Focused Ultrasound and Microbubble Treatment Increases Delivery of Transferrin Receptor-Targeting Liposomes to the Brain

Marieke Olsman,Viktoria Sereti,Melina Mühlenpfordt,Kasper Bendix Johnsen,Thomas Lars Andresen,Andrew James Urquhart,Catharina De Lange Davies

doi:10.1016/j.ultrasmedbio.2021.01.014

Abstract

The blood-brain barrier (BBB) is a major obstacle to treating several brain disorders. Focused ultrasound (FUS) in combination with intravascular microbubbles increases BBB permeability by opening tight junctions, creating endothelial cell openings, improving endocytosis and increasing transcytosis. Here we investigated whether combining FUS and microbubbles with transferrin receptor-targeting liposomes would result in enhanced delivery to the brain of post-natal rats compared with liposomes lacking the BBB-targeting moiety. For all animals, increased BBB permeability was observed after FUS treatment. A 40% increase in accumulation of transferrin receptor-targeting liposomes was observed in the FUS-treated hemisphere, whereas the isotype immunoglobulin G liposomes showed no increased accumulation. Confocal laser scanning microscopy of brain sections revealed that both types of liposomes were mainly observed in endothelial cells in the FUS-treated hemisphere. The results demonstrate that FUS and microbubble treatment combined with BBB-targeting liposomes could be a promising approach to enhance drug delivery to the brain.

Highlights

The blood-brain barrier (BBB) strictly controls the transport of substances into the brain, impeding the access of most drugs to the brain and preventing efficient treatment of many brain diseases (Abbott et al 2010; Pardridge 2012)
Increased BBB permeability after Focused ultrasound (FUS) treatment FUS exposure in the presence of MBs resulted in a gadolinium-induced increase of the signal intensity, demonstrating that the BBB permeability was increased
The observed intensity pattern of BBBD corresponded with the 6 £ 3 grid of spots used during the FUS treatment and was observed along the coronal and sagittal planes of the brain (Supplementary Figure S1a)

Summary

Introduction

The blood-brain barrier (BBB) strictly controls the transport of substances into the brain, impeding the access of most drugs to the brain and preventing efficient treatment of many brain diseases (Abbott et al 2010; Pardridge 2012). G., intranasal delivery, intracerebral/intraventricular injections, chemical mediation) have been proposed, but each of these approaches has several limitations, including low delivery efficiency, damage of healthy tissue and cytotoxic or adverse systemic effects (Rapoport 2000; Dhuria et al 2010; White et al 2011; Lochhead and Thorne 2012) To overcome these limitations, non-invasive approaches are highly needed for controlled transient and Extensive research has been done on the use of focused ultrasound (FUS) in combination with intravascular microbubbles (MBs) for a transient and safe increase in BBB permeability (Hynynen et al 2001; Meairs and Alonso 2007; McDannold et al, 2008a; McDannold et al, 2008b; Ting et al 2012; Burgess and Hynynen 2013; Liu et al 2014; Burgess et al 2015; Poon et al 2016). The exact mechanisms have still not been fully elucidated, but in the presence of ultrasound (US), MBs oscillate and apply biomechanical forces on the blood vessel wall, which potentially facilitate both trans- and paracellular transport across the capillary wall

Methods

Results

Conclusion