Microbubble-Size Dependence of Focused Ultrasound-Induced Blood–Brain Barrier Opening in Mice<i>In Vivo</i>

Choi, James J.; Feshitan, Jameel A.; Baseri, Babak; Wang, Shougang; Tung, Yu-Chi; Borden, Mark A.; Konofagou, Elisa E.

doi:10.1109/tbme.2009.2034533

Cited by 234 publications

(212 citation statements)

References 46 publications

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“…Other FUS parameters (for example, frequency, pulse length, and pulserepetition frequency), as well as MB characteristics (for example, resonant frequency, size, and shell properties) may also be correlated with BBB opening size. For example, one previous study by our group found that the BBB opening pressure threshold for the delivery of 3 kDa dextran was significantly lower with MBs of 4 to 5 mm than 1 to 2 mm in diameter, 28 which suggests that MB size may be an important factor influencing the BBB opening size. The impact of parameters other than acoustic pressure on the BBB opening size will be the focus of future studies.…”

Section: Discussionmentioning

confidence: 91%

The Size of Blood–Brain Barrier Opening Induced by Focused Ultrasound is Dictated by the Acoustic Pressure

Chen

Konofagou

2014

J Cereb Blood Flow Metab

225

195

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Focused ultrasound (FUS) in combination with microbubbles (MBs) has been successfully used in the delivery of various-size therapeutic agents across the blood-brain barrier (BBB). This study revealed that FUS-induced BBB opening size, defined by the size of the largest molecule that can permeate through the BBB, can be controlled by the acoustic pressure as dictated by cavitational mechanisms. Focused ultrasound was applied onto the mouse hippocampus in the presence of systemically administered MBs for trans-BBB delivery of fluorescently labeled dextrans with molecular weights 3 to 2,000 kDa (hydrodynamic diameter: 2.3 to 54.4 nm). The dextran delivery outcomes were evaluated using ex vivo fluorescence imaging. Cavitation detection was employed to monitor the MB cavitation activity associated with the delivery of these agents. It was found that the BBB opening size was smaller than 3 kDa (2.3 nm) at 0.31 MPa, up to 70 kDa (10.2 nm) at 0.51 MPa, and up to 2,000 kDa (54.4 nm) at 0.84 MPa. Relatively smaller opening size (up to 70 kDa) was achieved with stable cavitation only; however, inertial cavitation was associated with relatively larger BBB opening size (above 500 kDa). These findings indicate that the BBB opening size can be controlled by the acoustic pressure and predicted using cavitation detection.

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Section: Discussionmentioning

confidence: 91%

The Size of Blood–Brain Barrier Opening Induced by Focused Ultrasound is Dictated by the Acoustic Pressure

Chen

Konofagou

2014

J Cereb Blood Flow Metab

225

195

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“…To date, a wide class of albumin-and lipid-shelled as well as polydispersed and size-isolated microbubbles have been utilized and include Optison (1), SonoVue (19), Definity (2), and customdesigned microbubbles (9,20). Recent studies have shown that larger microbubbles (4-5 and 6-8 μm) have a lower PRP threshold for BBB disruption than smaller bubbles (1-2 μm) (9, 20) when using PLs greater than 66.7 μs.…”

Section: Discussionmentioning

confidence: 99%

“…Large radial bubble expansions may induce inertial cavitation activity, which may lead to bubble collapse due to the inertia of the surrounding media and affect the vascular physiology (8). Each type and magnitude of cavitation activity results in distinct vascular bioeffects and are dictated by the ultrasonic pulse shape and sequence, the microbubble composition and distribution (9), and the in vivo environment the microbubbles circulate (8,10). Selection of the exposure parameters is critical for effective drug delivery while minimizing side effects (11).…”

mentioning

confidence: 99%

Noninvasive and localized neuronal delivery using short ultrasonic pulses and microbubbles

Choi¹,

Selert²,

Vlachos³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

137

141

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Focused ultrasound activation of systemically administered microbubbles is a noninvasive and localized drug delivery method that can increase vascular permeability to large molecular agents. Yet the range of acoustic parameters responsible for drug delivery remains unknown, and, thus, enhancing the delivery characteristics without compromising safety has proven to be difficult. We propose a new basis for ultrasonic pulse design in drug delivery through the blood-brain barrier (BBB) that uses principles of probability of occurrence and spatial distribution of cavitation in contrast to the conventionally applied magnitude of cavitation. The efficacy of using extremely short (2.3 μs) pulses was evaluated in 27 distinct acoustic parameter sets at low peak-rarefactional pressures (0.51 MPa or lower). The left hippocampus and lateral thalamus were noninvasively sonicated after administration of Definity microbubbles. Disruption of the BBB was confirmed by delivery of fluorescently tagged 3-, 10-, or 70-kDa dextrans. Under some conditions, dextrans were distributed homogeneously throughout the targeted region and accumulated at specific hippocampal landmarks and neuronal cells and axons. No histological damage was observed at the most effective parameter set. Our results have broadened the design space of parameters toward a wider safety window that may also increase vascular permeability. The study also uncovered a set of parameters that enhances the dose and distribution of molecular delivery, overcoming standard trade-offs in avoiding associated damage. Given the short pulses used similar to diagnostic ultrasound, new critical parameters were also elucidated to clearly separate therapeutic ultrasound from disruption-free diagnostic ultrasound.F ocused ultrasound (FUS) and microbubble-based drug delivery systems (DDSs) can increase the dose of an agent in a target volume and has potential in applications such as blood-brain barrier (BBB) disruption for the treatment of neurological diseases (1, 2), molecular and viral treatment of tumors (3), gene therapy for treating heart conditions (4), and enhancement of renal ultrafiltration (5). In each method, biologically inert and preformed microbubbles, with a lipid or polymer shell, a stabilized gas core, and a diameter less than 10 μm, are systemically administered and subsequently exposed to noninvasively delivered FUS pulses. Microbubbles within the target volume are "acoustically activated" in a complex range of behaviors known as acoustic cavitation. In stable cavitation, the microbubbles expand and contract with the acoustic pressure rarefaction and compression over several cycles (6). This activity has been associated with a range of bioeffects including displacement of the vessel wall through dilation and contractions (7,8). Large radial bubble expansions may induce inertial cavitation activity, which may lead to bubble collapse due to the inertia of the surrounding media and affect the vascular physiology (8). Each type and magnitude of cavitation activity results...

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“…23,35−37 Other parameters such as microbubble size and dose can affect the extent of BBB disruption. 38,39 Numerous efforts have been made to optimize BBB disruption, but perhaps the biggest contribution has come from development of a real-time acoustic controller. 40 Acoustic emissions are monitored and used to actively control the pressure amplitude of the ultrasound leading to a consistent BBB disruption.…”

Section: Acs Chemical Neurosciencementioning

confidence: 99%

Noninvasive and Targeted Drug Delivery to the Brain Using Focused Ultrasound

Burgess

Hynynen

2013

ACS Chem. Neurosci.

114

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Brain diseases are notoriously difficult to treat due to the presence of the blood-brain barrier (BBB). Here, we review the development of focused ultrasound (FUS) as a noninvasive method for BBB disruption, aiding in drug delivery to the brain. FUS can be applied through the skull to a targeted region in the brain. When combined with microbubbles, FUS causes localized and reversible disruption of the BBB. The cellular mechanisms of BBB disruption are presented. Several therapeutic agents have been delivered to the brain resulting in significant improvements in pathology in models of glioblastoma and Alzheimer's disease. The requirements for clinical translation of FUS will be discussed. KEYWORDS:Focused ultrasound, blood-brain barrier, drug delivery B rain diseases, including psychiatric disorders, neurodegenerative diseases, and cancer, are among the most prevalent diseases worldwide. It has been estimated that 35% of all disease burden is attributable to brain disorders.1 Despite advancing research, which better understands the etiology and underlying mechanisms of disease, most of these diseases do not have effective treatments and essentially no cures exist.Designing therapeutic agents for the brain is very challenging. The brain is a well-protected organ, completely encased by the skull, making surgical access difficult and direct application of drugs impractical. However, perhaps the most limiting factor to successful treatment of brain disease is the blood-brain barrier (BBB) which prevents access of ∼98% of current pharmaceutical agents to the brain when delivered intravenously. ■ THE BLOOD-BRAIN BARRIER (BBB)The BBB is a specialized structure between the cerebral capillaries and the brain parenchyma that is relatively impermeable except for a selection of very small (<400 Da), lipophilic compounds. 3 The BBB is different from the barriers between the peripheral vasculature and other organs in the body due mainly to the presence of tight junctions between adjacent endothelial cells.3 Cell adhesion molecules, most notably claudins and occludins, connect the endothelial cells together to create the tight junctions. The intracellular domains of the proteins are anchored to the cytoskeleton and the extracellular domains form homodimers with proteins on adjacent endothelial cells. These independent tight junctional proteins work in concert to make the endothelial cellular layer impermeable to fluid thereby limiting paracellular transport mechanisms.

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Microbubble-Size Dependence of Focused Ultrasound-Induced Blood–Brain Barrier Opening in MiceIn Vivo

Cited by 234 publications

References 46 publications

The Size of Blood–Brain Barrier Opening Induced by Focused Ultrasound is Dictated by the Acoustic Pressure

The Size of Blood–Brain Barrier Opening Induced by Focused Ultrasound is Dictated by the Acoustic Pressure

Noninvasive and localized neuronal delivery using short ultrasonic pulses and microbubbles

Noninvasive and Targeted Drug Delivery to the Brain Using Focused Ultrasound

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