MAX1 is a 20 residue peptide capable of folding into a β-hairpin conformation that undergoes rapid assembly into a 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 negatively-charged surfaces of tumor cells. This binding event allows the peptide to adopt a bioactive β-hairpin conformation that permits intracellular transport of ligated small molecules (Fig. 1A). Biophysical studies show that SVS-1 preferentially delivers this cargo to the cytoplasm and nucleus of cells (Fig. 1B). To demonstrate SVS-1's utility for chemotherapeutic delivery, we conjugated the model hydrophobic drug Paclitaxel (PTX) to the peptide leading to a ~1000-fold improvement in drug solubility. The conjugate also successfully delivered and released PTX to cancer cells in vitro and tumor tissue in vivo without toxic adjuvants (Fig. 1C). Following this work, we have developed a new family of peptides that exclusively employ non-endocytic mechanisms to enter cells, allowing for the cytoplasmic delivery of a ligated molecule that is otherwise completely membrane-impermeable. Thus, these peptides represent simple, effective delivery platforms that can facilitate clinical translation of drug candidates previously eliminated from consideration due to poor solubility and low cell permeability.

Evolution of cancer-targeting peptides from hydrogel materials

251st National Meeting (2016)

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