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Mar 6, 2017 - Key Laboratory of Coastal Environmental Processes and Ecological Remediation, Yantai Institute of Coastal Zone Research (YIC),. Chinese ...
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An Optical Ion Sensing Platform Based on Potential-Modulated Release of Enzyme Jiawang Ding, Enguang Lv, Liyan Zhu, and Wei Qin Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.7b00072 • Publication Date (Web): 06 Mar 2017 Downloaded from http://pubs.acs.org on March 6, 2017

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Analytical Chemistry

An Optical Ion Sensing Platform Based on Potential-Modulated Release of Enzyme Jiawang Ding, Enguang Lv, Liyan Zhu, and Wei Qin* Key Laboratory of Coastal Environmental Processes and Ecological Remediation, Yantai Institute of Coastal Zone Research (YIC), Chinese Academy of Sciences (CAS); Shandong Provincial Key Laboratory of Coastal Environmental Processes, YICCAS, Yantai, Shandong 264003, P. R. China.*E-mail: [email protected]. Fax: +86535 2109000. ABSTRACT: We report here on an optical ion sensing platform, in which a polymeric membrane ion-selective electrode (ISE) serves as not only a potentiometric transducer for ion activities in the sample solution but also a reference electrode for the potential-modulated release of enzyme from an iron-alginate-horseradish peroxidase (HRP) thin film modified working electrode. The ISE and working electrode are physically separated by a salt bridge. The dissolution of the HRP-embedded thin film can be triggered by the reduction of Fe3+, which is modulated by the potential response of the ISE to the target ion in the sample. The released enzyme induces the oxidation of its substrate mediated by H2O2 to produce a visual color change. With this setup, an optical ion sensing platform for both cations (e.g., NH4+) and anions (e.g.,Cl-) can be obtained. The proposed platform provides a general and versatile visual-sensing strategy for ions and allows optical ion sensing in colored and turbid solutions.

With the introduction of new materials and novel sensing concepts, potentiometry based on polymeric membrane ionselective electrodes (ISEs) has been extensively used to develop highly sensitive and selective ion sensing and biosensing platforms.1-5 Typically, zero-current potentials are measured in these ion-sensing platforms.6 Alternatively, ion-selective membranes can be interrogated by dynamic electrochemistry techniques.7 Indeed, new ion-selective readout strategies based on current-dependent potentials,8-10 charges of transient current pulse,11 coulometric charges,12 voltammetric currents13,14 and transition times15 have been proposed for ion sensing. Besides the electrochemical methods, Bakker’s group developed a generic approach to provide an electrogenerated chemiluminescence (ECL) readout for potentiometric ion sensors.16,17 The proposed approach makes use of potentials generated at the interface of the ion-selective membrane to modulate the ECL signals. In a similar way, Wang’s group developed a portable, visual ion sensing platform based on the light emitting diode (LED).18 The coaxial potential signal of the selfreferencing ion selective field-effect transistor related to the sample concentration can be amplified to drive a LED for signal amplification. These promising systems enable the optical detection of various ions with high sensitivity and selectivity. However, the main barriers are expensive instruments and/or complicated operating steps. Therefore, a generic, convenient and integrated optical ion sensing platform based on modulation of membrane potentials of ISEs needs to be further explored. One of the significant advantages of stimulus-responsive materials is that an appropriate stimulus allows fine-tuning its function.19 Versatile substance-releasing systems activated by biochemical signals in bioelectronic systems have been extensively studied and designed for drug delivery, diagnostic vehicles, sensory systems and logic operations.20-23 In these methods, the producing reductive potentials/currents on one electrode can activate release of substances on the second electrode. Polymeric membrane ISEs doped with appropriate ionexchangers and/or ionophores exhibit rapid and reproducible potential responses toward target ions with high sensitivity. Moreover, ISEs provide information on ion activities and the measurements are independent on sample volumes.2,6 It is ex-

pected that the ion-induced potential change can be adopted as a stimulus.16 The combination of ISEs and potential-responsive materials could allow one to develop a generic and convenient potentiometric sensing platform with optical readouts. Unlike the previous researches based on biomolecular signal induced potentials/currents,23 a fixed potential difference is applied in between the working electrode and an ISE used as reference electrode, and the potential of the working electrode can be modulated by the potential response of the ISE. Sensing platforms based on the colorimetric assays have become important analytical tools. Among them, assays based on the specific reaction between a certain enzyme and the corresponding substrate and chromogenic agents to generate a color change have been studied extensively for different applications.24,25 A unique feature of the assays is the direct visualization of the target information with the naked eye at room temperature, which makes it more convenient than other methods that rely on instrumentation. Herein, we design a simple but effective strategy for the direct readout of ion activities with the naked eye. An enzyme-releasing system activated by an electrochemically applied potential is designed to light up colorimetric sensing, in which an exogenous stimulus related to the ion activities in the sample solution controls the release of the enzyme. The platform allows optical ion sensing in colored and turbid solutions. To demonstrate the proof of concept, an electrochemical setup with the sample and detection chambers was designed. As illustrated in Figure 1, a working electrode is modified with an iron-alginate-horseradish peroxidase (HRP) thin film and applied for potential-modulated release of enzyme. A polymeric membrane ISE serves as not only a potentiometric transducer for ion activities in the sample but also a reference electrode for the sensing platform. A fixed potential difference was applied in between the working and reference electrodes. The potential at the working electrode could be modulated by the potential response of the polymeric membrane ISE to the target ion in the sample solution, which leads to a change in the amount of the released enzyme and subsequently a color change of the chromogenic reaction catalyzed by HRP in the presence of H2O2 and 2,2’-azino-bis(3-ethylbenzothiozoline-6sulfonic acid (ABTS). It should be noted that by taking ad-

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vantage of the versatility of embedded molecules in potentialresponsive materials, the sensing strategy could also be configured for a broad range of optical assays.

EXPERIMENTAL SECTION Materials and Chemicals. The ammonium ionophore (nonactin), high molecular weight poly(vinyl chloride) (PVC), 2nitrophenyloctyl ether (o-NPOE), potassium tetrakis(4chlorophenyl)borate (KTClPB), tridodecylmethylammonium chloride (TDMACl), ABTS, poly(3-octylthiophene-2,5-diyl) (POT, regioregular), and horseradish peroxidase (lyophilized power, 200 unit mg-1 solid) were purchased from SigmaAldrich (St. Louis, MO, USA). More materials and chemicals are available in the supporting information. Ion-selective Electrode Preparation. The ammoniumsensitive membrane contained 1.0 wt% nonactin, 0.3 wt% KTClPB, 32.9 wt% PVC and 65.8 wt% o-NPOE.26 The ionselective membrane for chloride contained 34% PVC, 51% oNPOE and 15% TDMACl.27,28 It should be noted that the selectivity of the membrane can be further improved with the introduction of new ionophores.29 100 mg of the membrane components was dissolved in 1.0 mL of THF. Polished and well-rinsed glass carbon (GC) disk electrodes with an area of 0.07 cm2 were used as conducting substrates for solid-contact ISEs. POT was applied on the electrode by drop-casting 10 µL of a 50 mg/mL POT solution in CHCl3. After the POT film was dry, a piece of PVC tube was put on the tip. Finally, 100 µL of membrane cocktail was cast on the top of the electrode, and dried for 1 h at room temperature. The electrodes for NH4+ and Cl- were conditioned in 10−3 M NH4Cl and 10-3 M NaCl for 1 day, respectively. When not used, the electrodes were placed in the conditioning solutions. Preparation of the HRP-Loaded Alginate Thin Film. A clean GC electrode was immersed in a 3.0 mL 0.1 M Na2SO4 solution containing 2.0% w/w sodium alginate, FeSO4 (35 mM), and 2.0 U HRP. The electrodeposition procedures were used as described as before with some modifications.22 Briefly, a potentiostatic potential (+1.1 V versus Ag/AgCl (3.0 M KCl) ) was applied on the electrode to oxidize Fe2+ ions, resulting in the formation of Fe3+ and yielding the alginate crosslinking on the electrode surface. The solution was degassed by argon purging prior to the electrodeposition. The electrodeposition was performed for 600 s and then the modified electrodes were rinsed with water and soaked at room temperature in 0.1 M Na2SO4 solution for 45 min before use. Electrochemically Controlled Release of HRP and Optical Detection. HRP and iron ions entrapped in the alginate thin film were electrochemically released in 0.1 M Na2SO4 solution upon application of a reductive potential of −1.0 V to the working electrode for 3 min. 4.0 mM ABTS and 2.5 mM H2O2 were then added to the solution, which is not only for optical sensing but also for avoiding the decomposition of the alginate film by H2O2. After 3 min incubation at room temperature for the ABTS oxidation by H2O2 in the presence of HRP, the visible absorption spectra of the reaction product ABTS-• were measured with a Beckman Model DU-800 UV spectrophotometer. All the samples were diluted with 20 fold for absorbance measurements. Experimental Setup. All the measurements were carried out in 0.1 M Na2SO4 solution at 25 ± 2°C using a conventional three-electrode system with a modified glass carbon working electrode, a platinum electrode as auxiliary electrode and an

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ISE as reference electrode. Experiments were performed on a CHI 760C electrochemical workstation (Shanghai Chenhua Apparatus Corporation, China). The ISE is in contact with the sample solution and physically separated from the detection chamber by a salt bridge. A PVC tube filled with 0.1 M LiOAC was sealed with porous PVC and used as a salt bridge.

RESULTS AND DISCUSSION In this work, an alginate thin film modified electrode was produced as an output for colorimetric assays. A biocompatible hybrid material composed of iron-ion-crosslinked alginate (FeAlg) with embedded HRP was selected for the potential-triggered enzyme release. The biocomposite was electrodeposited on the working electrode. The processes of the thin-film formation and dissolution can be controlled by changing the oxidation state of the iron ions.22,30 In addition, the embedded enzyme in the alginate gel can retain their full biological activities. The photograph shows that the electrochemical oxidation of Fe2+ in the presence of soluble alginate can lead to the formation of gel (see Figure S1 in the supporting information). Moreover, a film with thickness of ca 1.0 µM could be obtaied.22

Figure 1. Schematic illustration of the optical ion sensing platform based on potential-modulated release of enzyme. The ISE is in contact with the sample solution and physically separated from the detection chamber by a salt bridge. Figure 2 shows the voltammograms of the thin film made with FeAlg. A redox process associated with the reduction/oxidation of iron ions which serve as the cross-linkers in the alginate thin-film can be observed (Figure 2A). Moreover, both cathodic and anodic peak currents from the electrode scale linearly with the scan rate. However, the peak-to-peak separation values (Figure 2A), are much larger than they might be expected for the surface-confined electrochemistry process, which is probably due to the repulsion interactions between Fe3+ species and the bulk reactions of the Fe3+ species in the film.22 In these cases, longer times and higher over-potentials are necessary to facilitate the electron transfer processes across the film. In the presence of HRP, the alginate film can physically entrap HRP during the electrochemical deposition process. Moreover, both negatively and positively charged proteins can be entrapped in the negatively charged alginate gel for controlled release.22 In order to minimize the spontaneous leakage of HRP from the polymer film, the release of HRP was investigated. Experiments showed that no obvious leakage of HRP was observed after soaking the HRP-loaded alginate thin film in 0.1 M Na2SO4 for 45 min (see Figure S2 in the supporting information).

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Figure 2. (A) Cyclic voltammograms obtained with the FeAlg-modified glass carbon electrode in 0.1 M Na2SO4 aqueous solution at different scan rates: (a) 5, (b) 10, (c) 20, (d) 50, and (e) 100 mV/s. (B) Relationship between scan rate and cathodic or anodic peak current. A fixed potential difference was applied in between the working and reference electrodes. The potential at the working electrode can be modulated by the potential change at the indicator electrode. To explore the potential-modulated system for optical ion sensing, a solid-contact ammonium-sensitive electrode was prepared and used as a model.26 As shown in Figure 3A, the sensor with the classical PVC membrane demonstrates a near-Nernstian response of -57.1 mV/decade for NH4+ with a detection limit of 5.0 × 10-6 M. Since the ISE in the sample solution is served as the reference electrode, the slope is negative and the sign of the potential is in the reverse direction. Therefore, by using the ISE as the reference electrode, the potential at the working electrode can be modulated. Under zero current conditions, the potential of GC/FeAlg electrode is probably dependent on the negatively charged alginate in the film and 0.1 M Na2SO4 as supporting electrolyte in the solution. As illustrated in Figure 3B, the redox potentials associated with the reduction/oxidation of iron ions shift to negative values with increase in the concentration of NH4+ in the sample solution. It should be noted that the potential change can also be used as a signal.

Figure 3. (A) Potential response trace of the working electrode obtained as of the logarithmic NH4+ concentration in the sample solution. (B) Observed potential shift as a function of (a) 1.0 × 10-1 M, (b) 1.0 × 10-3 M and (c) 1.0 × 10-5 M NH4+. The NH4+-ISE was used as a reference electrode. To evaluate whether the working electrode has the ability to release HRP in a potential-responsive manner, we measured the release profile of HRP by monitoring the UV-vis absorbance values of the solutions in the detection chamber at different reduction potentials. ABTS can be oxidized rapidly by H2O2 in the presence of HRP, resulting in an increase in absorbance at 418 nm.31 Therefore, ABTS was selected as the substrate for optical sensing. It should be noted that the noncontrolled leakage of HRP from the alginate matrix is negligible comparing to the target ion-stimulated release. According to the amount of the released enzyme and that of HRP entrapped, the percentage of the HRP release upon applications of various potentials can be calculated. As shown in Figure S3A, the HRP release is indeed potential dependent. The Fe3+ ions can be reduced more effectively at more negative poten-

tials, and the released amounts of HRP increase largely at potentials more negative than -0.8 V. Since the reductive potential is modulated by the magnitude of the membrane potential of the ISE, it needs to be optimized for any sensor under consideration.17 In this experiment, -1.0 V was selected for further experiments. The effect of dissolution time on the HRP release was also investigated. As shown in Figure S3B, an increase in the electrochemical release of HRP is observed with increasing the dissolution time. The release percentage tends to be constant after 3 min. Therefore, 3 min was selected as dissolution time for further experiments. It should be noted that the statistical modeling technique can be employed for multiparameter optimization of the film formation and decomposition.22 Under the optimized conditions, we demonstrated direct visual detection of the NH4+ concentration. An external voltage of -1.0 V led to the reduction of Fe3+ and release of HRP. This release of HRP was then accompanied by color change (Figure 4A). Experiments revealthat the absorbance decreases with increasing the NH4+concentration (Figure 4B). Importantly, the sensing system can be used for the visual detection of ions. The digital photograph shows that the colors of the test solutions change from green to colorless with increasing the NH4+ concentration in the sample (Figure 4C). The color change induced by 100 µM NH4+ can be readily observed with the naked eye. This system is well designed to identify the NH4+ concentrations above 10 µM. To demonstrate the genericity of the platform, direct visual sensing of Cl- was also investigated. Increasing the activities of Cl- leads to lower potentials at the ISE. Thus, the redox potentials associated with the reduction/oxidation of iron ions shift to positive values with increasing the Cl- concentration in the sample solution. In this case, iron ions can be more easily reduced when applying a fixed potential for higher concentrations of Cl-. Indeed, the solution colors changed from colorless to green with increasing the sample Cl- concentration (Figure S4). The color change induced by 100 µM Cl- could also be readily observed by the naked eye. The high diversity, excellent selectivity and good robustness of polymeric membrane ISEs make the sensing system ideal platform for optical ion detection. In summary, the present study demonstrates that an ionselective electrode can serve as not only a potentiometric transducer for ion activities in the sample solution but also a reference electrode for the sensing platform. Since different molecules can be entrapped in the proposed potentialresponsive materials, the system could also be applied to other optical assays, such as assays based on stimulus-responsive assembly or disassembly of nanoparticles or pH changes.32-34 This unique sensing strategy allows optical sensing in colored or turbid solutions and can be easily extended to other ions or molecules by simply integrating the corresponding ion selective electrodes. Compared to optical ion sensors based on ion selective bulk optodes or nano-optodes which measure not activities per se, but ratios or multiples of ion activities, the proposed method allows optical sensing of ion activities directly.35-37 Notably, although the finally measured signal is optical, the extra-thermodynamic assumptions, and the practical measures (e.g., salt bridge) used to assess the single ion activity are the same as in electrochemistry. On the other hand, compared to the ordinary ISEs, the present sensing strategy based on the ion-modulated controlled release of enzymes

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could increase the detection sensitivities due to the enzyme amplification effect. Moreover, the proposed platform is versatile and may find applications in sensing and actuating systems such as ion-modulated controlled drug release applications.20,23

Figure 4. (A) UV-vis spectra of the sensing system to (a) pure buffer, (b) 0, (c) 10-1 M, (d) 10-2 M, (e) 10-3 M and (f) 10-4 M NH4+. (B) Colorimetric responses of the sensing system to different concentrations of NH4+. (C) Photograph of the colorimetric responses to NH4+ at different concentrations: (-1), 101 M; (-2,) 10-2 M, (-3), 10-3 M; (-4), 10-4 M. HRP entrapped in the alginate thin-film was electrochemically released in 3.0 mL Na2SO4 solution. A reductive potential of -1.0 V was applied between the working and reference electrodes for 3 min. 4.0 mM ABTS and 2.5 mM H2O2 was added to the solution, which was used for visual sensing.

ASSOCIATED CONTENT Supporting Information Additional information about the photograph of the alginate gel formation, leakage of HRP from the film, effects of reductive potential and dissolution time on the release of HRP and the photograph of the colorimetric response to Cl-. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author *Telephone: +86 535 2109156. Fax: +86535 2109000. E-mail: [email protected].

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT This work was financially supported by the National Natural Science Foundation of China (21575158, 21475148), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA11020702), the Youth Innovation Promotion Association of CAS (2013139), and the Taishan Scholar Program of Shandong Province.

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