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WIREs Nanomed Nanobiotechnol
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Current status and prospects for microbubbles in ultrasound theranostics

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Abstract Encapsulated microbubbles have been developed over the past two decades to provide improvements both in imaging as well as new therapeutic applications. Microbubble contrast agents are used currently for clinical imaging where increased sensitivity to blood flow is required, such as echocardiography. These compressible spheres oscillate in an acoustic field, producing nonlinear responses which can be uniquely distinguished from surrounding tissue, resulting in substantial enhancements in imaging signal‐to‐noise ratio. Furthermore, with sufficient acoustic energy the oscillation of microbubbles can mediate localized biological effects in tissue including the enhancement of membrane permeability or increased thermal energy deposition. Structurally, microbubbles are comprised of two principal components—an encapsulating shell and an inner gas core. This configuration enables microbubbles to be loaded with drugs or genes for additional therapeutic effect. Application of sufficient ultrasound energy can release this payload, resulting in site‐specific delivery. Extensive preclinical studies illustrate that combining microbubbles and ultrasound can result in enhanced drug delivery or gene expression at spatially selective sites. Thus, microbbubles can be used for imaging, for therapy, or for both simultaneously. In this sense, microbubbles combined with acoustics may be one of the most universal theranostic tools. WIREs Nanomed Nanobiotechnol 2013, 5:329–345. doi: 10.1002/wnan.1219 This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Diagnostic Tools > In Vivo Nanodiagnostics and Imaging

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Two 3D images from the same sample volume acquired of a rat fibrosarcoma tumor model using traditional 30 MHz b‐mode imaging (left) and contrast‐enhanced acoustic angiography (right). Scale bars below the images indicate 1 cm. Cartoon in the center illustrates the approximate location of the tumor denoted by the red circle. (Source: courtesy of Ryan Gessner, unpublished data).

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Ultrasound molecular imaging used to evaluate the efficacy of an aurora kinase inhibitor in treating human pancreatic adenocarcinoma xenografts in a preclinical model. Data illustrate that molecular imaging indicates response to therapy prior to tumor size changes. (a) Ultrasound images of a representative treated and a representative untreated tumor, which were each acquired before and after treatment. The green color overlay illustrates contrast agent targeted to αvβ3, an angiogenic biomarker. The brightness of the green image overlay is assumed to be correlated with the degree of molecular marker expression. (b) Three‐dimensional ultrasound rendering of a treated pancreatic adenocarcinoma tumor on day 0. The green overlay represents the contrast agent targeting to αvβ3. A section is removed to illustrate the spatial variability of contrast targeting to αvβ3 biomarker expression. (c) Percent increase or decrease in volumetric contrast targeting before and after therapy (untreated − N = 5, treated − N = 5). *P < 0.05 compared with untreated tumors on day 2. (d) Percent increase or decrease in volume as measured by regions of interest from brightness mode ultrasound images taken at known distances across the tumor (untreated − N = 5, treated − N = 5). (Source: provided by Jason Streeter, Gabriela Herrera, and J.J. Yeh, unpublished data).

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Example of contrast‐enhanced destruction‐reperfusion imaging in a rodent tumor xenograft model, (a) prior to and (b) 48 h post antiangiogenic administration, illustrating reduction in tumoral blood flow in response to therapy. Grayscale indicates anatomical orientation, the colormap indicates blood flow, where red is slower flow and green is faster flow. (Source: courtesy of Steven Feingold, unpublished data).

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High‐speed optical photography of acoustically excited microbubbles illustrating microbubble fragmentation as well as stable oscillation. (a) Diameter versus time streak photography showing a 3‐µm bubble in response to two cycle insonation at approximately 1.5 MHz and 1200 kPa. The microbubble is observed to expand and contract substantially and then fragment (b). Standard two‐dimensional framing photography acquired simultaneously to the diameter versus time image presented in (a); (c) 20‐cycle insonation of a 3.5‐µm bubble at approximately3.5 MHz and 200 kPa, showing stable, linear, low‐amplitude oscillation. (Source: courtesy of Paul Dayton, unpublished data).

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Schematic of commonly used drug attachment strategies in microbubble mediated drug delivery. (a) Drugs can be dissolved in a secondary oil layer using a multilayer microbubble construction. (b) Therapeutic agents can be seeded within the thin encapsulating shell. (c) Nanoparticles or other therapeutics can be attached to the outside of the shell, such as tethered to PEG chains. (Source: image courtesy of Paul Sheeran).

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Illustration of three hypothesized methods of how microbubbles may cause enhanced permeability. (a) An ultrasound wave places a high pressure on the microbubble to compress it and is followed by low pressure that rapidly expands it creating several microhemorrhages due to mechanical stress. (b) An oscillating microbubble stimulates a cell to increase transcellular transport from the lumen of the vessel to the basal membrane. (c) A microbubble oscillates nonlinearly to the point of asymmetric collapse, producing a powerful microjet that breaches the endothelium.

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Diagnostic Tools > In Vivo Nanodiagnostics and Imaging
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