Chelating drug-induced labile Zn²⁺ with nanoparticle-encapsulated TPEN at low dose enhances lung cancer chemotherapy through inhibiting ABCB1

Chemotherapy resistance is still a great challenge for clinical treatment of lung cancer. Here, we found that doxorubicin (DOX) induced an increase of labile Zn²⁺ in lung cancer cells, and these labile Zn²⁺ protected tumor cells against DOX cytotoxicity. Nanoparticles encapsulating N,N,N',N'-Tetrakis (2-pyridylmethyl)-ethylenediamine (TPEN) were then constructed to chelate labile Zn²⁺ for tumor therapy. Application of nanoparticle-encapsulated TPEN at low dose not only avoided severe side effects caused by removing physiological Zn²⁺ but also effectively chelated drug-induced labile Zn²⁺, and thereby enhanced DOX cytotoxicity. Mechanistically, nanosized TPEN inhibits ABCB1-mediated drug export potentiated by drug-induced labile Zn²⁺. Finally, the results unraveled that nanosized TPEN at low dose endowed DOX with the killing ability on resistant tumor cells. Taken together, our results demonstrate that chelating drug-induced labile Zn²⁺ by nanosized TPEN at low dose enhances lung cancer chemotherapy by inhibiting ABCB1, providing a feasible strategy to overcome chemoresistance in lung cancer.