Drug and gene delivery across the blood–brain barrier with focused ultrasound

Abstract

The blood-brain barrier (BBB) remains one of the most significant limitations to treatments of central nervous system (CNS) disorders including brain tumors, neurodegenerative diseases and psychiatric disorders. It is now well-established that focused ultrasound (FUS) in conjunction with contrast agent microbubbles may be used to non-invasively and temporarily disrupt the BBB, allowing localized delivery of systemically administered therapeutic agents as large as 100 nm in size to the CNS. Importantly, recent technological advances now permit FUS application through the intact human skull, obviating the need for invasive and risky surgical procedures. When used in combination with magnetic resonance imaging, FUS may be applied precisely to pre-selected CNS targets. Indeed, FUS devices capable of sub-millimeter precision are currently in several clinical trials. FUS mediated BBB disruption has the potential to fundamentally change how CNS diseases are treated, unlocking potential for combinatorial treatments with nanotechnology, markedly increasing the efficacy of existing therapeutics that otherwise do not cross the BBB effectively, and permitting safe repeated treatments. This article comprehensively reviews recent studies on the targeted delivery of therapeutics into the CNS with FUS and offers perspectives on the future of this technology.

Ultrasound-Based Therapies for the Treatment of Cancer

“…These Circulating microbubbles oscillate in the ultrasonic field, producing forces that act on the vessel wall to generate three bioeffects that permit transport across the blood-brain barrier: disruption of tight juctions, sonoporation of the vascular endothelial cells and upregulation of transcytosis. 270 findings are in agreement with other studies suggesting that minor capillary damage and red blood cell extravasation is not expected to lead to long term effects 48,71 . Indeed, it is possible that such damage would be acceptable in treatment of debilitating or lifethreatening neurological diseases.…”

“…Regulation via astrocytes and pericytes maintain this barrier, preventing the passage of the vast majority of therapeutics. 270 lead to global BBB disruption, causing non-specific uptake and potentiating adverse offtarget effects. Infusion of mannitol into the carotid artery leads to an osmotic-driven movement of fluid out of endothelial cells 40 , shrinking them and leading to fenestration of cerebral vessels.…”

“…FUS can be guided with MR imaging and is capable of sub-millimeter resolution allowing precise targeting of structures in the CNS with minimal off-target effects. 270 pathway. A unique approach using two-photon microscopy provided further support for both paracellular and transcellular pathways.…”

“…FUSmediated delivery of BPNs is particularly intriguing, since little is known about the interactions between polymeric nanoparticles and FUS, and nothing of this size (~60 nm) has been delivered across the BBB or BTB with FUS and bears characterization. Noninvasive delivery of a systemically administered biodegradable particle would allow 270 repeated treatments for patients undergoing chemotherapy, and would also decrease the number of treatments (compared to unencapsulated drug), given the extended drug release profile of these BPNs.…”

“…Combined, they present a safe, repeatable, non-invasive method to deliver drugs to the brain. This delivery strategy could be used in a wide range of CNS disorders, including primary and metastatic cancers, Alzheimer's and Parkinson's, and depression and OCD 270 . Perhaps one of the most immediate applications for this technology is the treatment of GBM following surgical resection of the tumor bulk.…”