title: In vivo distribution and toxicity of PAMAM dendrimers in the central nervous system depend on their surface chemistry.
abstract: 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.
authors.affiliation: Center for Nanotechnology Innovation @NEST, Istituto Italiano di Tecnologia, Piazza San Silvestro 12, 56127 Pisa, Italy. L.Albertazzi@tue.nl
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Albertazzi
authors.forename: Lisa
authors.initials: L
authors.lastname: Gherardini
authors.forename: Marco
authors.initials: M
authors.lastname: Brondi
authors.forename: Sebastian
authors.initials: S
authors.lastname: Sulis Sato
authors.forename: Angelo
authors.initials: A
authors.lastname: Bifone
authors.forename: Tommaso
authors.initials: T
authors.lastname: Pizzorusso
authors.forename: Gian Michele
authors.initials: GM
authors.lastname: Ratto
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bardi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D050091:Dendrimers / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000633:toxicity; D004058:Diffusion; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009757:Nylons / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000633:toxicity; D014793:Visual Cortex / Q000187:drug effects / Q000378:metabolism
chemical_list: D050091:Dendrimers; D009757:Nylons; C104700:PAMAM Starburst; C520550:PAMAM-G4; D002118:Calcium