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WIREs Nanomed Nanobiotechnol
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Acoustically active liposome‐nanobubble complexes for enhanced ultrasonic imaging and ultrasound‐triggered drug delivery

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Ultrasound is well known as a safe, reliable imaging modality. A historical limitation of ultrasound, however, was its inability to resolve structures at length scales less than nominally 20 µm, which meant that classical ultrasound could not be used in applications such as echocardiography and angiogenesis where one requires the ability to image small blood vessels. The advent of ultrasound contrast agents, or microbubbles, removed this limitation and ushered in a new wave of enhanced ultrasound applications. In recent years, the microbubbles have been designed to achieve yet another application, namely ultrasound‐triggered drug delivery. Ultrasound contrast agents are thus tantamount to ‘theranostic’ vehicles, meaning they can do both therapy (drug delivery) and imaging (diagnostics). The use of ultrasound contrast agents as drug delivery vehicles, however, is perhaps less than ideal when compared to traditional drug delivery vehicles (e.g., polymeric microcapsules and liposomes) which have greater drug carrying capacities. The drawback of the traditional drug delivery vehicles is that they are not naturally acoustically active and cannot be used for imaging. The notion of a theranostic vehicle is sufficiently intriguing that many attempts have been made in recent years to achieve a vehicle that combines the echogenicity of microbubbles with the drug carrying capacity of liposomes. The attempts can be classified into three categories, namely entrapping, tethering, and nesting. Of these, nesting is the newest—and perhaps the most promising. This article is categorized under: Diagnostic Tools > Diagnostic Nanodevices Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

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A nested microbubble: a traditional microbubble, which comprises a gas core and a stabilizing shell, is shown alongside a nested configuration, in which the traditional microbubble is housed inside the aqueous core of a larger structure (e.g., polymeric microcapsule, vesicle, liposome, or polymersome). The presence of a second, outer nesting shell offers several advantages over traditional microbubbles: (1) larger drug carrying capacity; (2) a single configuration can be used for both hydrophilic and hydrophobic drugs; (3) protection against gas diffusion into the bulk aqueous phase and therefore longer lasting imaging (at least in vitro; clearance mechanisms in vivo might negate this effect); (4) protection against inertial cavitation and cell death; and (5) tunable acoustic properties, owing to controllable repulsive forces between the (inner) microbubble coating shell and the (outer) nesting shell. The fourth advantage is a two‐pronged effect; that is, the shell increases the peak negative pressure required for inertial cavitation, thus making inertial cavitation less likely to occur and the shell absorbs the energy of inertial cavitation when inertial cavitation does occur.
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Potential for tuning acoustic properties: the fact that the nesting shell must not remain stationary opens the possibility for tuning microbubble acoustic properties via wall–wall repulsive forces. That is, the microbubble wall and the nesting shell can be made to move at different speeds upon application of ultrasound. By selecting nesting shells with different chemistries, and therefore different material properties, one can tune the magnitude of repulsive forces—and when during the ultrasound cycle they arise—and thereby tune the microbubble resonance frequency, damping, and attenuation.
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Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease
Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
Diagnostic Tools > Diagnostic Nanodevices
Therapeutic Approaches and Drug Discovery > Emerging Technologies

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