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Brain-Penetrating Peptide Shuttles Across the Blood-Brain Barrier and Extracellular-like Space

preprint
submitted on 07.06.2019, 15:03 and posted on 12.06.2019, 12:45 by Xiujuan Peng, Xinquan Liu, Yen-Liang Liu, Jae You Kim, Yuan-I Chen, Phyllis Ang, Alex Nguyen, Jasmim Leal, Hsin-Chih Yeh, Debadyuti Ghosh
Here, we describe a combinatorial approach to identify peptide shuttles that successfully traverse the multiple barriers to systemic drug delivery to the brain--1. the blood-brain barrier (BBB) and the 2. extracellular space (ECS) of the brain. Leveraging the excellent molecular diversity of M13 phage libraries, we identified peptides that actively transport across the BBB and diffuse through the extracellular matrix of the ECS in cell culture and in mice. These peptides demonstrate higher accumulation in the brain than gold standard peptides used in clinical trials. Importantly, these findings suggest that different sized therapeutics that were previous poorly permeable into the brain can accumulate at higher concentrations, thereby improving the therapeutic index and ultimate efficacy of drugs into the brain.

Funding

NIH R01HL138251

NIH CA193038

PhRMA Foundation Research Starter Grant

Welch Foundation F-1833

Texas 4000 Foundation

History

Email Address of Submitting Author

dghosh@austin.utexas.edu

Institution

University of Texas at Austin

Country

United States

ORCID For Submitting Author

0000-0001-7552-363X

Declaration of Conflict of Interest

No conflict of interest

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