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Blood Brain Barrier Disruption Via Focused Ultrasound

Ultrasound-enhanced delivery of molecular imaging and therapeutic agents in Alzheimer's disease mouse models. Transgenic mice were sonicated at a single location determined from pre-treatment MR imaging and received intravenous MR-contrast agent and Trypan blue, an Ab-targeting red fluorophore, after sonication. (A–B) T1-weighted, contrast-enhanced MR images taken 5 minutes following FUS treatment. Intended sonication locations are indicated by blue ‘‘+’’. Enhancing volume noted with red. (C–D) Postmortem brain; the sonication location is visible as a blue spot in right hemisphere on photography (C) and red fluorescence (D) from Trypan blue staining. (E) Trypan blue-labeled amyloid plaques appear as punctate red fluorescence staining throughout the sonication location. Inset: black line indicates approximate location of section from whole brain. In (F–H), multiphoton images of 20 mm sections were stained with FITC-conjugated anti-Ab antibodies (3d6) to confirm Trypan blue staining. Green is FITC-3d6, red is Trypan blue. (G) 10x magnified view of untreated hippocampus. (H) Corresponding treated hippocampus from the same section. Scale bars: B, 1 cm, F, 1 mm, H, 200 mm.
Ultrasound-enhanced delivery of molecular imaging and therapeutic agents in Alzheimer's disease mouse models. Transgenic mice were sonicated at a single location determined from pre-treatment MR imaging and received intravenous MR-contrast agent and Trypan blue, an Ab-targeting red fluorophore, after sonication. (A–B) T1-weighted, contrast-enhanced MR images taken 5 minutes following FUS treatment. Intended sonication locations are indicated by blue ‘‘+’’. Enhancing volume noted with red. (C–D) Postmortem brain; the sonication location is visible as a blue spot in right hemisphere on photography (C) and red fluorescence (D) from Trypan blue staining. (E) Trypan blue-labeled amyloid plaques appear as punctate red fluorescence staining throughout the sonication location. Inset: black line indicates approximate location of section from whole brain. In (F–H), multiphoton images of 20 mm sections were stained with FITC-conjugated anti-Ab antibodies (3d6) to confirm Trypan blue staining. Green is FITC-3d6, red is Trypan blue. (G) 10x magnified view of untreated hippocampus. (H) Corresponding treated hippocampus from the same section. Scale bars: B, 1 cm, F, 1 mm, H, 200 mm.

With many available therapeutic and diagnostic agents unable to penetrate an intact blood-brain barrier (BBB), the vascular shield that protects the brain, treatment of the brain has been severely limited. Factors that limit passage through the BBB are lipid solubility, molecular size, and charge.

Temporary opening of the BBB has been achieved, however, in experiments led by NCIGT researchers who used focused ultrasound in the presence of a microbubble ultrasound contrast agent to deliver targeted drug delivery to the brain in vivo. Drug concentrations measured in sonicated brain tissue corresponded with cytotoxic levels measured in vivo in various human tumors. A strong correlation between MRI signal enhancement and drug absorption may indicate the capacity of MRI to be used as an indicator of BBB permeability during treatment. These results suggest the potential of MRI-guided focused ultrasound as an alternative to ionizing radiation therapy or invasive surgical resection for use in the treatment of primary or metastatic brain tumors.

Cancer treatment is not the only clinical application being evaluated. To non-invasively enable localized delivery of imaging fluorophores and immunotherapeutics directly to the amyloid plaques associated with Alzheimer's disease, NCIGT researchers used low-intensity focused ultrasound with a microbubble contrast agent to transiently disrupt the BBB in animal models.

The team administered intravenous Trypan blue, an amyloid staining red fluorophore and anti-amyloid antibodies concurrently with focused ultrasound therapy in plaque-bearing, transgenic mouse models of Alzheimer's disease with amyloid pathology. MRI guidance permitted selective treatment and monitoring of plaque-heavy anatomical regions, such as the hippocampus. Treated brain regions exhibited 16.5+/-5.4-fold increase in Trypan blue fluorescence and 2.7+/-1.2-fold increase in anti-amyloid antibodies that localized to amyloid plaques. Ultrasound-enhanced delivery was consistently reproduced in two different transgenic strains (APPswe:PSEN1dE9, PDAPP), across a wide age range (9-26 months), with and without MR guidance, and with little or no resulting tissue damage.

This ultrasound-mediated, transient BBB disruption enables the delivery of both therapeutic and molecular imaging agents in Alzheimer's mouse models that should aid preclinical drug screening and imaging probe development. Furthermore, this technique may be used to deliver a wide variety of small and large molecules to the brain for imaging and therapy in other neurodegenerative diseases.

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