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Theranostics ; 11(14): 7072-7091, 2021.
Article in English | MEDLINE | ID: mdl-34093872

ABSTRACT

Simultaneous targeting of both the tumor microenvironment and cancer cells by a single nanomedicine has not been reported to date. Here, we report the dual properties of zero-valent-iron nanoparticle (ZVI-NP) to induce cancer-specific cytotoxicity and anti-cancer immunity. Methods: Cancer-specific cytotoxicity induced by ZVI-NP was determined by MTT assay. Mitochondria functional assay, immunofluorescence staining, Western blot, RT-qPCR, and ChIP-qPCR assays were used to dissect the mechanism underlying ZVI-NP-induced ferroptotic cancer cell death. The therapeutic potential of ZVI-NP was evaluated in immunocompetent mice and humanized mice. Immune cell profiles of allografts and ex vivo cultured immune cells were examined by flow cytometry analysis, RT-qPCR assay, and immunofluorescence. Results: ZVI-NP caused mitochondria dysfunction, intracellular oxidative stress, and lipid peroxidation, leading to ferroptotic death of lung cancer cells. Degradation of NRF2 by GSK3/ß-TrCP through AMPK/mTOR activation was enhanced in such cancer-specific ferroptosis. In addition, ZVI-NP attenuated self-renewal ability of cancer and downregulated angiogenesis-related genes. Importantly, ZVI-NP augmented anti-tumor immunity by shifting pro-tumor M2 macrophages to anti-tumor M1, decreasing the population of regulatory T cells, downregulating PD-1 and CTLA4 in CD8+ T cells to potentiate their cytolytic activity against cancer cells, while attenuating PD-L1 expression in cancer cells in vitro and in tumor-bearing immunocompetent mice. In particular, ZVI-NPs preferentially accumulated in tumor and lung tissues, leading to prominent suppression of tumor growth and metastasis. Conclusions: This dual-functional nanomedicine established an effective strategy to synergistically induce ferroptotic cancer cell death and reprogram the immunosuppressive microenvironment, which highlights the potential of ZVI-NP as an advanced integrated anti-cancer strategy.


Subject(s)
Ferroptosis/drug effects , Iron/pharmacology , Lung Neoplasms/immunology , Lung Neoplasms/metabolism , Macrophages/drug effects , Metal Nanoparticles/chemistry , NF-E2-Related Factor 2/metabolism , Tumor Microenvironment/drug effects , AMP-Activated Protein Kinase Kinases , Allografts , Animals , Antineoplastic Agents/pharmacology , CD8-Positive T-Lymphocytes/immunology , Cell Line, Tumor , Cell Movement/drug effects , Cell Movement/immunology , Cell Survival/drug effects , Cell Survival/immunology , Chromatin Immunoprecipitation , Glycogen Synthase Kinase 3/metabolism , Humans , Iron/chemistry , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Macrophages/metabolism , Metal Nanoparticles/administration & dosage , Metal Nanoparticles/ultrastructure , Mice , Mice, Inbred BALB C , Mice, Nude , Mice, SCID , Microscopy, Electron, Transmission , Mitochondria/drug effects , Mitochondria/pathology , Mitochondria/ultrastructure , NF-E2-Related Factor 2/genetics , Oxidative Stress/drug effects , Protein Kinases , TOR Serine-Threonine Kinases/metabolism , Tumor Microenvironment/immunology
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