Focus ultrasound for augmenting convection-enhanced delivery of nanoparticles in the brain

Abstract

We previously demonstrated how ultrasound can enhance the dispersion of locally administrated nanoparticles within the extracellular/perivascular spaces in the ex vivo brain by non-destructively enlarging these regions. The current study aimed to translate these results in vivo, where custom, non-adhering brain-penetrating nanoparticles (BPN: 60, 200, and 500 nm), were administered directly into the brains of Sprague Dawley rats by convection-enhanced delivery. Non-invasive, transcranial focused ultrasound (TCFUS) was carried out using an MRI-guided system (1.5 MHz, 10 ms pulses, 10% duty cycle, and 2.3 MPa). 15 individual exposures in a 3 × 5 matrix (spacing: 1.5 mm) in one hemisphere were given, where the size of the focal zone (-6 dB) was 1 × 1 X 8 mm. At 2hrs post-treatment brains were harvested and sectioned, with digital images captured and processed using a custom MATLAB script. This involved the “Otsu” thresholding method, based on gray level histograms and threshold determinations for maximizing the interclass variance. As expected, BPN distributions in the non-treated brains decreased with an increase in diameter. Pretreating with TCFUS was found to significantly increase the distribution of the 200 nm BPNs. These results have broad implications for therapeutic delivery for a variety of brain diseases and disorders.