Fibroblast Growth Factor Receptor 1-Specific Dehydrogelation to Release Its Inhibitor for Enhanced Lung Tumor Therapy

Fibroblast growth factor receptor 1 (FGFR1) is emerging as a promising molecular target of lung cancer, and various FGFR1 inhibitors have exhibited significant therapeutic effects on lung cancer in preclinical research. Due to their low targeting ability or bioavailability, direct administration of these inhibitors may cause side effects. Herein, a hydrogelator, Nap-Phe-Phe-Phe-Glu-Thr-Glu-Leu-Tyr-OH (<b>Nap-Y</b>), was rationally designed to coassemble with an FGFR1 inhibitor nintedanib (<b>Nin</b>) to form a peptide hydrogel <b>Gel Y/Nin</b> for localized administration and FGFR1-triggered release of <b>Nin</b>. Upon specific phosphorylation by FGFR1 overexpressed on lung cancer cells, <b>Nap-Y</b> in <b>Gel Y/Nin</b> is converted to the hydrophilic product Nap-Phe-Phe-Phe-Glu-Thr-Glu-Leu-Tyr(H₂PO₃)-OH (<b>Nap-Yp</b>), leading to dehydrogelation of the gel and subsequent <b>Nin</b> release. <i>In vitro</i> experiments demonstrate that the release of <b>Nin</b> in a sustained manner from <b>Gel Y/Nin</b> significantly suppresses the survival, migration, and invasion of A549 cells by inhibiting FGFR1 expression and its phosphorylation function on downstream signaling molecules. Nude mouse studies show that <b>Gel Y/Nin</b> exhibits enhanced therapeutic efficacy on lung tumor than free <b>Nin</b>. We anticipate that <b>Gel Y/Nin</b> will be utilized for lung cancer treatment in clinical settings in the near future.