Focused Ultrasound Induced-Blood-Brain Barrier Opening in Post-Radiosurgery Mouse Brain for Locally-Enhanced Systemic Therapy

Abstract

Focused ultrasound (FUS) is a novel technique that is capable of non-invasively and transiently open the blood-brain barrier (BBB). It has been show that FUS can facilitate the delivery of systemically administered therapeutic agents. Our goal here is to investigate FUF induced BBB opening in a post stereotactic radiosurgery (SRS) mouse model for novel locally-enhanced systemic therapy. We hypothesized that microvascular effects of radiation could modulate the BBB-opening induced by FUS. In this study, normal brains of C57B5 mice were treated with a fractionated SRS dose, typically given to resected tumor cavities. A single beam radiation (6Gy x 5 daily fractions) was delivered through a 10×10 mm2 collimator to half of the mouse brain using the Small Animal Radiation Research Platform (SARRP). The dose delivered to the mice was verified via two mouse-like anthropomorphic phantoms in the axial and sagittal orientations. Upon the completion of SARRP treatments, mice were divided into two groups for FUS-induced BBB opening on day 7 (acute) and day 35 (chronic), respectively. A 1.5 MHz single element FUS transducer (-6dB focal zone was 1×1×7.5 mm3) was used for all sonications. The caudate-putamen (CPu) was the FUS target and four 30s sonications were delivered on each side of the brain. The BBB opening was confirmed with contrast-enhanced T1-weighted MRI scans, while dynamic MRI scans were also performed to evaluate the blood vessel permeability. The animals were sacrificed 2 hours post sonications and lectin was injected to label the vasculature. The isodose lines from the mouse-like phantom experiment agreed well with the projected values. BBB was successfully opened after FUS sonications on both sides of the brain (with or without radiation) as evidenced by contrast-enhanced MRI. In the acute group, higher gadolinium concentration (p = 0.072) was observed on the RT positive side. MR dynamic imaging revealed a similar trend in which RT positive side had a higher (p = 0.158) vascular permeability. Although the mean vessel area in the sonicated area remained similar between the two sides, significantly less lectin labeling (blood vessel density) was observed on the RT positive hemisphere (p = 0.003) in the acute group. These observations can be attributed to increased vasculature vulnerability immediately post SRS (within 2 days) resulting in more profound BBB opening. Interestingly, this difference diminished one month later in the chronic group, where FUS elicited comparable BBB openings and minimal vascular density changes in the CPu on both sides. Localized BBB opening can be successfully induced by FUS in previously stereotactically irradiated normal brains. BBB openings were evident in both acute and chronic settings with potentially more profound outcomes if FUS is performed within 2 days of RT treatment.