(197b) Intracellular Trafficking of Enzyme-Cleavable Peptide Amphiphiles

Acar, H., University of Chicago
Tirrell, M. V., University of Chicago
LaBelle, J. L., University of Chicago
Peptides are promising therapeutics to promote apoptosis by modulating protein-protein interactions (PPIs), offering superior specificity and fewer off-target effects than existing drugs. Peptide amphiphile technology that combines a peptide with a hydrophobic tail efficiently delivers peptide payloads into cells, obstacles remain for viable clinical translation. For example, PAs frequently accumulate within endosomal compartments thus limiting the ability of delivered peptides to target proteins within the cytosol, thereby lowering their therapeutic potency. Furthermore, the intracellular trafficking and ultimate fates of the hydrophobic tails and peptides are largely unknown.

Recently, we showed enhanced intracellular controlled release and accumulation of the peptides by introducing endosome-specific enzyme cleavable linkers between the hydrophobic tail and peptide of the PA building blocks. In addition to enhanced accumulation, the delivery platform that we showed offers the ability to track the individual therapeutic and hydrophobic components in real time using fluorescent labels to better understand and manipulate intracellular drug trafficking. Thus, this platform is a superior nanomedicine tool for enhanced intracellular delivery and tracking of therapeutics.

In this study, we studied the trafficking of the peptides after endosomal enzyme cleavage. We synthesized the peptide amphiphiles, as described in our previous study. In this follow-up study, we added endosomal escape groups to the peptides. Different organelle targeting peptides were selected and their co-localization was studied with different organelle fluorescent labels.