Microchim Acta DOI 10.1007/s00604-016-2037-7
ORIGINAL PAPER
Voltammetric determination of the anti-cancer drug nilutamide using a screen-printed carbon electrode modified with a composite prepared from β-cyclodextrin, gold nanoparticles and graphene oxide Raj Karthik 1 & Natarajan Karikalan 1 & Shen-Ming Chen 1 & Periyasami Gnanaprakasam 2 & Chelladurai Karuppiah 1,3
Received: 17 July 2016 / Accepted: 28 November 2016 # Springer-Verlag Wien 2016
Abstract The authors describe an electrochemical method for the determination of the anti-cancer drug nilutamide. The method is based on the use of a composite prepared from βcyclodextrin, gold nanoparticles and graphene oxide (βCD-AuNP/GO). An alkaline solution of glucose was used as a reducing agent to reduce the gold ions, rather than citric acid and a harmful reducing agent such as hydrazine and sodium borohydride. The structure and surface morphology of the βCD-AuNP/GO composite was characterized by Raman spectroscopy, transmission electron microscopy and energydispersive X-ray spectroscopy. A screen printed carbon electrode was modified with the nanocomposite, and the resulting electrode used as a disposable sensor for the determination of nilutamide by differential pulse voltammetry. Best operated at a working voltage of 0.43 V (vs Ag/AgCl), it exhibits excellent electrocatalytic activity and a detection limit as low as 0.4 nM. The sensor was applied to the determination of nilutamide in (spiked) human serum, as well as in a tablet, where it displays good recovery and accuracy. The sensor is repeatable, reproducible, stable and selective even in the presence of other aromatic nitro compounds.
* Shen-Ming Chen
[email protected]
1
Electroanalysis and Bioelectrochemistry Lab, Department of Chemical Engineering and Biotechnology, National Taipei University of Technology, No.1, Section 3, Chung-Hsiao East Road, Taipei 106, Taiwan, Republic of China
2
Department of Chemistry, Karunya University, Coimbatore, Tamil Nadu 641114, India
3
Department of Chemistry, National Taiwan University, No. 1, Section 4, Roosevelt Road, Taipei 106, Taiwan, Republic of China
Keywords Electroanalysis . Drugassay . Non-steroidal drug . Differential pulse voltammetry . Cyclic voltammetry . EDX . Raman spectroscopy . Serum analysis
Introduction Nilutamide (5,5-dimethyl-3-(4-nitro3-(trifluoromethyl)phenyl)imidazolidine-2,4-dione) is a nonsteroidal anti-androgen drug, mostly used for the treatment of metastatic (advanced stage) prostate cancer. It has control the function of testis by blocking the binding sites of androgen receptors [1]. Androgen is the steroidal hormone which stimulates or controls the progress of male characteristics, which includes the growth of normal and cancerous cells in the prostate [2]. Nilutamide can slow down the advancement of prostate cancer and extend a man’s life. However, it also causes some acute side effects such as liver failure, sexual dysfunction, decreased muscle mass, decreased bone mass, hot flushes, interstitial pneumonitis, depression and fatigue [3]. Owing to the severe adverse effects of nilutamide, the dosage should be controlled in medical practices. Hence, the critical determination of nilutamide in biological fluids is important. So far, only limited methods of analysis have been developed and reported for the detection of nilutamide, such as spectrophotometry, square wave voltammetry (SWV) and micellar electrokinetic chromatography [4–6]. In this case, the SWV is an electrochemical method which is faster, more selective and more sensitive for the determination of nilutamide than other techniques. However, the analytical performance of nilutamide detection is still to be improved, hence there is a need for different modified electrodes for the determination of nilutamide. An enormous variety of drugs and biomolecules are determined by various analytical techniques, such as
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chromatography, spectrophotometry, voltammetry, amperometry and stripping methods [7–10]. Nilutamide has been examined in very few reports, despite its various adverse pharmacological effects [4–6]. In recent years, various chemically and electrochemically modified electrodes have been reported for the determination of biomolecules and drugs. These include nanostructured carbonaceous materials (0D, 1D, 2D and 3D), metal nanoparticles and metal oxides [11–14]. Among the carbon materials, graphene oxide (GO) has been considered for nanocomposite preparation due to its large surface area and excellent mechanical and thermal properties. Moreover, the oxygen functionality of GO is more responsible for the incorporation of metal nanoparticles by electrostatic attraction [15]. In particular, gold nanoparticles (AuNP) are the better choice for electrode fabrication due to their good electrochemical properties and high stability over the range of pH associated with the electrolytes [16]. Cyclodextrins (CDs) are oligosaccharides constituted by six, seven, or eight glucose units linked by α-1,4-glucosidic linkages which are characterized as α-, β- and γ-CD, respectively [17]. Among these CDs, β-CD exhibited a high molecular selectivity to the target molecules, which bind into their cavities to form stable host–guest inclusion complexes with strong binding constants of more than 103 [18]. Apart from that, it is highly water soluble and used to improve the solubility and stability of the GO and AuNP [19]. Several studies for sensor applications have been reported based on β-CD and functionalized β-CD [20–22]. In particular, the β-CD is mainly used as a matrix for the enzyme immobilization process [23]. Furthermore, the gold ions are mostly reduced by harmful reducing agents. Later, AuNP are synthesized using plant extracts and citric acid. These greener methods produce nano sized AuNP capped by natural products, which possess various physicochemical properties. Therefore, we prepared βCD-AuNP/GO composite by means of the green method, using the alkaline solution of glucose as a reducing agent at room temperature. The composite was used to determine the nilutamide in real biological samples and displayed good rates of recovery.
voltammetry (CV), amperometry and differential pulse voltammetry (DPV) experiments were carried out using CHI 405a and CHI 900 electrochemical work stations. Surface morphology was probed using transmission electron microscopy (TEM- TECNAI G2) and the elemental analysis was carried out using a HORIBA EMAX X-ACT elemental analyzer. Raman spectra were performed using a Raman spectrometer (Dong Woo 500i, Korea) equipped with a chargecoupled detector.
Experimental section
Fabrication of β-CD-AuNP/GO composite modified electrode
Electrochemical measurements All the electrochemical studies were carried out in a conventional three electrode cell system consisting of a screen printed carbon electrode (SPCE with a working area of 0.196 cm2) as a working electrode, platinum wire as a counter electrode and saturated Ag/AgCl (saturated KCl) as a reference electrode. All the electrochemical experiments were taken in 0.05 M phosphate buffer (pH = 7.0) prepared from Na2HPO4 and NaH2PO4 solutions. Preparation of β-CD-AuNP decorated GO composite The GO was synthesized through a modified version of Hummers’ method, as reported previously. Briefly, 5 mg of GO was dispersed in 5 mL of de-ionized water and ultrasonicated for 30 min. At the same time, 5 mg of β-CD was added into 0.5 mM of H AuCl4 and ultrasonicated for 2 h to get β-CD stabilized gold ions. Then, both suspensions of GO and β-CD stabilized gold ions were added together and stirred for 30 min. After that, the alkaline solution of glucose (0.1 M glucose in 0.1 M NaOH) was added to the β-CDAu ion/GO suspension and stirred for an hour. Finally, the suspension was centrifuged and washed with de-ionized water to completely remove the excess alkali. The precipitate was then dried in an air oven at 40 °C for 2 h. This composite (βCD-AuNP/GO) was used for the further electrochemical studies. The AuNP was prepared for the comparison studies in the same manner. The overall synthesis process is given in Scheme 1.
Materials and methods Graphite powder, nilutamide, gold (III) chloride trihydrate, βcyclodextrin, glucose, dopamine, ascorbic acid, uric acid, glutaric acid, glycine, 4-nitroaniline, 4-nitrobenzene and 4nitrophenol were obtained from Sigma-Aldrich (http://www. sigmaaldrich.com/taiwan.html) and used without further purification. Screen printed carbon electrode (SPCE) was purchased from Zensor R&D Co., Ltd., Taipei, Taiwan (http://www.zensor.com.tw/about/about.htm). Cyclic
The SPCE was washed with ethanol and water to remove impurities on the electrode surface. Next, 5 mg of β-CDAuNP/GO composite was re-dispersed in 5 mL of deionized water and sonicated for 30 min. About the 14 μL of this composite suspension was coated onto the SPCE and dried at room temperature. Afterwards, this modified electrode can be used to further electrochemical studies. The other modified electrodes can be prepared using GO, AuNP and AuNP/GO in the same manner.
Microchim Acta Scheme 1 The overall synthesis process of β-CD-AuNP/GO composite
Results and discussion Choice of materials Many researchers have focused on the preparation of nanomaterials for the application of electrochemical sensors and biosensors. There has been particular concentration on the noble metals for the development of sensor electrodes due to their robustness and excellent electrochemical behavior. However, to improve the electrocatalytic active surface area and conductivity, graphene based materials can be used as a matrix. Hence, we have used the β-CD-AuNP/GO composite for the sensitive detection of the anti-cancer drug nilutamide. Here, GO and β-CD provide excellent support to the distribution of AuNP and increases the stability of AuNP in agglomerate. This composite have resulted in good electrochemical behavior for the determination of nilutamide and has achieved a superior limit of detection in comparison with the previously reported work [6]. Characterization of β-CD-AuNP decorated GO composite The structural disorder and surface morphology of β-CDAuNP/GO composite was probed by Raman spectroscopy and TEM. Figure 1d displays the Raman spectrum of β-CDAuNP/GO composite shows the peaks at 1349 and 1594 cm−1 for the D (disordered) band and G (graphitic) band. Here, the D band is related to the breaking of sp2 symmetry in the ordered carbon lattice by defects and structural disorder. The G band is associated with the first-order stretching vibration
mode (E2g) of sp2 carbon domains [24]. Generally, the GO exhibits an almost equal intensity for the G and D band with an intensity ratio (ID/IG) of 1. In our case, it was 0.91 [25]. This is due to the interaction of AuNP with the GO matrix and the immobilization of β-CD onto the surface of GO. This ID/ IG is directly proportional to the disorder of carbon per hexagonal unit cell. The surface morphology of β-CD-AuNP/GO composite was shown in Fig. 1a&b, which shows the spherical shape of AuNP covered by β-CD. The β-CD-AuNP was uniformly distributed on the surface of GO with an average size of 50 nm. Elemental analysis was used to confirm the presence of β-CD-AuNP on the GO matrix. Fig. 1c shows the EDX spectrum of β-CD-AuNP/GO composite, which displayed the peaks for C, O and Au. These results confirm that the β-CDAuNP was successfully decorated onto the GO matrix.
Electrochemical behavior of nilutamide at various modified electrodes The electrocatalytic behavior of nilutamide was evaluated in 0.05 M phosphate buffer (PB) solution containing 200 μM nilutamide on various modified SPCE’s, such as bare SPCE (a), AuNP (b), AuNP/β-CD (c), GO (d), GO/β-CD (e), AuNP/GO (f) and β-CD-AuNP/GO modified SPCE (g) at a scan rate of 50 mV·s−1 (Fig. 2a). Strong irreversible reduction peaks appeared in the potential window of −0.3 to −0.7 V for all modified SPCE’s, which corresponds to the direct reduction of the NO 2 group in nilutamide to aryl hydroxylamine [26]. It should be noted that the electrocatalytic performance
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Fig. 1 TEM images of β-CD-AuNP/GO composite, (a) low magnification, (b) high magnification and (c) the corresponding EDX spectra of β-CDAuNP/GO composite. (d) The Raman spectra of β-CD-AuNP/GO composite
of the nilutamide at β-CD-AuNP/GO/SPCE (g) show a very high electrocatalytic current (Ipc = 115 μA) and low potential (Epc = −0.45 V) when compared to the other modified electrodes. This high electrocatalytic activity of β-CD-AuNP/GO/ SPCE (g) arises from the effective interaction of β-CD and the nitro group of nilutamide. Herein, the functional groups on the β-CD provided a space for the specific adsorption of nilutamide, whereas the other modified electrodes do not display this characteristic. However, the AuNP/GO/SPCE (f) displayed a slightly negative reduction potential in comparison with that of GO/SPCE (d). Furthermore, the AuNP/ SPCE (b) has no appreciable electrocatalytic reduction of nilutamide. However, the activity of nilutamide reduction was enhanced when the AuNPs were decorated with β-CD and GO. Here, the GO can shift the reduction potential and β-CD can increase the reduction current of nilutamide. Hence, this ternary combination manifested a good electrocatalytic performance toward nilutamide reduction. Furthermore, all modified electrodes have the redox couple for the transformation of aryl hydroxylamine to nitrosobenzene [27]. In addition, the electrochemical
performance of nilutamide was studied in bare SPCE for comparison, which reveals no appreciable activity compared to other modified electrodes.
Effect of scan rate and pH The influence of scan rate on the determination of nilutamide was investigated for the β-CD-AuNP/GO/SPCE in 0.05 M PB solution containing 200 μM nilutamide. The irreversible reduction peak currents of nilutamide increased linearly when increasing the scan rates from 20 to 200 mV·s−1 (Fig. 2b). The observed reduction peak current (Ipc) was plotted (Fig. 2c) against the scan rate (ν) which exhibited the predominant adsorption process with a linear regression equation of Ipc (μA) = −0.40 × 10−6 ν (mV·s−1) – 37.23 μA (R2 = 0.9967). These results indicate that the electron transfer reaction of nilutamide was an adsorption-controlled process. The charge transfer coefficient of the nilutamide was calculated from the following equation, using the parameters observed in the plot (Fig. 2d) of reduction peak current vs. natural logarithm of scan rate (ln ν).
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Fig. 2 (a) CV of different modified electrodes of bare SPCE (a), AuNP (b), AuNP/β-CD (c), GO (d), GO/β-CD (e), AuNP/GO (f) and β-CDAuNP/GO modified SPCE (g) in the presence of 200 μM nilutamide, (b) CVs of nilutamide reduction at β-CD-AuNP/GO/SPCE for various scan
E pc
RT ¼E − lnv αnF
Where Epc is the cathodic peak potential, R is the gas constant, T is the standard temperature, α is the charge-transfer coefficient, ν is scan rate, n is the number of transferred electrons, Eo is the formal potential and F is the Faraday constant. These results revealed that the value of α is 0.52 by assuming the number of electrons (n) transferred was 4, which is associated with the reduction of nilutamide to aryl hydroxylamine. The pH of the electrolyte considerably alters the electrocatalytic performance of the nilutamide; therefore, the pH study was carried out in solutions ranging from pH 3.0 to pH 11.0. Figure 3a displays the electrocatalytic behavior of nilutamide in various pH values, which reveals that the electrocatalytic reduction potentials were shifted to the negative side while increasing the pH. At pH 3.0–5.0, more hydrogen ions participated in the nilutamide reduction process; hence, the redox peak current was higher than at other pH values. However, the
rates from 20 to 200 mV·s−1 and (c) the corresponding plot of peak current vs. scan rate and (d) the peak potential vs. natural logarithm of scan rate
direct irreversible reduction peak current of nilutamide was higher at pH 7.0, thus it was used for the further electrochemical studies.
Determination of nilutamide The DPV technique was employed to determine the nilutamide using the β-CD-AuNP/GO/SPCE in 0.05 M PB solution (pH 7.0). Figure 3b depicts that the electrocatalytic reduction of nilutamide by adding different concentrations of nilutamide from 0.01 to 1150 μM. The reduction peak current of nilutamide increased successively with increasing concentrations of nilutamide. Linearity was obtained for the peak current of the nilutamide reduction vs. concentration range from 0.01 to 193 μM with a linear correlation coefficient of R2 = 0.9699 (Fig. 3b (inset)). From this calibration plot, the lower detection limit (LOD) was calculated to be 0.4 nM (S/N = 3) and the sensitivity was 1.167 μAμM−1 cm−2. The analytical performance of the nilutamide reduction on the β-
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Fig. 3 (a) CVs of the reduction of nilutamide on β-CD-AuNP/GO/SPCE in various pH ranging from 3.0 to 11.0. (b) DPV of β-CD-AuNP/GO/ SPCE in various concentrations of nilutamide ranging from 0.01 to 1150 μM and the inset shows the corresponding calibration plot. (c) The interference studies of nilutamide (Nil, 100 μM) detection on βCD-AuNP/GO/SPCE in the presence of 100-fold excess of interfering
species (a) 4-nitrobenzene, (b) flutamide, (c) 4-nitroaniline, (d) 4-nitrophenol, (e) K+, (f) Fe2+, (g) glucose, (h) uric acid, (i) dopamine, (j) ascorbic acid, (k) glutaric acid, (l) glycine, (m) Ca2+ and (n) Na+. (d) Stability test of β-CD-AuNP/GO/SPCE in presence of 200 μM nilutamide for the 3500 s
CD-AuNP/GO/SPCE was compared with other previously reported analytical methods, as shown in Table 1. As stated earlier, only one electrochemical method (SWV) has been developed for nilutamide determination [6]. Comparatively,
the demonstrated disposable β-CD-AuNP/GO/SPCE exhibits good analytical performance in comparison with other reported nilutamide detection methods and achieved a very low LOD.
Table 1 Comparison of analytical performances of nilutamide determination with other analytical methods
Material
Method
Linear range
Limit of detection
Ref
-
Micellar electrokinetic chromatography UV-Visible Spectrophotometry Automatic micro-flow system Square wave adsorptive stripping voltammetry (SWASV) Differential pulse Voltammetry (DPV)
-
26 μg·L−1
[4]
10.0–50.0 μg·mL−1
0.0175 μg·mL−1
[28]
-
2.26 mg·L−1
[5]
0.076–0.3 μM
3 nM
[6]
0.01–193 μM
0.4 nM
This work
DDQ/PCA ZnONPs/CPE β-CD-AuNP/GO/SPCE
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Stability and reproducibility Stability is a major issue when fabricating a modified electrode. Hence, the prepared electrode was explored by means of a stability test for 3500 s in 0.05 M PB solution containing 200 μM nilutamide. Figure 3d shows the chronoamperometric responses of nilutamide reduction at β-CD-AuNP/GO/SPCE, which revealed a highly stable steady state current response up to 2000 s. After that, the reduction peak current was increased due to the further reduction of previously formed product. Nevertheless, the fabricated electrode shows high stability over the 2000 s, making it acceptable for practical electrochemical analysis. Meanwhile, the six independent electrodes were fabricated with β-CD-AuNP/GO composite and used for the determination of nilutamide, resulting in excellent reproducibility with an RSD of 3.90%. Moreover, the modified electrode was also examined for storage stability for successive weeks. The electrode retained a response current of about 90.15% of its initial response in 5 weeks, which indicates that the reported electrode material has excellent storage stability. These results show that the disposable β-CD-AuNP/GO/SPCE has excellent stability and reproducibility.
Selectivity study Selectivity is an important characteristic of electrochemical sensors. Hence, we have examined the selectivity of the βCD-AuNP/GO modified SPCE towards the determination of the anti-cancer drug nilutamide by the DPV. For this study, potential biologically active species and typical aromatic nitro compounds have been investigated in the aspect of pharmaceutical formulations. Figure 3c shows the interference effect of nilutamide on β-CD-AuNP/GO/SPCE with the addition of 100 μM nilutamide (Nil) and 100 fold excess concentrations of (a) 4-nitrobenzene, (b) flutamide, (c) 4-nitroaniline, (d) 4nitrophenol, (e) K+, (f) Fe2+, (g) glucose, (h) uric acid, (i) dopamine, (j) ascorbic acid, (k) glutaric acid, (l) glycine, (m) Ca2+ and (n) Na+. From the result, the response current of nilutamide reduction is not affected by other potentially
Table 2 Determination of nilutamide in real samples using disposable β-CD-AuNP/GO/ SPCE
Nilutamide tablet
Real sample analysis Practical applicability of the β-CD-AuNP/GO modified SPCE was explored in the real sample analysis for the determination of nilutamide in tablet and human serum samples. The human serum sample was nilutamide free; hence, it was spiked with nilutamide. The samples of human serum (nilutamide spiked) and nilutamide tablet were prepared by the appropriate dilution with 0.05 M PB solution (pH 7.0) and directly used for the determination of nilutamide. The previously reported standard addition method was used to calculate the recoveries. The recoveries range from from 98.66% to 102.2% for the nilutamide in human serum (spiked) and in the tablet, and the results are summarized in Table 2. They certify that the β-CD-AuNP/GO/SPCE has a good recovery for the determination of nilutamide and that it can be used for biosensors and pharmaceutical formulations.
Conclusions We described a simple and sensitive method based on β-CDAuNP/GO/SPCE for the determination of the anti-cancer drug nilutamide by the DPV method. The β-CD-AuNP/GO composite was confirmed by various physical characterizations and its electrochemical behavior was investigated for the detection of nilutamide. The electroanalytical studies demonstrate that the β-CD-AuNP/GO has much better electrocatalytic activity than the other modified electrodes.
Content (μM)
Added (μM)
Founda (μM)
Recovery (%)
R.S.D.b (%)
1 2 3 1
15.0
10.0 15.0 20.0 -
10.13 14.98 19.85 14.80
101.30 99.86 99.00 98.66
3.10 3.18 3.20 3.30
2 3
15.0 15.0
10.0 20.0
25.20 35.80
100.80 102.20
3.13 3.11
Sample Human serum (spiked)
interfering substances, even at high concentrations of the aforementioned interfering compounds. This is due to the low potential detection and specific intercalation of β-CD with nilutamide. This study supports the practical applicability of the β-CD-AuNP/GO/SPCE for the determination of nilutamide in potentially interfering biological or other compounds. Hence, the fabricated β-CD-AuNP/GO/SPCE can be used for the pharmaceutical formulations.
a
Standard addition method
b
Relative standard deviation for three measurements
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The β-CD-AuNP/GO/SPCE revealed a superior linearity over the concentration range from 0.01 to 193 μM and the lowest detection limit of 0.4 nM. The fabricated electrode attained high stability, selectivity and reproducibility towards the determination of nilutamide. Furthermore, the disposable β-CDAuNP/GO modified SPCE was used to determine the nilutamide in real biological and pharmaceutical samples. Acknowledgements This project was supported by the Ministry of Science and Technology, Taiwan (Republic of China). Compliance with ethical standards The author(s) declare that they have no competing interests.
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