Fluorinated Peptide Hydrogels Result in Longer In Vivo Residence Time after Subcutaneous Administration

Peptide-based hydrogels are of interest to biomedical applications. Herein, we have explored the introduction of fluorinated amino acids in hydrogelator H-FQFQFK-NH₂ (P1) to design a series of fluorinated peptide hydrogels and evaluate the in vitro and in vivo properties of the most promising analogues. The impact of fluorinated groups on peptide gelation, secondary structure, and self-assembly processes was assessed. We show that fluorine can significantly improve hydrogel stiffness, compared to the nonfluorinated reference P1. For P15 (H-FQFQF(o-CF₃)K-NH₂), P18 (H-FQFQF(F₅)K-NH₂), and P19 (H-FQFQM(CF₃)K-NH₂), microscopy studies scrutinized fiber morphologies and alignment in the network. In vitro release studies of hydrogels loaded with an opioid cargo suggested improved hydrogel stability for P15 and P18. This improved stability was further validated in vivo, notably for P15, giving the most significant increased gel residence time, with more than 20% of hydrogel still present 9 days post-injection, as monitored by nuclear SPECT-CT imaging.