Xu Yajun, Lv Jianlin, Kong Chaoying, Liu Ya, Wang Kun, Tang Zhaohui, Chen Xuesi
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China.
School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei 230026, China.
Natl Sci Rev. 2024 Feb 5;11(4):nwae038. doi: 10.1093/nsr/nwae038. eCollection 2024 Apr.
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 mm 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.
替拉扎明（TPZ）因其出色的抗癌潜力已被批准用于多项临床试验。然而，作为一种典型的乏氧激活前药（HAP），由于患者肿瘤中乏氧水平不足，TPZ在联合治疗的III期临床试验中未表现出生存优势。在本研究中，为提高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衍生物均表现出增强的乏氧细胞毒性（提高了9.51 - 30.85倍），同时保持乏氧选择性。这些衍生物之一的TPZP，其细胞毒性比TPZ高20倍，同时保持相似的乏氧细胞毒性比率。为了将TPZP高效递送至肿瘤并降低其对健康组织的副作用，我们进一步将TPZP制备成具有纤维蛋白靶向能力的纳米药物：FT11 - TPZP - NPs。血管破坏剂CA4 - NPs用于提高肿瘤内纤维蛋白水平并加剧肿瘤乏氧。通过与CA4 - NPs联合，FT11 - TPZP - NPs可在乏氧加剧的肿瘤中蓄积并充分激活以杀死肿瘤细胞。单剂量治疗后，FT11 - TPZP - NPs + CA4 - NPs对初始体积约为480 mm的CT26肿瘤模型显示出98.1%的高抑制率，六分之四的肿瘤被完全消除；从而发挥了显著的抗肿瘤作用。本研究为提高TPZ及其他HAPs在抗癌治疗中的疗效提供了新策略。
