Optical molecular imaging and theranostics in neurological diseases based on aggregation-induced emission luminogens

Abstract

Optical molecular imaging and image-guided theranostics benefit from special and specific imaging agents, for which aggregation-induced emission luminogens (AIEgens) have been regarded as good candidates in many biomedical applications. They display a large Stokes shift, high quantum yield, good biocompatibility, and resistance to photobleaching. Neurological diseases are becoming a substantial burden on individuals and society that affect over 50 million people worldwide. It is urgently needed to explore in more detail the brain structure and function, learn more about pathological processes of neurological diseases, and develop more efficient approaches for theranostics. Many AIEgens have been successfully designed, synthesized, and further applied for molecular imaging and image-guided theranostics in neurological diseases such as cerebrovascular disease, neurodegenerative disease, and brain tumor, which help us understand more about the pathophysiological state of brain through noninvasive optical imaging approaches. Herein, we focus on representative AIEgens investigated on brain vasculature imaging and theranostics in neurological diseases including cerebrovascular disease, neurodegenerative disease, and brain tumor. Considering different imaging modalities and various therapeutic functions, AIEgens have great potential to broaden neurological research and meet urgent needs in clinical practice. It will be inspiring to develop more practical and versatile AIEgens as molecular imaging agents for preclinical and clinical use on neurological diseases.

Keywords: Aggregation-induced emission; Brain vasculature; Fluorescence imaging; Neurological diseases; Theranostics.

Fig. 1

Schematic illustration of roles of AIEgens for optical molecular imaging and theranostics in neurological diseases

Fig. 2

Two-photon fluorescence imaging of brain vasculature through the cranial window on mice based on AIEgens. A Molecular structure and synthetic route of BTPEBT dots, time lapse (0–30 min), and different depths (0–424 μm) imaging for 3D reconstruction of mouse brain vasculature through two-photon fluorescence imaging. Adapted permission from Ref. [53]. Copyright © 2013 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim. B Molecular structure, synthetic route of BTPETQ dots, imaging of different depths (0–924 μm) through a two-photon microscope, and 3D reconstruction of mouse brain vasculature and visualization of brain capillaries with good spatial resolution comparing NIR-I and NIR-II at 500 μm and 788 μm. Adapted permission from Ref. [59]. Copyright © 2019 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim

Fig. 3

Three-photon fluorescence imaging of brain vasculature through the cranial window on mice based on AIEgens. A Molecular structure of TTF (TPETPAFN) and the corresponding NPs on different depths (0–550 μm) imaging of mouse brain vasculature through three-photon fluorescence imaging. Adapted permission from Ref. [66] Copyright © 2015 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim. B Molecular structure and synthetic route of TPATCN NPs and mouse brain vasculature imaging as deep as 875 μm with good SBR by three-photon microscope. Adapted permission from Ref. [65]. Copyright © 2017 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim

Fig. 4

Three-photon fluorescence imaging of brain vasculature without cranial window on mice based on AIEgens. A Molecular structure of DCDPP-2TPA, synthetic route, and emission spectrum of the corresponding NPs, and schematic illustration on mouse brain vasculature visualization at 0–300 μm with the intact skull which helped recognize 2.0 μm capillaries with 20.4 SBR. Adapted permission from Ref. [68]. Copyright © 2017, American Chemical Society. B Molecular structure of DCzPDI, synthetic route of the corresponding NPs, and 450 μm-deep vasculature 3D reconstruction of mouse brain without the intact skull. Adapted permission from Ref. [69]. Copyright © 2018, American Chemical Society. C Molecular structure of BTF, synthetic route of BTF dots, and nearly 0.95 μm spatial resolution of vessels in mouse brain vasculature without cranial window. Adapted permission from Ref. [67]. Copyright © 2020 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim

Fig. 5

Near-infrared imaging of brain vasculature without cranial window on rodents and nonhuman primates. A Molecular structure of BPST with AIE and NIR-II emission, synthetic route of L897 NPs based on BPST, and brain vessel imaging as deep as 1300 μm from the intact scalp and skull on mice. Adapted permission from Ref. [70]. Copyright © 2019 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim. B Molecular structure of OPTA-BTT and synthetic route of the corresponding dots, and brain vasculature visualization of thinned-skull marmoset with depth as 700 μm and detection of tiny capillaries as small as 5.2 μm. Adapted permission from Ref. [74]. Copyright © 2021 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim

Fig. 6

Optical molecular imaging of pathological changes in cerebrovascular disease based on AIEgens. A The sensitive detection of BBB leakage and damage on mouse models with suitable size of AIE NPs between 10, 30, and 60 nm based on TPETPAFN. Adapted permission from Ref. [79]. Copyright © 2016 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim. B BBB damage and microbleeding imaging with AIE-Gd dots compared with Evans Blue at 3 h after injection. Adapted permission from Ref. [81]. Copyright © 2017 Published by Elsevier Ltd. C Molecular structure and turn-on by nitroreductase of TPAQS-NO₂ and image hypoxia environment in brain on mouse models with cerebral ischemic stroke in vivo and ex vivo. Adapted permission from Ref. [84]. Copyright © 2020 Elsevier B.V. D) Synthetic route of TPAPhCN dots and visualization of atherosclerosis plaques in brain vessels. Adapted permission from Ref. [86]. Copyright © 2021 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim

Fig. 7

Optical molecular imaging for brain tumor visualization and delineation. A Photoacoustic imaging (PAI) by A1094@RGD-HBc for brain gliomas imaging in vivo, consistent with SPECT/CT. Adapted permission from Ref. [95]. Copyright © 2019 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim. B Molecular structure of TB1, synthetic route of TB1-RGD dots, and PA imaging to visualize brain tumor. Adapted permission from Ref. [96]. Copyright © 2018 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim. C Synthetic route of B-AIE dots (DT/AT/TT), illustrated endocytosis by gp60 overexpressed tumor cell and using B-TT AIE dots to achieve orthotopic glioma NIR-II imaging and image-guided surgery. Adapted permission from Ref. [97]. Copyright © 2022, American Chemical Society

Fig. 8

Synthetic route of NK@AIEdots by covering AIEdots as endoskeleton with NK cell membrane as skin to cross BBB and applied for NIR-II imaging of glioblastoma and efficiently suppress tumor growth by PTT in vivo. Adapted permission from Ref. [100]. Copyright © 2016 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim

Fig. 9

Amyloid fibrilization visualization by AIEgens in neurodegenerative disease. A Molecular structure of TPE conjugated with amyloid-like structures and detects Aβ fibril sensitively. Adapted permission from Ref. [106]. Copyright © 2015 American Chemical Society. B Illustrated principle of QM-FN-SO₃ for in vivo mapping of Aβ with high-fidelity application for Aβ imaging at 20 min after injection on APP/PS1 mice as AD models in vivo and confirmed ex vivo with Antibody-2454 in the hippocampus. Adapted permission from Ref. [112]. Copyright © 2019, American Chemical Society. C In vivo visualization of Aβ deposits in real time for 120 min in a 5*FAD and APP/PS1 mouse model by AIE-CNPy-AD. Adapted permission from Ref. [113]. Copyright © 2021, Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature