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 ( Nap-Y ), was rationally designed to coassemble with an FGFR1 inhibitor nintedanib ( Nin ) to form a peptide hydrogel Gel Y/Nin for localized administration and FGFR1-triggered release of Nin . Upon specific phosphorylation by FGFR1 overexpressed on lung cancer cells, Nap-Y in Gel Y/Nin is converted to the hydrophilic product Nap-Phe-Phe-Phe-Glu-Thr-Glu-Leu-Tyr(H 2 PO 3 )-OH ( Nap-Yp ), leading to dehydrogelation of the gel and subsequent Nin release. In vitro experiments demonstrate that the release of Nin in a sustained manner from Gel Y/Nin 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 Gel Y/Nin exhibits enhanced therapeutic efficacy on lung tumor than free Nin . We anticipate that Gel Y/Nin will be utilized for lung cancer treatment in clinical settings in the near future.