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

Authors: Timbie KF, Mead BP, Price RJ

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 100nm 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.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To comprehensively review recent studies on focused ultrasound–mediated blood–brain barrier disruption for targeted CNS therapeutic delivery and provide perspectives on its future applications.

MRI or image guidance method Magnetic resonance imaging (MRI) guidance

Route of administration Systemic (systemically administered; route None, typically intravenous)

Outcomes and Safety

Summary of Outcomes Focused ultrasound combined with microbubbles noninvasively, transiently and locally disrupts the blood–brain barrier to enable delivery of therapeutics up to ~100 nm into the CNS with MRI-guided, submillimeter precision through the intact skull; the review does not report specific tested ultrasound parameter sets.

Safety-related matter The paper states that focused ultrasound (FUS) can non-invasively and temporarily disrupt the BBB through the intact human skull, obviating the need for invasive and risky surgical procedures. It also notes that FUS-mediated BBB disruption may permit safe repeated treatments.

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

Introduction

Outcomes and Safety

Brain Region

Ultrasound Parameters