SPR Sensing of Bisphenol A Using Molecularly Imprinted

A slab-type optical waveguide (s_OWG)-based microfluidic SPR measurement system for bisphenol A was developed. This s_OWG possesses consecutive ...
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SPR Sensing of Bisphenol A Using Molecularly Imprinted Nanoparticles Immobilized on Slab Optical Waveguide with Consecutive Parallel Au and Ag Deposition Bands Coexistent with Bisphenol A-Immobilized Au Nanoparticles Yuki Taguchi, Eri Takano, and Toshifumi Takeuchi* Graduate School of Engineering, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan S Supporting Information *

ABSTRACT: A slab-type optical waveguide (s_OWG)-based microfluidic SPR measurement system for bisphenol A was developed. This s_OWG possesses consecutive parallel gold and silver deposition bands in the line of plasmon flow, allowing two individual SPR signals to be independently obtained as a result of the difference in resonant reflection spectra of these metals. As a molecular recognition element, molecularly imprinted polymer nanoparticles (MIP-Np) were employed and immobilized on the surface of each of the gold and silver deposition bands. The resonant reflection spectra were measured on the MIP-Np-immobilized consecutive parallel gold and silver deposition bands coexistent with BPA-AuNp. The Agbased SPR spectra showed a red shift (0.7 nm) when free BPA (0.1 mM) was passed over the BPA-AuNp/immobilized MIP-Np complexes formed on the s_OWG, unlike the case for the Au deposition band, while a large excess of BPA induced a blue shift due to the competitive desorption of BPA-AuNp from the immobilized MIP-Np on the s_OWG. By using the proposed detection system, binding events of other small molecules could be monitored in conjunction with the use of MIP-Np and labeled-AuNp.

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INTRODUCTION Surface plasmon resonance (SPR) sensors are sensitive to changes in refractive index and permittivity near the sensor surface, and have been extensively used for label-free sensing of target molecules in life science, biotechnology, and biomedical science,1,2 where surface plasmon refers to a surface electromagnetic wave on the boundary of a metal and an external medium, which is sensitive to the adsorption of molecules to the metal surface. A maximum extinction wavelength of SPR shifts toward longer wavelengths with increasing refractive index and/or permittivity due to the analyte binding, and vice versa when the analyte desorption occurs. Most reported SPR sensors have possessed prism-based configurations, measuring the angular reflection spectrum for monochromatic light.3−5 As an alternative way, optical waveguide surface plasmon resonance (OWG-SPR) sensors are available,6,7 wherein resonant reflection spectra are measured for collimated white light traveling inside the metal thin film-coated OWG. OWGSPR is based on propagating surface plasmon, which is charge density oscillations at a metal thin film deposited onto the surface of a dielectric material. Resonant reflection spectra can be observed due to the interaction of the surface plasmon with the evanescent wave generated by totally reflected light running within the OWG, and this spectra undergoes change when molecules are adsorbed within the near field on the metal thin film surface. © 2012 American Chemical Society

In this study, we employed slab-type optical waveguide (s_OWG), and constructed a microfluidic_OWG-SPR measurement system equipped with a high refractive index glass (n = 1.81)-based s_OWG. This s_OWG possesses consecutive parallel gold and silver deposition bands, allowing two individual SPR signals to be independently obtained as a result of the difference in resonant reflection spectra of these metals. As a molecular recognition element, molecularly imprinted polymer8−15 nanoparticles (MIP-Np) were employed and immobilized on the surface of each of the gold and silver deposition bands. Bisphenol A (BPA) was employed for a model target compound. As a common component of epoxy resins, it is believed that leached BPA from products may act as an estrogen-related endocrine disruptor. BPA is poorly soluble in water; thus organic solvent-based assays are more desirable for its detection. Consequently, the proposed s_OWG-SPR sensing system was constructed by using organic solventresistant materials. In general, SPR does not show the same degree of high sensitivity toward detection of small molecules such as BPA,16,17 as it does for macromolecules such as proteins and DNA. Since gold nanoparticles (AuNp) are reported to have enhanced the selectivity of SPR responses,18−21 here, BPA sensing was carried out on the immobilized MIP-Np in the Received: January 2, 2012 Revised: March 23, 2012 Published: April 18, 2012 7083

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presence of BPA-grafted-AuNp (BPA-AuNp) during the SPR measurements (Figure 1).

Figure 2. Preparation scheme of MIP-Np for BPA.

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EXPERIMENTAL SECTION

Materials. 3-Vinylbenzaldehyde, N,N′-diisopropylethylamine (DIEA), citric acid, and 2,2-azobis (2-methylpropion-amidine) dihydrochroride (AAPH) were purchased from Aldrich Chemical Corp. (St. Louis., U.S.). Styrene, divinyl benzene (DVB), hydrochloric acid (HCl), sodium chloride, magnesium sulfate, sodium hydroxide, acetic anhydride, potassium carbonate, hydrogen tetrachloroaurate (III) tetrahydrate, sodium borohydride, 4,4′-diaminodiphenylmethane (4,4′-DADPM), sodium hydrogen carbonate, methanol, dichloromethane, acetonitrile, and toluene were purchased from Wako Pure Chemical Industry (Osaka, Japan). Acetic acid, ethyl acetate (EtOAc), hydrogen peroxide (H2O2), acetone, ethanol and tetrahydrofuran (THF) were purchased from Nacalai Tesque (Kyoto, Japan). 4,4′Dihydroxy-2,2-diphenylpropane (Bisphenol A, BPA) and diphenolic acid were purchased from Tokyo Chemical Industry CO., Ltd (Tokyo, Japan). 11-Amino 1-undecanethiol hydrochloride was purchased from Dojindo Molecular Technologies, Inc. (Kumamoto, Japan). NHydroxy succinimide (NHS), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) were purchased from Watanabe Chemical Industries, Ltd. (Hiroshima, Japan). Styrene was used following treatment with an inhibitor remover (Aldrich). DVB, dichloromethane, and toluene were purified by distillation prior to use. All other reagents were used without further purification. Slab-type optical waveguides (s_OWG) used (high reflective index glass, L: 65 mm × W: 18 mm × thickness: 0.2 mm; refractive index: 1.81) having consecutive parallel gold and silver deposition bands (L: 2 mm × W: 18 mm × thickness 50 nm with 2 nm titanium adhesion layer for the deposition) were obtained from System Instruments Co., Ltd. (Tokyo, Japan). 4,4-Bis(4-hydroxyphenyl)pentanoyl(11-mercaptoundecyl)amide (BPA-thiol) was synthesized (see Supporting Information). Preparation of MIP-Np for BPA by Dummy Molecular Imprinting Technique. N,N′-Bis(3-vinylbenzylidene)-4,4′-diaminodiphenylmethane (template molecule, VB-DADPM) was synthesized as previously reported9 (see Supporting Information). Polystyrenepoly divinyl benzene seed-nanoparticles were synthesized via emulsifier-free seed polymerization. Seed polymerization was carried out under nitrogen atmosphere at 80 °C for 24 h (see Supporting Information). Next, VB-DADPM (35 mg, 0.08 mmol), styrene (50 mg, 0.5 mmol) and DVB (250 mg, 1.9 mmol) were added in the prepared seed emulsion (30 g) with magnetic stirring at 500 rpm.

Figure 1. Immobilization procedure of preparative procedure of MIPNp and BPA-AuNp on the sensor chip for the binding of free BPA.

MIPs are tailor-made synthetic materials capable of molecular recognition, in which specific binding cavities can be assembled through copolymerization carried out with template molecule-functional monomer complexes and crosslinkers, where the template molecule is either a target molecule or a structurally related derivative. After the removal of the template molecule, specific binding cavities toward the target molecules are left in the resulting polymers, which are composed of functional monomer residues assembled to fit the template molecule in size and shape. Since postimprinting modification has been reported as a way to construct binding sites only inside the imprinted cavity,22−27 a previously proposed dummy molecule imprinting technique conjunction with a postimprinting oxidation28 was employed in this study to generate BPA binding cavity, in which a structurally related dummy template, N,N′-bis(3-vinylbenzylidene)-4,4′-diaminodiphenylmethane (VB-DADPM) bearing a structure of diaminodiphenylmethane and 3-vinyl benzaldehyde connected by Schiff base linkage was used, instead of BPA derivatives (Figure 2). 7084

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Binding Behavior of free BPA on the MIP-Np-Immobilized s_OWG in the Presence of BPA-AuNp. The SPR spectra were measured when the incidence angle between the propagation direction of the light and the horizontal direction was adjusted to 10°, 12°, 14°, 18°, and 22° after the solvent (toluene/methanol 20:1 (v/v)) was flowed for 10 min. Next, a sequence of 2 wt % of MIP-Np emulsion (toluene), BPA-AuNp solution (THF), free BPA dissolved in toluene/ methanol 20:1 (v/v) and again toluene were passed in order. The SPR spectra were measured at each concentration. All of the solutions were flowed for 10 min at 50 μL/min at room temperature.

After the monomers were absorbed into the seed particle, AAPH (14 mg, 0.05 mmol) dissolved in water (500 mg) was added and further polymerization was carried out at 80 °C for 16 h. In order to cleave the Schiff base linkage for the removal of the template analogue, the emulsion (30 g) was suspended in 1 mM HCl aqueous solution and stirred at 250 rpm for 8 h. The obtained emulsion was then dispersed into a mixture of 0.04 M HCl and 1.1 M H2O2 aqueous solution and stirred at 250 rpm for 24 h for the oxidation of the benzaldehyde residues in the binding cavity, so as to create the binding sites for BPA in the particles. Finally, imprinted nanoparticles were separated by centrifugation and washed with 1 M HCl aqueous solution, water and methanol. The diameter of each particle was measured by dynamic light scattering (DLS) (DLS 7000, Otsuka Electronics Co.,Ltd., Osaka, Japan). A mean particle diameter of MIP-Np was 130 nm (PDI; 1.03). Synthesis of BPA-Grafted Gold Nanoparticles (BPA-AuNp). 29,30 BPA-thiol (10.9 mg, 23.2 μmol) was dissolved in 5.8 mM chloroauric acid (HAuCl4) (4 mL, 23.2 μmol) in methanol solution containing acetic acid (80 μL) and 0.4 M aqueous sodium borohydride (NaBH4) (0.8 mL) was added dropwise to the solution under stirring condition. After further stirring for 30 min, the solvent was removed under reduced pressure. The obtained nanoparticles were extracted with AcOEt/NaCl aqueous solution and the organic phase was dried with MgSO4. Filtration was carried out to remove MgSO4, BPA-AuNp in the filtrate was precipitate. Thus the aggregate was separated by centrifugation and dispersed in methanol. Nanoparticle yield for this stage was 17.3 mg. The resulting BPA-AuNp was characterized by DLS (DLS 7000, Otsuka Electronics Co., Ltd.), transmission electron microscopy (TEM) (H-7500, Hitachi High-Tech Fielding Corporation, Tokyo, Japan) and UV−vis spectrophotometry (V-560, JASCO Corporation, Tokyo, Japan). Preparation of BPA-Immobilized s_OWG. The Au and Ag deposited s_OWG was cleaned by methanol, then 1 mM solution of BPA-thiol in ethanol was dropped onto the optical waveguide, and spread out in a thin layer with the application of a cover glass. After standing two hours, the cover glass was removed and the optical waveguide was washed with methanol and dried in vacuo. Immobilization of MIP-Np Nanoparticles on the BPAImmobilized s_OWG. Optical waveguide surface plasmon resonance spectrometer (S-SPR-6000, System Instruments Co., Ltd.) was used for SPR measurements (Figure 3). At first, toluene was flowed for 10 min at 50 μL/min. Then 2 wt % of MIP-Np prepared in toluene was flowed at the same condition, allowing binding to the substrate. After methanol or THF was flowed through the instrument, it was followed by a toluene rinse, and the SPR spectrum was collected.

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RESULTS AND DISCUSSION Characterization of BPA-AuNp. UV−vis extinction of BPA-AuNp was measured, and peaks of 520 nm corresponding to AuNp and 279 nm corresponding to BPA-thiol derivative were observed in methanolic solution (Figure 1a). This result confirms the successful introduction of BPA moiety onto AuNp. The particle size of the BPA-AuNp was estimated to be approximately in the 3−5 nm range, as judged by a TEM image (Figure 4b). At higher concentrations, BPA-AuNp were seen to aggregate in methanol; however, the aggregation could be dispersed by ultrasonic irradiation. Optimization of Incidence Angle for SPR Signals from Au and Ag Deposition Bands on the s_OWG. Optimization of the incidence angle was first carried out for measurements of s_OWG-SPR by changing the incidence angle of white light introduced to the side of the s_OWG. Two peaks based on SPR from both Au and Ag deposition bands were clearly observed at around 600 and 550 nm, respectively. As the angle of incidence was increased, the resonant reflection peaks were red-shifted, and gradually overlapped one another (Figure 5). From these results, an angle of 12° between the propagation direction of the light and the horizontal direction was chosen for the proceeding experiments, as, under these conditions, the two peaks were clearly resolved with similar intensities. At this setting, the incident angle between the propagation direction of the light and the perpendicular direction inside the s_OWG was calculated to be 69.8° (refractive index of the layer: 1.81). Immobilization of MIP-Np on the Au and Ag Deposition Bands on the s_OWG. The Au and Ag deposition bands on the s_OWG were treated by BPA-thiol to prepare self-assembled monolayer (Figure 4a). This resulted in a highly dense BPA surface, onto which the MIP-Np suspended in toluene were continuously poured onto the s_OWG through the flow system to immobilize the MIP-Np. At that time, 20 to 25 nm of red shifts were observed for both deposition bands due to the binding of MIP-Np. After washing with methanol to remove insufficiently immobilized MIP-Np, blue shifts of 5.0 and 1.6 nm on the Au and Ag deposition bands were observed (Figure 6), suggesting that 93% and 74% of MIP-Np remained and stably immobilized on the Au and Ag deposition band, respectively. Effect of BPA-AuNp on the SPR Response. Effect of BPA-AuNp on the SPR response of the MIP-Np-immobilized Au and Ag deposition bands was examined by injecting various densities of BPA-AuNp dispersed in THF into the flow system (Figure 1b). It has been verified that the immobilized MIP-Np was not peeled off by the THF treatment. As the density of BPA-AuNp was increased, the peaks corresponding to the Auand Ag-based SPR was red-shifted reached a saturation point at 0.2 mg/mL of BPA-AuNp, and the degree of Δλ derived from the Ag-based SPR was approximately 4 times greater than that of Au deposition band (Figure 7). These phenomena may be considered reasonably acceptable as they are supported by

Figure 3. Schematic illustrations of apparatus. (a) slab optical waveguide surface plasmon resonance (s_OWG-SPR) sensing system; (b) s_OWG (L: 65 mm × W: 18 mm × thickness: 0.2 mm; refractive index: 1.81) having consecutive parallel gold and silver deposition bands (L: 2 mm × W: 18 mm × thickness 50 nm with 2 nm titanium adhesion layer for the deposition). 7085

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Figure 4. (a) UV−vis spectra of BPA-AuNp (solid line) and the BPA-thiol derivative (dashed line) in methanol; (b) Transmission electron microscope (TEM) images of BPA-AuNp (dispersion element ×200 000).

Figure 5. Effect of angles between the propagating direction of the light and the horizontal direction on (a) SPR spectra shifts in toluene/methanol (20:1, v/v) and (b) plots of the resonant reflection peak bottom vs the incidence angle on the Au and Ag deposition bands.

Figure 7. Peak shifts of SPR spectra on the addition of BPA-AuNp to MIP-Np-immobilized Ag (○) and Au (●) with the angle of 12° between the propagation direction of the light and the horizontal direction. MIP-Np immobilization: 2%(w/w) of MIP-Np in toluene was flowed into the BPA-immobilized s_OWG. BPA-AuNp binding: BPA-AuNp in THF (0, 0.05, 0.1, 0.2, 0.5 mg/mL) was flowed into the MIP-Np-immobilized s_OWG.

Figure 6. SPR spectral change on the adsorption of MIP-Np (gray bar) by 2 wt % of MIP-Np in toluene on the Au and Ag deposition bands modified by BPA-SH, and subsequent methanol wash for 10 min (white bar).

theoretical calculation from Homola et al.,31 who demonstrated a similar trend. Competitive Binding of Free BPA to the MIP-NpImmobilized Au and Ag Deposition Bands. It is expected that free BPA may compete with bound BPA-AuNp against the immobilized MIP-Np on the s_OWG, which would be indicated by a change in the SPR spectra (Figure 1c). However, since BPA is a relatively small molecule, it could be difficult to affect the signals directly in the refractive index of the near field solely based on the binding of free BPA on the surface of MIPNp-immobilized s_OWG. As expected, SPR spectra derived

from the Au deposition band on the s_OWG was not changed at 0 to 1.0 mM concentration range (Figure 8a), while at a higher concentration range, the blue shift was observed (Figure 8b). This shift was not observed in the absence of BPA-AuNp (data not shown), implying that MIP-Np are stably immobilized on the s_OWG under those conditions. The reason for the shift may be desorption of BPA-AuNp in competition with free BPA against the BPA binding sites on the immobilized MIP-Np, not desorption of the immobilized MIPNp from the s_OWG. 7086

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Figure 8. Peak shifts of SPR spectra by the addition of free BPA into MIP-Np-immobilized on the s_OWG after 0.5 mg/mL of BPA-AuNP in THF was flowed. (a) BPA conc. range: 0, 0.1, 0.5, and 1.0 mM; (b) BPA conc. range: 1000 and 2000 mM in toluene/methanol (20:1, v/v).

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Interestingly, the Ag-based SPR spectra showed a red shift (0.7 nm) when free BPA (0.1 mM) was passed over the BPAAuNp/immobilized MIP-Np complexes formed on the s_OWG when free BPA was flowed (Figure 8a). For a higher concentration range, the spectra were oppositely shifted to the longer wavelength, as is in the case of Au-based SPR spectra (Figure 8b). These results suggest that the signal caused by the BPA binding on the MIP-Np-immobilized Ag deposition band on the s_OWG was enhanced in the presence of BPA-AuNp. Similar to the case of the Au deposition band, such a spectral shift was not observed in the absence of BPA-AuNp (data not shown), suggesting that localized surface plasmon resonance on the BPA-AuNp would affect the surface plasmon resonance on the Ag deposition band.

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Corresponding Author

*Tel/Fax: +81-78-803-6158; e-mail: [email protected]. jp. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank Dr. H. Takahashi of System Instruments Co., Ltd (Tokyo) for his kind discussion on s_OWG-SPR. We would also appreciate Nippon Steel Kankyo Engineering for kindly providing s_OWG-SPR. A part of this work was carried out with financial aid from the industry/academia collaboration program of New Energy and Industrial Technology Development Organization (NEDO) with Nippon Steel Kankyo Engineering Co., Ltd. (Tokyo).

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CONCLUSIONS The potential for a BPA sensing device was demonstrated on the s_OWG-based SPR sensing system, in which resonant reflection spectra were measured on the MIP-Np-immobilized consecutive parallel gold and silver deposition bands coexistent with BPA-AuNp. Two SPR peaks around 600 and 550 nm derived from the Au and Ag deposition bands, respectively, were detected when the angle of 12° between the propagation direction of the light and the horizontal direction was chosen, so that the binding behaviors on both deposition bands were independently and simultaneously characterized. When free BPA was present with BPA-AuNp on the MIP-Np-immobilized Ag deposition band on the s_OWG, a red-shift was observed, unlike the case for the Au deposition band, meaning that BPA binding signal is enhanced in the presence of the AuNp. Consequently, label-free detection of BPA could be achieved by using the proposed s_OWG-SPR sensor in conjunction with the use of MIP-Np and BPA-AuNp. Furthermore, the use of not only Au and Ag, but also any kinds of metal pairs that are SPR active could be applied with appropriate light sources, therefore, the proposed method would extend SPR applications, which enables us to detect plural SPR characteristics based on different metals, simultaneously.

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AUTHOR INFORMATION

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REFERENCES

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ASSOCIATED CONTENT

S Supporting Information *

Experimental procedure for 1H NMR spectrum of BPA-thiol, synthesis of VB-DADPM (template molecule), polymer recipe of seed particle and the resulting particle diameter. This 7087

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