Anion-responsive self-assembled hydrogels of a phenylalanine-TREN conjugate allow sequential release of propranolol and doxorubicin.

Stimuli-responsive self-assembled and supramolecular hydrogels derived from peptide amphiphiles have opened exciting new avenues in biomedicine and drug delivery. Herein, we screened a series of phenylalanine-amphiphiles possessing polyamine and oxyethylene appendages for their self-assembly and anion-responsiveness and found that the tris(aminoethyl)amine (TREN) containing amphiphile NapF-TREN formed injectable hydrogels that could be disrupted upon the addition of stoichiometric amounts of tetrahedral monovalent anions such as HPO and HSO, while the addition of other anions such as Cl, HPO, CO, HCO or SO did not affect the gel stability. The anion-gelator interaction was investigated by H and P NMR spectroscopy as well as by Isothermal Titration Calorimetry (ITC). These studies confirmed a 1 : 1 stoichiometry and revealed negative enthalpy and negative entropy for the binding of HPO with NapF-TREN. Microscopic investigations by TEM, AFM, and SAXS revealed that HPO anions induced a nanofiber-to-nanoglobule morphological change in the aqueous self-assemblies of NapF-TREN. However, upon ageing the samples, slow reformation of the nanofibers was also observed, reflecting the reversibility of the anion-gelator interaction. The anion- and pH-responsive nature of the NapF-TREN hydrogels was exploited to program sequential release of entrapped drugs propranolol and doxorubicin.