Selective thrombosis of tumor for enhanced hypoxia-activated prodrug therapy

Abstract

One of the main challenges for tumor vascular infarction in combating cancer lies in failing to produce sustained complete thrombosis. Inspired by the capability of vascular infarction in blocking the delivery of oxygen to aggravate tumor hypoxia, we herein present the performance of selective tumor thrombus inducing hypoxia activation therapy to improve the therapeutic index of coagulation-based tumor therapy. By encapsulating coagulation-inducing protease thrombin and a hypoxia-activated prodrug (HAP) tirapazamine into metal-organic framework nanoparticles with a tumor-homing ligand, the obtained nanoplatform selectively activates the platelet aggregation at tumor to induce the thrombosis and vascular obstruction therapy by the exposed thrombin. Meanwhile, the thrombus can cut off the blood oxygen supply and potentiate the hypoxia levels to enhance the HAP therapy. This strategy not only addresses the dissatisfaction of vascular therapy, but also conquers the dilemma of inadequate hypoxia in the HAP treatment. Since clinical operations such as surgery can be used to induce the coagulation, the coagulation based synergistic therapy is promising to be translated into a clinical combination regimen.