Enhancing Luminescence Efficiency of NIR-II AIEgens for Dual-Model Image-Guided Surgery

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As an emerging diagnostic technology, fluorescence imaging has attracted significant research interest due to its advantages such as high speed, high sensitivity, high spatiotemporal resolution, and no radiation. Compared to visible light (VIS) and near-infrared region I (NIR-I) imaging, near-infrared region II (NIR-II, 900-1700 nm) fluorescence imaging exhibits greater advantages in terms of spatiotemporal resolution, signal-to-noise ratio, and imaging depth due to lower tissue absorption/scattering and autofluorescence effects. High-luminescence NIR-II fluorescent materials are key to achieving ideal imaging performance. However, compared to the numerous materials in the VIS range, there are relatively few structural frameworks 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, rapid radiative decay (k_r) and suppressed non-radiative decay (k_nr) rates are decisive factors for enhancing luminescence efficiency. However, achieving both rapid k_r and constrained k_nr simultaneously remains a challenge. On the other hand, when excited state electrons return to the ground state, radiative (luminescence) and non-radiative (heat generation) transitions are the main pathways for energy dissipation. Regulating radiative and non-radiative transition processes is crucial for developing multimodal diagnosis and treatment systems. Aggregation-induced emission (AIE) technology offers an effective strategy to address the above issues, as the active intramolecular motion of AIE molecules (AIEgens) provides a good platform to modulate the radiative and non-radiative transition processes. Preliminary work has shown that using long alkyl chains as spacer units can promote intramolecular motion in the excited state, allowing for effective conversion of excited state energy into heat in the aggregated state. Therefore, if aromatic segments are reasonably extended to enhance intermolecular interactions, it is theoretically possible to restrict the motion of excited state molecules, thereby suppressing non-radiative decay and activating radiative transitions. Additionally, substituting hydrogen atoms with larger mass and volume deuterium atoms can further suppress molecular rotation and reduce non-radiative decay caused by high-frequency vibrations. Therefore, employing both π-conjugation extension and deuteration strategies is expected to facilitate k_r while suppressing k_nr, leading to the construction of efficient NIR-II AIEgens.

Enhancing Luminescence Efficiency of NIR-II AIEgens for Dual-Model Image-Guided Surgery

On March 20, 2024, the research team of The Chinese University of Hong Kong, Shenzhen led by Academician Tang Benzhong and Professor Zhao Zheng published their 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” in ACS Nano. The first authors are Ma Fulong (currently a postdoc at Hong Kong University of Science and Technology), young teacher Jia Xi from Xi’an University of Electronic Science and Technology, and PhD student Deng Ziwei from The Chinese University of Hong Kong, Shenzhen, while the corresponding authors are Academician Tang Benzhong and Professor Zhao Zheng from The Chinese University of Hong Kong, Shenzhen.

Figure 1. Molecular structure design strategy, fluorescence/photoacoustic imaging, and surgical navigation applications.

This work constructed three donor-acceptor type NIR-II AIEgens by coupling the “propeller” shaped tetraphenylethylene group with thiophene dicarboxylic acid diimide. Through the π-conjugation structure extension and deuteration integration strategy, molecular rotation and high-frequency vibration processes were effectively suppressed, enhancing the k_r of AIEgens while reducing their k_nr, thereby significantly improving the luminescence efficiency of NIR-II AIEgens. Meanwhile, the high luminescence efficiency of AIEgens in the molecular state can be well maintained in the aggregated 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 and multimodal imaging-guided tumor resection surgeries in live mice (Figure 1).

Figure 2. Photophysical properties characterization of AIEgens.

Compared to NDA-TPE, the luminescence performance of NDA-PTPE and NDA-PDTPE shows significant improvement (Figure 2a,b). Kinetic parameters indicate that π-conjugation extension not only suppressed k_nr of NDA-PTPE but also promoted k_r. After introducing isotopes, k_nr of NDA-PDTPE can be further suppressed (Figure 2c). Fluorescence spectra in different ratios of DMF/water mixed solvents show that all three molecules exhibit typical AIE characteristics, and NDA-PTPE and NDA-PDTPE demonstrate more pronounced AIE effects (Figure 2d, e). Additionally, at 298 K, molecular emission is weak, while at 77 K, emission is significantly enhanced, further proving that the AIE property arises from restricted molecular motion (Figure 2f).

Figure 3. Theoretical simulation and calculation of the frontier orbital electron cloud distribution, reorganization energy, and zero-point energy of AIEgens.

The HOMO of NDA-TPE is only distributed in the TPE part, while the HOMOs of NDA-PTPE and NDA-PDTPE are more widely spread (Figure 3a, b), which is beneficial for enhancing oscillator strength (f), and increasing k_r. The reorganization energy of NDA-PTPE is 0.35 eV, lower than that of NDA-TPE (0.37 eV), indicating that the structure of NDA-PTPE is more rigid (Figure 3b). The root mean square deviation (RMSD) between the ground and excited states of NDA-PTPE is 0.41, much lower than that of NDA-TPE (0.65), indicating that after π-conjugation extension, the molecular rigidity of NDA-PTPE increases, and molecular deformation is suppressed, thereby reducing k_nr (Figure 3c). FT-IR spectral simulations show that some high-frequency C-H stretching modes of NDA-PDTPE shift from 3208 cm^-1 to 2375 cm^-1 (C-D), indicating that deuteration can suppress high-frequency vibrations. Furthermore, the zero-point energy (ZPE) of NDA-PDTPE is lower than that of NDA-PTPE, also indicating a reduction in high-frequency vibrations, further lowering k_nr. The above results indicate that the π-conjugation structure extension and deuteration integration strategy can simultaneously achieve rapid k_r and constrained k_nr.

Figure 4. Molecular dynamics simulation.

Molecular dynamics simulations indicate that in aggregates, NDA-TPE has a wider dihedral angle distribution in its innermost molecules, similar to that in the molecular state, suggesting active intramolecular motion exists in its aggregated state. In contrast, NDA-PTPE and NDA-PDTPE exhibit significantly narrowed dihedral angle distributions after forming aggregates, indicating that intramolecular motion has been effectively suppressed (Figure 4a-e). Simultaneously, NDA-PTPE and NDA-PDTPE show higher atomic contact rates, indicating stronger interactions between the groups in NDA-PTPE and NDA-PDTPE structures and surrounding molecules, effectively suppressing intramolecular motion and non-radiative transitions (Figure 4f).

Using amphiphilic polymers to encapsulate NDA-PDTPE in NPs, guided by photoacoustic and fluorescence imaging, mouse breast tumors were excised in situ, and the identification and removal of metastatic lymph nodes were also achieved, demonstrating good performance of NPs in surgical navigation guided by dual-modal imaging (Figure 5a, b). Biochemical analysis of mouse blood showed that all parameters remained within normal ranges after NPs injection (Figure 5c-w), and H&E staining of major organs in mice also showed no obvious histological changes (Figure 5x). The above results indicate that NPs have good biosafety and biocompatibility.

Figure 5. Surgical navigation and biosafety assessment of mouse breast tumors and lymphatic metastasis lesions.

In summary, the research focuses on the radiative and non-radiative transition processes of NIR-II AIEgens, achieving faster k_r and constrained k_nr 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, demonstrating outstanding performance in tumor and metastatic lymph node resection surgeries guided by dual-modal imaging. The π-conjugation extension and deuteration integration strategies proposed in this work are expected to provide a simple and feasible new strategy for constructing efficient NIR-II AIEgens.

This research was supported by the National Natural Science Foundation, Key Laboratory of Functional Materials for Aggregates, Shenzhen Science and Technology Program, and Shenzhen Basic Research Program.

Original link

https://doi.org/10.1021/acsnano.3c11078

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