MAX1 is a 20 amino acid peptide that under an exogenous stimulus folds into a β-hairpin conformation and undergoes rapid assembly into a highly crosslinked hydrogel network. Subsequent peptide engineering found that truncating the terminal residues of MAX1 afforded a peptide, named SVS-1, which no longer undergoes hydrogelation but instead selectively binds to the anionic surfaces of tumor cells. This binding event allows SVS-1 to adopt a bioactive β-hairpin conformation that permits intracellular transport of ligated small molecules via mechanisms involving physical translocation and endocytosis. Conjugation of the model hydrophobic drug Paclitaxel (PTX) to SVS-1 improved the drug's solubility by ~1000-fold, and allowed for successful delivery of PTX to cancer cells in vitro and in vivo. While studying SVS-1 we identified the intrinsically disordered peptide CLIP6, which exclusively employs non-endosomal mechanisms to cross cellular membranes while being remarkably biocompatible. Biophysical studies identified a single glutamate residue is responsible for maintaining CLIP6’s disordered bioactive state, defines its mechanism of cellular entry and is central to its biocompatibility. Delivery studies show CLIP6 affords successful cytoplasmic transport of a ligated small molecule that is otherwise completely cell-impermeable. Building upon this work, we recently synthesized a new family of ultrasound (US)-sensitive nanoparticle, termed “nano-peptisomes”, via templated assembly of peptide amphiphiles at the interface of fluorinated nanodroplets. Biomolecular cargo present during particle assembly is encapsulated within the nano-peptisome core and can be directly delivered to the cytoplasm of cells upon US-mediated particle rupture (see Fig. 1). Thus, nano-peptisomes represent a novel class of US-activated carriers that can shuttle membrane-impermeable biomolecules into cells with spatial and temporal precision.

Evolution of stimuli-responsive peptide nanocarriers from hydrogel materials

254th National Meeting (2017)

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