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Issue 46, 2019
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Chemical biology tools for probing transcytosis at the blood–brain barrier

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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.

Graphical abstract: Chemical biology tools for probing transcytosis at the blood–brain barrier

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Supplementary files

Article information


Submitted
12 Aug 2019
Accepted
07 Oct 2019
First published
08 Oct 2019

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2019,10, 10772-10778
Article type
Edge Article

Chemical biology tools for probing transcytosis at the blood–brain barrier

R. Beard, D. C. A. Gaboriau, A. D. Gee and E. W. Tate, Chem. Sci., 2019, 10, 10772
DOI: 10.1039/C9SC04024B

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