Intracerebral drug delivery using microbubble/nanodroplet-assisted ultrasound to address neurodegenerative diseases

Abstract

Background: The blood-brain barrier (BBB) is a selective and semi-permeable barrier essential for protecting the brain's parenchyma against pathogens and toxic molecules present in the bloodstream. It consists of a monolayer of brain capillary endothelial cells, pericytes, astrocytic end-feet, and neurons. The tight junctions between endothelial cells prevent paracellular transport, further reinforcing its selectivity. However, this high level of selectivity represents a significant challenge for the delivery of therapeutic molecules to the central nervous system. Aim: Microbubble-assisted ultrasound (US) is a promising strategy for transiently permeabilizing the BBB to enable safe, non-invasive, localized, and efficient drug delivery to the brain. This approach enhances drug extravasation and bioavailability. Recently, nanodroplets (NDs) have emerged as good candidates to replace MBs. The aim of this review is to provide an updated overview of the rapidly expanding field of MB/ND-assisted US for the treatment of neurodegenerative diseases. This exciting field bridges research in biology and chemistry (MBs, NDs), US technology and the development of new drugs, small molecules, and biomedicines. The review begins with an update on MBs and NDs and discusses laboratory-manufactured and clinically approved devices such as Sonocloud^®, NaviFUS^®, and ExAblate Neuro®. It then focuses on the potential use of MB/ND-assisted US in treating neurodegenerative diseases, particularly Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease (HD). Relevance for patients: Acoustically mediated BBB opening is an innovative and rapidly advancing strategy that holds great promise for improving the efficacy of existing treatments for neurodegenerative diseases. It also facilitates the discovery of new therapeutic molecules by enhancing their delivery to the brain.

Keywords

Blood-brain barrier opening / Sonoporation / Ultrasound / Microbubbles / Nanodroplets / Neurodegenerative diseases