Hypoxia-amplifying polymer nanoprodrugs by in-situ thrombogenesis for sonodynamic-chemotherapy of breast cancer and bone metastasis

Abstract

Reactive oxygen species (ROS)-producing treatment methods such as sonodynamic therapy (SDT) usually exhibit limited efficacy for solid tumors because of the hypoxic tumor microenvironment. To address this challenge, we report a hypoxia-amplifying polymer nanoprodrug (DPTT) for breast cancer and bone metastasis therapy via in-situ thrombogenesis to improve chemotherapy effect. Such nanoprodrugs (DPTT) are fabricated via co-loading a sonodynamic semiconducting polymer (SP) and a hypoxia-activated prodrug tirapazamine (TPZ) into a ROS-responsive nanomicelle with surface embellishing of thrombin. After enrichment at the tumor sites, DPTT can produce ROS under the ultrasound exposure by sonodynamic effect of SP for SDT, triggering ROS-responsive structural disintegration and subsequent controlled release of both thrombin and TPZ. The liberated thrombin induces fibrin formation and in-situ thrombogenesis in tumor tissues, disrupting vascular functions and oxygen supply to further intensify tumor hypoxia. As a consequence, TPZ prodrugs are activated in aggravated hypoxic regions to enable enhanced chemotherapeutic effect. Remarkably, this therapeutic approach is demonstrated to achieve near-complete eradication of subcutaneous 4T1 breast tumors and also substantial inhibition of bone metastasis progression in murine models. Our work presents a novel vascular disruption strategy for hypoxia potentiation, offering a promising therapeutic paradigm for treating hypoxic solid and metastatic tumors.