In Vivo Distribution and Toxicity of PAMAM Dendrimers in the Central Nervous System Depend on Their Surface Chemistry

被引:133
作者
Albertazzi, Lorenzo [1 ,2 ]
Gherardini, Lisa [3 ,4 ]
Brondi, Marco [1 ,2 ]
Sato, Sebastian Sulis [1 ,2 ]
Bifone, Angelo [1 ]
Pizzorusso, Tommaso [3 ,6 ]
Ratto, Gian Michele [2 ,5 ]
Bardi, Giuseppe [1 ]
机构
[1] Ist Italiano Tecnol, Ctr Nanotechnol Innovat NEST, I-56127 Pisa, Italy
[2] Scuola Normale Super Pisa, Lab NEST, I-56127 Pisa, Italy
[3] Inst Neurosci CNR, I-56124 Pisa, Italy
[4] Inst Clin Physiol CNR, I-53100 Siena, Italy
[5] Inst Nanosci CNR, I-56127 Pisa, Italy
[6] Univ Florence, Dept Psychol, I-50125 Florence, Italy
关键词
dendrimers; neurotoxicity; nanomaterials; neurons; central nervous system; POLY(AMIDOAMINE) DENDRIMERS; POLYAMIDOAMINE DENDRIMERS; CELLS; THERAPY; BRAIN; BIOCOMPATIBILITY; DELIVERY; TRAFFICKING; CARRIERS; GROWTH;
D O I
10.1021/mp300391v
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Dendrimers have been described as one of the most tunable and therefore potentially applicable nanoparticles both for diagnostics and therapy. Recently, in order to realize drug delivery agents, most of the effort has been dedicated to the development of dendrimers that could internalize into the cells and target specific intracellular compartments in vitro and in vivo. Here, we describe cell internalization properties and diffusion of G4 and G4-C12 modified PAMAM dendrimers in primary neuronal cultures and in the CNS of live animals. Confocal imaging on primary neurons reveals that dendrimers are able to cross the cell membrane and reach intracellular localization following endocytosis. Moreover, functionalization of PAMAMs has a dramatic effect on their ability to diffuse in the CNS tissue in vivo and penetrate living neurons as shown by intraparenchymal or intraventricular injections. 100 nM G4-C12 PAMAM dendrimer already induces dramatic apoptotic cell death of neurons in vitro. On the contrary, G4 PAMAM does not induce apoptotic cell death of neural cells in the sub-micromolar range of concentration and induces low microglia activation in brain tissue after a week. Our detailed description of dendrimer distribution patterns in the CNS will facilitate the design of tailored nanomaterials in light of future clinical applications.
引用
收藏
页码:249 / 260
页数:12
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