A hypoxia-activated and tumor microenvironment-remodeling nanoplatform for augmenting sonodynamic–chemodynamic-chemotherapy of breast cancer†

The tumor microenvironment (TME) offers a promising approach to enhancing cancer therapy by altering the conditions that support tumor growth and immune evasion. However, tumors are highly heterogeneous, and the TME can vary greatly even within different regions of the same tumor. Moreover, tumors can have evolving resistance mechanisms that limit the effectiveness of therapies. In this paper, we have designed a multifunctional nanoparticle named Lip-Ce6-MnO₂-TPZ, making sonodynamic therapy (SDT), chemodynamic therapy (CDT), and hypoxia-activated prodrugs work synergistically to maximize cancer treatment efficacy. The innovative Lip-Ce6-MnO₂-TPZ nanoparticle was constructed by loading Ce6, MnO₂, and hypoxia responsive drug tirapazamine (TPZ) together into a cytotoxic reactive oxygen species (ROS) responsive nanocarrier. Upon ultrasound (US) irradiation, ROS generated by Ce6 could not only induce cell apoptosis but also accelerate the disassembly of the nanoparticle for enhancing the release of TPZ and MnO₂. As a result, SDT consumed oxygen leading to the aggravation of the hypoxic condition in the tumor site for TPZ activation and DNA damage in tumor cells. Meanwhile, the MnO₂ was reduced to Mn²⁺ by GSH and caused antioxidant depletion. Mn²⁺ triggered CDT through a Fenton-like reaction by converting H₂O₂ to highly toxic •OH. Overall, the Lip-Ce6-MnO₂-TPZ platform could induce the generation of excess ROS combined with antioxidant depletion, resulting in oxidative stress and aberrant redox homeostasis of the TME. This strategy has brought forward the idea of inducing cancer cell death by synergistically working SDT, CDT, and hypoxia-activated prodrugs to maximize the therapeutic efficacy in cancer treatment.