Amyloid-β Deposits Target Efficient Near-Infrared Fluorescent Probes: Synthesis, in Vitro Evaluation, and in Vivo Imaging

Fu, Hualong; Tu, Peiyu; Zhao, Lu; Dai, Jiapei; Liu, Boli; Cui, Mengchao

doi:10.1021/acs.analchem.5b04441

Cited by 81 publications

(77 citation statements)

References 27 publications

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“…For enhanced fluorescence detection and imaging of pathologic Aβ aggregates in AD brain tissue, for example, conjugation to near-infrared (NIR) fluorophores or quantum dots could prove ideal, 30 as there is little to no tissue autofluorescence in the far-red or NIR regions of the electromagnetic spectrum. 42, 43 …”

Section: Resultsmentioning

confidence: 99%

Generation of Clickable Pittsburgh Compound B for the Detection and Capture of β-Amyloid in Alzheimer’s Disease Brain

et al. 2017

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The benzothiazole-aniline derivative Pittsburgh Compound B (PiB) is the prototypical amyloid affinity probe developed for the in vivo positron emission tomography (PET) detection of amyloid beta (Aβ) deposits in Alzheimer’s disease (AD). Specific high-affinity binding sites for PiB have been found to vary among AD cases with comparable Aβ load, and they are virtually absent on human-sequence Aβ deposits in animal models, none of which develop the full phenotype of AD. PiB thus could be an informative probe for studying the pathobiology of Aβ, but little is known about the localization of PiB binding at the molecular or structural level. By functionalizing the 6-hydroxy position of PiB with a PEG3 spacer and a terminal alkyne (propargyl) moiety, we have developed a clickable PiB compound that was derivatized with commercially available azide-labeled fluorophores or affinity-tags using copper-catalyzed azide-alkyne cycloaddition reactions, commonly referred to as “click” chemistry. We have determined that both the clickable PiB derivative and its fluorescently-labeled conjugate have low nanomolar binding affinities for synthetic Aβ aggregates. Furthermore, the fluorescent-PiB conjugate can effectively bind Aβ aggregates in human AD brain homogenates and tissue sections. By covalently coupling PiB to magnetic beads, Aβ aggregates were also affinity-captured from AD brain extracts. Thus, the clickable PiB derivative described herein can be used to generate a wide variety of covalent conjugates, with applications including the fluorescence detection of Aβ, the ultrastructural localization of PiB binding, and the affinity capture and structural characterization of Aβ and other co-factors from AD brains.

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Section: Resultsmentioning

confidence: 99%

Generation of Clickable Pittsburgh Compound B for the Detection and Capture of β-Amyloid in Alzheimer’s Disease Brain

et al. 2017

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“…The author further replaced benzene ring of DANIR-2c with naphthalene ring to synthesize DANIR-3c ( Figure 5), and the fluorescence emission wavelength was beyond 680 nm. [53] DANIR-8c performed better binding ability toward Adv Aβ aggregates, hydrophilicity, and brain kinetics. Toward this issue, the author introduced incorporating hydroxyethyl groups into the N,N-dimethyl moiety of DANIR-3c to synthesize the compound DANIR-8c ( Figure 5).…”

Section: The Detection Of Aβ Aggregatesmentioning

confidence: 95%

Fluorescence Detection and Dissociation of Amyloid‐β Species for the Treatment of Alzheimer's Disease

Shen

Zheng

et al. 2019

Advanced Therapeutics

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Alzheimer's disease (AD) is one of the most prevalent forms of neurodegenerative disease. It is well established that the β-amyloid peptide (Aβ) species existing in several forms, such as soluble monomers, oligomers, and insoluble aggregates, play an essential role in the pathophysiology of AD. Therefore, much effort has been made to specifically detect Aβ species and to inhibit Aβ aggregation for the treatment of AD. In this review, an overview of recent advances in detecting different Aβ forms mainly containing Aβ aggregates, Aβ oligomers, and Aβ protofibrils is provided. In addition, photodynamic therapy (PDT) and photothermal therapy (PTT) are considered to be promising modalities for the treatment of AD because of the minimal invasiveness and high spatial selectivity. Herein, the strategies of inhibiting Aβ aggregation and dissociating Aβ aggregates using PDT, PTT, and Aβ inhibitors for the treatment of AD are summarized.

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“…The experiments on fibrillar amyloids of hen egg white lysozyme showed that PD‐NA‐TEG had the best detection capability with a low limit of detection (LOD) of 63.71 × 10 −9 m . Moreover, these AIEgens, especially PD‐NA and PD‐NA‐TEG, exhibited excellent binding capacities to Aβ plaques in the mouse brain, as revealed by the overlapped images of them with 8C (a reported probe for β‐amyloid plaques) (red spots, Figure B). More importantly, ex vivo super‐resolution imaging of Aβ plaques in brain slices has also been successfully conducted to resolve the specific morphology in detail (Figure C–E).…”

Section: Disease Diagnosismentioning

confidence: 95%

Promising Applications of AIEgens in Animal Models

Situ

Zhao

et al. 2019

Small Methods

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organisms cannot be achieved from these static findings. Therefore, gaining in-depth insights into biological and physiological functions at the in vivo level is of great significance, and various imaging techniques have been explored for this purpose. [1] In addition to the clinically available magnetic resonance imaging (MRI), ultrasonic imaging, computed tomography (CT), positron emission tomography (PET), and single-photon emission computed tomography, fluorescence imaging (another distinct type of optical imaging [1c] from bioluminescence imaging [2] ) has attracted increasing attention, owing to its advantages of high temporal-spatial resolution and sensitivity, noninvasive, and real-time applications, and the ability to provide dynamic information for basic research and (pre-)clinical settings at cellular and subcellular levels. [3] Fluorescent probes or contrast agents are essential for fluorescence imaging. Compared with fluorescent proteins, [4] inorganic nanoparticles (NPs), [5] such as quantum dots, [6] upconversion NPs, [7] and metallic NPs, [8] and organic dyes [9] (e.g., U.S. Food and Drug Administration (FDA)-approved 5-ALA, indocyanine green (ICG), and methylene blue), organic NPs [10] have obvious advantages, such as easy preparation and good biocompatibility. However, many organic NPs show weak fluorescence because they are made with conventional organic dyes, which suffer from the aggregation-caused quenching (ACQ) effect, i.e., their fluorescence is partially or completely quenched in the aggregated state.The advent of the aggregation-induced emission (AIE) concept offers a new strategy to deal with ACQ. [11] AIE refers to the interesting photophysical phenomenon that luminogens are weakly fluorescent or nonfluorescent in solution but show greatly enhanced emission in the aggregated state, primarily because of restricted intramolecular motion. [12] The past 19 years have witnessed spectacular advances of AIEgens, [13] due to their advantages of structural variety, easy functionalization, strong luminescence, large Stokes shift, high photobleaching-resistance, and so on. In particular, various AIE bioprobes have been designed: [14] (i) water-soluble AIEgens, which are comprised of a hydrophobic AIE core and hydrophilic units (e.g., ionic groups, peptides, carbohydrates, DNA, aptamers, antibodies, and poly(ethylene glycol) (PEG)); (ii) bare AIEgen dots (nanoaggregates); iii) AIEgen/biopolymer dots, which can be obtained by loading AIEgens onto biopolymer matrixes covalently (e.g., chitosan, dextran, and starch) or noncovalently (e.g., bovine serum albumin, human serum albumin (HSA), and fetal bovine serum (FBS)); (iv)In vivo investigations using small animal models are of great significance for the comprehensive understanding of biological and physiological functions-seeing is believing. Fluorescence imaging can provide real-time and dynamic information of living systems. During the past few years, aggregation-induced emission luminogens (AIEgens) are widely and rapidly developed for biolog...

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Amyloid-β Deposits Target Efficient Near-Infrared Fluorescent Probes: Synthesis, in Vitro Evaluation, and in Vivo Imaging

Cited by 81 publications

References 27 publications

Generation of Clickable Pittsburgh Compound B for the Detection and Capture of β-Amyloid in Alzheimer’s Disease Brain

Generation of Clickable Pittsburgh Compound B for the Detection and Capture of β-Amyloid in Alzheimer’s Disease Brain

Fluorescence Detection and Dissociation of Amyloid‐β Species for the Treatment of Alzheimer's Disease

Promising Applications of AIEgens in Animal Models

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