Bolaamphiphiles as a novel drug delivery system in the treatment of diseases of the brain

The incidence of central nervous system (CNS) diseases, such as glioblastoma, Alzheimer’s disease and Parkinson’s disease, will increase substantially in the next few decades. However, treatment for diseases of the brain is limited due to the restrictive physical and functional blood-brain barrier (BBB) dividing the brain and the vascular system. Bolaamphiphilic (BA) vesicles, produced from vernonia oil, encapsulate a wide range of therapeutic molecules, and offer an alternative drug delivery system to penetrate the brain to treat diseases of the CNS. We present novel anionic BA vesicles that cross biological barriers including the blood-brain barrier. BA vesicles were characterised by dynamic light scattering, transmission electron microscopy, zeta potential analysis and size exclusion column chromatography. In vitro studies were performed on numerous CNS-representative and other cell lines - BV2 microglia, SH-SY5Y neurones, LN229 glioblastoma, HEK-293T epithelia, hCMEC/D3 endothelia and HASTR/ci35 astrocytes. In vivo studies were performed using C57BL/6 male mice. A novel methodology was developed to permit synthesis of the novel BAs first described here, directly from vernonia oil, the starting material. This study has shown that a novel preparation of anionic BA form vesicles that encapsulate a range of different cargoes including tracer dyes and antibody fragments albeit with a low encapsulation efficiency. They do not influence cell viability or cause an acute immune response. They have been shown to penetrate the BBB in vivo. Analysis of the original BA material has shown to consist of two compounds, both of which have been synthesised and characterised. The original material synthesised from vernonia oil and used to produce BA vesicles was thought to be cationic. However, after profiling the vesicles synthesised were found to have a negative zeta potential demonstrating that they are novel. They were further tested and found to cross biological barriers in vitro. Newly synthesised vesicles require further characterisation and optimisation to improve stability and encapsulation efficiency. The original anionic BA material has been shown to cross the BBB within 30 minutes of intravenous injection. These results demonstrate that whilst further studies are required this is a candidate drug delivery system to treat diseases of the brain.

Level dc:type.qualificationlevel

PhD thesis

Grantor dc:publisher.institution

University of Westminster

Year dc:date.issued

2020

Author dc:creator

• Maclatchy, A.

Identifier

oai:westminsterresearch.westminster.ac.uk:v1vv9

OAI identifier oai:identifier

oai:westminsterresearch.westminster.ac.uk:v1vv9