Repurposing antihistamine to chemotherapy via a molecular delivery platform co-targeting mitochondria and endoplasmic reticulum
Intracellular drug partitioning dictated by chemical structure constrains therapeutic efficacy. Covalent organelle-targeting conjugates have enabled mitochondria (Mito) or endoplasmic reticulum (ER) delivery, yet simultaneous co-targeting with controlled parent-drug release remains unaddressed. We report a molecular delivery platform (DDY) that loads desloratadine (Des), an antihistamine with negligible anticancer activity, and responds to glutathione (GSH) to release Des selectively within Mito and ER of cancer cells. DDY exploits the elevated GSH in tumor cells to trigger ferroptosis while sparing normal breast cells. In 4T1 orthotopic breast tumor-bearing mice, DDY reduced pulmonary metastatic nodules to 2.4 versus 21 in controls and 6.6 for free Des, and suppressed distal liver metastasis. Immunohistochemistry revealed decreased SLC7A11 and GPX4, confirming ferroptosis involvement. DDY also inhibited tumor angiogenesis and induced Mito dysfunction. Body weights remained stable, indicating manageable metabolic toxicity. The platform converts an approved antihistamine into an effective chemotherapeutic via organelle-level redistribution, broadening the chemical space for drug repurposing.