Aurora Kinase B-Instruct Release of AZD1152-HQPA from Hydrogel to Enhance Cervical Cancer Suppression

Aurora kinase B (AURKB) is an attractive and potential molecular target for cervical cancer therapy. To date, a variety of AURKB inhibitors are developed to suppress cervical tumors. Nevertheless, direct use of these small molecule inhibitors may cause severe side effects to patients, limiting their further clinical applications. Herein, a rationally designed hydrogelator Nap-Phe-Phe-Arg-Arg-Lys-Ser-OH (S) is employed to co-assemble AZD1152-HQPA (AZD, an AURKB inhibitor) to develop an AURKB-responsive hydrogel Gel S/AZD for enhanced cervical tumor suppression. Upon AURKB activation, hydrogelator S in Gel S/AZD evolves into its hydrophilic phosphate Nap-Phe-Phe-Arg-Arg-Lys-Ser(H2PO3)-OH (Sp), triggering the disassembly of Gel S/AZD to release AZD in a sustained manner. Cell assays reveal that AURKB-responsive release of AZD from Gel S/AZD potently induces the growth arrest and apoptosis of cervical cancer cells by downregulating the expression level of AURKB downstream protein phospho-histone H3 (pH3). In vivo studies demonstrate that compared with free AZD, Gel S/AZD shows a superior tumor suppressive effect in orthotropic cervical tumor models. It is envisioned that the Gel S/AZD might be applied in clinic cervical cancer treatment in the near future. Upon phosphorylation by Aurora Kinase B (AURKB) overexpressed in cervical tumor sites, hydrogelators in the AZD1152-coassembled hydrogel efficiently evolve into their hydrophilic phosphates, resulting in hydrogel dissassembly and the controlled release of AZD1152. The released AZD1152 in turn down-regulates AURKB activity and consequently inhibits histone H3 phosphorylation to induce growth arrest and apoptosis of the tumor cells.image