Benzobisthiadiazoles: From structure to function

Dyes and Pigments 171 (2019) 107746

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Benzobisthiadiazoles: From structure to function Fengying Ye, Weijie Chen, Yingle Pan, Sheng Hua Liu, Jun Yin

T ∗

Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan, 430079, China

ARTICLE INFO

ABSTRACT

Keywords: Fluorescent dyes Benzobisthiadiazole Near-infrared emission Semiconductor Bioimaging

Benzobisthiadiazole has been widely applied as a classic molecular backbone in the construction of various nearinfrared fluorescent materials due to its excellent photostability, thermostability, far fluorescence emission, large stoke shifts, and adjustable structures. In this review, we summarize the recent progress of benzobisthiadiazolebased fluorescent dyes on organic semiconductors and biomaterials and discuss in detail the relationship between molecular structures (e.g. functional groups, conjugation, shielding unit, etc.) and properties (e.g. UV–Vis absorption, emission, band gap, Stokes shift, quantum yields, semiconductor property, bioimaging performance, etc.). A thorough understanding of these properties and related mechanisms is pertinent for the molecular design of novel benzobisthiadiazoles. It will be helpful for the molecular design of novel benzobisthiadiazoles.

1. Introduction Near-infrared organic fluorescent dyes are generally defined as the absorption or emission spectra falling in the range from 700 nm to 2500 nm and have been applied in organic light emitting diodes [1], solar cells [2,3], bioimaging [4,5], optical communications [6,7]. According to their molecular structures, the types of near-infrared organic fluorescent dyes mainly include cyanines [8,9], hemicyanines [10,11], phthalocyanine [12,13], BODIPYs [14–16], benzothiadiazoles [17–20], xanthene-based derivatives [21,22], etc. Among these, the benzobisthiadiazole backbone has been attracting more and more attention due to its excellent photostability and thermostability, far fluorescence emission, large stoke shifts, adjustable structures, among other advantageous properties [23,24]. Furthermore, two main factors attribute to its superior quality: the presence of a hypervalent sulfur atom, leading to electron deficient behavior; the other one is that it adopts quinone structure or diradical character, making the electron density more delocalized on the whole molecular framework so as to narrow the band gap [25,26]. Because of its specific strong electron-withdrawing character and low band gap, it can serve as an efficient electron-acceptor to construct the donor-acceptor systems. In recent years, the functional benzobisthiadiazole derivatives have been widely reported and applied in the syntheses of numerous organic semiconductors and bioimaging materials [27,28]. (see Scheme 1) In consideration of the significance and requirements of new functional benzobisthiadiazoles, we summarize the recent progress of benzobisthiadiazole-based fluorescent dyes in order to gain insight into the relationship between molecular structure and properties in this review.

∗

In detail, we discuss the influence of functionalized moieties on benzothiadiazoles towards its optical behavior, fluorescence quantum yield, renal excretion rate, etc. It is expected that this work will be useful in the future design of benzobisthiadiazoles with novel molecular structures and advanced function. 2. Molecular structure and optical behavior The band gaps of the benzobisthiadiazole backbone 1 and its selenadiazole analogue 2 are 5.52 and 5.43 eV, respectively [29], while the isomer 3 of benzobisthiadiazole 1 and its derivative [1,2,5] thiadiazole [3, 4-g] quinoxaline 4 have higher band gaps (7.99 eV and 6.88 eV, respectively). This finding strongly suggests that benzobisthiadiazole 1 and benzobisselenadiazole 2 can serve as an effective electron-acceptor to construct the donor-acceptor molecular systems. Moreover, utilizing their large atomic orbital coefficients of 4- and 8- sites, different substituents can be installed on the 4- and 8- sites of benzobisthiadiazole and benzobisselenadiazole to regulate their photophysical properties. On account of the synthetic difficulty of benzobisselenadiazole, the vast majority of reported compounds are based on the backbone 4,7-dibromo-5,6-dinitrobenzo[c] [1,2,5]thiadiazole and its dibromide 5 which is easily obtained and functionalized [30–36]. As such, the relationship between the molecular structure and optical behavior via UV–Vis absorption and fluorescence spectral analysis is discussed. According to reported benzobisthiadiazoles, most of them were obtained by the Stille coupling or Suzuki coupling. Early in 1997, Yamashita et al. have synthesized 4,7-dibromobenzobisthiadiazole 5, which showed a maximum absorption wavelength at 524 nm and a

Corresponding author. E-mail address: [email protected] (J. Yin).

https://doi.org/10.1016/j.dyepig.2019.107746 Received 10 May 2019; Received in revised form 18 June 2019; Accepted 21 July 2019 Available online 23 July 2019 0143-7208/ © 2019 Elsevier Ltd. All rights reserved.

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Scheme 1. Chemical structures of varies fluorophores that have been studied.

maximum fluorescence emission at 557 nm [29]. Additionally, the same group also investigated the effect of other donor substituents towards optical behavior. For example, when phenyl was used as electron donor (e.g. compound 6), the absorption red-shifted to 558 nm and its fluorescence also shifted to 642 nm. It was worth noting that their absorption appeared in near-infrared region when the bromide of 5 was substituted by N, N-dimethyl phenyl (e.g. compound 7, maximum absorption wavelength at 732 nm) and morpholine (e.g. compound 8, maximum absorption wavelength at 764 nm, as shown in Table 1 [29]). In 2012, Wang and co-workers [30] introduced the tetraphenylethene backbone to benzobisthiadiazole to afford compounds 9 and 10, respectively. Compared with the previous use of donors such as phenyl, N, N-dimethyl phenyl, etc., the introduction of TPE further narrowed the band gap leading to a redshift in the fluorescence spectrum. Moreover, compounds 9 and 10 respectively exhibited maximum

emission at 787, 857 nm falling among the NIR-I region (700–900 nm). Particularly, the band gap narrowed down from 1.67 eV to 1.50 eV due to the electron-donating property of the methoxyl group, which generated a bathochromic shift in the fluorescence spectrum around 80 nm. These results manifest that increasing the electron donor capacity could obtain ideal compounds with longer fluorescence spectra (optical information is summarized in Table 1). In 2008 [32] and 2009 [31], Wang's group further put forward another theory that fluorescent molecules with a large band-gap D-A structure are usually limited in preparing red or far-red emission compounds (700–800 nm), but seldom have been used to build NIR-I region (800–1000 nm) and even NIR-II region (1000–1700 nm) fluorescent chromophores. On the other hand, introducing some appropriate molecular fragments as π spacer to compounds can facilitate intramolecular charge transfers or extend conjugated degrees in order to 2

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Scheme 1. (continued)

obtain fluorophores with a low band gap. Therefore, a series of fluorophores (11, 12, 13, 14, 15, 16, 17, 18) with a D-π-A-π-D framework were designed and synthesized by Wang's group to confirm the proposed theory. The maximum fluorescence emission of all fluorophores reached around 1000 nm and extended to 1600 nm, which cannot be realized by simple or common compounds with D-A structure. Among compounds 11, 12, 13, and 14, benzobisthiadiazole was employed as an electron-withdrawing block, different substituents modified with diamine as electron acceptors (e.g. phenyl, tolyl, and naphthyl), and benzene or thiophene moiety as a π-spacer. Significantly, incorporating thiophene as a π-bridge caused more electron delocalization and promoted intramolecular charge transfer effectively. Accordingly, the fluorescence emission of these four compounds all exceeded 1000 nm and red-shifted around 150–220 nm, exhibiting better photophysical properties compared with the previous reported fluorescence chromophores with D-A structure. Moreover, their excellent near-infrared II region fluorescence emission and high external quantum efficiency (EQE) (0.08%, 0.12%, 0.28%, of compounds 11, 12, 13, respectively, and not applicable of compound 14), endowed them the most potential

candidate for constructing NIR organic light-emitting diodes (OLEDs), as shown in Fig. 1. Moreover, slight changes in the structure of diamine, such as introducing a methyl phenyl or naphthyl group, caused no obvious difference or variation in the band gap (Table 2). Comparatively, introducing a different π-spacer largely impacted the optical properties of compounds. For example, compounds 11 and 14 both possessed the same donor and acceptor reported by Ma in 2009 [31]. However, compound 14 exhibited an emission peak at 1305 nm and showed a bathochromic shift around 230 nm with a remarkably low band-gap down to 0.73 eV, as illustrated in absorption and fluorescence emission spectra of compound 11–14 (Fig. 1). The findings suggested that the electron-rich nature of thiophene facilitated the qunoid structure, making the molecule more planar and, thus, favoring intramolecular charge transfer between the donor and acceptor in order to narrow down the band gap. This phenomenon could also be observed between compounds 11 and 15 and between compounds 16 and 17 [32]. Additionally, organic fluorophores with thiophene as the π-spacer also displayed a red-shift in the absorption and emission peak compared with 3,4-ethylenedioxy thiophene. Taking compounds 23 and 24 3

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Scheme 1. (continued)

[33,34] and compounds 25 and 26 [35] for example, the maximum emission of fluorophores 23 and 25 containing thiophene as spacers were at 1090 and 1120 nm, respectively, showing red-shifts around 43 and 96 nm remarkably. This could be explained by the fact that the dihedral angle between the bulky 3,4-ethylenedioxy thiophene spacer or donor and the acceptor benzobisthiadiazole (31–34°) was larger than that between thiophene and benzobisthiadiazole (0.7°), as shown in Fig. 2 of the three typical fluorophores 24, 23, and 35 [33]. The figure clearly indicates that the absorption and emission spectra would not perform a red-shift when selecting large hindrance groups as the πspacer or donor. Meanwhile, introducing donors or bridging units with

too-large volumes even caused hypochromic-shift in the absorption or emission band of chromophores. For instance, compound 30, with 3alkyl (octyl) substituted thiophene, displayed absorption and emission wavelengths respectively at 721 and 1005 nm. Fluorophore 30 also exhibited eye-catching blue-shifts around 168 and 65 nm compared with thiophene-modified fluorophore 31, of which absorption occurred at 889 nm and PL emission at 1070 nm [34] (concrete information is summarized in Table 2). In 2009, Wang et al. proposed a novel strategy to induce a redshift in spectra in which a bare hydrogen atom could form an intramolecular hydrogen bond with the nitrogen atom in an adjacent 4

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benzobisthiadiazole moiety [36]. Compound 19, with a pyrrole unit, absorbed at the longest wavelength of 1020 nm and emitted at 1213 nm with a bandgap of 0.86 eV, which also showed a large redshift around 172 and 158 nm respectively compared with compound 18, which implemented thiophene as a spacer with a 1.15 eV bandgap (Table 2). Here, the hydrogen bond mainly reduced the electron cloud density on benzobisthiadiazole so as to make the acceptor behave in a more electron-deficient state and narrow the band-gap. Compound 18 not only exhibited excellent NIR fluorescence emission, but also possessed outstanding electrochemical activity and was successfully applied in solar cells, as illustrated in Fig. 3. It is pertinent to mention that the absorption peak of compound 18-PCBM (PCBM [6,6]:-Phenyl-C61-butyric Acid Methyl Ester) exhibited a slight red-shift around 26 nm compared with that of bare compound 18, which could be explained by the charge transfer interaction between the compound and PCBM.

Table 1 The optical data of compounds 5–10. Comp.

donor

λabs [nm]

λem [nm]

Stokes shift [nm]

Energy gap [eV]

Ref.

5 6 7 8 9 10

bromide phenyl p-Me2NC6H4 morpholine TPE MTPE

524a 558a 732a 764a 612b 632b

557a 642a N.A. N.A 787b 857b

33 84 N.A. N.A. 175 225

N.A. N.A. N.A. N.A. 1.67 1.50

[29] [29] [29] [29] [30] [30]

TPE: tetraphenylethene. MTPE: 2, 2-bis(4-methoxyphenyl)-1-phenylethene. N.A.: not applicable due to its poor solubility. a Data were measured in dichloromethane. b Data were measured in THF.

Fig. 1. (a) Absorption spectra and (b) Fluorescence emission spectra of compounds 11–14 in dichloromethane. (c) Normalized electroluminescence spectra for OLEDs at 10 V recorded using a JYSPEX CCD3000 spectrometer. (d) Normalized NIR electroluminescence spectra for OLEDs at 10 V recorded using a PTI fluorescence spectrophotometer. (e) Energy diagram of the device based on compound 12 (relative to the vacuum energy level). (f) Current density (J)–voltage (V)–radiance (R) characteristics of the devices. (g) External quantum efficiency–current density characteristics of the devices. Reproduced from Ref. 31 with permission from John Wiley and Sons. Table 2 The optical data of compounds 11–17, 23–26, and 30, 31, 35, 18–20. Comp. 11 12 13 14 15 16 17 23 24 25 26 30 31 35 18 19 20

π-spacer phenyl phenyl phenyl thiophene thiophene phenyl thiophene thiophene EDOT thiophene EDOT 3-alkyl(octyl)- thiophene thiophene EDOT thiophene pyrrole thiophene

donor

λabs [nm] a

N,N-diphenylamino N-phenyl-N-(4-methylphenyl)amino N-phenyl-N-(4-naphthyl)amino N,N-diphenylamine TPA N,N-bis(4-octyloxyphenyl)amino 4-(N,N-bis(4-octyloxyphenyl)amino)phenyl fluorene fluorene fluorene fluorene fluorene fluorene alkoxy-dibenzene fluorene fluorene fluorene

700 713a 699a 945a 879b 763b 920b 815d 723d 738e 850e 721f 889f 725d 848b 1020b 1260b

λem [nm] a

1050 1080a 1040a 1285a 1120c 1065c 1125c 1090d 1047d 1024e 1120e 1005f 1070f 1047d 1055c 1213c N.A.

Stokes shift [nm]

Energy gap [eV]

Ref

350 367 341 340 241 302 205 275 324 286 270 284 181 322 207 193 N.A.

1.27 1.36 1.31 0.73 0.98 1.19 0.83 N.A. N.A. N.A. N.A. N.A. N.A. N.A. 1.15 0.86 N.A.

[31] [31] [31] [31] [32] [32] [32] [33] [33] [35] [35] [34] [34] [33] [32] [36] [36]

a/b/c/d/e/f: data were measured in dichloromethane/in Toluene at a concentration of 10−5 mol L−1/in toluene at a concentration of 10−4 mol L−1/in DMSO/in water/in Toluene. TPA: triarylated amine. EDOT: 3, 4-ethylenedioxy thiophene. 5

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Further, another approach is applicable to reduce the electron cloud density of core benzobisthiadiazole by which Lewis acids are added into compounds containing benzobisthiadiazole. As shown in Fig. 4b, the two absorption lines respectively represented compounds 18 and 20 (18 mixed with BF3) [32,36,52]. Compound 18 initially showed a single absorption peak at 834 nm, ranging from 600 to 1500 nm. After adding excess BF3, compound 20 exhibited three new absorption peaks at 620, 850, and 1260 nm, displaying a solution color change from yellowish green to dark blue as witnessed by the naked eye. Namely, adding a Lewis acid to compound 17 initiated a red-shift in the absorption spectrum around 426 nm, which provides a new method to design molecular compounds with fluorescence emission peaks over 1300 nm. In addition to implementing a triaromatic amine group as an electron donor, researchers have also utilized alkyl chains modified with fluorene, benzene, dibenzene et al. as electron donors, different substituents modified with thiophene or multithiophene as a conjugated bridge or other novel skeletons with shielding units, and functional groups to build a series of fluorescence molecules based on donor unit electron-withdrawing group benzobisthiadiazole to satisfy different functions. Fluorescence spectra of these compounds (21–42) fell in the fluorescence range from 1000 to 1400 nm, namely in the NIR-II region (1000–1700 nm). Since light scattering and biological tissue autofluorescence can be reduced under longer wavelengths, most of fluorophores based on benzobisthiadiazole have been employed in bioimaging for these superiorities. Moreover, imaging in the NIR region can provide deep tissue penetration, high spatial-temporal resolution,

Fig. 2. Dihedral angles of compound 24, 35, 23 in the S1 optimized geometries at the tuned- B 97XD*/6–31 G. Reproduced from Ref. 33 with permission from John Wiley and Sons.

Fig. 3. (a) Absorption spectra of the blend film of compound 18 with PCBM (1:1, w/w; solid line) and compound 18.(b) Cyclic voltammograms of compounds 18 (1 mmol/L concentration). Reproduced from Ref. 36 with permission from Canadian Science Publishing.

Fig. 4. (a) Molecular structures of compounds 18 and 20. (b) Normalized absorption spectra of compounds 18 (10−4 mol/L in THF) and 20 (a mixture of 18 with excess BF3). Reproduced from Ref. 52 with permission from John Wiley and Sons. 6

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Fig. 5. Fluorescences distribution profile. Reproduced from Ref. 37 with permission from the Royal Society of Chemistry.

Fig. 6. Fluorescence images of the cerebrovasculature of mice (n = 2) without craniotomy in the (a) NIR-I. (b) NIR-II, and (c) NIR-II b regions, with the corresponding SBR analysis shown in (d)–(f). Scale bars: 2 mm.(imaging agent: a: indocyanine green; b: HiPCO; c: SWNTs). Reproduced from Ref. 38 with permission from John Wiley and Sons. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 7. The general relationship between different electron donors and spectra value. R: different substituent groups have been reported.

and excellent imaging quality in vivo compared to traditional fluorescence imaging. Yet, it remains difficult to obtain organic small-molecular fluorophores with longer-wavelength emission peaks located in the NIR region (1500–1700 nm, NIR-II b region) instead of merely extending emission to the 1400 nm region. Imaging in the NIR region would provide clearer and sharper resolutions comparable to semiconducting single-wall carbon nanotubes (PL in 1500–1700 nm) with emission in the NIR-II b region, which was reported by Dai’ groups in 2015 [37,38]. Herein, the fluorescence map (Fig. 5) and a fluorescence imaging contrast diagram of the mice cerebrovasculature in different PL regions are provided to highlight the immense superiority of long-wave imaging (Fig. 6). Hence, it is extremely necessary to study and comprehend the influence of molecular structure on spectral characteristics and corresponding bathochromic shift strategies to acquire unique organic fluorophores with NIR-II b emission. Thus, we provide the general relationship between different electron donors based on core benzobisthiadiazole and its spectral values, as shown in Fig. 7.

3. Methods toward adjusting fluorescence quantum yield In 2009, Wang and co-workers [31] reported synthesis and application of four organic chromophores (11, 12, 13, 14) in constructing NIR organic light-emitting devices. The fluorescence quantum yields of the first three compounds (11: 7.4%, 12: 5.8%, 13: 6.3%) were significantly higher than that of compound 14 (0.5%), which was attributed to compound 14 that had the least positive oxidation potential, as illustrated in Table 3. It is also worth mentioning that the fluorescence quantum yield of these four compounds decreased along with the red shift of fluorescence spectrum. This phenomenon could also be observed in constructing NIR imaging contrast agents with longer wavelengths and higher quantum yields. In addition to utilizing longer wavelength emission to obtain high imaging quality, fluorophores with high quantum yield can also complement each other. High fluorescence intensity allows a greater penetrable depth of imaging, providing realtime detection at high speeds and frame rates within less exposure time. More than that, fluorophores with high fluorescence quantum yield 7

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Table 3 The optical data of compounds 11–14. Comp. 11 12 13 14 a b

π-spacer phenyl phenyl phenyl thiophene

donor N,N-diphenylamino N-phenyl-N-(4-methylphenyl)amino N-phenyl-N-(4-naphthyl)amino N,N-diphenylamine

Quantum yield % a

7.4 5.8a 6.3a 0.5a

E1/2(ΔEp)b [V]

Energy gap [ev]

Ref.

0.33(74), −1.2(99) 0.35(60), −1.16(100) 0.37(72), −1.2(99) −0.15(70), −0.04(78), −1.02(70), −1.58(64)

1.27 1.36 1.31 0.73

[31] [31] [31] [31]

Data were measured in Toluene, referred as IR-125 with QY 13% in DMSO. E1/2 = 1/2(Epa + Epc), ΔEp = Epa – Epc. Data were measured in DCM. Epa and Epc were anodic and cathodic potentials.

Fig. 8. (a) NIR-II fluorescent images (10 ms, 1100 LP) of compound 27 (CH-PEG) and compound 28 (CH-4T) in deionized water, FBS and PBS. (b) Photographs and corresponding NIR-II fluorescent images (10 ms, 1000 LP) of carbon nanotubes, compound 27 (CH-PEG) and compound 28 (CH-4T) in HSA, FBS and heated FBS. Reproduced from Ref. 40 with permission from Springer nature.

could reduce the amount of injection, thus shortening the retention time of fluorescence contrast agents in vivo so as to reduce the unknown long-term toxicity. However, to acquire longer-wavelength fluorescence emission, the frequently-used methods to design such molecules based on large conjugation with low band gaps usually are limited by low fluorescence intensity. The way usually increase the interaction between the conjugated backbone and other molecules or surrounding environment, such as water, which would promote nonradiative transitions resulting in low fluorescence quantum yield. Therefore, numerous researchers have paid more attention to improving the fluorophores' quantum yields with the purpose of constructing more NIR-II region molecules with excellent performance, further enriching the biomedical imaging system. Here, we analyze and summarize the relationships between molecular structure and fluorescence quantum yield, together with the rational methods of enhancing the chromophores’ fluorescence intensity. In 2015, Dai's group reported the first organic small-molecule NIR-II fluorophore based on acceptor, benzobisthiadiazole, namely, compound 22, which used for in vivo imaging. The compound also utilized triarylated amine with four carboxylic acid groups as the electron donor. To further increase its solubility in different solutions, 22 was modified with PEG-NH2 (compound 27). Unfortunately, compound 27 showed a low quantum yield only around 0.3% in aqueous solution, which was referred to as IR-26 with QY = 0.5% [39]. Later, Dai and Cheng et al. made small changes in the structure of compound 22, replacing carboxylic with sulfonic acid group, to acquire compound 28 [40]. Although no obvious improvement was seen in the fluorescence intensity in aqueous solution compared with that of compound 27, 28 displayed about 5% higher fluorescence intensity in fetal bovine serum (FBS) than that in phosphate buffered solution (PBS), as shown in below Fig. 8. Interestingly, heating the complexes of compound 28 and plasma proteins increased the fluorescence intensity to 11% compared with that of compound 27. Furthermore, after being

cooled down to the room temperature, the dye-protein complexes still maintained high fluorescence brightness. The authors propounded a theory to explain this phenomenon that the negatively charged sulfonate group of fluorophore 28 could be combined with serum protein surfaces through supramolecular self-assembly so as to enhance the fluorescence intensity. Heating the complexes was performed to find optimal binding between the dye and serum protein, or in other words, optimizing the interaction between dyes and proteins could improve the fluorescence quantum yield. In order to further verify outstanding performance of optimized compound 28-FPS-HT (HT: heated) with ultra-high fluorescence intensity, 1–3 mm penetration depth, and high spatial resolution, the authors conducted hemodynamic vessel imaging of mice injected with 28-FPS-HT [35]. As illustrated in Fig. 5, compounds 28, 28-FBS-HT, and 27 were injected into the hind limbs of mice with an equivalent dosage. After 10 min, compound 28-FBS-HT showed obvious and clear vascular tissue of mice in a lower exposure time (2 ms) at the fastest frame rate of 50 FPS (feet per second), providing a higher definition compared with free compound 28. In contrast, the fluorescence of the mice injected with compound 27 could not be captured even at a higher exposure time of 50 ms. Specific contrast can be distinctly observed in Fig. 9, which is was mainly due to the fact that compound 28 could hardly bind with serum proteins (concrete data are summarized in Table 4). Considering that dye equipped with negative sulfonate groups could bind with serum protein and increase fluorescence intensity after heating, Dai et al. acquired and subsequently applied two functional dyes, 25 and 26, in biological imaging and image-guided photothermal therapy. Different from compound 28-FBS-HT, the fluorescence quantum yield of complexes containing dye and proteins after heating was only 1.1% (compound 26-HT), which could be explained by the different molecular structures. It is worthy to note that compound 26, containing 3, 4-ethylene dioxythiophene as a π-spacer, showed higher 8

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Fig. 9. NIR-II fluorescent images of mouse hindlimb vasculature 10 min post-injection of (a) free compound 28, (b) compound 28 heated at 70 °C for 10 min in FBS (compound 28-FBS-HT) and (c) compound 27.Copied from Ref. 40 with permission from Springer nature. Table 4 The optical data of D-π-A compounds 27, 28, 28-HT, 25, 26, 26-HT. Comp.

27 28 28-HT 25 26 26-HT

π-spacer

Phenyl Phenyl Phenyl Thiophene EDOT EDOT

donor

N,N-diphenylamino N,N-diphenylamino N,N-diphenylamino fluorene fluorene fluorene

functional group

PEG sulfonic acid group sulfonic acid group sulfonate groups sulfonate groups sulfonate groups

QY %

Ref.

water

PBS

FBS

0.3 < 0.3 N.A. N.A 0.1 N.A.

N.A. 0.098 N.A. N.A. ≈0.95 N.A.

N.A. 4.8 10.8 ≈0.5 1 1.1

[39] [40] [40] [35] [35] [35]

PBS: phosphate-buffered solution. FBS: fetal bovine serum. QY: quantum yield measured as reference IR-26 of QY 0.5%. Fig. 10. (a) NIR-II fluorescence images of control (top), compounds 26 and 25 in water, PBS, and FBS); (b) NIR-II fluorescence images (200 ms, 1000 LP) of blank mouse blood, compound 26 in water, in mouse blood, heating at 37 or 70 °C for 10 min, RT is room temperature. Reproduced from Ref. 35 with permission from John Wiley and Sons.

could also have great impact on fluorescence quantum yield. More and more researchers have been focusing on solving the contradiction between large conjugated molecular skeletons and low fluorescence quantum yield, especially in aqueous solution. According to the analysis of the water molecules’ electrostatic potential, polarity and volume, they showed positive electrostatic potential and strongly interacted with the conjugated backbone containing benzobisthiadiazole, causing aggregation and low quantum yields of fluorophore in water [33,41,44]. In 2016, Dai and co-workers introduced 3, 4-ethylene dioxythiophene as a donor instead of thiophene with the purpose of protecting the conjugated molecular backbone from intramolecular and intermolecular interactions. The group also selected benzobisthiadiazole as the acceptor and 2, 6-dialkoxyl-subsitited benzene as the enveloping group to prevent molecules from aggregating together, namely compound 36, which was used to image traumatic brain injury in NIR-II and monitor dynamic vascular changes of an injured mouse brain. It exhibited a higher quantum yield around 0.7% relative to that of compound 27. Moreover, the group continued to use polyethylene glycol to increase its water solubility. Regrettably, such low fluorescence quantum yield of fluorophore usually lead to low temporal-spatial resolution and longer exposure time [42]. In order to obtain a fluorophore with higher fluorescence quantum

Fig. 11. Emission spectrum and quantum yield of compounds 24, 35, and 23 in H2O. Reproduced from Ref. 33 with permission from John Wiley and Sons.

fluorescence brightness than that of compound 25, which employed thiophene in different solvents [35] (e.g. H2O, PBS, FPS), as illustrated by the fluorescence emission intensity contrast Fig. 10a and b. This implies that different π-spacers, electron donors, and functional groups 9

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Table 5 The optical data of S-D-A-D-S compounds 23, 24, 35–40. Comp.

π-spacer/donor

Shielding unit

QY in water %

Imaging rate[frames' s]

Ref.

23 24 35 36 37 38 39 40

thiophene EDOT EDOT EDOT TEG-thiophene alkoxy-thiophene alkoxy-thiophene alkoxy-thiophene

fluorene fluorene alkoxy-dibenzene alkoxy-benzene fluorene 3 carbons-benzene 6 carbons-benzene 11 carbons-benzene

0.02 2 0.04 0.7 1.9 0.9 1.5 3

N.A. 26.5 (> 1100 nm) N.A. 3 (> 1300 nm) N.A. N.A. N.A. N.A.

[33] [33] [33] [42] [43] [44] [44] [44]

TEG-thiophene: tert (ethylene glycol) substituted thiophene. QY: quantum yield measured as reference HIPCO of QY 0.40%. Fig. 12. Molecular dynamics (MD) simulations of the NIR-II molecular fluorophores of compound 38, 39, 40 in aqueous environment (front view). PEG chain: purple; carbon atom: cyan; oxygen atom: red; sulfur atom: yellow; nitrogen: blue. Reproduced from Ref. 44 with permission from John Wiley and Sons. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Table 6 The optical data of S-D2-D1-A-D1-D2-S compounds 32 and 34. Comp.

donor1

donor2

Shielding unit

QY in water %

Imaging rate [frames' s]

Ref.

32 34

EDOT 3-alkyl(octyl)-thiophene

thiophene thiophene

fluorene fluorene

1.0 ± 0.04 5.3 ± 0.02

N.A. 26.5 (> 1200 nm)

[34] [34]

QY: quantum yield measured as reference HIPCO of QY 0.40%.

yield, the shielding unit concept was applied to prepare the chromophore. Dai's group reported a series of compounds constructed with an S-D-A-D-S structure [33,43] (S: shielding unit; D: donor unit; A: acceptor unit). The group selected thiophene, 3, 4-ethylene dioxythiophene, alkoxy-substituted dibenzene as electron donors and dialkylsubstituted fluorene and tert (ethylene glycol)-substituted thiophene as shielding groups to acquire four compounds: 23, 35, 37, and 24 with QY of 0.02%, 0.4%, 1.9%, and 2%, respectively, in water solution (Fig. 11, Table 5). From the preliminary analysis of fluorescence quantum yield, it could be seen that fluorophores with large steric hindrance donors, such as 3, 4-ethylene dioxythiophene, alkoxy-modified dibenzene, revealed higher quantum yields than those of compounds with a more planar thiophene unit. Not only that, the shielding group containing long alkyl or alkoxy chains further distorted the whole conjugated backbone and enhanced the quantum yield. For example, the long alkyl chains on fluorene or dibenzene exhibited more stretching out of the molecular plane, resulting in the molecule being more distorted and reducing nonradiative decay. This could also be confirmed by the dihedral angle between donors and shielding units in chromophores 24 (24°), 35 (25°), and 23 (18°). Although dibenzenesubstituted compound 35 showed a larger distortion than fluorenemodified compound 24, the quantum yield of 35 was lower than the latter. This was mainly due to the irresistible reason that compound 35 with the alkoxy dibenzene shielding unit would stack in a parallel manner, weakening the shielding effect.

Dai et al. put forward another theory to improve the QY of fluorophore by increasing alkyl chains on the shielding unit moderately. In Dai's work, 2, 6-dialkoxy substituted benzene was selected as the shielding group. With the number of carbons on alkoxy chains increasing from 3 to 6 and 11 [44], the fluorescence QY of organic dyes also ranged from 0.9% to 1.5% and 3% in aqueous solution referred as HiPCO carbon nanotube with 0.4% QY, respectively, exhibiting a positive correlation (Table 5). The specific influence mechanism between different lengths of alkoxy chains and fluorescence quantum yield can be described by molecular dynamics (MD) simulations, as illustrated in Fig. 10. Different lengths of shielding units exhibited different coverage areas over the whole molecular skeleton. For instance, chromophore 40 containing 11 carbons almost covered the entire backbone, effectively preventing the core benzobisthiadiazole from interacting with water molecules, while the two other chromophores, 38 and 39, only reached the donor or acceptor group (Fig. 12). In addition, Dai's group also proposed a new method to improve the fluorescence intensity by introducing another donor adjacent acceptor as the first electron donor (D1) with the purpose of adjusting the dihedral angle between the donor and acceptor. Thiophene was maintained as the second donor (D2) in order to increase the conjugation degree and acquire a novel molecular framework: S-D2-D1-A-D1-D2-S [34] (Table 6). Consequently, they employed bulky and hydrophobic octylthiophene as the first donor, thiophene as the second donor, and fluorene as

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Fig. 13. NIR-II fluorescence image of the left hindlimb of a mouse (a) by compound 34, (b) by compound 32 with an ultrafast frame rate of 25.6 frames per second. Reproduced from Ref. 34 with permission from American Chemical Society.

the shielding unit to obtain outstanding small-molecule fluorophore 34 with a higher quantum yield up to 5.3% in aqueous solution compared to compound 32 composed of 3, 4-ethylene dioxythiophene as the first donor (QY: 1.4%). The high fluorescence intensity endowed compound 34 with superior temporal and spatial resolutions in NIR-II imaging of the blood vessels in a mouse at an ultrafast frame rate of 25.6 frames per second. As indicated by the imaging contrast in Fig. 10, fluorophore 34, as the contrast agent, is clearly viewed in the blood vessels of the left hindlimb of the mouse, while the imaging picture obtained with compound 32 as the imaging agent with the same wavelength long pass filters is blurry (Fig. 13).

Currently, some organic fluorophores without hydrophilic groups exist, which are usually encapsulated in a polymer matrix, compensating for their hydrophobicity to achieve water dispersion and in vivo biological stability. However, most traditional aromatic fluorophores cause fluorescence weakening or even quenching when in the aggregation state due to a tight intramolecular π-π stacking interaction or other weak interaction, namely aggregation-caused quenching (ACQ). Luckily, in addition to the optimization of the molecular structure, some excellent researchers have captured the outstanding merits of fluorophores with aggregation-induced emission (AIE) [45–47]. When encapsulated in the hydrophilic polymer matrix, the fluorescence

Fig. 14. Scheme of fluorophores encapsulated in polymer matrix. (a) Compound 24 and the PS-g-PEG polymer. (b) Compound 41 and the ionomer. Reproduced from Ref. 49 with permission from springer nature, Ref. 50 with permission from American Chemical Society. 11

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Fig. 15. (a) Brain vasculature imaging of mice injected with ICG. (b) Brain vasculature imaging of mice injected with compound 27 (c) Fluorescence imaging of brain, hindlimb, and belly of mice injected with compound 24. Reproduced from Ref. 39, 49 with permission from Springer nature.

intensity remained unchanged or even enhanced. For example, in 2008, Liu and co-workers reported a bright AIE fluorophore 21 equipped with a rotary AIEgen of N,N-diphenylvinyl aniline as the donor and benzobisthiadiazole as the acceptor [48]. Fluorophore 21 was also encapsulated in a hydrophilic polymer matrix to demonstrate its biocompatibility, forming fluorophore 21 dots. The dots displayed a maximum emission peak at 1000 nm and a large extinction coefficient of absorption at 740 nm with high NIR-II QY of 6.2%, referred as IR-26. Then, the dots were applied to image NIR-II cerebrovascular structures with a high clarity of 38 μm and in NIR-I photoacoustic imaging of intracerebral tumors in mice with a detection depth of 2.0 mm. As for the polymer matrix used for encapsulation, several researchers have revealed another scheme to enhance fluorescence intensity. Some studies found that most NIR small-molecule fluorophores exhibited high fluorescence intensity in common solvents, such as toluene and dichloromethane. However, the fluorescence intensity decreased in aqueous solution due to either its poor solubility or interaction between molecular core and water [34,44]. Fortunately, some investigators suggested that small-molecule organic fluorophores could

be wrapped by amphiphilic polymers to avoid these problems. The hydrophobic interior of amphiphilic polymers could provide an organic solvent-like atmosphere for organic small-molecule fluorophores, thereby inhibiting intermolecular aggregation. The extended long alkoxy chains provided hydrophilicity so as to increase the overall water solubility and biocompatibility of fluorophores. For example, Dai's group utilized the amphiphilic polymer PS-g-PEG (ploy (styrene-cochloromethyl styrene)-graft-poly (ethylene glycol) to wrap fluorophore 24 with an estimated QY up to 16.5% in aqueous solution [49] (specific synthesis methods are shown in Fig. 14). Although fluorophore 24 showed a smaller NIR fluorescence emission at 1010 nm compared with other chromophores, its ultra-high fluorescence quantum yield provided a high spatial and temporal resolution and was successfully applied in noninvasive real-time fluorescence imaging of mice in vivo within a short exposure time of 2 ms. As clearly illustrated in Fig. 15, blood vessels in the brain, hindlimbs, and belly of mice could be more vividly observed compared with other low QY fluorophores imaging quality. Additionally, it was applied to the one-photon three-dimensional confocal imaging of cerebral vessels in mice, achieving a

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Fig. 16. Ex vivo confocal imaging of brain vasculatures of a mouse injected with compound 24. (a) Photo and wide-field NIR-II epi-fluorescence imaging of brain in a mouse injected with compound 24 (808 nm excitation, emission > 1200 nm) with exposure time of 5 ms. b–d Ex vivo confocal imaging of brain in a mouse injected with p-FE (785 nm excitation, emission > 1100 nm, laser power ∼30 mW, PMT voltage ∼ 500 V). (b) Small area (200 × 200 μm, x × y, step size: 1 μm) and (c) Large area (3000 μm × 2000 μm, x × y, step size: 1 μm). The deepest area could reach ∼1350 μm. (d) 3D reconstruction of vasculatures in brain: small area (left side, 200 μm × 200 μm × 200 μm, x × y × z, step size: 1 μm along x, y, and z directions, galvo mirror scanning, scanning speed: 2 s/frame) and large area (right side, 400 μm × 400 μm × 400 μm, x × y × z, step size: 2 μm along x and y directions, 2.7 μm along z direction, stage scanning, scanning speed 7.5 min frame−1). Scale bar represents 6 mm. Reproduced from Ref. 49 from springer nature.

fluorescence quantum yield are provided in Fig. 17. 4. Methods toward adjusting excretion rate Recently, low band gap small-molecule fluorophores based on benzobisthiadiazole have been developed and applied in NIR OLEDs and NIR biological imaging owing to their excellent properties, such as large stokes shift, far fluorescence spectrum emission, among others. Especially for biological imaging or clinical use, it is well known that a contrast agent should possess rapid excretion capacity and low tissue accumulation for its unpredictable long-term biological toxicity. Not only that, low toxicity and favorable excretion pharmacokinetics are two critical factors to gain approval of the US Food and Drug Administration (FDA) and for clinical translation. Therefore, to apply organic fluorophores based on benzobisthiadiazole to biological imaging and clinical applications, the exploration of the excretion rate and mechanism of these fluorophores is in high-demand. Hence, we mainly discuss and summarize the factors affecting the excretion pharmacokinetics and corresponding methods to optimize the excretion rate. Dai's group first reported a small-molecule fluorophore based on benzobisthiadiazole, denoted compound 27, for NIR-II bio-imaging and image-guided surgery. Fluorophore 27 is composed of acceptor benzobisthiadiazole and donor polyethylene glycol-modified triarylamine with 8.9 KDa molecular weight and 3 nm hydration diameter, which is below the filtration threshold of molecular weight 30–50 KDa or a kidney cutoff threshold of 5.5 nm [39]. The compound exhibited superior excretion behavior through urine in the first 24 h post-injection (P.I.) with a fast renal excretion of 83% and blood circulation half-life of 1 h without metabolism in vivo. However, some carbon nanotubes or

Fig. 17. The general strategies towards optimizing fluorescence quantum yield.

visualization of 5–7 μm blood vessel diameter at a 1.3 mm imaging depth, which is the deepest 3D brain tissue imaging depth of singlephoton confocal imaging that has been reported thus far (Fig. 16). Comparatively, some traditional NIR-II agents like compounds 24 and 32 with relatively low quantum yield could only be applied in traditional 2D fluorescence imaging. Moreover, Kim's research group took advantage of the unique properties of amphiphilic polymers as well. When near-infrared fluorescent molecules were decorated with poly[(ethylene oxide)-block(sodium 2-acrylamido-2-methyl-1-propane-sulfonate)], quantum yield increased around 5–10 times, such as that of compound 41 (from 0.1% to 1.2%) (Fig. 14) [50]. The general strategies towards optimizing

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Fig. 18. Selected time points from video-rate NIR-II imaging (1200 nm long-pass filter, 100 ms) of a mouse in the supine position after an intravenous injection of (a) compound 27 (b) and HiPCO SWCNTs showing disparate liver and bladder fluorescent signals (n = 3 mice).Reproduced from Ref. 39 with permission from springer nature.

interaction with water molecules. Although the fluorescence quantum yield was improved in this case, hydrophobic aggregation occurred immediately due to the hydrophobic effect among fluorophore molecules, resulting in excessive hydrated particle size over the cutoff of renal excretion, which was not conducive to exclusion. This problem is similar to that of hydrophobic aggregation or nonspecific binding in fluorophores composed of fluorene as a shielding group, which could also be explained by the poor excretory behaviors of compounds 24, 37, and 43 (Fig. 19) [44]. Significantly, molecular size was not the exclusive factor that determined renal excretion proposed by Chen's group [51]. Therefore, a NIR-II fluorophore 42 with a hydrodynamic diameter of 4.0 nm and benzobisthiadiazole core was synthesized using 3, 4-ethylene dioxythiophene as the spacer and dialkoxy substituted benzene as the shielding unit, exhibiting a maximum absorption at 725 nm and fluorescence emission at 1025 nm. Around 70% of the fluorescence agents in blood was cleared 3 min after injection and almost excreted completely 12 h post-injection, indicating excellent excretion. Considering the size of fluorophores, dye 24 possessed a particle size of 4.9 nm below the cutoff of the renal filtration threshold, similar to compound 42. Yet, it revealed a higher liver uptake behavior, totally different from renalexcreted compound 42, further supporting that a dye size less than the renal threshold is a sufficient and unnecessary condition for construction of functional dyes with rapid excretion. Consequently, Chen et al. presented that interaction with proteins, electrical neutrality of functional groups, and phagocytosis of macrophages also play essential roles in tuning the excretion rate. Subsequently, the researchers analyzed a kinetic binding assay between dyes and albumin, the uptake of macrophage cells, and surface chemistry of functional units, to determine that specific characteristics, such as fast dissociation rate with proteins, low phagocytosis value, and electroneutral functional groups like azide group would endow dyes with a superior excretion capability (Fig. 19b). This suggests that many potential parameters are urgently needed to be explored to fully comprehend renal or hepatic excretory mechanisms for creating more organic small-molecular functional dyes with outstanding performance. Finally, we also provide a concise diagram about the existing methods for modulating excretion rate of mice, as shown in Fig. 20.

other NIR-II nanofluorophores, single-walled carbon nanotubes (SWCNTs), remained in the reticuloendothelial system and excreted extremely slowly from haptic and spleen due to their large size, as illustrated in Fig. 18 of the biodistribution. In a later study, Dai et al. synthesized another imaging agent, compound 24 [33], which exhibited a higher fluorescence quantum yield of 2.0% in aqueous solution than compound 27 with 0.3% quantum yield. However, the excretion capacity of 24 showed to be inferior than 27. As demonstrated by the excretion data, approximately 38% of the fluorescence agents were eliminated through feces with the first 48 P.I., and the blood circulation half-time was up to 2 h. In addition to these, the biodistribution of fluorescence agents 24 demonstrated high liver uptake and a hydrodynamic size around 4.9 ± 0.1 nm, which is close to the excretion threshold. These results indicate that optimizing the molecular structure or modulating hydration diameter offers a potential method to improve excretion capacity. Therefore, by regulating the alkyl chains on shielding units to optimize the molecular structure and its excretion behavior, Dai's group obtained the excellent product–compound 39. This compound exhibited a rapid excretion, and around 91% of imaging agents were discharged through urine within the first 10 P.I. and a blood half-time of 24 min, which is faster than that of other fluorophores with 6 carbons, 11 carbons in the shielding group. Fig. 16 displays the excretion behaviors of compounds 38, 39, and 40, where fluorescence signals can be seen in the bladder of mice injected with compounds 38 and 39, while violent fluorescent signals were obtained 10 min post-injection of fluorophore compound 40 in the liver of mice. Worse still, compound 40 agent was mainly retained in the liver even at a longer circulation time up to 24 h, indicating a high liver uptake. The different excretion behaviors between 40 and 38, 39 could be explained by their different hydrodynamic sizes, as confirmed by dynamic light scattering analysis and TEM imaging. The hydration diameter of fluorophores increased with the extension of alkyl chains. Unfortunately, the hydrated particle size of compound 40 containing 11-carbons reached a striking size around 40 nm, far exceeding the renal excretion threshold (5.5 nm) and leading to a long reservation in the liver. This can be attributed to the fact that the long alkoxyl chains covered the entire conjugated backbone, reducing

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Fig. 19. (a) Wide-field fluorescence imaging of mice injected with compound 38, compound 39, or compound 40 as a function of time. (b) Selected time points from NIR-II imaging of the mice in the supine position after an intravenous injection of compound 37, compound 24, and compound 43, respectively. Reproduced from Ref. 44 with permission from John Wiley and Sons and Ref. 51 with permission from the Royal Society of Chemistry.

5. Conclusions and prospects

visualization of vascular diseases, brain blood flow monitoring, and tumor detection after trauma. However, for FDA approval and rapid implementation in clinic, it is highly pertinent that these small molecular fluorophores exhibit rapid excretion capability and low toxicity. Unfortunately, a conflict usually exists between long-wavelength emission, high fluorescence quantum yield in an aqueous solution or physiological environment, and fast renal excretion rate in currently available small fluorophores, making it is difficult to achieve an optimal balance. Considering the known advantages and difficulties of organic small-molecular fluorescence dyes with a benzobisthiadiazole backbone, we summarized the relationships between fluorophore structures and functions as well as the related optimization methods. A preliminary theoretical system is then proposed in the hope of providing a basis for the development of more new NIR-II molecules with excellent performance and, thus, potential application in NIR organic semiconductors and NIR imaging agents (see Table 7).

In recent years, D-A type organic small-molecular fluorescence dyes containing a strong electron-withdrawing benzobisthiadiazole core have been widely employed in the construction of organic semiconducting, biological imaging agents, due to their unique properties, including photostability, thermostability, large stokes shift, far fluorescence emission, and adjustable structures. Introducing different electron-donating groups into the molecular framework can result in various organic small-molecular fluorophores with fluorescence emissions ranging from 1000 to 1700 nm, namely in the far near-infrared region. Such long wavelength emission is beneficial to optimizing electrochemical properties of semiconductors, reducing the autologous fluorescence and light scattering of biological tissues in biological imaging, which could provide high spatial and temporal resolution or deeper tissue penetration superior to traditional imaging in the NIR-I (700–900 nm) area. For instance, these devices are widely used in the 15

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Fig. 20. The general methods towards improving mice excretion rate.

Table 7 General optical data and applications of compounds 1–42. Comp.

λabs [nm]

λem [nm]

Stokes shift [nm]

QY %

Applications

Ref.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

N.A. N.A. 283 N.A. 524 558 732 764 612 632 700 713 699 945 879 763 920 848 1020 1260 710 700

N.A. N.A. N.A. N.A. 557 642 N.A. N.A. 787 857 1050 1080 1040 1285 1120 1065 1125 1055 1213 N.A. 981 1055

N.A. N.A. N.A. N.A. 33 84 N.A. N.A. 175 225 350 367 341 340 241 302 205 207 193 N.A. 277 355

N.A. N.A. N.A. N.A. N.A. N.A. N.A. N.A. 13a 0.2a 7.4a 5.8a 6.3a 0.5a 4.9a 7.1a 5.3a 18.5a 0.3a N.A. 6.2 0.3b

N.A.

[29]

NIR OLEDs.

[30]

NIR OLEDs

[31]

NIR OLEDs

[32,52]

Solar cells

[36,52]

NIR-II fluorescence and NIR-I photoacoustic imaging of orthotopic brain tumors NIR lymphatic imaging; brain tumour imaging; image-guided surgery

[48] [39]

815

1047

232

0.02b

[33]

24 35 25 26 26-HT 28

733 725 738 850 N.A. 738

1047 1047 1024 1120 N.A. 1055

314 322 286 270 N.A. 317

Mouse hindlimb vasculature imaging; lymph node imaging

[40]

28-HT 29 30 31 32 33 34 36

N.A. 750 680 895 820 784 733 830

N.A. 1047 N.A. 1112 1100 1068 1040 1071

N.A. 297 N.A. 217 280 284 307 241

2b 0.04b ≈0.5d 0.1b; ≈0.95c; 1d 1.1d < 0.3b; 0.098c; 4.8d 10.8d ≈1.9b N.A. ≈0.1b ≈1.0b ≈1.4b 5.3b 0.7b

Dynamic tracking blood flow and tumor recognition; three dimensional imaging into biological tissues N.A. N.A. Imaging of the mice vascular system; Photothermal Therapy

N.A. N.A. N.A. N.A. N.A. Blood vessels imaging Traumatic brain injury imaging

[34]

23

27

[33] [33] [35]

[42]

(continued on next page) 16

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Table 7 (continued) Comp.

λabs [nm]

λem [nm]

Stokes shift [nm]

QY %

Applications

Ref.

37 38 39 40 41 42

745 714 736 763 814 725

1050 1047 1047 1047 1090 1028

220 333 311 284 276 303

1.9b 0.9b 1.5b 3b < 0.1b 1.8b

Biological systems imaging N.A. Molecular imaging of immune checkpoint PD-L1 N.A applied in vitro confocal microscopy; bioimaging imaging guided microsurgery

[43] [44] [44] [44] [50] [51]

N.A.: not applicable. HT: heated. a Data were measured in organic solvent. b Data were measured in aqueous solution. c Data were measured in PBS. d Data were measured in FBS.

Acknowledgments We acknowledge the National Natural Science Foundation of China (Nos. 21676113, 21402057, 21772054, 21472059), Distinguished Young Scholar of Hubei Province (No. 2018CFA079), Youth ChenGuang Project of Wuhan (No. 2016070204010098) for the financial support. This work is also supported by the 111 Project (No. B17019), the Ministry-Province Jointly Constructed Base for State Key LabShenzhen Key Laboratory of Chemical Biology (Shenzhen), the State Key Laboratory of Materials- Oriented Chemical Engineering (No. KL17-10), Open Project Fund of Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Yanbian University (No. NRFM201701), Ministry of Education, the foundation of Key Laboratory of Synthetic and Biological Colloids, Ministry of Education, Jiangnan University (No. JDSJ2017-07), self-determined research funds of CCNU from the colleges' basic research and operation of MOE (No.CCNU18TS012). Last but not least, I would like to thanks to Yisha Chen and Li Li for their contribution to the revision of the pictures in this review.

[11] [12] [13]

[14] [15] [16] [17] [18]

Appendix A. Supplementary data

[19]

Supplementary data to this article can be found online at https:// doi.org/10.1016/j.dyepig.2019.107746.

[20]

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[21]

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