FGFR2-responsive self-assembled hydrogel releases its inhibitor to suppress the progression of endometriosis

Fibroblast Growth Factor receptor 2 (FGFR2) has emerged as a highly promising therapeutic target due to its critical role in the pathogenesis and progression of endometriosis. To date, a variety of FGFR2 inhibitors have exhibited remarkable therapeutic efficacy against endometriosis in both preclinical studies and clinical trials. However, these small-molecule inhibitors suffer from drawbacks including poor targeting ability and high toxicity, and their direct administration has consequently limited their further clinical applications. In this study, a rationally designed hydrogenator, Nap-Phe-Phe-Phe-Asp-Asp-Asp-Tyr-OH (NapY), was co-assembled with the FGFR2 Inhibitor AZD4547 (AZD) to construct an FGFR2-responsive hydrogel, aiming to achieve precise targeted therapy for endometriosis. Under the specific phosphorylation by FGFR2 which is highly expressed in endometriotic lesions, Nap-Y in Gel Y/AZD is phosphorylated and converted into a hydrophilic product, Nap-Phe-Phe-Phe-Asp-Asp-Asp-Tyr(H₂PO₃)-OH (Nap-Yp). This process further triggers the disassembly of the hydrogel, enabling the responsive release of AZD. In vitro experimental results demonstrated that the sustained release of AZD from Gel Y/AZD could effectively suppress the viability, migration and invasion of 12Z-FGFR2 cells by inhibiting the expression of FGFR2 and the phosphorylation levels of its downstream signaling pathway molecules. In vivo studies confirmed that compared with endometriosis model mice treated with free AZD, those treated with Gel Y/AZD exhibited significantly superior inhibitory effects on the growth and metastasis of ectopic lesions. It is anticipated that this research will expect to be applied in the clinical treatment of endometriosis in the near future.