Silicon Quantum Dot-Based Fluorescence Turn-On Metal Ion Sensors

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Silicon Quantum Dots Based Fluorescence Turn-On Metal Ion Sensors in Live Cells Namasivayam Dhenadhayalan, Hsin-lung Lee, Kanchan Yadav, King-Chuen Lin, Yih-Tyng Lin, and Agnes H. H. Chang ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.6b07789 • Publication Date (Web): 19 Aug 2016 Downloaded from http://pubs.acs.org on August 22, 2016

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ACS Applied Materials & Interfaces

Silicon Quantum Dots Based Fluorescence Turn-On Metal Ion Sensors in Live Cells

Namasivayam Dhenadhayalan,#a Hsin-Lung Lee,#a Kanchan Yadav,a King-Chuen Lin,*a Yih-Tyng Lin,b and A. H. H. Changb

a

Department of Chemistry, National Taiwan University, Taipei 106, and Institute of

Atomic and Molecular Sciences, Academia Sinica, Taipei 106, Taiwan. b

Department of Chemistry, National Dong Hwa University, Shoufeng, Hualien 974,

Taiwan.

*Correspondence should be addressed. *E-mail: [email protected]; Fax: +886-2-23621483; Tel.: +886-2-33661162. #

Equal contribution

With Supporting Information

1

ACS Paragon Plus Environment


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Abstract Multiple sensor systems are designed by varying aza-crown ether moiety in silicon quantum dots (SiQDs) for detecting individual Mg2+, Ca2+, and Mn2+ metal ions with significant selectivity and sensitivity. The detection limit of Mg2+, Ca2+, and Mn2+ can reach 1.81, 3.15, and 0.47 µM, respectively. Upon excitation of the SiQDs which are coordinated with aza-crown ethers, the photoinduced electron transfer (PET) takes place from aza-crown ether moiety to the valence band of SiQDs core such that the reduced probability of electron-hole recombination may diminish the subsequent fluorescence. The fluorescence suppression caused by such PET effect will be relieved after selective metal ion is added. The charge-electron binding force between the metal ion and azacrown ether hinders the PET and thereby restores the fluorescence of SiQDs. The design of sensor system is based on the fluorescence ‘turn-on’ of SiQDs while in search of the appropriate metal ion. For practical application, the sensing capabilities of metal ions in the live cells are performed and the confocal image results reveal their promising applicability as an effective and non-toxic metal ion sensor.

Keywords: Silicon quantum dots, Sensors, Metal ion, Aza-crown ether, Photoinduced electron transfer, Bio-imaging.

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1. Introduction Chemosensors play a significant role in the chemical processes of life, especially in biological and medical field. However, the probable toxicity existing in the design of fluorescent chemosensors limits their applications. Quantum dots have enormously been used as materials for the design of fluorescent chemical and biosensors, and optical marker in biomedical applications,1-6 because of their excellent photostability, luminescence properties with narrow emission band, and higher fluorescent quantum yield. Among the fluorescent nanomaterials, silicon nanomaterials are of great interest in chemical and biological sensing applications.7-17 Their unique properties, such as nontoxicity, biocompatibility, and photostability, become a potential asset in developing silicon quantum dots (SiQDs) as a new material to function as chemosensors. The chemosensors are designed mainly by taking advantage of the photophysical phenomena involving such as photoinduced electron transfer (PET), intramolecular charge transfer (ICT), and fluorescence resonance energy transfer (FRET).18-22 Thus, it can be classified as PET or FRET-based chemosensors, which are characterized by the feature of spectral shifts, variation in the fluorescence intensity and/or lifetime, upon binding of ions with fluorophore. PET-based chemosensors especially for metal ion sensing have been extensively studied using various organic dyes as a fluorophore, in which the recognition moiety serving as an electron donor/acceptor interacts with metal ion to change the photophysical properties of the fluorophore.18,20,23-25 Generally, the fluorescence quenching of fluorophore in the absence of metal ions is anticipated to be due to the electron transfer from highest occupied molecular orbital (HOMO) of the attached ligand to the HOMO level of the fluorophore. Then, upon addition of metal ions, 3



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the HOMO level of donor may be significantly lowered in energy to hinder the PET occurrence and subsequently to restore the fluorescence of fluorophore.18 The recognition moiety such as crown ether, calixarene, and Schiff base shows a feature of strongly interacting with metal ions which act as a trigger to cause the fluorescence turn-on/off of the fluorophore.26-31 So far, the crown ether-attached fluorescent dye sensors have been extensively used for sensing the metal ions.32-35 Lochman et al. have recently studied the sensing of alkali and alkaline earth metal ions using different kind of aza-crown etherattached azaphthalocyanine fluorescence sensors.36 Bakthavatsalam et al. reported pentaaza macrocyclic ligand-attached BODIPY dye as a turn-on fluorescent sensor for Mn2+ ions based on the PET effect.37 As with the dye fluorophore, several groups have developed crown ether-labelled quantum dots sensors for metal ion detection.32,38-42 To the best of our knowledge, there is no report regarding fluorescent sensing of the metal ions by using crown ether-labelled SiQDs. In this work, we have synthesized three different kinds of silicon quantum dots coordinated

with

aza-crown

ether

(SiQDs/CE)

including

SiQDs/aza15C5,

SiQDs/aza18C6, and SiQDs/diaza18C6 (Scheme 1). The application of modified SiQDs may be potentially regulated as a PET probe for sensing the metal ions. This work aims to develop fluorescence turn-on SiQDs/CE sensors to inspect the effect of different metal ions on the PET process. Herein, the electron transfer takes place from the crown ether moiety which acts as an electron donor to the SiQD core through space, thereby causing the fluorescence quenching of SiQDs. Afterwards, the fluorescence of SiQDs will be restored upon addition of the appropriate metal ion. The study of the PET suppression with various metal ions (alkali, alkaline earth and transition metal ions) was performed 4


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for all three SiQDs/CE sensor systems using fluorescence titration method. This method has been popularly adopted with high selectivity and sensitivity in the detection of metal ions. We report the sensing of multiple metal ions including Mg2+, Mn2+, and Ca2+ ions by using diverse aza-crown ether-functionalized SiQDs based on the suppression of PET process and further demonstrate their sensing efficiency in live HeLa cells using confocal microscopy. In conjunction with binding energy calculations, the mechanism for suppression of PET process can be well understood.

Scheme 1. The structure of different aza-crown ether functionalized SiQDs.

2. Experimental Section 2.1. Materials and Methods All commercially available organic reagents were used without further purification unless otherwise stated. Carbonyldiimidazole, tetraoctylammonium bromide (TOAB), silicon tetrachloride (SiCl4), lithium aluminium hydride, hexachloroplatinic acid and crown ether were purchased from Sigma-Aldrich and Acros Organics company Ltd. Dichloromethane was distilled from calcium hydride under nitrogen atmosphere. Normal phase column chromatography was performed with silica gel Merck 60 (230-400 mesh ASTM). Reactions were carried out in dry solvents under argon atmosphere. Nuclear magnetic resonance (NMR) spectra were recorded with Bruker DPX 400MHz NMR (400 MHz for 1H NMR and 100 MHz for 5


13

C NMR) spectrometer.


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Chemical shifts were reported in ppm on the δ scale relative to residual CHCl3 (δ = 7.26 for 1H NMR and δ = 77.0 for

13

C NMR) as an internal reference, respectively.

Electrospray ionization mass spectrometry (ESI-MS) experiments were carried out with a Bruker microTOF-QII mass spectrometer. Infrared spectra were recorded with a Thermo Scientific Nicolet iS5 Fourier-transform infrared (FT-IR) spectrometer. Elemental analysis was carried out in Elementar Vario EL cube. Higher resolution transmission electron

microscope (HR-TEM) observations were conducted with a Philips Tecnai F20 G2 FEITEM. The absorption spectra were recorded with a Thermo Scientific evolution 220 UVvisible spectrophotometer. The fluorescence spectra were recorded with a Perkin-Elmer LS45 spectrophotometer. Confocal images of live Human cervical cancer cells (HeLa cells) were obtained by using LSM 510 Duoscan system (Zeiss Inc.) under 360 nm excitation. All the measurements were carried out at ambient temperature.

2.2. Characterization of Aza-Crown Ether Capping Agents 2.2.1. Aza-15-crown-5 4-pentenamide: 1H NMR (CDCl3, δ, ppm): 5.76 (m, 1H), 4.92 (m, 2H), 3.54 (m, 20H), 2.32 (m, 4H).

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C NMR (CDCl3, δ, ppm): 172.41, 137.41,

114.82, 71.35, 70.41, 70.10, 69.88, 69.85, 69.85, 69.50, 69.41, 50.12, 49.03, 32.19, 29.10. ESI-MS (m/z): calculated for [M + Na]+, 302.1967; found: 302.1974. Elemental analysis for C15H27NO5: calculated C, 59.78; H, 9.03; N, 4.65; found: C: 60.02; H, 9.10; N, 4.76. 2.2.2. Aza-18-crown-6 4-pentenamide: 1H NMR (CDCl3, δ, ppm): 5.82 (m, 1H), 4.97 (m, 2H), 3.61 (m, 24H), 2.38 (m, 4H).

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C NMR (CDCl3, δ, ppm): 172.45, 137.59,

114.92, 70.72, 70.63, 70.55, 70.53, 70.51, 70.43, 70.22, 69.87, 69.39, 48.83, 46.74, 32.26, 29.22. ESI-MS (m/z): calculated for [M + Na]+, 368.2049; found: 368.2039. Elemental 6


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analysis for C17H31NO6: calculated C, 59.11; H, 9.05; N, 4.05; found: C: 59.40; H, 9.15; N, 4.29. 2.2.3. Diaza-18-crown-6 4-pentenamide: 1H NMR (CDCl3, δ, ppm): 5.79 (m, 1H), 4.96 (m, 2H), 3.73 (s, NH), 3.58 (m, 20H), 2.78 (m, 4H), 2.34(m, 4H).

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C NMR (CDCl3, δ,

ppm): 172.18, 137.50, 114.92, 70.22, 70.15, 69.97, 69.68, 69.50, 69.36, 48.98, 48.91, 48.27, 45.95, 32.22, 29.15. ESI-MS (m/z): calculated for [M + H]+, 345.2389; found: 345.2394. Elemental analysis for C17H32N2O5: calculated C, 59.28; H, 9.36; N, 8.13; found: C: 57.22; H, 9.38; N, 7.89.

2.3. General Procedure for Sensing of Metal Ions The fluorescence intensity recovery of SiQDs/CE was monitored by observing the spectral change during the addition of different concentration of metal ion. In a typical procedure, all the metal ion solutions (0.05 M) were prepared in pH 7.2 HEPES buffer solution. Each SiQDs/CE stock solution (50 mL) was prepared by the dilution of concentrated SiQDs/CE with pH 7.2 HEPES buffer solution, and with the fixed absorbance value (A300 nm at 0.4). Then, the fluorescence titration measurements were carried out by adding individual metal ion (up to 20 µL, and the maximum concentration of metal ion in sample solution was 1 mM) to the SiQDs/CE solution (1 mL) in a quartz cuvette. Afterwards, the solution was incubated for 5 min and then the fluorescence spectra of sample solutions were recorded with an excitation wavelength of 360 nm. The selectivity experiments for Mg2+, Mn2+, and Ca2+ ions were carried out by adding diverse metal ions (fixed concentration) to the SiQDs/CE solution. In a typical assay, a set of metal ions each prepared at fixed volume were added to individual 7



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SiQDs/CE solution prepared at 1 mL, and then the mixture was made up to a 2 mL with pH 7.2 HEPES buffer solution. The resulting concentration of SiQDs/aza15C5+Mg2+ and SiQDs/diaza18C6+Ca2+ solution became 5×10-5 M with respective addition of a 10 µL of 0.01 M Mg2+ and Ca2+, while the SiQDs/aza18C6+Mn2+ solution became 5×10-6 M with addition of a 1.0 µL of 0.01 M Mn2+. Afterwards, the solution was incubated for 5 min and then the fluorescence spectra of sample solutions were recorded with an excitation wavelength of 360 nm. Further, the competitive metal ions studies were carried out for an individual Mg2+, Mn2+, and Ca2+ metal ions. For instance, to inspect the matrix interference for SiQDs/aza15C5 system, an additional 10 µL of 0.01 M matrix ion solution (50 µM) was added into the mixture of SiQDs/aza15C5 (1.0 mL) and Mg2+ (10 µL, 50 µM), and then the solution was made up to a 2 mL volume buffered with pH 7.2 HEPES. After incubation of all the sample solutions for 5 min, the fluorescence spectra were recorded. The sample solutions for SiQDs/diaza18C6+Ca2+ and SiQDs/aza18C6+Mn2+ systems were examined similarly for the matrix effect. The matrix ions including Na+, K+, Rb+, Cs+, Mg2+, Ca2+, Sr2+, Ba2+, Cr2+, Mn2+, Fe3+, CO2+, Ni2+, Cu2+, Zn2+, Hg2+, Pb2+, and Cd2+ were tested individually.

2.4. Theoretical Method Density functional B3LYP43,44 with basis set LanL2DZ45 calculations were carried out for systems of aza-crown ether and metal ions in water. The energy and harmonic frequencies of optimized geometry of aza-crown ether were obtained, and likewise the energies of metal ions. The zero of the energies for the aza-crown ether/metal ion systems 8


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was set at asymptotic limit. The energies for optimized bound aza-crown ether/metal ion species relative to the corresponding asymptotic values were then taken as binding energies. GAUSSIAN 09 program46 was employed in electronic structure calculations.

2.5. Cells Culture HeLa cells were maintained (at 37 °C, 5% CO2) in Dulbecco’s modified Eagle medium and were supplemented with 10% of fetal bovine serum and 1% penicillin/streptomycin overnight in a culture box.

3. Results and Discussion 3.1. Synthesis of Aza-Crown Ether Capping Agents Aza-crown ether capping agents were synthesized by common amide coupling reaction.47 In brief, a solution of carbonyldiimidazole (0.616 g) in THF (10 mL) was purged with argon for 15 min. Then, 4-pentenoic acid (0.43 mL) was added to the above solution and stirred for an hour. The aza-crown ether (1 eq) was added to the mixture which was then stirred for another 2 h at room temperature. After the reaction, the mixture was concentrated under vacuum condition, while the residue was dissolved in dichloromethane (20 mL). The mixture was washed by 0.25 M NaHCO3(aq) (3 x 30 mL), water (1 x 30 mL), and brine (1 x 30 mL), and then the organic phase was dried over MgSO4 and concentrated in vacuum. Finally, the obtained mixture was purified by silica gel column using ethyl acetate/hexane solvent as eluent. The final products were characterized by 1H NMR,

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C NMR and ESI-MS measurements (Figures S1-S6,

Supporting information). 9



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3.2. Synthesis and Characterization of Aza-Crown Ether Functionalized Silicon Quantum Dots (SiQDs/CE) All the aza-crown ether functionalized SiQDs were synthesized under argon atmosphere with Schleck line.48,49 The tetraoctylammonium bromide (TOAB, 1.5 g) surfactant was dissolved in 100 mL of anhydrous toluene, followed by freeze-pump-thaw cycles for three times. The solution was sonicated for 30 min to form reverse micelles. Silicon tetrachloride (SiCl4, 92 µL) as a precursor was added by gastight syringe and sonicated for 30 min. Then, 3 mL of lithium aluminium hydride as a reducing agent was injected into the solution to form hydrogen terminated SiQDs. After sonication of the mixture for 60 min, 20 mL of anhydrous methanol was added to quench excess reductant and further sonicated for 30 min. Finally, aza-crown ether functionalized SiQDs were formed by adding 0.1 mL of hexachloroplatinic acid and aza-crown ether capping agent into the reaction mixture which was then stirred for 60 min. SiQDs/CE solutions were purified by size exclusion chromatography. The solvent was removed by rotary evaporator, and 50 mL of water was added to dissolve SiQDs. The mixture was sonicated for 20 min and filtered off by Millex 0.45 µm filter unit (Millipore). The filtrate was concentrated to 1 mL and loaded into the PD-10 column (GE Healthcare). Each fraction was checked for photoluminescence under a 365 nm UV lamp and the fluorescent fractions were collected. The obtained pure SiQDs/CE were characterized by HR-TEM and FT-IR measurements. The HR-TEM images of all SiQDs show spherical dots with average size of 1.88 ± 0.7, 2.02 ± 0.9, 2.5 ± 0.8, and 1.98 ± 0.8 nm for SiQDs/aza15C5, 10


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SiQDs/aza18C6, SiQDs/diaza18C6, and SiQDs/COOH, respectively (Figure 1). The characteristic lattice spacing of 2.38 Å was found, in good agreement with the 〈111〉 spacing of Si crystal. The FTIR spectra were recorded to determine the surface functional groups of SiQDs/CE (Figures S7, Supporting information). All SiQDs/CE exhibit a peak at ∼2920 - 2850 cm−1 corresponding to the C−H stretching band. The peaks at ~1650 and ~1100 cm-1 are ascribed to C=O and C-O-C stretching band, respectively. The observed weak peak at 1250 cm-1 for all SiQDs/CE is assigned to the Si–C band. These results confirm that the crown ether moiety is attached on the surface of SiQDs. In contrast, the IR spectrum of SiQDs/COOH displays peaks at 1630 and 3380 cm−1 due to the stretching vibration of C=O (carbonyl) and O−H band, respectively, confirming that the carboxylic functional group exists on the surface.

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Figure 1. HR-TEM images of SiQDs/aza15C5 (a), SiQDs/aza18C6 (b), SiQDs/diaza18C6 (c), and SiQDs/COOH (d), inset figures show size distributions.

3.3. Fluorescence Sensing of Metal Ions The absorption and photoluminescence spectra of synthesized SiQDs/CE were recorded to understand their optical properties. It was observed that all SiQDs/CE display similar trends in absorption and fluorescence. For instance, the absorption spectrum of SiQDs/aza18C6 shows a strong absorption band in the UV region with a shoulder at ~280 nm (Figure 2). The fluorescence spectra of each SiQDs/CE were measured at different excitation wavelengths from 280 to 440 nm. The resultant fluorescence spectra reveal that the fluorescence intensity and maximum of SiQDs/CE were dependent on the excitation wavelengths. A higher intensity of fluorescence spectrum peaking at ~440±3 nm was observed upon excitation at 360 nm, as shown in Figure 2. The observed fluorescence may be ascribed to the direct electron–hole recombination in the SiQDs core.48,50,51 The excitation spectrum of SiQDs/CE was also recorded at a fixed emission wavelength of 440 nm and the resultant excitation spectrum exhibited a peak at ~360 ± 2 nm.

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Figure 2. The absorption, fluorescence and excitation spectra of SiQDs/aza18C6 in pH 7.2 HEPES buffer. The selectivity and sensitivity of metal ions with SiQDs/CE were investigated by using fluorescence titration method to understand the influence of metal ions on the SiQDs/CE

fluorescence

intensity.

The

fluorescence

titration

of

SiQDs/CE

(SiQDs/aza15C5, SiQDs/aza18C6, and SiQDs/diaza18C6) was carried out with different concentration of metal ions in buffered pH 7.2 HEPES. Interestingly, each SiQDs/CE sensor exhibited a different selectivity and sensitivity towards diverse metal ions. As in the presence of appropriate metal ions, a drastic fluorescence intensity enhancement of SiQDs/CE was observed. For instance, the fluorescence intensity of SiQDs/aza15C5 was gradually increased with increasing the Mg2+ concentration, while remaining the same profile maximum and shape (Figure 3a). For comparison, when other metal ions including Na+, K+, Rb+, Cs+, Ca2+, Sr2+, Ba2+, Cr2+, Mn2+, Fe3+, CO2+, Ni2+, Cu2+, Zn2+, Hg2+, Pb2+, and Cd2+ were added individually to replace Mg2+, the fluorescence intensity and maximum of SiQDs/aza15C5 did not change much even in the presence of metal ions condensed to 1.0 mM. Similarly, SiQDs/aza18C6 and SiQDs/diaza18C6 sensor systems showed significant selectivity towards the Mn2+ and Ca2+ ions, respectively. It was found that the fluorescence intensity of either SiQDs/aza18C6 or SiQDs/diaza18C6 was gradually increased with increasing concentration of Mn2+ and Ca2+ ions, respectively, as shown in Figure 3b and 3c. The fluorescence response of SiQDs/CE with diverse metal ions is shown in Figure 4. The association constant and stoichiometry for the interaction of SiQDs/CE with metal ions were determined by using the Benesi-Hildebrand method based on the change 13



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in the fluorescence intensity.32,52 As shown in Figure 4 (inset), the Benesi-Hildebrand plot of 1/(F−F0) versus 1/[Mn+] yielded a linearity for all SiQDs/CE with metal ion systems. Herein, F0 and F indicate the fluorescence intensity at the maximum of SiQDs/CE before and after addition of the metal ions, Mn+, respectively. This plot verifies a 1:1 stoichiometry between SiQDs/CE and respective metal ions; that is, a single Mg2+ ion can bind with one SiQDs/aza15C5. SiQDs/aza18C6+Mn2+ and SiQDs/diaza18C6+Ca2+ systems exhibit the same trend. Further, the association constant (Ka) was determined by a ratio of intercept/slope obtained from the straight line. The Ka values were thus obtained to be about 3×103, 11×104, and 9×103 M-1 or log Ka corresponded to about 3.48, 5.04, and 3.95 for SiQDs/aza15C5, SiQDs/aza18C6, and SiQDs/diaza18C6 systems, respectively. The detection limit for all the SiQDs/CE sensors was determined in terms of the relation, 3(σ/slope), where σ is the standard deviation of the fluorescence response. A plot of fluorescence intensity at the maximum as a function of metal ion concentration exhibited a good linear correlation in the concentration range of 0 to ~25 µM. The detection limit was thus estimated to be 1.81, 0.47 and 3.15 µM for Mg2+, Mn2+, and Ca2+ ions in coordination with SiQDs/aza15C5, SiQDs/aza18C6 and SiQDs/diaza18C6 systems, respectively.

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Figure 3. Fluorescence spectra of SiQDs/aza15C5 (a), SiQDs/aza18C6 (b), and SiQDs/diaza18C6 (c) with different concentration of Mg2+, Mn2+ and Ca2+ ions, respectively, in pH 7.2 HEPES-buffered water.

Figure 4. Fluorescence response of SiQDs/aza15C5 (a), SiQDs/aza18C6 (b), and SiQDs/diaza18C6 (c) sensors with diverse metal ions. Concentration of each metal ion for SiQDs/aza15C5 (a) and SiQDs/diaza18C6 (c) system is 5×10-5 M; for SiQDs/aza18C6 (b) system is 5×10-6 M. Inset: Benesi-Hildebrand plot of 1/(F-F0) versus 1/[M2+]. Further, the competitive studies were carried out to examine the effect of matrix metal ions on the interaction between SiQDs/CE and M2+ ions (Mg2+, Mn2+, and Ca2+) in pH 7.2 HEPES buffer solution. The fluorescence spectra of SiQDs/CE were acquired in the presence of each selective Mg2+, Mn2+, and Ca2+ along with diverse matrix metal ions, and the resultant fluorescence intensity responses are shown in Figure S8 (Supporting information). It was found that there was not much matrix interference in the detection of each Mg2+, Mn2+, and Ca2+ ions when several metal ions co-existed individually. However, Fe3+ ion involvement exhibited slight interference in all three systems. Accordingly, the SiQDs/CE sensors can be applied selectively and sensitively for the detection of metal ions. Especially, SiQDs/aza18C6 system shows better sensitivity 15



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towards Mn2+ ions detection mostly by a factor of 10 as compared to those reported (Table 1).53-57 Our result shows as comparable as that determined by Hu et al. using colorimetric sensor based on supramolecular silver nanoparticle clusters.61 Even for Mg2+ and Ca2+, their detection limits in this work appear to be comparable to those reported previously, as listed in Table 1.27,31,62-65

Table 1. Examples of some chemosensors for Mg2+, Mn2+ and Ca2+ detection

Sensors

Methods

Metal ion

Detection

References

limit (µM) Fluorescence

Mg2+

13.8

62

Schiff base

Fluorescence

Mg2+

0.28

63

CdSe/ZnS QDs

Fluorescence

Ca2+

2.0 to 35.0

27

CdS QDs

Fluorescence

Ca2+

4.00

64

Graphene nanosheets

Fluorescence

Mn2+

46.0

53

Schiff base

Colorimetric

Mn2+

6.03

54

Schiff base

Colorimetric

Mn2+

7.11

55

Schiff base

Colorimetric

Mn2+

5.00

57

Copper nanoparticles

Fluorescence

Mn2+

1.60

58

Silver nanoparticles

Colorimetric

Mn2+

0.50

61

SiQDs/aza15C5

Fluorescence

Mg2+

1.81

This work

SiQDs/aza18C6

Fluorescence

Mn2+

0.47

This work

SiQDs/diaza18C6

Fluorescence

Ca2+

3.15

This work

calix[4]arene-diamide phenanthroimidazole

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Regarding the fluorescence intensity enhancement of SiQDs/CE with selectivity towards metal ions, a plausible interpretation is proposed (Scheme 2). The aza-crown ether moiety was attached on the surface of SiQDs through covalent bond formation. Upon irradiation with UV light, the electron in the valence band is promoted to the conduction band, resulting in the formation of electron and hole charges in the SiQDs core. On the other hand, the aza-crown ether moiety has lone pair electrons on the nitrogen atom. Due to the electron deficiency in the valence band of SiQDs after excitation, electron transfer probably takes place from the aza-crown ether moiety to the valence band of SiQDs core through space. Consequently, the fluorescence efficiency of SiQDs was diminished by the PET effect, because of the reduced probability of electronhole recombination. When the metal ions were added to the SiQDs/CE solution, the appropriate metal ion could be trapped into the aza-crown ether moiety through the electrostatic attraction. SiQDs binding with the metal ions leads to its fluorescence enhancement as a result of the suppression of PET between crown ether and SiQDs core. Binding selectivity, i.e. the affinity of the crown ether for various metal ions, depends on the size of the crown ether as well as metal ion, because the interaction strength between electron donor from oxygen and nitrogen sites and the metal ion is controlled by the denticity of the polyether backbone in the crown ether.36,66 Both aza15C5 and aza18C6 contain one nitrogen atom, but the former cavity size about ~0.80 to 1.10 Å is smaller than the later one about ~1.30 to 1.60 Å.67,68 Given the ionic radii of Mg2+, Ca2+ and Mn2+ equal to ~0.65, 1.14 and 0.81 Å, respectively,36,69,70 we may readily understand why the

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relatively smaller size of Mg2+ could be appropriately trapped inside the crown ether of aza15C5.

Scheme 2. The schematic representation for the PET process and subsequent suppression of PET in the absence and presence of metal ions. Apart from the size of both metal ions and aza-crown ethers, the charge of the metal ion plays an important role in the binding selectivity. The divalent charged metal ions have comparatively higher electron density than the univalent charged metal ions (alkali metal ions), causing strong binding with aza-crown ether.36 Thus, Mg2+, Ca2+ and Mn2+ divalent ions exhibit stronger binding capability with respective aza-crown ether resulting in the fluorescence enhancement of SiQDs by the effect of PET suppression from aza-crown ether moiety to SiQDs core. The binding energies of aza-crown ether with metal ions were calculated. It was found that the energy state of aza-crown ether in 18


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the presence of a metal ion became lowered with respect to the aza-crown ether alone, indicating that the aza-crown ether was stabilized by the metal ion, and this fact led to the prevention of electron transfer from aza-crown ether to the SiQDs core. For instance, as shown in Figure 5, the binding energy of diaza18C6 was more stabilized by the presence of Ca2+ ion than other metal ions studied. The binding energy of diaza18C6 in the presence of Ca2+ was calculated to be 31.8 kcal/mol. Similarly, the binding energy of aza15C5 and aza18C6 in the presence of Mg2+ and Mn2+ was calculated to be 41.6 and 107.6 kcal/mol, respectively (Figure 6). An extremely higher binding energy between aza18C6 and Mn2+ completely hinders the PET effect, such that the fluorescence ‘turn-on’ of SiQDs/aza18C6 was achieved and the resulting detection limit of Mn2+ could reach as low as 0.47 µM. Apparently, the metal ion selectivity and sensitivity rely significantly on the extent of the binding capability with the aza-crown ether. However, the trend of binding energy is not the only factor to determine the metal ion selectivity. In general, the selectivity of metal ion may depend on several factors such as cavity size of crown ether, size and charge of metal ion, coordination capability of metal ion, and number of available heteroatoms (N, O) in the crown ether to coordinate with metal ion. The binding energy calculations might not account for all of these factors.

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Figure 5. The binding energies for diaza18C6 in the presence of diverse metal ions, calculated by using the B3LYP/LanL2DZ method.

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Figure 6. The binding energy for aza15C5 (a) and aza18C6 (b) in the presence of Mg2+ and Mn2+ ions respectively, calculated by using the B3LYP method. To clarify the essential mechanism for the fluorescence enhancement of SiQDs/CE when appropriate metal ion was added, control experiments were carried out with SiQDs/COOH (without crown ether) in the presence of Mg2+, Ca2+ and Mn2+ ions. It was found that the resultant fluorescence intensity of SiQDs/COOH does not change much upon addition of each above metal ions (Figure S9, Supporting information). These results provide strong support to the mechanism proposed for the fluorescence enhancement as a result of the effect of PET suppression from aza-crown ether to SiQDs core in the presence of metal ions. Inspired by the sensing results, we further examined the proficiency of each SiQDs/CE for monitoring the respective metal ions within HeLa cells by confocal microscopy. HeLa cells were incubated with individual SiQDs/CE solutions for 1 h at room temperature. After incubation, the fluorescence images of the cells were recorded with the excitation at 360 nm. The confocal images of SiQDs/CE exhibit weak fluorescence signal in cells as shown in Figure 7b, 8b and 9b. After treatment with their selective metal ions (concentration of metal ion is 70 µM) in the same cells for 30 min, significantly higher fluorescence signal was observed as compared to the case without metal ions involvement (Figure 7e, 8e and 9e). Note that the fluorescence stems from the cell membrane, instead of the nucleus, because crown ether moiety favors to attach to lipids via hydrophobic interaction. A quantitative variation for the observed fluorescence intensity of SiQDs/CE in the absence and presence of metal ions was estimated. The obtained histogram clearly confirms the fluorescence enhancement in the HeLa cells 21



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upon addition of metal ions (Figure S10, Supporting information). Hence, confocal fluorescence image results reveal that the SiQDs/CE nanomaterials can be utilized as a non-toxic sensor to detect these metal ions within the live cells.

Figure 7. Fluorescence images of HeLa cells with SiQDs/aza15C5 in the absence (a – c) and presence (d – f) of Mg2+ ions (70 µM). (a and d) the bright-field images; (b and e) the confocal fluorescence images; (c and f) the overlay of bright field and fluorescence images.

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Figure 8. Fluorescence images of HeLa cells with SiQDs/aza18C6 in the absence (a – c) and presence (d – f) of Mn2+ ions (70 µM). (a and d) the bright-field images; (b and e) the confocal fluorescence images; (c and f) the overlay of bright field and fluorescence images.

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Figure 9. Fluorescence images of HeLa cells with SiQDs/diaza18C6 in the absence (a – c) and presence (d – f) of Ca2+ ions (70 µM). Images (a and d) are the bright-field images; (b and e) the confocal fluorescence images; (c and f) the overlay of bright field and fluorescence images.

4. Conclusions We established the metal ion sensors based on the effect of PET suppression using the synthesized SiQDs/CE systems. When aza-crown ether is attached to SiQDs, the PET behavior may effectively diminish the fluorescence of SiQDs. When the appropriate metal ion is added, the binding capability of metal ions with the aza-crown ether hinders the PET effect and subsequently restores the fluorescence of SiQDs. Such fluorescence ‘turn-on’ response is adopted for the SiQDs/CE sensor design. The SiQDs/aza15C5, SiQDs/aza18C6, and SiQDs/diaza18C6 sensor systems show excellent selectivity and sensitivity towards the detection of Mg2+, Mn2+ and Ca2+ ions, respectively. The detection limit was estimated to be 1.81, 0.47 and 3.15 µM for Mg2+, Mn2+, and Ca2+ ions in coordination with SiQDs/aza15C5, SiQDs/aza18C6 and SiQDs/diaza18C6 systems, respectively. Apart from the detection in the bulk solution, confocal fluorescence measurements revealed that these sensors are cell-permeable and capable of detecting individual Mg2+, Mn2+, and Ca2+ ions within live cells.

Supporting Information

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The 1H NMR, 13C NMR and ESI-MS spectra for aza-crown ether ligands; FT-IR spectra for SiQDs/CE; fluorescence intensity responses of SiQDs/CE with diverse matrix metal ions; fluorescence spectra of SiQDs/COOH with metal ions; the bar chart plots of fluorescence intensity of SiQDs/CE.

Author Information Corresponding Author *E-mail: [email protected]. Fax: +886-2-2362-1483. Tel.: +886-2-3366-1162. Notes The authors declare no competing financial interest. #

Equal contribution

Acknowledgments This work was supported by Ministry of Science and Technology of Taiwan, Republic of China, under the contract number NSC 102-2113-M-002-009-MY3. N.D. wishes to thank both the National Taiwan University (under the contract number 104-R-4000) and Academia Sinica for post-doctoral fellowship, and Miss Shu-Chen Shen of Division of Instrument Service of Academia Sinica for her assistance in the confocal microscopic measurement.

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Silicon Quantum Dot-Based Fluorescence Turn-On Metal Ion Sensors

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