Vascular disrupting agent-induced amplification of tumor targeting and prodrug activation boosts anti-tumor efficacy

Vadimezan, one of the typical vascular disrupting agents (VDAs) currently in clinical trials, has been extensively implemented for cancer research, whereas its clinical efficacy is adversely affected by the inevitable side effects. Inspired by Vadimezan-induced intratumoral coagulation activation and hypoxia aggravation, we report a strategy by utilizing these biological effects to achieve targeted delivery and activation of hypoxia-activated prodrug (HAP) thus to maximize the therapeutic effect of Vadimezan. By encapsulating HAP tirapazamine into poly (lactic-co-glycolic acid) (PLGA) nanocarriers along with the modification of clot-binding peptide, the obtained nanoplatform could target tumors under the coagulation activation effect of Vadimezan Meanwhile, the aggravated hypoxia tumor microenvironment induced by Vadimezan can also boost hypoxia-activated chemotherapy. In the murine tumor model, this strategy showed 80.0% suppression of tumor growth, indicating its great potential in tumor treatment. This study offers an ingenious tactic for the combination of vascular disrupting therapy and hypoxia-activated chemotherapy, which may open up a window of the VDAs-based combination therapy.