title: Structural dependence of in vitro cytotoxicity, oxidative stress and uptake mechanisms of poly(propylene imine) dendritic nanoparticles.
abstract: The in vitro cytotoxic and intracellular oxidative stress responses to exposure to poly(propylene imine) (PPI) dendritic nanoparticles of increasing generation (number of repeated branching cycles) (G0-G4) were assessed in an immortal non-cancerous human keratinocyte cell line (HaCaT). Confocal fluorescence microscopy with organelle staining was used to explore the uptake and intracellular trafficking mechanisms. A generation- and dose-dependent cytotoxic response was observed, increasing according to generation and, therefore, number of surface amino groups. A comparison of the cytotoxic response of G4 PPI and the related G4 poly(amido amine) dendrimer indicates that the PPI with the same number of surface amino groups elicits a significantly higher cytotoxic response. The trend of cytotoxicity versus dendrimer generation and, therefore, size is discontinuous in the region of G2, however, indicating a difference in uptake mechanism for higher compared to lower generations. Whereas the higher generations elicit an oxidative stress response at short exposure times, the lower generations indicate an antioxidant response. Confocal microscopy indicates that, whereas they are prominent at early exposure times for the larger PPI dendrimers, no evidence of early stage endosomes was observed for lower generations of PPI. The results are consistent with an alternative uptake mechanism of physical diffusion across the semipermeable cell membrane for the lower generation dendrimers and are discussed in terms of their implications for predictive models for nanotoxicology and design strategies for nanomedical applications.
authors.affiliation: FOCAS Research Institute, Dublin Institute of Technology, Kevin Street, Dublin 8, Ireland.|School of Physics, Dublin Institute of Technology, Kevin Street, Dublin 8, Ireland.
authors.forename: Humza
authors.initials: H
authors.lastname: Khalid
authors.affiliation: Institute of Environmental Medicine (IMM), Karolinska Institute, Stockholm, Sweden.
authors.forename: Sourav Prasanna
authors.initials: SP
authors.lastname: Mukherjee
authors.affiliation: FOCAS Research Institute, Dublin Institute of Technology, Kevin Street, Dublin 8, Ireland.
authors.forename: Luke
authors.initials: L
authors.lastname: O'Neill
authors.affiliation: FOCAS Research Institute, Dublin Institute of Technology, Kevin Street, Dublin 8, Ireland.
authors.forename: Hugh J
authors.initials: HJ
authors.lastname: Byrne
mesh_terms: D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D050091:Dendrimers / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018613:Microscopy, Confocal; D015394:Molecular Structure; D053758:Nanoparticles / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects*; D011126:Polypropylenes / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D050091:Dendrimers; C104700:PAMAM Starburst; D011126:Polypropylenes; C443641:poly(propyleneimine)
keywords: Poly(amido amine) dendrimers; Poly(propylene imine) dendrimers; cytotoxicity; in vitro uptake mechanisms; oxidative stress; structure property relationships