A chemotherapy based on dual-targeted release of ciprofloxacin in mitochondrial and endoplasmic reticulum

Organelle-targeting drugs represent the next generation of precision chemotherapy. To achieve this, a specific organelle-targeting group is essential for various nano-medicines and prodrugs. Simultaneously targeting multiple organelles enhances drug efficacy by enabling lower dosage, minimizing side effects, and potentially altering the action mechanism of drugs through synchronous effects across organelles. However, designing a molecular platform capable of delivering drugs to multiple organelles remains challenging, which hinders the advancement of precise chemotherapy. Here, we conjugated a pyronine unit as a warhead to an antibiotic (ciprofloxacin, Cip) via a covalent linkage, developing a molecular platform termed CPY. This platform simultaneously targets mitochondria (Mito) and the endoplasmic reticulum (ER), releasing Cip in situ through a glutathione-mediated S_NAr pathway. CPY induced apoptosis in tumor cells and exhibited anti-tumor activity in a xenograft tumor model. These results demonstrate a feasible strategy for repurposing conventional non-antitumor drugs into chemotherapeutic agents.