Repurposing antihistamine to chemotherapy via a molecular delivery platform co-targeting mitochondria and endoplasmic reticulum

Drug distribution in cells depends on the partition nature determined by its chemical structure, which could influence drug concentration and efficacy. Conversely, precise delivery of a drug to the specific condensates in cells, such as organelles, means a distinct way to remodel the drug action. We here introduce an unprecedented molecular delivery platform with an accurate loading capacity of a drug, able to simultaneously target mitochondria (Mito) and endoplasmic reticulum (ER) while releasing the parent drug in situ. For our proof of concept, we used desloratadine (Des), a common anti-allergic drug, as the parent drug to develop a delivery platform (DDY) for chemotherapy. DDY can respond to the glutathione (GSH) levels, allowing for the selective release of Des in Mito and ER in cancer cells, which have higher GSH concentrations than normal cells. The release of Des in Mito and ER effectively and selectively induces tumor cells to ferroptosis while causing minimal toxicity to normal cells. DDY exhibits a satisfied chemotherapy efficacy in xenograft and metastasis cancer models, which should originate from the effects of Des in the two organelles. The result demonstrates the potential for developing chemotherapy from a currently approved drug with little anti-cancer activity through a precise distribution of it to organelles, significantly broadening the space of drug candidates for future chemotherapy.