Noninvasive and Transient Blood-Brain Barrier Opening in the Hippocampus of Alzheimer's Double Transgenic Mice Using Focused Ultrasound

Choi, James J.; Wang, Shougang; Brown, Truman R.; Small, Scott A.; Duff, Karen; Konofagou, Elisa E.

doi:10.1177/016173460803000304

Cited by 81 publications

(71 citation statements)

References 28 publications

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“…TEER values dropped to 79% for G2‐DSA ( n = 7 wells from three cultures, two‐way ANOVA, P < 0.01) and 73% for G3‐DSA ( n = 7 wells from three cultures, two‐way ANOVA, P < 0.001) within the first 40 h. However, barrier integrity recovered to 87% for G2‐DSA ( n = 7 wells from three cultures, two‐way ANOVA, P > 0.05) and to 89% for G3‐DSA ( n = 7 wells from three cultures, two‐way ANOVA, P > 0.05) at 72 h during DSA application. In agreement with previous studies and established therapies, a transient opening of the BBB does not have to be considered strictly as a deleterious event but could be considered as a system to better deliver molecules to the CNS 50. Additionally, zona occludens 1 (ZO1) staining as marker of tight junctions also show maintenance of intact tight monolayer in bEnd.3 cells treated for 24 h with DSA (45 µg mL −1 ) (Figure 5D).…”

Section: Resultssupporting

confidence: 88%

Brain Delivery of Multifunctional Dendrimer Protein Bioconjugates

Moscariello

Jansen

et al. 2018

Advanced Science

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Neurological disorders are undoubtedly among the most alarming diseases humans might face. In treatment of neurological disorders, the blood‐brain barrier (BBB) is a challenging obstacle preventing drug penetration into the brain. Advances in dendrimer chemistry for central nervous system (CNS) treatments are presented here. A poly(amido)amine (PAMAM) dendrimer bioconjugate with a streptavidin adapter for the attachment of dendrons or any biotinylated drug is constructed. In vitro studies on porcine or murine models and in vivo mouse studies are performed and reveal the permeation of dendronized streptavidin (DSA) into the CNS. The bioconjugate is taken up mainly by the caveolae pathway and transported across the BBB via transcytosis escaping from lysosomes. After transcytosis DSA are delivered to astrocytes and neurons. Furthermore, DSA offer high biocompatibility in vitro and in vivo. In summary, a new strategy for implementing therapeutic PAMAM function as well as drug delivery in neuropathology is presented here.

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Section: Resultssupporting

confidence: 88%

Brain Delivery of Multifunctional Dendrimer Protein Bioconjugates

Moscariello

Jansen

et al. 2018

Advanced Science

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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%

Noninvasive and localized neuronal delivery using short ultrasonic pulses and microbubbles

Choi¹,

Selert²,

Vlachos³

et al. 2011

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

Self Cite

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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“…76 The results of these first studies demonstrated that BBB disruption using FUS was not significantly different in AD transgenic mice, compared to wild-type controls. 77 Furthermore, in a similar AD mouse model, it was found that the opening of the BBB was comparable in aged mice (12 months vs 26 months), despite the increased brittleness of the skull and altered vasculature characteristic of the older transgenic animals. 78 Raymond and colleagues 78 also delivered amyloid beta antibodies to the brain of the AD mice and found they colocalized with the amyloid plaques, demonstrating the feasibility of using FUS for AD immunotherapy.…”

Section: ■ Fus Is An Effective Drug Delivery Methodsmentioning

confidence: 94%

Noninvasive and Targeted Drug Delivery to the Brain Using Focused Ultrasound

Burgess

Hynynen

2013

ACS Chem. Neurosci.

116

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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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Noninvasive and Transient Blood-Brain Barrier Opening in the Hippocampus of Alzheimer's Double Transgenic Mice Using Focused Ultrasound

Cited by 81 publications

References 28 publications

Brain Delivery of Multifunctional Dendrimer Protein Bioconjugates

Brain Delivery of Multifunctional Dendrimer Protein Bioconjugates

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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