A red-light activatable and mitochondrion-targeting Pt IV complex to overcome drug resistance.

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, PtIV-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. PtIV-PS2 very effectively accumulates in the mitochondria of cancer cells through active transport. After photoactivation, PtIV-PS2 showed higher cytotoxicity than cisplatin in the cisplatin-resistant carcinoma cells and the amount of Pt in genomic DNA was elevated. Moreover, PtIV-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.