Improving the Therapeutic Efficiency of Hypoxic-Activated Prodrugs by Enhancing Hypoxia in Solid Tumors

作者：Zhao, Gaoqian; Jin, Yan; Gao, Shutao; Xiao, Tingshan; Fan, Miao; Liu, Dandan; Zhang, Jinchao; Li, Zhenhua; Zhou, Xiaohan^*; Liu, Huifang^*

来源：ACS Biomaterials Science & Engineering, 2022, 8(4): 1604-1612.

DOI：10.1021/acsbiomaterials.2c00104

• hypoxic-activated prodrugs
• glucose oxidase
• tirapazamine
• mesoporous silica
• hypoxic region

The low sensitivity of hypoxic regions in solid tumors toradiotherapy and chemotherapy remains a major obstacle to cancertreatment. By taking advantage of hypoxic-activated prodrugs, tirapazamine(TPZ), generating cytotoxic reductive products and the glucose oxidase(GOx)-based glucose oxidation reaction, we designed a nanodrug-loadingsystem that combined TPZ-induced chemotherapy with GOx-mediatedcancer-orchestrated starvation therapy and cancer oxidation therapy. Inthis work, wefirst prepared mesoporous silica (MSN) loaded with TPZ.Then, in order to prevent the leakage of TPZ in advance, the surface wascoated with a layer of carMOF formed by Fe3+and carbenicillin (car), andGOxwas adsorbed on the outermost layer to form thefinal nanosystemMSN-TPZ@carMOF-GOx(MT@c-G). GOxcould effectively consumeoxygen and catalyzed glucose into gluconic acid and hydrogen peroxide.First, the generated gluconic acid lowered the pH of tumor tissues, promoted the decomposition of carMOF, and released TPZ.Second, oxygen consumption could improve the degree of hypoxia in tumor tissues, so that enhanced the activity of TPZ.Furthermore, GOxcould generate cancer-orchestrated starvation/oxidation therapy. Therefore, our study provided a new strategythat TPZ combined with GOxachieved starvation/oxidation/chemotherapy for enhancing anticancer effects in hypoxic regions

• 单位
  南方医科大学