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The Development of a Drug Delivery System Using Brain Endothelial Non-Antibody Binding Domains as Transport Carriers

Daas, Mohammad (2018). The Development of a Drug Delivery System Using Brain Endothelial Non-Antibody Binding Domains as Transport Carriers. PhD thesis The Open University.

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Abstract

The highly specialised brain capillary endothelial cells (BCEC) that constitute the blood brain barrier (BBB) exhibit high resilience to the penetration of xenobiotic and biologic therapeutics, making drug delivery to the central nervous system (CNS) a challenging feat. Endogenous BCEC receptors such as transferrin receptor (TfR) have been proposed as exploitable targets for therapeutic payload transport into the CNS, and have been successfully targeted using monoclonal antibodies to deliver therapeutic molecules into the brains of rodents and non-human primates via receptor mediated transcytosis (RMT).

The overall aim of this study was to develop a BCEC drug delivery system using alternative domains to antibodies e.g. peptides and ssDNA aptamers, as a means of exploiting endogenous receptor transport mechanisms to deliver macromolecular drugs into the CNS via RMT.

The expression of three receptor candidates, TfR, low-density lipoprotein receptor (LDLR) and low-density lipoprotein-related receptor protein 1 (LRP1) were characterised for use as selectable targets on the cell surface of Immortalised human brain endothelial cells (hCMEC/D3) by flow cytometric analysis. Aptamers and cyclic peptide domains were then selected via in vitro selection techniques.

The present findings highlight the selection of 13 peptides that demonstrate species cross-reactivity to human, mouse and rat TfR as determined by phage ELISA. Moreover, the lead candidate Pep1 was identified to share homology with a conserved 'DCSGNFCLF' motif found on transferrin. When expressed as a bivalent peptide-Fc fusion molecule, Pep1 was shown to internalise within the mouse and human brain endothelial cell lines, bEnd.3, and hCMEC/D3. Additionally, the overall enrichment of hTFR specific aptamers was demonstrated following twelve rounds of selection and high throughput sequencing of selected pools, data that warrants further investigation.

Item Type: Thesis (PhD)
Copyright Holders: 2017 The Author
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM)
Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Item ID: 55108
Depositing User: Mohammed Daas
Date Deposited: 05 Jun 2018 13:00
Last Modified: 14 Nov 2018 10:12
URI: http://oro.open.ac.uk/id/eprint/55108
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