Safety evaluation of frequent application of microbubble-enhanced focused ultrasound blood-brain-barrier opening

Abstract

Focused ultrasound (FUS) with the presence of microbubbles induces blood brain barrier (BBB) opening in targeted areas and facilitates drug delivery. However, recent studies have indicated that FUS-BBB opening with excessive exposure levels may be associated with inflammatory response and cellular/tissue damage. Multiple weekly FUS exposures have been shown to be safe for human subjects. However the effect of more frequent FUS exposures is still unknown. This study examines whether frequent focused ultrasound blood brain barrier opening is associated with aggravated behavioral, histopathologic change or brain tissue damage. Two protocols of focused ultrasound blood brain barrier opening were devised using different microbubble doses (0.15 µl/kg and 0.4 µl/kg). Focused ultrasound exposure at a threshold level of BBB-opening, below-threshold level, or above level for intracerebral hemorrhage were delivered every 2 days. Animal behavioral and physiological changes were examined and recorded. Brain tissue was examined for hemorrhage and apoptosis. Results indicate that frequent exposure of excessive focused ultrasound (1.4 mechanical index) produced minor and short-term behavioral changes despite significant tissue damage, while frequent BBB opening with threshold or below-threshold FUS exposure (0.33–0.8 mechanical index) did not cause behavioral or histological change. Immunofluorescent examination of rat brain tissue indicated that excessive doses of microbubble administration induce an apparent cellular apoptotic response, which may be exacerbated by intracerebral hemorrhage. Experimental results suggest that frequent focused ultrasound blood brain barrier opening with sufficient ultrasound exposure level and a microbubble dose can be safe and pose minimal risk to brain tissue.

Focused ultrasound blood brain barrier opening mediated delivery of MRI-visible albumin nanoclusters to the rat brain for localized drug delivery with temporal control

“…FUS BBB opening did not cause heightened GFAP expression. This supports 290 previous studies highlighting either no inflammatory response or a brief transient 291 inflammatory response following BBB opening [37,38]. In addition, the use of 292 albumin-based drug carriers have previously been shown to be safe to administer IV 293 [21,[39][40][41][42][43][44] [21], and our work showed no clear additional inflammatory response or 294 cellular toxicity with the presence of albumin NCs in the brain [42,45].…”

“…Furthermore, NC load remained inside the NC unless digested 37 with trypsin, and in vivo, NCs remained stable for up to 24 hours [25,26]. Here, we 38 investigated whether albumin-based NCs could be delivered to the rat hippocampus via 39 MRI guided transcranial FUS BBBO for localized drug delivery. We report that NCs 40 can encapsulate the neuromodulatory drugs glutamate and NBQX, and we show that 41 IV injected NCs in vivo can locally diffuse into the brain with FUS facilitated BBBO.…”

Ultrasound neuromodulation through nanobubble-actuated sonogenetics

“…Alternatively, GVs can also be delivered to targeted regions, since it is nano-sized. Microbubble-mediated ultrasonic bio-effects have been widely explored and utilized to open cell membranes and the blood-brain barrier 46,47,48,49,50 . However, the micrometer size of microbubbles limits spatial resolution and they are restricted to use in blood vessels due to their size and have a short half-life in vivo (<5 min in the blood) 51,52 .…”

Established and Emerging Strategies for Drug Delivery Across the Blood-Brain Barrier in Brain Cancer

“…To evaluate the safety of this approach, the group of Liu exposed rats to repetitive FUS at three different acoustic pressures defined as a function of erythrocyte extravasation and at different microbubble doses. The study concluded that high acoustic pressure and microbubble doses could cause brain hemorrhage, tissue necrosis, cell apoptosis, astroglial activation, and glial scarring [63]. However, moderate acoustic pressures and adequate microbubble administrations allowed for a safe breach of the BBB.…”

“…However, moderate acoustic pressures and adequate microbubble administrations allowed for a safe breach of the BBB. This work is fundamental in the field because it demonstrates the need to finely tune the conditions of the system to avoid tissue damage [63]. In support of this data, repetitive FUS applications were applied on primates by using an implantable ultrasound device to evaluate the long term effects of this procedure.…”