: Zhaomj_sicau@126.com. (M. Zhao).
target molecule by reason of its outstanding selectivity and strong affinity
[14–16]. For example, V. Syritski et al. constructed two MIP based sensors
for detection of antibiotics (erythromycin and amoxicillin), both of these
exhibited outstanding analytical performance [17,18]. However, because
of the poor conductivity and limited number of imprinted cavities of MIP,
the sensitivities of these MIP-based sensors are still not satisfactory. There-
fore, various materials (such as metal nanoparticles [19], graphene [20],
multi-wall carbon nanotubes [21], metal organic framework [22] and con-
ductive polymers etc. [15]) are frequently used as functional substances for
improving the binding sites and conductivities of MIP.
Among these materials, zeolitic imidazolate framework-67 (ZIF-67) as a
type of metal organic frameworks have attracted much attention owing to
its large surface, high porosity and biocompatibility. For instance, Zhang
et al. effectively enhanced the number of molecularly imprinted cavities
of MIP-based sensor by modifying GCE with ZIF-67, and the obtained sen-
sor exhibited excellent analysis performance for detection of dopamine in
real samples [23]. Nevertheless, the poor conductivity of ZIF-67 is obvious.
Thus, functionalization of ZIF-67 by conductive materials (such as metal
nanoparticles [24], graphene [25] and conductive polymers etc. [26]) is
necessary.
Among these materials, metal nanoparticles (such as Au [27], Ag [24]
and Pt [28]) are the promising materials for modifying ZIF-67 because of
their high conductivity, good biocompatibility and electrocatalytic activity.
For instance, Zhou et al. employed 1-pyrenebutyrate and Au NPs to

http://dx.doi.org/10.1016/j.jelechem.2020.114052
1572-6657/© 2020 Elsevier B.V. All rights reserved.
B. Chen et al.
decorate the mercapto-β-cyclodextrin functionalized reduced oxide
graphene for detection of quercetin [29].
Additionally, recent researches indicate that polythionine (pTH) as a
kind of conductive polymer is frequently used for construction of electro-
chemical sensors due to its good redox reversibility and stability [30,31].
Herein, a novel dual-signal electrochemical sensor based on MIP/pTH/
Au@ZIF-67/GCE is proposed for Tyr determination. As shown in Scheme 1,
initially, Au@ZIF-67 was synthesized via a wet chemical reduction method.
Then bare GCE was decorated with Au@ZIF-67, followed by, the pTH was
electropolymerized on the Au@ZIF-67 modified GCE surface. Finally, MIP
was prepared by cyclic voltammetry (CV). After removing Tyr from MIP
membrane, the resulting MIP sensor can recognize Tyr by π-π stacking in-
teractions and hydrogen binding [32]. Although Tyr molecules cannot gen-
erate electrochemical signal in low concentration, they occupy the channels
for electron transmission of pTH, thereby leading to the decrease of pTH
current. When the concentration of Tyr is increased to a quantitative
value, the peak current of Tyr emerges and the pTH current still decreases.
Hence, a dual-signal including current response increase of Tyr and de-
crease of pTH was established. This dual-signal strategy can efficiently re-
duce potential interferences from intrinsic background electrochemical
signals, thus improving the sensitivity and accuracy of the sensor. To the
best of our knowledge, it is the first time to present a facile strategy for
the preparation of MIP/pTH/Au@ZIF-67 modified electrode to detect
Tyr. The sensor exhibited satisfied selectivity, repeatability, high sensitiv-
ity, stability and a wide determination range. In addition, the presented sen-
sor was successfully employed to determine Tyr in real samples.
2. Experimental
All the chemicals and apparatus of this experiment, and the experimen-
tal procedures are described in Supporting information.
3. Results and discussion
3.1. Characterization
The phase and crystallographic structure of as-synthesized ZIF-67 and
Au@ZIF-67, and the chemical composition state of the Au@ZIF-67 are in
accord with the literature (Figs. S1 and S2) [23,33].
Scheme 1. Illustration of the MIP/pTH/Au@ZIF-67/GCE fabrication and electrochemical measurement process.
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Journal of Electroanalytical Chemistry 863 (2020) 114052
The morphologies of the different modified electrodes were studied via
scanning electron microscope (SEM). As displayed in Fig. 1A and insert I,
the ZIF-67 exhibits a 3-D and monodispersed rhombic dodecahedral archi-
tecture with a mean size of circa 600 nm. The high magnification image re-
veals that the surface of ZIF-67 is smooth. From Fig. 1B, Au@ZIF-67 still
keeps original morphology and size distribution. The high magnification
image (Fig. 1B, insert II) shows that the Au@ZIF-67 has a rough surface, in-
dicating the successful reduction of HAuCl4 on the surface of ZIF-67. After
electro-polymerization of thionine on the Au@ZIF-67, there is a network
structure comprised of thin film and particles and the shape of Au@ZIF-
67 becomes indistinct (Fig. 1C). Fig. 1D and E display the SEM images of
Tyr-imprinted polyaniline membrane and non-imprinted polyaniline mem-
brane on the pTH/Au@ZIF-67, respectively. Obviously, the MIP film is
rougher than NIP film. Moreover, the MIP membrane has a porous struc-
ture, which may be caused by removing Tyr template molecules from the
MIP film.
3.2. Electrochemical characterization
In an effort to investigate the electrochemical conductivity of the di-
verse electrodes during the step-by-step preparation process of MIP/
Pth/Au@ZIF-67/GCE, CV was conducted using 5 mM [Fe(CN)6]3−/4−
as probe in the potential range of 0.6 V to −0.2 V and scan rate of
100 mV s −1 . From Fig. 2A, the bare GCE exhibits two characteristic
redox peaks at 0.34 V and 0.26 V with a peak potential difference (Δp)
of 80 mV (a). The peak current intensity of ZIF-67/GCE decreased re-
markably (b) after bare GCE was modified with ZIF-67, which is caused
by the poor conductivity of ZIF-67. When the Au@ZIF-67 was deposited
on GCE, the current intensity of Au@ZIF-67/GCE was enhanced (c),
proving the good electron transfer ability of Au nanoparticles. As GCE
was modified with pTH/Au@ZIF-67, the peak current was observably
improved (d). This indicates that the pTH/Au@ZIF-67 can significantly
increase the electron transport rate between the [Fe (CN)6]3−/4− solu-
tion and the electrode interface, which is crucial for improving sensitiv-
ity. Owing to poor conductivity of MIP, the peak current was
dramatically reduced after electro-polymerization of MIP (e). This can
be attributed to that the MIP membrane hinders the entry of [Fe(CN)
3−/4−
6] into electrode. Molecularly imprinted cavities were left after
eluting Tyr from MIP, permitting the infiltration of [Fe(CN) 6 ] 3−/4−
into electrode. Thus, the peak current intensity was augmented (f). It
B. Chen et al.
Fig. 1. SEM of (A) ZIF-67, (B) Au@ZIF-67, (C) pTH/Au@ZIF-67, (D) MIP/pTH/Au@ZIF-67, (E) NIP/pTH/Au@ZIF-67. The insert: (I) high magnification image of ZIF-67, (II)
high magnification image of Au@ZIF-67.
is worth noting that there is no peak current for NIP/pTH/Au@ZIF-67/
GCE (Fig. 2A inset, II), which may be ascribed to the weak conductivity
of polyaniline film. On the other hand, there is no distinct current
change despite interaction with Tyr (Fig. 2A inset, II and III). This sug-
gests that the NIP/pTH/Au@ZIF-67/GCE cannot recognize Tyr.
The electrochemical impedance spectroscopy (EIS) is a useful means for
the characterization of diverse electrodes. As shown in Fig. 2B, the semicir-
cle domain of ZIF-67/GCE (b) is more broad than bare GCE (a), indicating
that ZIF-67 has a large electron-transfer resistance (Rct). This is because ZIF-
67 has poor electrical conductivity. The Au@ZIF-67/GCE (c) has smaller
Rct, which demonstrates Au nanoparticles can facilitate electron transfer.
On account of the excellent electron transfer ability of pTH, the Rct of
pTH/Au@ZIF-67/GCE (d) dropped dramatically after electro-
polymerization of thionine on the Au@ZIF-67/GCE. The Rct of the MIP/
pTH/Au@ZIF-67/GCE before removing Tyr(e) is larger than the Rct of the
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Journal of Electroanalytical Chemistry 863 (2020) 114052
MIP/pTH/Au@ZIF-67/GCE after removing Tyr (f), which is in accordance
with the results of CV characterization.
The electrochemical behavior of MIP/pTH/Au@ZIF-67/GCE was
assessed via CV scanning. The potential connection between peak currents
(Ip) and scan rate was used to speculate the electrochemical mechanism of
MIP/pTH/Au@ZIF-67/GCE. As presented in Fig. 3A, CV was implemented
in 5 mM [Fe(CN)6]3−/4− solution at diverse scan rates with scope of 25 to
300 mV s−1. On the basis of Fig. 3B, the redox peak current augments in
proportion to square root of the scan rate. The matching linear equations
are: Ip (A) = 0.0005ν1/2 (V1/2 s−1/2) + 6 × 10−5, R2 = 0.9984 and Ip
(A) = −0.0005ν1/2 (V1/2 s−1/2) + 7 × 10−6, R2 = 0.9931. indicating
the electrochemical process is diffusion control phenomenon at the surface
of the fabricated sensor [34,35]. Moreover, the active surface area of the
MIP/pTH/Au@ZIF-67/GCE is crucial for the loading more MIP and adsorp-
tion of more Tyr. Hence, the active surface area can be calculated by the
B. Chen et al. Journal of Electroanalytical Chemistry 863 (2020) 114052

Fig. 2. CV (A) and EIS (B) curves of different electrodes in 5 mM [Fe(CN)6]3−/4− containing 0.1 M KCl, bare GCE (a); ZIF-67/GCE (b); Au@ZIF-67/GCE (c); pTH/Au@ZIF-
67/GCE (d); MIP/pTH/Au@ZIF-67/GCE before (e) and after (f) removing Tyr. The inset of (A) is CV curves of bare GCE and NIP electrode under different conditions: bare
GCE (I); NIP/pTH/Au@ZIF-67/GCE before (II) and after (III) rebinding Tyr, the inset of (B) is the EIS plots of bare GCE (a); and pTH/Au@ZIF-67/GCE (d) in smaller
coordinate range.

Randles – Sevcik equation: [36].
I p ¼ 268600n3=2 AD1=2 Cν1=2 ð1Þ
where Ip represents the peak currents, and n signifies electron transfer
amount of [Fe(CN)6]3−/4− (n = 1). A stands for the active surface area
of MIP/pTH/Au@ZIF-67/GCE, D is the diffusion coefficient of the 5 mM
[Fe(CN)6]3−/4− solution, so D is equivalent to 6.7 × 10−6 cm2 s−1 [35].
Furthermore, C represents the concentration of [Fe(CN)6]3−/4− solution
(mol cm−3), and ν denotes scan rate (V s−1). In the light of the slope of Ip
vs ν1/2 in Fig. 3B, the active surface area of the MIP/pTH/Au@ZIF-67/
GCE is determined to be 0.14 cm2, which is greater than bare GCE
(0.07 cm2).
3.3. Optimization of experiment conditions
The number of imprinted sites of the MIP is directly related to the molar
ratio of the template molecule to the monomer. Accordingly, it is vital to ob-
tain the optimized mole ratio of Tyr to aniline. As shown in Fig. 4A, the in-
fluence of molar ratio was assessed in the range of 1:1 to 1:5. The result
displays that the MIP-based sensor constructed with mole ratio of 1:3
achieves the maximum current value. This means that the amount of avail-
able Tyr imprinted cavities increases with increasing aniline monomer,
while the superabundant aniline monomer would lead to self-
polymerization and reduce the specific binding sites instead. Thus, the
1:3 ratio of the Tyr template to aniline monomer is optimal and adopted.
The number of imprinted recognition sites can also be influenced by the
thickness of the MIP membrane, which can be readily regulated via chang-
ing the cycles of electro-polymerization. As presented in Fig. 4B, the current
intensity enhances as the number of polymerization cycles increases. With
cycles equal to 20, strongest peak current occurs. As the polymerization cy-
cles exceeds 20, the current intensity decreases. This can be ascribed to the
generation of less blotting sites at lower number of polymerization cycles. A
large number of polymerization cycles lead to form too thick MIP mem-
brane, causing difficulty in removing Tyr molecules. Accordingly, the opti-
mal number of electro-polymerization cycles is 20 cycles to prepare the MIP
sensor.
The pH has significant impact on the peak current response. From
pH = 4 to pH = 6 (Fig. 4C), the MIP sensor exhibits different current re-
sponses. The current intensity rises with increasing pH and a maximum is
obtained at pH = 5, and then decreases as the pH subsequently increases.
As a result, a pH = 5 is selected for use in this work.
The response of the MIP sensor is related to the compactness of the MIP
film, which can be regulated by altering the scan rate. Fig. 4D displays the
impacts of scan rate on current response. The current response increases
sharply from 20 mV s−1 to 50 mV s−1, followed by the current response re-
duces at higher scan rate. This phenomenon indicates that the compact MIP
membrane synthesized at a low scan rate makes it difficult to extract Tyr.
The rough and loose MIP film prepared at high scan rate results in poor rec-
ognition performance. Based on this, the scan rate of 50 mV s−1 is adopted.
The residual Tyr molecules can affect the precision of the MIP sensor. As
a consequence, it is crucial to use a sufficient long elution time to wash all
the remaining Tyr molecules from the MIP. The current intensity keeps

Fig. 3. (A) CV plots of MIP/pTH/Au@ZIF-67/GCE in 5 mM [Fe(CN)6]3−/4− containing 0.1 M KCl with different scan rates (from 0.025 to 0.3 V s−1). (B) The linear
relationship between Ip and v1/2.

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B. Chen et al.
Fig. 4. The optimized conditions for MIP film preparation. (A) molar ratio Tyr template to aniline monomer, (B) electro-polymerization cycles, (C) pH, (D) scan rate,
(E) elution time and (F) incubation time. The DPV currents were measured in 0.1 M PBS containing 0.5 μM Tyr and other conditions were the same.
rising in the range of 2 min to 8 min and maintains equilibrium after 8 min
(Fig. 4E). Therefore, the most suitable elution time is set as 8 min.
The response time is a crucial element to estimate the property of the
constructed MIP sensor. Accordingly, it is necessary to find the shortest in-
cubation time. The result (Fig. 4F) shows that the current intensity in-
creases as the incubation time increases, and the current intensity is
essentially stable after 10 min. It indicates that the incubation time of
10 min is the optimal incubation time in the following experiments.
3.4. The analytical performance of MIP/pTH/Au@ZIF-67/GCE
Owing to the low background current and comparatively sensitive re-
sponse, DPV was used to assess the analytical capability of the prepared
MIP-based sensor under optimized experiment qualifications. As presented
in Fig. 5A, the peak current of pTH decreases gradually as the amount of Tyr
increases, while no obvious oxidation current of Tyr appears until the con-
centration of Tyr reaches 6 × 10−8 M. It is worth noting that the current
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Journal of Electroanalytical Chemistry 863 (2020) 114052
response of pTH still reduces and the oxidation current of Tyr enhances
slowly when the Tyr concentration is greater than 6 × 10−8 M. Thus, a
dual-signal (Δi = |ΔiTyr| + |ΔiTH|) containing the current intensity increase
of Tyr (|ΔiTyr|) and the peak current decrease of pTH (|ΔiTH|) is established
to quantitatively analyze Tyr. As shown in Fig. 5B, Δi is proportional to the
concentration of Tyr between 1 × 10−8 and 4 × 10−6 M for MIP/pTH/
Au@ZIF-67/GCE (a). The correlative linear regression equation is Δi
(Δi = |ΔiTyr| + |ΔiTH|) (μA) = 8.452cTyr (μM) + 2.2502, R2 = 0.9991.
And the limit of detection (LOD) is 7.9 × 10−10 M, which was calculated
by the equation: LOD = 3σ/s, where s stands for the slope of the calibration
curve of Tyr and σ denotes the standard deviation of the peak currents of the
blank (n = 10). As for the single-signal current changes caused only by Tyr
in the concentration from 6 × 10−8 to 4 × 10−6 M for MIP/pTH/Au@ZIF-
67/GCE (b), the linear regression equation is Δi (Δi = |ΔiTyr|) (μA) =
4.3179cTyr (μM) + 0.2496, R2 = 0.997, and the LOD is 1.5 × 10−9 M.
By comparing the linear range and LOD of dual-signal and single-signal,
the dual-signal system shows a broader linear range and lower LOD to
B. Chen et al. Journal of Electroanalytical Chemistry 863 (2020) 114052

Fig. 5. (A) DPVs of the MIP/pTH/Au@ZIF-67/GCE sensor toward various concentrations of Tyr (a–j): 0, 0.01, 0.03, 0.06, 0.1, 0.3, 0.6, 1, 2, 4 μM in 0.1 M PBS (pH = 5.0).
(B) Calibration plot between Tyr concentration and dual-signal current changes (Δi = |ΔiTyr| + |ΔiTH|) with MIP/pTH/Au@ZIF-67/GCE (a) and NIP/pTH/Au@ZIF-67/GCE
(c), the calibration plot between Tyr concentration and single-signal current changes of Tyr (ΔiTyr) (b).

detect Tyr. Under the same conditions, the DPV was performed on NIP/ current (Ip(Tyr) + Ip(pTH)) after two weeks (Table S2), which demonstrates
pTH/Au@ZIF-67/GCE to analyze Tyr. There is no obvious linear relation- that the sensor can be employed to detect Tyr even after prolonged periods
ship between the Δi and the concentration of Tyr (c), and the DPV responses of storage.
of MIP/pTH/Au@ZIF-67/GCE are greater than NIP/pTH/Au@ZIF-67/
GCE, which is probably because the MIP/pTH/Au@ZIF-67/GCE possesses 3.6. Real analytical performance in serum
more binding sites and can specifically adsorb Tyr. In order to compare
with other electrochemical sensors, Table 1 lists the linear ranges and As a result of the good selectivity of the prepared sensor, the standard
LODs of other electrodes and the proposed electrode in this work. It can addition method was employed to estimate the practical analytical perfor-
be concluded that the fabricated MIP/pTH/Au@ZIF-67/GCE exhibits a mance in human serum. Each sample was measured three times in parallel.
broader linear range and a lower detection limit to detect Tyr. The HPLC results were used to verify the accuracy the results of the pre-
sented sensor. The differences between the two approaches are slight by
3.5. Selectivity, reproducibility and stability of the MIP based sensor contrast. From Table 2, the recoveries of the prepared sensor vary from
95.8% to 118.0%, which demonstrates that the proposed approach fur-
On account of the complexity of real samples and the similar structure nishes a practical and accurate way to quantitatively detect Tyr in human
and function of interferents, a promising MIP-based sensor should possess serum.
prominent specific identification for template molecules. Thus, selectivity
experiments were carried out in 0.1 M PBS containing 0.8 μM Tyr with 4. Conclusion
and without 16 μM different interferents. According to Fig. 6, the difference
of DPV current response of Tyr with and without different interferents is A highly sensitive and selective molecularly imprinted electrochemical
negligibly, and the current response of MIP-based sensor is greater than sensor based on dual-signal strategy was proposed to assay Tyr in human
the NIP-based sensor. It indicates that these analogs have no significant in- serum. The sensor was constructed by decorating GCE with MIP/pTH/
terference toward Tyr detection and the NIP-based sensor can not recognize Au@ZIF-67 composite. In this sensing system, the sign-on of Tyr and sign-
Tyr from its analogs. In other words, the MIP-based sensor exhibits strong
specific recognition to Tyr.
In order to study the reproducibility, the current responses of five MIP/
pTH/Au@ZIF-67/GC electrodes prepared in the same way were measured
by DPV in PBS containing 0.8 μM Tyr (Table S1). The relative standard de-
viation (RSD) of the peak currents (Ip(Tyr) + Ip(pTH)) is 1.5%, testifying the
proposed sensor has good reproducibility. In an effort to assess stability, the
MIP/pTH/Au@ZIF-67/GCE was stored in a freezer at 4 °C and the current
value (Ip(Tyr) + Ip(pTH)) was approximately 96.8% of the primitive peak

Table 1
Comparison of performance of other electrodes with the proposed electrode in our
work.
Electrode Linear range (M) Detection Reference
limit
(M)

1 × 10−7 − 2.88 ×
Hemin/PAMAM/MCNT/GCE 1.0 × 10−8 [37]
10−5
GR/ZnO/GSPE 1 × 10−6 − 8 × 10−4 3.4 × 10 −7
[8]
3 × 10−6 − 2 × 10−4
Graphene/Ta 6.0 × 10−7 [38]
2 × 10−4 − 8 × 10−4
NiO/CNTs/DPID/CPEs 5 × 10−6–7.5 × 10−4 1.0 × 10−6 [39]
PABSA/Au/GCE 1 × 10−6 − 1 × 10−4 4.0 × 10−7 [40] Fig. 6. Comparison of DPV responses of MIP and NIP modified electrodes in 0.1 M
UT-g-C3N4/Ag/GCE 1 × 10−6–1.5 × 10−4 1.4 × 10−7 [41]
PBS containing 0.8 μM Tyr with and without 16 μM analogs under the same
MIP/pTH/Au@ZIF-67/GCE 1 × 10−8 − 4 × 10−6 7.9 × 10−10 This work
conditions.

6
B. Chen et al. Journal of Electroanalytical Chemistry 863 (2020) 114052

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