A novel hypoxia-activated polymeric Tirapazamine derivative for enhanced antitumor therapy

Tirapazamine (TPZ, 3-amino-1,2,4-benzotriazine 1,4-dioxide), a representative hypoxia-activated prodrugs (HAPs), has entered Phase II/III clinical trials. Despite a promising phase II clinical trial results, TPZ does not bring benefits to cancer therapy in most phase III clinical trials, which making the clinical trials failed. To improve its therapeutic effects, in this study, we synthesize a novel TPZ derivative, 3-(3-(5-hydroxypentyl)ureido)benzo[e][1,2,4]triazine 1,4-dioxide (TPZH), and covalently conjugated it to poly (L-glutamic acid) (PLG) to obtain TPZH nanoparticles (TPZH-NPs). The TPZH-NPs shows prolonged blood circulation, enhanced tumor accumulation, and increased maximum tolerated dose (MTD) than TPZH. In addition, TPZH-NPs exhibits significantly enhanced antitumor therapeutic efficiency than free TPZH against 4T1 breast tumors.