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

The heterochiral triphenylalanine sequence L-Phe-D-Phe-L-Phe (FfF) with an ionizable C-terminus (pKa1 = 3.3) is N-capped with the so-called "vermellogen" motif (VH2+, pKa2 = 9) to provide a pseudopeptide hydrogelator (V-FfFH2·2Cl). This work details how the pH-responsiveness is then 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. Hence, whilst V-FfFH22+/V-FfFH+ form hydrogels in the broad 1 to 6 pH range, the material can be reversibly disassembled from pH 7 onwards upon formation of the zwitterionic V-FfF with overall neutral charge. Electron microscopy investigations enabled the correlation of varying viscoelastic properties with the nanostructure of the hydrogel matrices. Self-assembly of V-FfFH2·2Cl undergoes a peculiar evolution from nanofibers to nanotubes as regards its nanostructuration. This process depends on the degree of C-terminal 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 confirmed that the nanostructured gels are predominantly comprised of parallel β-sheets as primary self-assembling motifs, arranging VH2+ 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 V-FfFH·2Cl is evaluated in the proof-of-concept controlled release of the model drug 5-fluoruracil (5-FU), showing an appropriate kinetic profile and high cytocompatibility on fibroblast cells.