Graphitic Carbon Nitride Nanosheets-Based Ratiometric Fluorescent

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Graphitic Carbon Nitride Nanosheets-based Ratiometric Fluorescent Probe for Highly Sensitive Detection of H2O2 and Glucose Jin-Wen Liu, Ying Luo, Yu-Min Wang, Lu-Ying Duan, Jian-hui Jiang, and Ru-Qin Yu ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.6b11207 • Publication Date (Web): 18 Nov 2016 Downloaded from http://pubs.acs.org on November 21, 2016

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ACS Applied Materials & Interfaces

Graphitic Carbon Nitride Nanosheets-based Ratiometric Fluorescent Probe for Highly Sensitive Detection of H2O2 and Glucose ‡

‡

Jin-Wen Liu , Ying Luo , Yu-Min Wang, Lu-Ying Duan, Jian-Hui Jiang*, and Ru-Qin Yu* Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China ABSTRACT: Graphitic carbon nitride (g-C3N4) nanosheets, an emerging graphene-like carbon-based nanomaterial with high fluorescence and large specific surface areas, hold great potential for biosensor applications. Current g-C3N4 nanosheets based fluorescent biosensors majorly rely on single fluorescent intensity reading through fluorescence quenching interactions between the nanosheets and metal ions. Here we report for the first time that the development of a novel g-C3N4 nanosheets-based ratiometric fluorescence sensing strategy for highly sensitive detection of H2O2 and glucose. With o-phenylenediamine (OPD) oxidized by H2O2 in the presence of horseradish peroxidase (HRP), the oxidization product can assemble on the g-C3N4 nanosheets through hydrogen bonding and π−π stacking, which effectively quenches the fluorescence of g-C3N4 while delivers a new emission peak. The ratiometric signal variations enable robust and sensitive detection of H2O2. Based on the glucose convert into H2O2 through the catalysis of glucose oxidase, the g-C3N4-based ratiometric fluorescence sensing platform is also exploited for glucose assay. The developed strategy is demonstrated to give a detection limit of 50 nM for H2O2 and 0.4 μM for glucose, at the same time, it has been successfully used for glucose levels detection in human serum. This strategy may provide a cost-efficient, robust, and high-throughput platform for detecting various species involving H2O2-generation reactions for biomedical applications. KEYWORDS: graphitic carbon nitride nanosheets, ratiometric, H2O2, glucose

INTRODUCTION Hydrogen peroxide (H2O2), an important biochemical molecule, is involved in redox signaling pathways associated with cell proliferation, differentiation, and migration as well as disease progression, which is of practical importance in the adjustment of various biological processes including aging and carcinogenesis.1 Disorder or accumulation of H2O2 within cell can lead to the occurrence of several severe diseases such as cancer and central nervous system diseases.2-4 Therefore, the detection of H2O2 is crucial for clinical diagnosis and biomedical research. In the process of cellular metabolism, glucose is the major energy source, which also plays key function during the biological systems.5 It is well-known that the conversion of glucose into H2O2 can be easily achievable by glucose oxidase (GOx) because glucose can be catalyzed by glucose oxidase and produce its hydrolysates and H2O2.6 Usually, the blood glucose level is tightly related with hypoglycemia or diabetes.7-9 Hence, glucose detection is of great importance for the diabetes mellitus research and clinical monitoring. The deve-lopment of highly sensitive H2O2 and glucose assays is urgently needed for both fundamental research and clinical applications. Up until now, various methods for determination of H2O2 and glucose have been reported, such as colorimetry,10-13 electrochemistry14-17 fluorescence18-20 and nanoplasmonic.21 Among them, fluorescence technique is a

powerful tool because of its high sensitivity, convenience, and accessible instrument requirements. In recent years, some attractive fluorescent probes that exhibit high selectivity and sensitivity toward H2O2/glucose have been reported.22,23 However, a majority of these probes use a single fluorescent intensity as the sensing signal, and as a result they tend to be influenced by variations in probe concentrations, sample thickness, excitation intensity and emission collection effciency. On the other hand, ratiometric fluorescence measurement, which could afford simultaneous recording of two measurable signals under one excitation wavelength, has been widely used for biomolecules detection and cell imaging.24-26 The built-in correction capability afforded by ratiometric fluorescence assay provides the possibility of eliminating false signals from environmental effects and thus creating advantages in terms of improved sensitivity and precision.27,28 Graphitic carbon nitride (g-C3N4) nanosheets, an unique and new type of graphene-like carbon-based nanomaterial with high fluorescence quantum yield and high biocompatibility.29,30 Generally, the g-C3N4 nanosheets can be prepared through the pyrolysis of nitrogenrich precursors, and then exfoliated to ultrathin nanosheets of various size. The strong photoluminescence, owing to high-degree condensation of the tri-s-triazine unit in g-C3N4 nanosheets,31 along with its large specific surface areas have made g-C3N4 nanosheets a useful

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platform for the development of fluorescence biosensor applications. Currently, the g-C3N4 nanosheets based fluorescent biosensors majorly relying on fluorescence quenching interaction between g-C3N4 nanosheets and metal ions such as Cu2+, Fe3+, and Ag+. Moreover, these biosensors are exclusively performed through single fluorescent intensity reading, leading to low signal-tobackground ratios.32-37 As far as we know, the utility of gC3N4 nanosheets as bioprobe for ratiometric fluorescence detection is still largely unexplored. Scheme 1. Schematic illustration of g-C3N4 nanosheets based fluorescent probe for ratiometric detection H2O2 and glucose.

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format, impliying the potential of this strategy for highthroughput detection of H2O2/glucose in various biomedical applications.

EXPERIMENT SECTION Reagents and Materials. Glucose oxidase (GOx) and horseradish peroxidase (HRP) were obtained from SigmaAldrich (St. Louis, Mo, USA). Glucose, lactose, maltose, sucrose, fructose, and amino acids were purchased from Aladdin Industrial Inc. (Shanghai, China). Cyanamid, ophenylenediamine (OPD), hydrogen peroxide (H2O2, 30%, w/w) and all used salts in the experiment were purchased from Sinopharm Chemical Reagent Co., Ltd. (Shanghai, China). The real serum sample was obtained from a health volunteer in Xiangya Hospital (Changsha, China). All reagents we used were at least analytical grade and without further purification. The double-distilled water which was purified by a Milli-Q system (Millipore, Bedford, MA) and had an electric resistance >18.25 MΩ was used for prepared needed solutions. Characterizations. All the used instruments were consistent with those described in our previous literature.38 The experimental details have been provided in SI.

Herein, we report for the first time that the development of a novel g-C3N4 nanosheets-based ratiometric fluorescence sensing strategy for highly sensitive detection of H2O2 and glucose, as illustrated in Scheme 1. The as-prepared ultrathin g-C3N4 nanosheets display a fluorescence peak at 438 nm upon excitation at 355 nm. With o-phenylenediamine (OPD) as the substrate, horseradish peroxidase (HRP) can catalyze the oxidization of OPD in the presence of H2O2 to 2,3-diaminophenazine (OXOPD) (Scheme S1 in SI). The oxidation product is spontaneously assembled on the g-C3N4 nanosheets through hydrogen bonding and π−π stacking interactions, which not only deliver a new emission peak at 564 nm, but also effectively quenches the fluorescence of g-C3N4 nanosheets. The resulting decrease of the fluorescence peak at 438 nm together with the increase of emission peak at 564 nm, therefore, allows the development of a ratiometric fluorescence sensing strategy for detection of H2O2. Furthermore, based on the glucose convert into H2O2 via the enzyme catalysis of glucose oxidase (GOx), this strategy also provides a novel strategy for ratiometric sensing of glucose. Because of this developed ratiometric sensing strategy provides the possibility of minimizing false signal perturbations from environmental effects, it may create a useful robust technique for H2O2/glucose assays. Moreover, due to the easy synthesis of the nanosheets, this strategy can be realized cost-efficiently in a single step using a microplate

H2O2 Sensing. For the detection of H2O2, 1 µg/mL HRP and 0.5 mM OPD were mixed with as-prepared g-C3N4 nanosheets (final concentration of 5 µg/mL) by adding different concentrations of H2O2 into 10 mM pH 5.0 phosphate buffer. The result solution was incubated for 20 minutes at 37 °C. Afterwards, the fluorescence spectra were required under 355 nm excitation. Glucose Sensing. For the detection of glucose, 1.5 µL of 12 u/mL GOx and 15 µL of glucose of different concentrations in 13.5 µL 10 mM phosphate buffer (pH 7.0) were incubated at 37 °C for 30 min, afterwards, 1 µg/mL HRP, 0.5 mM OPD, 5 µg/mL g-C3N4 nanosheets and 10 mM phosphate buffer (pH 5.0) were added into the above 30 µL glucose reaction solution. The result solution was incubated for 20 minutes at 37 °C. Afterwards, the fluorescence spectra were required under 355 nm excitation. For the detection of serum glucose samples, Under the optimized detection conditions, the prepared serum samples were carried out for the glucose detection according to the process as mentioned above. RESULTS AND DISCUSSION Characterization of g-C3N4 Nanosheets. The ultrathin g-C3N4 nanosheets were prepared following our previous report.38 Transmission electron microscope (TEM, Figure 1A) showed the as-prepared nanosheets presented a sheet structure, with a diameter of 100 to 120 nm, which is agree with dynamic light scattering (DLS, Figure S1 in SI). Moreover, the g-C3N4 nanosheets possessed a ζ-potential value of 25.6 mV, which revealed a positive charged surface and was beneficial to keep their stability in water (Figure S2 in SI). In the XRD pattern of g-C3N4 nanosheets, the strong π-conjugated layers characteristic (002) peak at 27.4 was observed, indicating the typical graphitic struc-


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Figure 2. Fluorescence spectral responses of g-C3N4; gC3N4+H2O2; g-C3N4+HRP; g-C3N4+OPD; g-C3N4+HRP+H2O2; g-C3N4+HRP+OPD; g-C3N4+H2O2+OPD; H2O2+HRP+OPD; gC3N4+ H2O2+HRP+OPD. Reactions were performed at 37 °C for 20 min and H2O2 0.2 mM, HRP 1 µg/mL, OPD 0.5 mM and 5 µg/mL g-C3N4 were used for all experiments. The fluorescence spectra were recorded with 355 nm excitation.

Ratiometric Fluorescence Response for H2O2. When Figure 1. (A) TEM image of the g-C3N4 nanosheets. (B) XRD patterns of g-C3N4 nanosheets. (C) AFM image of the g-C3N4 nanosheets. (D) The height profile of corresponding section of (C). (E) Survey XPS spectrum of g-C3N4 nanosheets. (F) C1s spectrum of g-C3N4 nanosheets.

ture, which is in good agreement with that of g-C3N4 in the previous report.39 Atomic force microscope (AFM) images of the g-C3N4 nanosheets showed a thickness of about 1.5-2.1 nm (Figure 1C and 1D), combined with XRD (d = 0.326 nm in inter-layer distance), the nanosheets were estimated to be constitute of 4-7 CN atomic monolayers. In addition, FT-IR analysis also showed absorption peaks were assigned for accordingly vibration bonds (Figure S3 in SI).40,41 XPS measurements revealed g-C3N4 nanosheets are highly purity, it mainly contain C , N and O elements (Figure 1E), the relatively high oxygen content of the g-C3N4 nanosheets may be derived from chemical oxidation and liquid exfoliation. Moreover, the molar ratio of N/C for g-C3N4 nanosheets is about 1.35, closing to the stoichiometric ratio of g-C3N4 nanosheets about 1.33. The C 1s spectrum can be devided into two peaks which were separetely located at 284.6, and 288.0 eV. The peak at 284.6 eV which corresponds to sp3-bonded carbon with oxygen (C-OH), while the peak located at 288.0 eV is ascribed to sp2-bonded carbon (NC=N) (Figure 1F).42,43 The optical properties of g-C3N4 nanosheets are shown in Figure S4 in SI. There was a maximum absorbance at about 300 nm and a shoulder peak at 360 nm in the UV−vis spectra, the g-C3N4 nanosheets has a wide range of excitation band from 300 to 400 nm. In our experiments, upon exciting at 355 nm, the strong fluorescence emission peak was observed at 438 nm.

excitation at 355 nm, the as-prepared g-C3N4 nanosheets displayed a strong emission peak at 438 nm. However, when HRP, OPD, and H2O2 all existed, the fluorescence at 438

nm was quenched and a strong emission at 564 nm appeared. As shown in Figure 2, both HRP, OPD and H2O2 had almost no influence on the fluorescence of gC3N4 nanosheets, in contrast, in the reaction mixture of H2O2/HRP/OPD, HRP can catalyze OPD to the oxidized OPD (oxOPD), which showed a strong emission at 564 nm. Simultaneously, the benzene ring and amino group of resulted oxOPD made it enable easily assembly of oxOPD on the g-C3N4 nanosheets surface through hydrogen bonding and π−π stacking, furthermore, due to oxOPD was an excellent electron acceptor, the fluorescence of g-C3N4 nanosheets at 438 nm was remarkable decreased, these findings clearly demonstrated that HRP-catalyzed H2O2 mediated reaction with OPD can result in fluorescence quenching of the nanosheets. It was noted that there was no fluorescence signal output for OPD with 355 nm excitation (Figure S5 in SI), these further verify the emission at 564 nm was attributed to its oxidization product of oxOPD. The proposed method also provided the basis for ratiometric fluorescence detection of H2O2. The possible mechanism for g-C3N4 nanosheets quenching was probably due to photoinduced electron transfer (PET) effects. As a classic electron acceptor,44-46 oxOPD have been reported as an PET-induced quencher for fluorescence probes such as quantum dots.47 The time-resolved g-C3N4 nanosheets fluorescence decay towards oxOPD were performed to get further verify the quenching mechanism. As shown in Figure 3 and Figure S6, with the increase of oxOPD concentration, the fluorescence lifetime of g-C3N4 nanosheets gradually decreased, indicating a dynamic quenching process.



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Taken the large π-systems and high surface-to-volume ratio of the g-C3N4 nanosheets into consideration, the electron acceptor quencher oxOPD would be easily assembled on the its surface through hydrogen bonding and π−π stacking interactions, and then quenched the fluorescence of g-C3N4 nanosheets.

Figure 3. Fluorescence lifetime decay curves of g-C3N4 nanosheets with different concentrations of oxOPD in 10 mM PBS (pH 5.0).

Next, we investigated the ability of the g-C3N4-based ratiometric biosensor for quantitative assays of H2O2. To acquire high performance of this sensing system towards H2O2, we first optimized several important parameters, including the concentration of HRP and OPD, the pH value of solution and incubation time. Under the optimized experimental conditions (Figures S7-10), the fluorescence emission spectra of g-C3N4-based ratiometric sensing system in the presence of H2O2 at varying concentrations were measured. For the fluorescence detection of H2O2, different concentrations of H2O2 added in the g-C3N4/HRP/OPD mixtures for 20 min at 37 °C. As the concentration of H2O2 rising, the fluorescence at 438 nm was decreased gradually while the fluorescence at 564 nm was increased (Figure 4A). As shown in Figure 4B, there exhibited a good linear relationship between the ratiometric fluorescence intensity (I564/I438) and the H2O2 concentration in a four order of magnitudes range from 0.1 to 2000 μM (R2= 0.987, inset in Figure 4B), and it was estimated that the detection limit was as low as 50 nM, which was comparable or better than most of existing fluorescence probes for H2O2.48-51 These results demonstrated that the g-C3N4-based ratiometric fluorescence sensing platform hold great potential for highly sensitive detection of H2O2. In addition, the specificity of our method for H2O2 has been tested, and the results show that other radicals have little interference with the sensor system, which may ascribed to HRP catalytic specificity for H2O2 (Figure S11 in SI). Ratiometric Fluorescence Response for Glucose. Such a sensitive response of g-C3N4/HRP/OPD toward H2O2 provides a universal platform to detect any substrates involving H2O2-generation reactions for biomedical appli-

Figure 4. (A) Fluorescence spectra of g-C3N4 nanosheetsbased ratiometric probe in the presence of different concentrations of H2O2. The concentrations of H2O2 were increasing from 0 to 50 mM. (B) Fluorescence intensity ratio (I564/I438) versus the concentration of H2O2. The inset was the linear plot of the fluorescence intensity ratio against the H2O2 concentration.

cations. Many biological substrates, can be oxidized by their specific oxidoreductases to produces H2O2, including a large variety of metabolites in the human body (e.g, glucose, cholesterol, lactate, choline). Here, as the proofof-concept demonstration, we choose glucose as the model detective target. The specificity of the detection for glucose is ensured by the necessary addition of the corresponding enzyme-glucose oxidase (GOx) in the gC3N4/HRP/OPD solution. In that case, glucose can be specifically catalyzed by GOx and producing gluconic acid and H2O2, and then the produced H2O2 can rapid response to the g-C3N4/HRP/OPD sensing system. After optimizing the amount of GOx (Figures S12), as shown in Figure 5A, when adding different concentrations of glucose in the g-C3N4/HRP/OPD/GOx mixtures, the fluorescence at 438 nm was continuously quenched with the addition of glucose, and the fluorescence peak at 564 nm was increased. In contrast, only the addition of glucose or GOx into the mixtures, no obvious fluorescence changes were observed, suggesting that the glucose or GOx itself had no influence on the gC3N4/HRP/OPD nanosystem (Figure S13 in SI). The dependence of I564/I438 on glucose concentration is displayed in Figure 5B. It was estimated that the detection limit of glucose was 0.4 μM. Previous reports revealed the level of glucose in diabetes patients usually ≥7 mM,52,53 convenient and sensitive glucose detection enabled by


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this sensing technique is of importance for the diabetes diagnosis and can meet clinical application requirements.

revealed the results obtained by the proposed method are in good agreement with those of the glucometer methods. In addition, standard addition experiments display the recoveries were in the range from 97.8% to 103.2%, indicating this ratiometric sensing system is applicable for monitoring glucose levels in real serum samples.

Figure 6. The selectivity of the strategy for glucose sensing. Glucose is at a concentration of 0.1 mM. The concentration of metal ions, amino acids and other saccharides were 1 mM, and the concentrations of proteins including IgG and BSA were 0.1 mg /mL for the selectivity of glucose. Error bars are standard deviations of three repetitive experiments.

CONCLUSIONS

Figure 5. (A) Fluorescence spectra of g-C3N4 nanosheetsbased ratiometric probe in the presence of different concentrations of glucose. The concentrations of glucose were increasing from 0 to 4 mM. (B) Fluorescence intensity ratio (I564/I438) versus the concentration of glucose. The inset was the linear plot of the fluorescence intensity ratio against the glucose concentration.

In order to estimate the specificity of the strategy, we measured some common potentially interfering substances including relevant ions, proteins and amino acids and glucides. As shown in Figure 6, good selectivity is exhibited for the target glucose. It is important to notice that previous reports had testified Cu2+ can effectively quench the fluorescence of g-C3N4 nanosheets,36,37 however, compared to the blank sample, the ratiometric fluorescence measurement enable almost no change, these made samples eliminating the interference of the environment. The high selectivity of our method was attributed to the specifity of GOx and the intrinsic correction capability afforded by ratiometric fluorescence measurement. These results verified the sensing strategy had high selectivity and indicated that it is feasibility for glucose detection in biological samples. We further detected glucose levels in real clinical serum samples. The serum samples were collected from healthy volunteers. The analytical results are presented in Table S1. It clearly

In conclusion, by taking advantage of its large specific surface areas and high fluorescence properties, g-C3N4 nanosheets have been for the first time exploited as an efficient probes for establishing a new ratiometric fluorescence sensing platform for H2O2 and glucose detection. HRP-catalyzed reaction of H2O2 with OPD can form an oxidation product not only delivering a fluorescence peak at 564 nm, but also effectively quenching the fluorescence of g-C3N4 nanosheets at 438 nm. Based on the resulting decrease of the fluorescence peak at 438 nm together with the increase of emission peak at 564 nm, a robust ratiometric fluorescence sensing strategy for sensitive and selective sensing detection of H2O2 and glucose has been developed. The sensor has been demonstrated to give a detection limits of 50 nM and 0.4 μM for H2O2 and glucose, respectively. Moreover, The g-C3N4-based ratiometric sensing system has been used for sensitive detection of the levels of glucose in human serum, which was favourable for diabetes mellitus research and clinical diagnosis. This strategy may provide a cost-efficient, robust, and high-throughput platform for detecting various species involving H2O2-generation reactions for biomedical applications.

ASSOCIATED CONTENT Supporting Information Additional experimental details and figures. This material is available free of charge via the Internet at



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http://pubs.acs.org. Additional information as noted in the text, including oxidized route of OPD; DLS, zeta potential and FT-IR spectrum of the g-C3N4 nanosheets; UV-vis absorption spectra, emission and excitation spectra of g-C3N4 nanosheets; fluorescence spectrum of OPD and oxOPD; effect of reaction time and pH on the fluorescence intensity ratio; g-C3N4-based fluorescence ratiometric responses toward GOx, glucose, glucose + GOx; glucose levels detection in human serum samples.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. Tel.: 86-731-88821961. Fax: 86-731-88821916. *E-mail: [email protected]. Author Contributions ‡ These authors contributed equally. Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT This work was supported by NSFC (21527810, 21205034, 21190041, 21521063) and National Key Basic Research Program (2011CB911000).

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Graphitic Carbon Nitride Nanosheets-Based Ratiometric Fluorescent

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