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WIREs Nanomed Nanobiotechnol
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Multimodal micro, nano, and size conversion ultrasound agents for imaging and therapy

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Ultrasound (US) is one of the most commonly used clinical imaging techniques. However, the use of US and US‐based intravenous agents extends far beyond imaging. In particular, there has been a surge in the fabrication of multimodality US contrast agents and theranostic US agents for cancer imaging and therapy. The unique interaction of US waves with microscale and nanoscale agents has attracted much attention in the development of contrast agents and drug‐delivery vehicles. The dimensions of the agent not only dictate how it behaves in vivo, but also how it interacts with US for imaging and drug delivery. Furthermore, these agents are also unique due to their ability to convert from the nanoscale to the microscale and vice versa, having imaging and therapeutic utility in both dimensions. Here, we review multimodality and multifunctional US‐based agents, according to their size, and also highlight recent developments in size conversion US agents. WIREs Nanomed Nanobiotechnol 2016, 8:796–813. doi: 10.1002/wnan.1398 This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Schematic representations of nano‐ and microscale agents. (a) Nanoscale agents are able to extravasate out of the blood vessels into the tumor tissue due to the enhanced permeability and retention (EPR) effect. (b) Microscale agents are confined within the boundaries of blood vessels due to their large size. (c) Different strategies for developing multifunctional US‐based agents, where small molecules or nanoparticles of an additional functionality that can be tethered, adsorbed, encapsulated, or embedded into the US‐based agent.
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Size conversion of porphyrin microbubbles to nanoparticles. (a) Schematic of porphyrin microbubbles that convert to nanoparticles upon sonication with low frequency US. (b) Light microscopy image of porphyrin microbubbles and a transmission electron micrograph of porphyrin nanoparticles after sonication. (c) Multimodal imaging of the porphyrin microbubbles and the resulting nanoparticles in a gel phantom imaged with US, photoacoustic, and fluorescence imaging. Samples: (1) phosphate‐buffered saline, (2) porphyrin microbubbles without applying ultrasound pulses (zero pulses), and after applying (3) 1 pulse, (4) 2 pulses and (5) 10 pulses. (d) Delivery of porphyrin nanoparticles into a KB tumor xenograft in a mouse via the conversion of porphyrin microbubbles to nanoparticles. (Reprinted with permission from Ref . Copyright 2015 Macmillan Publishers Limited)
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Size conversion of porphyrin nanodroplets to microbubbles. (a) Schematic of a porphyrin nanodroplet and its conversion to a microbubble via the absorption of US energy or laser irradiation. (B) Cryo transmission electron micrograph of a porphyrin nanodroplet. (c) Size distribution of nanodroplets fabricated without the porphyrin and porphyrin nanodroplets with the addition of laser irradiation. (Reprinted with permission from Ref . Copyright 2015 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim)
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Size conversion of Indocyanine green (ICG) nanodroplets to microbubbles using an optical trigger. Nanodroplets in solution before (laser off) and after (laser on) laser irradiation. Three samples were compared of nanodroplets in water, ICG‐loaded nanodroplets in water, and pure nanodroplets in an aqueous solution of ICG (a–c). Only the samples with ICG loaded into the core of the nanodroplets underwent conversion to microbubbles upon laser irradiation. (Reprinted with permission from Ref . Copyright 2014 American Chemical Society)
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Size conversion of India ink nanodroplets to microbubbles using an optical trigger. (a) Schematic of the fabrication process of India ink nanodroplets. (b) Schematic of the resulting nanodroplet encapsulating India ink. (c) Scanning electron microscopy image of India ink nanodroplets. (d) Bright‐field optical microscopy image of nanodroplets prior to laser irradiation and the formation of microbubbles after laser irradiation. (e) Ultrasound image of a mouse tumor xenograft injected intratumorally with India ink nanodroplets, pre‐ and postlaser irradiation. Mice were injected with nanodroplets without India ink, free India ink, or India ink‐loaded nanoplets. The conversion of nanodroplets to microbubbles was only observed in animals injected with India ink nanodroplets and laser irradiation. (Reprinted with permission from Ref . Copyright 2014 Ivyspring International Publisher)
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Size conversion of doxorubicin‐loaded nanodroplets. Optical images of doxorubicin‐loaded nanodroplets in a plastic capillary. (a–d) Demonstrated the first heating and cooling cycle of the nanodroplets, where the nanodroplets in (a) grow to nanobubbles and coalesce to form microbubbles after heating. Upon cooling in (d), the microbubbles shrink to microdroplets, but the original size of the droplet is not restored due to coalescence in the initial heating cycle. (e–f) Demonstrated the second heating cycle of the droplets and their response to heating, resulting in their expansion into microbubbles. (Reprinted with permission from Ref . Copyright 2008 Elsevier)
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Doxorubicin‐loaded nanodroplets. (a) Schematic of doxorubicin‐loaded nanodroplets and their extravasation from the vasculature into the tumor tissue. Accumulation of nanodroplets in the tumor tissue results in coalescence to form microbubbles. (b) In vivo demonstration of nanodroplets in a human breast cancer xenograft in a mouse before (left) and 4 h after (right) intratumor injection of nanodroplets. (Reprinted with permission from Ref . Copyright 2008 Elsevier)
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Porphyrin microbubbles for ultrasound (US), photoacoustic and fluorescence imaging. (a) Schematic of trimodality porphyrin microbubbles. (b) In vivo US and photoacoustic images of porphyrin microbubbles before and after intravenous injection in a KB tumor xenograft bearing mouse. (c) Ex vivo fluorescence images of the tumor after injection of porphyrin microbubbles compared to unimodal microbubbles without porphyrin. (Reprinted with permission from Ref . Copyright 2014 American Chemical Society)
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Trimodal 99mTc‐superparamagnetic iron oxide nanoparticle (SPION)‐polyvinyl alcohol (PVA) microbubbles used to evaluate microbubble biodistribution in rats. (a) Negative enhancement of the healthy rat liver is visible in the T2*‐weighted magnetic resonance imaging (MRI) scans relative to the preinjection scan (a) at 2 h (c) and 24 h (e) post intravenous microbubble injection. SPECT/CT images at 2 h (b) and 24 h (d) demonstrate a redistribution of the microbubble components from the lungs to the liver. (Reprinted with permission from Ref . Copyright 2013 Springer)
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