Supramolecular hydrogels are emerging as next-generation alternatives to synthetic polymers for drug delivery applications. Self-assembling peptides are a promising class of supramolecular gelator for in vivo drug delivery that have been slow to be adopted despite advantages in biocompatibility due to the relatively high cost of producing synthetic peptide hydrogels compared to synthetic polymer gels. Herein we describe the development and use of inexpensive low molecular weight cationic derivatives of phenylalanine (Phe) as injectable hydrogels for in vivo delivery of an anti-inflammatory drug, diclofenac, for pain mitigation in a mouse model. N-Fluorenylmethoxycarbonyl phenylalanine (Fmoc-Phe) derivatives were modified at the carboxylic acid with diaminopropane (DAP) to provide Fmoc-Phe-DAP molecules that spontaneously and rapidly self-assemble in aqueous solutions upon addition of physiologically relevant sodium chloride concentrations to give hydrogels. When self-assembly occurs in the presence of diclofenac, the drug molecule is efficiently encapsulated within the hydrogel network. These hydrogels exhibit robust shear-thinning behavior, mechanical stability, and drug release profiles to enable application as injectable hydrogels for in vivo drug delivery. Delivery of diclofenac in vivo was demonstrated by a localized injection of an Fmoc-F5-Phe-DAP/diclofenac hydrogel into the ankle joint of mice with induced ankle injury and associated inflammation-induced pain. Remediation of pain in the ankle joint was observed immediately after initial injection and was sustained for a period of nearly two weeks while diclofenac controls remediated pain for less than one day. This data demonstrates the promise of these supramolecular hydrogels as inexpensive next-generation materials for sustained and localized drug delivery in vivo.
Keywords: Hydrogel; drug delivery; low molecular weight gelator; supramolecular materials; sustained release.