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A Photostable pH-Sensitive Near-Infrared AIE Luminogen for Long-Term Mitochondrial Tracking Xiujie Zhao, Yun Chen, Guiyu Niu, Dening Gu, Jianning Wang, Yanmei Cao, Yongmei Yin, Xiaogang Li, Dan Ding, Rimo Xi, and Meng Meng ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.9b02228 • Publication Date (Web): 22 Mar 2019 Downloaded from http://pubs.acs.org on March 23, 2019

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ACS Applied Materials & Interfaces

A Photostable pH-Sensitive Near-Infrared AIE Luminogen for Long-Term Mitochondrial Tracking Xiujie Zhao,† Yun Chen,† Guiyu Niu,† Dening Gu,† Jianning Wang,† Yanmei Cao,† Yongmei Yin,† Xiaogang Li,§ Dan Ding,‡ Rimo Xi,* † and Meng Meng*†

†

College of Pharmacy, State Key Laboratory of Medicinal Chemical Biology and

Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300353, China ‡

State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive

Materials, Ministry of Education, and College of Life Sciences, Nankai University, Tianjin 300071, China §

Peking Union Medical College Hospital, Peking Union Medical College and

Chinese Academy of Medical Science, Beijing, 100730, China

KEYWORDS: near-infrared (NIR) luminogens; aggregation-induced emission (AIE); mitochondria imaging; pH-sensitive probe

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ABSTRACT Mitochondria are crucial in the process of oxidative metabolism and apoptosis. Their morphology is greatly associated with the development of certain diseases. For specific and long-term imaging of mitochondrial morphology, we synthesized a new mitochondria-targeted near-infrared (NIR) fluorescent probe (TPE-Xan-In) by incorporating TPE with a NIR merocyanine skeleton (Xan-In). TPE-Xan-In displayed both absorption (660 nm) and emission peaks (743 nm) in NIR region. Moreover, it showed aggregation-induced emission (AIE) properties at neutral pH and specifically illuminated mitochondria with good biocompatibility, superior photostability and high tolerance to mitochondrial membrane potential changes. With a pH-responsive unit, hydroxyl-xanthene (Xan), the probe exhibited a pH-sensitive fluorescence emission in the range of pH 4.0 to 7.0, which indicated its potential in long-term tracking of pH and morphology changes of mitochondria in the biomedical researches.

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1. INTRODUCTION Mitochondria are the subcellular organelles that provide cellular energy in the form of adenosine triphosphate (ATP), therefore they play a crucial part in reactive oxygen species generation, cellular signaling and apoptosis. The morphology of mitochondria is found to be associated with cell-cycle stage, cellular metabolic state and cell functions. It has been reported that several neurological and cardiovascular diseases, even cancer, would affect the mitochondrial morphology.1,2 Microenvironment changes of live cells are one of the most important indicators relevant with these diseases, especially intracellular pH value. The functions of mitochondria are highly dependent on the intracellular pH as well.3 Hence, it is greatly desirable to discriminate mitochondria at different pH to investigate the relationship between morphology of mitochondria and intercellular pH changes. Several fluorescent probes have been developed to image mitochondria in living cells.4 These conventional fluorophores could suffer from low photostability and aggregated-caused quenching when applied in cells.5 In recent years, fluorescent chemical probes with aggregation-induced emission (AIE) properties have attracted great interest as a novel type of mitochondria-targeted luminogens.6–8 These probes are non-emissive in a dissolved state but dramatically luminescent when they aggregate, which offers the merits of high sensitivity and photobleaching tolerance for biological applications.9 Near-infrared (NIR) fluorescent probes (λem = 650–900 nm) are advantageous in

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minimal photodamage to biological samples, low background interference and deep penetration.10 However, there are limited works about AIE-fluorogens with NIR features to trace mitochondria. In 2015, Tang et al. incorporated indolium salt with an AIE core–tetraphenylethylene (TPE) and obtained a red emitting (λex = 450 nm, λex = 694 nm) mitochondria-targeted AIE probe TPE-Ph-In.11 Based on this structure, in this work, we designed and synthesized a new fluorescent probe (TPE-Xan-In, Scheme 1) using hydroxyl-xanthene (Xan) instead of the phenyl (Ph) group. The probe could specifically target mitochondria due to the attribution of indolium salt,4 with merocyanine (Xan-In) serving as a NIR emission skeleton.12–15 This is the first mitochondria-targeting AIE fluorogen that has both NIR absorption and emission (λex = 660 nm, λem = 743 nm). Moreover, the protonation/deprotonation of phenolic hydroxyl group in Xan could switch the occurrence of intramolecular charge transfer (ICT) and result in a pH-sensitive fluorescent emission from pH 4.0 to 7.0, which suggests that the probe would be hopefully applied in long-term tracking of pH and morphology variations of mitochondria.

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Scheme 1. Schematic illustration for structural design of TPE-Xan-In and its advantages in long-term tracking of mitochondria.

2. EXPERIMENTAL SECTION 2.1. Synthesis of Compound 1 5-Bromoresorcinol (27.0 mg 0.143 mmol), triethylamine (TEA, 0.15 mL) were dissolved in 2.0 mL of anhydrous DMF and stirred at room temperature under nitrogen for 10 min (Figure 1). Then 1.0 mL of anhydrous DMF containing 77.5 µmol IR780 iodide (50 mg) was carefully added and allowed to react at 85 ºC for 3 h. After DMF was evaporated, the crude product was purified by silica gel chromatography using CH2Cl2/CH3OH (v/v = 40:1) as an eluent to obtain compound 1 as a blue solid in 62.9% yield (30 mg).

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Figure 1. Synthetic route of TPE-Xan-In.

2.2. Synthesis of TPE-Xan-In In a two-necked round-bottom flask, compound 1 (30 mg, 0.048 mmol) was mixed with 1-(4-phenylboronic acid pinacol ester)-1,2,2-triphenylethene (40 mg, 0.087 mmol), K2CO3 (0.338 g, 2.45 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 4 µmol), and evacuated under nitrogen for three times. Then 4 mL of THF and 1 mL of ddH2O was added. After refluxed for 24 h, the reaction mixture was transferred to 5 mL of ddH2O and extracted with dichloromethane to collect the organic phase. After organic solvent was evaporated, the crude product was purified by silica gel column chromatography with CH2Cl2/CH3OH (v/v = 40:1) as eluent to obtain TPE-Xan-In as a blue solid in 24% yield (10 mg). 2.3. Cytotoxicity Assay of TPE-Xan-In HeLa cells were cultured at 37 ºC under a humidified 5% CO2 in high DMEM medium containing 10% FBS and 1% penicillin-streptomycin (10,000 U mL–1 penicillin and 10 mg mL−1 streptomycin). For cytotoxicity (MTT) assay, HeLa cells 6


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were seeded in a 96-well plate (2 × 104 cells per well) and cultured for 24 h. Different concentration (1, 3, 10, 33 and 100 μM) of TPE-Xan-In was added into the wells and incubated for 48 h. Then MTT solution (5 mg mL−1, 20 μL per well) was applied and removed after 4 h. To each well, 150 μL of DMSO was added and the absorbance at 570 nm was measured to calculate the percentage of cell viability as the following formula: Cell viability (%) = (Mean absorbance of treated cells – Mean absorbance of blank medium) / (Mean absorbance of untreated cells – Mean absorbance of blank medium) × 100 % 2.4. Long-term Tracking of Mitochondria by TPE-Xan-In HeLa cells were seeded into the culture dishes (3 × 105 cells per well). After incubation for 24 h, the culture medium was removed and added with freshly prepared FBS-free medium containing 2.5 μM TPE-Xan-In and 0.05 μM MitoTracker Green (MTG). After 30 min, the dishes were washed with PBS for confocal fluorescent microscopy imaging. To evaluate the affect of plasma or mitochondrial membrane potential changes on the mitochondrial tracing, HeLa cells (3 × 105 cells per well) were cultured in FBS-free medium containing 150 mM KCl or 1 μM FCCP for 60 min. Then solution of TPE-Xan-In (2.5 μM) and MTG (0.05 μM) was added. After incubation for 30 min, the cells were imaged under confocal fluorescent microscopy without washing. To track mitochondria in cells with different pH values, HeLa cells were treated with

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TPE-Xan-In and MTG as indicated above. After washed twice by PBS, the cells were incubated with a H+/K+ ionophore (5 μg mL–1 nigericin) in citric buffer with pH ranging from 4.0 to 7.0. After 30 min, the cells were imaged under confocal fluorescent microscopy. 3. RESULTS AND DISCUSSION 3.1. Characterization of TPE-Xan-In TPE-Xan-In was synthesized by two steps (Figure 1): 1) retro-Knoevenagel reaction of the starting material IR-780 with 5-bromoresorcinol to obtain compound 1, and 2) Suzzki-coupling reaction of compound 1 with 1-(4-phenylboronic acid pinacol ester)-1,2,2-triphenylethene to obtain TPE-Xan-In. The results of HRMS, 1H NMR and 13C NMR (Figure S1–S6) confirmed the right molecular structures of compound 1 and TPE-Xan-In. The fluorescent (FL) emission spectra of TPE-Xan-In (10 µM) were recorded to evaluate its AIE property at different pH. At acidic pH 4.0 (Figure 2a), the probe showed intense fluorescence emission at around 705 nm and 750 nm (λex = 660 nm). While the water fraction increased from 0% to 70%, the fluorescence intensity at both peaks decreased, indicating that the probe showed a traditional aggregation-caused quenching (ACQ) feature at pH 4.0. On the other hand, at neutral pH 7.0 (Figure 2b), TPE-Xan-In displayed little fluorescence emission at 705 nm but dramatic emission at 740–750 nm as water fraction increased to 70%. When water ratio reached 80% and 90%, the FL intensity at 740–750 nm remarkably decreased (Figure S7), which was probably caused by the hydrophilic unit of indolium. The

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particle size distribution and TEM images demonstrated that TPE-Xan-In was in an aggregated state (~90 nm) in 70% H2O (pH 7.0) but highly dispersed (< 5 nm) in 80% H2O (pH 7.0) (Figure S8). By comparing the FL spectra of TPE-Xan-In at pH 5.0 and 6.0 (Figure S9), we found that the probe started to exhibit an AIE characteristic at pH > 6.0. Then we investigated the pH effect on TPE-Xan-In aggregation in 70% H2O and found that the probe tended to aggregate more intensely at high pH (Figure 2c). Moreover, the fluorescence emission peak gradually shifted from 730 nm to 750 nm as the pH arose (Figure 2c). At neutral pH, the probe is superior to the published mitochondrial-targeting fluorogens in NIR absorption (660 nm) and emission (743 nm). UV–vis spectra of TPE-Xan-In in 70% H2O at different pH were then detected. At acidic pH 4.0 (Figure 2d), the probe showed an absorption at 608 nm. As pH ranged from 4.0 to 8.0, the absorbance decreased at 608 nm but obviously increased at 715 nm. This is possibly due to a pH-sensitive aggregation of TPE-Xan-In at neutral pH, since the particle size of TPE-Xan-In was about 90 nm at pH 7.0, but smaller than 5 nm at pH 4.0 (Figure S8). Then we hypothesized that the pH-dependent AIE properties might be caused by a switch of phenolate to phenolic form under different pH values (Figure S10).16 To prove this hypothesis, we recorded fluorescence intensity of TPE-Xan-In under different pH values (Figure S11-a) and calculated its pKa value according to the Henderson-Hasselbach equation: log[(Fmax – F)/(F – Fmin)] + pH = pKa. As illustrated

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in Figure S11-b, the pKa value of 6.20 was derived as the X-intercept from the plot. Therefore, it is reasonable that the probe is in a phenolate form at pH < 6.0 and hardly aggregates. When the pH is above 6.0, especially > 7.0, a phenolic form with lower solubility is generated and AIE response is activated as a result.

Figure 2. Aggregated-induced emission (AIE) evaluation and UV–vis spectra of TPE-Xan-In (10 μM) at different pH values (λex = 660 nm). a) Fluorescence emission spectra of TPE-Xan-In with different H2O/THF ratio at pH 4.0. b) Fluorescence emission spectra of TPE-Xan-In with different H2O/THF ratio at pH 7.0. c) Fluorescence emission spectra of TPE-Xan-In in H2O/THF (v/v = 70:30) with different pH. d) UV−vis absorption spectra of TPE-Xan-In in H2O/THF (v/v = 70:30) with different pH.

3.2. Application of TPE-Xan-In in Long-term Tracking of Mitochondria Before applying TPE-Xan-In for mitochondria imaging, we assessed the cytotoxicity of the probe on HeLa cells by a standard cell viability protocol (MTT assay). The cells were treated by different concentration of TPE-Xan-In for 48 h, and still highly

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viable (>85%) at a concentration up to 100 μM (Figure S12), which demonstrated a good biocompatibility of TPE-Xan-In.

Figure 3. Mitochondria imaging by TPE-Xan-In. a) Confocal laser scanning microscopy images for HeLa cells incubated with MitoTracker Green (MTG, 0.05 μM, green channel, λex = 488 nm) and TPE-Xan-In (2.5 μM, red channel, λex = 633 nm) at pH 7.0. b) Fluorescence intensity relationship between the two channels on the green line (Scale bar = 10 μm).

We then evaluated the organelle tracking of TPE-Xan-In by confocal laser scanning microscopy imaging and compared results with commercially available mitochondria tracker, MitoTracker Green (MTG) and lysosome tracker, LysoTracker Red. Being an AIE luminogen, TPE-Xan-In was allowed to use at a high concentration (2.5 μM). As shown in Figure 3a, a significant fluorescent emission of TPE-Xan-In was observed and overlapped well with that of MTG (Pearson Correlation Coefficient = 0.9012, Figure S13). On the contrary, it hardly merged with that of LysoTracker Red (Figure S14). These data suggested that TPE-Xan-In was able to illuminate mitochondria specifically. Next, we explored the role of plasma and mitochondrial membrane potential on the mitochondrial targeting of the probe. HeLa cells were pre-incubated with media

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containing 150 mM KCl or 1 μM FCCP, where K+ was used to decrease the plasma potential and FCCP was a chemical inhibitor of oxidative phosphorylation to reduce the mitochondrial membrane potential. Subsequent confocal fluorescence images demonstrated that both treatments would not influence the mitochondrial imaging (Figure S15). This is probably owed to the enhanced lipophilicity of TPE-Xan-In with four phenyl rings and a xanthene core.17 Compared with fluorescent cationic probes

(Rhodamine

123

and

JC-1)

and

AIE

luminogens

bearing

triphenylphosphonium (TPP) groups,18–20 TPE-Xan-In proves to be highly tolerant of mitochondrial potential change and is helpful in tracing dynamic morphology changes of mitochondria induced by FCCP. As shown in Figure S16, once added with FCCP, mitochondria immediately transformed from reticulum to dispersed fragments within 66 s.

Figure 4. Photostability evaluation of TPE-Xan-In in long-term tracking of mitochondria in living cells. a) Fluorescence images of HeLa cells stained with TPE-Xan-In (red channel) and MTG (green channel) at different scanning intervals (Scale bar = 75 μm). b) Fluorescence intensity decrease of HeLa cells stained with TPE-Xan-In and MTG at different scanning intervals, where I0 is the initial fluorescence intensity of the

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stained cells and I is the fluorescence intensity of the stained cells at specific scanning time points (n = 6).

Subsequently, we studied the photostability of the mitochondrial imaging by scanning the stained HeLa cells for different times (Figure 4a). After 25 scans within 355 s, the intensity loss of TPE-Xan-In was about 15%, much less than 50% for MTG group (Figure 4b). When the stained cells were further cultured, the fluorescence of TPE-Xan-In was still emissive, even for the fourth passage (Figure 5). In contrast, there was almost no fluorescence emission of MTG after two passages (Figure S17). Then we examined the photostability of the second passage of HeLa cells stained with TPE-Xan-In. After 50 scans within 10 min, the FL intensity loss of TPE-Xan-In and MTG staining was about 40% and 80%, respectively (Figure S18). These results demonstrated that TPE-Xan-In would be a potential candidate for long-term mitochondria imaging because of photooxidation resistance by the aggregated TPE-Xan-In.18

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Figure 5. Fluorescent images of HeLa cells stained with TPE-Xan-In (2.5 μM, red channel, λex = 633 nm, λem = 660–800 nm) and MTG (0.05 μM, green channel, λex = 488 nm, λem = 510–570 nm), and cultured for different cell passages (Scale bar = 50 μm).

3.3. pH-Sensitive Mitochondria Imaging by TPE-Xan-In To evaluate mitochondria imaging at different pH values, we first studied the influence of cell viability on the fluorescent emission of TPE-Xan-In by fixing the stained HeLa cells with 4% paraformaldehyde for 2 h. As indicated in Figure S19, a bright emission of TPE-Xan-In was observed, which means that the probe could locate well in the fixed cells. After that, we incubated live HeLa cells with TPE-Xan-In and MTG, then adjusted intracellular pH to be 4.0–7.0. Confocal fluorescence images (Figure 6) showed that at pH 4.0, there was little emission of TPE-Xan-In. As pH value increased, the fluorescence emission became more and 14


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more significant, and the FL intensity increased accordingly (Figure S20), while there was little response for MTG group. These results demonstrated a pH-dependent mitochondria imaging by TPE-Xan-In, and confirmed that the probe could be utilized to study the relationship of mitochondria morphology with intercellular pH changes (Table S1).

Figure 6. Fluorescence images of HeLa cells incubated with 2.5 μM TPE-Xan-In and 0.05 μM MTG solutions with different pH values containing 5 μg mL–1 nigericin (Scale bar = 60 μm).

4. CONCLUSION Here

we

reported

the

synthesis

and

application

of

a

novel

mitochondrial-targeted NIR fluorescent probe, TPE-Xan-In. The NIR probe could specifically illuminate mitochondria with good biocompatibility,

15



superior photostability and high tolerance to mitochondrial membrane potential changing. Moreover, TPE-Xan-In held a pH-sensitive FL emission feature in tracing mitochondria, which offers a potential fluorescent indicator to visualize morphology and pH of mitochondria.

ASSOCIATED CONTENT Supporting Information Characterization of compound 1 and TPE-Xan-In; AIE properties of TPE-Xan-In; pKa Measurement of TPE-Xan-In; Biocompatibility test of TPE-Xan-In; Lysosome imaging by the probe; Effect of mitochondria membrane potential on the imaging; More images for photostability evaluation and pH-dependent mitochondria tracking by TPE-Xan-In. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] *E-mail: [email protected] ORCID Dan Ding: 0000-0003-1873-6510 Yongmei Yin: 0000-0002-5172-6632 Meng Meng: 0000-0002-9715-6292 Notes 16


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The authors declare no competing financial interest. ACKNOWLEDGMENT This work was supported by the National Natural Science Foundation of China (No. 81573390) and the Natural Science Foundation of China of Tianjin City (No. 18JCYBJC24800).

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