A red-light activatable and mitochondrion-targeting PtIV complex to overcome drug resistance

Abstract

The therapeutic effects of platinum anticancer drugs are commonly whittled away by drug resistance, which is associated with drug efflux and the nucleotide excision repair (NER) pathway. Activation of drugs in a spatiotemporally controllable manner in the mitochondria of cancer cells is a very promising strategy to alleviate these problems. In this work, Pt^IV-PS₂, a cisplatin-based Pt^IV prodrug, was designed to release cisplatin inside the mitochondria on red light exposure. This Pt^IV complex could be effectively reduced to Pt^II species under irradiation. Pt^IV-PS₂ very effectively accumulates in the mitochondria of cancer cells through active transport. After photoactivation, Pt^IV-PS₂ showed higher cytotoxicity than cisplatin in the cisplatin-resistant carcinoma cells and the amount of Pt in genomic DNA was elevated. Moreover, Pt^IV-PS₂ decreased the cellular mitochondrial membrane potential (MMP) and the cellular content of ATP. This work developed a promising window for the design of controllably activated and mitochondrion-targeting Pt^IV prodrugs to overcome drug resistance of chemotherapy.