Salt‐Inducible Kinase 2‐Triggered Release of Its Inhibitor from Hydrogel to Suppress Ovarian Cancer Metastasis

Abstract Salt‐inducible kinase 2 (SIK2) is a promising target for ovarian cancer therapy due to its critical role in tumorigenesis and progression. Currently available SIK2 inhibitors have shown remarkable therapeutic effects on ovarian cancers in preclinical studies. However, direct administration of the SIK2 inhibitors may bring significant off‐target effect, limiting their clinical applications. In this work, by rational design of a hydrogelator Nap‐Phe‐Phe‐Glu‐Glu‐Leu‐Tyr‐Arg‐Thr‐Gln‐Ser‐Ser‐Ser‐Asn‐Leu‐OH ( Nap‐S ) to coassemble a SIK2 inhibitor HG‐9‐91‐01 ( HG ), a SIK2‐responsive supramolecular hydrogel ( Gel Nap‐S+HG ) for local administration and SIK2‐responsive release of HG is reported to efficiently suppress ovarian cancer metastasis. Under the activation of SIK2 overexpressed in ovarian cancers, Nap‐S in the hydrogel is phosphorylated to yield hydrophilic Nap‐Phe‐Phe‐Glu‐Glu‐Leu‐Tyr‐Arg‐Thr‐Gln‐Ser(H 2 PO 3 )‐Ser‐Ser‐Asn‐Leu ( Nap‐Sp ), triggering the disassembly of the hydrogel and a responsive release of the inhibitor. Cell experiments indicate that sustained release of HG from Gel Nap‐S+HG induce a prominent therapeutic effect on cancer cells by inhibiting SIK2 and phosphorylation of their downstream signaling molecules. Animal experiments demonstrate that, compared with those tumor model mice treated with free HG , Gel Nap‐S+HG ‐treatment mice show an enhanced inhibition on ovarian tumor growth and metastasis. It is anticipated that the Gel Nap‐S+HG can be applied for ovarian cancer therapy in clinic in the near future.