Core-shell heterostructured CuFe@FeFe Prussian blue analogue

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Core-shell heterostructured CuFe@FeFe Prussian blue analogue coupling with silver nanoclusters via a one-step bio-inspired approach: Efficiently nonlabel aptasensor for detecting bleomycin in various aqueous environments Nan Zhou, Long-Yu Yang, Bin Hu, Yingpan Song, Linghao He, Weizhe Chen, Zhihong Zhang, Zhongyi Liu, and Siyu Lu Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.8b03850 • Publication Date (Web): 22 Oct 2018 Downloaded from http://pubs.acs.org on October 23, 2018

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Analytical Chemistry

Core-shell heterostructured CuFe@FeFe Prussian blue analogue coupling with silver nanoclusters via a one-step bio-inspired approach: Efficiently non-label aptasensor for detecting bleomycin in various aqueous environments Nan Zhou*a, Longyu Yangb, Bin Hub, Yingpan Songb, Linghao Heb, Weizhe Chenc, Zhihong Zhang*b, Zhongyi Liud, Siyu Lu*d

a

Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University,

No. 1, Jianshe East Road, Zhengzhou 450052, P. R. China b

Henan Provincial Key Laboratory of Surface and Interface Science, Zhengzhou

University of Light Industry, No. 136, Science Avenue, Zhengzhou 450001, P. R. China c

The Center of Quality Supervision and Inspection of Xuchang, Xuchang, 461000, P. R.

China d

College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou,

450000, P. R. China

Corresponding authors ∗E-mail

addresses: [email protected], [email protected] or [email protected] 1

ACS Paragon Plus Environment

Analytical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Abstract: We synthesized a novel core-shell heterostructured Prussian blue analogue (PBA) nanospheres coupling with silver nanoclusters (AgNCs) via a one-step bio-inspired approach and further exploited as the aptasensor for detecting trace antibiotics, bleomycin (BLM). Using FeFe Prussian blue (FeFe PB) as core, bimetallic CuFe@FeFe-PBA layer was prepared by coupling with AgNCs synthesized by taking the BLM-targeted aptamer as template (denoted by AgNCs/Apt@CuFe@FeFe). The coupling of AgNCs/Apt via a one-step bio-inspired approach not only can improve the sensing performance of CuFe@FeFe-based aptasensor but also can shorten the aptasensor fabrication procedure. Owning to strong coordination interaction between abundant Fe(II) ions containing in CuFe@FeFe PBA nanospheres and BLM (represented by Fe(II)·BLM), the formed Fe(II)·BLM complex enables aptamer strands undergo an irreversible cleavage event that can result in a significant change in electrochemical activity. Electrochemical

results

displayed

that

both

CuFe@FeFe-

and

AgNCs/Apt@CuFe@FeFe-based aptasensors exhibited high sensitivity and selectivity, good stability and reproducibility, and acceptable applicability toward BLM. As compared with the pristine CuFe@FeFe-based aptasensor (the limit of detection (LOD) = 0.49 fg·mL−1 within the BLM concentration from 1.0 fg·mL−1 to 2.0 ng·mL−1), the as-prepared AgNCs/Apt@CuFe@FeFe-based one gave an extremely lower LOD of 0.0082 fg·mL−1 within a relatively narrow BLM concentration range (0.01 fg·mL−1 - 0.1 pg·mL−1). The proposed method can broaden the application of PBA nanomaterials in food safety and biosensing fields and provides a potential determination method for 2


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rapidly detecting BLM in various aqueous environments. Keywords: CuFe@FeFePBA-based Prussian blue analogue; Electrochemical Aptsensors; Detection of bleomycin; DNA-templated Ag nanoclusters

INTRODUCTION Various antibiotics were invented or discovered to treat diseases of the human beings. Among them, bleomycin (BLM), a clastogenic and radiomimetic antibiotic isolated from Streptomyces verticillus,1 has been used as a chemotherapeutic agent for the clinical treatment of certain cancers, including Hodgkin’s disease, non-Hodgkinlymphoma, testicular cancer, and malignant pleural effusions.2 In order to quantitatively monitor the BLM level, weaken the toxicity and achieve the optimal therapeutic effect, considerable effort has been devoted to develop reliable and sensitive methods for BLM quantification, such as high performance liquid chromatography,3 radioimmunoassay,4 enzyme immunoassay,5 fluorescence resonance energy transfer assays,6 surface plasmon resonance spectroscopy,7 colorimetric assay,8 and fluorescence.9 However, these methods often suffer from drawbacks, such as complex process, time-consuming, high determination cost, or hazards. Apparently, it still remains a challenge to construct simple, facile and label-free sensing probes with high sensitivity and selectivity in response to BLM in both pharmaceutical analysis and clinical medicine research.10 In the past few decades, electrochemical methods exhibit advantages of fast response, high sensitivity, low cost, miniaturization, and on-site analysis and have been a promising alternative to rapidly detect antibiotics.11 3



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Very recently, aptamers, RNA or DNA strands, are artificially synthesized oligonucleotides to bind diverse target molecules with high affinity and selectivity, such as cancer markers, antibiotics, metal ions, and so on.12 Aptamer-based biosensors (aptasensors) have attracted extensive interests to detect trace amounts of these targets owing to their high sensitivity, easy use, possible miniaturization and portability.13 The detection mechanisms for the routine aptasensors are based on the recognition of aptamer strands and their corresponding analytes.14 In terms of the BLM aptasensor mechanism, howbeit, it is based on the coordination between Fe(II) and BLM in the presence of oxygen, which subsequently leads to the oxidation of Fe(II) to Fe(III) and reduction of oxygen to free radicals, can enable aptamer strands to break and undergo an irreversible cleavage event that can result in a significant change in electrochemical conductivity.11 Various electrochemical assays for detecting BLM were fabricated based on BLM-induced DNA strand scission. For instance, the ferrocene (Fc)-modified DNA motif was employed as substrate for detecting BLMs, giving a limit of detection (LOD) of 100 pM.11 An ultrasensitive electrogenerated chemiluminescent (ECL) DNA-based biosensing switch for detecting BLM was developed based on Fe(II)-BLM-mediated hairpin DNA strand cleavage and a structure-switching ECL-dequenching mechanism.15 A bicyclo-hairpin probe mediated strand displacement amplification strategy was developed by Wang et al for BLM determination, exhibiting a detection limit of 0.34 nM.16 For these sensing systems for BLM, Fe(II) is often coexisted in BLM solution to form the activated metallobleomycin, which can mediate the oxidative signal probe 4


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destruction, further leading to the electrochemical signal change. Apparently, these literatures about the aptasensor for sensitively and selectively detecting BLM are still not fully exploited owing to some disadvantages of low sensitivity and fussy determination procedure. Considering the advantages of electrochemical techniques and aptasensors, it is necessary to develop electrochemical aptasensors for detecting BLM to enhance the determination efficiency and shorten the determination procedure. As an old metal organic framework (MOF), Prussian blue (PB) was firstly synthesized for use as a dark blue pigment in 1704 by Diesbach, which possesses a typical hexacyanoferrate coordination compound. PB [NaFe(III)Fe(II)(CN)6] and its analogues (NaxMFe(CN)6, M = Fe, Co, Ni and etc., denoted as PBAs) were widely developed and applied in various scientific fields due to their unique properties.17,18 Due to its cell structure and composition, PBs are much more stable than MOFs, especially in water, resulting in their potential application as highly efficient electrode modifier in aptasensor fabrication, such as DNA-grafted zirconium hexacyanoferrate ({Zr[Fe(CN)6]}n, represent by ZrHCF)

19

and PB-chitosan-glutaraldehyde.20 However, PB-modified electrodes are

often disrupted after a few potential scans at neutral pH which can further limits their use in biosensor fabrication. Combining PBs with other nanomaterials may be an effective method to increase the operational stability, such as Au nanoparticles (AuNPs),21 Ag nanoparticles (AgNPs),22 reduced graphene oxide,23 and chitosan.24 Additionally, the fabrication procedure of a biosensor usually is composed of three steps, including the platform preparation, the immobilization of probes, and the detection of targets.25 5



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Therefore, integrating probes with platform materials can shorten the biosensor development time and enhance the detection efficiency. In our previous work, aptamer strands were added into the MOFs preparation procedure to fabricate the aptasensors, which is called a one-step bio-inspired approach.26 These biosensing methods exhibited extremely high sensitivity and short detection time. Up to now, however, no report on the one-step fabrication of the PBs-based biosensor was observed. Recently, bimetallic Fe(III)-CN-Fe(II) PB (FeFe PB) and Fe(III)-CN-Cu(II) PBA (CuFe PBA) were exploited as the battery materials.27,28 Since CuFe-PBA and FeFe PB are composed of redox actives, such as Cu(I)/(II) and Fe(II)/(III) couples, they could be exploited as the bioplatform for sensing BLM via the coordination between Fe(II) and BLM. Core-shell heterostructured PBAs have been developed and applied as capacitors and

batteries,

such

as

CuFe-PBA@NiFe-PBA,

RbCoFe@KNiCr-PBA,29

and

NiCr@CoFe-PBA,30 but not for biosensing applications. The synthetic procedure allows the epitaxial growth of successive layers of different PBAs to generate core-shell PBA particles.31 By adapting this procedure, we have fabricated core-shell heterostructures with FeFe-PB core and a stable CuFe-PBA shell (represented by CuFe@FeFe PBA). As one scaffold for the AgNCs preparation, DNA oligonucleotides have been widely used as template.26 By combining the fabrication procedure of core-shell nanostructured CuFe@FeFe PBA and the aptamer-targeted AgNCs, one can anticipate to develop a novel

aptasensor

for

detecting

BLM

by

a

feasible

method

(denoted

as

AgNCs/Apt@CuFe@FeFe) without the aptamer strand immobilization and the usage of 6


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Fe(II) in analyte solution. Unlike the routine BLM aptasensors, large amounts of BLM molecules would be adsorbed into CuFe@FeFe PBAs by forming Fe(II)·BLM complex with Fe(II) ions, which can lead to the electrochemical conductivity of the electrode decrease. The electrochemical change caused by the BLM adsorption is larger than that of the cleavage of short DNA sequence from the sensing system. In the present work, we reported two novel kinds of aptasensors based on bimetallic core-shell CuFe@FeFe and AgNCs/Apt@CuFe@FeFe PBAs for sensitively detecting BLM for the first time (Scheme 1). CuFe@FeFe PBA embedded with AgNCs and aptamer strands (AgNCs/Apt@CuFe@FeFe) was constructed via a simple one-step bio-inspired approach, for which AgNCs was formed by using target aptamer strands as template.

It

demonstrates

that

the

biosensing

performance

of

the

AgNCs/Apt@CuFe@FeFe-based aptasensor outperforms the CuFe@FeFe-based one, giving an extremely low detection limit (0.0082 fg·mL−1) toward BLM, but together with a relatively narrower linear range of the BLM concentration than that of CuFe@FeFe-based one. As compared with routine BLM biosensors, the as-prepared CuFe@FeFe-based aptasensors exhibit superior sensing performances. It can be caused by the following reasons: (i) non-labeled and non-fluorescent CuFe@FeFe- and AgNCs/Apt@CuFe@FeFe-based aptasensors were fabricated by a feasible method; (ii) high sensing sensitivity and selectivity caused by the abundant aptamer strands and electrochemical active AgNCs, which were co-coupled with the core-shell CuFe@FeFe PBA; and (iii) core-shell nanostructured Fe(II)-rich CuFe@FeFe PBA shortens BLM 7



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detection steps. According to different determination requirements toward BLM, we can modulate sensing performances by changing the preparation procedure of bimetallic CuFe@FeFe

PBA.

As

anticipated,

both

the

AgNCs/Apt@CuFe@FeFe-

and

CuFe@FeFe-based aptasensors show high selectivity, good stability and reproducibility, and excellent applicability in milk, river water, and human serum samples. (A)

(B)

Scheme 1. Schematic diagram of (A) the fabrication of BLM aptasensors based on AgNCs/Apt@CuFe@FeFe PBA and CuFe@FeFe PBA and (B) BLM detection and electrochemical signal out.

EXPERIMENTAL SECTION Synthesis

of

CuFe@FeFe

and

AgNCs/Apt@CuFe@FeFe.

CuFe@FeFe

PBA

nanospheres were prepared according to the reported literature.32 Briefly, the as-prepared 20 mg FeFe PB nanocubes were dispersed into 30 mL of Milli-Q water, followed by the addition of 102.3 mg CuCl2·2H2O, 0.25 g sodium citrate, and 0.3 g PVP to form the solution A. Meanwhile, 66 mg K3Fe(CN)6 was dispersed into 20 mL of ultrapure water to form the solution B. Afterwards, the solution B was slowly added into the solution A, 8


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followed by stirring for 10 min and keeping static for 24 h. The product was centrifugally washed with ultrapure water and dried in vacuum at 60 °C for another 6 h and named as CuFe@FeFe PBA. As comparison, the core-shell MnFe@FeFe and NiFe@FeFe PBAs were synthesized by the same method, only replacing CuCl2·2H2O by MnCl2 and NiCl2·6H2O, separately. The used AgNCs/Apt was obtained using the BLM-targeted aptamer as the template in according to the previously reported literature.33 During the preparation procedure of AgNCs/Apt@CuFe@FeFe PBA nanospheres, 0.5 mL AgNCs/Apt (1.0 μM) was added into the synthesis system of the CuFe@FeFe PBA with vigorous stirring at room temperature for 5 min. Finally, the AgNCs/Apt@CuFe@FeFe PBA nanosphere was obtained. Fabrication of BLM aptasensors based on the as-prepared samples. CuFe@FeFe and AgNCs/Apt@CuFe@FeFe PBAs powder (1.0 mg) were separately dispersed in 1.0 mL of Milli-Q water and fully mixed by ultrasonic until the homogeneous CuFe@FeFe and AgNCs/Apt@CuFe@FeFe PBAs suspension were obtained, separately. Afterwards, 5.0 µL of CuFe@FeFe PBA suspension (1.0 mg mL−1) was dropped onto the pre-treated bare Au electrode (AE) surface and dried at room temperature (represented as CuFe@FeFe/AE). Subsequently, the modified AE was immersed in the aptamer solution (50 nM) for 30 min (represented as Apt/CuFe@FeFe/AE) to ensure that the aptamer strands were immobilized onto the electrode surface. Finally, the Apt/CuFe@FeFe/AE was immersed in the BLM solution for further electrochemical measurements 9



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(represented as BLM/Apt/CuFe@FeFe/AE). Similarly, the AgNCs/Apt@CuFe@FeFe-based aptasensor was fabricated by dropping AgNCs/Apt@CuFe@FeFe dispersion onto the AE surface and used to detect BLM. Accordingly,

each

step

was

marked

as

AgNCs/Apt@CuFe@FeFe/AE

and

BLM/AgNCs/Apt@CuFe@FeFe/AE, respectively.

RESULTS AND DISCUSSION Sensor

design.

Scheme

1

shows

the

fabrication

steps

of

the

AgNCs/Apt@CuFe@FeFe-based aptasensors for detecting BLM and their working mechanisms. As known, the aptamer strand contains a reported 16-nucleotide hairpin sequence,34 which can be simultaneously used as the template for the AgNCs preparation 7,35

and the probe toward BLM detection.36 This probe can self-hybridize into a hairpin

structure with a 6-base-pair stem and 4-nucleotide loop. In prior to the use, the hairpin structured aptamer strands were opened by annealing at 90 °C for 30 s. Owning to the inherent cavities of AgNCs/Apt@CuFe@FeFe frameworks, the small BLM molecules can access into the interior of CuFe@FeFe PBA nanospheres and bind with Fe(II) ions, of which the coordination of BLM·Fe(II) can exhibit sequence selective DNA strand scission predominantly at 5′-GC-3′ and 5′-GT-3′ sequences.37 As a result, the hairpin DNA sequence undergoes irreversible cleavage event by the oxidation caused by BLM with Fe(II). Each step would lead to the electrochemical activity variation of the modified electrode and can be transferred into the electrochemical signal change. Since larger amounts of aptamer strands together with AgNCs can be embedded within the 10


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CuFe@FeFe PBA interior, it can result in a highly sensitive detection of BLM. For comparison, the CuFe@FeFe-based aptasensor was fabricated by immobilizing the BLM-targeted aptamer strands. Due to the difference in the chemical structure and components and the crystal structure between AgNCs/Apt@CuFe@FeFe and CuFe@FeFe PBAs, these two kinds of aptasensors exhibit various sensing ability toward BLM. Basic characterizations of CuFe@FeFe and AgNCs/Apt@CuFe@FeFe PBAs. The chemical and crystal structure of pristine CuFe@FeFe and AgNCs/Apt@CuFe@FeFe PBAs were characterized by X-ray diffraction (XRD) (Figure S1a), Fourier transform infrared spectroscopy (FT-IR) (Figure S1b), and Raman spectroscopy (Figure S1c), which was supplied in S2 (See the Supporting Information). It is clear that adding the AgNCs/Apt does not affect the chemical and crystal structure of the CuFe@FeFe PBA. In order to further explore the chemical environment and valence state of each element containing in CuFe@FeFe and AgNCs/Apt@CuFe@FeFe PBAs, X-ray photoelectron spectroscopy (XPS) characterizations were also investigated (Figure S2). The detailed relevant discussion are supplied in S2 (See the Supporting Information). Briefly, Cu 2p, Fe 2p, and N 1s core-level XPS spectra of two samples were analyzed, as illustrated in Figure S3, together with the analysis of C 1s, O 1s, P 2p, and Ag 3d core-level XPS spectra (Figure S4). It is clear for that different valence states of Cu(I) and Cu(II) species containing in CuFe@FeFe and AgNCs/Apt@CuFe@FeFe PBA After combining with AgNCs/Apt, the content of Cu(II) specie containing in AgNCs/Apt@CuFe@FeFe PBA is 11



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higher than that of CuFe@FeFe PBA. The abundant Cu(II) can improve the AgNCs/Apt stabilitydue to the strong interaction between Cu(II) and DNA stands.38 Fe(0), Fe(II), and Fe(III) species are coexisted in CuFe@FeFe PBA, whereas only Fe(0) and Fe(II) are observed in AgNCs/Apt@CuFe@FeFe PBA. It suggests that all Fe(III) ions were reduced during the preparation procedure of AgNCs/Apt@CuFe@FeFe PBA. Consequently, strong interaction between Fe(II) and BLM would be taken place due to large amounts of Fe(II) ions containing in AgNCs/Apt@CuFe@FeFe PBA. Additionally, clear P and Ag(0) signals are observed in AgNCs/Apt@CuFe@FeFe PBA, indicating the presence of aptamer strands and formation of AgNCs. All of these results suggest that the addition of the AgNCs/Apt can modulate the chemical structure and covalent states of the CuFe@FeFe PBA, further leading to the variation of the electrochemical performances and biosensing. Surface

morphologies

and

microstructure

of

CuFe@FeFe

and

AgNCs/Apt@CuFe@FeFe PBAs were investigated by SEM and TEM. As shown in Figures S5a and S5b, CuFe@FeFe PBA presents sphere-like shape with rough surface with a diameter of around 220-290 nm. Compared to CuFe@FeFe PBA nanospheres, the AgNCs/Apt@CuFe@FeFe PBA exhibits similar surface morphology and appears to be more uniformly dispersed (Figure S5c), but with a smaller size of 218 ± 5 nm (Figure S5d). Figures 1a and 1b depict TEM images of CuFe@FeFe PBA at different magnifications, revealing a polyhedral morphology. From its HR-TEM image (Figure 1c), the lattice spacing of 0.507 nm corresponded to (200) plane of the FeFe PB is 12


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observed (JCPDS: 73-0687), which is in agreement with their XRD results. In terms of AgNCs/Apt@CuFe@FeFe PBA, the original sphere-like morphology of CuFe@FeFe PBA is well inherited with porous structure (Figure 1c). Nevertheless, close-up view reveals that large amounts of AgNCs with the size of about 2-7 nm are embedded within the CuFe@FeFe PBA nanospheres (Figure 1e), which is further confirmed by its HRTEM image. As shown in Figure 1f, the lattice spacing of 0.204 nm assigning to the (200) plane of face-centered cubic structure of Ag was clearly observed (JCPDS: 04-0783). It displays the successful combination of AgNCs with CuFe@FeFe PBA.

Figure 1. TEM and HRTEM images of (a, b, c) CuFe@FeFe and (d, e, f) AgNCs/Apt@CuFe@FeFe PBAs. Electrochemical

aptasensor

AgNCs/Apt@CuFe@FeFe

performances

PBAs

based

nanospheres.

on

CuFe@FeFe

CuFe@FeFe

and and

AgNCs/Apt@CuFe@FeFe PBAs nanoshperes were concurrently exploited as biosensing platforms to construct aptasensors, further providing their sensing ability toward BLM. The whole determination procedures for detecting BLM using these aptasensors were 13



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investigated by electrochemical impedance spectroscopy (EIS) (Figure S5), while the EIS plots were analyzed by the Randles equivalent circuit using Zview2 software. In the simulated circuit (the inset of Figure S6), the diameter of semicircle in EIS plots represents the charge transfer resistance (Rct) and is used to evaluate their electrochemical conductivities of different modified electrodes.39,40 In prior or the series measurements for detecting BLM, some experimental conditions, such as the used aptamer concentration and incubation time in BLM solution, were evaluated by EIS technique (Figures S7 and S8). The detailed results and discussion are supplied in S5 (See the Supporting Information). It shows that the aptamer solution with the concentration of 100 nM was chosen for fabricating the CuFe@FeFe-based aptasensor. Meanwhile, the optimal binding time of two kinds of aptasensors for detecting BLM is 30 min. As for the CuFe@FeFe-based aptasensor (Figure 2a), the bare AE exhibits a low Rct value of 0.027 kohm as expected, indicating its good electrochemical conductivity and fast electron transfer at the interface between the AE surface and the electrolyte solution.41 After the bare AE was modified with CuFe@FeFe PBA, the Rct value of the CuFe@FeFe/AE becomes slightly larger, 0.28 kohm. It hints that CuFe@FeFe PBA prevents electron from transferring at the interface between the electrode surface and electrolyte solution. When the aptamer strands were immobilized onto the CuFe@FeFe/AE, the Rct value of the Apt/CuFe@FeFe/AE substantially increases to be around 0.53 kohm. It is mainly attributed to the repulsion interaction between negative charged phosphate groups and the redox couple of [Fe(CN)6]3−/4− ions, further leading to 14


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slow electron transfer.42 When the developed aptasensor was used to determine BLM (0.01 pg·mL−1), the Rct value of BLM/Apt/CuFe@FeFe/AE continuously increases to 0.84 kohm, which is due to the formation of BLM·Fe(II) coordination can implement sequence selective DNA strand scission with aptamer strands, further resulting in the decline of electrochemical activity.15 Similarly, for the AgNCs/Apt@CuFe@FeFe-based aptasensor (Figure 2b), the Rct value of the bare AE is as low as 46.24 ohm, whereas the Rct value of the AgNCs/Apt@CuFe@FeFe/AE is slightly larger (0.175 kohm), indicating the electrochemical conductivity can be improved by adding AgNCs.43 When detecting BLM (0.01 pg·mL−1), the Rct value of BLM/AgNCs/Apt@CuFe@FeFe/AE increases to 0.67 kohm. As observed, both the modification of AgNCs/Apt@CuFe@FeFe and detection of BLM lead to the Rct increase, which is also owing to the electron transfer rate variation originated from different determination procedures.44 All of these results are consistent with those of CV measurements (Figure S9).

15



CuFe@FeFe/AE Apt/CuFe@FeFe/AE BLM/Apt/CuFe@FeFe/AE

-Z'' / kohm

0.6

0.6

0.4 0.2 0.0

1.2 0.9

0.5

1.0

1.5

Z' / kohm

0.2

Z' / kohm

0.9

1.2

1.5

1.8

Z' / kohm

1.2

0.3

1.6

0.6

(d)

bare AE FeFe PBA/AE Apt/FeFe PBA/AE BLM/Apt/FeFe PBA/AE

0.8

bare AE AgNCs/Apt@CuFe@FeFe/AE BLM/AgNCs/Apt@CuFe@FeFe/AE

0.4

(c)

0.6

0.0

(b)

0.0

2.0

Rct / kohm

-Z'' / kohm

0.8 (a)bare AE

-Z'' / kohm

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 34

2.4

3.2

Rct,material-Rct,AE Rct,Apt-Rct,material Rct,BLM-Rct,Apt

0.8 0.4 0.0

A e PB FeF

eFe e@F CuF

eFe e@F CuF @ t p Cs/A

AgN

Figure 2. EIS response for detecting BLM using (a) CuFe@FeFe-modified AE, (b) AgNCs/Apt@CuFe@FeFe-modified AE, and (c) FeFe PB-modified AE in 0.01 M PBS (pH 7.4) containing 5.0 mM [Fe(CN)6]3−/4− redox. (d) Differences in ΔRct values at each stage for detecting BLM using the above sensors. For comparison, FeFe PB nanocubes were also employed as platform for detecting BLM, of which the whole detection procedure was determined by EIS (Figure 2c). It displays that the Rct value continuously increases during the procedure for BLM detection.. Although FeFe PB also exhibits clear biosensing performance for detecting BLM, its electrochemical conductivity is poorer than that of CuFe@FeFe PBA. Consequently, the core-shell heterostructured CuFe@FeFe PBA can facilitate the electrochemical activity of the modified electrode, which can improve the detecting sensitivity. Furthermore, for comparison of detection efficiencies FeFe PB-, CuFe@FeFe-, AgNCs/Apt@CuFe@FeFe-based aptasensors, the Rct variation (ΔRct = Rct, i+1

− Rct, i) of each step were calculated and summarized in Figure 2d. The ΔRct value (Rct, 16


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material

− Rct, AE) for the modification with CuFe@FeFe PBA is 0.25 kohm, slightly higher

than that of AgNCs/Apt@CuFe@FeFe (0.13 kohm). As aforementioned, adding AgNCs can strength electrochemical activity of AgNCs/Apt@CuFe@FeFe. When these two modified AEs are used to detect BLM, the ΔRct value (Rct, Apt/CuFe@FeFe/AE

(0.32

kohm)

is

much

lower

BLM

− Rct,

than

Apt)

that

for of

AgNCs@Apt@CuFe@FeFe/AE (0.50 kohm). This is mainly because the embedment of aptamer-templated AgNCs renders the aptamer strands both adsorb onto CuFe@FeFe PBA surface and penetrate into its interior.26 It can improve the immobilization content of the aptamer strands and assists more BLM·Fe(II) ion coordination to exhibit sequence selective DNA strand scission with them, therefore leading to a larger variation of ΔRct value. As mentioned above, even the sensing performance of FeFe PB- and CuFe@FeFe-based aptasensors is similar, the FeFe PB exhibits very weak electrochemical conductivity, for which the electron transfer resistance is too high. Mechanism of CuFe@FeFe-based aptasensor for detecting BLM. In order to probe the sensing mechanism for detecting BLM, different aptasensors, including CuFe@FeFe PBA, FeFe PB, NiFe@FeFe PBA, MnFe@FeFe PBA, and CoCu PBA, were employed as bioplatforms without aptamer strand immobilization, as shown in Figure S10. It demonstrates that the substantial variations in Rct values for CuFe@FeFe-, FeFePB-, NiFe@FeFe-, and MnFe@FeFe-modified AEs when adding BLM solution, whereas no clear change was observed for the CoCu PBA-modified one. As discussed previously, BLM can coordinate with Fe(II) ions containing in FeFe-related PBA, hence leading to 17



Page 18 of 34

the Rct increase. Owning to the absence of Fe(II) ions containing in CoCu PBA, no substantial electrochemical activity change takes place, even after aptamer strand immobilization (Figure S11a). Interestingly, clear electrochemical signal was obtained for the CuCo PBA-immobilized with aptamer strands toward the mixed solution of BLM and Fe(II) ions (Figure S11b), further confirming the aforementioned sensing mechanism.45 The different variations of ΔRct values of each step for different sensing strategies are summarized in Figure S12. In order to probe how the BLM-targeted aptamer to affect the detecting efficiency, different interferents were employed to evaluate the selectivity of the CuFe@FeFe-based sensor (Figure S13) without aptamer immobilization. It shows that the caused signals by ampicillin (AMP), Ca2+, and Na+ are overt, indicating poor selectivity of the formed CuFe@FeFe-based sensor for directly detecting BLM. In consequence, the immobilization of aptamer strands over the CuFe@FeFe can enhance the sensing selectivity for BLM. From above discussion, it is clear for that other Fe-related nanomaterials also can be developed as the BLM aptasensors using this newly developed strategy, but giving poor electrochemical activity. Sensitivity

of

electrochemical

aptasensors

based

on

CuFe@FeFe

and

AgNCs@Apt@CuFe@FeFe PBA nanospheres. To investigate the dynamic range of the aptasensor and detection sensitivity toward BLM, the concentration titration measurements were performed by EIS. Figure 3a shows EIS responses of the constructed CuFe@FeFe-based aptasensor, which were exposed in different concentrations of BLM for 1 h, including 0.001, 0.01, 0.1, 1, 10, 100, 1000 and 2000 pg·mL−1. It clearly 18


Page 19 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


demonstrates that the Rct value of CuFe@FeFe-based aptasensor toward BLM increases along with increasing the BLM concentration. The sensitivity of the aptasensor was assessed by the limit of detection (LOD), which is represented by the lowest target concentration that can be detected with an acceptable accuracy.46 As illustrated in Figure 3b, the calibration plot shows a good linear relationship between ΔRct responses and the logarithmic value of BLM concentrations with the BLM concentration within the range from 1.0 fg·mL−1 to 2.0 ng·mL−1. The regression equation is ΔRct (kohm) = 0.696 + 0.213 log CBLM (pg∙mL−1), with a correlation coefficient (R2) of 0.9968. As a result, the calculation equation of the LOD is listed as: LOD = 3σ/s, where σ is the standard deviation of signal in a blank solution and s is the slope of the calibration curve. In this work, σ was obtained by computing a series of test data (Rct) at the BLM concentration of 0 (i.e., blank solution) at a signal-to-noise (s/n) ratio of 3.47 The LOD is estimated to be approximately 0.49 fg·mL−1 (0.32 fM) together with a relative standard deviation (RSD) of 3.5%. Similarly, Figure 3c shows the EIS response of the AgNCs/Apt@CuFe@FeFe-based aptasensor, which was also exposed in different BLM concentrations for 1.0 h, including 0.01, 0.1, 1.0, 10.0, 50.0 and 100 fg·mL−1. As shown in Figure 3d, within the range of BLM concentration from 0.01 fg·mL−1 to 0.1 pg·mL−1, the calibration curve shows a good linear relationship between the ΔRct responses and the logarithmic value of BLM concentrations, and the regression equation is ΔRct (kohm) = 0.624 + 0.085 log CBLM (pg∙mL−1) with R2 = 0.9988. The LOD value is estimated to be about 0.0082 fg·mL−1 19



(0.0053 fM) together with a RSD of 4.3%. It demonstrates that other aptasensors for detecting

BLM

using

strategy9,16,48,49

fluorescent

and

electrogenerated

chemiluminescence method (Table S1)50 often display low detection sensitivity, showing high LODs with nM level and pM level. Obviously, the sensing performances of the proposed CuFe@FeFe- and AgNCs/Apt@CuFe@FeFe-based aptasensors substantially outperform other aptasensors owning to their inherent chemical and crystal properties, core-shell heterostructure, and excellent electrochemical conductivity. (a)

(b) 1.6

0.3

Rct = 0.696 + 0.213 log CBLM

LOD = 0.49 fgmL

1

2

1.2 R = 0.9968

1.5

Rct / kohm

2 ngmL1

0.6

Rct / kohm

-Z'' / kohm

0.9

1.0

0.8

0.5

0.4

0.0

0.0

1

2

3

Z' / kohm

-2

0

(d) 0.6

500

0.0

1000

1.0

1.5

Z' / kohm

2.0

1500

2000

Rct = 0.623 + 0.085 log CBLM 1

Rct / kohm

0.5 R2 = 0.9988 0.4 0.3

0.5 0.4 0.3 0.2

0.2

0

0.5

Rct / kohm

1

0.1 pgmL

0.2

2

CBLM / pgmL-1

LOD = 0.0082 fgmL

0.4

0

log CBLM / pgmL-1

0.0

0 4

0.6 (c)

-Z'' / kohm

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 20 of 34

-4.5

-3.0

-1.5

log CBLM / pgmL-1

0.00

0.03

0.06

0.09

CBLM / pgmL-1

Figure 3. (a) EIS responses of the Apt/CuFe@FeFe/AE with different BLM concentrations (0.001, 0.01, 0.1, 1, 10, 100, 1000, and 2000 pg·mL−1); (b) Dependence of ΔRct on the BLM concentration based on the Apt/CuFe@FeFe/AE (Inset: the linear part of the calibration curve). (c) EIS responses of the AgNCs/Apt@CuFe@FeFe/AE with different BLM concentrations (0.01, 0.1, 1.0, 10.0, 50.0, and 100 fg·mL−1); (d) Dependence

of

ΔRct

on

the

concentration

of

BLM

based

on

AgNCs/Apt@CuFe@FeFe/AE (Inset: the linear part of the calibration curve). 20


Page 21 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Selectivity, reproducibility, and stability of the fabricated aptasensors. To evaluate the selectivity of the proposed BLM aptasensor based on CuFe@FeFe and AgNCs/Apt@CuFe@FeFe PBAs, some components possibly coexisted with BLM or other antibiotics, including prostate specific antigen (PSA), tetracycline (TC), bovine serum albumin (BSA), immunoglobulin G (IgG), streptomycin sulfate (RFP), Na+, Ca2+, AMP, oxytetracycline (OTC), tobramycin (TOB), and ochracin (OTA) were selected as possible interferents with the concentrations which are 100-folds of that of the BLM solution. According to Figure 4a1, as for the (0.01 pg·mL−1) results in a clear Rct variation, while adding other CuFe@FeFe-based aptasensor, it shows that the presence of BLM interferences (1.0 pg·mL−1) alone causes negligible signal responses. Also, it is worth noting that no remarkable change in Rct value can be observed toward the mixed solution of interferents and BLM as compared with individual BLM, which is basically ascribed to the specific interaction of the aptamer strands with BLM. Consequently, these results indicate that the developed aptasensor exhibits a satisfactory selectivity. In order to assess whether the fabricated CuFe@FeFe-based aptasensor can meet the requirement of long term testing, its reproducibility was first measured using the same five modified electrodes for EIS measurements. As shown in Figure 4a2, the caused ΔRct responses almost retain a comparable value (RSD = 4.3%, n = 3). Furthermore, the storage stability of the aptasensor was also evaluated by storing the modified electrode at 4 °C, which was continuously measured every day for 15 days. As displayed in Figure 4a3, it was found that about 94.6% of the initial value was retained after a long storage time of 15 days, 21



hinting the desirable stability of the developed aptasensor. The selectivity, reproducibility and stability of AgNCs/Apt@CuFe@FeFe were also tested in the same way. Adding other interferents causes negligible signal responses as compared with BLM (Figure 4b1). The RSD for reproducibility is 4.6% (Figure 4b2), whereas 92.2% of the initial ΔRct response was retained after a long storage time of 15 days (Figure 4b3). All results indicate that both the CuFe@FeFe- and AgNCs/Apt@CuFe@FeFe-based aptasensors exhibit high selectivity, good reproducibility, and stability. Mixtuire

0.24

0.15

0.18

0.05 0.00

1

2

3

4

Electrode numbers

(c1)

OTC

TOB OTA

+

(b2)

0.12 0.06 0.00

5

Ca AMP

Interferents

(b1) 0.20

0.10

Na

0.0

Interferents

2+

0.2 TC BSA IgG RFP

OTA

OTC

TOB

AMP

+

2+

Ca

RFP

Na

IgG

PSA

0.3

0.1

Rct / kohm

Rct / kohm

0.0

TC

0.1

BSA

0.2

0.4

PSA

0.3

BLM

Rct / kohm

0.4

(a2) 0.5

Rct / kohm

Mixture

(a1) BLM

0.5

1.00

1

2

3

4

Electrode numbers

5

(c2)

Rct / kohm

0.6

Rct / kohm

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 22 of 34

0.4 0.2 0.0

0

5

Days

10

15

0.75 0.50 0.25 0.00

0

5

Days

10

15

Figure 4. Selectivity, reproducibility, and stability of (a) CuFe@FeFe- and (b) AgNCs/Apt@CuFe@FeFe-based aptasensors. (a1, a2) Selectivity of the aptasensors by separately adding different interferents (1.0 pg∙mL−1), BLM (0.01 pg∙mL−1), and their 22


Page 23 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


mixture. (b1, b2) Reproducibility of the aptasensors for detecting BLM (0.001 pg∙mL−1). (c1, c2) Stability of the aptasensors for detecting BLM (1 pg∙mL−1) within 15 days. Real sample analysis. Owning to the comprehensive sensing performances of the CuFe@FeFe- and AgNCs/Apt@CuFe@FeFe-based aptasensors, the advantages endow them with potential applications in the identification of BLM in real systems. To evaluate practical applications of the fabricated aptasensors, we performed recovery experiments using the standard addition method. After different concentrations of BLM were spiked into 500-diluted pre-treated human serum, river water, and milk samples. These analyte solutions were determined using the as-proposed two kinds of BLM aptasensors. According to the calibration curve derived from the linear curve of the inset in Figures 3b and 3d, the calculated concentrations of these samples were displayed in Tables S2 and S3, respectively. It was found that the recovery changed within the range of 95.1%~104.9% together with a RSD between 1.7% and 5.1% for CuFe@FeFe-based aptasensor, as well as recovery of 95.2%~108.2% and RSD of 1.5%~4.7% for AgNCs/Apt@CuFe@FeFe-based

aptasensor,

respectively.

It

suggests

that

two

constructed aptasensors are quite suitable for monitoring BLM in real samples.

CONCLUSION In summary, two novel kinds of electrochemical aptasensors based on bimetallic core-shell heterostructured CuFe@FeFe and AgNCs/Apt@CuFe@FeFe PBAs were developed for ultra-sensitively detecting BLM. Taking FeFe PB as core, the AgNCs/Apt@CuFe@FeFe PBA was prepared by combining AgNCs/Apt with 23



Page 24 of 34

CuFe@FeFe PBA, for which the AgNCs was obtained via a one-step bio-inspired approach. Owning to abundant Fe(II) ions containing in these samples, both CuFe@FeFe adsorbed with BLM-targeted aptamer and AgNCs/Apt@CuFe@FeFe PBBAs exhibited highly sensitive and selective sensing performances toward BLM owning to the formation of Fe(II)·BLM complex. As compared with the CuFe@FeFe-based aptasensor, the AgNCs/Apt@CuFe@FeFe aptasensor displays much lower LOD toward BLM (0. 0.0082 fg·mL−1). Two kinds of aptasensors also exhibited good reproducibility, stability, and acceptable applicability, revealing its potential in food safety monitoring. Nevertheless, the preparation procedure of bimetallic CuFe@FeFe PBA includes multisteps, leading to the complexity of the aptasensor fabrication. Further investigation will be focus on how to simplify these kinds of nanomaterial synthesis procedures and broaden application ranges of PBA in biosensing and biomedical fileds.

ASSOCIATED CONTENT Supporting Information Experimental

section;

Electrochemical

Chemical

performances

for

structure

and

CuFe@FeFe

components and

of

two

samples;

AgNCs/Apt@CuFe@FeFe

nanospheres; Directly electrochemical biosensing of different PBAs toward BLM; Comparison of different sensors toward BLM; Sensitivity of the CuFe@FeFe-based sensor for directly detecting BLM; Real samples.

AUTHOR INFORMATION Corresponding Authors 24


Page 25 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


*E-mail: [email protected] (Nan Zhou); [email protected] (Zhihong Zhang); [email protected] (Siyu Lu) ORCID Zhihong Zhang: 0000-0002-5888-4107 Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes The authors declare no competing financial interest.

ACKNOWLEDGEMENTS This work was supported by Programs for the National Natural Science Foundation of China (NSFC: Account Nos. 81601082, 81371363, U1604127), and Innovative Technology Team of Henan Province (CXTD2014042).

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Core-shell heterostructured CuFe@FeFe Prussian blue analogue

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