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WIREs Nanomed Nanobiotechnol
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Ultra‐bright and stimuli‐responsive fluorescent nanoparticles for bioimaging

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Fluorescent nanoparticles (NPs) are unique contrast agents for bioimaging. Examples of molecular‐based fluorescent NPs with brightness similar or superior to semiconductor quantum dots have been reported. These ultra‐bright NPs consist of a silica or polymeric matrix that incorporate the emitting dyes as individual moieties or aggregates and promise to be more biocompatible than semiconductor quantum dots. Ultra‐bright materials result from heavy doping of the structural matrix, a condition that entails a close mutual proximity of the doping dyes. Ground state and excited state interactions between the molecular emitters yield aggregation‐caused quenching (ACQ) and proximity‐caused quenching (PCQ). In combination with Föster resonance energy transfer (FRET) ACQ and PCQ originate collective phenomena that produce amplified quenching of the nanoprobes. In this focus article, we discuss strategies to achieve ultra‐bright nanoprobes avoiding ACQ and PCQ also exploiting aggregation‐induced emission (AIE). Amplified quenching, on the other hand, is also proposed as a strategy to design stimuli‐responsive fluorogenic probes through disaggregation‐induced emission (DIE) in alternative to AIE. As an advantage, DIE consents to design stimuli‐responsive materials starting from a large variety of precursors. On the contrary, AIE is characteristic of a limited number of species. Examples of stimuli‐responsive fluorogenic probes based on DIE are discussed. WIREs Nanomed Nanobiotechnol 2015, 8:139–150. doi: 10.1002/wnan.1351 This article is categorized under: Diagnostic Tools > In Vitro Nanoparticle-Based Sensing Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Scheme of the mechanism of response of the fluorogenic nanoparticles (NPs) formed by P in phosphate buffered saline (PBS). NPs are not fluorescent due to aggregation‐caused quenching (ACQ). Adsorption by cells leads to disaggregation of the NPs and to fluorescence recovery of disaggregation‐induced emission (DIE). The cells become green fluorescent (case A, picture a) or red fluorescent (case B, picture a), respectively, at low and high NPs dosage. Exposure to strong visible light allows the photo tuning of the emission (PTE) of specific cellular compartments (C). Fluorescence images during irradiation are shown in the sequence c–e. Reproduced with permission from ref. 6; Copyright (2014) Royal Society of Chemistry.
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Left: chemical structure of PDI‐1 and LR dyes (a) and schematic presentation of dye‐doped poly(DL‐lactide‐co‐glycolide) (PLGA) nanoparticles (b). Right: confocal fluorescence imaging of HeLa cells cultured for 1 (a), 2 (b), and 6 (c) h in the presence of 1 wt% LR nanoparticles (NPs) and for 10 min in the presence of wheat germ agglutinin‐Alexa488 for labeling cell membranes. Reproduced with permission from ref. 74; Copyright (2014) Royal Society of Chemistry.
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Left: Chemical structures of DiI perchlorate and DiI‐TPB and schematic presentation of nanodroplet encapsulating them. Right: Single‐particle tracking of DiI‐TPB nanodroplets in zebrafish vessels. During the diastole, single particles were followed in consecutive frames (a). During the systole, the velocity was calculated from the shape of the line, which is a result of the movement of the particles during the line scanning (b). Reconstruction of the blood flow profile (c). Reproduced with permission from ref. 72; Copyright (2014) Elsevier.
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(a) Scheme of the preparation of silica nanoparticles (NPs) using Pluronic F127 micelles as templates. (b) Heavily coumarin‐doped NPs are poorly fluorescence because of the formation of weak emitting excimers and aggregates. (c) Coencapsulation of BODIPY as an excitation energy acceptor at low doping level activate a very efficient Föster resonance energy transfer (FRET) process that becomes the dominant channel of deactivation of coumarins and leads to ultra‐bright NPs. (d) Fluorescence images of equimolar suspensions of the two kinds of NPs. Reproduced with permission from ref. 81; Copyright (2013) Wiley.
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Most typical strategies to prepare ultra‐bright nanoparticles (NPs). aggregation‐caused quenching (ACQ) and proximity‐caused quenching (PCQ) can be prevented by controlling the dye distribution in the structure (left) or using specific dyes that do not give these kind of processes (right). <ϕ> is almost independent on the doping level and brightness increase together with <n> <ϵ> leading to ultra‐bright NPs.
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Effect of amplified aggregation‐caused quenching (ACQ) and proximity‐caused quenching (PCQ) on the brightness of nanoparticles (NPs). At low dye doping level (left) the emitting molecules do not interact: <ϕ> is maximum but <n> <ϵ> is low. At high doping level (right) ACQ and PCQ combined to Föster resonance energy transfer (FRET) cause an amplified quenching and a severe decrease of <ϕ>. These effects prevent the preparation of ultra‐bright NPs. Optimal loading window is shown in blue.
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Amplification of aggregation‐caused quenching (ACQ, left) and proximity‐caused quenching (PCQ) in NPs. The former process involve Föster resonance energy transfer (FRET) from ‘isolated’ excited dyes (A molecules) to nonluminescent aggregates already present before excitation because of the action of ground state interaction between B molecules. Amplified PCQ is analogous but takes place also in the absence of aggregates: FRET leads to excitation of molecule which are not aggregated (weak ground state interaction) but are close enough to bind after excitation to give quenched species.
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Left: scheme of the disassembly driven fluorescence turn‐on in micellar nanoparticles by intracellular reductive stimuli. Right: Fluorescent turn‐on of polymerized micelles in living HeLa cells under reductive stimuli. Fluorescence confocal images of HeLa cells incubated with NR12D (a, b) and MP2 (c, d) for 10 min (a, c) and 1 h (b, d). (e, f) Images of HeLa cells after 1 h incubation with MP2 before (e) and after (f) addition of 10 µM reducing agent (dithiothreitol, DTT). Concentration of NR12D and MP2 (expressed in amphiphile molecules) was 0.5 µM. The green fluorescence corresponds to the membrane marker wheat germ agglutinin‐Alexa Fluor 488, while the red fluorescence corresponds to the Nile Red‐based dyes. Reproduced with permission from ref. 81; Copyright (2014) Wiley.
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Diagnostic Tools > In Vivo Nanodiagnostics and Imaging
Diagnostic Tools > In Vitro Nanoparticle-Based Sensing
Nanotechnology Approaches to Biology > Nanoscale Systems in Biology

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