1.Introduction

Metronidazole,one of nitroimidazole derivative drugs(Fig.1)well-known for its antimicrobial properties, is effective against trichomonas[1–3],Vincent's organisms[4]and anaerobic bacteria [5–7].However,overuse and long-term use of metronidazole will cause toxicity[8],peripheral neuropathies[9]and opticneuropathy[10,11].Therefore,itisnecessary to monitor metronidazole concentration in patients under antibiotic therapy.Several analytical methods have been reported for the determination of metronidazole,including spectrophotometry[12,13]and chromatography[14–17].However,these methods could not realize high selectivity of metronidazole determination,and such determination processes were costly and time consuming.Hence,it is important to develop an alternative method for metronidazole determination with high sensitivity and selectivity.

选取在该科分娩的GDM双胎妊娠产妇33例为观察对象，年龄 24～43 岁，平均（31.6±2.9）岁，孕周 34～41周，平均（37.9±1.2）周，初产妇24例，经产妇9例。 选取同期在该科分娩的GDM单胎妊娠产妇33例为对照组，年龄 24～41 岁，平均（30.7±2.4）岁，孕周 37～41 周，平均（38.2±1.0）周，初产妇22例，经产妇11例。排除妊娠高血压及其他合并症、严重肝肾功能障碍者。患者均知情同意并经伦理委员会批准，两组一般资料比较差异无统计学意义（P＞0.05）。

Nowadays,electrochemical methods have been widely used in environmental analysis and biological samples analysis[18–22].Particularly,electrochemical sensors and biosensors have been developed for pharmaceutical, food, agricultural and environmental analyses due to the advantages of fast response and good sensitivity[23–26].

基于前人的经验及对Einthoven三角定律的深入解读[2-4]，我们尝试寻找一种不用记忆大量错接后心电图形特点规律，仅画图就能快速准确地判断出心电图的各类导联错接的方法，还原“犯罪现场”。

Electrochemical determination based on electrochemical sensor possesses the advantages of high sensitivity low cost and easy operation,which was widely used in analytical chemistry,and separation step is usually used to increase the selectivity prior to the determination[27–29].Electrochemical sensors fabricated by different modified electrode materials have been developed for electrochemical determination [27,29].Poly-dopamine is a conductive and biocompatible polymer,which has versatile applications due to its many attractive properties[30–33].Polydopamine can be coated on different materials and can be a good support for loading metal nanoparticle to form nanocomposites[34,35],which finally was applied in various electrochemical biosensors[36–39].Moreover,the polymerization method of dopamine was facile,and its surface morphology and layer thickness can be better controlled[40–42].Furthermore,polydopamine can be easily coated on the materials surface through a very strong chemical bond[43,44].Carboxylic muti-walled carbon nanotubes(MWCNTs–COOH)have been widely applied for the development of chemical sensors due to their excellent electrical conductivity,high surface area,remarkable mechanical strength and good chemical stability[45,46].

Where m is the slope of the calibration plot in the linear range,and Sb is the standard deviation of the blank response which was obtained from 20 replicate measurements of the blank PBS buffer solution.

Fig.1.Chemical structure of metronidazole.

Selectivity,stability and reproducibility of the proposed sensors are key factors for their practical application.The proposed sensor was not affected by additions of 100-fold concentrations of various inorganic ions(K+,Mg2+,Zn2+,Na+,Ca2+,PO43-,SO42-,F-,CO32-,NO3-and Cl-,signal change below 3%)and 10-fold concentrations of some organic compounds(oxalic acid,ascorbic acid,glucose,citric acid,cystine,alanine and tartaric acid,signal change below 6%).This results suggested that the proposed sensor possesses excellent selectivity for the determination of metronidazole.After the prepared electrode was stored at 4°C in a refrigerator for 1 month,the reduction peak current of metronidazole remained 95.2%of its initial value,indicating that the proposed sensor possesses good stability.Moreover,four modified electrodes were fabricated to estimate the sensor's reproducibility,and the relative standard deviation(RSD)of detection measurements was calculated to be 2.5%for metronidazole,suggesting that the proposed sensor possesses high reproducibility.Therefore,the polydopamine/MWCNTs–COOH nanocomposites/GCE sensor is promising for determination of metronidazole with excellent selectivity,stability and reproducibility.

2.Experimental

2.1.Reagents

Metronidazole(99%,analytical grade)was purchased from Macklin Biochemical Co.,Ltd.(Shanghai,China).Carboxylic multiwalled carbon nanotubes were purchased from Aladdin Industrial Company(Shanghai,China).Dopamine hydrochloride(98%,analytical grade)was purchased from J&K Chemical(Beijing,China).Drug samples were obtained from Huayueyang Biotechnology Co.,Ltd.(Beijing,China).All other reagents were of analytical grade and used without further purification.0.1 M phosphate buffer solution(PBS)was prepared by mixing NaH2PO4and Na2HPO4,and then adjusted to the required pH values with H3PO4or NaOH solution.All aqueous solutions were prepared with doubly distilled water.

2.2.Fabrication of polydopamine/MWCNTs–COOH nanocomposites/GCE sensor

In pH values of 9·0–11·0:

2.3.Apparatus and method

Cyclic voltammetry(CV),electrochemical impedance spectroscopy(EIS)and differential pulse voltammetry(DPV)experiments were performed on a CHI 660B electrochemical workstation,purchased from Chenhua Co,Ltd.(Shanghai,China).A conventional three-electrode system was used with a glassy carbon electrode(3 mm diameter)as the working electrode,a saturated calomel reference electrode(SCE)and a Pt wire as the counter electrode.The differential pulse voltammetry scans ranged from-0.4 V to-1.0 V with amplitude of 0.05 V,pulse width of 0.05 s,pulse period of 0.5 s,sampling width of 0.0167,and increment of 0.004 V.For CV,scan rate was 50 mV/s,sample interval was 0.001 V.Electrochemical impedense spectroscopy was obtained in 5 mmol/dm3K3[Fe(CN)6]/K4[Fe(CN)6]solution containing 0.1 M KCl under open circuit potential with frequency range from 0.1 Hz to 100 kHz and 5 mV amplitude.The surface morphology was characterized using a field emission scanning electron microscope(FE-SEM;Zeiss Ultra55,Germany).

For the determination of metronidazole,the detection limit(Cm)was obtained using the following equation:

独立女性陶艺家张婧婧同时也是陶瓷学院的教授，她的很多作品，尤其是代表作“弧”系列，单独看似乎仅仅是在探索一种陶瓷材料可塑造性，或者说制作工艺的可能性。但当你见到它们装置在某一空间，诸如画廊展厅或酒店大堂时，会立即对它们有质变的感官享受，仿佛此时的整个空间氛围乃至气质都在瞬间发生变化。

3.Results and discussion

3.1.Characterization of polydopamine/MWCNTs–COOH nanocomposites modified GCE

The SEM images of MWCNTs–COOH/GCE and polydopamine/MWCNTs–COOH nanocomposites/GCE are shown in Fig.2.The MWCNTs–COOH can be obviously observed in Fig.2A,when the polydopamine was electropolymerized onto the electrode surface,a rough polymer film could be obviously observed on the surface of MWCNTs–COOH,indicating the successful preparation of polydopamine/MWCNTs–COOH nanocomposites/GCE sensor(Fig.2B).

The detection limit of metronidazole was determined to be 0.25 μmol/dm3(S/N=3).Moreover,compared with recently most reported electrochemical sensors[49–55]for determination of metronidazole,our proposed nanocomposites sensor could fi nish the ultrasensitive determination of metronidazole with a much widerlinearrangesand a much lowerdetection limits(Table 2).

Fig.2.SEM images of(A)MWCNTs–COOH/GCE and(B)polydopamine/MWCNTs–COOH nanocomposites/GCE.

Fig.3.(A)Cyclic voltammograms and(B)Electrochemical impedance spectroscopy obtained at(a)bare GCE,(b)MWCNTs–COOH/GCE and(c)polydopamine/MWCNTs–COOH nanocomposites/GCE in 5 mmol/dm3K3[Fe(CN)6]/K4[Fe(CN)6]solution containing 0.1 M KCl.

Fig.4.(A)CVs and(B)DPVs of 500 μmol/dm3metronidazole in 0.1 M PBS(pH=10)buffer solution at(a)bare GCE and(b)polydopamine/MWCNTs–COOH nanocomposites/GCE.

Fig.5.(A)CVs of 500 μmol/dm3metronidazole at the polydopamine/MWCNTs–COOH nanocomposites/GCE in 0.1 M PBS(pH=10)buffer solution at different scan rates.(B)The relationship between the reduction peak currents and scan rates.

Fig.6.The effect of(A)accumulation time and(B)accumulation potential on the reduction peak current of 500 μmol/dm3metronidazole in 0.1 M PBS(pH=10)buffer solution at the polydopamine/MWCNTs–COOH nanocomposites/GCE.

Fig.7.(A)CVs of 500 μmol/dm3metronidazole in 0.1 M PBS(pH=10)buffer solution at different pH values at the polydopamine/MWCNTs–COOH nanocomposites/GCE.The relationship of(B)reduction peak potentials vs.pH values and(C)reduction peak currents vs.pH values.

Electrochemical impedance spectroscopy(EIS)is a powerful tool for studying the surface-modified electrode.Fig.3B shows the EISplotsofbareGCE,MWCNTs–COOH/GCE,polydopamine/MWCNTs–COOH nanocomposites/GCE at 5 mmol/dm3 K3[Fe(CN)6]/K4[Fe(CN)6]in 0.1 M KCl.The bare GCE(curve a)possesses a small resistance.When MWCNTs–COOH was modified onto the bare GCE surface(curve b),it displayed a straight line in the Nyquist plot because the resistance was significantly decreased.Moreover,thepolydopamine/MWCNTs–COOHnanocomposites/GCE(curve c)also displayed a straight line in the Nyquist plot,which almost showed the resistance same as MWCNTs–COOH/GCE,because polydopamine/MWCNTs–COOH nanocomposites also possess excellent electron transfer efficiency.Therefore,both the CV and EIS plots proved the successful preparation of polydopamine/MWCNTs–COOH nanocomposites/GCE sensor.

3.2.Electrochemical behavior of metronidazole at the polydopamine/MWCNTs–COOH nanocomposites/GCE sensor

The electrochemical behavior of bare GCE and polydopamine/MWCNTs–COOH nanocomposites/GCE for determination of 500 μmol/dm3metronidazole in 0.1 M PBS(pH 10.0)buffer solution is shown in Fig.4A.The reduction peak current and peak potential of metronidazole at the bare GCE(curve a)were Ip=-8.44 μA and Ep=-0.749 V.However,compared to the bare GCE,the polydopamine/MWCNTs–COOH nanocomposites/GCE(curve b)exhibited significantly increased reduction peak current(Ip=-41.12 μA)and significantly increased reduction peak potential(Ep=-0.721 V)of metronidazole.The significantly increased reduction peak potential and significantly increased reduction peak current both confirmed the polydopamine/MWCNTs–COOH nanocomposites possess strong catalytic activity towards the reduction of metronidazole.Moreover,the DPVs results in Fig.4B correspond with the CVs in Fig.4A.Therefore,the polydopamine/MWCNTs–COOH nanocomposites/GCE sensor can be successfully utilized for the determination of metronidazole.

3.3.The effect of scan rate

The CVs of polydopamine/MWCNTs–COOH nanocomposites/GCE in 500 μmol/dm3metronidazole at different scan rates are shown in Fig.5A,where the reduction peak currents showed linearity with the scan rates.And the linear regression equation can be expressed as Ip(μA)=-0.363ν(mV/s)-32.399(R=-0.9914)in Fig.5B,indicating that the reduction of the metronidazole is a typical adsorption controlled process.Therefore,it is necessary to study the effect of accumulation time and accumulation potential in order to obtain more sensitive determination for metronidazole.

3.4.The effect of accumulation time and accumulation potential

The quantitative determination of metronidazole at the polydopamine/MWCNTs–COOH nanocomposites/GCE was achieved by DPV under optimal conditions addressed above.As shown in Fig.8,the reduction peak currents of metronidazole at the polydopamine/MWCNTs–COOH nanocomposites/GCE increased linearly with concentration ranges of 5–300 μmol/dm3,300–800 μmol/dm3and 800–5000 μmol/dm3,and their corresponding linear regression equations are listed in Table 1.

3.5.The pH effect

The effect of pH value on the electrochemical response of 500 μmol/dm3metronidazole in 0.1 M PBS with pH value ranging from 5.0 to 11.0 at the polydopamine/MWCNTs–COOH nanocomposites/GCE was investigated by CV(Fig.7A).The reduction peak potentials showed linearity with pH values ranging from 5.0–9.0 and 9.0–11.0,with the linear regression equations of Ep=-0.0518pH–0.266(R=-0.9687)and Ep=-0.008pH–0.658(R=-0.9462),respectively(Fig.7B),indicating two different reaction mechanisms of metronidazole.According to previous reports[39,48],the reaction mechanisms of metronidazole are listed below:

Fig.8.DPVs of metronidazole at(A)5–800 μmol/dm3and(C)800–5000 μmol/dm3in 0.1 M PBS(pH=10)buffer solution at the polydopamine/MWCNTs–COOH nanocomposites/GCE.Linear relationships between reduction peak currents and concentrations at(B)5–800 μmol/dm3and(D)800–5000 μmol/dm3.

Table 1 Linear regression equations of metronidazole under different concentration rangs.

Equation Concentration range(μM)Linear regression equation R 1 5–300 Ip(μA)= –0.08837c(μM)–0.91 R=–0.9881 2 300–800 Ip(μA)= –0.0423c(μM) –14.71 R=–0.9842 3 800–5000 Ip(μA)= –0.02298c(μM)–29.78 R=–0.9813

In pH values of 5·0–9·0:

First,the bare GCE was polished with 0.3 and 0.05 μm of alumina powders,then rinsed ultrasonically with absolute alcohol and distilled water,and finally dried in the nitrogen stream.5μL of 0.5 mg/mL MWCNTs–COOH homogeneous suspension was dropped onto the electrode surface and then was dried under the infrared lamp,thus obtaining MWCNTs–COOH/GCE.Finally the polydopamine was electropolymerized onto thesurfaceof MWCNTs–COOH by cyclic voltammetry in 5 mmol/dm3dopamine in 0.1 M PBS(pH=5)between-0.4 V and+0.7 V at a scan rate of 50 mV/s for 10 cycles,thus obtained polydopamine/MWCNTs–COOH nanocomposites/GCE sensor.

Moreover,as shown in Fig.7C,because the reduction peak current achieved the maximum value in pH=10.0,the pH value of 10.0 was chosen as the best pH value for the determination of metronidazole.

3.6.The quantitative determination of metronidazole

The effect of accumulation time and accumulation potential for the determination of metronidazole was studied by DPVs in Fig.6.As shown in Fig.6A,at the accumulation potential of-0.5 V,the reduction peak current increased gradually with the accumulation time and reached the maximum value when the accumulation time was 200 s.However,the reduction peak current almost remained the same after 200 s due to the saturation of surface active catalytic sites of polydopamine/MWCNTs–COOH nanocomposites/GCE.Thus,the optimal accumulation time of 200 s was employed in our experiments.With the optimal accumulation time determined above,we further studied the effect of accumulation potential on reduction peak current of metronidazole.As shown in Fig.6B,the reduction peak current decreased gradually with the increase of accumulation potential;therefore,the accumulation potentialwaschosen at-0.5 V fordetermination ofmetronidazole in our later experiments.

Fig.3A shows cyclic voltammograms of bare GCE,MWCNTs–COOH/GCE and polydopamine/MWCNTs–COOH nanocomposites/GCE in the presence of 5 mmol/dm3K3Fe(CN)6]/K4[Fe(CN)6]solution containing 0.1 M KCl.A pair of reversible oxidation and reduction peaks were observed at 0.26 and 0.17 V,respectively,for the bare GCE(curve a).After being modified with the MWCNTs–COOH(curve b),it showed obvious increased redox peak currents because MWCNTs–COOH can dramatically increase the electrode surface area and possesses good electrical conductivity[47].Moreover,the polydopamine/MWCNTs–COOH nanocomposites/GCE(curve c)showed further enhanced redox peak currents compared with MWCNTs–COOH/GCE because polydopamine can accelerate the electron transfer eff i ciency between the electrode surface and solution.

Table 2 Comparison of performances of the polydopamine/MWCNTs–COOH nanocomposites/GCE with other modif i ed electrodes.

Electrode Detection limit/(μmol/dm3) Linear range/(μmol/dm3) Ref.P-AgSA-CE 0.6 2–100 [49]Carbon fiber microdisk electrode 0.5 1–22 [50]Carbon nanotubes/GCE 0.063 0.1–200 [51]DNA/GCE 1 1.0–54.3 [52]Activated GCE 1.1 2–600 [53]Graphene-ionic liquid/GCE 0.047 0.1–25 [54]Cu-poly(Cys)/GCE 0.37 0.5–400 [55]Polydopamine/MWCNTs–COOH nanocomposites/GCE 0.25 5–5000 This work

Table 3 Practical determination of metronidazole in real drug samples(n=3).(Sample responses are expressed as a confidence interval of 95%probability).

Sample Added(μmol/dm3) Founded(μmol/dm3) Recovery(%) RSD(%)1 20 23.66±1.86 118.3 3.2 2 50 55.70±3.97 110.1 2.9 3 200 206.64±3.21 103.3 0.6 4 300 291.39±3.84 93.4 0.6 5 500 506.70±2.35 104.9 0.2

3.7.Selectivity,stability and reproducibility of the polydopamine/MWCNTs–COOH nanocomposites/GCE sensor

In this work,we developed a novel electrochemical sensor based on polydopamine/MWCNTs–COOH nanocomposites,where polydopamine can be easily electropolymerized to the surface of MWCNTs–COOH to form nanocomposites,and f i nally successfully realized the ultrasensitive determination for metronidazole with a wide linear detection range from 5 to 5000 μmol/dm3and a low detection limit of 0.25 μmol/dm3(S/N=3).Most importantly,the proposed sensor has been successfully applied for the quantitative determination of metronidazole in real drug samples.This work would provide an effective analytical strategy for metronidazole determination in application of real pharmaceutical and biological samples analysis.

2016年河北省城镇居民的可支配收入为28 249元，2017年为30 548元；农村居民人均可支配收入2016年为11 919元，2017年为12 881元。2016年城镇居民人均消费支出19 106元，2017年为20 600元；2016年农村居民人均消费支出9 798元,2017年为10 536元。由统计数字可以看到，城乡居民年收入虽然增长较快，但是农村居民收入增长幅度小于城镇居民，且不同地域农村居民收入差距较大[2]。截至2017年底，河北省依然有39个国家级贫困县，195.67万人享受居民最低生活保障，其中，农村居民160.2万人，占81.87%，反映出城乡收入差距较大的现实问题。

3.8.Real samples determination

The practical analytical application of the polydopamine/MWCNTs–COOH nanocomposites/GCE sensor was evaluated by determination of metronidazole in real drug samples by standardaddition technique.Three parallel experiments were performed on all measurements.As shown in Table 3,the recovery of the real samples ranged between 93.4%and 118.3%,and the RSD values were less than 4%,indicating that the our proposed sensor can be successfully applied forthepracticaldetermination ofmetronidazole in real samples.

4.Conclusions

In summary,we successfully develop an ultrasensitive electrochemical sensor for metronidazole determination,which was based on polydopamine/MWCNTs–COOH nanocomposites.Moreover,the fabrication of polydopamine/MWCNTs–COOH nanocomposites/GCE sensor was simple,where polydopamine can coat on the surface ofMWCNTs–COOH via asimple electropolymerization process.Under optimized conditions,the proposed sensorshowed widerlineardetection range from 5 to 5000 μmol/dm3and a low detection limit of 0.25 μmol/dm3(S/N=3)for metronidazole,and was successfully applied for the practical determination of metronidazole in real drug samples.The proposed sensor shows broad potential in application of real pharmaceutical and biological samples analysis.

（4）壁參箕軫副辰星政，室嘴翼尾副熒惑政，斗奎并角副歲星政。（《太上說玄天大聖真武本傳神呪妙經註》卷一，《中华道藏》30/533）

对土地流转面积、流转形式的选择、流转收益的分配，基本上是与承包农户协商决定。全市尚未发现在土地流转中搞强迫命令强行推动的情况。

Conflicts of interest

The authors declare that there are no conflicts of interest.

第三，高等教育板块儿。主要是高水平大学建设，把广州大学、广州医科大学建设好。广州市也会针对两所大学提出有针对性的具体措施。同时，我们也要把几个高职院校做好，比如说国家示范校番禺职业技术学院，高职的骨干校广州铁路职业技术学院、广州城市职业学院等，都是我们在“十三五”期间要着力发展、重点建设的学校。另外，在终身教育这一块，我们在“十三五”期间也会以全民教育为目标，以终身教育为核心做大量的工作，积极谋划。特殊教育在“十三五”期间的目标是在国家中心城市当中走在前列，这里包括特殊学校的建设，也包括孤独症孩子重点群体的特殊教育，这是政府的责任。

This work was financially supported by the National Natural Science Foundation of China(Grant Nos.21475046,21427809).

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