College of Pharmaceutical Science, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, Baoding 071002, China.
Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Chemical Biology Key Laboratory of Hebei Province, Institute of Life Science and Green Development, Hebei University, Baoding 071002, China.
ACS Biomater Sci Eng. 2022 Apr 11;8(4):1604-1612. doi: 10.1021/acsbiomaterials.2c00104. Epub 2022 Mar 29.
The low sensitivity of hypoxic regions in solid tumors to radiotherapy and chemotherapy remains a major obstacle to cancer treatment. By taking advantage of hypoxic-activated prodrugs, tirapazamine (TPZ), generating cytotoxic reductive products and the glucose oxidase (GO)-based glucose oxidation reaction, we designed a nanodrug-loading system that combined TPZ-induced chemotherapy with GO-mediated cancer-orchestrated starvation therapy and cancer oxidation therapy. In this work, we first prepared mesoporous silica (MSN) loaded with TPZ. Then, in order to prevent the leakage of TPZ in advance, the surface was coated with a layer of carMOF formed by Fe and carbenicillin (car), and GO was adsorbed on the outermost layer to form the final nanosystem MSN-TPZ@carMOF-GO (MT@c-G). GO could effectively consume oxygen 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, GO could generate cancer-orchestrated starvation/oxidation therapy. Therefore, our study provided a new strategy that TPZ combined with GO achieved starvation/oxidation/chemotherapy for enhancing anticancer effects in hypoxic regions.
实体瘤缺氧区域对放疗和化疗的低敏感性仍然是癌症治疗的主要障碍。利用缺氧激活前药替拉扎胺（TPZ），生成细胞毒性还原产物和葡萄糖氧化酶（GO）介导的葡萄糖氧化反应，我们设计了一种纳米药物负载系统，将 TPZ 诱导的化疗与 GO 介导的肿瘤协调饥饿治疗和肿瘤氧化治疗相结合。在这项工作中，我们首先制备了负载 TPZ 的介孔硅（MSN）。然后，为了预先防止 TPZ 的泄漏，表面涂有一层由 Fe 和羧苄青霉素（car）形成的 carMOF，GO 吸附在最外层形成最终的纳米系统 MSN-TPZ@carMOF-GO（MT@c-G）。GO 可以有效地消耗氧气并将葡萄糖催化成葡萄糖酸和过氧化氢。首先，生成的葡萄糖酸降低了肿瘤组织的 pH 值，促进了 carMOF 的分解，并释放了 TPZ。其次，氧气消耗可以提高肿瘤组织的缺氧程度，从而增强 TPZ 的活性。此外，GO 可以产生肿瘤协调的饥饿/氧化治疗。因此，我们的研究提供了一种新策略，即 TPZ 与 GO 联合实现了缺氧区域的饥饿/氧化/化疗，以增强抗癌效果。
