Selective Thrombosis of Tumor for Enhanced Hypoxia‐Activated Prodrug Therapy

• Published in: Advanced materials (Weinheim) 2021-10, Vol.33 (41), p.e2104504-n/a
• Main Authors: Ma, Zhaoyu, Zhang, Yifan, Dai, Xinxin, Zhang, Weiyun, Foda, Mohamed F., Zhang, Jin, Zhao, Yanli, Han, Heyou
• Format: Article
• Language: English
• Subjects: Animals; Blood clots; cancer treatment; Cell Survival - drug effects; Coagulation; Hep G2 Cells; Humans; Hypoxia; Infarction; Materials science; Metal-organic frameworks; Metal-Organic Frameworks - chemistry; Mice; Mice, Nude; Nanoparticles; Nanoparticles - chemistry; Neoplasms - drug therapy; Neoplasms - pathology; Platelet Aggregation - drug effects; prodrug therapy; Prodrugs - chemistry; Prodrugs - pharmacology; Prodrugs - therapeutic use; Therapy; Thrombin; Thrombin - chemistry; Thrombosis; Thrombosis - pathology; Tirapazamine - chemistry; Transplantation, Heterologous; tumor hypoxia; Tumor Hypoxia - drug effects; Tumors
• ISSN: 0935-9648; 1521-4095
• DOI: 10.1002/adma.202104504

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, the performance of selective tumor thrombus inducing hypoxia activation therapy to improve the therapeutic index of coagulation‐based tumor therapy is presented. 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 platelet aggregation at the tumor to induce 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 HAP treatment. Since clinical operations such as surgery can be used to induce coagulation, coagulation‐based synergistic therapy is promising for translation into a clinical combination regimen. A multifunctional nanoplatform is developed by encapsulating coagulation‐inducing protease thrombin and a hypoxia‐activated prodrug tirapazamine into metal–organic framework nanoparticles with a tumor‐homing ligand, which can selectively activate platelet aggregation at a tumor to induce thrombosis and vascular obstruction therapy. Meanwhile, the thrombus can cut off the blood oxygen supply and potentiate the hypoxia level to enhance the prodrug therapy.