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WIREs Nanomed Nanobiotechnol
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Ultrasound imaging beyond the vasculature with new generation contrast agents

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Current commercially available ultrasound contrast agents are gas‐filled, lipid‐ or protein‐stabilized microbubbles larger than 1 µm in diameter. Because the signal generated by these agents is highly dependent on their size, small yet highly echogenic particles have been historically difficult to produce. This has limited the molecular imaging applications of ultrasound to the blood pool. In the area of cancer imaging, microbubble applications have been constrained to imaging molecular signatures of tumor vasculature and drug delivery enabled by ultrasound‐modulated bubble destruction. Recently, with the rise of sophisticated advancements in nanomedicine, ultrasound contrast agents, which are an order of magnitude smaller (100–500 nm) than their currently utilized counterparts, have been undergoing rapid development. These agents are poised to greatly expand the capabilities of ultrasound in the field of targeted cancer detection and therapy by taking advantage of the enhanced permeability and retention phenomenon of many tumors and can extravasate beyond the leaky tumor vasculature. Agent extravasation facilitates highly sensitive detection of cell surface or microenvironment biomarkers, which could advance early cancer detection. Likewise, when combined with appropriate therapeutic agents and ultrasound‐mediated deployment on demand, directly at the tumor site, these nanoparticles have been shown to contribute to improved therapeutic outcomes. Ultrasound's safety profile, broad accessibility and relatively low cost make it an ideal modality for the changing face of healthcare today. Aided by the multifaceted nano‐sized contrast agents and targeted theranostic moieties described herein, ultrasound can considerably broaden its reach in future applications focused on the diagnosis and staging of cancer. WIREs Nanomed Nanobiotechnol 2015, 7:593–608. doi: 10.1002/wnan.1326 This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
(a) Structure of a microbubble; (b) Microbubble linear oscillation under low acoustic power (MI < 0.1); (c) microbubble nonlinear oscillation under medium acoustic power (0.1 < MI < 0.5); (d) microbubble destruction under high acoustic power (MI > 0.5).
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(a) Scheme of the cross‐linked stabilized Pluronic nanobubble; (b) ultrasound decay of crosslinked bubbles (CL‐PEG‐NB) and noncrosslinked bubbles (PEG‐NB) over 1 h; (c) ultrasound decay rate over 24 h (Unpublished data. Perera R. H, Exner A.A.).
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Schematic diagram showing the theranostic effect of Pluronic nanobubble (a) Bubble injection; (b) ultrasound imaging using clinical ultrasound; (c) representative image showing enhanced contrast of tumor and kidney after bubble injection; (d) application of therapeutic ultrasound and radiofrequency (RF) ablation; (e) change in volume of tumors in mice relative to the initial size before the treatment.
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In vivo ultrasound images of subcutaneous tumors with injection of cy5.5‐nanobubble suspension. Ultrasound images were obtained with LOGIQ7 system with a thyroid transducer at 12 MHz. Top and bottom panels are images of the same tumor at orthogonal angles. The basal periphery of tumor was indicated with arrows in images (Reprinted from Ref . Copyright 2013 Mai et al).
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(a) Schematic of nanobubbles and functionality of Pluronic in changing lipid packing and increasing membrane flexibility; (b) B‐mode images of tumors after nanobubble and control microbubble administration; (c) histological analysis demonstrating DiI label (yellow color) Pluronic nanobubble extravasation into 4T1 breast cancer tumors compared to DiI‐labeled microbubbles. CD31 on the vasculature was stained green with FITC antibodies. (Unpublished data Wu H, Exner A.A.).
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(a) Unenhanced ultrasound image shows homogenously hypoechoic oval‐shaped solid mass (arrows) in fibroglandular tissue of breast with adenoma (22‐year‐old woman); (b) contrast enhanced ultrasound image of same area; (c) unenhanced ultrasound image shows lobulated hypoechoic mass (arrows) in fibroglandular tissue of papillotubular carcinoma (38‐year‐old woman); (d) contrast enhanced ultrasound image of same area shows clear internal defects. (Reprinted from Ref . Copyright 2014 Miyamoto, Y. et al. Reprinted with permission from the American Journal of Roentgenology).
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Therapeutic Approaches and Drug Discovery > Emerging Technologies
Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
Diagnostic Tools > In Vivo Nanodiagnostics and Imaging

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