Electrostatic interactions regulate the release of small molecules from supramolecular hydrogels

Supramolecular hydrogels have great potential as biomaterials for sustained delivery of therapeutics. While peptide-based supramolecular hydrogels have been developed that show promise for drug delivery applications, the high cost of production has limited their widespread adoption. Low molecular weight (LMW) supramolecular hydrogels are emerging as attractive and inexpensive alternatives to peptide-based hydrogels. We recently reported novel cationic fluorenylmethyloxycarbonyl-modified phenylalanine (Fmoc-Phe) hydrogels for localized and sustained in vivo release of an anti-inflammatory agent for functional pain remediation. In an effort to further elucidate design principles to optimize these materials for delivery of a variety of molecular agents, we herein report a systematic examination of electrostatic effects on the release of cargo molecules from Fmoc-Phe derived hydrogels. Specifically, we interrogate the release of cationic, anionic, and neutral cargo molecules from a series of cationic and anionic Fmoc-Phe derived hydrogels. We observed that cargo was readily released from the hydrogels except when the cargo and hydrogel network had complementary charges, in which case the cargo was highly retained in the network. These results demonstrate that the electrostatic characteristics of both the hydrogel network and the specific cargo are critical design parameters in the formulation of LMW supramolecular hydrogel systems in the development of next-generation materials for drug delivery applications.