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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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Publication details

The article was received on 12 Aug 2019, accepted on 07 Oct 2019 and first published on 08 Oct 2019


Article type: Edge Article
DOI: 10.1039/C9SC04024B
Chem. Sci., 2019, Advance Article
  • Open access: Creative Commons BY license
    All publication charges for this article have been paid for by the Royal Society of Chemistry

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    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, Advance Article , DOI: 10.1039/C9SC04024B

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