Introducing urea into tirapazamine derivatives to enhance anticancer therapy

Abstract

Tirapazamine (TPZ) has been approved for multiple clinical trials relying on its excellent anti-cancer potential. However, as a typical hypoxia-activated prodrugs (HAPs), TPZ did not exhibit survival advantages in phase III clinical trials when used in a combination therapy due to the insufficient hypoxia levels in patient's tumors. In this study, to improve the therapeutic effects of TPZ, we first introduced urea to synthesize a series of urea-containing derivatives of TPZ. All urea-containing TPZ derivatives showed increased hypoxic cytotoxicity (9.51∼30.85-fold) compared to TPZ, while maintaining hypoxic selectivity. TPZP, one of these derivatives, showed 20-fold higher cytotoxicity than TPZ while maintaining similar hypoxic cytotoxicity ratio (HCR). To highly efficient deliver TPZP to the tumors and reduce its side effects to healthy tissues, we further prepared TPZP into a nanodrug with fibrin-targeting ability, FT11-TPZP-NPs. CA4-NPs, a vascular disrupting agent, was used to increase fibrin level within tumors and exacerbate tumor hypoxia. By combining with CA4-NPs, FT11-TPZP-NPs can enrich abundantly in the hypoxia-aggravated tumors and activate sufficiently to kill tumor cells. After a single-dose treatment, FT11-TPZP-NPs + CA4-NPs showed a high inhibition rate of 98.1% against CT26 tumor models with an initial volume of approximately 480 mm3, and 4/6 tumors were completely eliminated, exerted a significant antitumor effect. This study provides a new strategy for improving the therapeutic effect of TPZ and other HAPs in anti-cancer therapy.