The role of autophagy in the neurotoxicity of cationic PAMAM dendrimers

Poly(amidoamine) (PAMAM) dendrimers, are among the most common classes of dendrimers that are intended for a wide range of biomedical applications and extensively investigated for brain-specific drug delivery, imaging and diagnosis. Unfortunately, neurotoxicity of PAMAM dendrimers, the underlying mechanism of which is poorly-elucidated, poses a far-reaching challenge to their practical applications. In this study, we reported that PAMAM dendrimers induced both cytotoxicity and autophagic flux in a panel of human glioma cell lines. Meanwhile, inhibition of autophagy significantly reversed cell death caused by PAMAM dendrimers, indicating the cytotoxic role of autophagy in neurotoxicity caused by PAMAM dendrimers. Akt/mTOR pathway was most likely to participate in initiation of PAMAM dendrimers-induced autophagy. Moreover, autophagy induced by PAMAM dendrimers might be partially mediated by intracellular ROS generation. Collectively, these data elucidated the critical role of autophagy in neurotoxicity associated with exposure to cationic PAMAM dendrimers in vitro, raising concerns about possible neurotoxic reaction caused by future clinical applications of PAMAM dendrimers and providing potential strategies to ameliorate toxic effects of PAMAM dendrimers.