具有聚集诱导发光性质的高灵敏度和高光稳定性的脂滴荧光探针

Novel AIE Fluorescent Probes for Ultrahigh Sensitivity and High Photostability in Lipid Droplets Imaging

摘要

设计合成了2种新型聚集诱导发光(AIE)探针TPA-H与TPA-2F. 这2种探针均表现出优异的生物相容性(浓度高达50 µmol/L时, 细胞存活率仍超过90%)和脂滴靶向特异性. 在3T3-L1脂肪细胞的早期分化过程中, TPA-2F与TPA-H均能清晰显像BODIPY难以检测的微小以及新生脂滴, 显示出更优的成像灵敏度. 此外, TPA-2F展现出高的光稳定性, 在连续100次激光扫描后, 其荧光强度仍保持初始值的90%以上. 研究结果不仅提供了2种高性能的脂滴成像工具, 更凸显了AIE发光材料在细胞器特异性生物成像中的应用潜力, 为脂质相关代谢疾病的早期诊断与机制研究提供了新的可能途径.

Abstract

Two novel aggregation-induced emission（AIE）-active probes， TPA-H and TPA-2F， were designed and synthesized based on a triphenylamine（TPA） core. Systematic characterization demonstrated that both probes exhibit excellent biocompatibility（cell viability>90% at concentrations up to 50 µmol/L） and outstanding LD-targeting specificity with minimal colocalization with other organelles such as mitochondria and lysosomes. During early differentiation of 3T3-L1 adipocytes， both TPA-2F and TPA-H clearly visualized small and nascent LDs that were difficult to be detected with BODIPY， indicating superior imaging sensitivity compared to the existing fluorescent probes for LDs. Moreover， TPA-2F demonstrated exceptional photostability， retaining over 90% of its initial fluorescence intensity after 100 continuous laser scanning cycles， significantly outperforming TPA-H. This work not only provides two high-performance LD imaging tools but also highlights the potential of AIE luminogens（AIEgens） in organelle-specific bioimaging， offering promising avenues for early diagnosis and mechanistic research of lipid-related metabolic diseases.

Graphical abstract

关键词

聚集诱导发光(AIE) / 荧光成像 / 脂滴 / 光稳定性

Key words

Aggregation-induced emission（AIE） / Fluorescence imaging / Lipid Droplets / Photostability

1 Introduction

Lipid droplets（LDs）， once considered inert intracellular lipid storage depots， are now recognized as dynamic organelles central to cellular energy metabolism， membrane biosynthesis， and signaling^［1—3］. Their dysregulation is closely implicated in metabolic disorders such as obesity， fatty liver disease， and diabetes^［4—6］. Consequently， precise visualization of LD dynamics — particularly their biogenesis， growth， and interaction — has become a critical objective in both basic cell biology and clinical research^［7—9］. Fluorescence microscopy serves as a primary tool for this purpose， with commercial dyes like BODIPY 493/503 being widely adopted. However， these conventional probes often suffer from limitations such as aggregation-caused quenching（ACQ）， which reduces their brightness in the densely packed LD core， and insufficient photostability， hindering long-term tracking ^{［10—12］}. Crucially， their sensitivity in detecting small， nascent LDs during early formation stages remains inadequate（Table S1， see the Supporting Information of this paper）， leaving a significant gap in our ability to monitor the initial phases of lipid accumulation， a key event in the pathogenesis of metabolic diseases^{［13—15］}.

Aggregation-induced emission luminogens（AIEgens） have emerged as a promising alternative to address these challenges^{［16—21］}. Compared to ACQ fluorophores， AIEgens exhibit enhanced fluorescence in the aggregated state， making them particularly suitable for imaging within the hydrophobic environment of lipid droplets（LDs）^{［22—24］}. Triphenylamine（TPA） has been identified in previous studies as an effective moiety for targeting LDs^{［25—29］}. For instance， Tang and co-workers developed a red-emissive AIE probe featuring a triphenylamine donor and a 2-benzothiazoleacetonitrile acceptor， which specifically stains LDs and enables visualization of their polarity distribution in live cells and tissues^［29］. However， most existing TPA-based AIE probes are excited at wavelengths below 500 nm， limiting their applicability for in vivo studies.

Herein， we report two triphenylamine-based molecules， TPA-2F and TPA-H， functionalized with a strong electron-accepting unit—either 2-（3-oxo-2，3-dihydroinden-1-ylidene） malononitrile or 2-（5，6-difluoro-3-oxo-2，3-dihydro-1H-inden-1-ylidene） malononitrile. The incorporation of these strong acceptors is expected to redshift their absorption and emission bands to the NIR region. The results show that both compounds exhibit aggregation-induced emission（AIE）， with absorption maxima near 600 nm and emission maxima longer than 700 nm. Moreover， these two compounds exhibit excellent specificity toward lipid droplets（LDs）， showing minimal off-target localization in other organelles such as mitochondria and lysosomes. Notably， the introduction of fluorine atoms in TPA-2F endows it with enhanced resistance to photobleaching^［30］. In cellular imaging， both TPA-2F and TPA-H outperformed the commercial dye BODIPY 493/503， particularly in visualizing small and

nascent LDs during the early stages of 3T3-L1 adipocyte differentiation. This heightened sensitivity enables the detection of initial lipid accumulation events that are otherwise difficult to observe. From a clinical perspective， the ability to monitor the formation of LD at an early stage enables these fluorescent probes to be a useful tool for studying the incipient phase of pathological lipid storage， which underlies conditions such as steatosis. Thus， these probes not only offer advanced imaging solutions for fundamental cell biology but also hold significant potential to facilitate early diagnosis and mechanistic investigation of lipid-associated metabolic disorders.

2 Experimental

2.1　Materials and Measurements

3-（Dicyanomethylidene） indan-1-one， 2-（5，6-difluoro-3-oxo-2，3-dihydro-1H-inden-1-ylidene） malononitrile were purchased from Energy Chemical（Shanghai， China）. 4-［Bis（4-methoxyphenyl） amino］ benzaldehyde was from Bide Pharmatech. Ltd.（Shanghai， China）. The reagents and starting materials were commercially available and used without any further purification unless otherwise specified.

NMR spectra were recorded on Bruker AVANCE III 400 MHz spectrometers using tetramethylsilane（TMS） as internal reference. MALDI-FTICR-MS weas measured with a Bruker Solarix-XR high-resolution mass spectrometer. Absorption spectra were recorded on the Hitachi UH4150 spectrophotometer. Emission spectra were recorded on the Hitachi FP-6000 spectrometer. The diffraction data for the single crystals were collected with a Rigaku Saturn diffractometer with a CCD area detector.

2.2　Synthesis and Characterization

2.2.1　General synthetic procedure for TPA-H and TPA-2F

To a solution of 1.0 mmol of 4-［bis（4-methoxyphenyl） amino］ benzaldehyde in 10 mL of dry ethanol was added 3-（dicyanomethylene） indolin-2-one derivatives（1.0 mmol）. The mixture was heated under reflux with stirring for 1 h. After cooling to room temperature， the resulting precipitate was collected by filtration， washed with ethanol， and recrystallized from ethanol to afford TPA-H and TPA-2F.

2.2.2　Synthesis of TPA-H

By following the above general procedure and using 3-（dicyanomethylidene） indan-1-one as the reagent， TPA-H was obtained in a 92.5% yield. ¹H NMR（400 MHz， chloroform-d）， δ： 8.66—8.64（m， 1H）， 8.45（s， 1H）， 8.20（d， J=8.7 Hz， 2H）， 7.87—7.85（m， 1H）， 7.75—7.67（m， 2H）， 7.16（d， J=8.4 Hz， 4H）， 6.94—6.83（m， 6H）， 3.84（s， 6H）. ¹³C NMR（101 MHz， chloroform-d）， δ： 187.08， 163.15， 158.00， 147.55， 139.69， 138.13， 137.39， 134.66， 134.12， 128.21， 124.87， 124.17， 123.66， 116.56， 115.19， 115.14， 114.93， 68.46， 55.56. HR-MS（MALDI， positive）： m/z calcd. for C₃₃H₂₃N₃O₃ ［M］⁺： 509.1734， found： 509.1732.

2.2.3　Synthesis of TPA-2F

By following the above general procedure and using 2-（5，6-difluoro-3-oxo-2，3-dihydro-1H-inden-1-ylidene） malononitrile as the reagent， TPA-2F was obtained in a 94.1% yield. ¹H NMR（400 MHz， chloroform-d）， δ： 8.51—8.47（m， 1H）， 8.42（s， 1H）， 8.20—8.16（m， 2H）， 7.61（t， J=7.7 Hz， 1H）， 7.19—7.15（m， 4H）， 6.95—6.91（m， 4H）， 6.83（d， J=8.9 Hz， 2H）， 3.84（s， 6H）. ¹³C NMR（101 MHz， chloroform-d）， δ： 184.77， 160.93， 158.15， 154.79， 153.02， 147.74， 138.58， 137.57， 136.21， 136.13， 136.09， 134.94， 128.23， 123.98， 122.84， 116.50， 115.22， 114.80， 114.59， 114.53， 114.38， 112.62， 112.44， 68.66， 55.58. HR-MS（MALDI， positive）： m/z calcd. for C₃₃H₂₁F₂N₃O₃ ［M］⁺： 545.1545， found： 545.1548.

2.3　3T3-L1 Cells Adipogenesis and Imaging

The 3T3-L1 preadipocytes were plated in DMEM（Gibco）， which was supplemented with 10% bovine calf serum（Gibco）. Two days following the attainment of confluence， the differentiation process was initiated by replacing the medium with DMEM supplemented with 10% FBS and the adipogenic cocktail， which consisted of 0.5 mmol/L IBMX（MedChemExpress）， 1.0 µmol/L dexamethasone（Alfa Aesar™）， and 10 µg/mL insulin（MedChemExpress）. Following a three-day incubation period， the differentiation medium was replaced with DMEM containing 10% FBS and 10 µg/mL insulin for a further two days. The cells should then be maintained in DMEM supplemented with 10% FBS， with the medium changed every two days.

A total of approximately 1.0 × 10⁶ induced cells were seeded into a confocal dish and incubated for a period of 24 h. The cells were initially stained with BODIPY 493/505（Beyotime， C2053） in accordance with the instructions provided for a period of 20 min. After three PBS washes， the medium was refreshed and the cells were separately incubated for 30 min with 10 µmol/L TPA-2F or 10 µmol/L TPA-H. After washing， the cells were observed under an Olympus FV3000 confocal laser scanning microscope， with images captured using 570 nm excitation and 650—750 nm emission. The fluorescence intensity was subsequently analyzed using Image J.

The photostability of probes TPA-2F and TPA-H was evaluated by continuous laser scanning. After incubating cells with 10 µmol/L of each probe for 30 min， sequential imaging was performed on an Olympus FV3000 confocal microscope. Cells were subjected to 200 cycles of scanning with the excitation wavelength of 570 nm， and the interval time between cycles was 10 s； thus， the total acquisition time was 2000 s（200 frames）. The photomultiplier tube（PMT） voltage was maintained at 10. Fluorescence intensity at each time point was quantified using ImageJ software， and the resulting data were analyzed with GraphPad Prism 9.

2.4　CCK-8 Assay

In order to ascertain the biocompatibility of the material in question， 3T3-L1 cells were incubated. Once the cells had reached 80% confluence， the medium was removed and the cells were gently washed three times with PBS. They were then treated with 0.25% trypsin for 1 min. For the purposes of experimentation， 3T3-L1 cells were subjected to centrifugation at 1200 r/min for a period of 3 min. Following this， a suspension of 8000 cells in fresh medium（100 μL） was introduced into each well of a 96-well plate. After overnight incubation， the medium was exchanged for fresh medium containing graded concentrations of TPA-2F or TPA-H（1， 10， 20， 50， 100， 150 and 200 µmol/L）， and the cells were cultured for a further 24 h. Subsequently， the medium of each well was removed and replaced with 100 μL of fresh medium containing 10% of the CCK-8 solution（Aoqing Biotechnology， AQ308） for 1 h at 37 ℃. The absorbance at 450 nm was then measured using a microplate reader（Thermo Scientific）. The OD values were subsequently used to evaluate cell viability with GraphPad Prism 9 software.

3 Results and Discussion

3.1　Synthesis and Characterization

As shown in Scheme 1， two triphenylamine（TPA）-based derivatives， TPA-H and TPA-2F， were synthesized via a Knoevenagel condensation between 4-［bis（4-methoxyphenyl） amino］ benzaldehyde and the corresponding 3-（dicyanomethylene） indolin-2-one derivatives， affording yields of 94.1% and 92.5%， respectively. The chemical structures of TPA-H and TPA-2F were fully characterized by ¹H NMR spectroscopy（Fig.S1 and Fig.S2， see the Supporting Information of this paper）， ¹³C NMR spectroscopy（Fig.S3 and Fig.S4， see the Supporting Information of this paper）， and high-resolution mass spectrometry（HRMS）. Furthermore， their molecular structures were unambiguously confirmed by single-crystal X-ray diffraction analysis［Fig.1（A） and （C）］.

Single-crystal X-ray diffraction analyses of TPA-H and TPA-2F［Fig.1（A） and （C）］ confirm that TPA-H adopts a donor-π-acceptor（D-π-A） architecture， comprising a triphenylamine donor（D）， a C=C double bond as the π-bridge， and a 3-（dicyanomethylene）indolin-2-one acceptor（A）. Except for the two terminal phenyl rings， the molecular skeleton exhibits a high degree of planarity， which facilitates electron delocalization over the whole π-system. The pronounced donor-acceptor interaction， extended π-conjugation， and overall structural planarity collectively contribute to the observed red-shift in both absorption and emission^{［31，32］}. TPA-2F shares the same D-π-A framework and shows similar characteristics； moreover， its molecular structure is even more planar than that of TPA-H.

Subsequently， density-functional-theory（DFT） calculations were performed on TPA-H and TPA-2F. Their HOMO orbitals are mainly localized on the triphenylamine group and the methoxy groups， while the LUMO orbitals are largely confined to the planar heterocyclic unit with only a weak contribution from the triphenylamine segment［Fig.1（B） and （D）］. These computational results clearly indicate the occurrence of intramolecular charge transfer in these D-A molecules. Moreover， the band gap of TPA-2F is narrower than that of TPA-H， agreeing well with their absorption spectra mentioned below.

We further investigated the photophysical properties of both compounds. Their absorption maxima in CH₂Cl₂ are located at 574 nm for TPA-H and 586 nm for TPA-2F， respectively［Fig.2（A）］. However， consistent with previous studies^［24］， the absorption maxima of both TPA-H and TPA-2F also exhibit a slight blue shift with increasing solvent polarity（Fig.S5， see the Supporting Information of this paper）.

Both TPA-H and TPA-2F show weak emission in CH₂Cl₂solution， a phenomenon attributed to the free rotation of C—C single bonds within their molecular structures as previously reported. In contrast， their fluorescence is significantly enhanced upon aggregation. As illustrated in Fig.2（B） and Fig.S6（see the Supporting Information of this paper）， the fluorescence spectra of TPA-H and TPA-2F were recorded during the gradual addition of hexane to their CH₂Cl₂ solutions. The fluorescence intensity of both compounds rises markedly with increasing hexane fraction， confirming their aggregation-induced emission（AIE） characteristics^{［33—35］}. Consistent with the trend observed in their UV absorption， the emission of TPA-2F is further red-shifted compared to that of TPA-H， likely due to the presence of fluorine atoms， with emission maxima located at 720 and 705 nm for TPA-2F and TPA-H， respectively.

The excitation wavelength is 580 nm for TPA-2F. The concentration is 10 μmol/L. DCM： CH₂Cl₂； Hex： hexane.

3.2　Performance in Visualizing Early-Stage and Small Lipid Droplets

Prior to biological imaging applications， the cytotoxicity of TPA-2F and 2FTPA-H was evaluated against 3T3-L1 preadipocytes using the CCK-8 assay. Cells were treated with a range of probe concentrations（1—200 µmol/L） for 24 h. Both compounds showed negligible cytotoxicity at concentrations up to 50 µmol/L， with cell viability remaining above 90%. At 100 µmol/L， viability dropped to approximately 50%［Fig.3（A） and （B）］. This concentration-dependent profile indicates a favorable safety window for imaging applications， confirming the suitability of both probes for subsequent live-cell studies.

Cell viability of 3T3-L1 cells after incubation with varying concentrations（1—200 µmol/L） of TPA-2F or TPA-H for 24 h， as determined by CCK-8 assay. Data are presented as mean±SD. Both probes show negligible cytotoxicity at concentrations up to 50 µmol/L， while a significant reduction in cell viability is observed at 100 µmol/L and above.

The subcellular localization of TPA-2F and TPA-H was examined using confocal laser scanning microscopy. Co-staining with commercially available organelle trackers revealed negligible overlap between the signals of both probes and those of LysoTracker Green（lysosomes） or MitoTracker Green（mitochondria）， indicating no significant colocalization with these organelles（Fig.S7， see the Supporting Information of this paper）. To further assess their targeting specificity toward lipid droplets（LDs）， we performed co-staining experiments with the commercial LD dye BODIPY 493/503. As shown in Fig.4， the red fluorescence from TPA-2F or TPA-H overlapped well with the green signal from BODIPY 493/503， confirming their selective accumulation in LDs.

Notably， compared with BODIPY 493/503， both TPA-2F and TPA-H exhibited a superior ability to visualize nascent and small LDs. During live-cell monitoring of LD formation， the TPA-based probes consistently highlighted numerous small， punctate cytoplasmic structures that were only faintly stained by BODIPY （Fig.4）. This enhanced performance is likely attributable to the aggregation-induced emission（AIE） character of the TPA scaffold. Unlike conventional dyes such as BODIPY， which often undergo aggregation-caused quenching in the crowded interior of LDs， AIE luminogens（AIEgens） emit strongly upon aggregation. This unique photophysical property allows them to become exceptionally bright within the confined， hydrophobic core of LDs， significantly improving the signal-to-noise ratio and enabling the detection of smaller， lipid-poor LDs at early stages of biogenesis.

3.3　Photostability of TPA-2F in vivo

Photostability is a critical parameter for long-term tracking and super-resolution imaging. The resistance to photobleaching of TPA-2F and TPA-H was evaluated systematically by continuously scanning stained cells under 570 nm excitation. Fluorescence intensity was recorded every 10 s over 200 scanning cycles. In contrast， TPA-H showed a faster decay in fluorescence， undergoing a significant drop after about 50 cycles［Fig.5（A） and （B）］. The superior photostability of TPA-2F is likely attributable to the presence of fluorine atoms， which may shorten the triplet-state lifetime， thereby reducing the probability of reactions with quenching species^［30］. This characteristic renders TPA-2F a more reliable probe for prolonged， real-time observation of lipid droplet（LD） dynamics.

4 Conclusions

In summary， we have developed two novel AIE-active luminescent probes， TPA-2F and TPA-H， for the specific and high-fidelity imaging of lipid droplets. Both probes display excellent biocompatibility within a practical concentration range and show outstanding targeting specificity toward LDs. Notably， their aggregation-induced emission（AIE） character enables high brightness in the densely packed core of lipid droplets， which allows more sensitive visualization of small and newly formed LDs by comparing with the reported fluorescent probes for LDs（Scheme S1 and Table S1， see the Supporting Information of this paper）. Moreover， the strategic introduction of fluorine atoms imparts TPA-2F with exceptional photostability， which significantly surpasses that of TPA-H， rendering it a robust tool for long-term， real-time tracking of LD dynamics. This work not only provides two highly effective probes for lipid droplet imaging， but also underscores the potential of AIEgens to address the limitations of conventional fluorophores in organelle-specific bioimaging.

The supporting information of this paper see http://www.cjcu.jlu.edu.cn/CN/10.7503/cjcu20200626.

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基金资助

国家自然科学基金(82530030)

国家自然科学基金(82270954)

国家自然科学基金(22021002)