Aptamer-Functionalized Iron-Based Metal-Organic Frameworks (MOFs) for Synergistic Cascade Cancer Chemotherapy and Chemodynamic Therapy.

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.