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.

SIK2: A critical glucolipid metabolic reprogramming regulator and potential target in ovarian cancer

“…Sustained release of HG‐9‐91‐01 inhibits the growth and metastasis of OC cells, on the one hand, and has significant therapeutic effects on OC cells by inhibiting SIK2 and phosphorylating its downstream signaling molecules, on the other. The GelNap‐S + HG is expected to be used in the clinical treatment of OC in the near future 66 . In a recent study, it was discovered that paclitaxel sensitivity in epithelial ovarian cancer (EOC) xenografts may be considerably improved by ultrasound and microbubble (US‐MB)‐mediated codelivery of SIK2 siRNA and antisense‐microRNA21 encapsulated in a folate‐lipid‐poly (lactic‐ co ‐glycolic acid) (FaLPHNPs) hybrid polymer nanoparticle.…”

“…The GelNap-S + HG is expected to be used in the clinical treatment of OC in the near future. 66 In a recent study, it was discovered that paclitaxel sensitivity in epithelial ovarian cancer (EOC) xenografts may be considerably improved by ultrasound and microbubble (US-MB)-mediated codelivery of SIK2 siRNA and antisense-microRNA21 encapsulated in a folate-lipid-poly (lactic-co-glycolic acid) (FaLPHNPs) hybrid polymer nanoparticle. The findings of this study demonstrate for the first time the enormous potential of delivering both RNAs simultaneously to decrease EOC tumors.…”

New trends in diagnosing and treating ovarian cancer using nanotechnology

“…The clinical uses of SIK2 inhibitors are restricted due to the potential for significant off-target effects when administered directly. Hua et al (2022) described a targeted nano-hydrogel for SIK2 inhibitor local administration to effectively impede the metastasis of OC. The desing and application strategy of this SIK2-responsive supramolecular hydrogel system is illustrated in Figure 6 .…”

“…(A) Gel Nap-S + HG is formed and then disassembled to release HG via SIK2-mediated Nap-S phosphorylation to Nap-Sp, as shown schematically. (B) OC cells can be effectively induced to undergo apoptosis via inhibition of SIK2 downstream protein phosphorylation, which can be achieved through Gel Nap-S + HG local delivery for SIK2-responsive and sustained HG release ( Hua et al, 2022 ).…”

Sustained Release of Neuroprotective Drugs Curcumin and Edaravone from Supramolecular Hydrogel for Ischemic Stroke Treatment

“…In recent years, our group designed a series of supramolecular peptide hydrogels to treat tumors, myocardial infarction, ovarian aging and so on. [33][34][35] Currently, efforts have mainly focused on developing synthetic (or naturally derived) injectable polymer hydrogels for poststroke brain repair applications. [28] For example, injectable hyaluronan hydrogels represent one type of popular, naturally-derived local drug delivery platform.…”