Issue 46, 2019

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

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

Supplementary files

Article information

Article type
Edge Article
Submitted
12 Aug. 2019
Accepted
07 Okt. 2019
First published
08 Okt. 2019
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2019,10, 10772-10778

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

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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