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

TY - JOUR

T1 - Chemical biology tools for probing transcytosis at the blood-brain barrier

AU - Beard, Rhiannon

AU - Gaboriau, David C.A.

AU - Gee, Antony D.

AU - Tate, Edward W.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85075720425&partnerID=8YFLogxK

U2 - 10.1039/c9sc04024b

DO - 10.1039/c9sc04024b

M3 - Article

AN - SCOPUS:85075720425

SN - 2041-6520

VL - 10

SP - 10772

EP - 10778

JO - Chemical Science

JF - Chemical Science

IS - 46

ER -