PDF(Pubmed)
Abstract：
Tirapazamine (TPZ) has been approved for multiple clinical trials relying on its excellent anticancer potential. However, as a typical hypoxia-activated prodrug (HAP), TPZ did not exhibit survival advantages in Phase III clinical trials when used in combination therapy due to the insufficient hypoxia levels in patients\' 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 with TPZ, while maintaining hypoxic selectivity. TPZP, one of these derivatives, showed 20-fold higher cytotoxicity than TPZ while maintaining a similar hypoxic cytotoxicity ratio. To highly efficiently deliver TPZP to the tumors and reduce its side effects on 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 the fibrin level within tumors and exacerbate tumor hypoxia. By being combined with CA4-NPs, FT11-TPZP-NPs can accumulate 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 ∼480 mm3 and four out of six tumors were completely eliminated; it thereby exerted a significant antitumor effect. This study provides a new strategy for improving the therapeutic effect of TPZ and other HAPs in anticancer therapy.
摘要：
Tirapazamine（TPZ）凭借其出色的抗癌潜力已被批准用于多项临床试验。然而,作为典型的缺氧激活前药（HAP），由于肿瘤患者缺氧水平不足，TPZ在III期临床试验中用于联合治疗时没有表现出生存优势。在这项研究中,为了提高TPZ的治疗效果，我们首先引入尿素合成了一系列含尿素的TPZ衍生物。与TPZ相比，所有含尿素的TPZ衍生物均显示出增加的缺氧细胞毒性（9.51-30.85倍），同时保持低氧选择性。TPZP,这些衍生物之一，显示比TPZ高20倍的细胞毒性，同时保持相似的缺氧细胞毒性比率。为了高效地将TPZP递送至肿瘤并减少其对健康组织的副作用，我们进一步将TPZP制成具有纤维蛋白靶向能力的纳米药物：FT11-TPZP-NP。CA4-NP,血管破坏剂,用于增加肿瘤内的纤维蛋白水平并加剧肿瘤缺氧。通过与CA4-NP结合，FT11-TPZP-NP可以在缺氧加重的肿瘤中积累并充分激活以杀死肿瘤细胞。单剂量治疗后,FT11-TPZP-NPs+CA4-NPs对初始体积为480mm3的CT26肿瘤模型显示出98.1%的高抑制率，六个肿瘤中有四个被完全消除；从而发挥了显著的抗肿瘤作用。本研究为提高TPZ和其他HAPs在抗癌治疗中的疗效提供了新的策略。
