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Facile syntheses of S,N-codoped carbon quantum dots and their applications to a novel off-on nanoprobe for detection of 6-thioguanine and its bioimaging Chunhe Yu, Xiaohua Jiang, Dongmiao Qin, Guichun Mo, Xiangfei Zheng, and Biyang Deng ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.9b02886 • Publication Date (Web): 27 Aug 2019 Downloaded from pubs.acs.org on August 28, 2019

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ACS Sustainable Chemistry & Engineering

Facile syntheses of S,N-codoped carbon quantum dots and their applications to a novel off-on nanoprobe for detection of 6-thioguanine and its bioimaging Chunhe Yu, Xiaohua Jiang, Dongmiao Qin, Guichun Mo, Xiangfei Zheng, and Biyang Deng* State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China

*Corresponding Author: Telephone: +86-773-5845726; Fax: +86-773-2120958. Email: [email protected]

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ABSTRACT The S,N-codoped carbon quantum dots (SNCQDs) with a quantum yield (QY) of 23% have been synthesized using lotus root as a carbon source and glutathione (GSH) as a nitrogen sulfur source. The obtained SNCQDs also exhibited many excellent features such as simple preparation process, highly fluorescent QY, satisfactory photostability, superior water solubility and biocompatibility. The SNCQDs combined with Cu2+ were used as a novel off–on nanoprobe for 6-thioguanine (TG). Initial fluorescence is significantly quenched in this sensing system via electron transfer from SNCQDs to Cu2+. Fluorescence is recovered after adding TG owing to Cu2+-TG complex formation between Cu2+ and TG. A novel off−on fluorescence nanoprobe was presented for highly sensitive determination of TG. Under optimal conditions, the nanoprobe exhibited a wide linearity range of 0.005-80 μmol/L for TG and a detection limit of 1.6 nmol/L. The designed off−on nanoprobe was successfully utilized for detecting TG in plasma and urine of leukemia patient, and imaging of TG in living T24 cells. KEYWORDS: S,N-codoped carbon quantum dots; Lotus root; GSH; 6-Thioguanine; Cell imaging

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INTRODUCTION 6-thioguanine (TG) is a popular thiopurine anti-cancer, anti-tumor and immunosuppressive medication. It is utilized for the clinical treatment of acute lymphoblastic leukemia, chronic myeloid leukemia, acquired immune deficiency syndrome, and inflammatory bowel disease. It is also used to treat myocarditis, cardiac shock, retinal hemorrhage after surgery, and the prevention of coronary atherosclerosis and hepatitis.1-4 However, excessive TG triggers serious adverse effects on the human body including gastrointestinal complications and bone marrow suppression. Due to the great therapeutic effects of TG as anti-cancer drug, the development of rapid and accurate method for the detection of TG is imperative. There are currently a range of typical analytical strategies for TG monitoring. They include fluorescence,5,6 surface plasmon resonance,7 high performance liquid chromatography,8-11 electroanalysis12-14 and chromatography.15,16 Although these methods could provide good precision and accuracy, they require the complicated operation, time-consuming, and expensive instruments. Some fluorescent probes are limited due to their cytotoxicity for TG detection in living cells. Hence, it is crucial to develop a novel fluorescent nanoprobe for trace TG detection with high selectivity, low cytotoxicity and easy operation. Carbon dots (CDs) are carbon based quasi zero dimension nanostructures that include carbon quantum dots (CQDs), graphene quantum dots (GQDs) and amorphous CDs (a-CDs). The superior optical and electronic properties of CQDs make them into an excellent material for wide application in photovoltaic devices, photocatalyst, bioimaging, chemical and biological sensing, energy conversion, and, diagnosis and treatment.17-20 CQDs are more attractive than semiconductor quantum dots and traditional fluorescence dyes due to their low toxicity, outstanding fluorescence brightness, facile preparation, good water solubility, high biocompatibility and excellent photostability.21-26 CQDs are one of the most promising materials in sensing due to their excellent optical properties and a large number of surface functional groups. Several approaches have been used to synthesize CQDs, including: microwave,27,28 acid assisted chemical oxidation,29 3



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ultrasonic,30 electrochemical oxidation,31 and laser ablation.32 However, most of these methods exhibited several drawbacks including expensive equipment, low fluorescence quantum yields and complicated preparations. Compared with the above methods, hydrothermal treatment method is simple, economical, high efficient and green, so as to provide the possibility for large-scale CQDs fabrication. Recent efforts have focused on N or S doped CQDs for superior and tunable optical properties.33,34 The nitrogen (N) atom can bond with carbon atom due to their similar of atomic sizes and the electron-withdrawing ability of five valence electrons of nitrogen atoms. Therefore, N-doped CQDs (N-CQDs) have higher fluorescence quantum yield.35-37 Sulfur (S) atom can provide state density and emission trap states (ETSs) for photo-excited electrons. This results in the emission redshift of CQDs and improves the fluorescence intensity of CQDs.38 Subsequently, S and N co-doped CQDs (SNCQDs) were synthesized using N and S as heteroatom dopants. Wang et al. described the preparation of SN co-doped CQDs having a quantum yield (QY) of 21.6% via hydrothermal treatment of ammonium persulfate, glucose, and ethylenediamine.39 Zhao et al. adopted garlic as the precursor material to synthesize CQDs with a QY of 17.6%.40 The N and S present in garlic results in the formation of SN co-doped CQDs and improving CQDs fluorescence performance. Biomass contains amounts of carbohydrates which are a source of carbon for CQDs synthesis. In addition, proteins and other molecules in biomass provide N and S. Test results show that biomass can be self-passivated during the carbonization without adding passivator.41 Current literature reports that heteroatoms in biomass are usually present on the surfaces of CQDs during biomass carbonization, but only N is involved in the synthesis.42-45 The reason is that the content of S in biomass is usually much lower compared to the contents of C, H, O and N. There is thus little chance for S to react with groups on the surface of CQDs. The S in biomass may be hard to transfer to the surface of CQDs.41 In particular, many traditional approaches for preparing heteroatom co-doped CQDs are expensive and not environmentally friendly. This limits their practical application. 4


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In this study, we successfully prepared novel sulfur and nitrogen co-doped carbon quantum dots (SNCQDs) by a simple, low-cost, green and one-step hydrothermal method using lotus root as C source and GSH as the provider of N and S. The blue-emitted SNCQDs were synthesized using the hydrothermal treatment of lotus root and GSH. The synthesized SNCQDs exhibit remarkable aqueous solubility, high photostability and good biocompatibility. Furthermore, the carboxyl and hydroxyl groups on the surface of SNCQDs can form a complex with Cu2+. The fluorescence of SNCQDs was quenched significantly on Cu2+ addition due to electron transfer. TG can restore the fluorescence of SNCQDs. According to the above fluorescence change, the SNCQDs-Cu2+ nanoprobe has been applied to detect TG in human serum and urine of leukemia patient for the first time. More importantly, the intracellular TG imaging was investigated using SNCQDs-Cu2+ nanoprobe due to excellent biocompatibility. The processes of SNCQDs synthesis and TG detection are shown in Figure 1.

Figure 1. Schematic illustration of SNCQDs synthesis, TG detection and cells imaging.

EXPERIMENTAL SECTION Materials and Apparatus. Lotus root was gained from local vegetable market (Guilin, China), GSH, NaH2PO4, H3PO4, NaOH, CuCl2, threonine (Thr), tyrosine (Tyr), L-tyrosine (L-Tyr), valine (Val), Glycine (Gly), alanine (Ala), lysine (Lys), arginine (Arg) and glutamic acid (Glu) came from Aladdin Chemistry Co. 5



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Ltd. (Shanghai, China). All chemicals were of analytical grade and did not require additional purification before use. Double-distilled water (DDW) was used throughout the experiment. The concentration of SNCQDs in this work is 10 μg/mL unless otherwise specified. UV-vis absorption spectra were measured using a Cary 60 UV-vis spectrophotometer (Agilent Technologies ， USA). Fourier transform infrared (FT-IR) spectroscopy was acquired by a PerkinElmer FT-IR spectrophotometer (Perkin-Elmer, USA). Transmission electron microscopy (TEM) images were achieved via a JEM-2100F transmission electron microscopy (JEOL, Japan). X-ray diffraction (XRD) measurement was carried out using a D/max-2500V/PC powder X-ray diffractometer (Rigaku, Tokyo, Japan). Fluorescence lifetime experiments were measured by a FL3-P-TCSPC time-resolved fluorescence spectrometer (Horiba Jobin Yvon, Longjumeau, France). X-ray photoelectron spectroscopy (XPS) measurements were performed using an ESCALAB 250 photoelectron spectrometer (Thermo Fisher Scientific, USA). Fluorescent (FL) spectra were carried out using a RF-5301 fluorescence spectrometer (Shimadzu, Japan). Fluorescence images were performed with a Zeiss LSM 710 confocal microscopy (Carl Zeiss, Oberkochen, Germany). Syntheses of SNCQDs. The SNCQDs were obtained through hydrothermal treatment of lotus root and GSH. The lotus root was crushed into a powder in a juicing machine. 7 g of lotus root and 0.3 g of GSH were mixed with 10 mL of DDW. The obtained mixture was placed in a 50 mL Teflon-lined autoclave. It was heated at 200 °C for 10 h. After air cooling to room temperature, the brown solution was centrifuged for 20 min at 12000 rpm and filtered through a 0.22 μm membrane filter. The collected brown mixture was further purified by a dialysis bag (molecular weight cut off 1000 Da) for 24 h. The product was stored at 4 °C. In order to obtain SNCQDs with a higher QY, we explored the synthetic conditions, including reaction temperatures (120, 140, 160, 180, 200, and 220 °C), reaction times (3, 5, 7, 10, and 12 h), and GSH amounts (0.04, 0.1, 0.15, 0.2, 0.3, 0.6, and 0.8 g). The optimization results were shown in Figure S1. 6


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Sample Preparation. The SNCQDs-Cu2+ sensor was used to detect TG in plasma and urine of leukemia patient after oral administration of TG. The blood and urine samples were taken from Guilin Fifth People's Hospital from a female leukemia patient (aged 50). After 2 mL blank blood sample was collected from the patient, 4 tablets of thioguanine (25 mg x 4) were taken with 250 mL warm water. An hour later, 2 mL blood sample was then drawn from an elbow vein. The sample was placed in a centrifugal test tube with heparin sodium. The blood samples were treated according to the previous report.46 The samples were centrifuged at 3500 rpm for 10 min to obtain the plasma. A total of 200 μL plasma was decanted into a centrifugal tube, and then 50 μL of 0.10 mol/L NaOH and 1 mL ethyl acetate were added into the centrifugal tube. This solution was centrifuged at 12000 rpm for 10 min after being whirlpool-oscillated for 5 min. The supernatant ethyl acetate was transferred into another tube. The residue at the bottom of the centrifuge tube was extracted twice again with ethyl acetate using the steps described above. The ethyl acetate extracts were then mixed and evaporated to dry under a dry nitrogen stream at 80 °C. The resulting residue was dissolved in 200 μL DDW. Sample solutions were filtered through 0.45 µm membrane prior to analysis. Urine samples were taken from the same patient. Four mL urine was decanted into a centrifugal tube, and then centrifuged at 1500 rpm for 5 min. The upper layer was filtered with 0.45 µm membrane filters for TG measurement. TG Detection and Living Cells Imaging. Twenty μL of SNCQDs solution, 100 μL of 80 μmol/L Cu2+ solution and 180 μL of PBS solution (0.05 mol/L, pH = 6) were mixed thoroughly. This was then diluted to 500 μL using DDW. After equilibration for 6 min, fluorescence intensity was recorded to establish an initial value (in F0). In order to analysize TG, 20 μL of SNCQDs solution, 100 μL of 80 μmol/L Cu2+ solution and 180 μL of PBS solution (0.05 mol/L, pH = 6) were mixed thoroughly. After reaction for 6 min, 100 μL of different TG concentration solution was added to the above mixture and diluted to 500 μL using DDW. After incubating for 4 min, the fluorescence intensity (in F) of the mixed solution containing TG was 7



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detected by fluorescence spectrometer using emission wavelength of 440 nm. Human bladder cancer T24 cells were grown in DMEM medium with 10 % fetal bovine serum in a humidified atmosphere containing 5 % CO2 for 24 h at 37 °C. Then, 100 μL SNCQDs solution (200 μg/mL) was added to above culture medium and incubated with the cells for 6 h at 37 °C. The SNCQDs loaded cells were rinsed thrice to remove the remaining SNCQDs outside of cells. The cells containing SNCQDs were then incubated with Cu2+ (80 μmol/L) for 1 h. The cells were initially incubated with 15 mmol/L N-ethylmaleimide for 30 min to eliminate biothiol interference. After rinsing with PBS thrice, the cells were treated with SNCQDs-Cu2+ solution for 1 h. After washing thrice again with the same PBS, the cells were further treated with TG (200 μmol/L) for 1 h. The PBS solution was used to wash the cells thrice to remove the remaining TG before the cells were examined with a confocal microscope using laser wavelength of 405 nm.

RESULTS AND DISCUSSION Morphological and Structural Studies of SNCQDs. To explore the morphology and size of SNCQDs, TEM of SNCQDs was studied. The TEM image reveals that the prepared SNCQDs are well-dispersed with a nearly spherical morphology (Figure 2a). A corresponding particle size distribution histogram of SNCQDs was obtained by counting one hundred of particles (Figure 2b). The SNCQDs display a size range of 1–3.8 nm with an average diameter of 2.1 nm. The HRTEM image of SNCQDs was obtained by measuring one particle which showed an ambiguous crystal structure with a lattice spacing of 0.23 nm. This agrees with the (100) diffraction facet of graphite diffraction (Figure 2a, inset). Other evidence was provided by a diffraction pattern (Figure 2c), which displayed a broad diffraction peak centered at about 25°, implying SNCQDs graphene structure.47 The characteristic peak at 3267 cm-1 is attributed to -OH/N-H stretching vibration (Figure 2d). The C-H 8


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stretching vibration generates a peak at 2924 cm-1. The bands at 1680 cm-1 and 1552 cm-1 associate with C=O, and C=C stretching vibrations, respectively. The distinct absorption band at 1403 cm-1 corresponds to the C-N stretching vibration. The peak at 1154 cm-1 represents C-S, C-N and C-O stretching vibrations.48 These results verified that N and S have been successfully doped into the CQDs. Hydroxyl and carboxylic groups on the surface of SNCQDs contribute to the highly hydrophilic nature of SNCQDs. XPS was employed to further validate the surface state of the SNCQDs (Figure S2). The results and discussion were shown in the Supporting Information.

Figure 2. (a) TEM image and HRTEM (inset) of SNCQDs, (b) size distribution of SNCQDs, (c) XRD pattern of SNCQDs, and (d) FTIR spectrum of SNCQDs. 9



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Optical Properties of SNCQDs. To explore the optical features of SNCQDs, fluorescence emission and UV−vis absorption spectroscopy of SNCQDs were recorded. The SNCQDs solution has a distinct absorption band at 273 nm. This is possibly caused by π–π* transitions of C=O bonds (Figure 3a). Under 334 nm excitation wavelength, the SNCQDs aqueous dispersion showed a maximal emission wavelength of 440 nm. The fluorescence quantum yield of SNCQDs was estimated to be 23% according to equation S1 (Figure S3). The SNCQDs solution was yellowish under sun light. A bright blue fluorescence appears under a UV lamp (365 nm) (Figure 3a, inset). When excitation wavelengths ranged from 330 to 430 nm, the emission wavelengths of SNCQDs red-shifted (Figure 3b). Although the exact mechanisms of SNCQDs remained unclear, previous studies confirmed that the excitation dependent behavior of SNCQDs may result from different particle sizes and diverse emission trap states of SNCQDs.36 They would facilitate their potential biological applications to cells multicolor imaging. CQDs surface functional groups and doped elements, such as nitrogen and sulfur, may lead to a photoluminescence red-shift. To prove the above explanation, using lotus root as a carbon source, CQDs were synthesized under the same experimental conditions without adding GSH. The maximum emission wavelength of CQDs solution was 420 nm. This is shorter than the maximum emission wavelength of SNCQDs (440 nm) (Figure 3a). The QY of CQDs was 7.8%. The QY of SNCQDs was obviously higher than that of the CQDs prepared by lotus root. This further confirms that the doped S and N can remarkably enhance the fluorescence emission intensity of CQDs. At absorption wavelengths below 440 nm, absorbance increased as absorption wavelength decreased. The absorption spectrum of SNCQDs has no effect on the emission wavelength of larger than 440 nm (Figure 3a). There is a small amount of absorption at emission wavelength of less than 440 nm.

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Figure 3. (a) UV-vis absorption spectra and fluorescence spectra of 8 μg/mL SNCQDs, and fluorescence emission spectra of 8 μg/mL CQDs; The inset consists of the photographs of the SNCQDs solution under visible light (left) and 365 nm UV light (right). (b) Fluorescence emission spectra of SNCQDs at different excitation wavelengths (λex = 330-430 nm). Stability of SNCQDs. The SNCQDs had strong fluorescence intensity in a pH range between 4 and 10 (Figure S4). When pH values were below 4.0 and above 10, the fluorescent intensity of SNCQDs displayed a significant decrease. At pH values less than 4, the interaction between the surface carboxylic groups of SNCQDs and H+ formed [SNCQDs-H]+. This results in the structure changes of SNCQDs, which led to SNCQDs luminescence quenching. The SNCQDs can form stable structures in the range of pH 4.0–10.0, which has high the fluorescence intensity. At a pH above 10, the destruction of SNCQDs functional groups was observed, which slightly reduced their fluorescence intensity. The SCQDs fluorescence intensity is nearly constant at concentrations of 1 mol/L NaCl, under continuous irradiation for 180 min, or after storing 90 days (Figure S3b-d). This suggests that SNCQDs are highly photostable. These excellent properties show their potential application in fluorescence detection. Sensing Mechanism for TG Detection. The fluorescence spectra of SNCQDs, SNCQDs-Cu2+, SNCQDs-TG, and SNCQDs-Cu2+-TG system solutions were recorded to study the detection mechanism. SNCQDs have a bright fluorescence emission, but the fluorescence was quenched dramatically after adding Cu2+ (Figure 4a). The quenched fluorescence of SNCQDs-Cu2+ system solution was recovered immediately 11



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after adding TG. However, the fluorescence intensity of SNCQDs did not change when only TG was added. This demonstrated that SNCQDs fluorescence recovery is due to the interaction between Cu2+ and TG. A complex interaction between the functional groups on the surface of SNCQDs and Cu2+ occurred. A nonradiative electron/hole recombination process was formed via an effectual electron transfer process. The excited state electrons of SNCQDs will transfer to the empty d orbits of Cu2+. This results in the fluorescence quenching. After adding TG, the thiol group (-SH) of TG molecule has binds more strongly with Cu2+ than do SNCQDs. TG can bond with Cu2+ to form a Cu2+-TG complex by Cu2+-S bond. This removes Cu2+ from SNCQDs surfaces and results in a recovery of SNCQDs fluorescence. The interactions among SNCQDs, Cu2+ and TG were studied by UV–vis spectroscopy and fluorescence decay curves (Figure 4b and c). The UV-vis spectrum of the SNCQDs solution exhibited strong absorption peak at 273 nm. The absorption peak decreased significantly after adding Cu2+. The results trend to prove that SNCQDs interact with Cu2+ and a SNCQDs-Cu2+ complex is formed. The zeta potentials of SNCQDs and SNCQDs-Cu2+ were measured to further confirm the binding of copper ion to SNCQDs (Figure S5). The SNCQDs zeta potential was −5.38 mV. After adding Cu2+, the SNCQDs zeta potential changed to +2.24 mV. The Cu2+ complexed with functional groups on the surface of SNCQDs was proved again. Therefore, Cu2+ resulted in SNCQDs fluorescence quenching. However, the absorption peak of SNCQDs was restored in the presence of TG. The results were consistent with the observations of the fluorescence spectra (Figure 4b). The fluorescence lifetimes of SNCQDs, SNCQDs-Cu2+, SNCQDs-TG, and SNCQDs-Cu2+-TG were measured to further elucidate the quenching mechanism. The fitting parameters of the decay curves can be found in Table S1. The average lifetime of SNCQDs was 4.61 ns before and after the addition of TG (Figure 4c). Average fluorescence lifetime was 2.69 ns after coordination with Cu2+. This indicated the average life time was virtually changed after adding Cu2+ into the SNCQDs solution. This implies that the fluorescence quenching of SNCQDs caused by Cu2+ is a dynamic quenching mechanism. The dynamic quenching 12


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involved the transfer of electron from the excited state of SNCQDs to ground state Cu2+, which further proved that the quenching process of Cu2+ to SNCQDs is electron transfer process. However, adding TG into SNCQDs-Cu2+ solution increases the fluorescence lifetime to 4.43 ns. This may specify that the formation complex of Cu2+-TG results in the recovery of SNCQDs luminescence.

Figure 4. (a) Fluorescence emission spectra of SNCQDs, SNCQDs-Cu2+, SNCQDs-TG, and SNCQDs-Cu2+-TG. (b) UV-Vis absorption spectra of SNCQDs (black), TG (green), SNCQDs-Cu2+ (blue), and SNCQDs-Cu2+-TG (red). (c) Fluorescence decay traces of SNCQDs, SNCQDs-TG, SNCQDs-Cu2+, and SNCQDs-Cu2+-TG. The concentrations of SNCQDs, Cu2+ and TG in Figure 4a and Figure 4c are 10 μg/mL, 120 μmol/L and 200 μmol/L, respectively. 13



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Optimizing Analytical Conditions. Cu2+ concentration, pH value and incubation time were optimized to obtain a high sensitivity for the TG detection. As Cu2+ concentration increased from 0 to 180 μmol/L, the fluorescence emission intensity of 10 μg/mL SNCQDs decreased accordingly (Figure S6). The 80 μmol/L was identified as the ideal Cu2+ concentration due to considering obvious fluorescence enhancement and avoiding excessive quenching. The fluorescence intensities of 10 μg/mL SNCQDs-80 μmol/L Cu2+ and 10 μg/mL SNCQDs80 μmol/L Cu2+-80 μmol/L TG were examined at pH values ranging from 1 to 12. The fluorescence intensity of 10 μg/mL SNCQDs-80 μmol/L Cu2+ reached the lowest when pH was 6 due to Cu2+ ions strong combination with SNCQDs (Figure S7a and inset). The fluorescence intensity of 10 μg/mL SNCQDs-80 μmol/L Cu2+-80 μmol/L TG restored to its maximum when pH was 6 (Figure S7b). This observation may be attributed to the fact that Cu2+ ions on the surface of SNCQDs can form a stable complex with TG when pH is 6 and SNCQDs were released from SNCQDs-Cu2+.49 Under alkaline conditions, Cu2+ reacts with OH- to form Cu(OH)2, which inhibits the interaction between Cu2+ and SNCQDs, and weakens the quenching effect of Cu2+. The influence of pH on TG sensing was evaluated (Figure S7b and inset). At low pH value, the protonation of thiol groups in TG lowered the interaction opportunities of TG with Cu2+ and limited the fluorescence recovery of SNCQDs-Cu2+. Under alkaline conditions, a large amount of OH− groups will bind to Cu2+. This restricted interaction between Cu2+ and TG, and limited SNCQDs-Cu2+ sensing behavior. The optimal pH value was set at 6 to gain a sufficiently sensitive and stable sensor for TG detection. The effect of incubation time on the fluorescence signal of reaction systems was further studied. The fluorescence intensity of SNCQDs is stable within the incubation times ranging from 1 to 20 min (Figure S7c). After adding Cu2+, the fluorescence intensity of SNCQDs decreased gradually and stabilized after 6 min. After adding TG, the fluorescence of SNCQDs-Cu2+ system was recovered. The restoration fluorescence reached a maximum value after 4 min. The following experiments were carried out at the 14


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optimal incubation time. Analytical Performance. The developed SNCQDs-Cu2+ system for TG detection was investigated using various TG concentrations (Figure 5a). The fluorescence intensity of SNCQDs-Cu2+ system at 440 nm enhanced gradually as the concentrations of TG increased. As shown in Figure 5b, the ratio of fluorescence intensity in the presence and absence of TG exhibits a linear correlation over the TG concentration range of 0.005~80 μmol/L. The linear equation is F/F0 = 1.052+0.02219C (R2 = 0.9976). Based on S/N = 3, the limit of detection was estimated to be 1.6 nmol/L. A comparison of the developed TG detection with other reported methods appears in Table S2. The proposed method possesses some merits in terms of wider linear range and lower detection limit to compare with previous TG detection methods.

Figure 5. (a) Fluorescence response of 10 μg/mL SNCQDs-80 μmol/L Cu2+ after adding various TG concentrations, TG concentrations (bottom to top) for 0, 0.005, 0.01, 0.1, 7, 15, 25, 40, 60, 80, 100, 120, 140, 160, 180, 200 μmol/L; (b) F/F0 of 10 μg/mL SNCQDs-80 μmol/L Cu2+ vs TG concentrations. In order to evaluate the selectivity of the SNCQDs-Cu2+ probe toward TG, the influence of some possible coexistence substances such as amino acids, some anions, GSH, glucose, sucrose, ascorbic acid, serum albumin, and urea were investigated. The most of coexisting substances showed no obvious interference except for GSH, Cys and Hcy (Figure 6). They partially restored SNCQDs-Cu2+ fluorescence. Their F/F0 values were less than that of TG, This is attributed to the strong binding affinity of Cu2+ with the thiol group of TG and the lower pKa (7.44) value of TG compared to GSH (9.20), Cys (8.00), and Hocy (8.87). TG is 15



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more likely to bind to Cu2+ than Cys, Hocy and GSH.50 Therefore, SNCQDs-Cu2+ has a high selectivity and can provide credible results for TG detection.

Figure 6. Fluorescence response of SNCQDs-Cu2+ in the presence of 200 μmol/L coexistence substances. Detection of TG in Real Sample. The proposed sensors were applied for detection of TG in plasma and urine of leukemia patient after 2.0 h of oral administration. The preparation and detection method of serum sample was described in Section 2.3. The concentrations of TG in plasma and urine of leukemia patient were 3.325 and 3.904 μmol/L, respectively (Table 1). The recoveries varied in the range of 99.00 %−104.6 % with relative standard deviations (RSDs, n = 5) of less than 2.6 %. This revealed high accuracy and good repeatability. The experimental results also confirmed the feasibility and reliability of SNCQDs-Cu2+ based sensor for TG detection in biological samples. Table 1. Analytical results of TG in plasma and urine of leukemia patient (n = 5). Sample

Original (μmol/L)

Added (μmol/L)

Found (μmol/L)

Recovery (%)

RSD (%)

Plasma

3.325

3.00

6.295

99.00

2.2

3.325

6.00

9.343

100.3

2.6

3.904

3.00

6.886

99.40

2.4

3.904

6.00

10.18

104.6

1.8

Urine

Cytotoxicity of SNCQDs-Cu2+ and Imaging of TG in T24 Cells. The SNCQDs-Cu2+ inherent 16


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cytotoxicity to T24 cells was evaluated by a standard MTT assay to confirm its potential application in bioimaging (Figure S8). T24 cells viability exceeded 90 % at a higher concentration of SNCQDs-Cu2+ up to 1200 μg/mL. In order to investigate the interference of N-ethylmaleimide (NEMI) on TG detection, the fluorescence spectra of SNCQDs, SNCQDs-Cu2+, SNCQDs-Cu2+-TG, and SNCQDs-Cu2+-TG-NEMI system solutions were investigated. The fluorescence intensity of SNCQDs-Cu2+-TG in the presence and absence of NEMI was unchanged (Figure S9). After incubating T24 cells with SNCQDs for 6 h at 37 °C, the fluorescence microscopy images of T24 cells were taken using a laser scanning confocal microscope. T24 cells incubated with SNCQDs to exhibit strong blue fluorescence (Figure 7A). This confirmed SNCQDs could penetrate cells membranes and translocate into cells by endocytosis. After being treated by adding Cu2+, the cells displayed weak blue light (Figure 7B). T24 cells were treated with 15 mmol/L NEMI for 30 min to consume all the thiols that present in the cells, and then incubated with the SNCQDs-Cu2+ probes. Almost no fluorescence was observed under the laser confocal microscope (Figure 7C). Strong blue fluorescence was detected under the laser confocal microscope when T24 cells loaded with SNCQDs-Cu2+ were treated with 200 μmol/L TG for 1 h (Figure 7D). This indicates the proposed SNCQDs-Cu2+ probes have excellent selectivity and could be used for semi-quantitative detection of TG in living cells.

Figure 7. (A) Confocal fluorescence image of T24 cells with 200 μg/mL SNCQDs incubation, (B) Confocal 17



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fluorescence image of T24 cells with 80 μmol/L Cu2+ incubation after incubating with 200 μg/mL SNCQDs, (C) Confocal fluorescence image of T24 cells with 80 μmol/L SNCQDs-Cu2+ incubation after treating with 15 mmol/L NEMI, and (D) Confocal fluorescence image of T24 cells with 200 μmol/L TG incubation after treating with 15 mmol/L NEMI and then treating with 200 μg/L SNCQDs-Cu2+. Incubation time was 6 h. Fluorescence image using excitation wavelength of 405 nm (first row) and bright field image (second row).

CONCLUSIONS A facile, green, one-step hydrothermal approach for synthesizing highly fluorescent SNCQDs was achieved. They exhibit strong fluorescence, excellent solubility, and good dispersibility. The fluorescence of SNCQDs could be quenched by Cu2+ and recovered after adding TG. The new, off−on fluorescence nanosensor was developed for highly sensitive determination of TG in plasma and urine of leukemia patient. The SNCQDs-Cu2+ probe could be also successfully applied to TG imaging in living cells. This fluorescent probe could hold promise as an efficient platform for other drug detection and bioimaging.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications Website at DOI: Calculation of Fluorescence Quantum Yield; Cellular Toxicity Assay; Optimization of Synthesis Conditions; Confirmation of SNCQDs Surface-State; Figures S1-S9; Tables S1-S2 (PDF). AUTHOR INFORMATION Corresponding Author *Telephone: +86-773-5845726; Fax: +86-773-2120958. Email: [email protected] Notes 18


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The authors declare no competing financial interest.

ACKNOWLEDGEMENTS This work was financially supported by the National Natural Science Foundation of China (grant numbers 21765004 and 21365006) and by the Guangxi Science Foundation of China (grant numbers 2014GXNSFDA118004 and 1598025-4), and by the Innovation Project of Guangxi Graduate Education (YCSZ2013039). The research fund of State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Guangxi Normal University) (CMEMR2017-A5) is gratefully acknowledged. We gratefully acknowledge Guilin Fifth People's Hospital (Guilin, China) for providing the blood and urine samples.

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S,N-codoped carbon quantum dots were used as a novel off-on nanoprobe for detection of 6-thioguanine and its bioimaging.

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Facile syntheses of S,N-codoped carbon quantum ... - ACS Publications

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