Fluorescence imaging in near-infrared IIb (NIR-IIb, 1500–1700 nm) spectrum holds a great promise for tissue imaging. While few inorganic NIR-IIb fluorescent probes have been reported, their organic counterparts are still rarely developed, possibly due to the shortage of efficient materials with long emission wavelength. Herein, we propose a molecular design philosophy to explore pure organic NIR-IIb fluorophores by manipulation of the effects of twisted intramolecular charge transfer and aggregation-induced emission at the molecular and morphological levels. An organic fluorescent dye emitting up to 1600 nm with a quantum yield of 11.5% in the NIR-II region is developed. NIR-IIb fluorescence imaging of blood vessels and deeply-located intestinal tract of live mice based on organic dyes is achieved with high clarity and enhanced signal-to-background ratio. We hope this study will inspire further development on the evolution of pure organic NIR-IIb dyes for bio-imaging. Light has limited penetration depth in vivo which has led to increasing interest in NIR-II fluorophores. Here, the authors report on the design and testing of an organic aggregation induced emission fluorophore with high quantum yield and demonstrate imaging of vasculature and intestines in live mice.

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Design of AIEgens for near-infrared IIb imaging through structural modulation at molecular and morphological levels.

The development of fluorophores for the second near-infrared window (NIR-II, 1000-1700 nm) represents an emerging, significant, and vibrant field in analytic chemistry, chemical biology, and biomedical engineering. The wavelength, brightness, and stability are three crucial factors that determine the performance of an NIR-II fluorophore. Up to now, significant progress has been made in the development of NIR-II fluorescence molecular probes, including the synthesis of D-A-D and D-π-A fluorophores with improved NIR-II fluorescence imaging performance and the construction of off-on probes and ratiometric probes via energy transfer or molecular structure modification. In this review, we summarize the most recent advances in molecular engineering design strategies of NIR-II fluorophores and probes, then highlight a selection of bioimaging and biosensing applications. We also provide perspectives on potential challenges and opportunities in this emerging field.

Molecular Engineering of NIR-II Fluorophores for Improved Biomedical Detection

Precise diagnostics are of significant importance to the optimal treatment outcomes of patients bearing brain tumors. NIR-II fluorescence imaging holds great promise for brain-tumor diagnostics with deep penetration and high sensitivity. This requires the development of organic NIR-II fluorescent agents with high quantum yield (QY), which is difficult to achieve. Herein, the design and synthesis of a new NIR-II fluorescent molecule with aggregation-induced-emission (AIE) characteristics is reported for orthotopic brain-tumor imaging. Encapsulation of the molecule in a polymer matrix yields AIE dots showing a very high QY of 6.2% with a large absorptivity of 10.2 L g-1 cm-1 at 740 nm and an emission maximum near 1000 nm. Further decoration of the AIE dots with c-RGD yields targeted AIE dots, which afford specific and selective tumor uptake, with a high signal/background ratio of 4.4 and resolution up to 38 µm. The large NIR absorptivity of the AIE dots facilitates NIR-I photoacoustic imaging with intrinsically deeper penetration than NIR-II fluorescence imaging and, more importantly, precise tumor-depth detection through intact scalp and skull. This research demonstrates the promise of NIR-II AIE molecules and their dots in dual NIR-II fluorescence and NIR-I photoacoustic imaging for precise brain cancer diagnostics.

Bright Aggregation-Induced-Emission Dots for Targeted Synergetic NIR-II Fluorescence and NIR-I Photoacoustic Imaging of Orthotopic Brain Tumors

Molecular science entails the study of structures and properties of materials at the level of single molecules or small interacting complexes of molecules. Moving beyond single molecules and well-defined complexes, aggregates (i.e., irregular clusters of many molecules) serve as a particularly useful form of materials that often display modified or wholly new properties compared to their molecular components. Some unique structures and phenomena such as polymorphic aggregates, aggregation-induced symmetry breaking, and cluster excitons are only identified in aggregates, as a few examples of their exotic features. Here, by virtue of the flourishing research on aggregation-induced emission, the concept of "aggregate science" is put forward to fill the gaps between molecules and aggregates. Structures and properties on the aggregate scale are also systematically summarized. The structure-property relationships established for aggregates are expected to contribute to new materials and technological development. Ultimately, aggregate science may become an interdisciplinary research field and serves as a general platform for academic research.

Aggregate Science: From Structures to Properties

Fluorescence imaging in the second near-infrared (NIR-II) window facilitated by aggregation-induced emission luminogens (AIEgens) is an emerging research field. NIR-II AIEgens overcome limitations imposed by penetration depth and fluorescence efficiency, offering high-performance imaging with enhanced precision. Some reported NIR-II AIEgens demonstrate capabilities for fluorescence and photoacoustic bimodal imaging, and fluorescence imaging guided photothermal therapy, which not only improves diagnosis accuracy but provides an efficient theranostic platform to accelerate preclinical translation as well. This minireview summarizes recent efforts on exploiting NIR-II AIEgens with regard to molecular design strategies and bioapplications, and puts forward current challenges and promising prospects. This timely sketch should benefit the further exploitation of diverse and multifunctional NIR-II AIEgens for a wide array of applications.

NIR‑II AIEgens: A Win–Win Integration towards Bioapplications

Near-infrared II fluorescence imaging holds great promise for in vivo imaging and imaging-guided surgery with deep penetration and high spatiotemporal resolution. However, most NIR-II aromatic luminophores suffer from the notorious aggregation-caused quenching (ACQ) effect in the aqueous solution, which largely hinders their biomedical application in vivo. In this study, the first NIR-II organic aggregation-induced emission (AIE) fluorophore (HLZ-BTED), encapsulated as nanoparticles (HLZ-BTED dots) for in vivo biomedical imaging, was designed and synthesized. The NIR-II AIE HLZ-BTED dots showed high temporal resolution, high photostability, outstanding water-solubility and biocompatibility in vitro and in vivo. The HLZ-BTED dots were further used for long-term breast tumor imaging and visualizing tumor-feeding blood vessels, long-term hind limb vasculature and incomplete hind limb ischemia. More importantly, as a proof-of-concept, this is the first time that non-invasive and real-time NIR-II imaging of the gastrointestinal tract in health and disease has been performed, making the AIE dots a promising tool for gastrointestinal (GI) tract research, such as understanding the healthy status of GI peristalsis, diagnosing and evaluating intestinal motility dysfunction, and assessing drug effects on intestinal obstruction.

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Novel near-infrared II aggregation-induced emission dots for in vivo bioimaging

Correction for ‘Novel near-infrared II aggregation-induced emission dots for in vivo bioimaging’ by Jiacheng Lin et al., Chem. Sci., 2019, 10, 1219–1226.

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Hanxing Tong

Papers

Novel near-infrared II aggregation-induced emission dots for in vivo bioimaging

Correction: Novel near-infrared II aggregation-induced emission dots for in vivo bioimaging