title: Insight on the fate of CNS-targeted nanoparticles. Part II: Intercellular neuronal cell-to-cell transport.
abstract: The application of polymeric nanoparticles (NPs) has a promising future for targeting and delivering drugs into the central nervous system (CNS). However, the fate of NPs once entered in the brain after crossing the blood-brain barrier (BBB) and taken up into neuronal cells is a neglected area of study. Thus, here, we investigate the possible mechanisms of a cell-to-cell transport of poly-lactide-co-glycolide (PLGA) NPs modified with a glycopeptide (g7-NPs), already demonstrated to be able to cross the BBB after in vivo administration in rodents. We also tested antibody (Ab) -modified g7-NPs both in vitro and in vivo to investigate the possibility of specific targeting. Our results show that g7-NPs can be transported intra- and inter-cellularly within vesicles after vesicular internalization. Moreover, cell-to-cell transport is mediated by tunneling-nanotube (TNT)-like structures in cell lines and most interestingly in glial as well as neuronal cells in vitro. The transport is dependent on F-actin and can be increased by induction of TNT-like structures overexpressing M-Sec, a central factor and inducer of TNT formation. Moreover, cell-to-cell transport occurs independently from NP surface modification with antibodies. These in vitro findings were in part confirmed by in vivo evidence after i.p. administration of NPs in mice.
authors.affiliation: Pharmaceutical Technology, Te. Far. T. I. group, Department of Pharmaceutical Sciences, University of Modena and Reggio Emilia, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tosi
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Italy.
authors.forename: Antonietta
authors.initials: A
authors.lastname: Vilella
authors.affiliation: WG Molecular Analysis of Synaptopathies, Neurology Dept., Neurocenter of Ulm University, Ulm, Germany.
authors.forename: Resham
authors.initials: R
authors.lastname: Chhabra
authors.affiliation: Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Schmeisser
authors.affiliation: Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany.
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Boeckers
authors.affiliation: Pharmaceutical Technology, Te. Far. T. I. group, Department of Pharmaceutical Sciences, University of Modena and Reggio Emilia, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Ruozi
authors.affiliation: Pharmaceutical Technology, Te. Far. T. I. group, Department of Pharmaceutical Sciences, University of Modena and Reggio Emilia, Italy.
authors.forename: Maria Angela
authors.initials: MA
authors.lastname: Vandelli
authors.affiliation: Pharmaceutical Technology, Te. Far. T. I. group, Department of Pharmaceutical Sciences, University of Modena and Reggio Emilia, Italy.
authors.forename: Flavio
authors.initials: F
authors.lastname: Forni
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Zoli
authors.affiliation: WG Molecular Analysis of Synaptopathies, Neurology Dept., Neurocenter of Ulm University, Ulm, Germany; Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany. Electronic address: andreas.grabrucker@uni-ulm.de.
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Grabrucker
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000008:administration & dosage / Q000737:chemistry; D001692:Biological Transport; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004622:Embryo, Mammalian; D006020:Glycopeptides / Q000008:administration & dosage* / Q000737:chemistry; D006624:Hippocampus / Q000166:cytology; D018960:Hyaluronan Receptors / Q000276:immunology; D019344:Lactic Acid / Q000008:administration & dosage* / Q000737:chemistry; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D019006:Neural Cell Adhesion Molecules / Q000276:immunology; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D011100:Polyglycolic Acid / Q000008:administration & dosage* / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000906:Antibodies; D006020:Glycopeptides; D018960:Hyaluronan Receptors; D019006:Neural Cell Adhesion Molecules; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid
keywords: M-Sec; Neuron; TNT; Tunneling nanotubes; g7-NPs