Chemical biology tools for probing transcytosis at the blood-brain barrier
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Published version
Author(s)
Beard, R
Gaboriau, D
Gee, A
Tate, E
Type
Journal Article
Abstract
Absorptive- and receptor-mediated transcytosis (AMT/RMT) are widely studied strategies to deliver therapeutics across the blood–brain barrier (BBB). However, an improved understanding of the mechanism surrounding trafficking is required that could promote delivery. Accordingly, we designed a flexible platform that merged AMT and RMT motifs on a single scaffold to probe various parameters (ligand, affinity, valency, position) in a screening campaign. During this process we adapted an in vitro BBB model to reliably rank transcytosis of the vehicle library. Our results demonstrate heightened uptake and trafficking for the shuttles, with a structure–activity relationship for transcytosis emerging. Notably, due to their small size, the majority of shuttles demonstrated increased permeation compared to transferrin, with the highest performing shuttle affording a 4.9-fold increase. Consequently, we have identified novel peptide conjugates that have the capacity to act as promising brain shuttles.
Date Issued
2019-12-14
Date Acceptance
2019-10-07
ISSN
2041-6520
Publisher
Royal Society of Chemistry
Start Page
10772
End Page
10778
Journal / Book Title
Chemical Science
Volume
10
Issue
46
Copyright Statement
© The Authors 2019. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence (https://creativecommons.org/licenses/by/3.0/).
Subjects
03 Chemical Sciences
Publication Status
Published
Date Publish Online
2019-10-08