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Synthesis of Water-Dispersible Molecularly Imprinted Electroactive Nanoparticles for the Sensitive and Selective Paracetamol Detection Jing Luo,* Qiang Ma, Wei Wei, Ye Zhu, Ren Liu, and Xiaoya Liu* The Key Laboratory of Food Colloids, Biotechnology, Ministry of Education, School of Chemical, Material Engineering, Jiangnan University, Wuxi, Jiangsu, China 214122 S Supporting Information *

ABSTRACT: A novel kind of water-dispersible molecularly imprinted electroactive nanoparticles was prepared combining macromolecular self-assembly with molecularly imprinting technique employing paracetamol (PCM) as template molecule. An amphiphilic electroactive copolymer (P(NVC-EHAAA), PNEA) containing carbazole group was first synthesized through a one-pot free radical copolymerization. The coassembly of the electroactive copolymers with the template molecules (PCM) in aqueous solution generated nanoparticles embedded with PCM, leading to the formation of molecularly imprinted electroactive nanoparticles (MIENPs). A robust MIP film was formed on the surface of electrode by electrodeposition of MIENPs and subsequent electropolymerization of the carbazole units in MIENPs. After the extraction of PCM molecules, a MIP sensor was successfully constructed. It should be noted that electropolymerization of the electroactive units in MIENPs creates cross-conjugated polymer network, which not only locks the recognition sites but also significantly accelerates the electron transfer and thus enhances the response signal of the MIP sensor. These advantages endowed the MIP sensor with good selectivity and high sensitivity for PCM detection. The MIP sensor could recognize PCM from its possible interfering substances with good selectivity. Under the optimal conditions, two linear ranges from 1 μM to 0.1 mM and 0.1 to 10 mM with a detection limit of 0.3 μM were obtained for PCM detection. The MIP sensor also showed good stability and repeatability, which has been successfully used to analyze PCM in tablets and human urine samples with satisfactory results. KEYWORDS: molecular imprinting, electroactive nanoparticle, macromolecular assembly, MIP sensor, electropolymerization

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INTRODUCTION In the past decades, molecular imprinting has become a powerful tool for preparing tailor-made affinity materials with molecular recognition ability. In contrast to the natural recognition materials (enzymes, antibodies, and hormone receptors), molecularly imprinted polymers (MIPs) possessed many distinct advantages such as chemical and thermal stability, low cost, intrinsic robustness, manufacturing potential, and long lifetime,1−4 and thus have been used in a variety of applications, such as separation, solid phase extraction, and biosensors. However, traditional MIPs are normally prepared in the form of monoliths and most of the imprinted sites are located at the deep interior of the bulky MIP material, leading to incomplete removal of template, small binding capacity, and poor site accessibility. To solve these problems, MIPs are preferred to be prepared into nanosized particles with well-defined structure.5−15 Nanosized MIPs have small dimensions with extremely high surface-to-volume ratio and increased total surface areas, hence most of template-imprinting sites are situated at or close to the materials surface, resulting in faster binding kinetics, more complete removal of templates, and higher binding capacity. © 2016 American Chemical Society

Up to now, various approaches have been used to synthesize nanosized MIPs, which include suspension, dispersion, precipitation, and emulsion seeded polymerization. However, the obtained MIPs from these methods are normally organic solvent-compatible. It has been demonstrated that the specific template binding of MIPs prepared in organic solvents is remarkably reduced in aqueous environments, which significantly limits their applications in the biotechnology field.16−19 Zhang’s group employed surface-initiated reversible addition− fragmentation chain transfer polymerization (RAFT) to prepare molecularly imprinted polymer microspheres with hydrophilic polymer shells, which had good dispersibility in aqueous solution and exhibited specific recognition in real biological samples.20−25 Zeng’s group prepared surface-imprinted polymer grafted with water-compatible external layer via RAFT precipitation polymerization which was further employed to construct highly selective and sensitive electrochemical assay.26,27 Zhao’s group developed a novel kind of waterReceived: May 6, 2016 Accepted: July 27, 2016 Published: July 27, 2016 21028

DOI: 10.1021/acsami.6b05440 ACS Appl. Mater. Interfaces 2016, 8, 21028−21038

Research Article

ACS Applied Materials & Interfaces Scheme 1. Synthetic Route of P(NVC-EHA-AA) (PNEA) Copolymer

soluble molecularly imprinted fluorescent nanoparticle based on the surface-core cross-linking of a surfactant micelle via click reaction.28−30 Recently, combining the self-assembly of an amphiphilic photo-cross-linkable copolymer and imprinting technology, our group prepared a series of molecularly imprinted nanoparticles in aqueous solution and successfully applied them to construct electrochemical sensor.31−34 The self-assembly of amphiphilic copolymer is a kind of microphase separation behavior that normally happens in a selective solvent: a mixture of two intermiscible solvents, one of which is a poor solvent for one component in the amphiphilic copolymer.35 Driven by the certain interactions (hydrogen bonding, electrostatic interaction) between the template molecule and the polymer as well as the hydrophobic effect, a great number of template molecules were incorporated into the self-assembled nanoparticles and the molecular imprinting was thus fulfilled during the self-assembly process. The imprinted nanoparticles were then immobilized onto the surface of electrode via electrodeposition and the recognition cavities were locked by the subsequent photo-crosslinking, leading to a robust MIP film. The whole strategy was carried out in aqueous solution, and the integration of the imprinted nanoparticles with transducer via electrodeposition was simple and controllable. The obtained MIP sensors showed good selectivity, broad linearity and excellent stability for the detection of template molecules. This strategy has also been demonstrated as a general way to prepare electrochemical MIP sensor, which has been extended to versatile amphiphilic polymers and various templates. However, the amphiphilic photosensitive polymers used to prepare the imprinted nanoparticles were normally nonelectroactive, which thus formed a serious barrier for electron transfer and greatly limited the efficiency of the signal transduction process. Thus, the sensitivity of the developed MIP sensors was seriously limited. In the meanwhile, the post photo-cross-linking of the MIP film required the incorporation of photosensitive functional groups (such as double bond or coumarin unit) into the backbone of the amphiphilic copolymer, which made the design and synthesis of the amphiphilic copolymer rather complicated and complex. In this work, a novel kind of water-dispersible electroactive molecularly imprinted nanoparticles was prepared by selfassembly of an amphiphilic electroactive copolymer with PCM in aqueous solution and employed as molecular recognition element to construct a electrochemical MIP sensor for voltammetric sensitive and selective sensing PCM. The resulted molecularly imprinted electroactive nanoparticles and MIP electrode have been fully characterized. The detecting performance such as selectivity, linearity, sensitivity, and stability of the MIP sensor was investigated and the results are exhibited below.

2. EXPERIMENTAL SECTION 2.1. Chemicals and Reagents. Acrylic acid (AA), uric acid (UA), paracetamol (PCM), 4-nitrophenol (4-NP), 4-aminophenol (4-AP), 2,2-azobis(isobutyronitrile) (AIBN), petroleum ether, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), and acetonitrile were supplied by Sinopharm Chemical Reagent Co., Ltd. Ethylhexyl acrylate (EHA), acrylic acid (AA), N-vinyl carbazole (NVC), paracetamol (PCM), lithium perchlorate (LiClO4) were purchased from Shanghai Aladdin Chemical Reagent Company (Shanghai, China). All the other chemicals and reagents were of analytical grade and used as received. All the solutions were prepared with ultrapure water (18.2 MΩ cm) from a NW Ultrapure Water System (Heal Force). 2.2. Preparation of Amphiphilic PNEA Copolymer and Molecularly Imprinted Electroactive Nanoparticles (MIENPs). The amphiphilic PNEA copolymer was synthesized according to Scheme 1. As a typical synthetic route, N-vinyl carbazole (1.86 g, 9.6 mmol), ethylhexyl acrylate (2.95 g, 16 mmol), acrylic acid (1.15 g, 16 mmol) and 1,4-dioxane (20 mL) were added into a round-bottom flask and purged with nitrogen gas for half an hour. Azobis(isobutyronitrile) (AIBN, 1 wt % of monomers) as initiator was added into the flask. The polymerization proceeded for 20 h at 75 °C with stirring. The resulted polymer was purified by being precipitated into petroleum ether for three times. Finally, the obtained P(NVCEHA-AA) (PNEA) copolymer was collected and dried in a vacuum oven at 35 °C for 48 h as white powder (4.96 g, 83.1% yield). To prepare the imprinted nanoparticles, 0.1 g of PNEA copolymer and 0.02 g of paracetamol were dissolved in DMF (10 mL) to give a 10 mg/mL copolymer solution, which was kept stirring overnight to ensure the complexation of paracetamol with the amphiphilic copolymer. Ten mL of water as poor solvent was then added into the polymer solution to induce the coassembly of PNEA copolymer and paracetamol to form the imprinted nanoparticles. The pH of the solution was kept at about 6.0 during the whole procedure to ensure the deprotonation of the carboxyl groups in the copolymer. The prepared MIENPs solution was dialyzed against water for 3 days to remove DMF and free PCM molecules with a final mass concentration of 0.5 wt %. The MIENPs samples for the characterization are obtained from the freeze-drying of the MIENPs solution. The PCM content incorporated in the polymeric micelle was assayed by HPLC. For this purpose, 10 mg of imprinted nanoparticles was dissolved in 1 mL THF. The THF solution was filtered before injection. Paracetamol was quantified by UV detection (λ = 315 nm). The area of each eluted peak was integrated and used for paracetamol quantification. The percentage of incorporation (I.E.) (%) was expressed as the percentage of PCM in the produced nanoparticles with respect to the initial amount (mg) used for the preparation of nanoparticles, which was calculated as 64.7%. Nonimprinted electroactive nanoparticles (NIENPs) were prepared similarly but in the absence of the template molecules. 2.3. Preparation of the MIP Sensor. A bare glass carbon electrode (GCE) was polished by alumina particles and washed by ethanol and ultrapure water under ultrasonication. The cleaned electrode was then subjected to cyclic sweeping between −0.40 and 1.60 V in 1.0 M H2SO4 until a stable cyclic voltammogram was obtained. The MIENPs solution prepared in advance was employed as a bath solution for electrodeposition. After electrodeposition was 21029


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ACS Applied Materials & Interfaces

Scheme 2. Schematic Illustration of the MIP Sensor Fabrication Using the Self-Assembled Molecularly Imprinted Electroactive Nanoparticles (MIENPs) and Electropolymerization

carried out via controlled potential electrolysis (CPE) at 1.5 V for 300 s, the electrode was covered with a MIP film which then subjected to electrochemical polymerization to induce the cross-linking of the MIP film. Electrochemical polymerization was performed via cyclic voltammetry (CV) with the scan range of 0 to 1.5 V at a potential scan rate of 100 mV s−1 for 18 cycles in a solution of 0.1 M LiClO4 dissolved in acetonitrile (ACN). Finally PCM molecules were washed from the MIP film with a mixture of acetic acid and methanol (1:4, v/ v) to generate the namely “MIP electrode” (or MIP sensor). Extraction of PCM was monitored by differential pulse voltammetry (DPV), until the oxidation peaks of paracetamol disappeared in the DPV curves. The cross-linked nanocomposite film was thoroughly cleaned with deionized water and was dried in nitrogen before its analysis. For comparison, a nonimprinted control electrode (NIP electrode) was constructed following the same procedure for the MIP sensor, but using nonimprinted electroactive nanoparticles (NIENPs) instead of MIENPs. 2.4. Characterization and Instruments. The chemical structures of PNEA copolymers were determined by 1H NMR with an AVANCE III 400 MHz Digital NMR spectrometer (DMSO as solvent) and FTIR spectroscopy on a FTLA20002104 infrared Fourier transform spectroscope (Canada ABB). The molecular weight and distribution of PNEA copolymer were investigated by gel permeation chromatograph (Waters GPC 486, USA) with DMF as eluent. Polystyrene standards were used to estimate the molecular weight. The mean particle size and size distribution of MIENPs were determined by dynamic light scattering (DLS) measurements (ALV-5000/E DLS). The morphology of MIENPs and NIENPs was examined by TEM measurements using a JEOL JEM-2100 microscope operated at 200 kV. SEM measurements were carried out on a Hitachi s-4800 microscope. Controlled potential electrolysis (CPE), differential pulse voltammetry (DPV), cyclic voltammetry (CV), and electrochemical impedance spectroscopy (EIS) were performed with a three-electrode system using CHI 660C electrochemical analyzer (Chenhua Corp., Shanghai, China). The MIP or NIP film modified electrode was used as the working electrode (WE), a saturated calomel electrode (SCE) as the reference electrode (RE), and a platinum wire as the counter electrode (CE). All potentials applied to the working electrode were referred to SCE. 2.5. Electrochemical Studies of Paracetamol on the MIP and NIP Sensor. The MIP/NIP sensors were placed in different

concentrations of PCM (0.1 M phosphate buffer) solution for 3 min. Following this incubation step, the electrodes were rinsed with water and then transferred into a fresh phosphate buffer solution, and the DPV voltammograms were finally recorded.

3. RESULTS AND DISCUSSION The whole strategy is depicted in Scheme 2. First, an amphiphilic electroactive copolymer (P(NVC-EHA-AA), PNEA) containing carbazole group was synthesized through a simple one-pot free radical copolymerization. The amphiphilic PNEA copolymer could coassemble with PCM in aqueous solution, during which PCM was embedded in the assembled nanoparticles, leading to the formation of molecularly imprinted electroactive nanoparticles (MIENPs). Then, the MIENPs were immobilized onto the electrode surface to form a MIP film via electrophoretic deposition. The subsequent electropolymerization of the electroactive carbazole units in MIENPs creates cross-conjugated polymer network, which not only locks the recognition sites but also enhances the electrical conductivity of the MIP film. It is quite expected that the good conductivity of the in situ formed polycarbazole network could provide a platform to accelerate the electron transfer and facilitate the signal transduction from the binding cavities to the electrode, leading to high sensitivity as well as good recognition capacity of the electrochemical MIP sensor. In addition, with the cross-conjugated conductive polymer network, no photocross-linking was further required to lock the recognition sites, which greatly simplifies the synthesis of the amphiphilic copolymer. Finally, the extraction of the PCM molecules from the film leads to spatially organized cavities (rebinding sites) to generate the MIP electrode (MIP sensor), which has specific recognition toward PCM template. 3.1. Preparation and Characterization of the Copolymer PNEA and Its Self-Assembled Micelle. GPC analysis revealed that PNEA copolymer had a molecular weight (Mn) of 8600 and a polydispersity index (PDI) of 1.83. The structure of PNEA was characterized by 1H NMR spectrum and the signals 21030


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PCM sensing. The related characterization and discussion have been provided in the Table S1 and Figures S1. In neutral or alkaline conditions, the carboxylic acid (AA) units become deionized and bear negative charges, thus becoming highly hydrophilic. Whereas NVC and EHA units in PNEA copolymer are hydrophobic, so the obtained PNEA copolymer is an amphiphilic macromolecule which can selfassemble into nanoparticles in aqueous solution by simply adjusting the pH value. The imprinted electroactive nanoparticles (MIENPs) were prepared by the coassembly of PNEA copolymer with template molecules. As shown in Scheme 2, when water as a poor solvent was gradually added to the DMF solution containing the PNEA copolymer and PCM, the hydrophobic moieties (NVC and EHA units) of the copolymer started to associate to form hydrophobic microphase, whereas the hydrophilic segments (carboxylic units) was exposed to the aqueous phase to stabilize the formed hydrophobic microphase. Owing to the hydrogen bond (formed between the carbamate and ester groups in the copolymer and the amide and hydroxyl groups in PCM) and π−π interaction between PCM and PNEA copolymer, PCM molecules took part in the assembly of the PNEA chains and entrapped into the assembled PNEA micelles, thus producing the imprinted nanoparticles. Besides the hydrogen bonding and π−π interaction, the hydrophobic effect also takes part in driving PCM into the PNEA micelle. The formation of MIENPs was confirmed by the DLS and TEM investigations. As a control sample, nonimprinted nanoparticles (NIENPs) were also prepared by the selfassembly of PNEA copolymer in aqueous solution under the same conditions only without the addition of PCM molecules. The size distribution curves of PNEA copolymer with different NVC:EHA:AA feeding ratios was shown in Figure S2. Considering the size, stability of the MIENPs and electrochemical property of the resulted MIP film (Figure S3), PNEA with NVC:EHA:AA feeding ratio of 3:5:5 was chosen as the optimized copolymer to prepare the imprinted nanoparticles and MIP sensor in the following work. As shown in Figure 3A, the mean particle size of the NIENPs is 44 nm. With the entrapment of PCM molecules, the average size of the MIENPs increases to about 50 nm. The increase in diameter of micelles with the incorporation or loading of other molecules has been reported by literatures.37 TEM images showed that the prepared MIENPs and NIENPs were in approximately spherical shape with average hydrodynamic diameters of 40− 50 nm, which is in accordance with the DLS results. The nanosize of the MIENPs can provide a large number of recognition cavities and ensure fast removal of imprinted molecules owing to their high specific surface area, which is beneficial for molecular imprinting. It should also be noted that the zeta potential of the MIENPs was about −38 mV at pH 6.0 (Figure S4) because of the deprotonation of carboxylic groups in PNEA chains, which makes it possible for the immobilization of MIENPs on the surface of GCE via electrodeposition. To further confirm the entrapping of PCM molecules and the successful preparation of the imprinted nanoparticles, the FTIR spectra of MIENPs and PCM template were also measured and provided in Figure 2. It can be easily observed that in addition to the characteristic peaks of PNEM copolymer (curve b), the FTIR spectrum of MIENPs (curve a) exhibits several distinct new peaks from 3400−3000, 1600−1500, 900−750 cm−1, which just coincides with the typical absorption peaks of paracetamol (curve c). The above results showed that PCM molecules have been incorporated inside the assembled

corresponding to the characteristic protons from both NVC, EA and AA monomers were assigned by numbers as shown in Figure 1. The signal at 12.5 ppm (H2) is attributed to the

Figure 1. 1H NMR spectrum of P(NVC-EHA-AA) (PNEA) copolymer.

proton of carboxylic acid groups. The signals at 6.4−7.9 ppm (H4, H5, H6, H7) are assigned to the aromatic protons of carbazole groups. The multipeaks between 0.5 and 2.0 ppm (H1, H8, H10−19) are ascribed to the methyl protons and the methylene protons in the polymer backbone and the side chain of EA segment. By comparing the integration areas of these characteristic protons, the composition of the PNEA copolymer could be determined and the molar ratio of NVC/EA/AA in the copolymer was estimated to be 3:4.8:4.8, which was roughly in accordance with the feeding ratio of NVC, EA and AA (3:5:5). The structure of the PNEA copolymer was further confirmed through FTIR spectrum analysis. The FTIR spectrum of PNEA was shown in Figure 2 (curve b). The

Figure 2. FT-IR spectra of (a) imprinted electroactive nanoparticles (MIENPs), (b) PNEA copolymer, and (c) PCM.

band at 1720 cm−1 corresponds to the CO stretching mode of carboxylic group in PNEA. Characteristic peaks of carbazole segment were observed at 1328 and 747 cm−1, corresponding to C−N stretching of aromatic bonds, and C−H out of plane deformation of the C−H bond in benzene ring, respectively.36 The above results confirmed the incorporation of NVC, EA, and AA units in the copolymer and thus verified the successful synthesis of PNEA copolymer. It should be noted that a series of PNEA copolymers with different compositions have been synthesized by changing the feeding ratio of NVC:EHA:AA (3:5:3, 3:5:5, 3:5:8, 3:5:12, 3:5:16) to establish the optimum copolymer compositions in obtaining the best MIP film for 21031


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depicted in Figure S5. It is shown that oxygen evolution reaction at the anode surface during the electrodepositing process generated low localized pH environment. When the imprinted nanoparticles bearing negative charges move to the vicinity of the anode, they switched from soluble to insoluble due to the protonation of the carboxylic groups and thus precipitated on the surface of the electrode. Figure 4 shows that the current decreased monotonously with prolonging deposition time and tended to become stable after 300 s, indicating the deposition of MIENPs on the electrode surface. The SEM images reveal presence of the nanostructured agglomerated particles with rough topology after depositing 300 s, as shown in Figure 4B(b). After the MIENPs were immobilized on the surface of electrode, electropolymerization was subsequently carried out owing to the existence of a large amount of carbazole groups in MIENPs. Carbazole is a well-known electro-active moiety which could electropolymerize to create a large conjugated polycarbazole structure.36,38−42 The electropolymerization of carbazole moieties could form a conjugated conducting network containing both inter- and intramolecular crosslinkages between the pendant carbazole units (the inset of Figure S6) throughout the electrodeposited film, which played two important roles for the preparation of high-performance MIP sensors. On the one hand, with the formation of crossconjugated conductive polymer network, the electrical property of the imprinted film was greatly enhanced, which could accelerate the electron transfer and facilitate the signal transduction from the binding cavities to the electrode. On the other hand, the cross-linking of the obtained MIP film induced by electropolymerization locks the recognition sites and generates a robust MIP film, which construct a rigid threedimensional structures around the PCM molecule and resist the solvent extraction step. It should be noted that in our previous publications, photo-cross-linking was normally employed to

Figure 3. (A) Size distribution and (B) TEM images of (a) PNEA selfassembled nanoparticles (nonimprinted nanoparticles, NIENPs) and (b) imprinted nanoparticles (MIENPs).

micelles, demonstrating the successful preparation of the imprinted nanoparticles. 3.2. Fabrication of the MIP Sensor. The molecularly imprinted electroactive nanoparticles (MIENPs) were then immobilized on GCE surface via electrodeposition to form MIP film using controlled potential electrolysis (CPE) technique. The mechanism of electrodeposition of the MIENPs was

Figure 4. (A) Current−time curve of MIENP electrodeposition performed with CPE. Bath solution: 0.5 wt % MIENPs solution; applied potential: 1.5 V; deposition time: 300 s. (B) SEM images of (a) the bare electrode, (b) the electrode covered with the MIENPs, and (c) the modified electrode after electropolymerization. 21032


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Figure 5. (A) Electrochemical impedance spectroscopy (EIS) and (B) CV of (a) bare GCE, the MIP film modified GCE (b) before and (c) after electropolymerization in 0.1 M KCl electrolyte solution containing 0.01 M Fe(CN)63−/4−. Scan rate: 100 mV s −1.

the value of 300 Ω (Rct). After modified by the MIP film (curve b), the Rct increased to about 7.8 kΩ. The much larger Rct value than that of the bare GCE indicates that MIP film modified GCE has a large electron transfer resistance, evidencing the presence of the insulating MIP film on the surface of GCE. However, after electropolymerization, the semicircle was reduced to 3.5 kΩ (curve c), which is more than two times lower than the value before electropolymerization. The significantly decreased Rct demonstrated the accelerated electron transfer between the electrode and electrolyte and the improved conductivity of the MIP film. CV curves also demonstrated the deposition of MIP film and the improved electrical properties after electropolymerization. As shown in Figure 5B, the redox peak of Fe(CN)63−/4− almost disappeared after the electrodeposition of MIENPs, indicating the formation of a compact insulating MIP film on the electrode. After electropolymerization, an almost 2-fold increase in the peak current response was observed, further confirming the improved electrical properties of the MIP film. 3.3. Performance of the MIP Sensor. 3.3.1. Electrochemical Behavior of PCM on the MIP and NIP Sensor. Paracetamol, an aromatic compound, can be electrochemically oxidized into N-acetyl-p-quinoneimine on solid electrodes, giving a well-defined oxidation peak.44 The differential pulse voltammetry (DPV) curve of MIP sensor without incubation was recorded in which no detectable peak was observed (Figure 6, curve d), indicating the entire removal of PCM after

lock the recognition sites. But to induce photo-cross-linking, double bond was required to be incorporated in the side chains of the amphiphilic copolymer, which made the whole synthesis strategy quite complicated. The electrochemical cross-linking of the carbazole groups was carried out by CV and the first 18 cycles were shown in Figure S6. It is also noted from the SEM images that the nanostructured particles in Figure 4B(b) become linked to each other to some extent after electropolymerization (Figure 4B(c)), which should be attributed to the cross-linking of the nanoparticles induced by the electropolymerization. It should be noted that electropolymerization of carbazole derivatives in molecular imprinting has been previously reported. Advincula prepared an electropolymerized molecularly imprinted polymer (E-MIP) film by a one-pot electropolymerization of terthiophene and carbazole monomer in the presence of bisphenol A (BPA).43 By optimizing the potential window, number of cyclic scans, and monomer composition, the best film was obtained that exhibited high sensitivity and selectivity toward BPA. In our work, the MIENPs solution that was prepared in advance by the coassembly of PNEA copolymer and template was used as bath solution for electrodeposition instead of the monomer (terthiophene and carbazole) and BPA complex. So besides the electrodeposition conditions, the obtained MIP film in our work could be further tuned by optimizing the composition of PNEA copolymer and the assembly conditions. In addition, our imprinting process was carried out in aqueous solution instead of organic solvent (acetonitrile) in Advincula’s work, which is particularly important for imprinting biomolecules and its application in real biological samples. Although our preparation procedure involves more steps than the direct electropolymerization of monomer and BPA complex, the monomers employed in our work are commercially available whereas the terthiophene monomer in Advincula’s work involved complicated synthesis steps. The electrodeposition of MIENPs onto the GCE surface to form MIP film and the subsequent electropolymerization were further investigated by electrochemical impedance spectroscopy (EIS). Figure 5A shows the impedance spectra of bare GCE, MIP film before and after electropolymerization. Obviously, the impedance spectra of three electrodes are composed of a semicircle region at higher frequencies and a straight line at lower frequencies. The semicircular region is related to the electron transfer limited process, and the diameter equals to the electron transfer resistance (Rct). As shown in the inset of Figure 5A, bare GCE exhibits a small semicircle domain with

Figure 6. DPV voltammograms of the (a) MIP sensor, (b) NIP sensor, and (c) the MIP sensor without electropolymerization recorded in PBS buffer (pH 7.0) after incubation in 1 mmol L−1 PCM solution for 3 min. (d) DPV voltammogram of MIP electrode recorded in PBS buffer without incubation. 21033


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of imprinted PCM molecules from the MIP film and easy accession for PCM in the solution to the imprinted sites. Thus, the incubation time was set to be 3 min for the determination of PCM. 3.3.3. Selectivity Evaluation of the MIP Sensor. Specific recognition of the target analyte is an important merit for a MIP sensor, which allows discrimination of the interfering species having similar electroactivities and structures. To evaluate the selectivity of the MIP sensor, 4-nitrophenol (4NP) and 4-aminophenol (4-AP) were chosen as the interfering species based on structural similarity, their functional groups and interaction types. In addition, ascorbic acid (AA) and uric acid (UA) were also chosen because they are frequently found in biological fluids and have similar oxidation potential to PCM. Figure 8 showed the current responses of the MIP and NIP

extraction. After incubation, a distinct characteristic peak of PCM at around 325 mV was observed on the MIP sensor (curve a). Because the electrochemical measurements were performed in PCM-free solutions, it indicates that the redox peaks could be entirely attributed to the oxidation−reduction of PCM molecules which had been adsorbed into the MIP film. In comparison, the NIP sensor exhibits relatively much smaller signal response at 325 mV (curve b), which should be attributed to the nonspecifically adsorbed PCM molecules onto the NIP film. The higher response signal of MIP sensor suggested that there were a large number of binding sites in the MIP film, which would allow it to adsorb more target molecules. To evaluate the effect of electropolymerization on the sensing behavior, the DPV voltammogram of the MIP sensor obtained without electropolymerization was also investigated and provided in Figure 6 (curve c). It can be seen that the signal response of PCM on the MIP sensor without electropolymerization is very low, which is only onefifth of the same electrode after electropolymerization. It means that the electropolymerization of carbzaole could significantly enhance signal response of PCM on the MIP sensor, which could be attributed to the formation of conductive polycarbazole network greatly enhanced the electrical conductivity of MIP film and allowed direct electrical connection between the recognition sites and the electrode. The enhanced electroanalytical response by electropolymerization is quite expected to improve the sensitivity of the MIP sensor for PCM detection. 3.3.2. Incubation Time. Response time to the target analytes was an important parameter in evaluating the performance of a sensor. Figure 7 shows the change of the peak current with

Figure 8. Selectivity of the MIP sensor. DPV current response recorded on the MIP and NIP sensor after incubating in PCM or its analogs solution with the same concentration of 1 mmol L−1 for 180 s. (a) Paracetamol, PCM; (b) 4-nitrophenol, 4-NP; (c) 4-aminophenol, 4-AP; (d) ascorbic acid, AA; (e) uric acid, UA.

Figure 7. Peak currents of PCM recorded on the MIP sensor incubated in 0.1 mmol/L PCM for different incubation times.

sensors toward paracetamol, 4-nitrophenol, 4-aminophenol, ascorbic acid, and uric acid. It can be seen that the current response of the MIP sensor toward PCM was nearly 5 times that of the NIP sensor. The selectivity of PCM imprinted sensor was evaluated by calculating the imprinting factor (IF)

different incubation times. It was found that the peak current of the MIP sensor increased rapidly in the first 1 min and then reached a steady-state current after 2 min, implying a saturation state of the adsorption of PCM. Obviously, the MIP sensor showed a very fast adsorption kinetics, which can be attributed to a moderate thickness of the MIP film. Compared to other immobilization techniques integrating MIP with the transducer, electrodeposition technique has an intrinsic ability to control the film thickness by adjusting the deposition conditions such as deposition time, applied potential and bath condition during the electrodeposition process. In our experiment, the deposition time (300 s) and the applied voltage (1.5 V) as well as bath condition (0.5 wt % MIENPs solution) were carefully adjusted to finally achieve a MIP film with appropriate thickness about 80−100 nm, which ensures complete extraction

IF = IMIP/INIP

(1)

where IMIP and INIP are the peak currents of species on MIP and NIP sensors. The IF of PCM is about 5, significantly higher than those of other four nonimprinted species, indicating that the MIP sensor exhibited good specific recognition ability toward PCM. Figure 8 also shows that the response of the MIP sensor toward PCM was significantly stronger than that toward the other species. The ratios of peak current of 4-NP, 4-AP, AA, and UA to PCM at the MIP sensor are 0.15, 0.13, 0.11, and 0.05, respectively. In contrast, the responses of the NIP sensor for PCM and its analogs are quite similar. The above results 21034


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Figure 9. (A) Different pulse voltammograms of paracetamol at MIPs electrode. Paracetamol concentration: 0.001, 0.01, 0.04, 0.1, 0.4, 1.0, 4.0, 7.0, 10.0, 20 mmol L−1 (from bottom to top). (B) Calibration curves corresponding to the response recorded on the MIP sensor (a) after electropolymerization and (c) before electropolymerization and (b) NIP sensor versus the concentration of PCM.

clearly evidence that the MIPs sensor had high selectivity for PCM due to the imprinting effect. The high selectivity was due to the functional groups and shape of the cavities in the imprinted film that specifically interacted with the PCM molecules, so they cannot bind other analogues tightly. 3.3.4. Analytical Performance. Figure 9 shows the DPV voltammograms of PCM with different concentrations recorded on the MIP sensor. The DPV peak currents of the MIP sensor rose with the increasing PCM concentration and showed linear relationships ranging from 0.001 to 10 mmol/L. The calibration curve in Figure 9B reveals that the peak currents were proportional to the concentrations of PCM in two segments: the first linear segment increases from 0.001 to 0.1 mmol L−1 with a linear regression equation of ip (uA) = 0.0022−4.9377 CPCM (R2 = 0.9992), and the second linear segment increases from 0.1 to 10 mmol L−1 with a linear regression equation of ip(uA) = −1.1741−0.2886 CPCM (R2 = 0.9856). The detection limit (LOD = 3Sb/m, where Sb is the standard deviation for 4 replicates of blank and m is calibration curve slope) was calculated to be 0.3 μmol L−1. In contrast, the response of the NIP sensor (curve b) was not significantly influenced by the concentration of PCM, and stayed at relatively low values within the whole testing range. It should also be noted that the response signal of the MIP sensor without electropolymerization (curve c) is much weaker than the corresponding MIP sensor (after electropolymerization), giving a good evidence of the enhanced sensitivity of the MIP sensor via electropolymerization. Additionally, we did a comparison of our MIP sensor with other previously reported MIP sensors45−47 for detecting PCM. As can be seen in Table 1, our MIP sensor presents a wide linear dynamic range, acceptable detection limit and good selectivity. It should be noted that its detection linear ranges cover 1−10000 μM, which is the widest in all. The wide linear range was attributed to the large specific surface area of the nanosized imprinted nanoparticles, which could accommodate a great number of recognition sites with the high surface-tovolume ratio and thus create more effective binding cavities in the fabricated MIP film. As for the detection limit, it is lower than most of PCM sensors although it is not the lowest. In addition, our MIP sensor showed good selectivity for PCM due to the imprinting effect. The influence of interfering species with similar electroactivities and structures can almost be excluded. This good selectivity can be hardly achieved for the common electrochemical sensors without imprinting effect

Table 1. Comparison of the Sensing Performance of our MIP Sensor with Previously Reported PCM Electrochemical Sensors electrodea MIP sensor PIP/PGE imprinted TiO2 film MIP-CFME MIP- MCNTs MIP micelle/gold electrode AuNP-PGA/ SWCNT PANI/MCNTs/ GCE boron-doped diamond DLC:VACNT MWCNT/GO graphene− CoFe2O4 D50wx2−GNP

linear range (μM)

detection limit (μM)

selectivityb

ref

1−100 100−10000 5−500 1−100

0.3

good

present work

0.79 0.8

good good

45 46

6.5−2000 10.0−130.0 10−8000

1.5 2.7 1

good good good

47 48 49

8.3−145.6

1.18

a

50

1−100

0.25

NA

51

0.4−100

0.21

b

52

10−100 0.5−400 0.03−12.0

0.28 0.047 0.025

NA NA b

53 54 55

0.0344−42.2

0.005

b

56

a

Abbreviations: PIP, paracetamol imprinted polypyrrole; PGE, pencil graphite electrode; PGA, poly(glutamic acid); MCNTs, multiwalled carbon nanotubes; PANI, polyaniline; CFME, carbon fiber microelectrodes; DLC, porous diamond-like carbon; VACNT, vertically aligned multiwalled carbon nanotubes; D50wx2, a cation exchanger resin; GNP: gold nanoparticles bGood, the effect of interfering species with similar electroactivities and structures was quite low; a, only the interference of ascorbic acid was investigated; b, the interference of some ions and organic compounds (glucose, urea, uric acid, and ascorbic acid, amino acids) was low, but the effect of some interfering species with similar electroactivities and structures was not investigated.

despite of their lower detection limit (for example, MWCNT/ GO, graphene−CoFe2O4 and D50wx2−GNP). This comparison demonstrated that our MIP provides an excellent platform for the electrochemical sensing PCM. 3.3.5. Stability and Repeatability. Good stability and reproducibility are also important factors for a successful sensor. To investigate the repeatability of the MIP sensor, we independently fabricated five MIP film modified electrodes under the same conditions and measured their responses. The 21035


Research Article

ACS Applied Materials & Interfaces response peaks of the five modified electrodes toward a certain concentration of PCM showed a relative standard deviation of 4.5%, indicating a good reproducibility of the preparation of the proposed sensor. The stability of our MIP sensor was also explored by measuring the current response of the same electrode every 7 days. The peak current of PCM on the MIP sensor did not have a great change for about 4 weeks with only a slight decrease in the current (Figure S7), demonstrating a high stability of the MIP sensor. Hence, it could be used for about a month with reliable results. 3.3.6. Detection of PCM in Real Samples. To evaluate the practical performance of the developed MIP sensor, we determined three commercial PCM tablets (150 mg/tablet) on MIP sensor. The tablets were ground to powder and then dissolved in PBS (pH 7). After the centrifugation, the supernate was collected and diluted to a working concentration range for electrochemical detection. The concentration of PCM in tablets was determined using the prepared MIP sensor in triplicate under the same conditions. As shown in Table 2, the results

network, which not only locks the recognition sites but also significantly accelerates the electron transfer and thus enhances the response peak current of the MIP sensor. These advantages endowed the prepared MIP sensor with high sensitivity and good selectivity for PCM detection. Good stability and repeatability of the MIP sensor were also demonstrated. As a practical application, the fabricated MIP sensor was successfully and accurately employed to detect the amount of PCM present in commercial PCM tablets and urine samples with satisfactory results. As an ongoing work in our lab, this strategy is being extended to imprinting biomolecules (such as cholesterol) considering the water compatibility of the molecular imprinted nanoparticles and good results have been achieved, implying that our strategy could be generalized to other template systems.

■

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsami.6b05440. 1 H NMR and FT-IR spectra of PNEA copolymers with different feeding ratios of monomer (Figure S1); size distribution of imprinted nanoparticles from various PNEA copolymers (Figure S2); influence of the PNEA copolymers with different feeding ratios on the peak current of the resulted MIP sensors (Figure S3); influence of pH on zeta-potential of imprinted nanoparticles (Figure S4); schematic illustration of the mechanism of MIENPs electrodeposition (Figure S5); CV curves for the electropolymerization of MIP film (Figure S6); different pulse voltammograms of one MIP sensor in 1 mM PCM measured every 7 days and peak currents of one MIP sensor every 7 days (Figure S7) (PDF)

Table 2. Determination of PCM in Pharmaceutical Samples revealed sample

declared (g tablet−1)

sensor (g tablet−1)

1 2 3 4

0.15 0.15 0.15 0.15

0.1725 (RSD = 5.1%) 0.2011(RSD = 5.3%) 0.1418 (RSD = 2.4%) 0.1295 (RSD = 3.8%)

HPLC (g tablet−1) 0.1676 0.1879 0.1443 0.1392

(RSD (RSD (RSD (RSD

= = = =

3.2%) 4.6%) 2.9%) 2.7%)

were in good agreement with the manufacturers’ stated contents of PCM. In addition, the HPLC method was also employed to determine the amount of paracetamol in the same commercial tablets and the results obtained are also provided in Table 2. There was no great difference between our method and the values found by HPLC. The MIP sensor was also validated with paracetamol-spiked human urine samples, and the recovery of the spiked sample was between 96.1 and 103.5% (Table 3). The recovery rates and the relative standard

■

spiked (mmol L−1)

recovery (%)

RSD (%)

1 2 3 4

0.01 0.05 0.1 0.5

96.1 98.6 103.5 102.2

4.7 2.8 1.6 3.1

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. Tel: 86-510-85917763. Fax: 86-510-85917763. *E-mail: [email protected].

Table 3. Determination of PCM in Urine Samples sample

ASSOCIATED CONTENT

S Supporting Information *

Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We acknowledge financial support from the National Natural Science Foundation of China (under Grant 51573072), the Fundamental Research Funds for the Central Universities (JUSRP 51305A), and MOE & SAFEA for the 111 Project (B13025).

derivations (RSDs) for these urine samples are found to be highly acceptable. These results indicate that the sensor developed in this work has good practical analytical utility.

■

■

CONCLUSION In this work, the preparation of a selective and sensitive electrochemical sensor based on a novel kind of molecularly imprinted electroactive nanoparticles (MIENPs) and its selective detection for paracetamol are investigated. The MIENPs was prepared via macromolecule self-assembly of an amphiphilic electroactive copolymer (PNEA) in the presence of PCM and electrodeposited on the GC electrode with subsequent electropolymerization to produce a robust MIP film. The electropolymerization of the electroactive units (carbazole) in MIENPs creates cross-conjugated polymer

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