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Near Infrared Fluorescent Dyes with Aggregation-Induced Emission

Fei Ren , Jianbing Shi , Bin Tong , Zhengxu Cai , Yuping Dong

Progress in Chemistry ›› 2021, Vol. 33 ›› Issue (3) : 341 -354.

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Progress in Chemistry ›› 2021, Vol. 33 ›› Issue (3) : 341-354 DOI: 10.7536/PC200614
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Near Infrared Fluorescent Dyes with Aggregation-Induced Emission
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Abstract

The discovery of the aggregation-induced emission(AIE) phenomenon provides the best solution to solve the problem of fluorescence quenching of traditional organic fluorescent molecules at high concentrations and aggregation state. AIE molecules are widely used in many fields such as photoelectric devices, chemical sensing, biological imaging and targeting therapy. With the deepening of the research on the emissive mechanism of AIE, the AIE molecular system has been greatly expanded. Among them, a class of AIE molecules with donor-acceptor structures can significantly reduce the molecular energy gap and extend the emission wavelengths of molecules from the visible light region(400~700 nm) to the near infrared(NIR) region(700~1700 nm). Due to the unique advantages of NIR fluorescent molecules in the field of biomedicine, they have become the hot topic of AIE research. With the continuous exploration of the design and application of NIR molecules, AIE molecules with different functions and longer emission wavelengths have also been developed, and realized the application of NIR fluorescence imaging, photoacoustic imaging, photodynamic therapy and photothermal therapy to specific tissues of organisms. This article summarizes the structure of NIR fluorescent molecules with AIE performance in recent years and their related applications in the field of biomedicine.

Contents

1 Introduction

2 The discovery and mechanism of aggregation-induced emission

3 the advantages of NIR and The partition of fluorescent windows

4 Principle of molecular design of NIR dyes

5 NIR fluorescent dyes with AIE property and their applications

5.1 Design and application of benzothiadiazole NIR dyes

5.2 Design and application of malononitrile NIR dyes

5.3 Design and application of ionic NIR dyes

6 Conclusion

Graphical abstract

Keywords

aggregation-induced emission(AIE) / donor-acceptor(D-A) / near infrared(NIR) / photoacoustic imaging(PAI) / photodynamic therapy(PDT) / photothermal therapy(PTT)

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Fei Ren, Jianbing Shi, Bin Tong, Zhengxu Cai, Yuping Dong. Near Infrared Fluorescent Dyes with Aggregation-Induced Emission. Progress in Chemistry, 2021, 33(3): 341-354 DOI:10.7536/PC200614

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1 Introduction

In 2001, Tang Benzhong of Hong Kong University of Science and Technology discovered the phenomenon of Aggation-Induced Emission (AIE) and studied its mechanism[1]. The concept of AIE provides a new solution to the problem of fluorescence quenching caused by the aggregation of traditional dyes, and AIE molecules have attracted wide attention of many researchers because of their excellent luminescent properties. With the development of AIE field, many AIE systems have been developed, such as hexaphenylthiophene (HPS) system, tetraphenylethylene (TPE) system, polyarylbutadiene system, polyarylpyrrole system and 9,10-bis ( (E) -styryl) anthracene (DSA) system[2][3][4][5][6].
With the development of AIE research, not only the mechanism of AIE has been better understood, but also the development of new AIE molecules has made great progress. From hydrocarbons to heteroatomic compounds, from small molecules to large molecules, from organic to inorganic or organometallic compounds, various types of AIE molecules are constantly expanding[7,8]. AIE molecules are not only limited to the increase of the number of new molecules, but also widely used in chemical sensing, biological sensing, high-performance optoelectronic devices and other fields as efficient solid-state light-emitting materials with good thermal stability and photostability[9]. The advantages of AIE materials in biomedicine are particularly obvious. Fluorescence technology provides a direct visualization tool for real-time and non-invasive monitoring of analytes at the molecular level, and provides important information on complex biological structures[10,11].
In the development of AIE molecular system, a class of molecules with red or Near Infrared (NIR) fluorescence emission have become a hot research topic because of their strong tissue penetration ability, small background light interference and no light damage to biological tissues. Although there is no unified definition for the division of NIR bands, according to the application window of biological tissues, the wavelength of 700-900 nm is generally regarded as NIR-I, and the wavelength of 1000-1700 nm as NIR-II[12,13]. In recent years, with the deepening of NIR research and the continuous expansion of its application fields, NIR luminescent materials have been widely used not only in the field of organic optoelectronics,Such as quantum dots, organic solar cells, optical communication, information encryption display and organic light-emitting diodes, and also has important application potential in the field of life sciences, such as biological enzyme detection, biological fluorescence imaging, targeted therapy and other fields[14⇓⇓~17][18,19]. In this review, the design and applications of NIR luminescent molecules with AIE properties are summarized.

2 Discovery and mechanism of aggregation-induced luminescence

There is a common photophysical phenomenon in the field of luminescence research: traditional organic fluorescent molecules mostly exist in planar aromatic polycyclic structures, and the π-π stacking interaction between molecules in the aggregated state promotes the non-radiative dissipation of excited state energy, which leads to fluorescence quenching, commonly known as aggregation-induced fluorescence quenching (ACQ)[9]. In 2001, Tang Benzhong et al. Discovered a photophysical phenomenon, namely AIE phenomenon, which is diametrically opposite to ACQ. The discovery of this phenomenon solves the problem of fluorescence quenching caused by aggregation of traditional fluorescent molecules in practical applications, so that chromophores with weak luminous efficiency can be effectively enhanced by forming aggregates. Therefore, molecules with AIE properties show great application value in the fields of fluorescence detection, fluorescence imaging and optoelectronic devices.
After the concept of AIE was proposed, many research groups are actively exploring the mechanism behind the AIE phenomenon. With the abundance of AIE molecules, the exploration of their morphological structure and related applications provides experimental data support for the study of AIE mechanism. According to the study of different AIE molecular systems, researchers have proposed several mature AIE luminescence mechanisms. For example, Tang Benzhong et al. Proposed the intramolecular rotation limited (RIR) mechanism through the difference of luminescence intensity of a class of molecules with typical propeller structure (HPS, TPE, etc.) Under the influence of different solvent systems, temperatures and viscosities, which is applicable to most AIE systems[7]. With the deepening of research, researchers have found that a class of molecules without multi-rotor also show typical AIE properties. Although this kind of molecule has no rotatable group, the molecular vibration in the monomolecular state will consume the excited state energy and quench the fluorescence. However, in the aggregated state, the molecular vibration is limited, and the distorted molecular configuration avoids the π-π stacking between molecules, which makes them show the typical AIE properties. The intramolecular vibration limited (RIV) mechanism is proposed to reasonably explain the luminescence phenomenon of these molecules. Both RIR and RIV mechanisms are referred to as the restricted molecular motion (RIM) mechanism[20]. In addition, the packing state of the molecules in the aggregation state also has a greater impact on their AIE properties. Due to the planar structure and π-π interaction between molecules, the molecules of traditional fluorescent molecules are packed in a face-face manner and form H-aggregates, which lead to fluorescence quenching. The parallel stacked molecules are translated along the long axis direction, and when the translation distance is long enough, the molecules are dislocated and stacked in parallel to form J-aggregates, so that the π-π stacking between the molecules is avoided, and the luminescence of the aggregates is facilitated. In addition, distorted intramolecular charge transfer (TICT) and excited-state intramolecular proton transfer (ESIPT) are also beneficial to the fluorescence enhancement of aggregates[21,22][23,24]. In 2019, Tang Benzhong et al. Proposed the "dark channel limited (RADS)" mechanism for some AIE molecules containing heteroatoms, which supplemented and improved the connotation of RIM mechanism[25]. The in-depth exposition of AIE mechanism lays a theoretical foundation for the development of different functional AIE molecular systems.

3 Advantages of NIR and Luminescent Window Partition

Fluorescence imaging can acquire wide field of view images with high signal-to-noise ratio and high spatiotemporal resolution in real time. However, fluorescence imaging also has some problems, such as autofluorescence interference, aggregation quenching, photobleaching and weak tissue penetration. Compared with fluorescence imaging in the visible region (400-700 nm), fluorescence imaging in the NIR window (700-1700 nm) has significant advantages in reducing photon scattering and interference from tissue absorption and autofluorescence. As shown in fig. 1, NIR fluorescence has a deeper tissue penetration ability than ultraviolet and visible light (fig. 1A), and NIR fluorescent dyes can significantly reduce the light scattering of tissue under the excitation of light source, which can achieve high-resolution and high signal-to-noise ratio fluorescence imaging (fig. 1b). Advances in biomedical fluorescence imaging in the NIR range have focused on the first NIR window (NIR-I, 700-900 nm) and have now been extended to the second NIR window (NIR-II, 1000-1700 nm). Tissue absorption and background fluorescence are low in vivo under the NIR-I window, which is traditionally defined as the "biological transparency NIR window". The NIR-Ⅱ window shows higher sensitivity and resolution for in vivo imaging[12]. Smaller optical windows, such as NIR-Ⅱa (1300-1400 nm) and NIR-Ⅱb (1400-1700 nm), provide further improvements in fluorescence imaging[13].
In addition to the above application advantages, NIR fluorescent materials with AIE properties can also overcome the defect of fluorescence quenching caused by the aggregation of traditional fluorescent materials in vivo. Targeted AIE probes can achieve focused imaging in specific parts of the body, effectively avoiding the interference of autofluorescence. In addition, the AIE fluorescent probe exists in the form of aggregation, so that the fluorescent molecules are isolated from the external environment, thereby avoiding chemical photobleaching with external substances under illumination conditions, and showing excellent photobleaching resistance. Among them, some functional AIE dyes have shown great potential in molecular diagnostic and therapeutic applications[26,27].

4 Chemical Structure Design of NIR Dyes

Given the appropriate energy to the molecule, the electron can jump from the occupied low energy molecular orbital to the vacant high energy molecular orbital, resulting in a transition corresponding to an absorption band in the spectrum. For fluorescent molecules, an electron radiates from an excited state back to the ground state by a radiative transition of a photon. The energy difference between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) is called the HOMO-LUMO energy gap, which is closely related to the absorption and emission wavelengths of molecules. For fluorescent molecules with low energy gap, the maximum wavelength of absorption and emission spectra will be in the longer wavelength region[28].
Organic NIR fluorescent dyes usually have two kinds of structures: one is π-conjugated system with large planar structure, such as pyrrolopyrrole diketones (DPP), indocyanine green (ICG), boron dipyrrole methylene (BODIPY) derivatives, etc.These molecules have a planar conjugated structure, and the π-π stacking between molecules in the aggregation state will lead to fluorescence quenching, showing the ACQ phenomenon, or the polyene molecular structure will quickly react with singlet oxygen in the environment under light conditions to quench fluorescence, showing poor photostability in general[29][30][31][32,33]; The other is molecules with strong donor-acceptor structure, such as tetraphenylbutadiene, triphenylamine, carbazole and pyrrole, which are commonly used in the design of NIR fluorescent dyes[34]. The D-a interaction can not only greatly reduce the energy gap between HOMO and LUMO, resulting in the red shift of the absorption and emission spectra, but also ensure the AIE properties of the molecule. In this paper, the structure design of NIR fluorescent dyes with AIE properties and their applications in biomedical fields are summarized.

5 NIR fluorescent dye with AIE property and its application

5.1 Design and Application of Benzothiadiazole NIR Dy

Benzothiadiazoles (BBT) are electron acceptors for the design of NIR fluorescent dyes due to their strong electron-deficient properties. The BBT molecule has two sites which are easy to react, and the designed NIR fluorescent molecule should adopt the molecular configuration of D-A-D. The D-A-D structure has strong intramolecular charge transfer (ICT), which can significantly reduce the molecular energy gap and make its luminescence in the NIR region. The NIR molecules developed based on BBT are similar in structural design, and the fluorescent probes with different properties can be designed by adjusting the donor structure and extending the conjugate length of the molecule. For example, Liu et al. designed a new NIR-II fluorescent molecule TB1 (Fig. 2a) using bisbenzothiadiazole (BBTD) as the acceptor and tetraphenylethylene derivative as the donor.
The TB1 molecule exhibits typical AIE properties, with a maximum emission wavelength up to 1000 nm (Fig. 2 C) and a high extinction coefficient (10.2 L·g-1·cm-1) at 740 nm. AIE nanoparticles (Fig. 2e) prepared by the nano-deposition method showed a high fluorescence quantum yield (6.2%) and were used for in situ brain tumor imaging in mice (Fig. 2F). The targeted AIE nanoparticles prepared by further modification with c-RGD can be specifically taken up by tumors. This study demonstrates the potential application of AIE nanoparticles in the NIR-II region in the field of precise brain cancer diagnosis[35].
Hong et al. introduced two N, N-diethylamine groups on TPE as electron donors, and connected 3,4-ethylenedioxythiophene between the donor and BBTD as an electron bridge to extend the conjugation length of the molecule, and synthesized a NIR-II fluorescent dye HLZ-BTED with a lower energy gap (Fig. 3A). The compound exhibits typical AIE properties with a maximum fluorescence emission wavelength of over 1000 nm (fig. 3B). The HLZ-BTED nanoparticles coated with DSPE-mPEG have good water solubility and biocompatibility, and can be used for NIR-II biomedical imaging in vivo. The nanoparticle has good passive targeting property and stable NIR-II fluorescence imaging property. HLZ-BTED nanoparticles, as NIR-II imaging contrast agents, provide high spatiotemporal resolution of tumor feeding vessels (Fig. 3C), allowing precise monitoring of occluded sites of incomplete ischemia and long-distance ischemia in the hindlimb[36].
Xiao et al. designed and synthesized a molecule HQL2 with NIR-II luminescence (Fig. 4A) by connecting triphenylamine as an electron donor to the BBTD acceptor through a thiophene group, and its fluorescence emission tail can extend to the NIR-IIa and NIR-IIb regions (Fig. 4B). The NIR-IIAIE nanoparticles prepared by the nano-deposition method showed good water solubility, biocompatibility and high quantum yield (QY = 1.19%), and were able to realize the tumor vascular imaging of NIR-IIa and NIR-Ⅱb in mice under the excitation of 808 nm light source (Fig. 4 C and d)[37].
Based on the above work, Xiao et al designed and synthesized a series of NIR-II fluorescent molecules HL1-HL3 by introducing different donors and distortion groups (Fig. 5A). Among them, HL3 molecule has a highly distorted D-a structure and shows typical AIE properties. The HL3 nanoparticles prepared by the nano-deposition method show excellent water solubility, photostability and biocompatibility, and exhibit ultra-high quantum yields in aqueous solution, i.e., the quantum yields in the NIR-Ⅱ (> 1000 nm) and NIR-Ⅱb (> 1550 nm) regions are 11. 7% and 0. 05%, respectively. High quality NIR-Ⅱb (above 1550 nm) imaging was obtained in the mouse cerebral vascular and lymphatic drainage system (Fig. 5 B ~ G)[38].
Tang et al. Used triphenylamine group as electron donor and thiophene bridge as electron transport channel to prepare NIR-II luminescent AIE molecule 2 TT-oC6B, and used nano-deposition method to prepare AIE nanoparticles (Fig. 6a). The AIE nanoparticles were applied to NIR-II fluorescence imaging of the mouse ureter with high spatial resolution, deep tissue penetration, low light scattering, and weak tissue autofluorescence, enabling timely and accurate detection of intraoperative ureteral injuries and common ureteral diseases (Fig. 6C). The particles have a high quantum yield (11%) in the NIR-II luminescence region and are much better than the commercial indocyanine green dye in terms of light intensity and penetration depth (fig. 6d)[39].
Sun et al. designed a fluorescent molecule (SYL) with multifunctional DD-A-DD structure by connecting diphenylamine group with fluorene to prepare electron donor and connecting it with BBTD through 3,4-ethylenedioxythiophene bridge (Fig. 7A). It was incorporated into DSPE-mPEG5000 to construct a biocompatible NIR-II fluorescent nanoprobe. In vivo experiments in mice showed that the SYL nanoparticles showed strong NIR-II fluorescence and PA signal in the tumor area and showed a high signal to noise ratio (fig. 7B). At the same time, SYL nanoparticles can significantly inhibit tumor growth when excited by 808 nm light source. The experimental results show that SYL nanoparticles have potential applications in cancer diagnosis (NIR-Ⅱ imaging field) and therapy[40].
Recently, Liu et al designed and synthesized NIR-II photoactivated photosensitizer TQ-BTPE with AIE properties by using benzothiadiazole derivative TQ as electron acceptor. TQ-BTPE shows good two-photon absorption and bright NIR-Ⅰ fluorescence emission after NIR-Ⅱ laser excitation. In aqueous medium, TQ-BTPE has high ROS generation efficiency under white light irradiation. NIR-II light source excitation has super tissue penetration ability, which makes it have stronger two-photon photosensitization and better cancer cell ablation performance, showing the broad prospects of NIR-II photosensitizer for deep tissue photodynamic therapy (Fig. 8)[41].
At present, benzothiadiazole receptors are one of the most commonly used and effective receptors for developing NIR fluorescent dyes. By fine-tuning their structures, the emission wavelength and quantum yield of luminescent molecules can be continuously improved in order to obtain fluorescence images with ultra-high signal-to-noise ratio. In addition, multifunctional photosensitizers are developed by using the receptors to realize multi-modality imaging or treatment in the biological field. It is a very challenging task to modify the target groups on the existing NIR dye molecules to achieve the targeted recognition and location of single-molecule photosensitizers, and to integrate precise imaging and diagnosis and treatment in specific biological tissues.

5.2 Design and Application of Malononitrile NIR Dy

The C and N atoms of the cyano group (CN) in the malononitrile molecule are hybridized by sp, which has a strong electron-deficient property, thus activating the hydrogen of the methylene group connected with the two cyano groups. A variety of strong electron acceptor groups, such as 2-dicyanomethylene-3-cyano-4,5,5-trimethyl-2,5-dihydrofuran (TCF), 2- (3-oxo-2,3-dihydro-1H-inden-1-yl) malononitrile, 2,2 '- (1H-indene-1,3 (2H) -dialkylene) dimethylnitrile, and quinolylmalononitrile (QM), can be derived from activated hydrogen as a reaction site, and these groups can be used to design highly efficient[42,43][44,45][45][46][47]. Zhu et al. developed a new receptor QM based on malononitrile, and synthesized a series of AIE molecules with NIR fluorescence emission, as shown in Figure 9a. QM-1, QM-2, QM-3, QM-4 and QM-5 are all NIR fluorescent molecules with AIE properties[46]. The self-assembly morphologies (from rod-like to spherical) of the molecules can be well controlled by adjusting the ratio of the good solvent to the poor solvent, and the nanoparticles with regular morphologies have good biocompatibility and can be used for NIR fluorescence imaging of tumor targeting. Noninvasive imaging of tumor-bearing mice after injection of QM-5 (0.15 mg/kg) (Fig. 9b) and 3D fluorescence imaging 24 H after injection (Fig. 9c) further confirmed the accumulation of NIR fluorescent molecules in the tumors[48].
Subsequently, Zhu et al successfully prepared NIR water-soluble fluorescent probes with AIE properties by introducing hydrophilic sulfonate groups to the acceptor groups and introducing π-conjugated thiophene bridges between the donor and the acceptor through structural design (Fig. 10a ~ C). The ability to eliminate the self-quenching distortion signal of the commercial dye ThT and the "false positive" signal caused by the initial aggregation of the AIE probe prior to binding to amyloid-beta plaques resulted in ultra-high resolution imaging (Fig. 10 d-g). The probe showed high signal to noise ratio, strong tissue affinity, blood-brain barrier permeability and other advantages (Fig. 10 H and I), and achieved accurate and sensitive detection of amyloid-beta plaques in vivo[49].
Tang et al. Developed a fluorescent probe TFM with strong absorption in the NIR region using the malononitrile group as an acceptor (fig. 11A). The compound has a rotator like twisted structure and exhibits typical AIE properties. The molecules in the TFM aggregates are loosely packed in an amorphous manner, and the efficient intramolecular motion enhances the energy dissipation of the thermal inactivation pathway. The TFM nanoparticles prepared by the nano-deposition method (fig. 11B) showed high photothermal conversion efficiency (51.2%) and reactive oxygen species (ROS) generation efficiency, enabling photoacoustic imaging and PDT of EMT-6 tumors in mice (fig. 11c)[50].
Ding et al. Designed and synthesized an NIR fluorescent probe with AIE properties using QM as an acceptor (Fig. 12A). This molecule was co-assembled with a chemiluminescent molecule to form nanoparticle AGL AIE dots with NIR afterglow luminescence (fig. 12b). Through a series of chemical reactions or physical actions in the nanoparticles, such as the production of singlet oxygen by AIE molecules, the formation and decomposition of dioxetane and the energy transfer of chemical excitation energy to AIE molecules, AGL AIE dots have strong NIR afterglow luminescence. After the first excitation, the energy was transferred to AIE molecules by chemical excitation through the decomposition of dioxetane, and the afterglow remained for 10 days. After intravenous injection of AGL AIE dots into peritoneal cancer mice, AGL AIE dots have rapid quenching characteristics in normal tissues such as liver, spleen and kidney, which makes the afterglow signal ratio of tumor and liver 100 times higher than that of fluorescence imaging. AGL AIE dots have an ultra-high tumor to liver signal ratio and low afterglow background signal in precision image-guided cancer surgery (fig. 12c)[51].
Liu et al. Designed an AIE fluorescent probe TPACN with NIR luminescence using malononitrile as an acceptor and triphenylamine as an electron donor (Fig. 13 a). Combine that probe with D-alanine (D-Ala) to form a cell metabolism probe TPACN-D-Ala; The TPACN-D-Ala probe showed low fluorescence signal and strong ROS generation in a complex biological environment (fig. 13d). TPACN-D-Ala exhibits excellent water solubility, is very small in size (0.5 nm) under physiological conditions, readily diffuses into bacteria and participates in peptidoglycan biosynthesis to form peptidoglycan-TPACN, allowing AIE molecules to bind to the bacterial wall for targeted fluorescence imaging (Fig. 13 B). Compared with the traditional two-step labeling method, the fluorescent probe is more suitable for labeling bacteria in vivo. More importantly, TPACN-D-Ala can intelligently identify bacteria hiding in host cells or biofilms, and effectively kill them through PDT, which is a non-antibiotic strategy for in vivo bacterial killing[52].
Xu et al. designed and synthesized the photosensitizer TTD (Fig. 14) with D-π-A-π-D structure by using 2- (4H-pyran-4-alkylene) malononitrile as the acceptor group and TPA-TPE as the electron donor. The molecule has NIR luminescence and typical AIE properties. Subsequently, they assembled AIE molecule TTD, upconversion nanoparticles UCNPs and cyclic peptide cRGD into nanoparticles UCNP @ TTD-cRGD NP using amphiphilic polymer DSPE-PEG2000-MAL. The nanoparticles had high photostability, and the fluorescence intensity remained above 70% after 30 days. Under NIR light excitation, a large amount of ROS production was detected even when 6 mm thick tissue was covered. UCNP @ TTD-cRGD NPs can specifically target and selectively kill cells overexpressing αvβ3 integrin (MDA-MB-231). Intravenous injection of UCNP @ TTD-cRGD NPs under NIR light irradiation can target tumor cells in mice and achieve the therapeutic effect of PDT[53].

5.3 Design and Application of Ionic Salts NIR Dy

NIR fluorescent probes with AIE properties have been widely used in the field of biological imaging and targeted therapy.However, the aqueous environment of organisms leads to poor compatibility between organic fluorescent molecules and the target application environment, which has a certain impact on the targeted imaging and therapeutic effect of the probes. The commonly used solution is to assemble amphiphilic polymers and AIE molecules into nanoparticles, which can play a role in the form of passive targeting at specific biological sites. However, the AIE molecules coated by the polymer have been immobilized in the aggregation state, which greatly reduces the AIE characteristics of the fluorescent probe in the aggregation process. Ionic salts are electron-deficient groups and have good water solubility, which are ideal receptors for designing water-soluble or amphiphilic NIR fluorescent dyes. In addition, some ionic salt groups (such as indole salts and pyridine salts) have certain targeting effects on specific biological organelles. Therefore, the introduction of ionic salt groups into the AIE system can not only increase the biocompatibility of fluorescent probes, but also improve the targeting of molecules. Our research group developed a class of NIR fluorescent dyes (TPP-1, TPP-2, and TPP-3) using indole salts as electron acceptors and triphenylpyrrole derivatives as donors (Fig. 15A), which all showed typical AIE properties and could realize wash-free imaging of mitochondria in different cells[43]. Among them, TPP-2 molecules stain mitochondria in various living cells in less than 10 s, and the whole process can make full use of the characteristics of fluorescent molecules gathering on mitochondria to track the opening of signals (Fig. 15B). In addition, the dye shows excellent light stability under the irradiation of an excitation light source for a long time[54].
Wang et al. designed and synthesized an AIE fluorescent probe MTi with D-π-a structure based on indole salt as electron acceptor (Fig. 16A). MTi can be specifically targeted to mitochondria through indole cations, and the D-π-a conjugate structure can efficiently generate ROS. NIR nanoparticles (PMTi) based on polydopamine (PDA) can significantly enhance the therapeutic effect and improve the stability of fluorescent probes in aqueous phase. PMTi has good PDT and PTT effects and can induce apoptosis of cancer cells and inhibit tumor growth (fig. 16 B). The AIE properties of PMTi allow it to maintain long-term fluorescence imaging at the tumor site without significant toxicity to the physiological function of the organ[55].
Ding et al. designed and synthesized the NIR fluorescent dye TPE-DPA-TcyP based on the pyridinium group (fig. 17A). The AIE fluorescent probe can specifically induce oxidative stress of mitochondria in cancer cells to kill immunogenic cells, and is an inducer of immunogenic cell death (ICD). Experiments show that the effect of the mitochondria-targeted ICD inducer is obviously superior to that of commercial Ce6, PPa and oxaliplatin. TPEDPA-TCyP has better effectiveness and robustness in inducing anti-tumor immunity and immune memory effect. Immunocytochemical analysis demonstrated the underlying mechanism of action of the probe, which triggers both innate and adaptive immune systems (fig. 17b). This study is the first to reveal the relationship between mitochondrial oxidative stress and ICD[56].
Tang et al. designed and synthesized a far infrared/NIR emitting fluorescent molecule MeTTPy with AIE properties (Figures 18a and B) by using pyridinium salt as the acceptor. The AIE molecule has the advantages of simple chemical structure, excellent photostability, large Stokes shift, high quantum efficiency and good biocompatibility. At the same time, the molecule has an ultra-high ROS production efficiency (90.7%) and can specifically ablate cancer cells on normal cells without additional targeting ligands. Using ultra-low power lamps (18 mW·cm-2) irradiation, tumor-targeted PDT effects can be achieved without significant impact on the health of the organism (figs. 18c and d)[57].
Subsequently, Tang et al. replaced the thiophene in the above work with a furan group as a π-conjugated bridge between the donor-acceptor to synthesize three pyridinium derivatives (TFPy, TFVP, TPE-TFPy). These three molecules specifically target three key subcellular organelles, namely mitochondria, cell membranes, and lysosomes, respectively (fig. 19A). All AIE molecules showed strong fluorescence emission properties in the far infrared/NIR region and had high ROS generation efficiency. In vitro and in vivo PDT evaluation showed that the combination therapy of three AIE molecules could produce better therapeutic effect than single AIE molecule at the same total concentration, achieving synergistic photodynamic therapy of "1 + 1 + 1 > 3" (Fig. 19b)[58].
Tang et al. Also used a hydrophilic pyridinium salt and a hydrophobic triphenylamine to form an amphiphilic stilbene derivative (AS2CP-TPA) (Fig. 20 a), which could stain cell membranes and monitor membrane morphology under different conditions. Due to the strong D-a interaction and AIE properties, AS2CP-TPA exhibits weak luminescence in aqueous solution, but it can aggregate on the plasma membrane of HeLa cells and produce NIR luminescence under the excitation wavelength of 460 nm. AS2CP-TPA specifically stains the plasma membrane and is highly photostable, allowing long-term monitoring of morphological changes in the cell membrane during Hg2+ and trypsin treatment (figs. 20b-d)[59].
At the same time, Tang Benzhong et al designed and synthesized a water-soluble NIR fluorescent probe TTVP with AIE characteristics, using triphenylamine as electron donor, thiophene ring as electron transport bridge and pyridinium salt as electron acceptor. TTVP was able to selectively target Gram-positive bacteria after an incubation time of only 3 s by a wash-free procedure. Moreover, TTVP has an extremely high active oxygen generation efficiency and excellent photodynamic antibacterial treatment performance (fig. 21)[60].

6 Conclusion

Since the discovery of AIE phenomenon in 2001, AIE molecular families with different functions have been growing and their application fields have been expanding. In the field of biological applications, the developed NIR fluorescence probes with AIE properties are mostly concentrated in the NIR-I region (700-900 nm), while the NIR-II region (1000-1700 nm) fluorescence probes have the advantages of more sensitivity, higher resolution and deeper penetration into biological tissues, and have potential application value in clinical medicine. Therefore, the development of multifunctional NIR-Ⅱ fluorescent probes will become the focus of NIR dye research in the future. Therefore, the design of NIR-Ⅱ fluorescent probes with AIE properties will become the research focus of AIE dyes. At present, the acceptor groups used in the design of NIR-Ⅱ fluorescent dyes with AIE properties are relatively single, and most of them are bisbenzothiadiazole structures. Therefore, the development of new acceptor groups is the key to expand the variety of NIR-Ⅱ dyes. In addition, the designed NIR molecules were coated with amphoteric polymers to prepare nanoparticles in biological applications, which not only increased the biocompatibility of the molecules, but also made the nanoparticles with uniform size easier to be ingested by cells. However, nanoparticles are passively targeted to specific sites in vivo for imaging and therapeutic purposes through the high permeability and retention (EPR) effect of tumors, resulting in low material utilization and increased risk of side effects. Therefore, the design of NIR-Ⅱ fluorescent probes with AIE properties, single-molecule targeting and good biocompatibility will be a challenge in the future. In addition, the current research of NIR fluorescent dyes mainly focuses on basic research, and there is still a long way to go for clinical application. Therefore, animal model evaluation, toxicology, pharmacokinetics and other studies before the clinical application of NIR dyes are particularly important for clinical application. In a word, the development and application of AIE NIR dyes will open up a new way in many fields, such as bioluminescence imaging, photoacoustic imaging, photothermal therapy and photodynamic therapy.

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Funding

the National Natural Science Foundation of China(21875019)

the National Natural Science Foundation of China(51673024)

the National Natural Science Foundation of China(21975020)

the National Natural Science Foundation of China(51803009)

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