NIR-II Aggregation-Induced Emission Luminogens for Tumor Phototheranostics

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Dong Wang	+ 2526 word(s)	2526	2022-01-27 07:05:16	\|
2	format correction	Peter Tang	+ 2 word(s)	2528	2022-02-16 02:13:40	\|

This entry is adapted from the peer-reviewed paper 10.3390/bios12010046

aggregation-induced emission NIR-II emission phototheranostics cancer treatment

1. Introduction

Cancer, one of the deadliest diseases in recent decades, has remained a global health concern due to its growing morbidity rate, developing relapse rate, and low survival rate ^[1]^[2]^[3]. Traditional cancer diagnostic methods, including magnetic resonance imaging (MRI), positron emission tomography (PET), and computed tomography (CT), exhibit some respective and collective drawbacks such as insufficient sensitivity and specificity, high cost, and cumbersome instrumentation ^[4]^[5]. Those conventional therapeutic methods toward cancers (such as surgical removal, chemotherapy, and radiotherapy) commonly cause side effects, systematic toxicity, unavoidable invasion, and high relapse rate ^[6]. In general, conventional protocols for cancer diagnostics and therapeutics are individually conducted, which could result in the inefficiency of the curing process and the inaccuracy of treatments. Given the circumstances, tremendous efforts have been made to explore more effective approaches for cancers treatment, among which phototheranostics is a significant advancement that enables the ingenious integration of precise photodiagnostic imaging with phototherapeutic intervention in a single system within spatial colocalization ^[7]^[8]^[9]. This inspiration stirs researchers’ increasing interest in both fundamental studies and clinical trials, mainly on account of its intrinsic advantages, such as simultaneously accurate diagnosis with in situ effective therapy, improved pharmacokinetics, maximized efficacy, optimized drug safety, elevated sensitivity, and specificity in comparison with traditional cancer treatments.

Various modalities are involved in phototheranostic systems, including therapeutic methods such as photodynamic therapy (PDT) and photothermal therapy (PTT), and diagnostic technologies such as photothermal imaging (PTI), photoacoustic imaging (PAI), and fluorescence imaging (FLI). As an emerging strategy for cancer treatments via generating reactive oxygen species (ROS) with the assistance of light, tissue oxygen, and photosensitizer (PS), PDT has a remarkable light-controllable ability, specific spatiotemporal selectivity, and minimized invasiveness ^[10]. PTT is another effective light-triggered cancer therapy modality, which affords excellent tumor suppression by sufficient thermal production upon photoirradiation ^[11]. Moreover, the thermal signal generated during PTT can be detected by thermal imaging systems for PTI, providing images with great temperature sensitivity for tumor detection. Apart from that, the generated thermal signal gives rise to the rapid thermoelastic expansion of tissue, based on which the light-triggered diagnostic protocol, PAI, can be established, sufficing to provide imaging with high penetration depth and portray clear tumor profiles ^[12]. Among all photodiagnostic modalities, FLI has aroused intense interest on account of its simple operation, high sensitivity, noninvasive features, and preferable biosafety especially organic fluorophores ^[13]^[14]^[15]. However, FLI generally suffers from some drawbacks in terms of tissue penetration and spatial resolution, which hinders its practical utilization. Moreover, conventional organic fluorophores are ordinarily hydrophobic, which inherently form aggregates in a physiological environment that is generally composed of water, causing local concentration increasing and fluorescence quenching, which is the notorious aggregation-caused quenching (ACQ) effect, consequentially leading to unsatisfactory imaging outcomes.

Fortunately, aggregation-induced emission (AIE), a unique phenomenon discovered in 2001 by Tang, has solved this predicament, which is shown in some twisted-structure molecules with propeller-shaped conformation, tetraphenylethene (TPE) derivatives, for instance. The emissions of AIEgens demonstrate a low intensity in a single molecular state but are enhanced in aggregated state, exhibiting completely contrary features to ACQ ^[16]^[17]^[18]. Numerous endeavors have been made to explore the mechanism of AIE phenomenon, and the restriction of intramolecular motion (RIM) that includes restriction of intramolecular rotation (RIR) and restriction of intramolecular vibration (RIV) has been widely approved, according to which the twisted structure and the sufficient structural rotors and/or vibrators jointly endow AIE luminogens (AIEgens) with the distinct characteristics ^[7]^[19]. Due to the structural superiorities, most of the excited-state energy of AIEgens can be consumed through the nonradiative decay pathway, resulting from vigorous intramolecular motions in the single molecular state, consequently promoting photothermal conversion. On the contrary, the intramolecular motions can be suppressed in an aggregated state; thus, the radiative decay pathway is in the dominant position, consequently boosting fluorescent emission. In addition, AIEgens have been recognized to possess many intrinsic advantages including good biocompatibility, large Stokes shift, excellent tolerance for high concentration, turn-on feature, high photobleaching threshold and outperformed photosensitizing features, which all allow the great potential for efficient phototheranostics.

On the other hand, enthused by the remained shortcomings of fluorescence imaging with visible (400–680 nm) and first near-infrared region (NIR-I, 700–900 nm), including low tissue penetration, unsatisfactory spatial resolution, etc., researchers pay attention to develop fluorescent materials with emission in the range of second near-infrared (NIR-II) window to overcome these drawbacks ^[20]^[21]^[22]^[23]^[24]^[25]. NIR-II fluorophores possess the capability of surmounting the inherent deficiencies of conventional FLI, by virtue of its remarkable features including deep penetration, reduced tissue scattering, minimal damage, and high spatial resolution endowed by the extremely long wavelength ^[26]^[27]^[28]. The combination of the advantages of both NIR-II fluorophores and AIEgens unprecedentedly complemented each other with excellent imaging and extraordinary therapy, thus allowing a better application in the clinical field and accelerating the progression of contemporary precision medicine ^[29]^[30].

2. NIR-II FLI-Guided PTT

Nowadays, FLI in NIR-II has become a momentous facility for cancer diagnosis owing to its prominent merits for in vivo monitoring and visualizing of lesions ^[31]^[32]. Additionally, the combination of NIR-II FLI and PTT could provide unlimited prospects to construct outstanding theranostic systems ^[33]^[34]. As illustrated in Figure 1a ^[35], when a fluorophore absorbs photons or other energy, it can be promoted to the excited states (S_n) from the ground state (S₀) and transfers back to the ground state via either radiative or nonradiative decay. Nevertheless, it is not difficult to find that these two modes of energy dissipation are in competition with each other since energy is conserved. As a result, the strategy to keep the equilibrium between fluorescence (radiative decay) and photothermal effect (nonradiative decay) is the focus of FLI-guided PTT.

Figure 1. (a) Schematic illustration of Jablonski diagram; (b) the illustration of TICT mechanism.

Fortunately, AIEgens exhibit free-moving molecular rotators or vibrators in their structure, which are ideal agents to keep the equilibrium between fluorescence and photothermal effect ^[36]. Using reverse thinking of the AIE process, researchers devised numerous strategies to maximize molecular motion in the aggregated state of AIEgens to exhibit superior heat transitions without compromising FLI ^[37]. In addition, it was found that twisted intramolecular charge transfer (TICT) states in AIEgens typically abate the fluorescence signals but enhance their photothermal capability, which quickly sparked strong interest among researchers ^[38]^[39]^[40].

AIEgens with long emission wavelengths generally have powerful electron donor (D)–acceptor (A) strength and, therefore, are candidates to modulate TICT formations, since increasing the D–A effect can achieve red-shifted emission and stabilize the TICT state by facilitating charge separation (Figure 1b) ^[41]^[42]. When AIEgen is under unbound and free rotating conditions, nonradiative decay would dominate the excited-state energy consumption. In contrast, upon reaching an aggregated state, the physical constraints disable TICT formations; thus, the equilibrium moves to the radiative decay pathway accompanied withbright fluorescence ^[43]^[44]. Therefore, tailoring intramolecular motion is a feasible strategy to realize a subtle balance between fluorescence and photothermal effect ^[45]^[46].

Lu et al. ^[47] reported a strategy inspired by the theory of RIR to tailor the equilibrium of fluorescence and photothermal efficiency. They combined NIR-II AIEgen (BPBBT, Figure 2a) with human serum albumin (HSA), in order to restrict the intramolecular rotation of BPPBT. Fluorescence emission spectra demonstrated that the fluorescence intensity of BPBBT decreased at a fraction value of water (f_w) below 30% but increased when further raising f_w. This phenomenon could be explained by the fact that BPBBT transitioned from LE state to TICT state when the polarity of solvent elevated, then the increase in poor solvent contributed to forming the aggregated state of BPBBT, which prevented TICT formations and enhanced the fluorescence emission (Figure 2b). It was found that with the enhancement of the HSA ratio in BPBBT/HSA complexes (BPBBT NPs), the photothermal effect was further increased. The energy difference between S₁ and S₀ of BPBBT at NPs state was determined to be narrower than at the AIE state but broader than at the TICT state (Figure 2c), which evinced that the addition of HSA successfully altered LE and TICT state by raising the dihedral angles to provide a chance for the equilibrium to move to the TICT state. In vivo biological imaging showed that fluorescence signal was detected in orthotopic and metastatic tumors accurately and reached a maximum at 30 h postinjection. Notably, NIR-II imaging-guided PTT based on BPBBT NPs could precisely distinguish lesions with dimensions as small as 0.5 mm × 0.3 mm and completely cure tumor-bearing mice with the optimized laser doses (5 out of 5) without recurrence in 30 days (Figure 2d). Additionally, compared with HSA/indocyanine green (ICG) complexes that were applied to NIR-I imaging-guided PTT, BPBBT NPs provided more accurate and sensitive imaging and exhibited a higher photothermal conversion effect and better photostability, which dramatically enhanced the efficiency of PTT and prevented from omitting small lesions. Above all, the BPBBT NPs displayed great potential in NIR-II FLI-guided PTT, particularly for colon cancer theranostics.

Figure 2. (a) Chemical structure of BPBBT; (b) plot of fluorescence intensity ratio of BPBBT (10 µM) in water/THF mixture; (c) the illustration of has-altering radiative decay and nonradiative decay of BPBBT; (d) the in vivo fluorescence imaging of BALB/c mice bearing orthotopic CT26 colon cancer before or after different treatment (n = 5).

Thus far, there are few reliable strategies available for through-skull imaging and therapy, because blood–brain barrier (BBB) is an intractable obstruction for various nanoparticles/macromolecule into the brain ^[36]^[48]. Tang group ^[49] developed the natural killer (NK) cell-mimic nanorobots with highly bright NIR-II fluorescence, named NK@AIEdots, to construct smart and safe multifunctional nanoplatforms for BBB-crossing and brain-tumor-targeting through-skull imaging and therapy (Figure 3a). NK@AIEdots wrap a natural kill cell membrane on a reported highly bright NIR-II AIE-active conjugated polymer nanoendoskeleton, PBPTV. The inspiration for this strategy came from the remarkable properties of NK cells whose membrane can form a “green channel” to help NK@AIEdots realize the BBB crossing ^[50]. PBPTV is the low-bandgap-conjugated polymer with a high quantum yield (QY) up to 8.6%, which is constructed by using a strong and twisted dual-electron acceptor (BPT). BPT results in long-wavelength absorption and also promotes the intramolecular motion, thus tailoring the equilibrium of the TICT and AIE states (Figure 3b). It was observed that NK@AIEdots displayed bright and long emissions at the NIR-II region, as well as having outstanding photothermal effects (Figure 3c,d). Meanwhile, NK@AIEdots could successfully pass through the BBB and spontaneously accumulate in glioma cells in vivo owing to tumor-targeting proteins of the NK cell membrane, as well as lit up the glioma as intense NIR-II fluorescence even at 48 h postinjection. Moreover, upon NIR light irradiation, NK@AIEdots could effectively inhibit the growth of brain tumor cells with less weight loss in mice, compared with the two control groups. In brief, the NK@AIEdots-based theranostics platform successfully applied to the BBB-crossing and brain-tumor-targeting through-skull FLI-guided PTT.

Figure 3. (a) Schematic illustration of the preparation and assembly process of NK-cell-mimic AIE nanoparticles (NK@ AIEdots); (b) plot of fluorescence intensity of PBPTV in dichloromethane/hexane mixtures; (c) fluorescence spectra of BPBBT, AIEdots (BPBBT), NK@AIEdots (BPBBT) in water; (d) photothermal effect of PBS, AIEdots, and NK@AIEdots.

3. PAI-Guided PTT Based on NIR-II Fluorophores

With the explorations of the potential of NIR-II phototheranostics, the phenomenon that the brightness of organic fluorophores including AIEgens generally decreases with the bathochromic shift of emission wavelength has become significant in the NIR-II region. Tang et al. ^[51] have synthesized a series of NIR-II emissive fluorophores, whose emissions are all located in the NIR-II region with the presence of common solvents (including PhMe, DCM, CHCl₃, THF, and DMF), while the emission intensities are relatively inferior for FLI. On the basis of the “energy gap law”, the situation above can be attributed to the ascendancy of nonradiative decay pathways when the electronic bandgap decreases, and these inherent features endow the NIR-II fluorophores with the intrinsic superiority in PAI-guided PTT, because both PAI and PTT are closely associated with the nonradiative decay ^[52]^[53].

In terms of PAI, it relies on the signal of phonons generated by the light irradiation, exceeding the traditional optical diffusion limit caused by photons after light excitation, which endows it the ability to provide higher spatial resolution ^[54]^[55]^[56]^[57] and penetrate deeper depths as high as 11 cm in NIR-II region ^[58]^[59]. More specifically, photons are converted into localized heat that induces transient thermoelastic expansion and wideband acoustic waves in the process of PAI, according to which the process of photo-to-thermo transitions is involved ^[60]^[61]^[62]. Therefore, the nonradiative decay pathway is closely related to the photothermal conversion property, and NIR-II fluorophores exhibit good potential for PAI.

As for the PTT process, the NIR-II fluorophores demonstrate relatively better photothermal conversion efficiency, compared with those emissions within visible spectroscopy, whose temperature variation generated by photothermal effect reaches merely 13 °C ^[63]. Thus, the strategy to enhance nonradiative decay, which significantly improves photothermal conversion efficiency to achieve PAI-diagnosis-guided PTT, is another appealing approach of the utilization of NIR-II fluorophores in the phototheranostic field.

Inspired by the inherent superiorities mentioned above, Tang et al. put forward a strategy to boost nonradiative decay so as to elevate the photothermal conversion efficiency using reverse thinking of the AIE process, aiming to maximize molecular motions in the aggregated state to enhance heat transitions through extending the side chain length or adding twisted groups, among which the studies of Liu et al. ^[51] have unprecedentedly integrated the superiorities of reversed AIE and dark TICT to achieve improved photothermal conversion, which can be described as “adjusting TICT in aggregates for boosting photothermal properties”.

4. Multimodal Imaging-Guided Synergistic Therapy

Although AIEgens displayed great potential in FLI/PAI-guided PTT, difficulties are still remained in realizing the optimal treatments via one-to-one modality. For instance, the imaging information with both favorable sensitivity and penetration depth is not able to be obtained by a single imaging modality ^[57]^[64]^[65]^[66]^[67], and it is also burdensome to achieve satisfactory treatment via PDT or PTT alone, which is attributed to hypoxic tumor microenvironment for PDT and heat shock effect in PTT ^[68]^[69]. Constructing multimodality phototheranostic platforms is a smart strategy that is able to achieve “1 + 1 > 2” to solve these problems, which can afford precise diagnosis and efficacious therapy via combining different kinds of imaging technologies with therapy methods, and has induced great interest recently. However, it is a challenging task because keeping the equilibrium between radiative and nonradiative decays is intractable for conventional materials, which is crucial to building up a versatile phototheranostic system with favorable fluorescent and photothermal properties concurrently. By virtue of affluent free-motioned molecular rotators or vibrators in structure, the photophysical properties of AIEgens could be manipulated easily by boosting or inhibiting intramolecular motions ^[16]^[20]^[70]. Furthermore, endowing AIEgens with twisted conformations could lead to relatively loose packing in the aggregated state through tactful molecular regulation, which is beneficial to balance radiative and nonradiative decays.

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Subjects: Biochemical Research Methods

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Dong Wang

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