A multifunctional cascade enzyme system for enhanced starvation/chemodynamic combination therapy against hypoxic tumors

Abstract

Starvation therapy has shown promise as a cancer treatment, but its efficacy is often limited when used alone. In this work, a multifunctional nanoscale cascade enzyme system, named CaCO₃@MnO₂-NH₂@GOx@PVP (CMGP), was fabricated for enhanced starvation/chemodynamic combination cancer therapy. CMGP is composed of CaCO₃ nanoparticles wrapped in a MnO₂ shell, with glucose oxidase (GOx) adsorbed and modified with polyvinylpyrrolidone (PVP). MnO₂ decomposes H₂O₂ in cancer cells into O₂, which enhances the efficiency of GOx-mediated starvation therapy. CaCO₃ can be decomposed in the acidic cancer cell environment, causing Ca²⁺ overload in cancer cells and inhibiting mitochondrial metabolism. This synergizes with GOx to achieve more efficient starvation therapy. Additionally, the H₂O₂ and gluconic acid produced during glucose consumption by GOx are utilized by MnO₂ with catalase-like activity to enhance O₂ production and Mn²⁺ release. This process accelerates glucose consumption, reactive oxygen species (ROS) generation, and CaCO₃ decomposition, promoting the Ca²⁺ release. CMGP can alleviate tumor hypoxia by cycling the enzymatic cascade reaction, which increases enzyme activity and combines with Ca²⁺ overload to achieve enhanced combined starvation/chemodynamic therapy. In vitro and in vivo studies demonstrate that CMGP has effective anticancer abilities and good biosafety. It represents a new strategy with great potential for combined cancer therapy.

Keywords: Ca(2+) overload; Chemodynamic therapy; Combined cancer therapy; Nanoenzymatic cascade system; Starvation therapy.