Supramolecular self-assembly offers promising new ways to control nanostructure morphology and respond to external stimuli. A pH-sensitive self-assembled system was developed to both control nanostructure shape and respond to the acidic microenvironment of
tumors using self-assembling
peptide amphiphiles (PAs). By incorporating an oligo-
histidine H6 sequence, we developed two PAs that self-assembled into distinct morphologies on the nanoscale, either as nanofibers or spherical
micelles, based on the incorporation of the aliphatic tail on the N-terminus or near the C-terminus, respectively. Both cylinder and sphere-forming PAs demonstrated reversible disassembly between pH 6.0 and 6.5 upon protonation of the
histidine residues in acidic solutions. These PAs were then characterized and assessed for their potential to encapsulate hydrophobic
chemotherapies. The H6-based nanofiber assemblies encapsulated
camptothecin (
CPT) with up to 60% efficiency, a 7-fold increase in
CPT encapsulation relative to spherical
micelles. Additionally, pH-sensitive nanofibers showed improved
tumor accumulation over both spherical
micelles and nanofibers that did not change morphologies in acidic environments. We have demonstrated that the morphological transitions upon changes in pH of supramolecular nanostructures affect drug encapsulation and
tumor accumulation. Our findings also suggest that these supramolecular events can be tuned by molecular design to improve the pharmacologic properties of nanomedicines.