(85b) Self-Assembling Nanoparticles for Peptide Delivery with Enhanced Stability

Authors: 
Acar, H., University of Chicago
Tirrell, M. V., University of Chicago
LaBelle, J. L., University of Chicago
Schnorenberg, M. R., University of Chicago
Peptides are promising tools for manipulating disease processes within cells, but their delivery to and into cells remains a major obstacle. Peptide amphiphiles (PAs), a peptide conjugated to a hydrophobic tail, are one tool to enable the intracellular delivery of therapeutic peptides. The hydrophobic tails drive nanoparticle (NP) self-assembly, which are optimally sized (10-20 nm) to promote accumulation in tumor tissues via the enhanced permeability and retention effect, and their structure prevents hydrolysis and proteolysis of peptides in circulation. The internalization mechanisms have not been fully elucidated, but it is known that endocytosis plays an important role. Despite these delivery benefits, internalized PA NPs mostly remain trapped in endosomes preventing them from reaching their cytoplasmic targets and thus reducing their therapeutic efficacy. Introduction of endosomal cleavage and escape groups into the building blocks of the nanoparticles requires intake through endocytosis.

An additional challenge to overcome for the PA NPs is their limited circulation time in the body. NP formation of PAs occurs through the hydrophobic interactions of the tail. These interactions are strong enough to form NPs in aqueous medium. Nevertheless, the hydrophobic components in body serum cause the disassembly of the NPs. Because of this reason, in vitro experiments should be performed in FBS free medium. Free PAs are vulnerable to proteases and too small to internalize through endocytosis. As a result, the stability of the NPs should be improved to ensure the increased circulation period and endocytosis.

Therefore, we studied the stability of engineered self-assembling nanoparticles with controlled disassembly characteristics. We mixed biocompatible UV cross-linkable hydrophobic components with peptide amphiphiles prepared with DSPE-PEG(2000) during the self-assembly process. The crosslinking components were encapsulated in the core and enhanced the stability through entanglement of the hydrophobic tails after UV crosslinking. We controlled the stability of the self-assembling NPs against temperature by altering the crosslinking components. Furthermore, we showed the enhanced circulation time by in vivo experiments. This design enhances the stability of NPs after self-assembly through crosslinking the core. Thus, the engineered PA located on the NP surface is not affected by the crosslinking. Furthermore, this strategy can enable the intake of NPs through endocytosis, which is convenient for engineering endosomal cleavable and escape domains to deliver the therapeutic peptides.

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