Development of Gold Nanocarriers to Deliver Proteins and Peptides to the CNS

McQuaid, Conor (2020). Development of Gold Nanocarriers to Deliver Proteins and Peptides to the CNS. PhD thesis The Open University.



Treatment of many CNS disorders, specifically neurodegenerative disorders are severely limited at present, and with an increase in the aging population, research into an effective treatment is necessary. A major issue is that many therapeutic agents cannot access the brain, due to a structure termed the blood brain barrier (BBB), which excludes many potential therapeutic drugs from the CNS of the drugs that could possibly treat these disorders. Cellular delivery of bioactive molecules e.g. antibodies, peptides and cytokines are a growing area of research due to their possible therapeutic potential. There have been several cytokines which have been successfully used in experimental models of many neurodegenerative diseases but have had difficulty in being translated into clinical trials. These cytokines do not cross the BBB by themselves but if attached to an effective nanocarrier that is able to cross this barrier, could be translated into a much-needed treatment. Gold Nanoparticles (AuNP) have been selected due to their numerous useful characteristics, such as easy production, biological compatibility and chemical stability. Previous research has shown that glucose derived-coated gold nanoparticles can bind to, and cross human brain endothelial cells in vitro and rat brain endothelial cells in vivo.

15 formulations of ligand coated AuNPs were investigated using a simple model of the BBB, to determine which formulation could cross the brain endothelium most efficiently. PEGamine/GalactoseC2 and GlucoseC2 ligand coated AuNPs were able to cross most effectively and were taken forward for further experimentation; GalactoseC2 coated AuNPs were used as a control ligand coating.

BDNF, the chosen cytokine of interest for attachment to AuNP, was mutagenically altered (Histidine→Cysteine) in the His tag region of a plasmid used to produce recombinant human BDNF to produce a free thiol group on the Cysteine allowing a place-exchange reaction onto the surface of the AuNP. We optimized the production of our modified BDNF (BDNF-H9C) and developed effective techniques to measure the quantity and biological activity of the protein produced (ELISA and TrK-B Assay). However insufficient quantity of BDNF-H9C could be produced from transfected cells and purified to perform an exchange reaction.

A series of peptides was analysed for their ability to bind the transferrin receptor expressed on brain endothelium in vitro (hCMEC/D3 cells). One strongly-binding peptide was selected for attachment to AuNPs and this was found to increase the amount of AuNP that crossed a BBB model.

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