Cationic Liposomes Induce Cell Necrosis Through Lysosomal Dysfunction and late-stage Autophagic Flux Inhibition

Abstract

Aim: The application of cationic liposomes (CLs) as nonviral vectors is hampered by their cellular toxicity. Thus we aim to investigate the mechanisms underlying the cellular toxicity of CLs. Materials & methods: The effect of CLs on the autophagic flux, autophagosome-lysosome fusion, lysosome membrane permeabilization and cell necrosis of liver cells was investigated. Results & conclusion: Our results reveal a novel mechanism of CL-induced cell necrosis involving the induction of lysosome membrane permeabilization and late-stage autophagic flux inhibition that resulted in cytoplasmic release of cathepsin B, mitochondrial dysfunction and reactive oxygen species production, which are the key mediators of cell necrosis. Our study is important for revealing the cellular toxicity of CLs and designing safer gene delivery systems.

Keywords:

• autophagic flux
• cationic liposomes
• cellular toxicity
• gene therapy
• lysosome membrane permeabilization
• necrosis

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Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at:www.tandfonline.com/doi/full/10.2217/epi-2016-0184

Additional information

Supporting Information Available: Additional tables and figures as described in the text. Characterization of cationic liposomes and the cytotoxic effect of CLs in the presence of N-acetyl cysteine (NAC) in Huh7 and PLC/PRF/5 cells.

Financial & competing interests disclosure

This work was supported by the National Natural Science Foundation of China (project number: 81472829), Shanghai Young Rising Star of Science (project number: 12QB1402400), 863 program projects (project number: 2012AA020809) and National Key Project for Infectious Diseases (2012ZX10002012009). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.