School of Pharmacy, Qingdao University, Qingdao 266021, China.
Department of Pharmacy, Zaozhuang Municipal Hospital, Zaozhuang 277102, China.
Molecules. 2022 Jun 30;27(13):4247. doi: 10.3390/molecules27134247.
Hypoxia-activated prodrugs (HAPs) with selective toxicity in tumor hypoxic microenvironments are a new strategy for tumor treatment with fewer side effects. Nonetheless, the deficiency of tumor tissue enrichment and tumor hypoxia greatly affect the therapeutic effect of HAPs. Herein, we design an active targeted drug delivery system driven by AS1411 aptamer to improve the tumor tissue enrichment of HAPs. The drug delivery system, called TPZ@Apt-MOF (TA-MOF), uses iron-based MOF as a carrier, surface-modified nucleolin aptamer AS1411, and the internal loaded hypoxia activation prodrug TPZ. Compared with naked MOF, the AS1411-modified MOF showed a better tumor targeting effect both in vitro and in vivo. MOF is driven by GSH to degrade within the tumor, producing Fe, and releasing the cargo. This process leads to a high consumption of the tumor protective agent GSH. Then, the Fenton reaction mediated by Fe not only consumes the intracellular oxygen but also increases the intracellular production of highly toxic superoxide anions. This enhances the toxicity and therapeutic effect of TPZ. This study provides a new therapeutic strategy for cancer treatment.
乏氧激活前药（HAPs）在肿瘤乏氧微环境中具有选择性毒性，是一种副作用较小的肿瘤治疗新策略。然而，肿瘤组织的富集和肿瘤乏氧的不足极大地影响了 HAPs 的治疗效果。在此，我们设计了一种基于 AS1411 适体的主动靶向药物传递系统，以提高 HAPs 的肿瘤组织富集。该药物传递系统称为 TPZ@Apt-MOF（TA-MOF），它使用基于铁的 MOF 作为载体，表面修饰核仁素适体 AS1411，并内部装载缺氧激活前药 TPZ。与裸 MOF 相比，AS1411 修饰的 MOF 在体外和体内均显示出更好的肿瘤靶向效果。MOF 在肿瘤内被 GSH 驱动降解，产生 Fe 并释放货物。这一过程导致肿瘤保护剂 GSH 的大量消耗。然后，Fe 介导的芬顿反应不仅消耗细胞内的氧气，还增加细胞内高毒性超氧阴离子的产生。这增强了 TPZ 的毒性和治疗效果。本研究为癌症治疗提供了一种新的治疗策略。
