Inhibition of autophagy protects against PAMAM dendrimers-induced hepatotoxicity

Abstract

Toxicity of nanomaterials is one of the biggest challenges in their medicinal applications. Although toxicities of nanomaterials have been widely reported, the exact mechanisms of toxicities are still not well elucidated. Consequently, the exploration of approaches to attenuate toxicities of nanomaterials is limited. In this study, we reported that poly-amidoamine (PAMAM) dendrimers, a widely used nanomaterial in the pharmaceutical industry, caused toxicity of human liver cells by inducing cell growth inhibition, mitochondria damage, and apoptosis. Meanwhile, autophagy was activated in PAMAM dendrimers-induced toxicity and inhibition of autophagy-rescued viability of hepatic cells, indicating that autophagy played a key role in PAMAM dendriemrs-induced hepatotoxicity. To further explore approaches to attenuate PAMAM dendrimers-induced liver injury, effects of autophagic inhibitors on PAMAM dendrimers’ hepatotoxicity were investigated in an in vivo model. Autophagy blockage in PAMAM dendrimers-administered mice led to weight restoration, damage reversion of liver tissue, and protection against changes of serum biochemistry parameters. Moreover, inhibition of Akt/mTOR and activation of Erk1/2 signaling pathways were involved in PAMAM dendrimers-induced autophagy. Collectively, these findings indicated that autophagy was associated with PAMAM dendrimers-induced hepatotoxicity, and supported the possibility that autophagy inhibitors could be used to reduce hepatotoxicity of PAMAM dendrimers.

• Autophagosomes
• cytotoxicity
• liver injury
• nanomaterials

Acknowledgements

The authors would like to acknowledge Professor Chen Jiang and Rongqin Huang for their technical supports.

Declaration of interest

The authors declare that they have no conflict of interest. This work is supported by grants from Shanghai Science and Technology Funds (11431920104), the National Key Basic Research Program of China (2013CB932502) and The Open Project Program of Key Lab of Smart Drug Delivery (Fudan University), Ministry of Education, China (SDD2013-02).

Author contributions: Y. L. and D. J. designed the experiments. Y. L., X. Z., S. W., Y. S., Z. W., P. S., and J. F. performed and analyzed experiments. Y. L., X. Z., and S. W. wrote the manuscript. D. J. conceived and supervised the study. All authors edited or commented on the manuscript.

Supplementary material available online Supplementary Figures 1–5.