Fluorinated Peptide\nHydrogels Result in Longer <i>In Vivo</i> Residence Time\nafter Subcutaneous Administration

Peptide-based\nhydrogels are of interest to biomedical\napplications.\nHerein, we have explored the introduction of fluorinated amino acids\nin hydrogelator H-FQFQFK-NH<sub>2</sub> (<b>P1</b>) to design\na series of fluorinated peptide hydrogels and evaluate the <i>in vitro</i> and <i>in vivo</i> properties of the\nmost promising analogues. The impact of fluorinated groups on peptide\ngelation, secondary structure, and self-assembly processes was assessed.\nWe show that fluorine can significantly improve hydrogel stiffness,\ncompared to the nonfluorinated reference <b>P1</b>. For <b>P15</b> (H-FQFQF(<i>o</i>-CF<sub>3</sub>)K-NH<sub>2</sub>), <b>P18</b> (H-FQFQF(F<sub>5</sub>)K-NH<sub>2</sub>), and <b>P19</b> (H-FQFQM(CF<sub>3</sub>)K-NH<sub>2</sub>), microscopy\nstudies scrutinized fiber morphologies and alignment in the network. <i>In vitro</i> release studies of hydrogels loaded with an opioid\ncargo suggested improved hydrogel stability for <b>P15</b> and <b>P18</b>. This improved stability was further validated <i>in vivo</i>, notably for <b>P15</b>, giving the most significant\nincreased gel residence time, with more than 20% of hydrogel still\npresent 9 days post-injection, as monitored by nuclear SPECT-CT imaging.