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(H2 PO3 )-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.