Bimetallic nanoplatform for synergistic sonodynamic-calcium overload therapy utilizing self-supplied hydrogen peroxide and relieved hypoxia

Abstract

Sonodynamic therapy (SDT) has emerged as a potential alternative to traditional cancer treatments as it offers deep cellular penetration and reduced invasivity. Sonosensitizers generate reactive oxygen species (ROS) under ultrasound activation, focusing the ultrasound energy on malignant sites located deep in tissues and causing cell apoptosis and necrosis. However, due to tumor hypoxia and the limited levels of intracellular endogenous hydrogen peroxide (H₂O₂ is a fundamental species for supplying oxygen via catalase activity), SDT efficacy is still insufficient. In this study, a bimetallic and multifunctional system (Fe₃O₄-TAPP@PVP-CaO₂) was prepared by using ferrosoferric oxide (Fe₃O₄) as a carrier loaded with 5,10,15,20-tetrakis(4-aminophenyl), porphyrin (TAPP), that was then coated with polyvinyl pyrrolidone (PVP) and calcium peroxide (CaO₂). The CaO₂ layer elevated the levels of H₂O₂ and Ca²⁺ in the tumor microenvironment when exposed to intracellular acidity, providing essential elements for oxygen generation. Intracellular hypoxia was alleviated via the catalase-like activity of Fe₃O₄ inducing calcium overload. Under ultrasonic irradiation, SDT generated toxic reactive oxygen species (ROS, singlet oxygen) and activated calcium influx through acoustic cavitation. Meanwhile, calcium overload therapy efficiently induced cell apoptosis at the moment of uncontrollable cellular accumulation of Ca²⁺. In addition, we modified the PVP on the surface to make it more stable. This study presents a bimetallic nanoplatform that can efficiently induce cancer cell death by synergistic sonodynamic-calcium overload therapy via modulation of O₂/ROS/Ca²⁺ species, indicating its potential for multi-modality cancer therapy.