title: Evaluation of quantum dot cytotoxicity: interpretation of nanoparticle concentrations versus intracellular nanoparticle numbers.
abstract: While substantial progress has been achieved in the design of more biocompatible nanoparticles (NP), detailed data are required on the precise interactions of NPs and their environment for more reliable interpretation of toxicity results. Therefore, this study aims to investigate the interaction of two quantum dots (QDs) of the same core material CdSe/ZnS coated with two different amphiphilic polymers, with two well-established mammalian cell lines representing possible sites of QD accumulation. Results are linked to either extracellular QD concentrations (given dose) or cellular QD levels (number of internalized particles). In this study, QD internalization, effects on cellular homeostasis, and consequent inflammatory and cytoskeletal alterations caused by these QDs were explored. Fluorescence imaging techniques, including; image-based flow cytometry, confocal microscopy and high-content imaging with the InCell analyzer were used in a multiparametric methodology to evaluate cell viability, induction of oxidative stress, mitochondrial health, cell cytoskeletal functionality and changes in cellular morphology. Gene expression arrays were also carried out on 168 key genes involved in the cytoskeletal architecture and inflammatory pathway accompanied with the analysis of focal adhesions as key markers for actin-mediated signaling. Our results show distinct differences between the PMA and PTMAEMA-stat-PLMA coated QDs, which could mainly be attributed to differences in their cellular uptake levels. The toxicity profiles of both QD types changed drastically depending on whether effects were expressed in terms of given dose or internalized particles. Both QDs triggered alterations to important but different genes, most remarkably the up-regulation of tumor suppression and necrosis genes and the down regulation of angiogenesis and metastasis genes at sub-cytotoxic concentrations of these QDs.
authors.affiliation: a Department of Imaging and Pathology , Biomedical NMR Unit/MoSAIC, KU Leuven Campus Gasthuisberg , Leuven , Belgium .
authors.forename: Bella B
authors.initials: BB
authors.lastname: Manshian
authors.affiliation: b Department of Physics , Philipps University of Marburg , Marburg , Germany .
authors.forename: Abuelmagd M
authors.initials: AM
authors.lastname: Abdelmonem
authors.affiliation: b Department of Physics , Philipps University of Marburg , Marburg , Germany .
authors.forename: Karsten
authors.initials: K
authors.lastname: Kantner
authors.affiliation: b Department of Physics , Philipps University of Marburg , Marburg , Germany .
authors.forename: Beatriz
authors.initials: B
authors.lastname: Pelaz
authors.affiliation: c Max Planck Institute for Polymer Research , Mainz , Germany , and.
authors.forename: Markus
authors.initials: M
authors.lastname: Klapper
authors.affiliation: c Max Planck Institute for Polymer Research , Mainz , Germany , and.
authors.forename: Catarina
authors.initials: C
authors.lastname: Nardi Tironi
authors.affiliation: b Department of Physics , Philipps University of Marburg , Marburg , Germany .|d CIC biomaGUNE , San Sebastián , Spain.
authors.forename: Wolfgang J
authors.initials: WJ
authors.lastname: Parak
authors.affiliation: a Department of Imaging and Pathology , Biomedical NMR Unit/MoSAIC, KU Leuven Campus Gasthuisberg , Leuven , Belgium .
authors.forename: Uwe
authors.initials: U
authors.lastname: Himmelreich
authors.affiliation: a Department of Imaging and Pathology , Biomedical NMR Unit/MoSAIC, KU Leuven Campus Gasthuisberg , Leuven , Belgium .
authors.forename: Stefaan J
authors.initials: SJ
authors.lastname: Soenen
mesh_terms: D019187:Cadmium Compounds / Q000737:chemistry; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D020099:Coated Materials, Biocompatible / Q000737:chemistry; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D018613:Microscopy, Confocal; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D011108:Polymers / Q000737:chemistry; D045663:Quantum Dots / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D018036:Selenium Compounds / Q000737:chemistry; D013054:Spectrophotometry, Atomic; D013440:Sulfides / Q000737:chemistry; D013499:Surface Properties; D017967:Zinc Compounds / Q000737:chemistry
chemical_list: D019187:Cadmium Compounds; D020099:Coated Materials, Biocompatible; D003598:Cytoskeletal Proteins; D011108:Polymers; D017382:Reactive Oxygen Species; D018036:Selenium Compounds; D013440:Sulfides; D017967:Zinc Compounds; C058667:cadmium selenide; C031238:zinc sulfide
keywords: Cellular uptake; polymer coating; quantum dot; toxicity