Highlights
- • We developed a platform technology which allows us to deliver therapeutic cargo across the blood-brain barrier (BBB)
• This technology uses non-ionic surfactant vesicles coated with glucosamine to target GLUT1 on the brain endothelia to facilitate passage across the BBB
• We determined the vesicle platform traverses the using a clathrin-independent, dynamin dependent endocytic pathway.
• We successfully used this platform to deliver anti-VEEV monoclonal antibody Hu1A3B-7 during an in vivo Venezuelan equine encephalitis virus model and enhanced the outcome of infection over the antibody on its own
• Our platform has wider potential application for delivering new therapeutic cargos
Abstract
The field of brain drug delivery faces many challenges that hinder development and testing of novel therapies for clinically important central nervous system disorders. Chief among them is how to deliver large biologics across the highly restrictive blood-brain barrier. Non-ionic surfactant vesicles (NISV) have long been used as a drug delivery platform for cutaneous applications and have benefits over comparable liposomes in terms of greater stability, lower cost and suitability for large scale production. Here we describe a glucosamine-coated NISV, for blood-brain barrier GLUT1 targeting, capable of traversing the barrier and delivering active antibody to cells within the brain.
In vitro, we show glucosamine vesicle transcytosis across the blood-brain barrier with intact cargo, which is partially dynamin-dependent, but is clathrin-independent and does not associate with sorting endosome marker EEA1. Uptake of vesicles into astrocytes follows a more classical pathway involving dynamin, clathrin, sorting endosomes and Golgi trafficking where the cargo is released intracellularly.
In vivo, glucosamine-coated vesicles are superior to uncoated or transferrin-coated vesicles for delivering cargo to the mouse brain. Finally, mice infected with Venezuelan equine encephalitis virus (VEEV) were successfully treated with anti-VEEV monoclonal antibody Hu1A3B-7 delivered in glucosamine-coated vesicles and had improved survival and reduced brain tissue virus levels. An additional benefit was that the treatment also reduced viral load in peripheral tissues. The data generated highlights the huge potential of glucosamine-decorated NISV as a drug delivery platform with wider potential applications.