Fluorescent probes, known for their high sensitivity, selectivity, and ease of operation, have played a crucial role in various fields such as chemical biology, biochemistry, pharmacology, environmental science, and medical diagnostics since Sir George Gabriel Stokes proposed the concept of fluorescence in 1845. Among them, fluorescent probes based on the twisted intramolecular charge transfer (TICT) mechanism have become a research hotspot in recent years due to their unique responsiveness to environmental factors (such as solvent polarity and micro-viscosity) and the ability to achieve ratio detection. However, these probes still face challenges such as low fluorescence quantum yield (due to non-radiative transitions), insufficient photostability, and the need for improved biocompatibility. Additionally, designing highly specific probes for different targets (such as ions, small molecules, and biomacromolecules) and achieving multimodal imaging to meet complex scenario requirements remain pressing scientific issues in the field.
A comprehensive review article titled “Twisted Intramolecular Charge Transfer (TICT) Based Fluorescent Probes and Imaging Agents” was co-authored by Tony D. James and Simon E. Lewis from the University of Bath, Hanafy M. Ismail from the Liverpool School of Tropical Medicine, He Xiaopeng from East China University of Science and Technology, and Han Haihao and Li Jia from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences. This article systematically outlines the design principles, mechanisms, and application scenarios of TICT fluorescent probes, covering everything from fundamental mechanisms to specific applications, as well as composite strategies and future directions.
The review starts with the core mechanism of TICT, using 4-Dimethylaminobenzonitrile (DMABN) as a classic model: upon photoexcitation, DMABN enters a locally excited state (LE) and maintains a coplanar conformation in non-polar solvents, emitting only short-wavelength “normal” B-band fluorescence. In polar solvents, however, the dimethylamino group twists, causing the molecule to transition from the LE state to the TICT state, where electrons transfer from the donor (dimethylamino) to the acceptor (benzonitrile), resulting in the emission of long-wavelength “abnormal” A-band fluorescence, accompanied by significant redshift and large Stokes shift. This characteristic also lays the foundation for the environmental responsiveness of the probes. Based on this, the design of TICT probes is mainly divided into two strategies: “turn-on” and “turn-off” (Figure 1): turn-on probes have free-rotating molecular rotors that enable the TICT process when not bound to a target, resulting in weak fluorescence; upon interaction with the target, rotor rotation is blocked, TICT is suppressed, and fluorescence is significantly enhanced, achieving fluorescence activation. Conversely, turn-off probes start with restricted rotors, TICT is off, and fluorescence is strong; after binding to the target, the rotor is released, TICT resumes, leading to fluorescence quenching.
Figure 1: Schematic diagram of the most common strategies in the design of fluorescent probes based on the twisted intramolecular charge transfer (TICT) mechanism: (A) “turn-on” type and (B) “turn-off” type.
In terms of application classification, the review covers a wide range of targets from inorganic ions to biomacromolecules. Furthermore, to overcome the limitations of the single TICT mechanism, the review highlights composite probe strategies that integrate other fluorescence mechanisms. For example, PeT/TICT composite probes enhance performance through “cascade control”; AIE/TICT composite probes utilize aggregation-induced emission (AIE) to restrict molecular motion, reducing non-radiative transitions caused by TICT; TICT/ESIPT (excited-state intramolecular proton transfer) composite probes combine the large Stokes shift of ESIPT with the environmental sensitivity of TICT; additionally, there are AIE/ESIPT/TICT and FRET/TICT composite systems that further expand the functionality of the probes. Finally, the review discusses TICT probes with continuous, logical, dual, or multiple responses, which can simultaneously detect two or more targets or microenvironments.
This review not only comprehensively summarizes the fundamental theories and design strategies of TICT probes but also showcases their application potential in environmental monitoring, biological imaging, and disease diagnosis through numerous examples. At the same time, the review points out current challenges in the field: how to further improve fluorescence quantum yield, enhance photostability and biocompatibility, and develop intelligent probes with multi-stimulus responses and targeted delivery. In the future, with the development of NIR-I/II region probes and the integration of multimodal imaging technologies, TICT fluorescent probes are expected to play a greater role in non-invasive disease diagnosis, surgical navigation, and build a more efficient bridge for chemical sensing and biomedical research.
Original link:
https://doi.org/10.1039/D3CS01118F