Fibroblast Growth\nFactor Receptor 1‑Specific\nDehydrogelation to Release Its Inhibitor for Enhanced Lung Tumor Therapy

Fibroblast growth factor receptor 1 (FGFR1) is emerging\nas a promising\nmolecular target of lung cancer, and various FGFR1 inhibitors have\nexhibited significant therapeutic effects on lung cancer in preclinical\nresearch. Due to their low targeting ability or bioavailability, direct\nadministration of these inhibitors may cause side effects. Herein,\na hydrogelator, Nap-Phe-Phe-Phe-Glu-Thr-Glu-Leu-Tyr-OH (<b>Nap-Y</b>), was rationally designed to coassemble with an FGFR1 inhibitor\nnintedanib (<b>Nin</b>) to form a peptide hydrogel <b>Gel\nY/Nin</b> for localized administration and FGFR1-triggered release\nof <b>Nin</b>. Upon specific phosphorylation by FGFR1 overexpressed\non 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(H<sub>2</sub>PO<sub>3</sub>)-OH (<b>Nap-Yp</b>), leading to dehydrogelation\nof the gel and subsequent <b>Nin</b> release. <i>In vitro</i> experiments demonstrate that the release of <b>Nin</b> in\na sustained manner from <b>Gel Y/Nin</b> significantly suppresses\nthe survival, migration, and invasion of A549 cells by inhibiting\nFGFR1 expression and its phosphorylation function on downstream signaling\nmolecules. Nude mouse studies show that <b>Gel Y/Nin</b> exhibits\nenhanced therapeutic efficacy on lung tumor than free <b>Nin</b>. We anticipate that <b>Gel Y/Nin</b> will be utilized for\nlung cancer treatment in clinical settings in the near future.