An Easily Available Ratiometric Reaction-Based AIE Probe for Carbon

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An Easily Available Ratiometric Reaction-based AIE Probe for Carbon Monoxide Light-up Imaging Jianguo Wang, Chunbin Li, Qingqing Chen, Hongfeng Li, Lihua Zhou, Xing Jiang, Mengxue Shi, Pengfei Zhang, Guoyu Jiang, and Ben Zhong Tang Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.9b02691 • Publication Date (Web): 18 Jul 2019 Downloaded from pubs.acs.org on July 18, 2019

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Analytical Chemistry

An Easily Available Ratiometric Reaction-based AIE Probe for Carbon Monoxide Light-up Imaging Jianguo Wang,†,‡,# Chunbin Li,‡,§,# Qingqing Chen,‡ Hongfeng Li,§ Lihua Zhou,§ Xing Jiang,§ Mengxue Shi,‡ Pengfei Zhang,§,* Guoyu Jiang†,‡,* and Ben Zhong Tang⊥,* †College

of Chemistry and Chemical Engineering, Inner Mongolia Key Laboratory of Fine Organic Synthesis, Inner Mongolia University, Hohhot 010021, China. * E-mail: [email protected] ‡Key Laboratory of Organo-Pharmaceutical Chemistry, Gannan Normal University, Ganzhou 341000, China. §Guangdong

Key Laboratory of Nanomedicine, CAS Key Laboratory of Health Informatics, Shenzhen Bioactive Materials Engineering Lab for Medicine, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China. * E-mail: [email protected] ⊥Department

of Chemistry, Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, Institute for Advanced Study, Division of Biomedical Engineering, Division of Life Science, State Key Laboratory of Molecular Neuroscience and Institute of Molecular Functional Materials, The Hong Kong University of Science and Technology (HKUST), Clear Water Bay, Kowloon, China. HKUST Shenzhen Research Institute, No. 9 Yuexing 1st RD, South Area Hi-tech Park, Nanshan, Shenzhen 518057, China. * E-mail: [email protected] ABSTRACT: Carbon monoxide (CO) is a significant gasotransmitter that naturally modulates inflammatory responses. Visualization of CO in situ would help to reveal its physiological/pathological functions. Unfortunately, most of existing CO fluorescent probes show aggregation-caused quenching (ACQ) properties. Herein, we report the reaction-based fluorescent probe (BTCV-CO) with aggregation-induced emission (AIE) characteristics for CO detection and imaging. This ratiometric AIE probe showed excellent stability, high sensitivity (detection limit of 30.8 nM) and superior selectivity. More importantly, this CO-responsive AIE probe could be facilely designed and easily obtained by two-step synthesis with high yield, providing easy-to-handle AIE toolbox for real-time visualization of CO in living system.

Carbon monoxide (CO) is notorious for its high toxicity and lethal effect (above 35 ppm) to animals. However, since the first report that CO is a normal neurotransmitter1 and naturally modulates inflammatory responses,2 CO has received great attention as a biological regulator. For example, CO modulates functions of the cardiovascular system, inhibits blood platelet aggregation and adhesion, suppresses, reverses, and repairs the damage caused by inflammatory responses.3 Abnormalities in CO metabolism have been linked to a variety of diseases, including neurodegenerations, hypertension, heart failure, and pathological inflammation.4 In many tissues, CO is known to act as anti-inflammatories, vasodilators and promoters of neovascular growth. Moreover, it could also be used as potential therapeutic agent.5 Clinical trials of small amounts of CO for the prevention of vascular dysfunction, inflammation, tissue ischemia and organ rejection are ongoing.6 Unfortunately, CO is colorless, odorless and tasteless. Deep understanding its physiological/pathological functions relies on powerful tools to selectively visualize CO in situ. Fluorescent probes8-13 have aroused great interest because of their high specificity and sensitivity, simple

operation, non-invasive detection and imaging capability.14-17 Pioneered by the work of He’s group18 and Chang’s group,19 several fluorescent CO probes have been reported (Table S1).20-37 However, most of the current probes suffered from the notorious aggregation-caused quenching (ACQ) effect after they accumulated in cells, making the fluorescence emission much weaker than that in solution.38 Thus, it is highly desirable to develop antiACQ fluorescent probes for CO detection and imaging. Luminogens with aggregation-induced emission (AIE) characteristics may be the ideal candidate for development of anti-ACQ fluorescent probes for CO detection and imaging. Contrast to traditional ACQ luminophores, AIE luminogens (AIEgens) exhibited strong emission in high concentrations or the aggregation state. Since it was firstly proposed by Tang’s group in 2001,38 various AIEgens have been developed for biosensing and bioimaging.38-48 However, there is no attempt to develop AIE-active CO probes. Herein, we describe the reaction-based ratiometric fluorescent probe (BTCV-CO) with AIE characteristics for CO detection and visualization. As demonstrated in Scheme 1, BTCV-CO was designed based on the in situ

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reduction ability of CO to convert Pd2+ to Pd0 and the subsequent Pd0-mediated Tsuji-Trost reaction. BTCV-CO is expected to be weakly emissive in solution due to the fast non-radiative decay of the singlet excited state that is facilitated by cis-trans isomerization about the C-C double bond of the alkene linker.49 AIE curves verify that BTCVCO is AIE-active, which is favorable both for reducing the background fluorescence and for enhancing the signal to noise ratio. Restricting the rotation of the C-C double bond would result in significant emission enhancement. We expected that the CO-promoted removal of allyl group in BTCV-CO would generate the phenolate intermediate, which will undergo rapid cyclization and thus restrict the rotation of C-C double bond to give the highly fluorescent benzithiazolyl iminocoumarin (BTIC), which is also confirmed to be AIE-active. The fabrication of reaction based AIE-active BTCV-CO may result in an efficient probe for sensitive sensing and long time tracking of CO with high photostability and large stokes’ shift. Fortunately, BTCV-CO exhibited ratiometric change in the presence of CO, which could be used for CO detection and selectively light up CO in live cells and in vivo with high signal-tonoise ratio. These impressive data with the excellent parameters of BTCV-CO would not only make it a readyto-use tool for in situ and real time imaging of CO in live samples, but also shed new light on the deep understanding of CO physiological/pathological functions in live animals. BTCV-CO was easily synthesized and purified as shown in Figure 1A via a two-step process. BTIC was obtained through a similar procedure (Scheme S1). All the compounds were characterized by 1H NMR, 13C NMR and high resolution mass spectrometry (HRMS) (Figure S1-S8).

N

S

Pd2+ CO

NC O

N

S

N

the formation of aggregates, resulting in greatly hindered cis-trans isomerization of the C-C double bond in the alkene linker and thus boosting the emission. Moreover, fluorescence quantum yield of BTCV-CO in the solid state was measured to be 6.5%. These data verified that BTCVCO featured the unique AIE characteristics. The AIE feature of BTIC was also confirmed in toluene/DMSO mixtures (Figure S9). Furthermore, we examined the response of BTCV-CO (5 μM) in PBS buffer (pH 7.4, containing 5% DMSO) toward CO. A water soluble CO-releasing molecule [Ru(CO)3Cl2]2 (CORM-2), was used as CO donor.20-37 As shown in Figure S10B, BTCV-CO displayed weak emission in PBS solution. The addition of PdCl2 (5 μM) has negligible influence on the PL spectra of BTCV-CO. While in stark contrast, the subsequential addition of CORM-2 (50 μM) greatly lighted up the fluorescence of BTCV-CO, with a new peak appeared at 546 nm. According to our design concept depicted in Shceme 1, the CO-promoted removal of allyl group in probe BTCV-CO would generate the phenolate intermediate, which will undergo rapid cyclization and thus restrict the rotation of C-C double bond to BTIC. As shown in Figure S11, high resolution mass spectrometry (HRMS) results verified that in the presence of PdCl2, incubation of probe BTCV-CO with CORM-2 resulted in a peak of m/z = 350.1317, which is consistent with the [M+H]+ peak of BTIC. The response of BTCV-CO toward CO was studied in presence of PdCl2 with different concentrations (0.2 μM, 0.5 μM and 1 μM). As shown in Figure S12, even when the concentration of PdCl2 is low to 0.2 μM, BTCVCO still displayed sensitive response to CO. All these data verified our initial design concept of probe BTCV-CO shown in Scheme 1.

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HN

NC O

O

Pd0

N

BTCV-CO Weak red emission

N

N

BTIC Strong green emission

AIE feature

Scheme 1. Schematic illustration of ratiometric detection of CO using AIE-active fluorescent probe BTCV-CO.

To verify the initial design concept, the optical properties of BTCV-CO were first investigated. As shown in Figure 1B, BTCV-CO exhibited absorption maxima at 465 nm and wide emission ranging from 500 to 800 nm in 5% DMSO/PBS mixed solution (ΦF=0.5%). The AIE property of BTCV-CO was confirmed in toluene/DMSO mixtures with different toluene volume fractions (Figure 1C). The photoluminescence (PL) intensity of BTCV-CO decreased slowly in toluene/DMSO mixtures with toluene fraction lower than 90%, which could be ascribed to the twisted intramolecular charge transfer (TICT) effect. Afterward, the PL intensity intensified swiftly. As toluene is a poor solvent of BTCV-CO, the addition of toluene would induce

Figure 1. (A) Synthetic route to probe BTCV-CO. (B) Excitation and emission spectra of BTCV-CO (5 μM) in 5% DMSO/PBS mixed solution (pH 7.4). (C) Plot of PL intensity of BTCV-CO at maximum emission wavelength vs. the toluene fraction in the toluene/DMSO mixtures.

To optimize the experimental conditions, the time courses of the PL intensity of BTCV-CO after incubation with different concentrations of CORM-2 (0-10 μM) in PBS

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were measured. The data were processed respectively by using PL intensity ratio changes based on a single emission wavelength ((I-I0)/I0 at 546 nm) (turn-on mode) or two separate emission wavelengths (I546/I710) (ratiometric response mode). As shown in Figure S13, both ratios increased gradually as the reaction time of BTCV-CO with CORM-2 prolonged and leveled off after 20 min. Notably, at the same concentration of CORM-2, the PL intensity ratio changes based on two separate emission wavelengths (I546/I710) displayed over 11-fold enhancement than that based on a single emission wavelength ((I-I0)/I0 at 546 nm after 20 min incubation. These indicated that ratiometric response mode could provide higher sensitivity than solely turn-on mode. Moreover, the PL intensity ratios of BTCVCO without any CORM-2 were barely changed within a time period of 35 min, indicating high stability of BTCVCO. 48

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Figure 2. (A) PL spectra of BTCV-CO (5 μM in PBS solution, pH 7.4, containing 5% DMSO) after incubation with CORM-2 (0-80 μM) for 20 min. Inset showed the enlarged spectra in the red region (680-800 nm). (B) The PL intensity ratios (I546/I710) of BTCV-CO vs. the concentration of CORM-2 (0-80 μM). (C) The linear fitting of the PL intensity ratios (I546/I710) vs. the concentration of CORM-2 (1-5 μM). Y=1.3539 X+1.89931, R2=0.998. Excitation wavelength (λex) = 465 nm. (D) The PL intensity ratios (I546/I710) of BTCV-CO toward various biomolecules (Concentration: 100 μM).

To further confirm that ratiometric response mode may provide higher sensitivity than solely turn-on mode, fluorescence titration experiment was carried out. As shown in Figure 2A, the PL intensity of the probe BTCVCO enhanced gradually with increase of CORM-2 addition. Turn-on mode gave only 17-fold enhancement for 40 μM CO (Figure S14). While ratiometric response mode displayed 39-fold enhancement (Figure 2B). I546/I710 exhibited linearity ranging from 1-5 μM and detection limit of 21.6 nM to CORM-2 (Figure 2C).50-51 The release of CO from CORM-2 was assessed spectrophotometrically by measuring the conversion of deoxymyoglobin (deoxy-Mb)

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Selectivity is also critical for fluorescent probes design. As shown in Figure 2D and Figure S16, the fluorescent responses of BTCV-CO toward common anions, amino acids, reactive oxygen species, reactive nitrogen species, and reductive substances were investigated. The results clearly displayed that the ratio I546/I710 of BTCV-CO was barely varied by the addition of these species. Moreover, I546/I710 ratio of BTCV-CO toward CO was also not interfered, revealing the excellent specificity of BTCV-CO (Figure S17). As shown in Figure S18, the ratio I546/I710 exhibited negligible changes within pH values from 3-11, which is highly desirable for bioimaging applications in living systems.

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to carbonmonoxy myoglobin (MbCO) (Figure S15). The results indicate that each mole of CORM-2 can liberate 0.7 moles of CO in solution, which is consistent with the reported paper.52 The detection limit of CO was thus calculated to be 30.8 nM. All these results verified that ratiometric detection gave better performance, consistent with our initial design and previous reports. 35-37

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Analytical Chemistry

Figure 3. Cell imaging of probe system (BTCV-CO + PdCl2, 5 μM each for 15 min at 37 oC) with different concentrations of CORM-2 (0, 10, 20 and 50 μM for 30 min). (Scale bar: 20 μm). λex = 476 nm.

Encouraged by the excellent properties, the potential applications of BTCV-CO for imaging of CO in living cells were investigated. MTT assays showed that BTCV-CO has very low cytotoxicity to living cells even it was used up to 25 μM (Figure S19). Since BTCV-CO is highly sensitive to CO, 5 μM of probe was used for fluorescent imaging of CO in living cells followed by the addition of CORM-2 (CO donor, 0–50 μM). As shown in Figure 3, the cells treated with the probe system without the addition of CORM-2 exhibited faint emission both in the green channel and the red channel. While after the addition of CORM-2 (0-50 μM), the emission in red channel displayed little enhancement. However, remarkable enhancement of the green signal could be observed. The overlay images verified that the emission was evident in cells, indicating the good

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permeability of our probe BTCV-CO. Moreover, the ratios of Igreen/Ired displayed gradual increase in a concentrationdependent manner (Figure S20), which was well consistent with the CO-induced ratiometric fluorescence responses obtained in buffers, demonstrating that BTCV-CO can be successfully used for imaging of CO in living cells. We further evaluated the potential application of BTCVCO for imaging of CO on live animal level. The live mice were divided into two groups. The mice injected with only BTCV-CO probe system showed negligible fluorescence change during a long time period of 55 min (Figure S21 and Figure S23). On the contrast, the mice injected with BTCVCO probe system, followed by injection of CORM-2 displayed a time-dependent fluorescence increase (Figure S22 and Figure S23), demonstrating that BTCV-CO could be potentially used for imaging CO in vivo. In summary, a new kind of CO-responsive AIE probe (BTCV-CO) for ratiometric sensing and real-time imaging in vivo was developed. BTCV-CO was fabricated through a simple two-step process. As-prepared AIE-active probe exhibited fast response, high sensitivity, and excellent selectivity toward CO in living cells and living animals with high signal-to-noise ratio. This work opened a new avenue to generate easy-to-handle reaction-based AIE probe for real-time visualization of CO in living system and shed new light on deep understanding of the physiological/pathological functions of CO in situ.

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Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Materials and methods, characterization, figures of compounds, supplementary data (PDF)

AUTHOR INFORMATION #These

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authors contributed equally to this work.

Notes The authors declare no competing financial interest.

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ACKNOWLEDGMENT We thank National Natural Science Foundation of China (21663005, 21871060), the Natural Science Foundation of Jiangxi Province (2018ACB21009, 20181BAB213007) and Science and Technology Plan of Shenzhen (JCYJ20170818113538482) for the financial support.

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BTIC Strong green emission BTIC

√ Ratio probe √ Fast response √ High specificity √ High sensitivity √ Excellent stability √ AIE characteristic

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Analytical Chemistry

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