Noninvasive and targeted drug delivery to the brain using focused ultrasound

Abstract

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.

Figure 1

Components of the blood-brain barrier (BBB). The BBB exists between the cerebral vasculature and the brain parenchyma. Transmembrane proteins connect adjacent endothelial cells to each other, creating tight junctions and making the endothelial cell layer impermeable to water. The endothelial cells are supported by a layer of basal lamina, pericytes, and astrocytes. The astrocyte endfeet provide a direct link between the cerebral capillaries and the neurons.

Figure 2

Methods to circumvent the BBB. Advantages and limitations of the different methods used to circumvent the BBB for drug delivery to the brain are compared.

Figure 3

Acoustic cavitation and BBB disruption. Microbubbles (white) are injected intravenously at the onset of sonication. When the intravascular microbubbles enter the ultrasound field, they expand and contract at the frequency of the ultrasound. This leads to interaction with the endothelial cells and eventual BBB disruption.

Figure 4

Targeting and monitoring of BBB disruption with MRI. (A) T2-weighted images (acquired on 7T Bruker Biospin 7030, Germany) were used for targeting. Four spots in the dorsal hippocampus were chosen, and each spot was marked with an x. (B) Following sonication, gadolium contrast agent (0.2 mL/kg; Omniscan, GE Healthcare, Milwaukee, WI) was injected in the tail vein and T1-weighted images were acquired. Areas of hyperintensity are indicative of BBB disruption. Four hyperintense spots corresponding to the targeted locations are clearly visible, indicating that the sonication was successful.