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.