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Probing Mannose-Binding-Proteins that Express on Live Cells and Pathogens with a Diffusion-to-Surface Ratiometric Graphene Electrosensor Donghao Xie, Xueqing Feng, Xi-Le Hu, Lin Liu, Zhihong Ye, Jun Cao, Guo-Rong Chen, Xiao-Peng He, and Yi-Tao Long ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.6b08566 • Publication Date (Web): 02 Sep 2016 Downloaded from http://pubs.acs.org on September 6, 2016
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Probing Mannose-Binding-Proteins that Express on Live Cells and Pathogens with a Diffusion-to-Surface Ratiometric Graphene Electrosensor Donghao Xie,a1 Xue-Qing Feng,b1 Xi-Le Hu,b Lin Liu,a Zhihong Ye,a Jun Cao,a* Guo-Rong Chen,b* Xiao-Peng He,b* and Yi-Tao Longb a
Department of Pharmacy & Department of Interventional Oncology, Dahua Hospital, Xuhui District, Shanghai, 200237, PR China b
Key Laboratory for Advanced Materials & Institute of Fine Chemicals, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237, PR China 1
Equal contribution
ABSTRACT: This paper describes the development of a “diffusion-to-surface” ratiometric graphene electrosensor for the selective detection of live cells and pathogens that highly express mannose binding proteins (MBPs). MBPs have been implicated in many pathological processes, and are identified on specific types of bacteria. As a consequence, MBPs are a promising biomarker for targeted disease diagnosis and therapy. Here we develop a unique electrosensor that features a ratiometric voltammetric signal for the selective probing of MBPs. Self-assembly of mannosyl anthraquinone (AQ) to a graphene oxide-decorated screen printed electrode produces the sensor with an inherent surface-controlled voltammetric signal. Subsequently, addition of a redox-probe (RP) imparts the system with a diffusion-controlled current, thus enabling a ratiometric sensing rationale for which AQ serves as a reference. While the reference current is hardly compromised by adding analytes, RP exhibits a concentration-dependent current quenching on addition of mannose-selective lectins over other proteins. Importantly, this ratiometric electrosensor has proven to be applicable for the ratiometric probing of alternatively activated macrophages and a gram-negative bacterium highly expressing MBPs, but shows minimal response to a series of control live cells and bacteria without MR expression. KEYWORDS: Graphene, Anthraquinone, Electrochemistry, Cell, Bacteria, Sensor
Introduction Biological recognitions between ligands and proteins are important physiological interactions that control a number of cellular processes. The fact that these recognitions have also been implicated in a range of pathological actions including cancer metastasis, inflammation, virus invasion and bacteria adhesion makes ligand-binding proteins ideal biomarkers for disease diagnosis.1-6 For example, the mannose receptor (MR) is a C-type lectin existing on the surface of macrophages and dendritic cells. Whereas the classically activated (M1) macrophage is required for the clearance of foreign organisms, the alternatively activated (M2) macrophage, which overexpresses MR, can facilitate tumorigenesis and cancer metastasis.7 Another mannose-binding protein (MBP), the FimH (a mannose-specific adhesin) has been identified on Escherichia coli (E. coli), which is among the most infectious pathogens that cause severe urinary tract infections through binding to mannosylated proteins of bladder
cells.8-10 As a consequence, MR is a promising biomarker for disease diagnosis and therapy. However, conventional techniques for the detection of protein-ligand interactions have drawbacks in terms of high technical requirement, laborious analytical procedures and the consumption of expensive biochemical reagents (such as antibodies). In particular, these techniques need the lysis of live cells and pathogens to obtain the proteins of interest. The lysis may increase the complexity accompanied with the techniques and compromise the structural and functional integrities of the proteins. As a result, the development of advanced and simple approaches for the probing of transmembrane receptors on live cells and pathogens still remains challenging. Electrochemistry is a sensitive technique that is easy to manipulate and that uses portable analytical facilities (e.g. a portable electrochemical workstation in connection with a personal laptop). It has been widely employed in the development of economic and on-demand sensors for disease diagnosis.11 In general, the functionalization of
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electrode surfaces simply involves deposition of a ligand molecule, followed by the addition of a solution-based redox probe as signal reporter. When the ligand molecule captures an analyte of interest, the redox activity of the probe is weakened, leading to a signal variation. As a consequence, no analyte-tagging is needed (label-free), largely reducing the complexity associated with the sensor preparation and manipulation. a
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standardization23,24 and the production of the ratiometric signal with a diffusion-controlled redox probe (RP), [Fe(CN)6]3-/4-. This electrosensor has proven amenable to probing a mannose-selective lectin and M2 macrophage and E. coli expressing MBPs, selectively, over other control cells without MBP expression.
Results and discussion Three mannosyl anthraquinones (Man-AQs) with linker of different lengths that couple Man with AQ were synthesized by a click reaction (1-3, Fig. 1 and Scheme S1). The mannose ligand can selectively bind to MBPs, and the AQ may 1) facilitate the binding of the Man-AQs to the GO-coated working electrode of a screen-printed electrode (SPE) and 2) act as a surface-controlled reference signal. In addition, the solution-diffused RP was used to detect the recognition between the surface-immobilized Man and a Man-selective lectin (concanavalin A – Con A) and live cells and pathogens that express MBPs. The adhesion of the bioanalytes to the Man-confined electrode surface diminishes the diffusion-based electron transfer of RP, leading to a quenched RP signal. In contrast, the AQ reference signal is not compromised by adding analyte, thus enabling the ratiometric sensing.
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Here we show that a mannosyl anthraquinone (AQ) molecule, when immobilized on graphene oxide (GO) coated electrode through self-assembly, can be used to produce a unique diffusion-to-surface ratiometric sensor for MBPs (Fig. 1). We determined that AQ could serve as a surface-controlled current reference for both electrode
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Traditional surface-functionalization approaches rely on the pre-derivatization of electrodes, followed by covalent coupling of ligand molecules to the derivatized surface. To simplify the procedures, self-assembly methods have been developed, which mainly focus on the alkenethiol-gold self-assembly12-16 and low-dimensional carbon material-based immobilization of probe molecules.1724 Considering the potentially lower cost and the unique optoelectronic properties of low-dimensional carbon materials, the use of carbon nanotube and graphene as working electrodes has been of increasing interest in recent years. However, the production and sensing performance of these functionalized electrodes can hardly be qualitycontrolled because of the lack of a signal reference on the electrode surface, leading to difficulty towards commercialization.
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Figure 1. (a) Structures of the mannosyl anthraquinones (Man-AQs) 1-3 and (b) cartoon depicting the use of AQs as a reference for the diffusion-to-surface ratiometric sensing of live cells and pathogens that express the mannose receptor by a graphene oxide (GO) coated screen printed electrode (RP = redox probe).
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Figure 2. (a) Transmission electron microscopic (TEM) images (scale bar = 400 nm) of graphene oxide (GO) used for electrode coating (Fields 1-3 show three independent fields of TEM). (b) Dynamic light scattering of Man-AQ (1) (1 μM), GO (2 mg mL-1) and the composite of 1 and GO (1 μM/2 mg mL-1). (c) Raman spectroscopy of Man-AQ (1) (1 μM), GO (2 mg mL-1) and the composite of 1 and GO (1 μM/2 mg mL-1).
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Figure 3. Cyclic voltammetry of (a) redox probe (RP) ([Fe(CN)6]3/[Fe(CN)6]4-, 5 mM) and (c) 1 (Man-AQ) immobilized graphene electrode. Plotting the peak currents of (b) RP and (d) Man-AQ (1) as a function of scan rate. All first scans were initiated in the positive direction from -0.2 V and -1.0 for RP and AQ, respectively.
The electrosensor was constructed by a sequential coating of GO and then the Man-AQs to the working electrode of our previously developed SPE.21-24 To test the electroactivity of the sensor, we first measured the redox properties of both the solution-diffusing RP and surfacecontrolled AQ (Fig. 3). Cyclic voltammetry (CV) used to record the redox processes produced the typical anthraquinone/anthra(hydro)quinone peaks at -0.6/-0.77 V (Fig. 3c), and those of [Fe(CN)6]3-/[Fe(CN)6]4- at 0.17/0.08 V (Fig. 3a). In the meanwhile, by increasing the scan rate from 0 to 160 mV, the anodic and cathodic peak currents of AQ (Fig. 3d) and RP (Fig. 3b) scaled linearly with the scan rate and the square root of scan rate, respectively.
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Figure 4. Differential pulse voltammetry of electrodes confined with (a) Man-AQ 1, (b) Man-AQ 2 and (c) Man-AQ 3 in the presence of redox probe (RP) ([Fe(CN)6]3-/[Fe(CN)6]4-, 5 mM) with or with Con A (25 μM).
With the electrosensor constructed, we then measured the current change of AQ and RP in the presence of Con A with electrodes coated by the Man-AQs of different linker lengths (1-3). Shown in Fig. 4 is the differential pulse voltammetry (DPV) of the electrosensors coated with different Man-AQs. We observed that the RP signal of all the electrodes quenched with Con A. This could be a result of the adhesion of lectin to the mannosyl layer on the electrode, compromising the electron transfer of RP.23,24 However, the AQ reference signal of the 2-coated (Fig. 4b) and 3-coated (Fig. 4c) electrodes also decreased with Con A, suggesting their instability in the presence of the lectin. The compromised AQ signal could be a result of the formation of lectin-Man-AQ complexes, thereby leading to a detachment of the ligands from the electrode surface. In contrast, Man-AQ 1 with the longest linker did not show any AQ signal quenching (Fig. 4a), but the largest RP quenching, implying that proper adjustment of the distance between AQ and Man ligand is important for achieving an optimal sensing efficiency. Notably, these pieces of data also suggest that the presence of AQ imparts the electrode system with an intrinsic current signal to control the quality of the electrosensor.
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GO produced by the modified Hummer’s method was characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS) and Raman spectroscopy (Fig. 2). Objects observed in the TEM images shown in Fig. 2a appeared to be thin flakes, which are characteristic of graphene sheets. We also observed that the mixing of Man-AQ 1 with GO evidently increased the particle size of the latter (Fig. 2b), suggesting the coating of the compound onto the material surface, probably by πstacking.21-26 In addition, the increased ID/IG (intensity of D/G band) ratio of the Man-AQ/GO composite (0.89) with respect to GO alone (0.84) probably suggests an increased disorder in carbon sp2-hybridization of the material (Fig. 2c). These results suggest that the Man-AQ molecules can attach to GO surface, making possible the construction of the GO electrosensor.
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Figure 5. (a) Differential pulse voltammetry of RP ([Fe(CN)6]3/[Fe(CN)6]4-, 5 mM) using Man-AQ 1 (normalized current intensity) as a reference in the presence of increasing Con A (0-20 μM). (b) Plotting electrode sensitivity as a function of Con A concentration
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(where IAQ and IRP are the current intensity of AQ and RP in the presence and absence of Con A, respectively). (c) Ratiometric current intensity change of RP in the presence of different proteins (Con A = concanavalin A; PNA = peanut agglutinin; BSA = bovine serum albumin; Pep = pepsin; SBA = soybean agglutinin).
Next, we tested the current variation of RP in the presence of selective and unselective proteins using the normalized Man-AQ 1 current as a reference. As shown in Fig. 5a, with increasing Con A, the current intensity of RP gradually dropped and that of AQ reference remained consistently unchanged. The current quenching of RP could also be described by the ratio of IRP to IAQ, with good linearity over an increasing range of Con A concentration (Fig. 5b). Subsequently, with this ratiometric rationale we determined that the ratio of the two redox species did not changed in the presence of a panel of unselective proteins including galactose-selective peanut agglutinin (PNA), N-acetyl galactosamine-selective soybean agglutinin (SBA), bovine serum albumin (BSA) and pepsin (Fig. 5c). This suggests the good selectivity of the ratiometric electrosensor system established.
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were used. M2 macrophage that expresses the mannose receptor by an activation of RAW264.7 (a mouse macrophage cell line) with interleukin-4 (Fig. 6),22 and a gramnegative E. coli strain, MG1655, which highly expresses MBP8-10 were employed to interact with the sensor (Fig. 6). The RAW264.7 cell line and Top10 E. coli strain9 without expression of MBPs were used as control. We observed a concentration-dependent current drop of RP in the presence of both M2 (Fig. 6a) and MG1655 (Fig. 6d) with good linearity over an increasing cell concentration range (Fig. 6b for MG1655 and Fig. 6e for M2). In contrast, the presence of control samples including live cells (RAW264.7, Hep-G2 [human hepatoma cell line] and HeLa [human cervical cell line]) (Fig. 6c) and pathogens (Top10, KPN4347 and ATCC13883 [K. pneumonia]) (Fig. 6f) hardly caused the RP signal to vary, suggesting the good biospecificity of the system for recognition of live cell and pathogen expressing a specific MBP. Importantly, the AQ reference signal remained unchanged with all the analytes, suggesting its suitability as a reference for the ratiometric analysis of live cells in complex biological samples. A survey of very recent literature unveils a continuing activity in developing electrosensors based on sugarprotein interactions, providing elegant tools for clinical diagnosis.27-33 However, electrosensors that achieve ratiometric sensing of receptor proteins at the cellular level have been elusive, despite the advancement of dualelectro-signal DNA sensors.15,34,35 The merit of the ratiometric sensing rationale as developed in this study lies in the capacity in surface-quality-control (because of the presence of a surface-immobilized reference signal) and producing the signal ratio to potentially improve the accuracy of analyses.
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Figure 6. Differential pulse voltammetry of RP ([Fe(CN)6]3/[Fe(CN)6]4-, 5 mM) using Man-AQ 1 (normalized current intensity) as a reference in the presence of (a) increasing M2 cells (alternatively activated macrophage with mannose binding protein) (0-5×105 cells mL-1) and (d) increasing MG1655 (E. coli with mannose binding protein) (0-108 CFU mL-1). Plotting the ratiometric current change of RP as a function of (b) increasing M2 cells and (e) increasing MG1655. Current intensity change of RP in the presence of (c) different cells (RAW264.7: mouse macrophage cell line; Hep-G2: human hepatoma cell line; HeLa: human cervical cell line) and (f) different pathogens (Top10: E. coli without MBP; KPN4347: K. pneumonia; ATCC13883: K. pneumonia).
To probe the biospecificity of the electrode system with more complex biological samples, live cells and pathogens
To conclude, we have developed a surface-to-diffusion ratiometric electrosensor for probing mannose-selective lectins and live cells and pathogens that express MBPs. Anthraquinone, while conjugated with a ligand molecule, has proven to be suitable as a signal reference for both the quality control of electrosensor and production of the ratiometric signal. With this research we envision that similar types of ratiometric electrosensors could be easily constructed by coupling a diverse range of other ligand molecules (such as peptides, nucleotides and other smallmolecular natural products) to AQ or other aromatic electroactive compounds for the self-assembly with graphenecoated electrodes.
ASSOCIATED CONTENT Supporting Information. Experimental section and compound synthesis and characterization. This material is available free of charge via the Internet at http://pubs.acs.org.
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Corresponding Author *Email:
[email protected] (J. Cao)
[email protected] (G.-R. Chen)
[email protected] (X.-P. He)
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ACKNOWLEDGMENT This research is supported by the 973 project (2013CB733700), the National Natural Science Foundation of China (21572058 and 21576088), the Shanghai Health and Family Planning Commission Research Fund (201540158) and the Shanghai Rising-Star Program (16QA1401400). Prof. Jia Li and Prof. Yi Zang are warmly thanked for their help in cellular experiments. Prof. Daijie Chen is warmly thanked for his help in bacteria detection.
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TOC only RP = Redox Probe AQ = Anthraquinone
Live cells/ Pathogens Screen Printed Electrode RP: Active
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AQ: Active
Screen Printed Electrode RP: Inactive /
AQ: Active
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