The pursuit of polymethine fluorophores with NIR-II emission and high brightness for in vivo applications

Abstract

Polymethine cyanine dyes, as the most important class of organic near-infrared-II (NIR-II) fluorophores, recently received increasing attention due to their high molar extinction coefficients, intensive fluorescence brightness, and flexible wavelength tunability for fluorescent bioimaging applications. Very recently, remarkable advances have been made in the development of NIR-II polymethine fluorophores with improved optical performance, mainly including tunable fluorescence, improved brightness, improved water solubility and stability. In this review, we summarize the recent research advances in molecular tailoring design strategies of NIR-II polymethine fluorophores, and then emphasize the representative bioimaging and biosensing applications. The potential challenges and perspectives of NIR-II polymethine fluorophores in this emerging field are also discussed. This review may provide guidance and reference for further development of high-performance NIR-II polymethine fluorophores to boost their clinical translation in the future.

Fig. 1. Typical chemical structures of NIR-II polymethine fluorophores applied for NIR-II bioimaging and biosensing are listed in the timeline.

Fig. 2. Schematic diagram of structure tailoring strategies for longer-wavelength polymethine fluorophores. (A) Representative design strategies for longer emission wavelengths; (B) extending the conjugation chain; (C) heterocycle involved; (D) exchanging of heteroatoms; (E) donor and accept modifications; (F) constructing fluorophore J-aggregates. Reproduced with permission from ref. . Copyright 2021 American Chemical Society.

Fig. 3. Schematic illustration of the strategies to improve fluorescent brightness of NIR- II polymethine fluorophores. (A) Scheme of the effective strategies to improve the brightness for polymethine fluorophores including (i) introducing large steric hindrance, (ii) self-assembling with protein, and (iii) improving the molecular rigidity. (B) Introducing large steric hindrance. Reproduced with permission from ref. . Copyright 2022 Wiley-VCH and ref. . Copyright 2022 American Chemical Society. (C) Assembly of NIR-II polymethine fluorophores and protein for improved optical performance. Reproduced with permission from ref. . Copyright 2018 Wiley-VCH. (D) enhancing the molecular rigidity. Reproduced with permission from ref. . Copyright 2020 Wiley-VCH.

Fig. 4. Typical NIR-II polymethine fluorophores for dynamic and multiplexed imaging. (A) The hydrophobic fluorophore 5H5 was transformed into 5H5-PEG₈-cRGDfk through PEGylation which was used for in vivo NIR-II or NIR-IIa tumor targeted imaging. Reproduced with permission from ref. . Copyright 2019 American Chemical Society. (B) The water-soluble fluorophore LZ1105 was employed for dynamic tracking and imaging of the carotid artery, and the dynamic process of thrombolysis after injection of thrombolytics was distinctly visualized (yellow arrows). Reproduced with permission from ref. . Copyright 2020, Springer Nature. (C) HC1222/F5-TPB (λ_ex = 1120 nm) and HC1342/F5-TPB (λ_ex = 1319 nm) were employed to perform the dual-color imaging in living mice. Reproduced with permission from ref. . Copyright 2022 Wiley-VCH. (D) MeOFlav7 (λ_ex = 980) and JuloFlav7 (λ_ex = 1064 nm) combining with ICG (λ_ex = 785) were used for three-colour real time in vivo imaging. Reproduced with permission from ref. . Copyright 2020, Springer Nature. (E) Combining ICG (λ_ex = 785 nm), JuloChrom5 (λ_ex = 892 nm), Chrom7 (λ_ex = 968 nm), and JuloFlav7 (λ_ex = 1065 nm) can realize the four-color video-rate imaging in mice. Reproduced with permission from ref. . Copyright 2022 American Chemical Society.

Fig. 5. Representative NIR-II off–on and ratiometric probes based on polymethine fluorophores. (A) Schematic illustration of the off–on and ratiometric probe sensing mechanism and corresponding fluorescence spectra change pattern. (B) Catalyzed mechanism of the probe IR1048-MZ activated by NTR. Reproduced with permission from ref. . Copyright 2018 Wiley-VCH. (C) Responsive mechanism of PN910 and NIR-II-HD5-analyte (ONOO⁻, GSH, and ALP) activated by the corresponding analytes of interest based on ICT mechanism. Reproduced with permission from ref. and . Copyright Wiley-VCH. (D) The viscosity-activatable probe LET-1052 was used to evaluate the therapeutic efficacy. Reproduced with permission from ref. . Copyright 2022 Wiley-VCH. (E) Chemical structure of BTC1070 and its fluorescence spectra at varied pH values and fluorescence imaging of gastric pH in mice stomach. Reproduced with permission from ref. . Copyright 2020, Springer Nature. (F) Top left: chemical structure and spectra of CX derivatives; bottom left: the schematic illustration of the detection mechanism of PN1100; top right: fluorescence spectra at 920 nm and 1130 nm; bottom right: ratiometric fluorescence images of the mice livers. Reproduced with permission from ref. . Copyright Wiley-VCH.

Xuan Zhao

Fan Zhang

Zuhai Lei