Hexagonal Cobalt OxyhydroxideâCarbon Dots Hybridized Surface

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Hexagonal Cobalt Oxyhydroxide-Carbon Dots Hybridized Surface: High Sensitive Fluorescence Turn-on Probe for Monitoring of Ascorbic Acid in Rat Brain Following Brain Ischemia Linbo Li, Chao Wang, Kangyu Liu, Yuhan Wang, Kun Liu, and Yuqing Lin Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/ac5046609 • Publication Date (Web): 20 Feb 2015 Downloaded from http://pubs.acs.org on March 1, 2015

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Analytical Chemistry

Hexagonal Cobalt Oxyhydroxide-Carbon Dots Hybridized Surface: High Sensitive Fluorescence Turn-on Probe for Monitoring of Ascorbic Acid in Rat Brain Following Brain Ischemia Linbo Li, †,‡ Chao Wang, † Kangyu Liu,† Yuhan Wang,§ Kun Liu,§ Yuqing Lin*,† †

Department of Chemistry, Capital Normal University, Beijing 100048, China

‡

College of Resources Environment and Tourism, Capital Normal University, Beijing

100048, China §

Capital University of Physical Education and Sports, Beijing 100191, P. R. China

*Corresponding Author. Fax:+86- 10-68903047; E-mail: [email protected]

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Abstract: In this study, we report a novel and efficient fluorescence probes synthesized

by

tris(hydroxymethyl)aminomethane-derived

carbon

dots

(CDs)-modified hexagonal cobalt oxyhydroxide(CoOOH) nanoflakes (Tris-derived CDs-CoOOH) for monitoring of cerebral ascorbic acid (AA) in brain microdialysate. The as-prepared Tris-derived CDs with the fluorescence quantum yield of 7.3% are prepared by one-step pyrolysis strategy of the sole precursorand used as the signal output. After hybridized with CoOOH nanoflakes to form Tris-derived CDs-CoOOH, the luminescence of the Tris-derived CDs can be efficiently quenched by CoOOH via fluorescence resonance energy transfer (FRET). Due to the specific redox reaction between the enediol group of AA and hexagonal CoOOH nanoflakes, AA can reduce the hexagonal CoOOH nanoflakes in the Tris-derived CDs-CoOOH and lead to collapse of the hybrized structure, then the release of Tris-derived CDs and thus finally the fluorescence recovery. Moreover, cobalt ions (II), generated by CoOOH nanoflakes oxidizing AA, almost has no obvious interference on the fluorescence probe i.e. Tris-derived CDs, which could be ascribed to the surface of Tris-derived CDs containing few strong chelation group such as amino/carboxyl/thiol groups, instead of plenty of -OH groups with week chelation with Co2+.Based on this feature, the Tris-derived CDs-CoOOH fluorescent probe demonstrates a linear range from 100 nM to 20 µM with the detection limit ~50 nM, i.e. with an improved sensitivity toward AA detection. Compared with other turn-on fluorescent method using convenient fluorophore-nitroxide fluorescent probe for detection of AA, the method demonstrated here possesses a facial synthesis route, lower limit of detection, and wider linear range, which validates sensing of AA in the cerebral systems during the calm/ischemia process. This study provides a fluorescence assay for the simple yet facial detection of AA in the cerebral systems and assists understanding of the biological processes in the physiological and pathological study.

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INTRODUCTION Ascorbic acid (AA) is one kind of most important neurochemicals in cerebral systems, not only functions as an antioxidant in the intracellular antioxidant system playing a vital role in neuroprotection but also acts as a neuromodulator of both dopamine and glutamate-mediated neurotransmission.1 In addition, the level of AA related to some diseases, for instance, inadequate AA intake will reduce the symptoms of scurvy while excess AA intake will induce urinary stone, diarrhea and stomach convulsion.2 In this regard, simple and effective measurements of AA in the cerebral neuron system of living animals are of great physiological and pathological importance.3 Many elegant methods including electrochemistry, liquid chromatography (LC) assay,

microfabricated electrophoresis chips, and high

performance liquid

chromatography coupled with electrochemical detector (HPLC-ED) have previously been reported for in vitro measurements of AA since in physiological solutions, AA can be electrochemically oxidized through a two-electron and one-proton pathway.4, 5 However, these sample separation-based methods for the determination of AA in the brain microdialysates suffers from limitations of low time resolution and much instrumentation as well as the degradation of AA during the separation procedure. To resolve these problems, for the first time, Mao group successfully developed electrochemical methods with high selectivity and good reproducibility for in vivo/online measurement of AA by taking advantage of the excellent electrochemical properties of carbon nanotubes for facilitating the oxidation of AA. 5a, 1a Nevertheless, more methods for simple but effective measurements of AA in the cerebral systems are still urgently desired. Fluorescent probes sensing strategies have drawn rising attention due to the intrinsic advantages such as high sensitivity and selectivity, direct monitoring the target analytes of live cells, tissues, and animals6 without complicated pretreated process and instrumentation during the assay operations. Several efficient organic fluorescent probes have been designed for determination of AA,7 Maki et.al developed 3 / 23



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a perylenebisimide-linked nitroxide fluorescent probe for selective determination of AA by flow injection method,7a Yuta et.al displayed a rapid and convenient fluorophore-nitroxide fluorescent probe for detection of AA.7b As for these nitroxide based probes, costly and complex synthesis, difficult separation, poor photostability are involved and a relatively narrow linear range limit the further application in investigation of extracellular AA level changes in physiological and pathological processes.8 Recently, some novel and efficient nano-fluorescent probes based on the specific reaction between the nanomaterials and reactive species provide promising pathway for the determination of reactive species.9 For instance, Liu’s group developed a method based on the specific reaction of MnO2 and glutathione (GSH) for rapid and selective detection of GSH in living cells. 9b Tang’s group designed a CoOOH-modified persistent luminescence nanoparticles (Sr2MgSi2O7:1% Eu, 2% Dy) for determination and screening of AA in living cells and in vivo based on the specific reaction of CoOOH.

9a

However, the preparation of costly nanoparticles is still

complicated and involves in multi-steps with harsh condition, such as concentrated nitric acid under vigorous stirring, fired at 1000 °C for 10 h and a weak reductive atmosphere using 10% H2, 90% Ar. Consequently, it is still highly demanded to design simple, efficient, and novel fluorescent probes for AA investigation in brain system in physiological and pathological processes. Fluorescent carbon dots (CDs) as an exciting carbon nanomaterial, have emerged as potential new platform in designing and tuning fluorescent biosensing. Compared with persistent luminescence nanoparticles (Sr2MgSi2O7:1% Eu, 2% Dy), CDs have excellent properties in size-tunable optical properties, easy to functionalization and large-scale synthesis, low cost, good water-solubility and being both excellent electron donors and excellent electron acceptors. 10 Inspired by the nano-fluorescent probes from Tang’s and Liu’s group based on the specific reaction between the nanomaterials and reactive species, and in order to escape the drawbacks of previous fluorescent probe, we design a simple and efficient fluorescence probes. i.e. tris-derived carbon dots (CDs)-modified hexagonal CoOOH nanoflakes (Tris-derived CDs-CoOOH) for monitoring of cerebral AA in microdialysate. Herein, the 4 / 23


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as-prepared Tris-derived CDs as the strong signal output simply synthesized by one-step pyrolysisstrategy (230 ºC) using tris as the sole precursor and hybridized with CoOOH nanoflakes to form the fluorescence probe Tris-derived CDs-CoOOH. The luminescence of the Tris-derived CDs can be efficiently quenched here by CoOOH via fluorescence resonance energy transfer (FRET).9

a)

Pump aSCF, 3µL/min

Microdialysis Probe Brain Dialysates

Hybridization

b)

CoOOH HN HO C

EG

OH

Off

On

HO

Tris-derived CDs

Probe

= Co2+

Scheme 1.a) Sensitive fluorescence turn-on detection of AA in rat brain usingTris-derived CQDs-CoOOH probe; b) Principle of AA-induced fluorescence change of Tris-derived CQDs-CoOOHhybridized surface. In the carbon dots-metal oxyhydroxide probe (Scheme 1), hexagonal CoOOH nanoflakes are employed as the recognition unit due to its specific redox reaction with the enediol group of AA making high selective to detect AA. Importantly, cobalt ions (II) generated from AA reacting with CoOOH nanoflakes almost has no obvious interference on the probe, which can be ascribed to Tris-derived CDs, lacking of the strong chelation group such as amino/carboxyl/thiol groups, mainly modified with −OH groups displaying week chelation with Co2+. Furthermore, the Tris-derived CDs-CoOOH probe shows a linear range from 100 nM to 20 µM with the detection 5 / 23



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limit 50 nM, which is one of the most sensitive carbon dots based fluorescent methods of our the best of our knowledge. The large surface area of the hexagonal nanoflakes endows it sensitive reacting with trace of AA, accounting for the high sensitivity. The high sensitivity makes it successful determination of cortical AA level in a rat brain during the calm/ischemia process. Combined with the simplicity in operation and instrumentation of this method, these properties of the proposed probe make it a great promise for determination of cerebral AA in a rat brain. EXPERIMENTAL SECTION Chemicals and Materials. Tris, Sodium ascorbate, citric acid (CA), glycine (Gly), cysteine (Cys), Glutamic (Glu), ethylene glycol (EG), dopamine (DA) hydrochloride, 3,4-Dihydroxyphenylaceticacid (DOPAC), uric acid (UA)and sodium hydroxide were all purchased from Sigma. Sodium hypochlorite (NaClO), hydrogen peroxide (H2O2, 30%), concentrated hydrochloric acid (HCl, 37%), NaCl, KCl, CuCl2·2H2O, Zn(NO3)2·6H2O, CaCl2, MgSO4·2H2O, MnSO4·H2O, NiCl2·6H2O, Pb(NO3)2, CoCl2·6H2O, CdSO4·2H2O, NaH2PO4, Na2HPO4·3H2O were purchased from Beijing Chemical Reagent Company.. All reagents are of analytical reagent grade and used as received. And all aqueous solutions were prepared with double-distilled water produced by a Milli-Q system (Millipore, Bedford, MA, USA, 18.2 MΩ.cm). Synthesis of Tris-derived CDs. The Tris-derived CDs were prepared by pyrolyzing carbonization method.11 Briefly, 0.5 g tris was put into a 5 mL beaker and heated to 230ºC using a heating mantle. The color of the liquid was changed from colorless to wine after 30min later, indicating the formation of Tris-derived CDs. Then obtained orange liquid was immediately added drop by drop into 10 mL of double-distilled water solution, after neutralized to pH 7.3 with 1 M HCl solution as pH regulating medium under stirring, the aqueous solution of Tris-derived CDs was obtained. It is noted that the resultant solution was dialyzed in a dialysis bag for 24 h (retained molecular weight: 1000 Da, Shanghai Green Bird Science &Technology Development Co., China) to further purifying the CDs, and the purified CDs solutions were stored under 4 ºC before further study. The measurements of fluorescence quantum yield 6 / 23


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(QY) of the Tris-derived CDs was determined and showed in Table S1 (Supporting Information). Fabrication of Hexagonal CoOOH. Firstly, 250 µL of sodium hydroxide(NaOH,1.0 M) was added to 1mL of CoCl2 (10 mM) solution, then the mixture was sonicated for 1 min. Finally, 50 µL sample of sodium hypochlorite (NaClO, 0.9 M) was added to the sonicated mixture, and then the mixture was sonicated for 10 min. Subsequently, the mixed solution was adjusted the pH to 7.3 by adding 1.0 M HCl solution with stirring. For the characterization of the CoOOH, a part of neutralized solution was centrifugated and washed three times with deionized water, and dried in an oven, and then the brownish black CoOOH powder was fabricated. Preparation of Tris-derived CDs-CoOOH. Based on the procedure of “Fabrication of hexagonal CoOOH”, 10 mL as-synthesized Tris-derived CDs solution and 5.5 mL EG as the example at the following experiments were added to the neutralized CoOOH solution, then the mixture was sonicated for 10 min. After that, Tris-derived CDs-CoOOH probe as standardized example was prepared. Stability of Tris-derived CDs-CoOOH. Various volumes of EG (0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL) were added to a series of 1mL standardized as-synthesized Tris-derived CDs solution and 1mL non-standardized as-prepared Tris-derived CDs-CoOOH solution without adding the EG, respectively, then fluorescence spectra the influence factors of time (0-60 min) on the intensity of non-standardized as-prepared Tris-derived CDs-CoOOH and volume on the intensity of standardized as-synthesized Tris-derived CDs were recorded by operating the fluorescence spectrophotometer. The fluorescence spectra of the mixture of 0.5 mL EG added to 1mL non-standardized Tris-derived CDs-CoOOH solution with different pH values (6.5-8.5) were also recorded. In Vivo Microdialysis. Microdialysis experiments in vivo were performed as reported previously.8 Briefly, The rats with guide cannula were anesthetized with chloral hydrate(350 mg/kg i.p.). The microdialysis probe (2 mm in length; Bioanalytical Systems Inc. (BAS), BAS Carnegie Medicine) was implanted into the brain cortex region through the guide cannula and was perfused with artificial 7 / 23



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cerebrospinal fluid (aCSF) (126 mM NaCl, 2.4 mM KCl, 1.1 mM CaCl2, 0.85 mM MgCl2, 27.5 mM NaHCO3, 0.5 mM Na2SO4, 0.5 mM KH2PO4, pH 7.0) at a flow rate of 3µL/min driven by a microinjection pump (CMA/100; CMA Microdialysis AB, Stockholm, Sweden). After equilibrating for 90 min by continuously perfusing aCSF through the probes for equilibration, every 30µL of brain dialysates were collected for AA sensing. Sensing of Cerebral AA. To evaluate the sensitivity towards AA of the fluorescence probe, all the different final concentrations (diluted 50 times) of AA solution were added into the standardized Tris-derived CDs-CoOOH solution and the mixed solutions were equilibrated for 20 min before spectral measurements. The sensing of cerebral AA of rats and selectivity for AA was perfomed by adding co-exist small molecules and metal ions in a similar way as described above. Instruments and Characterizations. Fluorescence and UV-visible absorption spectra were obtained using a Fluorescence F-4500 (Hitachi, Japan) and UV-2550 UV-vis spectrophotometer (Shimadzu, Japan)using a 1 cm path length quartz cell at room temperature, respectively. Fourier transform infrared (FT-IR) spectra of Tris,Tris-CQDs, CoOOH and Tris-CQDs-CoOOH were performed by Equinox 55 spectrophotometer (BRUKER, Germany), the specimen of Tris-CQDs and Tris-CQDs-CoOOH

were

characterized

by

a

freshly

CaF2

window

(transmittance >90%, 0.13 µm~9.0 µm, Beijing Scitlion Technology Co., Ltd), while the sample of Trisand Tris-CQDs-CoOOH power were synthesized with KBr wafer technique. Transmission electron microscope (TEM) and high-resolution TEM (HRTEM) images were collected on a JEM-2100F Transmission Electron Microscope (Japan) operated at 200 kV. The crystal structure was identified by powder X-ray diffraction (XRD) analysis (Bruker D8, Germany) using Cu Kα radiation in the 2θ range 5–80o. All the examples used to characterize were not contain the EG and all pH measurements were performed with a PB-10 digital pH meter (SARTORIUS, Germery). Energy Dispersive X-Ray Spectroscopy (EDX) of Tris-CQDs-CoOOH nanocomposite was characterized by FE-SEM (SU8010, Hitachi, Japan). 8 / 23


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RESULTS AND DISCUSSION Characterization of Tris-derived CDs and Tris-derived CDs-CoOOH Probe. The typical TEM and HRTEM images of the Tris-derived CDswere shown in Figure 1, as shown in Figure 1A, uniform carbon dots have been formed through the synthesis processes with the fluorescence quantum yield of 7.3% when excited at 365 nm (Table S1, Supporting Information), and the as-prepared Tris-derived CDs exhibit an narrow size distribution around 2.5~5.0 nm with an average diameter of 3.6 nm, as judged from image analyses of 100 individual particles. The TEM image of Tris-derived CDs-CoOOH (Figure 1B) clearly reveals that the morphology of fabricated CoOOHnanoflakes are mainly hexagonal, which agrees well with the previously report.12 Importantly, large surface area of fabricated hexagonal nanoflakes provides an essential platform for reacting with trace of AA, and eventually benefits to the high sensitivity of the probe. To know the subtle structure of the as-synthesized carbon dots and probe, Figure 1C shows the HRTEM image of Tris-derived CDs, documenting that the lattice spacing of the synthesized highly crystalline carbon dots is around 0.239 nm, which is similar to the (1120) lattice fringes of grapheme and further revealing the existence of amorphous oxidized debris in the highly crystalline Tris-derived CDs after hydrothermal treatment.10c,d,e From HRTEM image of Tris-derived CDs-CoOOH showed in Figure 1D, it indicates that a new lattice spacing about 0.226 nm is well consistent with the d-spacing of the (012) plane of CoOOH,13 along with the d-spacing of Tris-derived CDs, which indicated that Tris-derived CDs are attached to the surface of the CoOOH nanoflakes. Besides, the EDX spectrum (Supporting Information FigureS1) of Tris-derived CDs-CoOOH reveals that the element of cobalt and nitrogen are in the Tris-derived CDs-CoOOH, silica signal appearing in the EDX spectrum is attributed to silica wafer. The UV-visible absorption spectra of Tris and Tris-derived CDs are shown in Figure 1E, at 250-380 nm, Tris-derived CDs with excellent photostability (Supporting Information Figure S2a) has an obvious wide absorption band representing a typical absorption of an 9 / 23



aromatic π system, which is similar to that of polycyclicaromatic hydrocarbons.14 Furthermore,the wide absorptionband can be ascribed to the trapping of excited state energy of the surface states of carbon dots, leading to strong fluorescence as inset of Figure 1E shown.15 It is noted that the tris solution itself only has absorption below 230 nm and nonemissive in the visible region, confirming the cyan fluorescence (inset of Figure 1E) produced from the synthesized Tris-derived CDs. Meanwhile, the emission wavelength of Tris-derived CDs (Supporting Information FigureS2b) shifts from 420 to 550 nm with the excitation wavelength increased gradually from 320 to 520 nm. The excitation-dependent fluorescence behavior can be attributed to effects from particles of different sizes in the sample and non-uniform surface state of sp2clusters contained in carbon dots.16

C

D

2.5

B

E Tris Tris-derived CDs

2.0 1.5 Abs.

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A

1.0 0.5 0.0 200

300

400 500 600 Wavelength (nm)

Figure 1. A) TEM image of Tris-derived CDs; B) TEM image of Tris-derived CDs-CoOOH; C) HRTEM images of Tris-derived CDs; D) HRTEM images of Tris-derived CDs-CoOOH; E) UV-Vis absorption of Tris and Tris-derived CDs. Inset: photographs of the solution of Tris-derived CDs under visible light (left) and 365 nm UV light (right).

The surface structure and composition of Tris, the as-synthesized Tris-derived 10 / 23


700

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CDs, CoOOH and Tris-derived CDs-CoOOH were then investigated. The FT-IR spectrum of the tris is given in Figure 2a, the double bands at ~3348 cm-1 and ~3289 cm-1 are attributed to the N–H out-plane stretching, while the bands at ~3195 cm-1with ~2082 cm-1 and ~1589 cm-1 are assigned toN–H in-plane stretching and N–H bending vibration.10e These data indicated the existence of –NH2 group of tris. Then, the peaks at 2940, 2840, 1463 and 1289 cm-1 are corresponded to C–H vibration, and the peaks at 1398 and 1042 cm-1 are ascribed to the C-OH and CH2-OH groups.17As shown in Figure 2b, the broad band of Tris-derived CDs at 3500-3200 cm-1 and ~1589 cm-1almost disappears compared to tris, indicating the dehydration and disappear of–NH2 groups in Tris-derived CDs after pyrolysis treatment of tris. In addition, two new peaks obtained at 2999 and 1631 cm-1 are corresponded to the C-H and C=C stretching of polycyclic aromatic hydrocarbons,16 further indicating the synthesized carbon dots contained aromatic π system, which are well agreed with the UV analysis. In addition, the peaks of C-OH and CH2-OH groups can be obtained at 1403 and 1058 cm-1, respectively. From the Figure 2c, the broad band of CoOOH at 3429 cm-1 is attributed to the bond stretching of the H-bonded hydroxyl group(−OH). The peak at 1639 cm-1 is characteristic of the Co−O double bond in the crystal structure of CoOOH.18

Finally,

Tris-derived

CDs-CoOOH

nanocomposite

prepared

by

Tris-derived CDs hybridized to CoOOH surface, the Figure 2d shows that the existence of −OH (ν-OH at 3443 cm-1), N−H (νN−H at 2128 cm-1 and 1594 cm-1), Co=O/C=C (vibration at 1641 cm-1), C-OH (νC-OH at 1413 cm-1) and CH2-OH (νCH2-OH at 1050 cm-1). The broad bond of Tris-derived CDs-CoOOH nanocomposite can be attributed to the synergistic effect of –OH group of both Tris-derived CDs and CoOOH. Figure S3 (Supporting Information) shows the XRD spectrum (black curve) of the CoOOH powder sample. It can be observed that the peaks at 20.19°, 38.99°and 50.68°correspond to the (003), (012), and (018) peaks of CoOOH based on the standard JCPDS card (No. 07-0169), confirming that the CoOOH nanoflakes is successfully prepared. In contrast, the stronger and sharper peaks, especially (003) peak at 20.14°, corresponding to characterization peaks of CoOOH in the Tris-derived 11 / 23



CDs-CoOOH powder (green curve) display that Tris-derived CDs can enhance the degree of crystallinity of CoOOH after hybridized with Tris-derived CDs and

2094

3348 3298 3195

a

2082

3189 2999 2940 2849

b

3429

c

4000

3500

3000 2500 2000 Wavenumber (cm-1)

1050

1641 1594 1413

3443

d

1639 1589 1631 1463 1463 1403 1398 1297 1289 1160 1058 1042

2128

obviously improve the oriented growth of the (003) plane of CoOOH in particular.19

Transmittance (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1500

1000

Figure 2. FT-IR spectra of Tris (a),Tris-derived CDs (b), CoOOH (c) and Tris-derived CDs-CoOOH.

The Mechanism of AA Sensing by Tris-derived CDs-CoOOH Probe. To prove the interaction between AA with Tris-derived CDs-CoOOH probe, the optical properties of Tris-derived CDs-CoOOH probe was firstly investigated. As shown in the Figure S4 (Supporting Information), the UV−vis absorption spectroscopy revealed that the absorption peak of CoCl2 was located at 510 nm. After the CoOOH nanoflakes were formed, the absorption peak was blue-shifted to about 410 nm. Significantly, the CoOOH nanoflakes as a quencher can make the photoluminence (PL) intensity of Tris-derived CDs efficiently decreased, due to the absorption band (Supporting Information Figure S5) of CoOOH nanoflakes (dash line) overlaps with the emissions area from 350 to 630 nm of the Tris-derived CDs, hence enabling the generation of FRET.9 To the best of our knowledge, the strong reductive of AA is originated from 12 / 23


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the enediol group which reduce CoOOH nanoflakes to Co2+accompanying with the collapse and decompose of CoOOH from Tris-derived CDs (Scheme 1). As previously reports showed, heavy metal ions are the common effective quenchers to carbon dots.10, 20As a result, the PL properties of effect of Co2+ on the Tris-derived CDs is also investigated. Figure 3A shows different concentration of Co2+ from 10-400 µM in the Tris-derived CDs solutions did not produce obvious fluorescence quench effect on the Tris-derived CDs, confirming the Co2+ has no distinct interference with the probe.

The Factors Affecting Stability of Tris-derived CDs-CoOOH Probe. For better sensing performances, the experimental conditions were optimized. As shown in Figure 3B, with increasing of the volume ratio of ethylene glycol to standardized Tris-derived CDs aqueous, the PL intensity of Tris-derived CDs solutions are decreased successively. The quenching effect by EG can be ascribed to the solvent effect accompanied with the dilution of the carbon dots.21The PL activity of the Tris-derived CDs-CoOOH probe was found to be pH-dependent (Figure3D). As pH increase from 6.5 to 7.3, the intensity of Tris-derived CDs-CoOOH probe is gradually increased, while as pH > 7.3,the quenching effect occurs, which reaches the maximum in the pH range of7.1−7.5. In view of the redox reaction of AA andCoOOH (AA:CoOOH: H+ = 1: 2: 4) and the physiological conditions in cerebral dialysates of rats, the favorable condition (pH 7.3)of pH-dependent tris-derived CDs-CoOOH probe was selected in the later sensing processes. Due to the heavy density of the heavy metal oxyhydroxide (CoOOH), the Tris-derived CDs-CoOOH nanocomposites tend to sedimentate with time going (Supporting Information Figure S6). In this regard, due to the surface activity and viscidity of EG, EG as a dispersant was introduced into the Tris-derived CDs-CoOOH sensing system to improve the stability of probe. As exhibited in Figure 3C, the intensity stability of probe is clearly improved with the volume ratio of ethylene glycol to non-standardized Tris-derived CDs-CoOOH aqueous increasing (the ratio > 0.5:1, probes were keep stable with time from 0 to 50 min), confirming EG can be a good dispersant and stabilizer to the Tris-derived CDs-CoOOH sensing system. Considering the quenching effect of EG on 13 / 23



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the Tris-derived CDs solution and PL intensity stability of probe, the volume ratio of ethylene glycol to non-standardized Tris-derived CDs-CoOOH aqueous and the equilibration time (Supporting Information Figure S7) for sensing AA were chosen to be 0.5:1 and 20 min, respectively.

Figure 3. (A) The effect of concentration of Co2+ on standardized Tris-derived CDs. From 0 to 8 representing for 0 µM, 10 µM, 20 µM, 40 µM, 60 µM,100 µM, 200 µM, 300 µM and 400 µM Co2+, respectively. (B) The effect of volume ratio of ethylene glycol to standardized Tris-derived CDs aqueous (1 mL) on the intensity of Tris-derived CDs. The ratio from top to bottom: 0:l; 0.1:1; 0.2:1; 0.3:1; 0.4:1; 0.5:1; 0.6:1; 0.7:1; 0.8:1; 0.9:1. (C) The effect of time on the stability of different Tris-derived CDs-CoOOH probe with corresponding volume ratio of ethylene glycol to non-standardized Tris-derived CDs-CoOOH aqueous. All the experiments were performed with excitation at 365 nm. (D) The effect of values of pH on the intensity of standardized Tris-derived CDs-CoOOH probe (The volume ratio of ethylene glycol to Tris-derived CDs-CoOOH aqueous: 0.5:1). 14 / 23


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Determination of AA Using Tris-derived CDs-CoOOH Probe.

Figure 4. Fluorescence emission spectra of standardized Tris-derived CDs-CoOOH solution upon addition of various concentrations of AA (from top to bottom: 400 µM, 300 µM, 200 µM, 100 µM, 20 µM, 10 µM, 2 µM, 1 µM, 200 nM, 100 nM), excitation at 365 nm. Inset: The linear relationship between (F1 – F0) / F1 with the AA concentrations in the range from 100 nM to 20 µM. F0 and F1 are the emission fluorescence intensities of Tris-derived CDs-CoOOH aqueous solution at 455 nm in the absence and presence of AA, respectively. With the respect to complexity of the brain system, the sensitivity and selectivity assays of physiological species, i.e. AA in this study were firstly measured. Underthe optimized conditions discussed above, a series of AA solutions with different final concentrations were added into the homogeneous system and incubated for 20 min. As Figure 4 shown, the probe reveals good response to AA with the concentration of AA increasing, the relationship between the fluorescence intensity and the concentration of AA (inset of Figure 4) shows a good linear correlation (R2 = 0.9907) from 0.1 µM to 20 µM ((F1 – F0) / F1 = 0.0939 + 0.0288 [AA]/µM) with a detection limit of ∼0.05 µM at a signal-to-noise ratio of 3. Compared with those reported AA fluorescent probes (Table S2,Supporting Information),the present carbon dots−metal 15 / 23



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oxyhydroxide probe exhibited higher sensitivity and lower detection limit. Moreover, highly sensitive sensors allow a sufficient sample dilution during assay, which can effectively reduce the interference from the complicated matrix (physiological species),22 which provide an essential condition for sensing the cerebral AA. Selectivity is an important factor to investigate the sensing property of our method. In order to better simulate the reaction in physiological environment, we investigate the fluorescence interference from metal ions as well as others including Fe3+, K+, Na+, Ca2+, Mg2+, Cu2+, Cd2+, Mn2+, Zn2+, Pb2+, Ni2+, Cys, Gly, Glu (Glutamic), H2O2, UA, DA and DOPAC in the resultant solution, i.e. the solution AA has already reacted with Tris-derived CDs-CoOOH, in which the carbon dots may already release from Tris-derived CDs-CoOOH. The high selective property of the probe can be ascribed to the enediol group as the reductive unit of AA and can specifically react with oxide (CoOOH) to generate Co2+, and then release the Tris-derived CDs as the signal output. Approximate oxidation potential for the common reductive species were previously reported with AA, DA, DOPAC to be 0.2 V and UA to be 0.3 V vs Ag/AgCl, 23 which indicate DA and DOPAC may have the similar reductive ability as AA to involve the redox reaction between CoOOH. However, in our study, Tris-derived CDs-CoOOH probe show a highly selective turn-on effect toward AA against other species, which could be ascribed a relatively fast dynamic reaction process between CoOOH and AA than DA, DOPAC and UA. In this study, to form the selective turn-on effect of the Tris-derived CDs-CoOOH by the AA, two efficient processes should be involved: quencher, i.e. CoOOH be removed and the signal output unit, i.e. Tris-derived CDs, be released effectively. On the other hand, it is crucial that the Co2+, produced from CDs-CoOOH reacting with the AA, has no obvious quenching effect on the Tris-derived CDs, the signal output (Tris-derived CDs) are recover closely to its original maximum values and endow the proposed probe high sensitivity indirectly, which can be ascribed to that Tris-derived

CDs,

lacking

of

the

strong

chelation

group

such

as

amino/carboxyl/thiol groups, mainly were modified with -OH groups has week chelation with Co2+.6a

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Figure 5. PL response of pre-treated Tris-derived CDs-CoOOH solution by 10 µM AA in the presence of different final concentration of ions and biomolecules: 1mM for K+, Na+, Ca2+, Mg2+, and 10 µM for Cu2+, Cd2+, Mn2+, Zn2+, Pb2+, Ni2+, Fe3+, UA, DOPAC, AA and 1 µM for Cys, Gly, Glu (Glutamic), H2O2 and DA. Excitation at 365 nm.

Determination of Cortical AA in Rat Brain Microdialysates During Cerebral Calm/Ischemia Process. Combing with the good properties of higher sensitivity and lower detection limit of the proposed fluorescent probe, the further application of Tris–derived CDs-CoOOH probe is evaluated by rat brain microdialysates of cortex region during cerebral calm/ischemia process. A 5 µL aliquot of this rat brain microdialysates samples was added in the sensing system and reacted for 20 min, and then the fluorescence intensity was measured (Scheme 1a). As shown in Figure 6, it can be seen that in the calm period (60 min), the basal level of cortical AA was 3.72 ± 0.44 µM, during the surgery of pre-ischemia around 20 min, the microdialysate AA level keep slowly increased to 4.33 ± 0.43 µM, while in 60 min after cerebral ischemia, the AA level in the cortex region increased and was determined to be 20.91 ± 2.10 µM, which was almost consistent with the previous reports.8 These results suggest that the recorded changes in the extracellular AA level fundamentally indicate 17 / 23



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the complicated neurochemical changes during the acute period of cerebral ischemia and may thus be useful for understanding the neurochemical processes of cerebral ischemia, and that the synthesized probe can be a potential sensing platform for monitoring AA in rat brain.

Calm

Surgeries Ischemia

Figure 6. Statistical results of AA level in the microdialysates from cortex of a rat brain under different physiological conditions: calm, ischemia. Error bars represent the standard deviations of replicate measurements with n = 3.The brain microdialysate was collected every 10 min in the surgeries of cerebral calm/ischemia process. CONCLUSIONS In summary, by applying the specific redox reaction between AA and CoOOH and taking full advantage of the excellent optical property of carbon dots derived from Tris as the sole precursor of carbon dots, we have successfully designed a turn-on carbon dots-metal oxyhydroxide fluorescent probe, illustrating a highly sensitive and selective property for monitoring cerebral AA in rat brain following the cerebral calm/ischemia. The simplicity in operation and instrumentation of this method make it more convenient and more readily adopted by physiologists. This study not only provides a new fluorescence assay for the simple detection of ascorbate in the cerebral 18 / 23


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systems, but also potentially offers an analytical platform for understanding the role of AA in physiological and pathological investigations.

ACKNOWLEDGMENTS This work was financially supported by National Natural Science Foundation (21375088), Scientific Research Project of Beijing Educational Committee (KM201410028006), Youth Talent Project of the Beijing Municipal Commission of Education (CIT&TCD201504072), Scientific Research Base Development Program of the Beijing Municipal Commission of Education and the 2013 Program of Scientific Research Foundation for the Returned Overseas Chinese Scholars of Beijing Municipality. ASSOCIATED CONTENT Supporting Information Available Additional information as noted in the text. This material is available free of charge via the Internet at http://pubs.acs.org.

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For TOC only

Turn-Off

Ascorbic Acid of Brain Microdialysates

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Hexagonal Cobalt OxyhydroxideâCarbon Dots Hybridized Surface

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