PDF file - 349K, Figure S2: Histology after volumetric sonication in the hippocampus/LGN in monkey 4. This target was sonicated ~2h before the animal was sacrificed and in seven prior sessions over several months. (A) Contrast-enhanced T1-weighted MRI showing BBB disruption. The region with contrast enhancement is indicated (red dotted line). Inset: Low-magnification microphotograph showing histology in the hippocampus/LGN. The approximate location of this section is indicated in the MR image by the white rectangle. (B) Low- and (C) high-magnification views of the LGN showing normal cell layers and undamaged nerve fibers, respectively. (D) Low and (E) high-magnification views showing normal-appearing granular cell layer of hippocampus. (F): Small capillaries in the LGN found with a few extravasated red blood cells, presumably from the last sonication session. Only a very small number of such extravasations were found. (B, F: H&E; C: H&E-LFB D, E: Nissl; scale bars: A: 1 cm, B, D: 1 mm, C,E-F: 200 Mum)
ARTICLE ABSTRACTThe blood–brain barrier (BBB) prevents entry of most drugs into the brain and is a major hurdle to the use of drugs for brain tumors and other central nervous system disorders. Work in small animals has shown that ultrasound combined with an intravenously circulating microbubble agent can temporarily permeabilize the BBB. Here, we evaluated whether this targeted drug delivery method can be applied safely, reliably, and in a controlled manner on rhesus macaques using a focused ultrasound system. We identified a clear safety window during which BBB disruption could be produced without evident tissue damage, and the acoustic pressure amplitude where the probability for BBB disruption was 50% and was found to be half of the value that would produce tissue damage. Acoustic emission measurements seem promising for predicting BBB disruption and damage. In addition, we conducted repeated BBB disruption to central visual field targets over several weeks in animals trained to conduct complex visual acuity tasks. All animals recovered from each session without behavioral deficits, visual deficits, or loss in visual acuity. Together, our findings show that BBB disruption can be reliably and repeatedly produced without evident histologic or functional damage in a clinically relevant animal model using a clinical device. These results therefore support clinical testing of this noninvasive-targeted drug delivery method. Cancer Res; 72(14); 3652–63. ©2012 AACR.