Review
Aggregation-induced emission fluorophores towards the second near-infrared optical windows with suppressed imaging background

https://doi.org/10.1016/j.ccr.2022.214792Get rights and content

Highlights

  • The chemical design of AIE molecules with strong emission beyond 1300 nm is reviewed.

  • The AIE fluorophores assisted NIR-IIa or NIR-IIb functional bioimaging is summarized.

  • The development prospects and current challenges are discussed.

Abstract

Fluorescence bioimaging in the second near-infrared (NIR-II) region can visualize deep bioinformation in real time with high sensitivity. Especially, NIR-IIa (1300–1400 nm) and NIR-IIb (1500–1700 nm) windows possess extremely low imaging background and have attracted much research interest recently. Towards the two imaging windows, NIR-IIa or NIR-IIb emissive fluorescent probes for biomedical research and translational applications have been increasingly explored, along with which the enough integrated NIR-IIa or NIR-IIb fluorescence intensities become one of the key points. Among many NIR fluorescent materials, organic fluorescent nanoprobes with aggregation-induced emission (AIE) properties are widely used in biomedical imaging research due to the tunable spectral responses, high brightness, and low biological toxicity. This review focuses on the structure design of AIE molecule with ultra-bright NIR-IIa or NIR-IIb emission and the AIE fluorophores assisted NIR-IIa or NIR-IIb bioimaging applications. In addition, the development prospects and current challenges in this new field are given. It is hoped that this review can encourage more innovative designs of NIR-IIa or NIR-IIb luminescent materials and meaningful bioimaging applications.

Introduction

In recent years, in vivo fluorescence imaging in the second near-infrared region (NIR-II, 900–1880 nm) has attracted much attention [1], [2]. Compared with visible (360–760 nm) and the first near-infrared (NIR-I, 760–900 nm) spectral regions, the NIR-II window offers deeper tissue penetration and lower photon scattering disturbance [3], [4], [5], [6], [7], [8]. Scientists have achieved in vivo lymphatic imaging, vascular imaging, tumor imaging and precise surgery by drawing the light excitation or emission collection to the NIR-II window [9], [10], [11], [12], [13], [14], [15]. Meanwhile, the emerging requirements for better imaging performance urge researchers to be committed to the development of near-infrared fluorescent materials with stronger and longer-wavelength emission.

The photons propagating in the biological tissues are always scattered and absorbed, which seriously impedes the high-resolution visualization, as shown in Fig. 1a. It is known from Mie and Rayleigh theory that the longer the wavelength of light is, the less the photon scatters [18] as displayed in Fig. 1b. Besides, the excitation-induced autofluorescence of the tissues is also nonnegligible. Fig. 1c shows that the autofluorescence of biological tissue is extremely low beyond 1300 nm [16]. Recent researches [19], [20], [21] revealed that moderate light absorption can efficiently restrain the highly scattered photons with long optical path, which had been extremely unfavorable for biological imaging for a long while. Compared to the NIR-I window, the light absorption of tissues (mainly caused by water, Fig. 1d) increases, which significantly restrains the imaging background, especially beyond 1300 nm. Owing to the excellent imaging performance, the spectral region beyond 1300 nm is regarded as the promising imaging window in which 1300–1400 nm is defined as the NIR-IIa region, 1500–1700 nm is considered as the NIR-IIb region, 1400–1500 nm is called as the NIR-IIx region. However, the NIR-II fluorophores with fluorescence emission beyond 1300 nm are still rare. In 2014, Dai’s group [22] achieved high-resolution brain imaging in the NIR-IIa window using single-walled carbon nanotubes. This work opens the door to the inorganic materials assisted NIR-II imaging in vivo. Then, many kinds of inorganic nanomaterials with excellent luminescence properties including quantum dots [23], [24], [25], [26], single-walled carbon nanotubes (SWCNTs) [27], [28], rare earth doped nanoparticles [29], [30], [31], [32] have been rationally designed. However, inorganic nanomaterials have always been considered to possess potential side effects such as long-term retention in the liver and spleen, potential immunogenic reactions and other unknown biological toxicity, which greatly limits the possibility of further clinical translation [33], [34], [35], [36], [37]. Compared to the inorganic materials, organic dyes have the advantages of excellent biocompatibility, and ease of modification, showing lower biosafety risks and more potential for clinical translation. For example, some fluorescent molecular dyes such as indocyanine green and methylene blue have been approved by the FDA for clinical use [38], [39], [40]. Nowadays, constructing fluorescent dyes with NIR-IIa or NIR-IIb emission via small organic molecule has been an important research direction, and more and more excellent NIR-II fluorescent dyes have been developed by many research groups such as Zhang [41], [42], Tan [43], Sletten [44], and Yang [45] etc. However, few dyes with peak optical responses in the NIR-IIa or NIR-IIb windows have been reported. The current mainstream approach is to draw the broad emission to the long-wavelength range and strengthen the integrated emission, leading to the strong NIR-IIa or NIR-IIb tailing emission. General methods of the wavelength red-shift in organic molecule are listed in the following ways: (a) increasing the electron-donating (D) and electron-accepting (A) abilities of the molecule, and reducing the band gap between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO). (b) extending the conjugated structure is an effective way to red-shift the wavelength of organic molecule dyes. However, such a large π-conjugated structure will bring about a decrease in the chemical stability of organic dye molecule and a strong intermolecular π-π in the aggregation state. The interaction usually leads to the fluorescence quenching, which is known as aggregation-caused quenching (ACQ). Although scientists improve the chemical stability of molecule and reduce aggregation by various ways. For example, a simple and straightforward method is to dope the fluorescent dyes as a guest into the host material to reduce the concentration and reduce aggregation. Smith’s group [46] used rotaxane to coat the squaraine dye, and the rotaxane effectively protected the core structure of squaraine from the attack of nucleophiles. Researchers have also tried to prevent aggregation by covalently introducing groups such as rigid cubes, branches and helical structures. The strategy proposed by Smith’s research group [47] is to increase the large steric hindrance on the core structure of the dye to reduce aggregation and improve stability. Nevertheless, aggregation is a spontaneous process of molecule, and inhibiting this process by physical or chemical means can induce negative effects. The large π-π conjugated system of small organic molecule provides long absorption, but also brings ACQ. Thus, the development of bright NIR-IIa or NIR-IIb fluorescent dyes is still challenging.

In 2001, the Tang’s group firstly proposed the concept of a unique way of light emission, which is called aggregation-induced emission (AIE), bringing a potential solution to the above concerns [48], [49], [50]. AIE molecule emits weak or even no light in dilute solution, but the fluorescence intensity increases significantly as molecular aggregation occurs. Compared with the ACQ phenomenon of traditional molecule, the fluorescence enhancement in AIE system shows unique advantages. The main reason for AIE is the restriction of intramolecular rotation and restriction of intramolecular vibration, which can be mainly summarized as the restriction of intramolecular motions. Therefore, the non-radiative transitions remarkably reduce, so that the most energy of the excited state is released in the form of radiative transitions. The twisted structure of AIE molecule can effectively avoid intermolecular π-π stacking. Besides, AIE molecule always maintains good photobleaching resistance even in the physiological environments. The unique luminescence properties enable AIE dyes to be coated with a variety of biocompatible reagents, such as liposomes, proteins, Pluronic F-127, DSEP-PEG etc [51], [52]. After coating, the biocompatibility of the fluorophores would be improved and the biotoxicity could be significantly reduced. These advantages have greatly promoted AIE fluorophores to be applied in the biomedical field, including the imaging from the cellular level to living tissue [9], [53], [54], [55], [56], [57], [58], [59], [60]. Developing NIR-IIa or NIR-IIb fluorescent materials with AIE properties is an important direction at present.

In recent years, some NIR-IIa or NIR-IIb fluorescent molecule with AIE characteristics have been developed [38], [61], [62]. Functional in vivo imaging assisted by AIE fluorophores, including long-term imaging of whole-body blood vessels, high-resolution imaging of cerebral blood vessels, and non-invasive gastrointestinal (GI) imaging in rodents or non-human primates, was realized. To date, several review articles on the NIR-II fluorophores [63], [64], [65], [66], [67] have been published. Furthermore, this review focuses on the structural design of the AIE molecules towards the more effective background-suppressed imaging windows such as NIR-IIa and NIR-IIb windows. The development direction and current challenges of this new field are summarized in the end. It is hoped to encourage more innovative designs of NIR-IIa or NIR-IIb emissive fluorophores and related bioimaging applications, eventually accelerating the future clinical translation.

Section snippets

NIR-II optical window

With the deepening of the understanding of the interaction between light and biological tissues, the imaging window has been extended from the visible region to the NIR band. In particular, fluorescence imaging in the NIR-II window (traditional definition is 1000–1700 nm) is considered to be a promising technique for biomedical and even clinical applications [6].

Energy loss when light propagates in biological media can be attributed to absorption attenuation and scattering disturbance.

Design of NIR-IIa or NIR-IIb emissive molecule based on donor–acceptor (D-A) structure

Fluorescence imaging has shown great application prospects in the detection of disease pathogenesis and direct visualization [68], [69], [70], [71]. However, organic fluorophores reported have short peak emission wavelength, fluorescence tailing to short-wavelength NIR-II region (900–1300 nm) and low fluorescence quantum yield (QY, <1 %). To develop NIR-II molecule with better properties, precise molecular engineering techniques have been reported. Zhang’s group reported CX series dyes with

Advanced NIR-IIa or NIR-IIb fluorescence bioimaging

Many efforts have been made for the design and synthesis of longer and brighter NIR-II emissive molecule with AIE properties, however, few bright AIE fluorophores could possess maximal emission beyond 1300 nm or 1500 nm. Fortunately, the bright tailing emission in the NIR-II window of the fluorescent probes could be utilized in intravital imaging [105]. The same ideas have also been proposed in many fluorophores including AIE nanoparticles [68] and the clinically approved dyes [21] with peak

Summary and outlook

The advanced NIR-IIa or NIR-IIb fluorescence imaging technique not only brings high temporal and spatial resolution, but also greatly improves the depth of imaging in vivo. For bioimaging applications, small organic molecules are known for precise and tunable fluorescence properties, excellent biocompatibility and low biosafety risks. The organic fluorescent dyes assisted NIR-IIa or NIR-IIb fluorescence bio-imaging holds clinical translation potentials. Design of novel structure has

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgment

This work was supported by the National Natural Science Foundation of China (61975172 and 82001874), Fundamental Research Funds for the Central Universities (2020-KYY-511108-0007) and China Postdoctoral Science Foundation funded project (No. BX20220260).

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    There authors contributed equally: Jin Li, Zhe Feng.

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