title: Unraveling the effects of siRNA carrier systems on cell physiology: a multiparametric approach demonstrated on dextran nanogels.
abstract: OBJECTIVE
  The extent of cell-nanoparticle interactions between a polycationic siRNA nanocarrier system (dextran nanogels) and cultured cells was analyzed.
  
  
  METHODS
  A multiparametric methodology is introduced to examine the cytotoxic effects of a model siRNA carrier (dextran nanogels) on different cell types, including primary human cells. Using this methodology, the nontoxic concentration of nanogels could be defined and the mechanisms contributing to their toxic profile were unraveled.
  
  
  RESULTS
  Above the toxicity threshold, nanogels were found to induce oxidative stress and destabilize the plasma membrane. Furthermore, nanogel-induced cellular stress led to DNA damage, impeded cell functionality and intracellular signaling, resulting in unspecific regulation of gene expression.
  
  
  CONCLUSIONS
  This methodology shows that current toxicity assays such as the 3-(4,5-dimethylthiazol-2yl-)-2,5-diphenyl tetrazolium bromide assay are not adequate to assess the full spectrum of cell-nanoparticle interactions and more in-depth studies are required.
authors.affiliation: Laboratory of General Biochemistry & Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Harelbekestraat 72, B-9000 Ghent, Belgium.
authors.forename: Stefaan J
authors.initials: SJ
authors.lastname: Soenen
authors.forename: Lynn
authors.initials: L
authors.lastname: De Backer
authors.forename: Bella
authors.initials: B
authors.lastname: Manshian
authors.forename: Shareen
authors.initials: S
authors.lastname: Doak
authors.forename: Koen
authors.initials: K
authors.lastname: Raemdonck
authors.forename: Jo
authors.initials: J
authors.lastname: Demeester
authors.forename: Kevin
authors.initials: K
authors.lastname: Braeckmans
authors.forename: Stefaan
authors.initials: S
authors.lastname: De Smedt
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D003911:Dextrans / Q000008:administration & dosage* / Q000737:chemistry; D004337:Drug Carriers; D005786:Gene Expression Regulation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D000080385:Nanogels; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry; D011094:Polyethyleneimine / Q000008:administration & dosage* / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D051381:Rats
chemical_list: D003911:Dextrans; D004337:Drug Carriers; D000080385:Nanogels; D034741:RNA, Small Interfering; C413692:polyethylene glycol polyethyleneimine nanogel; D011092:Polyethylene Glycols; D011094:Polyethyleneimine