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A multifunctional quinoxalin-based AIEgen used for fluorescent thermo-sensing and image-guided photodynamic therapy
Sensors & Actuators: B. Chemical 301 (2019) 127139
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Sensors and Actuators B: Chemical journal homepage: www.elsevier.com/locate/snb
A multifunctional quinoxalin-based AIEgen used for fluorescent thermosensing and image-guided photodynamic therapy
T
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Yuanyuan Lia,1, Qiuchen Penga,b,c, ,1, Shijun Lib,1, Yuchen Caid, Bin Zhangb, Kai Sunb, ⁎ ⁎ Junbao Mab, Cuiping Yangb, Hongwei Houb, Huifang Suc,d, , Kai Lib, a
School of Chemistry and Chemical Engineering, Henan University of Technology, Henan, 450001, PR China College of Chemistry and Molecular Engineering, Zhengzhou University, Henan, 450001, PR China c Department of Osteology, The First Affiliated Hospital of Zhengzhou University, Henan, 450001, PR China d Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, PR China b
A R T I C LE I N FO
A B S T R A C T
Keywords: Aggregation-induced emission D-π-A structure Fluorescent thermometer Lipid droplet imaging Photodynamic therapy
Luminogens with aggregation-induced emission (AIE) characteristic drew extraordinary attention owing to their excellent luminescence properties in aggregated state or solid state, which showed wide application prospect in chemical sensing, bioimaging, lighting material and display material. In this work, a novel AIE molecule of (2,3bis(4-(dimethylamino)phenyl)quinoxalin-6-yl)(phenyl)methanone (designated as LD-red) was facilely synthesized through a single-step reaction with commercially available materials. Based on its intrinsic twisted intramolecular charge transfer (TICT) characteristic, LD-red was successfully utilized as a reversible fluorescent thermometer. More importantly, LD-red exhibited good biocompatibility, which not only can be used as a probe for lipid droplets-specific imaging, but also can work as a promising photosensitizer to kill cancer cells through generation of reactive oxygen species (ROS) upon white light irradiation. LD-red enriches the kinds of AIEgens and, more importantly, this work provides a new strategy for constructing multifunctional AIEgen with TICT characteristic.
1. Introduction Because of the strong luminescence properties in aggregated state and solid state, aggregation-induced emission luminogens (AIEgens) have been widely used in the fields of chemosensors, process visualization, lighting devices, bio-imaging, diagnosis and therapy [1–12]. After nearly 20 years of development, thousands of AIEgens have been developed, which exhibited diverse chemical/physical characteristics [13–18]. Among these AIEgens, the ones with twisted intramolecular charge transfer (TICT) characteristic have attracted extraordinary attention due to their intrinsic electroactivity and photoactivity, which are beneficial for the applications in biochemical fluorescent technology, organic light-emitting diodes (OLEDs), and environmentally sensitive fluorescent chemosensors [19–26]. Unfortunately, it was usually costly to get AIEgens with TICT characteristics since large molecule structures and complicated synthesis processes are seemingly inescapable [27–33]. On one hand, AIEgens usually possess propellerlike structure, whose π-conjugated moieties are connected by rotatable
single bonds [34–36]; On the other hand, rotatable D-π-A structure, in which electron donors (D) and accepters (A) groups are connected via π-conjugated linkers with rotatable single bonds, is indispensable in the molecule with TICT characteristic [37–39]. These intricate structures make it difficult to get a molecule with all these features through facilely synthesis process. Therefore, development of multifunctional AIEgens with TICT characteristics and facilely synthesis process is still highly needed and challenging. In this work, a novel AIE molecule of (2,3-bis(4-(dimethylamino) phenyl)quinoxalin-6-yl)(phenyl)methanone designated as LD-red was facilely synthesized through a single-step reaction with commercially available materials (Scheme 1). LD-red showed propeller-like structure with a maximum α-AIE value of 35. In addition, the D-π-A structure endows LD-red with TICT characteristic, which makes it suitable to be used as a reversible fluorescent thermometer. In THF, LD-red showed proportional temperature-dependent emission from 10 °C to 60 °C with excellent fatigue resistance. More importantly, LD-red exhibited good biocompatibility and lipid droplets (LDs)-specific imaging property.
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Corresponding authors. E-mail addresses: [email protected] (Q. Peng), [email protected] (H. Su), [email protected] (K. Li). 1 These authors contributed equally to this work. https://doi.org/10.1016/j.snb.2019.127139 Received 8 August 2019; Received in revised form 29 August 2019; Accepted 11 September 2019 Available online 13 September 2019 0925-4005/ © 2019 Elsevier B.V. All rights reserved.
Sensors & Actuators: B. Chemical 301 (2019) 127139
Y. Li, et al.
(t, J =1.1 Hz, 1 H), 8.18 (d, J =1.2 Hz, 2 H), 7.95-7.87 (m, 2 H), 7.687.58 (m, 3 H), 7.53 (dd, J = 10.0, 5.2 Hz, 4 H), 6.70 (dd, J = 8.6, 3.0 Hz, 4 H), 3.03 (d, J =6.5 Hz, 12 H). 13C NMR (400 MHz, CD3Cl) δ (ppm): 40.25, 40.28, 111.67, 111.77, 128.44, 128.69, 129.22, 130.13, 130.82, 131.09, 132.36, 132.54, 137.01, 137.61, 139.75, 142.90, 150.86, 150.99, 154.67, 155.21, 196.14. HRMS spectrometry: m/z calcd for [C31H28N4O + H]+: 473.2336; found: 473.2315. Scheme 1. Synthetic route to LD-red.
2.4. DFT and TD-DFT calculation Meanwhile, the D-π-A structure renders LD-red a small energy gap between the lowest singlet excited state and triplet excited state, which could facilitate the intersystem crossing for efficient photosensitization. Based on these characteristics, LD-red was successfully used in imageguided photodynamic therapy (PDT). LD-red enriches the kinds of AIEgens and, more importantly, this work provides a new strategy for constructing multifunctional AIEgen with TICT characteristic.
All the theoretical calculations in the study were performed using Gaussian16 program package. The geometries were optimized with the M06-2X density functional and the 6-31 G (d,p) basis set. Then TD-DFT study was conducted at same level within the adiabatic approximation to predict the excitation energies. Furthermore, the calculation for locating the excited state structure of LD-red has also been performed in order to account for the fluorescence properties.
2. Experimental section
2.5. Cell imaging and confocal colocalization
2.1. Reagents
HeLa cells were grown in a Petri dish (35 mm) with a coverslip at 37 °C. The live cells were incubated with 10 μmol/L LD-red or BODIPY493/503 Green for 10 min. Then the dye-labelled HeLa cells were mounted and imaged using a laser scanning confocal microscope. The wavelength of the laser was 488 nm and the emission signal in the range of 550–600 nm was collected for cell imaging.
Unless otherwise stated, all commercially available reagents and solvents of analytical grade were used as received in this work. 4,4’-bis (dimethylamino)benzil and 3,4-diaminobenzophenone were purchased from Energy Chemical Co., Shanghai, China. BODIPY493/503 Green was purchased from J&K Chemical Co., Beijing, China. DCFH-DA was purchased from Sigma-Aldrich Chemical Co., Shanghai, China. Other reagents such as organic solvents and metal salts are purchased from Sinopharm Chemical Reagent Beijing Co., Beijing, China.
2.6. Reactive oxygen species (ROS) generation DCFH-DA was used as an indicator ROS generation. A white light with the optical power density of 5 mW/cm2 was employed as the irradiation source. In the experiments, 10 μmol/L of LD-red, 5 μmol/L of DCFH-DA and a mixture of 10 μmol/L of LD-red and 5 μmol/L of DCFHDA were irradiated by white light, and the emission at 534 nm was recorded at various irradiation periods.
2.2. Apparatus Fluorescence spectra were recorded on a JASCO FP-8300 spectrometer with 1 cm quartz cell. etc-815 peltier thermostatted single cell holder was used to control the temperature of fluorescence measurements, which offered a temperature control accuracy of ± 0.1 °C. Absorption spectra were recorded on a JASCO V-750 UV–vis spectrometer with 1 cm quartz cell. Dynamic light scattering (DLS) experiments were performed on a NanoPlus-3 dynamic light scattering particle size/zeta potential analyzer at room temperature. X-ray single crystal diffraction data was collected by a Rigaku Saturn 724 CCD diffractometer with Mo Kα radiation (λ =0.71073 Å) at room temperature. Thermogravimetry analysis was conducted on a SHIMADZU TGAQ50 thermogravimetric analyzer from room temperature to 400 °C at a heating rate of 10 °C/min under N2 atmosphere. pH values of the solutions were determined by a Mettler Toledo FE20/EL20 pH meter. Nuclear magnetic resonance (NMR) spectra were detected on a Bruker 400 Avance NMR spectrometer. Electrospray ionization mass spectrometry (ESI-MS) was conducted on an Agilent Technologies 6420 triple quadruopole LC/MS apparatus without using the LC part. Laser confocal scanning microscopy images were collected on a Zeiss laser scanning confocal microscope (LSM7 DUO) and analyzed using ZEN 2009 software (Carl Zeiss). The photographs were taken by a Nikon D5500 camera.
2.7. Cytotoxicity study MTT assays were used to evaluate the cytotoxicity of LD-red. HeLa cells were seeded in 96-well plates with a density of 6000–8000 cells per well. After growing overnight, the medium in each well was replaced with 100 mL fresh medium containing different concentrations of LD-red. 24 h later, 10 mL MTT solution (5 mg/mL in PBS) was added into each well. After incubation for another 4 h, the absorption of each well at 595 nm was recorded via a Perkin-Elmer Victor3™ plate reader. 2.8. PDT study For PDT study, HeLa cells were seeded in 96-well plates with a density of 6000–8000 cells per well. After growing overnight, the medium in each well was replaced with 100 mL fresh medium containing different concentrations of LD-red. After incubation for 5 min, the plates containing HeLa cells were exposed to white light for 10 min. Meanwhile, another array of plates with cells was kept in the dark as the control. Then the absorption of each well at 595 nm was recorded via a Perkin-Elmer Victor3™ plate reader.
2.3. Synthesis 3. Results and discussion (2,3-bis(4-(dimethylamino)phenyl)quinoxalin-6-yl)(phenyl)methanone (LD-red). 4,4′-bis(dimethylamino)benzil (5 mmol, 1.48 g) and 3,4diaminobenzophenone (5 mmol, 1.06 g) were dissolved in 10 mL acetic acid. The mixed solution was stirred and refluxed at 110 °C for 3 h. After cooling to room temperature, an orange-red precipitate was obtained. The precipitate was suction filtered and washed with 10 mL acetic acid. After drying in a vacuum oven for 12 h, orange-yellow powder was obtained (1.94 g, yield 82%). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.45
3.1. Synthesis of LD-red LD-red was readily synthesized with good yield (82%) by the coupling of 4,4’-bis(dimethylamino)benzil and 3,4-diaminobenzophenone in glacial acetic acid (Scheme 1). The structure of LD-red was characterized by NMR, HRMS and X-ray single crystal diffraction analysis. Detailed synthetic procedures and characterization data can be found in 2
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Fig. 1. A) Fluorescence photographs taken under an irradiation of UV light. B) Fluorescence spectra of LD-red in H2O/EtOH mixtures with different fw. C) Fluorescence intensity of LD-red at 580 nm as a function of fw. Inset: photographs of LD-red in solid state excited by day light and UV light. The concentration of LDred was 10 μmol/L.
S2, LD-red exhibits typical propeller-like structure, whose conjugate planes are connected by rotatable CeC single bonds and extend in different directions. Meanwhile, the minimum distance between the adjacent conjugate planes was 5.14 Å, suggesting that there was no π-π staking interaction in the crystal (normally, the necessary condition for π-π staking interaction is that the distance between the adjacent conjugate planes should be smaller than 3.8 Å) [43,44]. All of these structural features suggested that the AIE character of LD-red could be originated from the restricted intramolecular rotation (RIR) process [45]. Specifically, when LD-red was in dispersed state, the conjugate planes undergo dynamic intramolecular rotations, resulting in excited state non-radiative transitions and fluorescence quenching. In contrast, when LD-red was in aggregated state, the rotations of conjugate planes are limited effectively. Then the radiative transition became the primary pathway for the excited state electrons back to the ground state, resulting in intense fluorescence emission. Meanwhile, the propellerlike structure effectively avoided the fluorescence quenching originated from π-π staking interaction.
ESI. 3.2. AIE characteristic of LD-red The fluorescence characteristic of compound LD-red was first investigated in mixed solvents of H2O/EtOH. As shown in Fig. 1A, compound LD-red exhibited almost no fluorescence in H2O/EtOH mixtures with water fraction (fw) lower than 70%. When fw was higher than 70%, intense orange-red emission could be observed. This emission was highly similar to that of LD-red in solid state (Fig. S1), which suggested that the emission enhancement of LD-red in the mixed solvents with high fw might be originated from its aggregated state, i.e., an AIE emission. The maximum αAIE value was as high as 35 (αAIE = I/I0, I is emission intensity in aggregated state, I0 is emission intensity in EtOH) [40]. The quantum yield data of LD-red in solution, aggregates, and solid state was 0.51%, 18.72% and 13.95%, respectively. The aggregation of LD-red was supported by absorption spectra and dynamic light scattering (DLS) measurements (Fig. 2). In pure EtOH, LD-red showed no level-off tail in the visible region in absorption spectrum. On the contrary, strong level-off tails was observed in the visible region in 90% H2O/EtOH (v/v) solution, which could be attributed to the light scattering of the aggregated suspensions [41,42]. Furthermore, DLS results confirmed that there were nano-particles with diameter around 1000 nm in 90% H2O/EtOH (v/v) solution while no particles can be observed in pure EtOH. To understand the origin of the AIE character of LD-red, its crystal structure was further investigated. Single crystal of LD-Red was obtained from methanol/THF mixture by a slow solvent evaporation method. The crystal was characterized by X-ray crystallography and its crystallographic data can be found in Table S1. As shown in Figs. 3 and
3.3. TICT characteristic of LD-red It was noticed that there are electron donors (N, N-dimethylaminophenyl) and electron accepter (carbonyl) in LD-red molecule, which are connected by a π-conjugated linker (quinoxalin) with rotatable CeC single bonds (Fig. 4A). This means that there is a rotatable D-π-A structure in LD-red, suggesting that LD-red might exhibit TICT characteristic. According to literature, luminogens with TICT characteristic possess two excited states (Fig. 4B) [46]. One excited state is locally excited (LE) state, which is the excited singlet state produced by light absorption. In LE state, the donor and acceptor in the excited luminogen 3
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Fig. 2. Absorption spectra of LD-red in H2O/EtOH mixtures with different fw. DLS results of LD-red in 90% H2O/EtOH (v/v). The concentration of LD-red was 10 μmol/L.
3.4. The application of LD-red as fluorescent thermometer The above results indicate that the emission of LD-red can be precisely regulated by the polarity of solvents. Normally, the polarity of solvent was dependent on temperature. Because higher temperature will lead to more active molecular motion, apparent solvent polarity will decrease, which accordingly decreased the transition probability from LE state to TICT state [50,51]. Thus, LD-red shows great potential as a fluorescent thermometer due to its solvent polarity-assisted emission property. As shown in Fig. 6A, the fluorescence intensity of LD-red in THF doubled when the temperature increased from 10 °C to 60 °C. Meanwhile, a blue shift of the emission peak from 580 nm to 550 nm with distinct color change from orange to yellow was clearly observed (Fig. 6B inset). More importantly, the emission intensity of LD-red at 580 nm increased linearly with the increase of temperature, which provided a prominent positive linear relationship with a correlation coefficient (R2) of 0.998 (n = 3). Similarly, the emission intensity of LD-red in 1,4-dioxane also increased linearly with the increase of temperature (Fig. S3), which afforded an excellent positive linear relationship with a correlation coefficient (R2) of 0.999 (n = 3). The heat stability and fatigue resistance are important indicators for the practicability of a fluorescent thermometer. As shown in Fig. S4, thermogravimetric analysis (TGA) results showed that the heat stability of LDred was excellent under 350 °C. To evaluate the fatigue resistance, LDred was toggled repeatedly between the two temperatures of 10 °C and 60 °C in THF for ten times. The emission intensity at 580 nm remained almost constant without any apparent degradation (Fig. 6C). These results suggested that LD-red can be used as a reversible fluorescent thermometer with a positive temperature coefficient.
Fig. 3. Crystal structure of LD-red.
tend to be coplanar. The other excited state is TICT state, which has a more twisted structure with a charge separation between donor and acceptor moieties. LE state is in equilibrium with solvent molecules in nonpolar solvents. It can transform to TICT state by intramolecular rotation of its donor and acceptor units when the luminogen is in polar solvents. Normally, because of the charge separation, the TICT state produces more bathochromic shifted emission when back to ground state than LE state. Therefore, luminogen with TICT characteristic usually exhibits solvent polarity-assisted emission property [47,48]. To confirm its TICT characteristic, fluorescence spectra of LD-red in solvents with different polarities were systematically investigated. As shown in Fig. 4C, LD-red exhibited various colors from blue to orange in different solvents. The emission peak in the fluorescence spectra showed corresponding movements from 474 nm to 581 nm along with the increase of polarity of solvents. In high-polar solvents such as acetonitrile, acetone, methanol, etc., the fluorescence of LD-red was too weak to be observed (Fig. 4D). The polarity function (Δf ) of solvents was further adjusted continuously by mixing THF with toluene. The absorption maxima, fluorescence maxima and Stokes shift (Δυ¯ ) in THF/ toluene mixtures were measured and shown in Table S2. As shown in Fig. 5, Δ υ¯ and Δf can be fitted well with Lippert-Mataga plot:
Δυ¯ = Δυ¯0 +
2(μe − μg )2 hcr 3
Δf
3.5. The application of LD-red in image-guided PDT To further understand the luminescence mechanism of LD-red in aggregated state, density functional theory (DFT) and time dependent density functional theory (TD-DFT) calculations were carried out using the Gaussian16 program package. It is known that introducing D-A structures to AIEgens could reduce HOMO-LUMO overlap, leading to small energy gap (ΔEst) between the lowest singlet excited state (S1) and triplet excited state (T1) [52]. As shown in Fig. 7A, the highest occupied molecular orbital (HOMO) of LD-red is mostly positioned on its electron donor moieties while the lowest unoccupied molecular orbital (LUMO) is mainly located on its electron accepter moieties. These distinct charge distributions in LD-red enable it to undergo a typical TICT process, which is in accordance with the reported TICT luminogens [53–55]. More importantly, ΔEst of LD-red was calculated as 0.59 eV, which could facilitate the intersystem crossing for efficient
(1)
In Eq. 1, Δυ¯0 is the Stokes shift of the fluorophore in non-polar solvent, h is Plank’s constant, c is the velocity of light, r is the radius of the Onsager cavity around the fluorophore, μe and μg is excited state dipole moment and ground state dipole moment, respectively [49].
4
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Fig. 4. A) The rotatable D-π-A structure in LD-red. B) Energy diagram of TICT process. C) Fluorescence photographs taken under an irradiation of UV light. D) Fluorescence spectra of LD-red in different solvents. The concentration of LD-red was 10 μmol/L.
reconstructed with LD-red. As shown in Fig. 9 and Video 1, fluorescence was barely observed out of the HeLa cells after 30 min incubation, suggesting an excellent cell permeability of LD-red. The long-term cell tracing property of LD-red was also investigated. As shown in Fig. S5, after continuous cell culture for one week, the fluorescence profile from LDs can be still clearly distinguished, suggesting a good stability of LD-red in live cells. Apart from a LDs probe, LD-red is also a promising photosensitizer for PDT due to its TICT characteristic. The generation of ROS by LD-red upon white light irradiation was investigated (Fig. 10). The ROS generation efficiency of LD-red was determined using DCFH-DA as a ROS indicator, which emits green fluorescence in presence of ROS [61–63]. As shown in Fig. 10A, the fluorescence of DCFH-DA with LD-red was gradually enhanced along with the irradiation time. After 10 min
photosensitization (Fig. 7B). Meanwhile, this feature is beneficial to produce ROS, which could effectively kill cancer cells [56,57]. Thus, the photodynamic therapy property of LD-red was carefully investigated. Firstly, the bioimaging properties of LD-red in live cells were investigated by confocal laser scanning microscopy. After incubation in live HeLa cells with LD-red for 30 min, bright fluorescence from the droplet structures in cytoplasm could be clearly observed, which is a typical morphology for LDs (Fig. 8). To confirm that LD-red was located in LDs, costain experiment was carried out with BODIPY493/503 Green, which is a commercially available dye for LDs-staining [58–60]. As shown in Fig. 8C, the emission signal of LD-red displayed excellent overlap with that of BODIPY493/503 Green (co-localization coefficient was 93%). Furthermore, 3D fluorescent images were successfully
Fig. 5. A) Normalized fluorescence spectra of LD-red in THF/toluene with different THF fraction (fTHF). B) Lippert-Mataga plot of LD-red. The concentration of LDred was 10 μmol/L. 5
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Fig. 6. A) Temperature-dependent fluorescence spectra of LD-red in THF. B) Emission intensity of LD-red in THF at 580 nm as a function of temperature and the associated best-fit equations. C) Fatigue resistance of the fluorescence intensity of LD-red during ten heating/cooling cycles in THF. The concentration of LD-red was 10 μmol/L.
Fig. 7. A) The Frontier molecular orbitals of LD-red obtained via DFT calculations. The value of the contour envelopes is 0.03 au. B) A simplified Jablonski diagram to show the production of ROS. 6
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Fig. 8. Colocalization imaging of HeLa cells stained with A) 1 μmol/L LD-red and B) 0.1 μmol/L BODIPY493/503 Green. C) Merged image of panels A) and B). D) Brightfield image. The concentration of LD-red was 1 μmol/L.
Fig. 9. Reconstructed 3D fluorescent microscopic images of live HeLa cells stained with 1 μmol/L LD-red for 30 min.
irradiation, the fluorescence intensity was 191-fold higher than that of the unirradiated one. On the contrary, there was barely emission change for DCFH-DA or LD-red alone. These results indicated that LDred is an efficient photosensitizer for ROS generation. Because excessive amount of ROS are detrimental to live cells, the PDT application of LD-red was further explored on HeLa cells by a standard CCK-8 (Cell Counting Kit-8) assay. Killing efficiency of LD-red was determined in both the absence and presence of white light irradiation (Fig. 10B). The
dose-dependent toxicity results suggested that LD-red exhibited low cytotoxicity under dark conditions. In contrast, under white light irradiation, the viability of HeLa cells dropped rapidly to 12.8% with a concentration of 1 μmol/L. When the concentration of LD-red was higher than 2 μmol/L, the cells can be killed nearly completely under white light irradiation. While 85% viability was maintained in the cells incubated with 2 μmol/L of LD-red under dark conditions. These results demonstrated that LD-red can be used for image-guided PDT. 7
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Fig. 10. A) Fluorescence intensity changes at 534 nm of DCFH-DA, LD-red, mixtures of DCFH-DA and LD-red in PBS upon white light irradiation for different times. Concentrations: 10 μmol/L (LD-red) and 5 μmol/L (DCFH-DA). Light power: 5 mW/cm2. B) Viability of HeLa cells stained with different concentrations of LD-red in the presence or absence of white light irradiation for 10 min. Light power: 5 mW/cm2.
4. Conclusions
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In summary, a novel multifunctional AIEgen of LD-red was facilely synthesized through a single-step reaction with high yield. The maximum αAIE value of LD-red was calculated as 35. The D-π-A structure endows LD-red with typical TICT characteristic, which makes it suitable for temperature sensing and image-guide PDT. As a fluorescent thermometer, LD-red showed proportional temperature-dependent emission from 10 °C to 60 °C with excellent fatigue resistance in THF. LD-red can exclusively target LDs in live cells. As a photosensitizer, LDred exhibited good biocompatibility, low toxicity for live cells in dark while effective ROS generation upon white light irradiation. LD-red enriches the kinds of AIEgens and, more importantly, this work provides a new strategy for constructing multifunctional AIEgen with TICT characteristic. Declaration of Competing Interest There are no conflicts to declare. Acknowledgements This work was supported by the National Natural Science Foundation of China (21501150, 51502079, 81902356 and 21601156), the Training Program for Young Backbone Teachers of Henan University of Technology, the Science and Technology Key Project of Henan Education Department (18A150026), the Open Foundation of Guangxi Key Laboratory of Processing for Non-ferrous Metals and Featured Materials, Guangxi University (2019GXYSOF12), the Joint Coconstruction Research Project of Henan Medical Science and Technology Research Plan (2018020025). Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.snb.2019.127139. References [1] Y. Cheng, J. Wang, Z. Qiu, X. Zheng, N.L.C. Leung, J.W.Y. Lam, B.Z. Tang, Multiscale humidity visualization by environmentally sensitive fluorescent molecular rotors, Adv. Mater. 29 (2017) 1703900. [2] K. Li, J. Wang, Y. Li, Y. Si, J. He, X. Meng, H. Hou, B.Z. Tang, Combining two different strategies to overcome the aggregation caused quenching effect in the design of ratiometric fluorescence chemodosimeters for pH sensing, Sens. Actuators B Chem. 274 (2018) 654–661. [3] J. Qian, B.Z. Tang, AIE luminogens for bioimaging and theranostics: from organelles to animals, Chemistry 3 (2017) 56–91. [4] J. Yang, B. Yang, G. Wen, B. Liu, Dual sites fluorescence probe for H2S and Hg2+ with “AIE transformers” function, Sens. Actuators B Chem. 296 (2019). [5] Y. Cheng, J. Dai, C. Sun, R. Liu, T. Zhai, X. Lou, F. Xia, An intracellular H2O2responsive AIEgen for the peroxidase-mediated selective imaging and inhibition of
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Dr. Yuanyuan Li received her B.Sc. in the School of Materials, Wuhan University of Technology in 2009. She obtained her Ph.D. degree from the Department of Chemistry, Tsinghua University in 2014. Then, she joined the School of Chemistry and Chemical Engineering, Henan University of Technology as associate professor. Her research interests are focused on the detection of food safety and small molecular fluorescence probe. Qiucheng Peng received his B.Sc. in the School of Chemistry and Chemical Engineering, Henan University of Technology in 2018. He is a master candidate in the College of Chemistry and Molecular Engineering, Zhengzhou University. His research interests are aggregation-induced emission material and fluorescence probe. Dr. Shijun Li received his B.Sc. in the College of Chemistry and Molecular Engineering, Zhengzhou University in 2013. Then, he obtained his Ph.D. degree in 2018 from Beijing Normal University. Currently, he is a postdoctoral fellow at College of Chemistry and Molecular Engineering, Zhengzhou University. His research direction is theoretical and computational chemistry. Dr. Yuchen Cai received her B.Sc. in the School of Medicine, Sun Yat-Sen University in 1999. She obtained her Ph.D. degree from Sun Yat-Sen University Cancer Center in 2009. Then, she joined Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine as associate professor. Her current research interests are Cancer prevention. Dr. Bin Zhang received his B.Sc. and Ph.D. in the College of Chemistry and Molecular Engineering, Zhengzhou University in 2008 and 2014. Then he joined the College of Chemistry and Molecular Engineering, Zhengzhou University as associate professor. His research direction is organometallic photoelectric functional material Kai Sun received his B.Sc. in the College of Chemistry and Molecular Engineering, Zhengzhou University in 2013. He obtained his master degree in 2016 from the College of Chemistry and Molecular Engineering, Zhengzhou University. He is a doctoral candidate in the College of Chemistry and Molecular Engineering, Zhengzhou University. His research interests are organic synthesis methodology and aggregation-induced emission material. Junbao Ma received his B.Sc. in the College of Chemistry and Molecular Engineering, Zhengzhou University in 2019. His research interests are aggregation-induced emission material and fluorescence probe. Cuiping Yang received her B.Sc. in the College of Material and Chemical Engineering from Henan University of Engineering in 2015. She is a master candidate in the College of Chemistry and Molecular Engineering, Zhengzhou University. Her research interests are aggregation-induced emission material and fluorescence probe.
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received Ph.D in Sun Yat-Sen University Cancer Center in 2017. His current research interests are cancer prevention and aggregation-induced emission material.
Dr. Hongwei Hou received his Ph.D. degree from Nanjing University in 1995. He began the postdoctoral research at Hong Kong University of Science and Technology and the National University of Singapore from 1995 to 1998. At the end of 1999, he joined Zhengzhou University as a professor. His research interests are the crystalline centralmetal transformation and the nonlinear optical properties of the coordination compounds.
Dr. Kai Li received his B.Sc. and Ph.D. in Analytical Chemistry from Tsinghua University in 2008 and 2014, respectively. Then he joined the College of Chemistry and Molecular Engineering, Zhengzhou University as associate professor. His current research interests are focused on the photochromic material, aggregation-induced emission material and small molecular fluorescence probe.
Dr. Huifang Su received his B.Sc. in the Chengde Medical College in 2010. He obtained his master degree in 2012 from School of Medicine, Sun Yat-Sen University. Then, he
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Sensors and Actuators B: Chemical journal homepage: www.elsevier.com/locate/snb
A multifunctional quinoxalin-based AIEgen used for fluorescent thermosensing and image-guided photodynamic therapy
T
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Yuanyuan Lia,1, Qiuchen Penga,b,c, ,1, Shijun Lib,1, Yuchen Caid, Bin Zhangb, Kai Sunb, ⁎ ⁎ Junbao Mab, Cuiping Yangb, Hongwei Houb, Huifang Suc,d, , Kai Lib, a
School of Chemistry and Chemical Engineering, Henan University of Technology, Henan, 450001, PR China College of Chemistry and Molecular Engineering, Zhengzhou University, Henan, 450001, PR China c Department of Osteology, The First Affiliated Hospital of Zhengzhou University, Henan, 450001, PR China d Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, PR China b
A R T I C LE I N FO
A B S T R A C T
Keywords: Aggregation-induced emission D-π-A structure Fluorescent thermometer Lipid droplet imaging Photodynamic therapy
Luminogens with aggregation-induced emission (AIE) characteristic drew extraordinary attention owing to their excellent luminescence properties in aggregated state or solid state, which showed wide application prospect in chemical sensing, bioimaging, lighting material and display material. In this work, a novel AIE molecule of (2,3bis(4-(dimethylamino)phenyl)quinoxalin-6-yl)(phenyl)methanone (designated as LD-red) was facilely synthesized through a single-step reaction with commercially available materials. Based on its intrinsic twisted intramolecular charge transfer (TICT) characteristic, LD-red was successfully utilized as a reversible fluorescent thermometer. More importantly, LD-red exhibited good biocompatibility, which not only can be used as a probe for lipid droplets-specific imaging, but also can work as a promising photosensitizer to kill cancer cells through generation of reactive oxygen species (ROS) upon white light irradiation. LD-red enriches the kinds of AIEgens and, more importantly, this work provides a new strategy for constructing multifunctional AIEgen with TICT characteristic.
1. Introduction Because of the strong luminescence properties in aggregated state and solid state, aggregation-induced emission luminogens (AIEgens) have been widely used in the fields of chemosensors, process visualization, lighting devices, bio-imaging, diagnosis and therapy [1–12]. After nearly 20 years of development, thousands of AIEgens have been developed, which exhibited diverse chemical/physical characteristics [13–18]. Among these AIEgens, the ones with twisted intramolecular charge transfer (TICT) characteristic have attracted extraordinary attention due to their intrinsic electroactivity and photoactivity, which are beneficial for the applications in biochemical fluorescent technology, organic light-emitting diodes (OLEDs), and environmentally sensitive fluorescent chemosensors [19–26]. Unfortunately, it was usually costly to get AIEgens with TICT characteristics since large molecule structures and complicated synthesis processes are seemingly inescapable [27–33]. On one hand, AIEgens usually possess propellerlike structure, whose π-conjugated moieties are connected by rotatable
single bonds [34–36]; On the other hand, rotatable D-π-A structure, in which electron donors (D) and accepters (A) groups are connected via π-conjugated linkers with rotatable single bonds, is indispensable in the molecule with TICT characteristic [37–39]. These intricate structures make it difficult to get a molecule with all these features through facilely synthesis process. Therefore, development of multifunctional AIEgens with TICT characteristics and facilely synthesis process is still highly needed and challenging. In this work, a novel AIE molecule of (2,3-bis(4-(dimethylamino) phenyl)quinoxalin-6-yl)(phenyl)methanone designated as LD-red was facilely synthesized through a single-step reaction with commercially available materials (Scheme 1). LD-red showed propeller-like structure with a maximum α-AIE value of 35. In addition, the D-π-A structure endows LD-red with TICT characteristic, which makes it suitable to be used as a reversible fluorescent thermometer. In THF, LD-red showed proportional temperature-dependent emission from 10 °C to 60 °C with excellent fatigue resistance. More importantly, LD-red exhibited good biocompatibility and lipid droplets (LDs)-specific imaging property.
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Corresponding authors. E-mail addresses: [email protected] (Q. Peng), [email protected] (H. Su), [email protected] (K. Li). 1 These authors contributed equally to this work. https://doi.org/10.1016/j.snb.2019.127139 Received 8 August 2019; Received in revised form 29 August 2019; Accepted 11 September 2019 Available online 13 September 2019 0925-4005/ © 2019 Elsevier B.V. All rights reserved.
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(t, J =1.1 Hz, 1 H), 8.18 (d, J =1.2 Hz, 2 H), 7.95-7.87 (m, 2 H), 7.687.58 (m, 3 H), 7.53 (dd, J = 10.0, 5.2 Hz, 4 H), 6.70 (dd, J = 8.6, 3.0 Hz, 4 H), 3.03 (d, J =6.5 Hz, 12 H). 13C NMR (400 MHz, CD3Cl) δ (ppm): 40.25, 40.28, 111.67, 111.77, 128.44, 128.69, 129.22, 130.13, 130.82, 131.09, 132.36, 132.54, 137.01, 137.61, 139.75, 142.90, 150.86, 150.99, 154.67, 155.21, 196.14. HRMS spectrometry: m/z calcd for [C31H28N4O + H]+: 473.2336; found: 473.2315. Scheme 1. Synthetic route to LD-red.
2.4. DFT and TD-DFT calculation Meanwhile, the D-π-A structure renders LD-red a small energy gap between the lowest singlet excited state and triplet excited state, which could facilitate the intersystem crossing for efficient photosensitization. Based on these characteristics, LD-red was successfully used in imageguided photodynamic therapy (PDT). LD-red enriches the kinds of AIEgens and, more importantly, this work provides a new strategy for constructing multifunctional AIEgen with TICT characteristic.
All the theoretical calculations in the study were performed using Gaussian16 program package. The geometries were optimized with the M06-2X density functional and the 6-31 G (d,p) basis set. Then TD-DFT study was conducted at same level within the adiabatic approximation to predict the excitation energies. Furthermore, the calculation for locating the excited state structure of LD-red has also been performed in order to account for the fluorescence properties.
2. Experimental section
2.5. Cell imaging and confocal colocalization
2.1. Reagents
HeLa cells were grown in a Petri dish (35 mm) with a coverslip at 37 °C. The live cells were incubated with 10 μmol/L LD-red or BODIPY493/503 Green for 10 min. Then the dye-labelled HeLa cells were mounted and imaged using a laser scanning confocal microscope. The wavelength of the laser was 488 nm and the emission signal in the range of 550–600 nm was collected for cell imaging.
Unless otherwise stated, all commercially available reagents and solvents of analytical grade were used as received in this work. 4,4’-bis (dimethylamino)benzil and 3,4-diaminobenzophenone were purchased from Energy Chemical Co., Shanghai, China. BODIPY493/503 Green was purchased from J&K Chemical Co., Beijing, China. DCFH-DA was purchased from Sigma-Aldrich Chemical Co., Shanghai, China. Other reagents such as organic solvents and metal salts are purchased from Sinopharm Chemical Reagent Beijing Co., Beijing, China.
2.6. Reactive oxygen species (ROS) generation DCFH-DA was used as an indicator ROS generation. A white light with the optical power density of 5 mW/cm2 was employed as the irradiation source. In the experiments, 10 μmol/L of LD-red, 5 μmol/L of DCFH-DA and a mixture of 10 μmol/L of LD-red and 5 μmol/L of DCFHDA were irradiated by white light, and the emission at 534 nm was recorded at various irradiation periods.
2.2. Apparatus Fluorescence spectra were recorded on a JASCO FP-8300 spectrometer with 1 cm quartz cell. etc-815 peltier thermostatted single cell holder was used to control the temperature of fluorescence measurements, which offered a temperature control accuracy of ± 0.1 °C. Absorption spectra were recorded on a JASCO V-750 UV–vis spectrometer with 1 cm quartz cell. Dynamic light scattering (DLS) experiments were performed on a NanoPlus-3 dynamic light scattering particle size/zeta potential analyzer at room temperature. X-ray single crystal diffraction data was collected by a Rigaku Saturn 724 CCD diffractometer with Mo Kα radiation (λ =0.71073 Å) at room temperature. Thermogravimetry analysis was conducted on a SHIMADZU TGAQ50 thermogravimetric analyzer from room temperature to 400 °C at a heating rate of 10 °C/min under N2 atmosphere. pH values of the solutions were determined by a Mettler Toledo FE20/EL20 pH meter. Nuclear magnetic resonance (NMR) spectra were detected on a Bruker 400 Avance NMR spectrometer. Electrospray ionization mass spectrometry (ESI-MS) was conducted on an Agilent Technologies 6420 triple quadruopole LC/MS apparatus without using the LC part. Laser confocal scanning microscopy images were collected on a Zeiss laser scanning confocal microscope (LSM7 DUO) and analyzed using ZEN 2009 software (Carl Zeiss). The photographs were taken by a Nikon D5500 camera.
2.7. Cytotoxicity study MTT assays were used to evaluate the cytotoxicity of LD-red. HeLa cells were seeded in 96-well plates with a density of 6000–8000 cells per well. After growing overnight, the medium in each well was replaced with 100 mL fresh medium containing different concentrations of LD-red. 24 h later, 10 mL MTT solution (5 mg/mL in PBS) was added into each well. After incubation for another 4 h, the absorption of each well at 595 nm was recorded via a Perkin-Elmer Victor3™ plate reader. 2.8. PDT study For PDT study, HeLa cells were seeded in 96-well plates with a density of 6000–8000 cells per well. After growing overnight, the medium in each well was replaced with 100 mL fresh medium containing different concentrations of LD-red. After incubation for 5 min, the plates containing HeLa cells were exposed to white light for 10 min. Meanwhile, another array of plates with cells was kept in the dark as the control. Then the absorption of each well at 595 nm was recorded via a Perkin-Elmer Victor3™ plate reader.
2.3. Synthesis 3. Results and discussion (2,3-bis(4-(dimethylamino)phenyl)quinoxalin-6-yl)(phenyl)methanone (LD-red). 4,4′-bis(dimethylamino)benzil (5 mmol, 1.48 g) and 3,4diaminobenzophenone (5 mmol, 1.06 g) were dissolved in 10 mL acetic acid. The mixed solution was stirred and refluxed at 110 °C for 3 h. After cooling to room temperature, an orange-red precipitate was obtained. The precipitate was suction filtered and washed with 10 mL acetic acid. After drying in a vacuum oven for 12 h, orange-yellow powder was obtained (1.94 g, yield 82%). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.45
3.1. Synthesis of LD-red LD-red was readily synthesized with good yield (82%) by the coupling of 4,4’-bis(dimethylamino)benzil and 3,4-diaminobenzophenone in glacial acetic acid (Scheme 1). The structure of LD-red was characterized by NMR, HRMS and X-ray single crystal diffraction analysis. Detailed synthetic procedures and characterization data can be found in 2
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Fig. 1. A) Fluorescence photographs taken under an irradiation of UV light. B) Fluorescence spectra of LD-red in H2O/EtOH mixtures with different fw. C) Fluorescence intensity of LD-red at 580 nm as a function of fw. Inset: photographs of LD-red in solid state excited by day light and UV light. The concentration of LDred was 10 μmol/L.
S2, LD-red exhibits typical propeller-like structure, whose conjugate planes are connected by rotatable CeC single bonds and extend in different directions. Meanwhile, the minimum distance between the adjacent conjugate planes was 5.14 Å, suggesting that there was no π-π staking interaction in the crystal (normally, the necessary condition for π-π staking interaction is that the distance between the adjacent conjugate planes should be smaller than 3.8 Å) [43,44]. All of these structural features suggested that the AIE character of LD-red could be originated from the restricted intramolecular rotation (RIR) process [45]. Specifically, when LD-red was in dispersed state, the conjugate planes undergo dynamic intramolecular rotations, resulting in excited state non-radiative transitions and fluorescence quenching. In contrast, when LD-red was in aggregated state, the rotations of conjugate planes are limited effectively. Then the radiative transition became the primary pathway for the excited state electrons back to the ground state, resulting in intense fluorescence emission. Meanwhile, the propellerlike structure effectively avoided the fluorescence quenching originated from π-π staking interaction.
ESI. 3.2. AIE characteristic of LD-red The fluorescence characteristic of compound LD-red was first investigated in mixed solvents of H2O/EtOH. As shown in Fig. 1A, compound LD-red exhibited almost no fluorescence in H2O/EtOH mixtures with water fraction (fw) lower than 70%. When fw was higher than 70%, intense orange-red emission could be observed. This emission was highly similar to that of LD-red in solid state (Fig. S1), which suggested that the emission enhancement of LD-red in the mixed solvents with high fw might be originated from its aggregated state, i.e., an AIE emission. The maximum αAIE value was as high as 35 (αAIE = I/I0, I is emission intensity in aggregated state, I0 is emission intensity in EtOH) [40]. The quantum yield data of LD-red in solution, aggregates, and solid state was 0.51%, 18.72% and 13.95%, respectively. The aggregation of LD-red was supported by absorption spectra and dynamic light scattering (DLS) measurements (Fig. 2). In pure EtOH, LD-red showed no level-off tail in the visible region in absorption spectrum. On the contrary, strong level-off tails was observed in the visible region in 90% H2O/EtOH (v/v) solution, which could be attributed to the light scattering of the aggregated suspensions [41,42]. Furthermore, DLS results confirmed that there were nano-particles with diameter around 1000 nm in 90% H2O/EtOH (v/v) solution while no particles can be observed in pure EtOH. To understand the origin of the AIE character of LD-red, its crystal structure was further investigated. Single crystal of LD-Red was obtained from methanol/THF mixture by a slow solvent evaporation method. The crystal was characterized by X-ray crystallography and its crystallographic data can be found in Table S1. As shown in Figs. 3 and
3.3. TICT characteristic of LD-red It was noticed that there are electron donors (N, N-dimethylaminophenyl) and electron accepter (carbonyl) in LD-red molecule, which are connected by a π-conjugated linker (quinoxalin) with rotatable CeC single bonds (Fig. 4A). This means that there is a rotatable D-π-A structure in LD-red, suggesting that LD-red might exhibit TICT characteristic. According to literature, luminogens with TICT characteristic possess two excited states (Fig. 4B) [46]. One excited state is locally excited (LE) state, which is the excited singlet state produced by light absorption. In LE state, the donor and acceptor in the excited luminogen 3
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Fig. 2. Absorption spectra of LD-red in H2O/EtOH mixtures with different fw. DLS results of LD-red in 90% H2O/EtOH (v/v). The concentration of LD-red was 10 μmol/L.
3.4. The application of LD-red as fluorescent thermometer The above results indicate that the emission of LD-red can be precisely regulated by the polarity of solvents. Normally, the polarity of solvent was dependent on temperature. Because higher temperature will lead to more active molecular motion, apparent solvent polarity will decrease, which accordingly decreased the transition probability from LE state to TICT state [50,51]. Thus, LD-red shows great potential as a fluorescent thermometer due to its solvent polarity-assisted emission property. As shown in Fig. 6A, the fluorescence intensity of LD-red in THF doubled when the temperature increased from 10 °C to 60 °C. Meanwhile, a blue shift of the emission peak from 580 nm to 550 nm with distinct color change from orange to yellow was clearly observed (Fig. 6B inset). More importantly, the emission intensity of LD-red at 580 nm increased linearly with the increase of temperature, which provided a prominent positive linear relationship with a correlation coefficient (R2) of 0.998 (n = 3). Similarly, the emission intensity of LD-red in 1,4-dioxane also increased linearly with the increase of temperature (Fig. S3), which afforded an excellent positive linear relationship with a correlation coefficient (R2) of 0.999 (n = 3). The heat stability and fatigue resistance are important indicators for the practicability of a fluorescent thermometer. As shown in Fig. S4, thermogravimetric analysis (TGA) results showed that the heat stability of LDred was excellent under 350 °C. To evaluate the fatigue resistance, LDred was toggled repeatedly between the two temperatures of 10 °C and 60 °C in THF for ten times. The emission intensity at 580 nm remained almost constant without any apparent degradation (Fig. 6C). These results suggested that LD-red can be used as a reversible fluorescent thermometer with a positive temperature coefficient.
Fig. 3. Crystal structure of LD-red.
tend to be coplanar. The other excited state is TICT state, which has a more twisted structure with a charge separation between donor and acceptor moieties. LE state is in equilibrium with solvent molecules in nonpolar solvents. It can transform to TICT state by intramolecular rotation of its donor and acceptor units when the luminogen is in polar solvents. Normally, because of the charge separation, the TICT state produces more bathochromic shifted emission when back to ground state than LE state. Therefore, luminogen with TICT characteristic usually exhibits solvent polarity-assisted emission property [47,48]. To confirm its TICT characteristic, fluorescence spectra of LD-red in solvents with different polarities were systematically investigated. As shown in Fig. 4C, LD-red exhibited various colors from blue to orange in different solvents. The emission peak in the fluorescence spectra showed corresponding movements from 474 nm to 581 nm along with the increase of polarity of solvents. In high-polar solvents such as acetonitrile, acetone, methanol, etc., the fluorescence of LD-red was too weak to be observed (Fig. 4D). The polarity function (Δf ) of solvents was further adjusted continuously by mixing THF with toluene. The absorption maxima, fluorescence maxima and Stokes shift (Δυ¯ ) in THF/ toluene mixtures were measured and shown in Table S2. As shown in Fig. 5, Δ υ¯ and Δf can be fitted well with Lippert-Mataga plot:
Δυ¯ = Δυ¯0 +
2(μe − μg )2 hcr 3
Δf
3.5. The application of LD-red in image-guided PDT To further understand the luminescence mechanism of LD-red in aggregated state, density functional theory (DFT) and time dependent density functional theory (TD-DFT) calculations were carried out using the Gaussian16 program package. It is known that introducing D-A structures to AIEgens could reduce HOMO-LUMO overlap, leading to small energy gap (ΔEst) between the lowest singlet excited state (S1) and triplet excited state (T1) [52]. As shown in Fig. 7A, the highest occupied molecular orbital (HOMO) of LD-red is mostly positioned on its electron donor moieties while the lowest unoccupied molecular orbital (LUMO) is mainly located on its electron accepter moieties. These distinct charge distributions in LD-red enable it to undergo a typical TICT process, which is in accordance with the reported TICT luminogens [53–55]. More importantly, ΔEst of LD-red was calculated as 0.59 eV, which could facilitate the intersystem crossing for efficient
(1)
In Eq. 1, Δυ¯0 is the Stokes shift of the fluorophore in non-polar solvent, h is Plank’s constant, c is the velocity of light, r is the radius of the Onsager cavity around the fluorophore, μe and μg is excited state dipole moment and ground state dipole moment, respectively [49].
4
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Fig. 4. A) The rotatable D-π-A structure in LD-red. B) Energy diagram of TICT process. C) Fluorescence photographs taken under an irradiation of UV light. D) Fluorescence spectra of LD-red in different solvents. The concentration of LD-red was 10 μmol/L.
reconstructed with LD-red. As shown in Fig. 9 and Video 1, fluorescence was barely observed out of the HeLa cells after 30 min incubation, suggesting an excellent cell permeability of LD-red. The long-term cell tracing property of LD-red was also investigated. As shown in Fig. S5, after continuous cell culture for one week, the fluorescence profile from LDs can be still clearly distinguished, suggesting a good stability of LD-red in live cells. Apart from a LDs probe, LD-red is also a promising photosensitizer for PDT due to its TICT characteristic. The generation of ROS by LD-red upon white light irradiation was investigated (Fig. 10). The ROS generation efficiency of LD-red was determined using DCFH-DA as a ROS indicator, which emits green fluorescence in presence of ROS [61–63]. As shown in Fig. 10A, the fluorescence of DCFH-DA with LD-red was gradually enhanced along with the irradiation time. After 10 min
photosensitization (Fig. 7B). Meanwhile, this feature is beneficial to produce ROS, which could effectively kill cancer cells [56,57]. Thus, the photodynamic therapy property of LD-red was carefully investigated. Firstly, the bioimaging properties of LD-red in live cells were investigated by confocal laser scanning microscopy. After incubation in live HeLa cells with LD-red for 30 min, bright fluorescence from the droplet structures in cytoplasm could be clearly observed, which is a typical morphology for LDs (Fig. 8). To confirm that LD-red was located in LDs, costain experiment was carried out with BODIPY493/503 Green, which is a commercially available dye for LDs-staining [58–60]. As shown in Fig. 8C, the emission signal of LD-red displayed excellent overlap with that of BODIPY493/503 Green (co-localization coefficient was 93%). Furthermore, 3D fluorescent images were successfully
Fig. 5. A) Normalized fluorescence spectra of LD-red in THF/toluene with different THF fraction (fTHF). B) Lippert-Mataga plot of LD-red. The concentration of LDred was 10 μmol/L. 5
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Fig. 6. A) Temperature-dependent fluorescence spectra of LD-red in THF. B) Emission intensity of LD-red in THF at 580 nm as a function of temperature and the associated best-fit equations. C) Fatigue resistance of the fluorescence intensity of LD-red during ten heating/cooling cycles in THF. The concentration of LD-red was 10 μmol/L.
Fig. 7. A) The Frontier molecular orbitals of LD-red obtained via DFT calculations. The value of the contour envelopes is 0.03 au. B) A simplified Jablonski diagram to show the production of ROS. 6
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Fig. 8. Colocalization imaging of HeLa cells stained with A) 1 μmol/L LD-red and B) 0.1 μmol/L BODIPY493/503 Green. C) Merged image of panels A) and B). D) Brightfield image. The concentration of LD-red was 1 μmol/L.
Fig. 9. Reconstructed 3D fluorescent microscopic images of live HeLa cells stained with 1 μmol/L LD-red for 30 min.
irradiation, the fluorescence intensity was 191-fold higher than that of the unirradiated one. On the contrary, there was barely emission change for DCFH-DA or LD-red alone. These results indicated that LDred is an efficient photosensitizer for ROS generation. Because excessive amount of ROS are detrimental to live cells, the PDT application of LD-red was further explored on HeLa cells by a standard CCK-8 (Cell Counting Kit-8) assay. Killing efficiency of LD-red was determined in both the absence and presence of white light irradiation (Fig. 10B). The
dose-dependent toxicity results suggested that LD-red exhibited low cytotoxicity under dark conditions. In contrast, under white light irradiation, the viability of HeLa cells dropped rapidly to 12.8% with a concentration of 1 μmol/L. When the concentration of LD-red was higher than 2 μmol/L, the cells can be killed nearly completely under white light irradiation. While 85% viability was maintained in the cells incubated with 2 μmol/L of LD-red under dark conditions. These results demonstrated that LD-red can be used for image-guided PDT. 7
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Fig. 10. A) Fluorescence intensity changes at 534 nm of DCFH-DA, LD-red, mixtures of DCFH-DA and LD-red in PBS upon white light irradiation for different times. Concentrations: 10 μmol/L (LD-red) and 5 μmol/L (DCFH-DA). Light power: 5 mW/cm2. B) Viability of HeLa cells stained with different concentrations of LD-red in the presence or absence of white light irradiation for 10 min. Light power: 5 mW/cm2.
4. Conclusions
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In summary, a novel multifunctional AIEgen of LD-red was facilely synthesized through a single-step reaction with high yield. The maximum αAIE value of LD-red was calculated as 35. The D-π-A structure endows LD-red with typical TICT characteristic, which makes it suitable for temperature sensing and image-guide PDT. As a fluorescent thermometer, LD-red showed proportional temperature-dependent emission from 10 °C to 60 °C with excellent fatigue resistance in THF. LD-red can exclusively target LDs in live cells. As a photosensitizer, LDred exhibited good biocompatibility, low toxicity for live cells in dark while effective ROS generation upon white light irradiation. LD-red enriches the kinds of AIEgens and, more importantly, this work provides a new strategy for constructing multifunctional AIEgen with TICT characteristic. Declaration of Competing Interest There are no conflicts to declare. Acknowledgements This work was supported by the National Natural Science Foundation of China (21501150, 51502079, 81902356 and 21601156), the Training Program for Young Backbone Teachers of Henan University of Technology, the Science and Technology Key Project of Henan Education Department (18A150026), the Open Foundation of Guangxi Key Laboratory of Processing for Non-ferrous Metals and Featured Materials, Guangxi University (2019GXYSOF12), the Joint Coconstruction Research Project of Henan Medical Science and Technology Research Plan (2018020025). Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.snb.2019.127139. References [1] Y. Cheng, J. Wang, Z. Qiu, X. Zheng, N.L.C. Leung, J.W.Y. Lam, B.Z. Tang, Multiscale humidity visualization by environmentally sensitive fluorescent molecular rotors, Adv. Mater. 29 (2017) 1703900. [2] K. Li, J. Wang, Y. Li, Y. Si, J. He, X. Meng, H. Hou, B.Z. Tang, Combining two different strategies to overcome the aggregation caused quenching effect in the design of ratiometric fluorescence chemodosimeters for pH sensing, Sens. Actuators B Chem. 274 (2018) 654–661. [3] J. Qian, B.Z. Tang, AIE luminogens for bioimaging and theranostics: from organelles to animals, Chemistry 3 (2017) 56–91. [4] J. Yang, B. Yang, G. Wen, B. Liu, Dual sites fluorescence probe for H2S and Hg2+ with “AIE transformers” function, Sens. Actuators B Chem. 296 (2019). [5] Y. Cheng, J. Dai, C. Sun, R. Liu, T. Zhai, X. Lou, F. Xia, An intracellular H2O2responsive AIEgen for the peroxidase-mediated selective imaging and inhibition of
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Dr. Yuanyuan Li received her B.Sc. in the School of Materials, Wuhan University of Technology in 2009. She obtained her Ph.D. degree from the Department of Chemistry, Tsinghua University in 2014. Then, she joined the School of Chemistry and Chemical Engineering, Henan University of Technology as associate professor. Her research interests are focused on the detection of food safety and small molecular fluorescence probe. Qiucheng Peng received his B.Sc. in the School of Chemistry and Chemical Engineering, Henan University of Technology in 2018. He is a master candidate in the College of Chemistry and Molecular Engineering, Zhengzhou University. His research interests are aggregation-induced emission material and fluorescence probe. Dr. Shijun Li received his B.Sc. in the College of Chemistry and Molecular Engineering, Zhengzhou University in 2013. Then, he obtained his Ph.D. degree in 2018 from Beijing Normal University. Currently, he is a postdoctoral fellow at College of Chemistry and Molecular Engineering, Zhengzhou University. His research direction is theoretical and computational chemistry. Dr. Yuchen Cai received her B.Sc. in the School of Medicine, Sun Yat-Sen University in 1999. She obtained her Ph.D. degree from Sun Yat-Sen University Cancer Center in 2009. Then, she joined Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine as associate professor. Her current research interests are Cancer prevention. Dr. Bin Zhang received his B.Sc. and Ph.D. in the College of Chemistry and Molecular Engineering, Zhengzhou University in 2008 and 2014. Then he joined the College of Chemistry and Molecular Engineering, Zhengzhou University as associate professor. His research direction is organometallic photoelectric functional material Kai Sun received his B.Sc. in the College of Chemistry and Molecular Engineering, Zhengzhou University in 2013. He obtained his master degree in 2016 from the College of Chemistry and Molecular Engineering, Zhengzhou University. He is a doctoral candidate in the College of Chemistry and Molecular Engineering, Zhengzhou University. His research interests are organic synthesis methodology and aggregation-induced emission material. Junbao Ma received his B.Sc. in the College of Chemistry and Molecular Engineering, Zhengzhou University in 2019. His research interests are aggregation-induced emission material and fluorescence probe. Cuiping Yang received her B.Sc. in the College of Material and Chemical Engineering from Henan University of Engineering in 2015. She is a master candidate in the College of Chemistry and Molecular Engineering, Zhengzhou University. Her research interests are aggregation-induced emission material and fluorescence probe.
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Y. Li, et al.
received Ph.D in Sun Yat-Sen University Cancer Center in 2017. His current research interests are cancer prevention and aggregation-induced emission material.
Dr. Hongwei Hou received his Ph.D. degree from Nanjing University in 1995. He began the postdoctoral research at Hong Kong University of Science and Technology and the National University of Singapore from 1995 to 1998. At the end of 1999, he joined Zhengzhou University as a professor. His research interests are the crystalline centralmetal transformation and the nonlinear optical properties of the coordination compounds.
Dr. Kai Li received his B.Sc. and Ph.D. in Analytical Chemistry from Tsinghua University in 2008 and 2014, respectively. Then he joined the College of Chemistry and Molecular Engineering, Zhengzhou University as associate professor. His current research interests are focused on the photochromic material, aggregation-induced emission material and small molecular fluorescence probe.
Dr. Huifang Su received his B.Sc. in the Chengde Medical College in 2010. He obtained his master degree in 2012 from School of Medicine, Sun Yat-Sen University. Then, he
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