AbstractParkinson’s disease (PD) is a progressive neurodegenerative disorder, which has a devastating impact on the lives of patients, characterised primarily by the loss of dopamine-producing neurons in the brain. Drug delivery to the mammalian brain is notoriously difficult due to the physical and chemical restrictions presented by the blood brain barrier (BBB), a major contributing factor to the lack of disease-modifying treatments currently available for PD. This means that recovery from PD is not currently possible and clinical treatment is aimed at controlling symptom progression.
Neurotrophic factors (NTF) are promising treatments for the regeneration of dopaminergic (DA) neurons and offer the possibility of functional recovery in PD. However, the short half-life of NTF and invasive means of administration are limiting features in clinical trials of such promising treatments. Endogenous receptors expressed at the BBB and throughout the central nervous system (CNS) might present viable targets for achieving highly effective drug delivery to the brain in a non-invasive manner via peptide ligand-facilitated transport. Rabies virus-derived peptide (RDP) is a 39-amino acid derivative of the rabies virus glycoprotein (RVG) which has shown promise as an in vivo brain targeting ligand. RDP has gained attention for features such as neural cell targeting specificity and in vivo safety, making it an attractive ligand for development within brain delivery systems.
The experimental work reported herein describes the formulation and characterisation of RDPconjugated polymeric nanoparticles (NP), which exhibited enhanced payload accumulation in neural cell types. It was demonstrated that cellular uptake was mediated by the neuronal nicotinic acetylcholine receptor (nAchR) specifically. RDP optimisation studies lead to the development of a smaller 18-amino acid analogue of RDP termed DAS, which showed enhanced serum stability whilst retaining neural-specific activity when tested in various cell types in vitro. A human-derived in vitro BBB model was designed and developed using a triple culture of brain microvascular endothelial cells (HBMVEC), astrocytes and pericytes. Transport studies using this BBB model revealed the significant targeting advantage of both RDP and DAS ligands iv (compared to the unlabelled NP) in the ability to deliver a payload across this simulated biological barrier
RDP and derivatives such as DAS may offer a solution to the challenge of delivering therapeutics across the BBB. The development of a nanoparticulate drug delivery system decorated with an RDP derivative offers specific, non-invasive targeting to the brain alongside protection of unstable or sensitive cargo. Such drug delivery systems may be beneficial for the treatment of PD, as a means of depositing regenerative NTF directly to the diseased brain.
|Date of Award||May 2019|
|Sponsors||Dowager Countess Eleanor Peel Trust & DEL|
|Supervisor||Paul Mc Carron (Supervisor) & Susan Hawthorne (Supervisor)|
- Drug delivery vehicle