Sulfonated vitamin K3 mediated bimetallic metal-organic framework for multistage augmented cancer therapy

Chemodynamic therapy (CDT) relying on Fenton reaction has emerged as a promising strategy for tumor treatment. However, its clinical efficacy is hindered by the inadequate reactive oxygen species (ROS) and the potential cytotoxicity towards normal cells. To address these challenges, we have successfully developed a multistage augmented cancer therapy system based on bimetallic metal-organic framework (BMOF) that amplifies ROS and facilitates tumor-specific therapeutic effects. By employing a simple one-pot self-assembly approach, we synthesized SVK3@ZnCo-ZIF in which sulfonated vitamin K3 (SVK3) was encapsulated within ZnCo-ZIF BMOF. The results revealed that the incorporation of Zn atoms significantly diluted the Fenton activity of Co atoms towards normal cells. Notably, SVK3@ZnCo-ZIF underwent pH-controlled decomposition triggered by the tumor microenvironment (TME), thus releasing SVK3, Co²⁺ and Zn²⁺. Specifically, the H₂O₂ levels in tumors was effectively elevated by the interaction of SVK3 with NAD(P)H quinone oxidoreductase-1 (NQO-1). It thus enhanced the Fenton activity of Co²⁺. Moreover, the release of Zn²⁺ ions can induce cellular dysfunction and mitochondrial damage, thereby promoting the generation of ROS and subsequent cell death. The synergistic combination of CDT, SVK3 chemotherapy, and Zn²⁺-interfered therapy greatly facilitated apoptosis of tumor cells. Collectively, our investigations demonstrate the efficacy of such system in selectively inducing toxicity in cancer cells while minimizing detrimental effects on normal cells.