Metal-Organic Framework Enhances Aggregation-Induced

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Metal-Organic Framework Enhances Aggregation-Induced Fluorescence of Chlortetracycline and the Application for Detection Long Yu, Hongxia Chen, Yue Ji, Xinfeng Chen, Mingtai Sun, Hua Tan, Abdullah M. Asiri, Khalid A. Alamry, Xiangke Wang, and Suhua Wang Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.9b00319 • Publication Date (Web): 15 Apr 2019 Downloaded from http://pubs.acs.org on April 16, 2019

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Analytical Chemistry

Metal-Organic Framework Enhances Aggregation-Induced Fluorescence of Chlortetracycline and the Application for Detection Long Yu,† Hongxia Chen,† Ji Yue,† Xinfeng Chen,† Mingtai Sun,*,†,‡ Hua Tan,§ Abdullah M. Asiri,﹟ Khalid A. Alamry,﹟ Xiangke Wang,† and Suhua Wang,*,†, ‡,﹟ †MOE

Key Laboratory of Resources and Environmental System Optimization, College of Environmental Science and Engineering, North China Electric Power University, Beijing 102206, China ‡Institute of Intelligent Machines, Chinese Academy of Sciences, Hefei, Anhui 230031, China §College of Chemistry, Guangdong University of Petrochemical Technology, Maoming, 525000, China #Chemistry

Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia

ABSTRACT: The development of analytical method for selective and sensitive detection of chlortetracycline (CTC), an often over-used broad spectrum antibiotic, is important and challenging in environmental and health monitoring. This paper reports a zinc based metal-organic framework of pyromellitic acid (Zn-BTEC), which has been found to greatly enhance the aggregation-induced emission (AIE) of chlortetracycline. The unique emission response of CTC on Zn-BTEC has been extensively examined and applied for the sensitive detection of CTC on the basis of fluorescence intensity of AIE, and a limit of detection (LOD) was estimated to be 28 nM. A rational mechanism has been proposed based on the porous structure of Zn-BTEC, and the CTC molecules would defuse into the rigid MOF structure and assembly or aggregate, leading to fluorescence enhancement of CTC. Interestingly, the Zn-BTEC materials could discriminate CTC from other TCs antibiotics with high selectivity. We have further demonstrated that the Zn-BTEC materials are successfully applied for the sensitive and selective determination of CTC in real samples of fish and urine.

INTRODUCTION Chlortetracycline (CTC), a broad spectrum antibiotic belongs to the family of tetracyclines (TCs) that possess broad antimicrobial activity against Gram-positive and Gramnegative bacteria,1 has been widely used as the drugs of infectious diseases in the treatment and therapy of human and as the feed additives in animal growth.2-4 However, constant and extensive applications of TCs including tetracycline (TC), chlortetracycline (CTC), doxycycline (DOX), oxytetracycline (OTC) and minocycline hydrochloride (MOC) have resulted in antibiotic residues in our food products, such as milk,5-8 eggs,9 meat,10 and honey,11 which may cause serious side effects to some hypersensitive individuals.2 Among the above TCs, CTC is a semi-synthetic tetracycline antibiotic derived from OTC, showing a relatively long half-life in animal tissues12 which raised the concerns of CTC residue in food. Therefore, a sensitive and selective detection method for CTC is demanded to prevent the residues in food safety and drinking water. The main challenge of selectively detecting CTC is that these TC derivatives have similar chemical structures, and exhibit no specific response to most of the existing techniques, such as microbiological methods,13 colorimetric method,14 electrochemical,15 ultraviolet visible spectroscopy method16 and high performance liquid chromatography.17 Analytical methods based on fluorescence have prominent advantages in excellent sensitivity and selectivity and are promising for both environmental and bioimaging applications.18-22 Recently, several fluorescent probes have been reported for the

recognition of above-mentioned tetracyclines, which are mainly based on the europium (Eu3+) modified complexes as recognition sites for TC,23-25 while usually lack specificity among the tetracycline antibiotics. In order to improve the selectivity of the fluorescent probe, several selective fluorescence probes have been developed. Zhu et al. reported a fluorescent probe for the detection of oxytetracycline via sequential addition of Fe3+ and analyte based on fluorescence “turn-off-on” mode.26 Similarly, Lin et al. developed carbon dots based probes whose fluorescence were efficiently quenched by three metal ions and then turned on in the presence of various antibiotics.27 In addition, a series of fluorescent probes for the detection of oxytetracycline have been developed.28-31 Until recently, a fluorescent Au/Pt nanoclusters (NCs) capped with polyethyleneimine was developed for specific detection of chlortetracycline,32 but it could be quenched by all TCs, which would affect the accuracy. Actually, most of these probes are based on fluorescence turn-off, in which the fluorescence signal is quenched by the target analyte. Compared with fluorescence turn-off mode, methods based on fluorescence turn-on or enhancement is more attractive due to its higher sensitivity and better anti-interference of background signal. However, the methods based on turn-on fluorescence mode for selective and sensitive detection of CTC without further modification have seldom been reported up to now. Metal−organic frameworks (MOFs), also known as porous coordination polymers which can be constructed from a

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variety of molecular complexes, have been shown promise for wide applications in sensing, energy storage, catalysis, drug delivery, separation, and imaging.33-35 The rigid framework and crystalline structure of MOFs contributed their huge potential for chemical sensing and explosive detection.36 However, MOF based fluorescence sensing assay are still in a preliminary stage and only a few examples have been reported due to the difficulty for designing an efficient sensing mechanism. The majority of reported MOF sensors are based on luminescence quenching of lanthanide ions or aromatic fluorophores which have been used as corners and struts, respectively.33 Recently, several turn-on fluorescence mechanisms based MOFs sensors have been reported and offer great opportunities for the development of fluorescence turnon probes.33,37-41 Herein, we designed a zinc based metal-organic framework of pyromellitic acid (Zn-BTEC) and investigated its potential as a platform for the application of selective and quantitative detection. It has been found that the material can greatly enhances the fluorescence of CTC, which shows initial weak fluorescence. The fluorescence enhancement has been proposed as the aggregation-induced emission of CTC when they defused and assembled in the MOF. The as-prepared MOF showed no fluorescence itself while showed bright fluorescence upon the addition of traces of CTC, as illustrated in Scheme 1. To the best of our knowledge, this is the first time that zinc based metal-organic framework has been applied for the detection of antibiotics based on fluorescence turn-on through aggregation-induced emission mechanism. Interestingly, the Zn-BTEC could discriminate CTC from other TCs antibiotics by exhibiting special fluorescence emission wavelength and degradation characteristics. The probe Zn-BTEC has further been applied for CTC determination in real samples including fish and urine with a good sensitivity and selectivity, implying its practical application for CTC detection. Scheme 1. Illustration of sensing process for CTC using metal-organic framework Zn-BTEC as a fluorescent probe based on AIE mechanism. Photographs were taken under Nikon fluorescence microscope and UV lamp (365 nm)

EXPRIMENTAL SECTION Materials and Reagents. Pyromellitic acid (H4BTEC) was purchased from Sigma-Aldrich. Zinc oxide (ZnO 50 ± 10 nm), tris(hydroxymethyl)aminomethane, N,N-Dimethylformamide (DMF), chloramphenicol (CLP), kanamycin sulfate (KMS), streptomycin sulfate (SMS), L-penicillamine (LPA), ampicillin (AMP), minocycline (MOC), doxycycline (DOX), tetracycline (TC), oxytetracycline (OTC), chlorotetracycline hydrochloride (CTC) ascorbic acid (Vc), histidine (His) and

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alanine (Ala) were purchased from Aladdin Chemistry Co. Ltd. (Shanghai, China). Hydrochloric acid (HCl) and methanol were purchased from Beijing Chemical Works. Ethanol absolute, sodium chloride (NaCl), potassium chloride (KCl), barium chloride (BaCl), zinc sulfate heptahydrate (ZnSO4•7H2O), magnesium sulfate anhydrous (MgSO4) and copper sulfate pentahydrate (CuSO4•5H2O) were purchased from Sinopharm Chemical Reagent Co. Ltd. All chemical reagents were of analytical reagent grade, without any treatment unless otherwise unique noted. Ultrapure water (18.2 MΩ•cm) was obtained from Millipore water purification system and used for the preparation of all aqueous solutions. Apparatus and Methods. The pH of Tris-HCl buffer solution was adjusted and measured with a PHS-3C pH meter. Fluorescence spectra were collected on a fluorescence spectrophotometer (Perkin-Elmer LS-55 luminescence spectrometer). UV–vis absorption spectra were obtained with a Shimadzu UV-2550 spectrometer. Fourier transformed infrared (FTIR) spectra of the MOFs were performed on the FTIR spectrophotometer at room temperature. The structures of prepared samples were observed using scanning electron microscopy (S4800, Hitachi). X-ray photoelectron spectroscopy (XPS) and X-ray powder diffraction (XRD) patterns were obtained with an ESCALAB Mark II spectrometer (250xi) and a XRD diffractometer (Rigaku, Japan), respectively. The content of zinc atoms was measured by ICP. Dynamic light scattering (DLS) was measured on Zetasizer Nano ZS (Mastersizer 3000, Malvern). The Brunauer–Emmett–Teller (BET) surface area was measured at 77 K using Micromeritics (TriStar 3020 ). Synthesis of Zn-BTEC. The materials were synthesized according to a previous literature with modification of precursors and procedures.42 Briefly, pyromellitic acid (2.5 mmol，0. 6375 g), nanometer sized ZnO (~ 50 nm in diameter, 2.5 mmol，0.2034 g), 1 mL ultrapure water and 10 mL DMF were placed in a beaker and sonicated for ten minutes. While being completely dissolved, they were transferred to a cleaned Teflon reaction vessel, which was then sealed in stainless steel autoclave and heated at 180 °C for 3.5 days. After the reaction was completed, the mixture solution was taken out and washed three times with ultrapure water, each time requiring ultrasonic for ten minutes (ultrasonic power 100%), centrifugation 5000 rpm for 5 minutes, and the supernatant was discarded. The solid product of Zn-BTEC was then washed three times with anhydrous ethanol, followed by treating with ultrasonic and centrifugation. The washed product was placed in a vacuum drying oven for 3 days at 50 °C. For application, a stock suspension of Zn-BTEC was prepared by directly dispersing in water at 1 mg/mL and kept in the fridge for future use. Fluorescence responses to chlortetracycline. The fluorescence response upon the interaction between CTC and Zn-BTEC was carried out in the optimal conditions (10 mM Tris-HCl buffer, pH = 8). To measure CTC concentration in Tris-HCl buffer solution, 300 L of stock solution (1 mg/mL) of probe Zn-BTEC in ultrapure water was first diluted in 1.7 mL of Tris-HCl buffer to obtain a final probe solution with concentration of 0.15 mg/mL. Then, different volumes of CTC were added to the above solution. The final concentrations of CTC were 0, 0.3, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7 and 8 M, respectively. The fluorescence spectra were observed in the


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range from 400 to 750 nm using a 365 nm excitation wavelength with a filter of 430 nm and a 500 nm/min scan rate. After incubation for 2 h, the spectra were plotted again under the same conditions. Specific recognition of CTC over other TCs. In order to explore the specific recognition of CTC among the TC derivatives, different volumes of stock solution of CTC, DOX, TC, OTC and MOC were added to the Zn-BTEC solution followed by recording the fluorescence spectra before and after 2 h at room temperature. Fluorescence responses to other biological reagents and metal ions. To investigate the selectivity of the experiment, several common biological reagents and metal ions were selected as coexisting substances. In order to further validate the method, anti-interference study of fluorescence probe for CTC was carried out by adding nearly 10 fold mixture of biological reagents and metal ions. The final concentrations of chloramphenicol (CLP), kanamycin sulfate (KMS), streptomycin sulfate (SMS), L-penicillamine (LPA) ampicillin (AMP) ascorbic acid (Vc), histidine (His), alanine (Ala) and other metal ions were 40 M, respectively. After one min, the fluorescence spectra were recorded. Then CTC was added into the probe mixture and fluorescence spectra were subsequently recorded. Analysis of CTC in real fish and urine samples. Fresh crucian was purchased from local supermarkets and two samples were prepared by homogenizing 5 g of crucian with 0.0102 g and 0.0051g of CTC, respectively, in 20 mL methanol at high speed for 5 min. The final concentration of CTC was calculated to be 1 mM and 0.5 mM. The homogenate was centrifuged at 6000 rpm for 5 minutes, and the supernatant was kept in the fridge for future measurements. Human urine samples were collected from one healthy male adult volunteer. Urine samples were only filtered through 0.45 m membrane to remove possible solid suspensions. 0.0051 g CTC and 0.0025g CTC was dissolved in 10 mL of urine to give final concentrations of the urine samples at 1 mM and 0.5 mM, respectively. These fish and urine samples with different concentrations of CTC were added to the sensing system, and the resultant solutions were mixed well before recording their emission spectra. For un-spiked real samples, 10 zebra fishes were first raised in a beaker with clean water without food for 7 days, in an incubator at 25 C and photometric quantity at 33%. The fishes were then fed with 20 mg of CTC fine powder two times in 24 hours. After another 24 hours, the fishes were collected and treated with 15 mL of methanol by ultrasonication and centrifugation to get methanol supernatant. The fluorescence spectra were measured by addition of 100 L of the methanol supernatant into the MOF Zn-BTEC suspension in Tris-HCl buffer (pH = 8, 1.9 mL). The contents of CTC in the methanol supernatant was determined based on the absorbance at 381 nm for comparison. REASULT AND DISCUSSION Materials synthesis and Characterization. The synthesis of Zn-BTEC was carried out by heating a solution mixture of pyromellitic acid and nanometer sized ZnO in DMF/H2O (10/1) at 180 °C for 3.5 days. The microstructures and morphology details of Zn-BTEC were examined with scanning electron microscopy (SEM). As shown in Figure 1A, the solid exhibited layer crystal morphology consists of irregular folded

flakes with approximately several micrometers in size. The porous structural properties of Zn-BTEC were investigated by BET measurement before and after interaction with CTC (Figure S1), and powder XRD (Figure 1B) of ZnO, H4BTEC, and zinc pyromellitic complex. As it can be seen that the XRD pattern of MOF Zn-BTEC is different from the starting materials, and it is also distinguished from the zinc pyromellitic acid complex crystal which was synthesized from zinc acetate by solid state reaction43. The sharp and intense XRD peak centered at 2θ = 8.1° (d = 10.8 Å) is corresponding to typical Zn-BTEC zinc functionalized metal-organic framework as previously reported,44 suggesting an ordered pore structure. The nitrogen adsorption–desorption isotherms of Zn-BTEC takes the Type IV and exhibits distinct H1-type hysteresis loops45 and a specific surface area of 31.17 m2/g was obtained, which is close to the similar MOF materials46. After interaction with CTC, the specific surface area was decreased to 22.93 m2/g due to the adsorption of CTC molecules in the pores. To prove the successful doping of zinc atom and explore the chemical composition of the as-prepared Zn-BTEC, FTIR, ICP, and XPS measurements were also performed. As shown in Figure 1C, the peaks between 3000 and 3600 cm−1 are attributed to O−H stretching.47 The peaks around 1630–1605 cm-1 and 1492–1360 cm-1 represent the symmetric and asymmetric carboxylate stretching vibrations, indicating the unidentate terminal mode of coordination of the carboxylate groups.48 The value of  (difference in as(COO) and s(COO)) in Zn-BTEC (218 cm-1) is smaller than sodium carboxylate (95 cm-1 in Na4BTEC), indicating that the carboxylate groups coordinate to the Zn(II) atoms are both in monodentate and in bidentate fashions.49 Elemental analysis and ICP test showed that Zn-BTEC contained three major chemical elements (C, O, Zn) with a C/O/Zn ratio of 0.227/0.454/0.288. As shown in Figure 1D-G, the C1s spectrum showed two peaks, centered at 284.8 eV and 289.0 eV. The intense component with the lowest binding energy (284.8 eV) corresponds to aromatic carbon atoms of benzene ring, and the band with the highest energy of 289.2 eV corresponds to carbon atoms from the -COOH groups.50 Similarly, the O1s also showed two peaks. The peak of 532 eV belongs to the oxygen atoms of carboxylate group, and the peak of 533.5 eV corresponds to the oxygen atom derived from water molecules.50 The two peaks appeared at 1022.3 eV and 1045.3 eV can be assigned to Zn 2p1/2 and 2p3/2, respectively.51 These results suggested that zinc functionalized metal-organic coordination polymer has been prepared successfully with the ratio of metal ion/ligand at 4/1. Optimization condition of pH. Degradation is an important conversion method of tetracycline antibiotics. The degradation rates of tetracycline antibiotics are also affected by conditions such as pH and temperature.52 In order to achieve more accurate detection condition, the pH effect on the fluorescence of CTC before and after incubation for a certain period of time was examined (Figure S2A). CTC showed weak fluorescence in acid and neutral environment (pH 5~7) and did not change substantially after 45 min incubation. While it gave a distinct emission peak at 540 nm in alkaline solutions (pH > 8) and a new peak would appear at 446 nm after incubation for 45 min. To evaluate the time dependent degradation of CTC, the fluorescence spectra was measured every 5 min for 1.5 h in Tris-HCl buffer. The emission peak at 446 nm increased with



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time and reached the maximum in 1.5 h, while no fluorescence intensity enhancement at 540 nm was observed (Figure S2B). These results suggested that Tris-HCl buffer at pH 8 was appropriate as the assay conditions for the next measurement.

Figure 1. (A) SEM image of Zn-BTEC. (B) XRD patterns of Zn-BTEC, H4BTEC, ZnO and Zn-complex, . (C) FTIR spectrum of ZnBTEC. (D) XPS spectrum of Zn-BTEC. (E) Zn2p spectrum of Zn-BTEC. (F) O1s spectrum of Zn-BTEC. (G) C1s spectrum of Zn-BTEC.

Responses of Zn-BTEC toward CTC. Zn-BTEC exhibited no fluorescence background in Tris-HCl buffer (pH = 8) or ethanol solution, which is advantages for sensitive detection application. Most importantly, no fluorescence spectra change was observed when the solution of Zn-BTEC was irradiated with 365 nm light for 2 hours with 5 min duration for each time (Figure S3A) or once a day for one month (Figure S3B), indicating its good photostability for reliable practicability. Figure 2A showed the UV−vis absorption spectra of CTC, and Zn-BTEC in the absence and presence of CTC, respectively. Clearly, the mixture of Zn-BTEC upon addition of CTC showed a strong absorption peak at 381 nm which should be attributed to CTC, indicating that no new absorption peaks are produced in this case. While CTC itself showed a weak fluorescence centered at 540 nm, the fluorescence intensity of the mixture of Zn-BTEC and CTC increased visibly with

about 10-fold increment (Figure 2B). This property allowed Zn-BTEC to be an excellent “turn-on” probe for the detection of CTC. In addition, there was no shift of the emission peak at 540 nm of the mixture in Tris-HCl buffer solution as the excitation wavelengths changing from 355 nm to 395 nm, indicating that it was not an excitation wavelength dependent emission spectral system (Figure S4). In order to avoid the fluorescence caused by the influence of pH on CTC, we tested the fluorescence in a complete ethanol solution. CTC dissolved in ethanol solution showed weak fluorescence with a broad emission spectrum. The exposure of Zn-BTEC to CTC resulted in a rapid and dramatic fluorescence turn on at 540 nm (Figure S5). The larger concentration of Zn-BTEC and CTC, the stronger fluorescence of the solution become. More interestingly, the dried mixture obtained from rotary


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evaporation of ethanol solution of CTC and Zn-BTEC could illuminate with bright green fluorescence in a solid state. Mechanism study. Combined with above mentioned spectroscopic phenomenon, it is rational that the compound CTC would exhibit strong fluorescence upon assembly into the rigid MOF structure of Zn-BTEC. To further examine the sensing mechanism of Zn-BTEC towards CTC, a series of experiments have been carried out to confirm this hypothesis, including FT-IR, XPS and dynamic light scattering (DLS) of Zn-BTEC before and after adding with CTC. There is no apparent absorption peaks change in the IR spectrum of ZnBTEC in the presence of CTC (Figure S6), which could be viewed as a spectrum of two spectra superimposed together. In addition, no obvious change in the spectra of O1s and Zn2p was observed after adding of CTC (Figure S7). These results suggested that no chemistry reaction between Zn-BTEC and CTC happened. DLS experiments revealed a mean size of 1896 nm of Zn-BTEC (Figure S8A). After adding of CTC, the DLS revealed a mean size of 2063 nm (Figure S8B), which demonstrated aggregation between Zn-BTEC and CTC. A series of control experiments were performed on silica nanospheres, zinc oxide nanoparticles, and zinc BTEC complexes for CTC interaction. And there were no any similar phenomena of fluorescence enhancement were observed for these relevant materials, thus it can be carefully assumed that the CTC molecules probably aggregate and fluoresce in the pores of the MOF. Furthermore, a pore size about 3.5 nm of the MOF was estimated from the adsorption isotherm (Figure S9), and this size is large enough to accommodate the CTC molecules, which have a largest dimension of 13 Å between the farthest interatoms calculated through visual molecular dynamics (VMD) method. When CTC defused into the pores of the MOF, the coordination between the zinc atoms and CTC molecules could fasten CTC molecules, and then a pi-pi stacking induced the aggregate of CTC because they have piconjugated 6 member rings, as evidenced by red-shift of the emission (Figure S10). In addition, to examine the interaction between the two materials, zeta potential was tested in pH 8. The obtained zeta potential of Zn-BTEC was found to be -28.45 mV. The zeta

potential of the mixture of Zn-BTEC and CTC was found to

Figure 2. (A) Absorption spectra of compound CTC, Zn-BTEC and the mixture of CTC and Zn-BTEC in Tris-HCl buffer solution (pH = 8). (B) Emission spectra of compound CTC, Zn-BTEC and the mixture of CTC and Zn-BTEC in Tris-HCl buffer solution (pH = 8).

be -25.56 mV, indicating that Zn-BTEC and CTC tends to attract each other to form aggregates. These phenomena validate the hypothesis of CTC aggregation on Zn-BTEC. In order to verify that the CTC responded only to the synthesized material, not to the residual reactants, the reaction of CTC with the same concentration of nanometer sized zinc oxide and pyromellitic acid was examined. The result showed that the fluorescence could not be turned on under the assay conditions (Figure S11). To further verify that the aggregation-induced emission of CTC is only specific to Zn-BTEC, we used silica gel and ferric hydroxide colloid to adsorb CTC, however, no obvious fluorescence enhancement was observed (Figure S12) for both materials. These phenomena surely suggest that the aggregation-induced emission of CTC can only respond to ZnBTEC due to its specific physical structure.



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Figure 4. Structure of tetracyclines (TCs). Chlortetracycline (CTC), doxycycline (DOX), tetracycline (TC), oxytetracycline (OTC) and minocycline (MOC) have similar chemical structures.

Figure 3. (A) Fluorescence spectra of the probe Zn-BTEC (0.15 mg/ml) in the presence of different concentrations of CTC in TrisHCl buffer solution (pH = 8), and the inset photographs were obtained under illumination by a 365 nm UV lamp in the dark. (B) The linear relationship between the fluorescent intensity of probe at 540 nm and CTC concentration.

Quantitative determination of CTC based on AIE. In order to investigate the sensing performance of the probe to CTC, the fluorescence response time of the probe to CTC was first investigated prior to the sensitivity study. The results showed that the fluorescence could be turned on immediately upon addition of CTC and remained unchanged with a further increase of incubation time (Figure S13). Figure 3A shows the spectral responses of the probe Zn-BTEC in tris-HCl buffer solution to various concentrations of CTC. Clearly, the fluorescence intensity at 540 nm increased gradually with the addition amount of CTC. Meanwhile, the solution changed from no fluorescence to bright green fluorescence under a UV lamp, which could be clearly visualized with the naked eye (Figure 3A). The fluorescence intensity ratio of F/F0 displays a good linear correlation (R2 = 0.998) with CTC concentration in the range of 0-8 µM (Figure 3B). The limit of detection (LOD) was estimated as 28 nM according to the definition of the three times of the blank signal deviation (3). After incubation for 2 h, interestingly, the fluorescence spectra of the reaction mixture would show a new peak at 446 nm, which was produced by the degradation of CTC in this particular environment of Zn-BTEC (Figure S14). The sensor of MOF could be reused again after CTC was removed by ultrasonication in methanol, but at the cost of tedious washing procedure. The fluorescence intensity enhanced again when the recycled MOF was exposed to CTC (Figure S15).


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Figure 5. (A) Fluorescence spectra of Zn-BTEC (0.15 mg/ml) in the presence of MOC (5 M), CTC (5 M), OTC (3.15 M), TC (3.25 M), and DOX (3 M) under optimal conditions, respectively. Fluorescence spectra of (B), (C), (D), (E) and (F) were obtained before and after 2 h incubation in the same conditions. Emission spectra of the probe Zn-BTEC (0.1 mg/ml) upon addition of CTC (4 M), DOX (3 M), TC (3.25 M), OTC (3.15 M) and MOC (5 M) in Tris-HCl buffer solution (10 mM, pH = 8), respectively.

Specific recognition of CTC over other TCs. TC derivatives has high structural similarity which cannot be discriminated easily with existing methods (Figure 4). With regard to this, the selectivity of the fluorescence probe was carefully examined under the optimal conditions (Tris-HCl buffer solution, pH=8) for TC derivatives. As it can be seen in Figure 5A, the fluorescence spectrum of CTC had a unique peak at 540 nm, which was different from the peak displacement of other TCs. The results showed that MOC did not response to Zn-BTEC, however, the fluorescence of OTC, TC, and DOX could be turned on at about 530 nm. To further investigate the difference of CTC from other TCs, the fluorescence spectra of CTC, DOX, TC, OTC and MOC were collected before and after 2 h incubation at room temperature, as shown in Figure 5B-F. Only CTC generated a new peak at

446 nm under optimal conditions, while other TCs gave only a change in fluorescence intensity. These two special phenomena make it easy to distinguish CTC from other TCs. Effect of biological reagents and metal ions on the measurement of CTC. The selectivity and anti-interference of the fluorescence probe was studied in the presence of a variety of other antibiotics and metal ions such as chloramphenicol (CLP), kanamycin sulfate (KMS), streptomycin sulfate (SMS), L-penicillamine (LPA) ampicillin (AMP) ascorbic acid (Vc), histidine (His), alanine (Ala), K+, Na+, Mg2+, Zn2+, Ba2+ and Ca2+ as shown in Figure S16. The results show that no obvious fluorescence intensity changes were observed after adding with biological reagents or metal ions, but the probe has high selectivity towards to CTC. In order to further validate the selectivity of the probe, anti-



interference study of Zn-BTEC for CTC was carried out by adding nearly 10 fold of biological reagents or metal ions (Figure 6). As it can be seen that excessive interference biological reagents or metal ions had no remarkable changes on the fluorescence response of probe, which shows the excellent selectivity towards CTC compared with other biological reagents or metal ions.

fish samples

2 4 urine samples 2 4

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108.5 107.2 91.5 103.7

1.4 4.3 3.8 5.2

Paper-based sensor for visual detection of CTC. Finally, we prepared portable test strips by immobilizing the MOF

materials on filter paper for rapid and visual detection of

Figure 6. Anti-interference study of the probe Zn-BTEC (0.15 mg/ml) to biological reagents and metal ions in Tris-HCl buffer solution (10 mM, pH = 8). The concentration of CTC was 4 M and the concentrations of CLP, KMS, SMS, LPA, AMP, Vc, His, Ala, K+, Na+, Mg2+, Zn2+, Ba2+ and Ca2+ were 40 M.

Detection of CTC in real fish and urine samples. Due to the high sensitivity and selectivity of the probe Zn-BTEC for the sensing of CTC, the Zn-BTEC MOF materials was applied for the analysis of CTC in fish and urine samples, which are significant for food safety and human health. Spike and recovery tests were carried out in the treated solutions. Briefly, the prepared fish and urine samples with known concentrations were introduced to the Zn-BTEC solution, and the fluorescence spectra and intensities were collected. As shown in table 1, the recoveries of various spiked CTC were obtained from 91.5% to 108.5% in fish samples and urine samples. The relative standard deviations (RSD) of 1.4% to 5.2% were generally satisfactory, showing the reliability of the probe Zn-BTEC for CTC determination in real samples. The method was further evaluated by application for contaminated zebra fishes, which were treated with methanol for CTC extraction. The fluorescence spectra were measured by addition of 100 L of the methanol supernatant into the MOF Zn-BTEC suspension in Tris-HCl buffer (pH = 8, 1.9 mL) and the content of CTC were calculated to be 10 M based on the linear equation (Figure 3). For comparison, the contents of CTC in the methanol supernatant was determined to be 11 M based on the calibration curve calculated from the absorbance at 381 nm (Figure S17). Clearly, the two values are very close, showing its potential application for un-spiked real samples contaminated by CTC. Table 1. Recovery test of CTC spiked in fish and urine samples. Samples

Spiked (M)

Detected (M)

Recovery (%)

RSD (%, n=3)

CTC. The paper of CTC sensor was made of polyvinylidene fluoride microporous filter membrane. The round test paper was dipped in Zn-BTEC solution (1 mg/mL), and was further treated with filter paper to be desiccative and kept in dark for future use. These test paper sensors showed almost invisible fluorescence under 365 nm UV light illumination. Before the test, the stock solution of different concentrations of CTC (5 M, 10 M, 50 M, 100 M, 500 M, 1 mM) were prepared. For each sensor, 4 uL CTC solutions with various concentrations were pipetted to the surface of the test paper. Figure 7A shows the identical test paper under natural light, and no obvious change could be observed. However, the fluorescence of the Zn-BTEC test paper was immediately turned on in varying brightness upon addition of different concentrations of CTC, showing bright green spots against dark-blue fluorescence background, which can be clearly seen under a 365 nm UV illumination (Figure 7B-C). Such fluorescence color changes on the test paper roughly indicate the concentration range for CTC visual detection.

Figure 7. Photographs of the filter paper loaded with Zn-BTEC upon addition of 4 L of CTC solution at different concentrations (from left to right: 0, 5 M, 10 M, 50 M, 100 M, 500 M, 1 mM). (A) under natural light; (B) the test paper loaded with ZnBTEC without CTC as control under 365 nm UV light; (C) under 365 nm UV light illumination.

CONCLUSIONS We have synthesized a novel zinc based MOF of pyromellitic acid and applied it for the sensitive detection of CTC on the basis of aggregation-induced emission which has been greatly enhanced. The mechanism was based on the unique interactions between CTC and Zn-BTEC, the compound CTC assembly into the rigid MOF frame and aggregate, which results in fluorescence enhancement. A good limit of detection at 28 nM in buffer solution was obtained, which is superior to many other reported methods. The method has further been applied for the determination of CTC in real samples of fish and urine. This work has harnessed the specific and excellent performance of MOF and promoted further progress in analytical and material research field.

ASSOCIATED CONTENT Supporting Information Additional information as noted in the text (Figures S1−S17).


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The Supporting Information is available free of charge on the ACS Publications website.

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

ACKNOWLEDGMENT We acknowledge the financial support from the National Key Research and Development Program of China (2017YFA0207003), the National Natural Science Foundation of China (2177504, 221475134, and 21675158) and the Fundamental Research Funds for the Central Universities (2016ZZD06).

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