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Nitrogen-doped carbon quantum dots as a “turn off-on” fluorescence sensor based on the redox reaction mechanism for the sensitive detection of dopamine and alpha lipoic acid
Journal of Photochemistry & Photobiology A: Chemistry 392 (2020) 112438
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Journal of Photochemistry & Photobiology A: Chemistry journal homepage: www.elsevier.com/locate/jphotochem
Nitrogen-doped carbon quantum dots as a “turn off-on” fluorescence sensor based on the redox reaction mechanism for the sensitive detection of dopamine and alpha lipoic acid
T
Ruxia Zhang, Zhefeng Fan* Department of Chemistry, Shanxi Normal University, Linfen 041004, PR China
ARTICLE INFO
ABSTRACT
Keywords: Nitrogen-doped carbon quantum dots Fluorescence probe Dopamine Alpha lipoic acid Tyrosinase
A simple and reliable fluorescence sensing strategy, which depends on the strong fluorescence emission of nitrogen-doped carbon quantum dots (N-CQDs) and efficient catalytic oxidation of tyrosinase (Tyr), was demonstrated for the sensitive detection of dopamine (DA) and alpha lipoic acid (ALA). Under optimized conditions, the fluorescence intensity of N-CQDs was easily quenched by dopamine oxidation product dopaquinone with the addition of Tyr. When ALA was introduced into the sensing system, ALA could inhibit and reduce the oxidation process of DA, resulting in the fluorescence recovery of N-CQDs. This sensing platform showed a sensitive relationship to the DA and ALA concentrations within certain ranges of 0.05–15 and 0.5−55 μM, and low detection limits of 0.035 and 0.39 μM, respectively. Given the above mechanisms, the proposed biosensor was utilized for the detection of DA and ALA in real samples with satisfactory results. Moreover, we successfully measured ALA through spectrometry, which is expected to provide valuable information in medical and disease diagnosis.
1. Introduction Dopamine (DA), an important catecholamine in the central nervous system of mammals, is a monoamine neurotransmitter synthesized by the pars compacta of the substantia nigra and plays crucial roles in many physiological activities of human and mammals, that are closely related to human’s motor and mood regulation, learning, and memory [1–3]. Abnormal levels of DA in human beings can result in nervous system diseases, including schizophrenia, depression, and Parkinson’s syndrome [4–6]. The sensitive detection of DA activity has exhibited broad prospects for cellular metabolism and signaling [7,8]. Therefore, a simple and reliable method to detect DA activity is urgently needed for disease diagnosis and drug research [3,6,9]. Alpha lipoic acid (ALA) is considered a complement to the α-ketoacid dehydrogenase complex in mitochondria, existing naturally in prokaryotic and eukaryotic cells [10]. ALA does not only eliminate free radicals that cause accelerated aging and disease but is also used as a metal scavenger because of its strong chelation with metal ions, such as zinc, copper, and mercury. As a clinical drug for the treatment of diabetes, ALA significantly increases the sensitivity of cells to insulin in patients with diabetes, thereby improving diabetic myocardial lesions [11–13]. However, long-term intake of high-dose ALA may increase the
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level of lipid peroxidation, cause oxidative protein damage, and induce gastrointestinal symptoms and allergic reactions [14,15]. Therefore, developing a sensitive and accurate sensor that detects the levels of DA and ALA is a significant work for biomedical diagnosis and health monitoring [16,17]. At present, some analytical methods such as colorimetry [18,19], chemiluminescence [20], electrochemical methods [21–26], and liquid chromatography-mass spectrometry [27] have been developed for the detection of DA and have shown sensitive detection and good performance. However, these methods demonstrate some shortcomings during actual detection as they require time-consuming pre-processes, complex chemical modifications, or relatively expensive equipment. Thus, a simple and sensitive strategy for DA detection is necessary. In the past few decades, most of the explorations on ALA focused on biomedical and clinical fields with less chemistry, only used as a ligand modification [28]. Given the strong coordination interaction between ALA and metals, ALA is often utilized to modify nanomaterials, but its individual detection in real samples is rare. Wang et al. [29] detected ALA by semi-differential cathodic stripping voltammetry. However, their results were unsatisfactory, and there are still some drawbacks, including relatively low sensitivity and cumbersome operation, which indicates a simple, high-sensitivity ALA detection method is warranted
Corresponding author. E-mail address: [email protected] (Z. Fan).
https://doi.org/10.1016/j.jphotochem.2020.112438 Received 12 December 2019; Received in revised form 1 February 2020; Accepted 4 February 2020 Available online 05 February 2020 1010-6030/ © 2020 Elsevier B.V. All rights reserved.
Journal of Photochemistry & Photobiology A: Chemistry 392 (2020) 112438
R. Zhang and Z. Fan
in the field. Carbon quantum dots (CQDs), as members of carbon nanostructure families, have attracted extensive attention due to their excellent luminescence properties and good stability; they are widely used in chemical sensing, nanomedicine, and catalysis [30,31]. Compared with semiconductor quantum dots, CQDs are considered one of the best candidates in the bio-imaging and biomedical field, which based on the fact that CQDs surfaces are easily modified and functionalized and have low toxicity, good water solubility, and smaller size (< 10 nm) [32,33]. In addition to exploring simple synthesis methods of CQDs with good optical properties, researchers are committed to building a novel and sensitive sensing platform based on the many merits of CQDs. Therefore, we successfully constructed a fluorescence sensor using Tyr as an oxidant for determination of DA and ALA in real samples based on onestep hydrothermally synthesized N-CQDs in the present work. The sensing system presents several advantages including simplicity, novelty, and easy to operate, which not only satisfies the highly sensitive sensing of DA and ALA, but also brings many merits with the introduction of Tyr. Tyr, as a catalytic oxidation medium, has more efficient oxidizing capacity, uses fewer doses, and is more environmentally friendly than other metal ions of different valence states as oxidants [34,35]. At the same time, the complicated operation of modifying CQDs with specific functions can also be avoided [36]. A novel, simple, and sensitive N-CQDs/DA/Tyr/ALA-based fluorescence sensor was developed in the present study for the detection of DA and ALA in human fluids. DA could be absorbed on the surface of NCQDs to form a blue fluorescence complex through intermolecular electrostatic interactions and hydrogen bonding. When Tyr was added to the system, the catechol portion of DA would complex with the binuclear copper center site of Tyr and be oxidized to dopaquinone, and the fluorescence of N-CQDs was quenched via electron transfer between N-CQDs/DA and dopaquinone. ALA can block the oxidation of Tyr and reduce dopaquinone to DA, which leads to the fluorescence recovery of the system. After continuous redox, the N-CQDs fluorescence “turn offon” system was formed, as presented in Scheme 1. This method is the first to use spectroscopy to determine ALA in real samples. This method is also expected to be used for the determination of DA, ALA, and Tyr, and it provides ideas for the research and exploration of other phenolic substances.
(C5H9NO4), and glycine (C2H5NO2) were provided by Sinopharm Chemical Reagent Beijing Co., Ltd. L-Glutamate (C5H9NO4), L-histidine (C6H9N3O2), DL-proline (C5H9NO2), and L-arginine (C6H14N4O2) were provided by the Tianjin Kwangfu Chemical Industry Research Institute. Tyr was obtained from Cool Chemical Science and Technology Co., Ltd (Beijing, China). Tianjin Kemiou Chemical Reagent Co., Ltd provided Lcysteine (C3H7NO2S). None of the above reagents required further purification and were used directly during the experiments. Ultrapure water was used in all other processes except for the preparation of ALA solution using ethanol. Ultrapure water (18.2 MΩ) was made by the United States Milli-Q purification system. 2.2. Apparatus Fluorescence emission spectra were recorded on a LS-55 photoluminescence spectroscope (Perkin Elmer, USA) under the excitation wavelength of 350 nm. Ultraviolet-visible (UV–vis) absorption spectra were obtained on a Cary 300 UV–vis spectrophotometer (Varian, USA) using a 1 cm path length quartz cell. TEM images were collected using a Teenai G2 F20 (FEI, USA) at a voltage of 200 kV. In addition, every sample was prepared by placing a drop of sample solution onto the copper grids covered in a dry air atmosphere. X-ray diffraction (XRD) patterns were obtained using an Ultima IV (Rigaku, Japan) spectrometer equipped with monochromatized Al Kα excitation. The surface functional groups of the fluorescent probe were studied using a Nicolet 380 spectrophotometer (Thermo Electron Corp., USA) through potassium bromide pellet technique ranging from 500 cm−1 to 4000 cm-1. 2.3. Preparation of N-CQDs fluorescent probe Researchers have developed a number of methods for preparing fluorescent carbon dots. A simple, fast and high-fluorescence yield method for carbon synthesis was modified and used in our system [37,38]. In brief, 2 g of anhydrous citric acid was added to 40 mL of ultrapure water containing 1 mL of ethylenediamine. The uniform solution was placed in a Teflon-lined 100 mL reactor for 2 h at 150 °C. After the reactor was cooled to room temperature, a uniformly dispersed brown solution was obtained. For the obtained fluorescent carbon dots to have uniform particle size and high yield, the solution was transferred to a dialysis bag with a cut-off amount of 3000 Da purified in ultrapure water for 48 h at room temperature. Finally, a light brown solid was obtained through freeze drying.
2. Experimental 2.1. Materials
2.4. Experimental procedures for the sensing of DA and ALA
ALA (C8H14O2S2) and anhydrous citric acid (C6H8O7) were purchased from Shanghai Macklin Biochemical Co., Ltd. Ethylenediamine (C2H8N2) and DA (C8H11NO2) were purchased from Aladdin Industrial Corporation. PBS buffer solution was prepared by using NaH2PO4·2H2O and Na2HPO4·12H2O, which were produced by Shen Tai Huagong Reagents Co., Ltd (Tianjin, China). DL-Phenylalanine, L-glutamate
The detection procedure for DA is described below. The 0.1 mg/mL standard solution of N-CQDs was prepared with ultrapure water for subsequent experiments. The entire experimental process was carried out under optimized experimental conditions, including optimal pH, reaction temperature, time, and activity of enzyme. For DA detection,
Scheme 1. Preparation and principle of the N-CQDs probe for DA and ALA sensing. 2
Journal of Photochemistry & Photobiology A: Chemistry 392 (2020) 112438
R. Zhang and Z. Fan
30 μL of N-CQDs, 10 mM PBS buffer solution (pH = 5.5), 0.16 U/mL Tyr, and DA solution at different concentrations (ranging from 0.00 μM to 15.00 μM) were mixed in 10 mL colorimetric tubes; diluted with ultrapure water to 5 mL; shaken thoroughly; and incubated at 37 °C for 35 min to quench the fluorescence of N-CQDs. A fluorescence spectrum with an emission wavelength range of 380−650 nm was recorded when the excitation wavelength was set at 350 nm. The slit widths of emission and excitation were set to 5 nm and 10 nm, respectively. For ALA detection, the test procedure was basically the same as that of DA. Different concentrations of ALA were added in 10 mL colorimetric tubes containing 30 μL of N-CQDs, 10 mM PBS buffer solution (pH = 5.5), 0.16 U/mL Tyr, and 15 μM DA of the above optimized concentration, which were prepared as a 5 mL mixed solution, followed by incubation at 37 °C for 35 min to recover the fluorescence of the NCQDs/DA system. Similarly, the fluorescence spectra were obtained under the same emission wavelength range, excitation wavelength, and silt width as DA detection.
2934 cm−1 was attributed to the stretching vibration of CeH. In addition, the three characteristic peaks of 1568–1708 cm−1 represented the bending vibration of NeH and the stretching vibrations of C]O/ C]N, whereas 1400 cm−1 may be caused by the asymmetric vibration of COO−. We also conducted a high-resolution TEM image survey of NCQDs. The results indicated that the fluorescent carbon dots were nearly spherical in shape with mainly amorphous carbon structures, and a clear lattice fringe was observed (Fig. 2A). The crystallization degree of solid powders was investigated by XRD and laser Raman spectroscopy. A broad peak was observed around 23.5° using an X-ray diffractometer, as shown in Fig. 2B, which correspond to the (002) lattice spacing of carbon-based materials [40]. Meanwhile, Fig. 2C illustrates two peaks around 1333 and 1526 cm−1, respectively, which were detected by Raman spectroscopy. These peaks reflect the degree of disorder of the crystal structure and numerous defects in the carbon skeleton by the incorporation of nitrogen atoms [41,42]. Thus, nitrogen atoms were successfully doped in N-CQDs.
2.5. Analysis of DA and ALA in real samples
3.2. Optimization of the sensing procedure
The feasibility of the system we built can be verified by measuring the analyte in actual samples. We separately added different concentrations of DA and ALA in the actual blood and urine samples. The urine of a patient who has been diagnosed with diabetes was used as an actual sample. First, 5 mL of urine was mixed with 10 mL of acetonitrile to remove large molecules and precipitate proteins in urine. After standing for 10 min, the product was centrifuged for 12 min at 5000 r/ min, and the supernatant was filtered through a 0.22 μm aqueous system. Finally, the solution was adjusted to slightly acidic with PBS buffer solution (pH = 5.5) and diluted 50 times with ultrapure water. Different concentrations of ALA were added into urine to prepare the spiked samples. To analyze the DA content, we collected the blood samples of volunteers from the University Hospital. The collected serum was diluted 100-fold without further processing. Finally, the spiking experiment was carried out under the optimized conditions in accordance with the designed test procedure.
The optimization of experimental parameters has an impact on the good analytical performance of fluorescent nanosensors in the detection process. We investigated the influence of Tyr activity, incubation time, pH of the reaction system, and reaction temperature in the sensor platform we designed, which were related to the sensitivity of the proposed biosensor. First, we optimized the amount of catalytic oxidase, which is essential for the catalytic oxidation of DA quenching system. The fluorescence intensity of the quenching system gradually decreased with the introduction of Tyr activity varying from 0.04 U/mL to 0.16 U/mL, as illustrated in Fig. 3A. However, the fluorescence intensity tended to be relatively stable when the activity of Tyr exceeded 0.16 U/mL, and the results indicated that the fluorescence quenching effect of dopaquinone was maximized. Thus, 0.16 U/mL was adopted as the activity of Tyr in further experiments. We further studied the effect of pH on the fluorescence quenching and recovery efficiency of the system. The efficiencies were calculated by the following equations, respectively:
3. Results and discussion
(1)
Effq = (Fo
F )/Fo
3.1. Characterization of N-CQDs
Effr = (Fr
F )/(Fo
First, we explored the optical properties and surface functional groups of the hydrothermally synthesized fluorescent probe via UV–vis, fluorescence, and FTIR spectroscopy. Curve (c) in Fig. 1A shows the UV absorption spectrum of N-CQDs we prepared. We observed a distinct absorption band at 350 nm, which may be caused by the electron transitions from n-π* [37,39]. In addition, a weak absorption peak near 253 nm was observed because of the π-π* transitions in the carbonyl and amide bonds (C]C/C]O) of fluorescent carbon dots. Strong blue fluorescence photographs were exhibited in a 365 nm ultraviolet box. As shown in the curve (d), a high-intensity fluorescence emission peak centered at 445 nm was revealed when the excitation wavelength was set to 350 nm. We also measured the fluorescence emission spectra of N-CQDs at different excitation wavelengths. As shown in Fig. 1C, the maximum emission wavelength of the fluorescence probe was basically no shift with the change of the excitation wavelengths, and reached a maximum when excited at 350 nm. In summary, we can infer that the excitation-independent properties of N-CQDs can be better applied in biological imaging to avoid the autofluorescence. Fig. 1B displays an obvious change in fluorescence intensity of the system when the quencher and recovery agent were introduced. The surface of quantum dots contained a large number of oxygen-containing groups to help enhance water solubility and stability, which was successfully confirmed by FTIR spectroscopy. As shown in Fig. 2D, the OeH/NeH stretching vibration peaks in the carboxyl and amide groups of N-CQDs were exhibited at 3423 and 3250 cm−1, respectively. The peak of
Where Fo and F represent the fluorescence intensity of the sensing system in the absence and presence of DA, respectively; Fr indicate recovered fluorescence intensity of N-CQDs in presence of ALA. As displayed in Fig. 3B, when the pH changed from 4.5 to 5.5, the fluorescence quenching efficiency (Effq) of DA increased slightly and reached a maximum. However, at the pH range of 5.5–9.0, the quenching efficiency decreased and remained stable. These results may be attributed to neutral and alkaline environments that did not favor the quenching efficiency of DA. Moreover, the concentration of DA has been reported to be more accurately determined in weak acidic solution, which also avoids the effect of self-polymerization of DA on the catalytic oxidation of DA itself to dopaquinone under alkaline conditions [43]. Fig. 3B shows that the fluorescence recovery efficiency (Effr) of ALA to the sensing system remained unchanged with the increase in pH from 4.5–9.0. The efficiency of fluorescence recovery reached a maximum when the pH was 5.5, indicating that a high pH environment was not conducive to the reduction of ALA. Therefore, weak acidic conditions (pH = 5.5) are suitable for this sensing system. Furthermore, we studied the suitable incubation time in PBS (pH = 5.5) at 37 °C. As illustrated in Fig. 3C, the quenching and recovery efficiency of the fluorescent system reached a maximum and remained stable after 35 min, showing that the oxidation catalytic reaction of the copper-centered active site of Tyr and phenolic hydroxyl group of DA was completed in 35 min. To make the reaction more complete, we chose 35 min as the optimal incubation time for the 3
F)
(2)
Journal of Photochemistry & Photobiology A: Chemistry 392 (2020) 112438
R. Zhang and Z. Fan
Fig. 1. (A) UV–vis spectra of the (a) N-CQDs/DA/Tyr/ALA recovery system, (b) N-CQDs/DA/Tyr quenching system and (c) N-CQDs, and (d) fluorescence emission spectra of N-CQDs. (B) The fluorescence spectra of N-CQDs, N-CQDs/DA/Tyr/ALA, and N-CQDs/DA/Tyr systems. (inset: the blue fluorescence image of fluorescent probe under 365 nm ultraviolet box). (C) Fluorescence emission spectra of N-CQDs at different excitation wavelengths.
detection of DA and ALA in subsequent experiments. We also investigated the effect of the reaction temperature on the proposed system, as shown in Fig. 3D. The fluorescence quenching and recovery efficiency of the monitoring system reached the highest at 37 °C. These results may be explained by the temperature mainly affecting the activity of Tyr. Under different temperatures, the enzyme may be in different conformations, and the high temperature also facilitated the inactivation the enzyme [44]. Thus, the optimal reaction temperature of the fluorescence system was 37 °C in the further experiments. Regarding the above experimental results, 0.16 U/mL Tyr, pH 5.5, 40 min of incubation time, and 37 °C of interaction temperature were selected for the whole experimental process.
calculated as three times the noise of the response signal (3 δ/S), and it was as low as 0.035 μM. What’s more, we compared the constructed system with other sensor strategies for detecting DA and summarized them in Table 1 [34,36,45–50]. The table shows that the present method performed well in terms of the sensitive and highly selective detection of DA. The incubation time of the constructed system in the quantitative determination of DA was almost comparable and relatively shorter than previously reported sensing system [34,36,49,50]. In addition, no complicated material preparation compared to other systems [45–47,48], which also saves more time for the entire experimental process. On the other hand, the recovery effect of ALA on the fluorescence intensity of the sensing system was studied under optimal experimental conditions. Accompanied with the amount of ALA varying from 0 μM to 55 μM, the fluorescence intensity of the quenching system at 445 nm gradually returned to a maximum, as shown in Fig. 5A. In addition, Fig. 5B illustrates a good linear relationship between the fluorescence intensity ratios (Fr-Fro)/Fro and the concentrations of ALA in the range of 0.5–15 and 15−55 μM. Fr and Fro represent the fluorescence intensities of the N-CQDs/DA/Tyr system in the presence and absence of ALA, respectively. The linear regression equation of the working curve (F (Fr Fro)/Fro = 0.03175 + 0.10671[ALA] and was r Fro)/ Fro = 1.15332 + 0.0333[ALA]. The correlation coefficients (r) were 0.995 and 0.999. The LOD for ALA was 0.39 μM. According to the above performance, the proposed method is expected to be successfully applied for DA and ALA determination in real samples.
3.3. DA and ALA assay based on fluorimetric method To verify the feasibility and practicality of detecting DA and ALA based on the present fluorescence sensing platform, we added a series of different DA and ALA concentrations to the quenching and recovery system under the optimal conditions. As displayed in Fig. 4A, the fluorescence intensity of the N-CQDs/DA/Tyr system decreased significantly with the increase in DA content, whereas the fluorescence value became stable after 15 μM. As plotted in Fig. 4B inset, an excellent linear relationship between the fluorescence intensity and the concentration of DA was exhibited in the range of 0.05-0.5 and 0.5−15 μM with corresponding regression coefficients (r) of 0.994 and 0.992, respectively. The linear regression equations were (Fo F )/ Fo = 0.00204 + 0.50082[DA] and (Fo F )/ Fo = 0.21865 + 0.03982[DA], where Fo and F represent the fluorescence intensity of the sensing system in the absence and presence of DA, respectively. The limit of detection (LOD) for DA based on the constructed system was
3.4. Selectivity and interference of DA and ALA To validate the high accuracy and selectivity of the fluorescence 4
Journal of Photochemistry & Photobiology A: Chemistry 392 (2020) 112438
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Fig. 2. (A) HR-TEM image of N-CQDs in 5 nm, (B) XRD pattern of N-CQDs, (C) Raman spectra, and (D) FTIR spectra of N-CQDs.
Fig. 3. (A) Effect of different Tyr activity on fluorescence quenching strength of N-CQDs/DA system, (B) effect of solution pH, (C) incubation time, and (D) reaction temperature on the fluorescence intensity of N-CQDs/DA/Tyr and N-CQDs/DA/Tyr/ALA system. 5
Journal of Photochemistry & Photobiology A: Chemistry 392 (2020) 112438
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Fig. 4. (A) Fluorescence quenching of N-CQDs with the addition of DA. (B) Linear relationship of fluorescence intensity in the presence of different concentrations of DA. Table 1 Comparison of the proposed method with different DA detection methods. Method
System
Incubation time (min)
Linear Range (μM)
LOD (μM)
Reference
Electrochemical Colorimetric Colorimetric Fluorescence Fluorescence Fluorescence Fluorescence Fluorescence Fluorescence
BSA-AgInS2 QD/AuNRs/GO TMB-H2O2-Co3O4@NiO Cu-MOXs-TMB-H2O2 CDs-TYR NaGdF4:Tb NPs DA-GQDs-Cu2+-AA Ru-CIP-SDBS DA-PEI-PDA N-CQDs/DA/Tyr/AA
– 7 20 150 5 60 60 30 35
0.3–10 1–20 0.5–20 0.1–6 0–10 0.5–120 0.1–10 1–200 0.05–15
0.067 1.21 0.085 0.06 0.03 0.16 0.006 0.3 0.035
[45] [46] [47] [36] [48] [34] [49] [50] This work
concentrations of coexisting materials to DA or ALA and measuring the above mixtures under the same experimental conditions. Fig. 6 displays that the simultaneous presence of interfering substances and analytes did not significantly affect the quenching and recovery of the fluorescent system. Thus, our proposed fluorescence sensing strategy may be promising for the biomedical field.
sensing platform for DA and ALA detection, we further investigated the applicability of the proposed system in the presence of multiple interfering substances. These substances included some common amino acids (200 μM), such as glycine, DL-phenylalanine, histidine, arginine, cysteine, tyrosine (50 μM), L-glutamic acid, proline, lysine, tryptophan, glutathione, uric acid (200 μM), Na+, K+, Ca2+, and Mg2+ (1000 μM), under the optimized experimental conditions. First, the high selectivity of the fluorescence sensing platform for quenchers and restorers was determined when DA (10 μM) and ALA (20 μM) were added to the system separately with a high concentration of other coexisting substances, as shown in Fig. 6. The fluorescence intensity of the sensing system in the presence of DA and ALA was obviously reduced and enhanced compared with when other coexisting substances were added. These results indicated that the established method has high selectivity for the detection of DA and ALA, so it is expected to be used in practical testing. We also performed interference measurement, by adding high
3.5. Determination of DA and ALA in real samples The recovery study of the analytes in real samples is also one of the criteria for assessing the good performance of the biosensor, and the standard addition method was applied for the detection of DA and ALA in human serum and urine samples. Different concentrations of DA (0.8, 5, and 10 μM) and ALA (10 and 40 μM) were added to 50-fold diluted human serum and urine samples. The fluorescence intensity values of this sensing system were recorded, and the analytical results are listed
Fig. 5. (A) Fluorescence recovering of N-CQDs with the addition of ALA. (B) Linear relationship of fluorescence intensity with different ALA concentrations added. 6
Journal of Photochemistry & Photobiology A: Chemistry 392 (2020) 112438
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Fig. 6. Selectivity (A) and interference (B) of the N-CQDs system toward DA and ALA over other substances, respectively.
Appendix A. Supplementary data
Table 2 Detection of DA and ALA in real samples. Sample
Spiked (μM)
Found (μM)
Recovery (%)
RSD (n = 3,%)
Human serum (DA)
0.8 5.0 10.0
0.81 ± 0.10 5.08 ± 0.09 10.03 ± 0.21
101 102 100
2.4 2.6 2.8
Human urine (DA)
0.8 5.0 10.0
0.78 ± 0.07 5.01 ± 0.15 9.82 ± 0.10
97 100 98
2.5 1.9 2.0
Human urine (ALA)
10.0 40.0
10.12 ± 0.20 39.70 ± 0.15
101 99
3.0 3.2
Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.jphotochem.2020. 112438. References [1] M.L.J. Wightman R M, A.C. Michael, Detection of dopamine dynamics in the brain, Anal. Chem. 60 (1988) 769A–793A. [2] W.R.M. Venton B J, Psychoanalytical Electrochemistry: Dopamine and Behavior, (2003). [3] P. Damier, E.C. Hirsch, Y. Agid, A.M. Graybiel, Psychoanalytical electrochemistry: dopamine and behavior, Anal. Chem. (2003). [4] H.E.C. Damier P, Y. Agid, et al., The substantia nigra of the human brain: II. Patterns of loss of dopamine-containing neurons in Parkinson’s disease, Brain 122 (1999) 1437–1448. [5] D. Merims, N. Giladi, Dopamine dysregulation syndrome, addiction and behavioral changes in Parkinson’s disease, Parkinsonism Relat. Disord. 14 (2008) 273–280. [6] P.J. Gaskill, D.R. Miller, J. Gamble-George, H. Yano, H. Khoshbouei, HIV, Tat and dopamine transmission, Neurobiol. Dis. 105 (2017) 51–73. [7] D.Q. Zhang, K.Y. Wong, P.J. Sollars, D.M. Berson, G.E. Pickard, D.G. McMahon, Intraretinal signaling by ganglion cell photoreceptors to dopaminergic amacrine neurons, Proc. Natl. Acad. Sci. U. S. A. 105 (2008) 14181–14186. [8] C.A. Heidbreder, E.L. Gardner, Z.X. Xi, P.K. Thanos, M. Mugnaini, J.J. Hagan, C.R. Ashby Jr., The role of central dopamine D3 receptors in drug addiction: a review of pharmacological evidence, Brain Res. Brain Res. Rev. 49 (2005) 77–105. [9] J.H. An, D.K. Choi, K.J. Lee, J.W. Choi, Surface-enhanced Raman spectroscopy detection of dopamine by DNA Targeting amplification assay in Parkisons’s model, Biosens. Bioelectron. 67 (2015) 739–746. [10] T. Ide, A. Tanaka, Alpha-Lipoic acid ameliorated oxidative stress induced by perilla oil, but the combination of these dietary factors was ineffective to cause marked deceases in serum lipid levels in rats, Nutr. Res. 48 (2017) 49–64. [11] E.J. Henriksen, Exercise training and the antioxidant alpha-lipoic acid in the treatment of insulin resistance and type 2 diabetes, Free Radic. Biol. Med. 40 (2006) 3–12. [12] L. Holmquist, G. Stuchbury, K. Berbaum, S. Muscat, S. Young, K. Hager, J. Engel, G. Munch, Lipoic acid as a novel treatment for Alzheimer’s disease and related dementias, Pharmacol. Ther. 113 (2007) 154–164. [13] A. Maczurek, K. Hager, M. Kenklies, M. Sharman, R. Martins, J. Engel, D.A. Carlson, G. Munch, Lipoic acid as an anti-inflammatory and neuroprotective treatment for Alzheimer’s disease, Adv. Drug Deliv. Rev. 60 (2008) 1463–1470. [14] K.P. Shay, R.F. Moreau, E.J. Smith, A.R. Smith, T.M. Hagen, Alpha-lipoic acid as a dietary supplement: molecular mechanisms and therapeutic potential, Biochim. Biophys. Acta 1790 (2009) 1149–1160. [15] A. Gorąca, H. Huk-Kolega, A. Piechota, P. Kleniewska, E. Ciejka, B. Skibska, Lipoic acid – biological activity and therapeutic potential, Pharmacol. Rep. 63 (2011) 849–858. [16] N. Namazi, B. Larijani, L. Azadbakht, Alpha-lipoic acid supplement in obesity treatment: a systematic review and meta-analysis of clinical trials, Clin. Nutr. 37 (2018) 419–428. [17] S. Lai, L. Petramala, M. Muscaritoli, R. Cianci, S. Mazzaferro, A.P. Mitterhofer, M. Pasquali, V. D’Ambrosio, M. Carta, M. Ansuini, C. Ramaccini, A. Galani, M.I. Amabile, A. Molfino, C. Letizia, Alpha lipoic acid in patients with autosomal dominant polycystic kidney disease, Nutrition (2019) 110594. [18] Y. Zheng, Y. Wang, X. Yang, Aptamer-based colorimetric biosensing of dopamine using unmodified gold nanoparticles, Sens. Actuators B Chem. 156 (2011) 95–99. [19] J.-M. Liu, X.-X. Wang, M.-L. Cui, L.-P. Lin, S.-L. Jiang, L. Jiao, L.-H. Zhang, A promising non-aggregation colorimetric sensor of AuNRs–Ag+ for determination of dopamine, Sens. Actuators B Chem. 176 (2013) 97–102. [20] A. Joshi, W. Schuhmann, T.C. Nagaiah, Mesoporous nitrogen containing carbon
in Table 2. The average recoveries of DA and ALA were in the range of 96 %–102 % and 99 %–101 %, respectively. The relative standard deviation (RSD) of DA and ALA was lower than 2.8 % and 3.2 %, respectively. The obtained results revealed that the proposed fluorescence sensing platform can be applied for sample detection and exhibits satisfactory performance in DA and ALA detection for real samples. 4. Conclusion A highly sensitive and practical fluorescent biosensing platform was built for the rapid detection of DA and ALA based on the simple redox reaction and charge transfer mechanism of the N-CQDs/DA/Tyr/ALA “turn off-on” strategy. Utilizing the fluorescence probe, we performed the accurate detection of DA and ALA in human serum and urine, and achieved satisfactory results. Moreover, the proposed method is simple, environment-friendly, inexpensive, reliable, and avoids complex pretreatment. Notably, the establishment of this method provides additional ideas for the detection of ALA using optical sensors, which can bring in numerous application prospects for biomedical diagnosis. This research did not receive any secific grant from funding agencies in the public, commercial, or not-for-profit sectors. CRediT authorship contribution statement Ruxia Zhang: Investigation, Writing - original draft, Formal analysis, Writing - review & editing. Zhefeng Fan: Writing - review & editing, Supervision, Funding acquisition. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. 7
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[21]
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Journal of Photochemistry & Photobiology A: Chemistry journal homepage: www.elsevier.com/locate/jphotochem
Nitrogen-doped carbon quantum dots as a “turn off-on” fluorescence sensor based on the redox reaction mechanism for the sensitive detection of dopamine and alpha lipoic acid
T
Ruxia Zhang, Zhefeng Fan* Department of Chemistry, Shanxi Normal University, Linfen 041004, PR China
ARTICLE INFO
ABSTRACT
Keywords: Nitrogen-doped carbon quantum dots Fluorescence probe Dopamine Alpha lipoic acid Tyrosinase
A simple and reliable fluorescence sensing strategy, which depends on the strong fluorescence emission of nitrogen-doped carbon quantum dots (N-CQDs) and efficient catalytic oxidation of tyrosinase (Tyr), was demonstrated for the sensitive detection of dopamine (DA) and alpha lipoic acid (ALA). Under optimized conditions, the fluorescence intensity of N-CQDs was easily quenched by dopamine oxidation product dopaquinone with the addition of Tyr. When ALA was introduced into the sensing system, ALA could inhibit and reduce the oxidation process of DA, resulting in the fluorescence recovery of N-CQDs. This sensing platform showed a sensitive relationship to the DA and ALA concentrations within certain ranges of 0.05–15 and 0.5−55 μM, and low detection limits of 0.035 and 0.39 μM, respectively. Given the above mechanisms, the proposed biosensor was utilized for the detection of DA and ALA in real samples with satisfactory results. Moreover, we successfully measured ALA through spectrometry, which is expected to provide valuable information in medical and disease diagnosis.
1. Introduction Dopamine (DA), an important catecholamine in the central nervous system of mammals, is a monoamine neurotransmitter synthesized by the pars compacta of the substantia nigra and plays crucial roles in many physiological activities of human and mammals, that are closely related to human’s motor and mood regulation, learning, and memory [1–3]. Abnormal levels of DA in human beings can result in nervous system diseases, including schizophrenia, depression, and Parkinson’s syndrome [4–6]. The sensitive detection of DA activity has exhibited broad prospects for cellular metabolism and signaling [7,8]. Therefore, a simple and reliable method to detect DA activity is urgently needed for disease diagnosis and drug research [3,6,9]. Alpha lipoic acid (ALA) is considered a complement to the α-ketoacid dehydrogenase complex in mitochondria, existing naturally in prokaryotic and eukaryotic cells [10]. ALA does not only eliminate free radicals that cause accelerated aging and disease but is also used as a metal scavenger because of its strong chelation with metal ions, such as zinc, copper, and mercury. As a clinical drug for the treatment of diabetes, ALA significantly increases the sensitivity of cells to insulin in patients with diabetes, thereby improving diabetic myocardial lesions [11–13]. However, long-term intake of high-dose ALA may increase the
⁎
level of lipid peroxidation, cause oxidative protein damage, and induce gastrointestinal symptoms and allergic reactions [14,15]. Therefore, developing a sensitive and accurate sensor that detects the levels of DA and ALA is a significant work for biomedical diagnosis and health monitoring [16,17]. At present, some analytical methods such as colorimetry [18,19], chemiluminescence [20], electrochemical methods [21–26], and liquid chromatography-mass spectrometry [27] have been developed for the detection of DA and have shown sensitive detection and good performance. However, these methods demonstrate some shortcomings during actual detection as they require time-consuming pre-processes, complex chemical modifications, or relatively expensive equipment. Thus, a simple and sensitive strategy for DA detection is necessary. In the past few decades, most of the explorations on ALA focused on biomedical and clinical fields with less chemistry, only used as a ligand modification [28]. Given the strong coordination interaction between ALA and metals, ALA is often utilized to modify nanomaterials, but its individual detection in real samples is rare. Wang et al. [29] detected ALA by semi-differential cathodic stripping voltammetry. However, their results were unsatisfactory, and there are still some drawbacks, including relatively low sensitivity and cumbersome operation, which indicates a simple, high-sensitivity ALA detection method is warranted
Corresponding author. E-mail address: [email protected] (Z. Fan).
https://doi.org/10.1016/j.jphotochem.2020.112438 Received 12 December 2019; Received in revised form 1 February 2020; Accepted 4 February 2020 Available online 05 February 2020 1010-6030/ © 2020 Elsevier B.V. All rights reserved.
Journal of Photochemistry & Photobiology A: Chemistry 392 (2020) 112438
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in the field. Carbon quantum dots (CQDs), as members of carbon nanostructure families, have attracted extensive attention due to their excellent luminescence properties and good stability; they are widely used in chemical sensing, nanomedicine, and catalysis [30,31]. Compared with semiconductor quantum dots, CQDs are considered one of the best candidates in the bio-imaging and biomedical field, which based on the fact that CQDs surfaces are easily modified and functionalized and have low toxicity, good water solubility, and smaller size (< 10 nm) [32,33]. In addition to exploring simple synthesis methods of CQDs with good optical properties, researchers are committed to building a novel and sensitive sensing platform based on the many merits of CQDs. Therefore, we successfully constructed a fluorescence sensor using Tyr as an oxidant for determination of DA and ALA in real samples based on onestep hydrothermally synthesized N-CQDs in the present work. The sensing system presents several advantages including simplicity, novelty, and easy to operate, which not only satisfies the highly sensitive sensing of DA and ALA, but also brings many merits with the introduction of Tyr. Tyr, as a catalytic oxidation medium, has more efficient oxidizing capacity, uses fewer doses, and is more environmentally friendly than other metal ions of different valence states as oxidants [34,35]. At the same time, the complicated operation of modifying CQDs with specific functions can also be avoided [36]. A novel, simple, and sensitive N-CQDs/DA/Tyr/ALA-based fluorescence sensor was developed in the present study for the detection of DA and ALA in human fluids. DA could be absorbed on the surface of NCQDs to form a blue fluorescence complex through intermolecular electrostatic interactions and hydrogen bonding. When Tyr was added to the system, the catechol portion of DA would complex with the binuclear copper center site of Tyr and be oxidized to dopaquinone, and the fluorescence of N-CQDs was quenched via electron transfer between N-CQDs/DA and dopaquinone. ALA can block the oxidation of Tyr and reduce dopaquinone to DA, which leads to the fluorescence recovery of the system. After continuous redox, the N-CQDs fluorescence “turn offon” system was formed, as presented in Scheme 1. This method is the first to use spectroscopy to determine ALA in real samples. This method is also expected to be used for the determination of DA, ALA, and Tyr, and it provides ideas for the research and exploration of other phenolic substances.
(C5H9NO4), and glycine (C2H5NO2) were provided by Sinopharm Chemical Reagent Beijing Co., Ltd. L-Glutamate (C5H9NO4), L-histidine (C6H9N3O2), DL-proline (C5H9NO2), and L-arginine (C6H14N4O2) were provided by the Tianjin Kwangfu Chemical Industry Research Institute. Tyr was obtained from Cool Chemical Science and Technology Co., Ltd (Beijing, China). Tianjin Kemiou Chemical Reagent Co., Ltd provided Lcysteine (C3H7NO2S). None of the above reagents required further purification and were used directly during the experiments. Ultrapure water was used in all other processes except for the preparation of ALA solution using ethanol. Ultrapure water (18.2 MΩ) was made by the United States Milli-Q purification system. 2.2. Apparatus Fluorescence emission spectra were recorded on a LS-55 photoluminescence spectroscope (Perkin Elmer, USA) under the excitation wavelength of 350 nm. Ultraviolet-visible (UV–vis) absorption spectra were obtained on a Cary 300 UV–vis spectrophotometer (Varian, USA) using a 1 cm path length quartz cell. TEM images were collected using a Teenai G2 F20 (FEI, USA) at a voltage of 200 kV. In addition, every sample was prepared by placing a drop of sample solution onto the copper grids covered in a dry air atmosphere. X-ray diffraction (XRD) patterns were obtained using an Ultima IV (Rigaku, Japan) spectrometer equipped with monochromatized Al Kα excitation. The surface functional groups of the fluorescent probe were studied using a Nicolet 380 spectrophotometer (Thermo Electron Corp., USA) through potassium bromide pellet technique ranging from 500 cm−1 to 4000 cm-1. 2.3. Preparation of N-CQDs fluorescent probe Researchers have developed a number of methods for preparing fluorescent carbon dots. A simple, fast and high-fluorescence yield method for carbon synthesis was modified and used in our system [37,38]. In brief, 2 g of anhydrous citric acid was added to 40 mL of ultrapure water containing 1 mL of ethylenediamine. The uniform solution was placed in a Teflon-lined 100 mL reactor for 2 h at 150 °C. After the reactor was cooled to room temperature, a uniformly dispersed brown solution was obtained. For the obtained fluorescent carbon dots to have uniform particle size and high yield, the solution was transferred to a dialysis bag with a cut-off amount of 3000 Da purified in ultrapure water for 48 h at room temperature. Finally, a light brown solid was obtained through freeze drying.
2. Experimental 2.1. Materials
2.4. Experimental procedures for the sensing of DA and ALA
ALA (C8H14O2S2) and anhydrous citric acid (C6H8O7) were purchased from Shanghai Macklin Biochemical Co., Ltd. Ethylenediamine (C2H8N2) and DA (C8H11NO2) were purchased from Aladdin Industrial Corporation. PBS buffer solution was prepared by using NaH2PO4·2H2O and Na2HPO4·12H2O, which were produced by Shen Tai Huagong Reagents Co., Ltd (Tianjin, China). DL-Phenylalanine, L-glutamate
The detection procedure for DA is described below. The 0.1 mg/mL standard solution of N-CQDs was prepared with ultrapure water for subsequent experiments. The entire experimental process was carried out under optimized experimental conditions, including optimal pH, reaction temperature, time, and activity of enzyme. For DA detection,
Scheme 1. Preparation and principle of the N-CQDs probe for DA and ALA sensing. 2
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30 μL of N-CQDs, 10 mM PBS buffer solution (pH = 5.5), 0.16 U/mL Tyr, and DA solution at different concentrations (ranging from 0.00 μM to 15.00 μM) were mixed in 10 mL colorimetric tubes; diluted with ultrapure water to 5 mL; shaken thoroughly; and incubated at 37 °C for 35 min to quench the fluorescence of N-CQDs. A fluorescence spectrum with an emission wavelength range of 380−650 nm was recorded when the excitation wavelength was set at 350 nm. The slit widths of emission and excitation were set to 5 nm and 10 nm, respectively. For ALA detection, the test procedure was basically the same as that of DA. Different concentrations of ALA were added in 10 mL colorimetric tubes containing 30 μL of N-CQDs, 10 mM PBS buffer solution (pH = 5.5), 0.16 U/mL Tyr, and 15 μM DA of the above optimized concentration, which were prepared as a 5 mL mixed solution, followed by incubation at 37 °C for 35 min to recover the fluorescence of the NCQDs/DA system. Similarly, the fluorescence spectra were obtained under the same emission wavelength range, excitation wavelength, and silt width as DA detection.
2934 cm−1 was attributed to the stretching vibration of CeH. In addition, the three characteristic peaks of 1568–1708 cm−1 represented the bending vibration of NeH and the stretching vibrations of C]O/ C]N, whereas 1400 cm−1 may be caused by the asymmetric vibration of COO−. We also conducted a high-resolution TEM image survey of NCQDs. The results indicated that the fluorescent carbon dots were nearly spherical in shape with mainly amorphous carbon structures, and a clear lattice fringe was observed (Fig. 2A). The crystallization degree of solid powders was investigated by XRD and laser Raman spectroscopy. A broad peak was observed around 23.5° using an X-ray diffractometer, as shown in Fig. 2B, which correspond to the (002) lattice spacing of carbon-based materials [40]. Meanwhile, Fig. 2C illustrates two peaks around 1333 and 1526 cm−1, respectively, which were detected by Raman spectroscopy. These peaks reflect the degree of disorder of the crystal structure and numerous defects in the carbon skeleton by the incorporation of nitrogen atoms [41,42]. Thus, nitrogen atoms were successfully doped in N-CQDs.
2.5. Analysis of DA and ALA in real samples
3.2. Optimization of the sensing procedure
The feasibility of the system we built can be verified by measuring the analyte in actual samples. We separately added different concentrations of DA and ALA in the actual blood and urine samples. The urine of a patient who has been diagnosed with diabetes was used as an actual sample. First, 5 mL of urine was mixed with 10 mL of acetonitrile to remove large molecules and precipitate proteins in urine. After standing for 10 min, the product was centrifuged for 12 min at 5000 r/ min, and the supernatant was filtered through a 0.22 μm aqueous system. Finally, the solution was adjusted to slightly acidic with PBS buffer solution (pH = 5.5) and diluted 50 times with ultrapure water. Different concentrations of ALA were added into urine to prepare the spiked samples. To analyze the DA content, we collected the blood samples of volunteers from the University Hospital. The collected serum was diluted 100-fold without further processing. Finally, the spiking experiment was carried out under the optimized conditions in accordance with the designed test procedure.
The optimization of experimental parameters has an impact on the good analytical performance of fluorescent nanosensors in the detection process. We investigated the influence of Tyr activity, incubation time, pH of the reaction system, and reaction temperature in the sensor platform we designed, which were related to the sensitivity of the proposed biosensor. First, we optimized the amount of catalytic oxidase, which is essential for the catalytic oxidation of DA quenching system. The fluorescence intensity of the quenching system gradually decreased with the introduction of Tyr activity varying from 0.04 U/mL to 0.16 U/mL, as illustrated in Fig. 3A. However, the fluorescence intensity tended to be relatively stable when the activity of Tyr exceeded 0.16 U/mL, and the results indicated that the fluorescence quenching effect of dopaquinone was maximized. Thus, 0.16 U/mL was adopted as the activity of Tyr in further experiments. We further studied the effect of pH on the fluorescence quenching and recovery efficiency of the system. The efficiencies were calculated by the following equations, respectively:
3. Results and discussion
(1)
Effq = (Fo
F )/Fo
3.1. Characterization of N-CQDs
Effr = (Fr
F )/(Fo
First, we explored the optical properties and surface functional groups of the hydrothermally synthesized fluorescent probe via UV–vis, fluorescence, and FTIR spectroscopy. Curve (c) in Fig. 1A shows the UV absorption spectrum of N-CQDs we prepared. We observed a distinct absorption band at 350 nm, which may be caused by the electron transitions from n-π* [37,39]. In addition, a weak absorption peak near 253 nm was observed because of the π-π* transitions in the carbonyl and amide bonds (C]C/C]O) of fluorescent carbon dots. Strong blue fluorescence photographs were exhibited in a 365 nm ultraviolet box. As shown in the curve (d), a high-intensity fluorescence emission peak centered at 445 nm was revealed when the excitation wavelength was set to 350 nm. We also measured the fluorescence emission spectra of N-CQDs at different excitation wavelengths. As shown in Fig. 1C, the maximum emission wavelength of the fluorescence probe was basically no shift with the change of the excitation wavelengths, and reached a maximum when excited at 350 nm. In summary, we can infer that the excitation-independent properties of N-CQDs can be better applied in biological imaging to avoid the autofluorescence. Fig. 1B displays an obvious change in fluorescence intensity of the system when the quencher and recovery agent were introduced. The surface of quantum dots contained a large number of oxygen-containing groups to help enhance water solubility and stability, which was successfully confirmed by FTIR spectroscopy. As shown in Fig. 2D, the OeH/NeH stretching vibration peaks in the carboxyl and amide groups of N-CQDs were exhibited at 3423 and 3250 cm−1, respectively. The peak of
Where Fo and F represent the fluorescence intensity of the sensing system in the absence and presence of DA, respectively; Fr indicate recovered fluorescence intensity of N-CQDs in presence of ALA. As displayed in Fig. 3B, when the pH changed from 4.5 to 5.5, the fluorescence quenching efficiency (Effq) of DA increased slightly and reached a maximum. However, at the pH range of 5.5–9.0, the quenching efficiency decreased and remained stable. These results may be attributed to neutral and alkaline environments that did not favor the quenching efficiency of DA. Moreover, the concentration of DA has been reported to be more accurately determined in weak acidic solution, which also avoids the effect of self-polymerization of DA on the catalytic oxidation of DA itself to dopaquinone under alkaline conditions [43]. Fig. 3B shows that the fluorescence recovery efficiency (Effr) of ALA to the sensing system remained unchanged with the increase in pH from 4.5–9.0. The efficiency of fluorescence recovery reached a maximum when the pH was 5.5, indicating that a high pH environment was not conducive to the reduction of ALA. Therefore, weak acidic conditions (pH = 5.5) are suitable for this sensing system. Furthermore, we studied the suitable incubation time in PBS (pH = 5.5) at 37 °C. As illustrated in Fig. 3C, the quenching and recovery efficiency of the fluorescent system reached a maximum and remained stable after 35 min, showing that the oxidation catalytic reaction of the copper-centered active site of Tyr and phenolic hydroxyl group of DA was completed in 35 min. To make the reaction more complete, we chose 35 min as the optimal incubation time for the 3
F)
(2)
Journal of Photochemistry & Photobiology A: Chemistry 392 (2020) 112438
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Fig. 1. (A) UV–vis spectra of the (a) N-CQDs/DA/Tyr/ALA recovery system, (b) N-CQDs/DA/Tyr quenching system and (c) N-CQDs, and (d) fluorescence emission spectra of N-CQDs. (B) The fluorescence spectra of N-CQDs, N-CQDs/DA/Tyr/ALA, and N-CQDs/DA/Tyr systems. (inset: the blue fluorescence image of fluorescent probe under 365 nm ultraviolet box). (C) Fluorescence emission spectra of N-CQDs at different excitation wavelengths.
detection of DA and ALA in subsequent experiments. We also investigated the effect of the reaction temperature on the proposed system, as shown in Fig. 3D. The fluorescence quenching and recovery efficiency of the monitoring system reached the highest at 37 °C. These results may be explained by the temperature mainly affecting the activity of Tyr. Under different temperatures, the enzyme may be in different conformations, and the high temperature also facilitated the inactivation the enzyme [44]. Thus, the optimal reaction temperature of the fluorescence system was 37 °C in the further experiments. Regarding the above experimental results, 0.16 U/mL Tyr, pH 5.5, 40 min of incubation time, and 37 °C of interaction temperature were selected for the whole experimental process.
calculated as three times the noise of the response signal (3 δ/S), and it was as low as 0.035 μM. What’s more, we compared the constructed system with other sensor strategies for detecting DA and summarized them in Table 1 [34,36,45–50]. The table shows that the present method performed well in terms of the sensitive and highly selective detection of DA. The incubation time of the constructed system in the quantitative determination of DA was almost comparable and relatively shorter than previously reported sensing system [34,36,49,50]. In addition, no complicated material preparation compared to other systems [45–47,48], which also saves more time for the entire experimental process. On the other hand, the recovery effect of ALA on the fluorescence intensity of the sensing system was studied under optimal experimental conditions. Accompanied with the amount of ALA varying from 0 μM to 55 μM, the fluorescence intensity of the quenching system at 445 nm gradually returned to a maximum, as shown in Fig. 5A. In addition, Fig. 5B illustrates a good linear relationship between the fluorescence intensity ratios (Fr-Fro)/Fro and the concentrations of ALA in the range of 0.5–15 and 15−55 μM. Fr and Fro represent the fluorescence intensities of the N-CQDs/DA/Tyr system in the presence and absence of ALA, respectively. The linear regression equation of the working curve (F (Fr Fro)/Fro = 0.03175 + 0.10671[ALA] and was r Fro)/ Fro = 1.15332 + 0.0333[ALA]. The correlation coefficients (r) were 0.995 and 0.999. The LOD for ALA was 0.39 μM. According to the above performance, the proposed method is expected to be successfully applied for DA and ALA determination in real samples.
3.3. DA and ALA assay based on fluorimetric method To verify the feasibility and practicality of detecting DA and ALA based on the present fluorescence sensing platform, we added a series of different DA and ALA concentrations to the quenching and recovery system under the optimal conditions. As displayed in Fig. 4A, the fluorescence intensity of the N-CQDs/DA/Tyr system decreased significantly with the increase in DA content, whereas the fluorescence value became stable after 15 μM. As plotted in Fig. 4B inset, an excellent linear relationship between the fluorescence intensity and the concentration of DA was exhibited in the range of 0.05-0.5 and 0.5−15 μM with corresponding regression coefficients (r) of 0.994 and 0.992, respectively. The linear regression equations were (Fo F )/ Fo = 0.00204 + 0.50082[DA] and (Fo F )/ Fo = 0.21865 + 0.03982[DA], where Fo and F represent the fluorescence intensity of the sensing system in the absence and presence of DA, respectively. The limit of detection (LOD) for DA based on the constructed system was
3.4. Selectivity and interference of DA and ALA To validate the high accuracy and selectivity of the fluorescence 4
Journal of Photochemistry & Photobiology A: Chemistry 392 (2020) 112438
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Fig. 2. (A) HR-TEM image of N-CQDs in 5 nm, (B) XRD pattern of N-CQDs, (C) Raman spectra, and (D) FTIR spectra of N-CQDs.
Fig. 3. (A) Effect of different Tyr activity on fluorescence quenching strength of N-CQDs/DA system, (B) effect of solution pH, (C) incubation time, and (D) reaction temperature on the fluorescence intensity of N-CQDs/DA/Tyr and N-CQDs/DA/Tyr/ALA system. 5
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Fig. 4. (A) Fluorescence quenching of N-CQDs with the addition of DA. (B) Linear relationship of fluorescence intensity in the presence of different concentrations of DA. Table 1 Comparison of the proposed method with different DA detection methods. Method
System
Incubation time (min)
Linear Range (μM)
LOD (μM)
Reference
Electrochemical Colorimetric Colorimetric Fluorescence Fluorescence Fluorescence Fluorescence Fluorescence Fluorescence
BSA-AgInS2 QD/AuNRs/GO TMB-H2O2-Co3O4@NiO Cu-MOXs-TMB-H2O2 CDs-TYR NaGdF4:Tb NPs DA-GQDs-Cu2+-AA Ru-CIP-SDBS DA-PEI-PDA N-CQDs/DA/Tyr/AA
– 7 20 150 5 60 60 30 35
0.3–10 1–20 0.5–20 0.1–6 0–10 0.5–120 0.1–10 1–200 0.05–15
0.067 1.21 0.085 0.06 0.03 0.16 0.006 0.3 0.035
[45] [46] [47] [36] [48] [34] [49] [50] This work
concentrations of coexisting materials to DA or ALA and measuring the above mixtures under the same experimental conditions. Fig. 6 displays that the simultaneous presence of interfering substances and analytes did not significantly affect the quenching and recovery of the fluorescent system. Thus, our proposed fluorescence sensing strategy may be promising for the biomedical field.
sensing platform for DA and ALA detection, we further investigated the applicability of the proposed system in the presence of multiple interfering substances. These substances included some common amino acids (200 μM), such as glycine, DL-phenylalanine, histidine, arginine, cysteine, tyrosine (50 μM), L-glutamic acid, proline, lysine, tryptophan, glutathione, uric acid (200 μM), Na+, K+, Ca2+, and Mg2+ (1000 μM), under the optimized experimental conditions. First, the high selectivity of the fluorescence sensing platform for quenchers and restorers was determined when DA (10 μM) and ALA (20 μM) were added to the system separately with a high concentration of other coexisting substances, as shown in Fig. 6. The fluorescence intensity of the sensing system in the presence of DA and ALA was obviously reduced and enhanced compared with when other coexisting substances were added. These results indicated that the established method has high selectivity for the detection of DA and ALA, so it is expected to be used in practical testing. We also performed interference measurement, by adding high
3.5. Determination of DA and ALA in real samples The recovery study of the analytes in real samples is also one of the criteria for assessing the good performance of the biosensor, and the standard addition method was applied for the detection of DA and ALA in human serum and urine samples. Different concentrations of DA (0.8, 5, and 10 μM) and ALA (10 and 40 μM) were added to 50-fold diluted human serum and urine samples. The fluorescence intensity values of this sensing system were recorded, and the analytical results are listed
Fig. 5. (A) Fluorescence recovering of N-CQDs with the addition of ALA. (B) Linear relationship of fluorescence intensity with different ALA concentrations added. 6
Journal of Photochemistry & Photobiology A: Chemistry 392 (2020) 112438
R. Zhang and Z. Fan
Fig. 6. Selectivity (A) and interference (B) of the N-CQDs system toward DA and ALA over other substances, respectively.
Appendix A. Supplementary data
Table 2 Detection of DA and ALA in real samples. Sample
Spiked (μM)
Found (μM)
Recovery (%)
RSD (n = 3,%)
Human serum (DA)
0.8 5.0 10.0
0.81 ± 0.10 5.08 ± 0.09 10.03 ± 0.21
101 102 100
2.4 2.6 2.8
Human urine (DA)
0.8 5.0 10.0
0.78 ± 0.07 5.01 ± 0.15 9.82 ± 0.10
97 100 98
2.5 1.9 2.0
Human urine (ALA)
10.0 40.0
10.12 ± 0.20 39.70 ± 0.15
101 99
3.0 3.2
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in Table 2. The average recoveries of DA and ALA were in the range of 96 %–102 % and 99 %–101 %, respectively. The relative standard deviation (RSD) of DA and ALA was lower than 2.8 % and 3.2 %, respectively. The obtained results revealed that the proposed fluorescence sensing platform can be applied for sample detection and exhibits satisfactory performance in DA and ALA detection for real samples. 4. Conclusion A highly sensitive and practical fluorescent biosensing platform was built for the rapid detection of DA and ALA based on the simple redox reaction and charge transfer mechanism of the N-CQDs/DA/Tyr/ALA “turn off-on” strategy. Utilizing the fluorescence probe, we performed the accurate detection of DA and ALA in human serum and urine, and achieved satisfactory results. Moreover, the proposed method is simple, environment-friendly, inexpensive, reliable, and avoids complex pretreatment. Notably, the establishment of this method provides additional ideas for the detection of ALA using optical sensors, which can bring in numerous application prospects for biomedical diagnosis. This research did not receive any secific grant from funding agencies in the public, commercial, or not-for-profit sectors. CRediT authorship contribution statement Ruxia Zhang: Investigation, Writing - original draft, Formal analysis, Writing - review & editing. Zhefeng Fan: Writing - review & editing, Supervision, Funding acquisition. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. 7
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