Capsicum-Derived Biomass Quantum Dots Coupled with Alizarin Red

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Capsicum-Derived Biomass Quantum Dots Coupled with Alizarin Red S as an Inner-Filter-Mediated Illuminant Nano-System for Imaging of Intracellular Calcium Ions Dongxia Chen, Jingjin Zhao, Liangliang Zhang, Rongjun Liu, Yong Huang, Chuanqing Lan, and Shulin Zhao Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.8b04055 • Publication Date (Web): 17 Oct 2018 Downloaded from http://pubs.acs.org on October 17, 2018

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Analytical Chemistry

Capsicum-Derived Biomass Quantum Dots Coupled with Alizarin Red S as an Inner-Filter-Mediated Illuminant NanoSystem for Imaging of Intracellular Calcium Ions Dongxia Chen,‡ Jingjin Zhao,‡ Liangliang Zhang,* Rongjun Liu, Yong Huang, Chuanqing Lan, Shulin Zhao* State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Guilin 541004, China ABSTRACT: Calcium ion (Ca2+) plays crucial roles in the signal transduction pathways associated with various physiological and pathological events. Monitoring intracellular Ca2+ is of great significance for cell biology research. Here, we report the use of biomass quantum dots (BQDs) as a fluorescent reporter for imaging of intracellular Ca2+, based on the inner-filter-mediated luminescence which was assisted by a Ca2+ chelator alizarin red S (ARS). BQDs were prepared by hydrothermal heating of capsicum. The absorption of ARS overlaps with the excitation of the BQDs, making the fluorescence of BQDs can be quenched through the inner filter effect. But the absorption of Ca-ARS complex red shifts and shows a poor inner filter effect. Thus, Ca2+ can be detected by the inner-filter-mediated luminescence using BQDsARS nanohybrid system. Using the proposed nano-system, the imaging of intracellular Ca2+ and real-time monitoring Ca2+ level change under histamine stimulation were also achieved. Thus, this nano-system holds the potential applications in other Ca2+-related signal transduction study.

Calcium ion (Ca2+) is one of the most important biological cations as a widespread secondary messenger in eukaryotic cells.1 The Ca2+ signaling regulates various of essential cellular functions from proliferation to death and mediated the cellular response to external stimuli.1,2 Obviously, intracellular Ca2+ concentration is related to many physiological and pathological responses.1,3-6 The cytosol Ca2+ concentration commonly maintained at the nanomolar range which is much lower than that of the extracellular Ca2+.1 The stimulation can induced the increase of cytosol Ca2+ concentration by the entry of Ca2+ from extracellular milieu or the release of Ca2+ from intracellular stores like endoplasmic reticulum.1 In these biological processes, the intracellular Ca2+ concentration is finely controlled by ion channels, co-factors and pumps.3 Monitoring the intracellular Ca2+ and studying its dynamics changes are important for cell biology and biomedicine research. Currently, two types of probes are mainly used for intracellular Ca2+ monitoring. One type is based on genetically encoded fluorescent proteins,7,8 and the other is based on fluorescent small organic molecules.9 In the past few years, to better investigate the relationship between the Ca2+ concentration and biological events in living cells, several new fluorescent organic fluorescent probes have been synthesized to image intracellular Ca2+. For examples, Nagano and coworkers reported a far-red to near-infrared fluorescent probe (CaSiR-1),10 which can be used to visualize the neuronal Ca2+ dynamics.

Hanaoka’s group developed a red fluorescent probe (CaTM-2 AM) to monitor the stimulus-induced cytoplasmic Ca2+ oscillations in HeLa cells.11 Recently, because of the easy modification and multifunction, fluorescent nanoprobe as a promising alternative for living cell imaging and intracellular biosensing has received numerous attentions from the researchers in the chemical, biological and medical fields. But to the best of our knowledge, only two fluorescent nanoprobes that is available for Ca2+ tracing in living cells have been reported so far.12,13 Therefore, developing fluorescent nanoprobe with a low cytotoxicity and high photostability for Ca2+ is still highly desirable. Fluorescent carbon dots (CDs) are a new type of zerodimensional carbon nanomaterial that possess the advantages of easy preparation, high photostability and good biocompatibility, and have aroused the interest of researchers.14-19 Using biomass to prepare CDs which can be named as biomass quantum dots (BQDs) is attractive because it’s green, cheap and it can be employed for largescale preparation.20-22 More importantly, since the raw material comes from natural biomass, BQDs exhibit low cytotoxicity, which is particularly suitable for bioapplications.23,24 Developing CDs-based nanoprobes for Ca2+ imaging is challenging, because Ca2+, not like some other metal ions, can’t directly induce the fluorescence response of almost all CDs. So, in this work, we employed a novel strategy in which the BQDs don’t directly respond to Ca2+ but selectively respond via an inner-filter-

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mediated luminescence (as shown in Scheme 1). Here, BQDs were prepared by hydrothermal treating of capsicum. The obtained BQDs show a maximum excitation wavelength around 405 nm and a maximum emission wavelength around 510 nm. Alizarin red S (ARS), a Ca2+ chelator, exhibits a maximum absorption wavelength at 435 nm, while the chelate of ARS and Ca2+ displays a maximum absorption at 557 nm. The absorption of ARS overlaps with the excitation band of BQDs greatly, while the absorption of Ca-ARS complex only exhibits a small overlap with the BQDs’ excitation band though it has partial overlap with the BQDs’ emission band. It has been reported that if the absorption bands of absorbers overlap with the excitation or emission bands of fluorophores, the fluorescence signal can be quenched by the absorber. This is the so-called inner-filter effect, in which the fluorescence can be modulated by overlap efficiency and the linking of absorbers and fluorophores commonly is not necessary.25,26 So, the fluorescence of BQDs in BQDs-ARS mixture can be quenched through the inner filter effect, and the reduced fluorescence may be restored by Ca2+ via the formation of Ca-ARS complex which has poor inner filter effect on BQDs. This enlightened us that we could construct an inner-filter-mediated fluorescent BQDs-ARS nanohybrid system to monitor Ca2+. In addition, using BQDs as the fluorescence reporter can offer good photostability and biocompatibility which are benefit for potential real-time intracellular imaging. Scheme 1. Schematic diagram of the BQDs preparation and imaging of intracellular Ca2+ under histamine-stimulation using BQDs-ARS nano-system.

(DMEM, high-glucose), and calcium-free DMEM (high glucose, no glutamine, no calcium) were purchased from Thermofisher. T24 cells (human bladder cell line) were purchased from Beijing Dingguo Biotechnology Co., Ltd. The water for the experiments was ultrapure with a resistance of ≧18.2 MΩ. Synthesis of CDs. CDs were synthesized by the hydrothermal treatment of capsicum in an autoclave. Typically, 50 g of fresh capsicums were crushed and transferred to a 50 mL Teflon-lined autoclave. Then 20 mL of ultrapure water was added, and the autoclave was heated for 10 h at 240 °C. After the reaction mixture cooled to room temperature, the supernatant was filtered with a 0.22 μm filter. The collected brown solution was dialyzed for 12 h through a dialysis membrane (MWCO = 1000 Dalton) against ultrapure water. The obtained dialysate was lyophilized and stored at -20 °C. Determination of Ca2+ Based on the BQDs-ARS Inner-Filter System. Typically, 100 μL mixture of BQDs and ARS (CDs: 80 μg/mL; ARS: 13 μM) contained with Ca2+ at different concentrations was incubated at room temperature for 3 min in 1×PBS buffer solution (pH=7.27.4, no magnesium, no calcium, Beijing Leagene Biotechnology Co., Ltd.). After incubation, the fluorescence spectrum of the sample was measured at an excitation wavelength of 405 nm. Three parallel tests were carried for each Ca2+ concentration. Intracellular Ca2+ Imaging. The T24 cells were seeded in 35-mm confocal dish and cultured in normal DMEM with 10% fetal bovine serum (FBS), penicillin (100 units/mL), and streptomycin (100 μg/mL) at 37 °C in a humidified atmosphere of 5% CO2 for 12 h. Then the cells were rinsed with 1×PBS buffer three times. The pre-mixed BQDs-ARS mixture solution (100 μg/mL BQDs and 20 μM ARS) was added and incubated with cells in calcium-free DMEM medium for 12 h before imaging. In control experiment, the cells were pretreated with EGTA (10 μM) for 6 h firstly, and then incubated with BQDs-ARS mixture for 12 h after discarding the supernatant medium. After removing the supernatant and washing with 1×PBS three times, the stained cells were imaged by a confocal laser scanning microscopy with a 40 × objective. To monitor the histamine-induced Ca2+ dynamic change, the cells were incubated with BQDs-ARS mixture (100 μg/mL BQDs and 20 μM ARS) in calcium-free DMEM medium for 12 h firstly and then stimulated with 10 μM histamine in 1×PBS after washing. The fluorescence images were collected at different time intervals using confocal laser scanning microscopy with a 63× oil-immersion objective.

RESULTS AND DISCUSSION

EXPERIMENTAL SECTION Reagents and Materials. Capsicum was bought from local vegetable market (Guilin, China). CaCl2, FeCl3, CuCl2, MnCl2, NaCl, MgCl2, AlCl3, KCl, ZnCl2, HgCl2, ethylenebis(oxyethy-lenenitrilo)-tetraacetic acid (EGTA) and ARS were purchased from Aladdin. Other solvents and reagents were of analytical grade without additional purification. Normal Dulbecco's Modified Eagle Medium

Characterization of BQDs. The BQDs were prepared using the biomass capsicum as the raw material under the hydrothermal treatment. Figure 1A illustrates the transmission electron microscopy (TEM) images of the obtained capsicum-derived BQDs, which indicates the asprepared BQDs have a good dispersity with an average size of 3 nm (Figure S1). The X-ray diffraction (XRD)


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Analytical Chemistry spectrum (Figure S2) displays a broad peak at 2θ=23.43°, which corresponds to the (002) plane of graphite and indicates that the graphitic carbon domain is present in the prepared BQDs.19 The elements contained in the BQDs was investigated by X-ray photoelectron spectroscopy (XPS). The result in Figure 1B shows that the BQDs are mainly composed of C, N, and O. The relative atomic percentages of C, N, and O are 49.20%, 16.82% and 33.98%, respectively. The high-resolution XPS spectrum (Figure S3A) indicates that the surface states of C1s are mainly C=C (284.4 eV), C-C (284.8 eV), C-N (285.5 eV), CO (286.4 eV), and C=O (287.8 eV).18,19 Two types of N are present on the surface of BQDs (Figure S3B): pyridine-like N (399.6 eV) and pyrrole-like N (400.2 eV).27 The O1s XPS spectrum demonstrates the existence of C=O (531.3 eV), C-O (532.2 eV), and O-C=O (533.0 eV) bonds on the BQDs surface (Figure S3C). The Fourier transform infrared (FTIR) spectrum in Figure S4 further confirms there are hydroxyl, carboxyl and amino groups on the BQDs surface, which make the BQDs to be water-soluble.

absorption spectrum of ARS effectively overlaps with the fluorescence excitation spectrum of the BQDs. Based on the inner-filter effect, the fluorescence of the BQDs can be quenched by ARS, as illustrated in Figure 2C. In addition, from Figure 2D, we can find that with increasing ARS proportion in BQDs-ARS mixture solutions, the fluorescence reduces gradually, and no obvious fluorescence can be observed when the concentration ratio between ARS and BQDs was 13: 80 (μM: μg/mL). However, the absorption spectrum of the Ca-ARS complex is greatly red-shifted to 557 nm compared to that of free ARS (Figure 2B). So, we think that Ca-ARS complex maybe has a poor inner filter effect on BQDs, and the quenched fluorescence of BQDs-ARS mixture can be restored by Ca2+ via the formation of the Ca-ARS complex. As expected, we observed a recovery of fluorescence after adding Ca2+ into the BQDs-ARS mixture solution (Figure 2C). Thus, BQDs coupled with ARS can be used as a nano-system with inner-filtermediated luminescence for Ca2+ detection. It should be noted that, in the BQDs-ARS mixture, the ARS can be adsorbed on the BQDs surface through the π-π interaction, but free ARS may also be present. However, this does not affect the Ca2+ detection, because the linking of absorber and fluorophore is not usually necessary in the inner-filter-based fluorescence assay.26

Figure 1. TEM image (A) and XPS spectra (B) of the capsicum-derived BQDs.

Optical Propriety of BQDs. UV-vis absorption and fluorescence spectra were recorded to study the optical properties of the BQDs in aqueous solution. The black curve in Figure 2A shows the UV-vis absorption spectrum of BQDs, which displays a strong absorption peak at 282 nm from π-π* electron transition of molecular orbital in the BQDs.28 The yellow aqueous BQDs solution emitted a strong fluorescence signal under the UV light irradiation (Figure 2A, inset). The fluorescence intensity and emission wavelength of BQDs also exhibit an excitationdependent fluorescence, like most typical CDs. A largest fluorescence intensity was achieved under the excitation of 405 nm (Figure S5), and the emissions spectrum of BQDs under 405 nm excitation is also shown in Figure 2A. The fluorescence quantum yield of the synthesized BQDs is about 21.71% using quinine sulfate as the reference. The obtained BQDs exhibit good photostability under UV light irradiation, and they are stable in a long-time storage (Figure S6A and S6B). The solution pH has a slight effect on the fluorescence, while negligible effect of ionic strength on the fluorescence was observed (Figure S6C and S6D). The good photobleaching resistance and stability make the BQDs to be a promising fluorescence probe. Inner-Filter-based BQDs-ARS Nano-System. We then employed this BQDs to construct an inner-filterbased Ca2+-specific detection system using ARS as the Ca2+ recognition unit. As can be seen in Figure 2B, the UV

Figure 2. (A) UV-vis absorption and fluorescence emission spectra of the BQDs. Inset is the photos of the BQDs solution under day light (left) and 365 nm UV irradiation (right). (B) Fluorescence excitation spectrum of the BQDs, and absorption spectra of ARS and the Ca-ARS complex. (C) Fluorescence emission spectra of the free BQDs, BQDs-ARS and BQDs-ARS-Ca2+ systems. (D) Plot of the intensity ration I/I0 (I is the peak fluorescence intensity in the presence of ARS and I0 is the peak fluorescence intensity of free BQDs) against the concentration ration of ARS to BQDs (μM: μg/mL).

Assay Performance of BQDs-ARS Nano-System. To examine the response performance of the BQDs-ARS nano-system towards Ca2+, we added Ca2+ with different concentrations into an aqueous solution containing BQDs and ARS. The fluorescence intensity of the system increased with increasing Ca2+ concentration (Figure 3A),



and about 280-fold enhancement of peak intensity was achieved. The peak intensity of the system showed a good linear relationship with the Ca2+ concentration in the range of 0.09~14 μM (Figure 3B). The detection limit was about 5 nM (3S0/k, S0 is the standard deviation of the blank signal; k is the slope of the linear standard curve). This low detection limit makes the proposed nano-system hold the potential application in imaging Ca2+ in living cells, because the intracellular cytosolic Ca2+ concentration is around 100 nM while it will increase to micromole level after external stimulation.1 To evaluate the selectivity of BQDs-ARS nano-system for Ca2+, we explored the fluorescence response of some other metal ions. As shown in Figure S7, K+, Na+, Zn2+, Mg2+, Cu2+, Fe3+, Hg2+, Al3+ and Mn2+ can’t induce the recovery of the fluorescence of BQDs-ARS solution, indicating that the BQDs-ARS nano-system is selective for Ca2+.

BQDs-ARS nano-system for imaging intracellular Ca2+. The normal cultured T24 cells were incubated with the BQDs-ARS mixture in calcium-free DMEM for 12 h and then analyzed using laser scanning confocal microscopy equipped with a 405 nm laser. As shown in Figure 4, green fluorescence was observed in the BQDs-ARSincubated T24 cells which mainly located in the cytosol. The generation of fluorescence signal here is because the chelation of ARS and cytosol free Ca2+ makes the BQDs can be excited. To confirm that the fluorescence signal really comes from the free Ca2+ in cells, T24 cells were pre-treated with EGTA (as strong Ca2+ chelator) for 6 h firstly, and then incubated with the BQDs-ARS for 12 h. The imaging results showed that no obvious fluorescence signal in the cells was observed (Figure 4), because cytosol free Ca2+ was depleted by EGTA12 and Ca-EGTA complex is more stable than the Ca-ARS complex. This result confirmed that the BQDs-ARS nano-system with inner-filter-mediated luminescence can be used for imaging intracellular cytosol Ca2+.

Figure 4. The fluorescence images of the BQDs-ARS-loaded T24 cell and the EGTA-pretreated T24 cells. The images were collected using the excitation and emission windows with λex = 405 nm and λem = 480-550 nm, respectively. The scale bars are 25 μm.

Figure 3. (A) Fluorescence spectra of the BQDs-ARS nanosystem in the presence of Ca2+ at different concentrations (0, 0.09, 0.50, 1, 1.25, 1.75, 3.0, 4.25, 6.0, 7.4, 8.0, 9.5, 11, 12.4, 14, 18, 25, 35 μM). (B) Calibration curve for Ca2+ detection.

Imaging Intracellular Ca2+. The cytotoxicity of the proposed BQDs-ARS nano-system was investigated for its potential biological applications. T24 cells were used to examine the cytotoxicity of BQDs-ARS nano-system by MTT assay. As shown in Figure S8, the present BQDs-ARS system has a low cytotoxicity, which offers the ability for bio-applications. After that, we attempted to use this

Imaging Ca2+ under Histamine Stimulation. We further studied the potential of BQDs-ARS as a new Ca2+specific fluorescent nano- system for imaging intracellular cytosol free Ca2+ dynamics under histamine-stimulation. Histamine can induce the release of Ca2+ from endoplasmic reticulum to cytosol, through activating the interaction between inositol 1,4,5-trisphosphate and its receptor after histamine-receptor recognition on the cell surface (Scheme 1).6 Here, T24 cells were loaded with the BQDs-ARS firstly and then stimulated with histamine in the absence of extracellular Ca2+. The fluorescence images were then collected at different time points, as shown in Figure 5A. The real-time curve of normalized fluorescence intensity obtained from images was illustrated in Figure 5B. The fluorescence signal instantly increases after histamine stimulation and plateaued after 5 s, which suggests the histamine-stimulated Ca2+ release from intracellular store to cytosol. It also indicates an irreversible response of BQDs-ARS nano-system. The above results imply that the proposed BQDs-ARS nano-


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Analytical Chemistry system can be used for real-time imaging the level change of cytosol free Ca2+.

The Supporting Information is available free of charge on the ACS Publications website. Supporting experimental sections including apparatus, estimation of fluorescence quantum yield and cytotoxicity test; supplementary ﬁgures including the size distribution of BQDs, XRD spectrum, highresolution XPS spectra, FT-IR spectrum, excitationdependent emission of BQDs, stability of BQDs, selectivity of BQDs-ARS nano-system, and cytotoxicity test of BQDs-ARS nano-system. (PDF)

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] *E-mail: [email protected]

Author Contributions ‡ D.C. and J.Z. contributed equally.

Notes Figure 5. (A) Real-time fluorescence images of intracellular cytosol Ca2+ under histamine stimulation in T24 cells. The scale bars are 15 μm. (B) Real-time fluorescence intensity of under histamine stimulation. The images were collected using the excitation and emission windows with λex = 405 nm and λem = 480-550 nm, respectively.

CONCLUSIONS In summary, we reported an inner-filter-mediated illuminant nano-system for imaging intracellular Ca2+ using ARS as the recognition unit and BQDs as the signal indicator. BQDs were prepared by the hydrothermal treatment of biomass capsicum and could be excited at 405 nm to emit a green fluorescence. ARS quenches the fluorescence of BQDs through the inner-filter effect, while the complex of Ca-ARS has poor inner-filter ability due the red-shift of its absorption, thus affording the possibility of Ca2+ detection. Using biomass-derived BQDs as the fluorescence reporter allows the preparation to be green, cheap and provides the good photostability. The inner-filter-based signal transition mode employed here makes the construction of the BQDs-ARS nano-system does not need covalent coupling of ARS and BQDs. This nano-system shows good sensitivity and selectivity to Ca2+, and it also exhibits low cytotoxicity. The imaging of intracellular cytosol Ca2+ and real-time monitoring cytosol Ca2+ level change under histamine stimulation were also achieved, indicating the potential further applications in Ca2+-related signal transduction study. This is also the first example of inner-filter-based fluorescence turn-on nanohybrid system used in living cell imaging, which may promote the development of construction strategy of nanoprobe for other living cell applications.

ASSOCIATED CONTENT Supporting Information

The authors declare no competing financial interest.

ACKNOWLEDGMENT This work was supported by the National Natural Science Foundation of China (No. 21575031, No. 21775030, No. 21765003), Natural Science Foundation of Guangxi Province (No. 2015GXNSFDA139006, No. 2017GXNSFFA198014), and BAGUI Scholar Program.

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Capsicum-Derived Biomass Quantum Dots Coupled with Alizarin Red

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