First Author:Dr. Ma Fulong, Dr. Jia Xi, Dr. Deng Ziwei
Corresponding Authors:Professor Tang Banzhong; Professor Zhao Zheng
Affiliation:The Chinese University of Hong Kong (Shenzhen), School of Science and Engineering
Full Text Link:https://doi.org/10.1021/acsnano.3c11078
NIR-II; Aggregation-Induced Emission; Molecular Motion; Radiative and Non-Radiative Transitions; Surgical Navigation
As an emerging diagnostic technology, fluorescence imaging offers advantages such as fast speed, high sensitivity, high spatiotemporal resolution, and no radiation, attracting significant research interest. Compared to visible light (VIS) and near-infrared I (NIR-I) imaging, near-infrared II (NIR-II, 900-1700 nm) fluorescence imaging exhibits lower tissue absorption/scattering and autofluorescence effects, thus demonstrating greater advantages in terms of spatiotemporal resolution, signal-to-noise ratio, and imaging depth. High-luminescence NIR-II fluorescent materials are key to achieving ideal imaging performance. However, compared to many materials in the VIS range, there are relatively few scaffolds and modulation strategies for constructing NIR-II fluorophores. Therefore, developing efficient NIR-II fluorophores for biological imaging remains a significant challenge.
When constructing NIR-II fluorescent molecules, fast radiative decay (kr) and suppressed non-radiative decay (knr) rates are crucial for enhancing luminescence efficiency. However, achieving both fast kr and constrained knr simultaneously remains a challenge. On the other hand, when excited state electrons return to the ground state, radiative (luminescence) and non-radiative (thermal) transitions are the main energy dissipation pathways. Regulating the radiative and non-radiative transition processes is significant for developing multimodal diagnostic and therapeutic systems. Aggregation-induced emission (AIE) technology provides an effective strategy to address these issues, where the active intramolecular motion of AIE molecules (AIEgens) offers a good platform to modulate radiative and non-radiative transition processes. Previous work has indicated that by using long alkyl chains as spacer units to promote intramolecular motion in the excited state, the excited state energy can be effectively converted into heat in the aggregate state. Therefore, if aromatic fragments are rationally extended to enhance intermolecular interactions, it is theoretically possible to restrict the intramolecular motion of excited state molecules, thereby suppressing non-radiative decay and activating radiative transitions. In addition, replacing hydrogen atoms with larger deuterium atoms can not only further suppress molecular rotation but also reduce non-radiative decay caused by high-frequency vibrations. Therefore, simultaneously applying π-extension and deuteration strategies is expected to promote kr while suppressing knr, constructing efficient NIR-II AIEgens.
This work constructs three types of donor-acceptor NIR-II AIEgens by coupling a “propeller” shaped tetraphenylethylene group with thiophene-2,5-dicarboxylic acid diimide. Through the π-conjugated structure extension and deuteration integration strategy, the rotation and high-frequency vibration processes of the molecules are effectively suppressed, improving AIEgens kr while reducing knr, significantly enhancing the luminescence efficiency of NIR-II AIEgens. At the same time, the high luminescence efficiency of AIEgens in the molecular state can be well maintained in the aggregate state. Nanoparticles (NPs) prepared based on NIR-II AIEgens exhibit high brightness, large Stokes shift, and good photostability, demonstrating good application effects and potential value in high-contrast vascular imaging in live mice and multimodal imaging-guided tumor resection surgeries (Figure 1).
Figure 1. Molecular Structure Design Strategy, Fluorescence/Photoacoustic Imaging, and Surgical Navigation Applications
Figure 2. Photophysical Properties Characterization of AIEgens
Compared to NDA-TPE, NDA-PTPE and NDA-PDTPE exhibit significant improvements in luminescence performance (Figure 2a,b). Kinetic parameters indicate that π-conjugated extension not only suppresses NDA-PTPE’s knr but also promotes kr. After introducing isotopes, NDA-PDTPE’s knr can be further suppressed (Figure 2c). Fluorescence spectra in mixed solvents of different DMF/water ratios show that all three molecules exhibit typical AIE characteristics, with NDA-PTPE and NDA-PDTPE demonstrating more pronounced AIE effects (Figure 2d, e). Furthermore, when at 298 K, the molecular emission is weak, but when the temperature drops to 77 K, the emission significantly enhances, further confirming that the AIE property arises from limited molecular motion (Figure 2f).
Figure 3. Theoretical Simulation and Calculation of Frontier Orbital Electron Cloud Distribution, Reorganization Energy, and Zero-point Energy
The HOMO of NDA-TPE is only distributed in the TPE part, while NDA-PTPE and NDA-PDTPE have wider HOMO extensions (Figure 3a, b), which is beneficial for promoting oscillator strength (f) and enhancing kr. NDA-PTPE’s reorganization energy is 0.35 eV, lower than NDA-TPE’s (0.37 eV), indicating that NDA-PTPE’s structure is more rigid (Figure 3b). The root mean square deviation (RMSD) between the ground state and excited state of NDA-PTPE is 0.41, much smaller than NDA-TPE’s (0.65), indicating that after π-conjugated extension, NDA-PTPE’s molecular rigidity increases, and molecular deformation is suppressed, thereby reducing knr (Figure 3c). FT-IR spectral simulations indicate that some high-frequency C-H stretching modes of NDA-PDTPE shift from 3208 cm-1 to 2375 cm-1 (C-D), which suggests that deuteration can suppress high-frequency vibrations. Additionally, NDA-PDTPE’s zero-point energy (ZPE) is lower than NDA-PTPE’s, which can also indicate the reduction of high-frequency vibrations, further lowering knr. The above results demonstrate that the π-conjugated structure extension and deuteration integration strategy can achieve both fast kr and constrained knr simultaneously.
Figure 4. Molecular Dynamics Simulation
Molecular dynamics simulations indicate that within aggregates, NDA-TPE’s inner molecular dihedral angle distribution is broad, similar to the molecular state, suggesting active intramolecular motion exists in its aggregate state. In contrast, NDA-PTPE and NDA-PDTPE exhibit significantly narrower dihedral angle distributions after forming aggregates, indicating effective suppression of intramolecular motion (Figure 4a-e). Simultaneously, NDA-PTPE and NDA-PDTPE demonstrate higher atomic contact rates, indicating that the groups in NDA-PTPE and NDA-PDTPE structures interact more strongly with surrounding molecules, effectively suppressing intramolecular motion and non-radiative transitions (Figure 4f).
Figure 5. Surgical Navigation and Biosafety Evaluation of Mouse In Situ Breast Tumors and Lymphatic Metastasis
Utilizing amphiphilic polymers to encapsulate NDA-PDTPE in NPs, guided by photoacoustic and fluorescence imaging, mouse breast tumor resection surgeries were performed while identifying and removing metastatic lymph nodes, demonstrating the excellent performance of NPs in dual-modal imaging-guided surgical navigation (Figure 5a, b). Biochemical analyses of mouse blood showed that all parameters remained within normal ranges post-injection of NPs (Figure 5c-w), and H&E staining of major organs in mice showed no significant histological changes (Figure 5x). These results indicate that NPs possess good biosafety and biocompatibility.
This work focuses on the radiative and non-radiative transition processes of NIR-II AIEgens, achieving faster kr and constrained knr through rational molecular structure design that suppresses deformation and high-frequency vibrations in the excited state, constructing high-luminescence efficiency NIR-II AIEgens. The prepared NPs exhibit high brightness, large Stokes shift, and excellent photostability, showing outstanding performance in dual-modal imaging-guided tumor and metastatic lymph node resection surgeries. The π-extension and deuteration integration strategies proposed in this work provide a simple and feasible new approach for constructing efficient NIR-II AIEgens.
Related work titled “Boosting Luminescence Efficiency of Near-Infrared-II Aggregation-Induced Emission Luminogens via a Mash-Up Strategy of π‑Extension and Deuteration for Dual-Model Image-Guided Surgery” was published in ACS NANO (10.1021/acsnano.3c11078). The first authors are Dr. Ma Fulong (currently a postdoc at the Hong Kong University of Science and Technology), young teacher Dr. Jia Xi from Xi’an University of Electronic Science and Technology, and PhD student Deng Ziwei from The Chinese University of Hong Kong (Shenzhen), with corresponding authors being Academician Tang Banzhong and Professor Zhao Zheng from The Chinese University of Hong Kong (Shenzhen). This research was supported by the National Natural Science Foundation of China, Key Laboratory of Functional Materials for Aggregation, Shenzhen Science and Technology Program, and Shenzhen Basic Research Program.
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