Engineering elastin-like polypeptides for polyphenol capture and permeation through an in vitro nasal mucosa barrier

Abstract

Intranasal (IN) administration provides a potential drug delivery route to the brain without passing the blood-brain barrier, allowing for the delivery of larger therapeutics for diseases such as Alzheimer's disease (AD). However, effective IN administration is compromised by mucociliary clearance (MCC) and the use of complex formulations of thermo-gelling modalities to reduce MCC. This study uses biomimetic elastin-like polypeptides (ELPs) to gel at nasal passage temperatures, capture an AD-relevant polyphenol, vescalagin (VSG), and deliver VSG through a nasal mucosa model. First, a library of ELPs was produced bearing either tyrosine, phenylalanine, serine, or leucine guest residues. The phenyl-bearing ELPs elicit a physiologically relevant gelation temperature and have the best VSG drug binding, as determined by a pull-down assay. Next, a di-block ELP was produced with a tyrosine-bearing block for drug binding and phase separation and a leucine-bearing block that remains soluble and presents a polyarginine tag (10xR) for cell interaction. While the di-block ELP resulted in stable microgels compared to mono-block ELPs upon phase separation, adding the 10xR tag mitigated this stability, returning the di-block ELP to coalescence behavior. However, the 10xR tag elicited ELP interaction with RPMI cells, enhanced VSG accumulation at the cell-mucous surface of an in vitro nasal mucosa model, and increased VSG permeation compared to un-tagged ELP or VSG alone. Future work can use these findings to improve ELP design for IN applications and investigate in vivo efficacy.