Effect of pH on the Emergent Viscoelastic Properties of Cationic Phenylalanine-Derived Supramolecular Hydrogels

Supramolecular hydrogels formed by the self-assembly of low-molecular-weight (LMW) agents are promising next-generation biomaterials for drug delivery, tissue engineering, and regenerative medicine. Phenylalanine (Phe) derivatives have emerged as a privileged class of LMW supramolecular gelators due to their strong propensity to self-assemble into emergent hydrogel networks with demonstrated biocompatibility. We have previously reported a series of cationic Phe-derived gelators in which fluorenylmethoxycarbonyl (Fmoc) phenylalanine (Phe), 3-fluorophenylalanine (3F-Phe), and pentafluorophenylalanine (F₅-Phe) are functionalized at the C-terminus with diaminopropane (DAP). These gelators (Fmoc-Phe-DAP, Fmoc-3F-Phe-DAP, and Fmoc-F₅-Phe-DAP) are water-soluble and undergo spontaneous self-assembly and gelation upon an increase in the ionic strength of the solution caused by addition of sodium chloride. Herein, we report the effects of pH on the self-assembly and gelation of Fmoc-Phe-DAP, Fmoc-3F-Phe-DAP, and Fmoc-F₅-Phe-DAP. We also describe the effects that pH has on the emergent properties of these hydrogel networks, including assembly morphology and hydrogel viscoelasticity. These studies indicate that pH has varying effects on the properties of the hydrogels that are also dependent on the molecular structure of the Fmoc-Phe-DAP derivative. Fmoc-Phe-DAP hydrogels are highly sensitive to changes in solvent pH, forming strong hydrogels only near neutral pH. In contrast, hydrogels of Phe derivatives with fluorinated side chains (Fmoc-3F-Phe-DAP and Fmoc-F5-Phe-DAP) have consistent emergent viscoelastic properties across a wider range of acidic to basic pH values.