Supramolecular Phenylalanine-Derived Hydrogels for the Sustained Release of Functional Proteins

Protein-based therapeutics have emerged as next-generation pharmaceutical agents for oncology, bone regeneration, autoimmune disorders, viral infections, and other diseases. The clinical application of protein therapeutics has been impeded by pharmacokinetic and pharmacodynamic challenges including off-target toxicity, rapid clearance, and drug stability. Strategies for the localized and sustained delivery of protein therapeutics have shown promise in addressing these challenges. Hydrogels are critical materials that enable these delivery strategies. Supramolecular hydrogels composed of self-assembled materials have demonstrated biocompatibility advantages over polymer hydrogels, with peptide and protein-based gels showing strong potential. However, cost is a significant drawback of peptide-based supramolecular hydrogels. Supramolecular hydrogels composed of inexpensive low-molecular-weight (LMW) gelators, including modified amino acid derivatives, have been reported as viable alternatives to peptide-based materials. Herein, we report the encapsulation and release of proteins from supramolecular hydrogels composed of perfluorinated fluorenylmethyloxcarbonyl-modified phenylalanine (Fmoc-F₅-Phe-DAP). Specifically, we demonstrate release of four model proteins (ribonuclease A (RNase A), trypsin inhibitor (TI), bovine serum albumin (BSA), and human immunoglobulin G (IgG)) from these hydrogels. The emergent viscoelastic properties of these materials are characterized, and the functional and time-dependent release of proteins from the hydrogels is demonstrated. In addition, it is shown that the properties of the aqueous solution used for hydrogel formulation have a significant influence on the in vitro release profiles, as a function of the isoelectric point and molecular weight of the protein payloads. These studies collectively validate that this class of supramolecular LMW hydrogel possesses the requisite properties for the sustained and localized release of protein therapeutics.