Cancer-specific pro-oxidant therapy using low-toxic polypeptide micelles encapsulating piperlongumine

Pro-oxidant therapy utilizing pro-oxidant drugs that can induce cytotoxic oxidative stress in cancer cells has attracted widespread attention for cancer-specific therapy. Piperlongumine (PL) has gained great interest as a novel pro-oxidant agent because it can exhibit cancer-specific cytotoxicity via elevation of intracellular reactive oxygen species (ROS) in cancer cells. However, its therapeutic efficacy has been limited by its poor water-solubility, which necessitates developing suitable drug carriers for PL delivery. In this study, low-toxic poly(ethylene glycol)-poly(histidine) [PEG-poly(His)] copolymer was developed for effective intracellular delivery of PL. Stable micelles composed of a PEG shell and a poly(His) core encapsulating PL were prepared. In vitro study revealed that plain PEG-poly(His) micelles without PL were low-toxic. Importantly, PL-PEG-poly(His) micelles showed superior cytotoxicity in cancer cells over normal cells due to the PL-induced, dramatic increase of intracellular ROS in cancer cells in comparison with normal cells. PL-PEG-poly(His) micelles were further modified with folic acid (FA) to enhance their cancer-specific pro-oxidant therapy. As compared to FA-free micelles, FA-PL-PEG-poly(His) micelles revealed more facilitated cellular uptake and anticancer efficacy in folate receptor-positive cancer cells. This study demonstrates that PL-PEG-poly(His) micelles are efficient and low-toxic carriers for PL delivery, thus leading to effective and cancer-targeted pro-oxidant therapy.