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

Abstract

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 H₂PO₄⁻ and HSO₄⁻, while the addition of other anions such as Cl⁻, HPO₄²⁻, CO₃²⁻, HCO₃⁻ or SO₄²⁻ did not affect the gel stability. The anion–gelator interaction was investigated by ¹H and ³¹P 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 H₂PO₄⁻ with NapF-TREN. Microscopic investigations by TEM, AFM, and SAXS revealed that H₂PO₄⁻ 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.