Dual pH-Responsive Pseudopeptide: Hydrogelation and Self-Assembly into Single-and Multi-Walled Nanotubes

Abstract

This work reports the heterochiral tripeptide L-Phe-D-Phe-L-Phe, N-capped with vermellogen, as an ionizable pseudopeptide hydrogelator, and how the pH-responsiveness is transferred from the molecular to the nanoscale, and all the way up to the macroscale through self-assembly. In particular, the protonation of the vermellogen moiety is responsible for hydrogelation, while that of the peptide fine-tunes the matrix nanostructure and viscoelastic properties. Electron microscopy reveals the correlation of varying viscoelastic properties with the nanostructure of the hydrogel matrices. Self-assembly of the pseudopeptide undergoes a peculiar evolution from nanofibers to nanotubes. This process depends on the degree of Cterminal deprotonation, notably with the gradual increase in the internal diameter of the resulting nanotubes as the deprotonation progresses to completion. State-of-the-art characterization techniques confirm that the nanostructured gels are predominantly comprised of parallel β-sheets as primary self-assembling motifs, arranging vermillogen units in a clockwise helical pattern, which minimizes electrostatic repulsions. The evolution from nanofibers to nanotubes appears to be driven by a long-range hydrogen bonding interaction, involving the hydrazone group and the deprotonated C-terminus of adjacent β-sheets. The potential biomedical application of the gels is demonstrated through the controlled release of a model anticancer drug, and in vitro cytocompatibility assays.