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WIREs Nanomed Nanobiotechnol
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Breaking free from vascular confinement: status and prospects for submicron ultrasound contrast agents

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The development of encapsulated microbubbles (~1–6 μm) has expanded the utility of ultrasound from soft tissue anatomical imaging to not only functional intravascular imaging, but therapeutic interventions, with compelling studies of elicited biological effects. The large diameter of these bubbles has confined their utility to the vasculature, but converging interdisciplinary research pathways are giving rise to new submicron ultrasound contrast agents capable of extending their effects beyond the vascular compartment. This article reviews the status and prospects of exogenous agents including nanobubbles, echogenic liposomes, gas vesicles, cavitation seeds, and nanodroplets, and assesses outstanding criticisms preventing their advance. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Emerging Technologies
Schematic of ultrasound‐stimulated microbubble behaviors and biophysical effects. (a) Mechanical stresses of bubble oscillation cause overexpansion and contraction of the vessel walls, and (b) circulating fluid flow patterns or acoustic streaming around the bubble give rise to shear stress at the lumen surface of endothelial cells. Larger oscillation amplitudes can lead to inertial cavitation and bubble collapse, with (c) microjetting capable of perforating the vessel wall, and (d) violent shock waves with accompanying temperature and pressure elevations and the release of reactive oxygen species.
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Classes of submicron ultrasound contrast agents, including nanobubbles, echogenic liposomes, gas vesicles, cavitation seeds, and nanodroplets. Various encapsulating shells have been reported, including lipids, polymers, and proteins, and perfluorocarbon cores. These exogenous agents vary in size from 20 nm to several microns.
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In contrast to healthy tissue, tumors demand a high supply of nutrients and oxygen, and will invade existing vessels and develop new ones to meet these demands. However, uneven angiogenic signaling from the tumor results in vessels abnormal in form and architecture, characterized by haphazard dilated, tortuous channels lacking the organization and hierarchy of healthy blood vessels. This vascular heterogeneity is coupled with structural abnormalities; a defective endothelium barrier, with larger gaps and poorly adherent pericytes. While microbubbles are confined to remain in the vasculature, physiological consequences of tumor microvasculature afford opportunities for nanoscale agents to escape the intravascular space and expand bubble‐mediated potential.
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Therapeutic Approaches and Drug Discovery > Emerging Technologies
Diagnostic Tools > In Vivo Nanodiagnostics and Imaging

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