Cell Penetrating Peptide Biopolymers for Drug Delivery to the Central Nervous System

Abstract

Drug delivery to the central nervous system (CNS) is significantly hindered by the blood brain barrier (BBB), but the use of cell penetrating peptides (CPP) allows conjugated molecules transport through the BBB and greatly enhances cellular uptake throughout the CNS. Many CPPs work through unknown mechanisms and vary in cell penetration ability and toxicity. Therefore, determining which CPP is the most effective for CNS delivery is crucial. Elastin like polypeptide (ELP) is a thermally responsive polypeptide used as a carrier and stabilizer, making conjugated biomolecules more resistant to proteolysis and extending their half-lives in vivo. In our lab, we have used systemically administered CPP-fused ELPs conjugated to the therapeutic peptides with promising results in disease models. Currently, we are assessing the utilization of the intranasal (IN) delivery route to bypass the BBB and facilitate delivery of ELP-fused therapeutics to the CNS. We chose three commonly used and well-studied CPPs to conjugate to the ELP carrier: TAT, SynB1, and Bac. Fluorescently-labeled CPP-ELP conjugates were delivered via IN and intravenous (IV) routes, and tissue, plasma, and cerebrospinal fluid samples were collected at various time points after administration. Polypeptide levels were determined using direct fluorescence measurements in fluid samples and quantitative tissue imaging. Polypeptide distribution throughout the brain was determined by scanning thin sections of the tissues, and fluorescence microscopy was used to determine intracellular localization. These data demonstrate the utility of intranasally-administered CPP-ELP for delivering therapeutics to the CNS. JWDM is supported by the Robert Currier Pre-doctoral Fellowship in Translational Neuroscience.