title: The role of autophagy in the neurotoxicity of cationic PAMAM dendrimers.
abstract: 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.
authors.affiliation: Department of Biosynthesis & Key Lab of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhang Heng Road, Shanghai 201203, PR China.
authors.forename: Shaofei
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Biosynthesis & Key Lab of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhang Heng Road, Shanghai 201203, PR China.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Biosynthesis & Key Lab of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhang Heng Road, Shanghai 201203, PR China.
authors.forename: Jiajun
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Biosynthesis & Key Lab of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhang Heng Road, Shanghai 201203, PR China.
authors.forename: Ziyu
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Biosynthesis & Key Lab of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhang Heng Road, Shanghai 201203, PR China.
authors.forename: Xian
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Department of Biosynthesis & Key Lab of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhang Heng Road, Shanghai 201203, PR China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Biosynthesis & Key Lab of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhang Heng Road, Shanghai 201203, PR China.
authors.forename: Ping
authors.initials: P
authors.lastname: Song
authors.affiliation: Department of Biosynthesis & Key Lab of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhang Heng Road, Shanghai 201203, PR China. Electronic address: dianwenju@fudan.edu.cn.
authors.forename: Dianwen
authors.initials: D
authors.lastname: Ju
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D002412:Cations / Q000633:toxicity*; D045744:Cell Line, Tumor; D050091:Dendrimers / Q000633:toxicity*; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D002412:Cations; D050091:Dendrimers; C104700:PAMAM Starburst; D017382:Reactive Oxygen Species; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: Autophagy; Cell death; Neurotoxicity; PAMAM dendrimers