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LRP-1-mediated blood brain barrier transcytosis: mechanisms and therapeutic applications

Nyberg, SEL; (2016) LRP-1-mediated blood brain barrier transcytosis: mechanisms and therapeutic applications. Doctoral thesis , UCL (University College London). Green open access

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Abstract

The endothelial cells lining the brain microvasculature make up the blood-brain barrier (BBB) of the central nervous system (CNS), physically restricting access of blood-borne compounds to the brain. Very few drugs possess the narrow set of physicochemical characteristics required to cross the BBB, causing a hurdle in delivering therapeutics to the CNS without using invasive methods or disrupting the BBB. However, several transporters at the BBB mediate import and export of macromolecules in a process called transcytosis. The work presented in this thesis explores the use of polymeric nanoparticles or ‘polymersomes’ as drug delivery vehicles to the brain. Through attaching a peptide ligand to LRP-1 receptor expressed at the BBB, polymersomes were provided with a targeting mechanism to achieve transportation across the blood-brain barrier in a non-disruptive manner. It is shown herein that Angiopep-2-POEGMA-PDPA (A-EP) polymersomes are able to transverse brain endothelial cells through transcytosis upon interaction with the LRP-1 receptor. However, transcytosis at the BBB is a poorly characterised process. Efforts to elucidate the mechanism by which LRP-1 mediates A-EP transcytosis at the BBB were undertaken through 3D or 4D confocal microscopy in conjunction with immunocytochemistry or small molecule inhibitors of various endocytic processes. This work was completed in parallel with fluorescence quantification of A-EP fluorescence in the rat brain, confirming that A-EP polymersomes enter the brain in vivo. Finally, applications for delivery of macromolecular therapeutics to the CNS in vivo were explored with the chief aim to achieve clinical translation.

Type: Thesis (Doctoral)
Title: LRP-1-mediated blood brain barrier transcytosis: mechanisms and therapeutic applications
Event: University College London
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/1477369
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