title: Induction of autophagy in porcine kidney cells by quantum dots: a common cellular response to nanomaterials?
abstract: Quantum dots (QDs) are being investigated as novel in vivo imaging agents. The leaching of toxic metals from these QDs in biological systems is of great concern. This study compared the cytotoxic mechanisms of two QD species made of different core materials (cadmium selenide [CdSe] vs. indium gallium phosphide [InGaP]) but similar core sizes (5.1 vs. 3.7 nm) and surface compositions (both ZnS capped, lipid-coated and pegylated). The CdSe QD was found to be 10-fold more toxic to porcine renal proximal tubule cells (LLC-PK1) than the InGaP QD on a molar basis, as determined by MTT assay (48 h IC(50) 10nM for CdSe vs. 100nM for InGaP). Neither of the QD species induced appreciable oxidative stress, as determined by lipid peroxide and reduced glutathione content, suggesting that toxicity was not metal associated. In agreement, treatment of cells with CdSe QDs was not associated with changes in metallothionein-IA (MT-IA) gene expression or Cd-associated caspase 3 enzyme activation. By contrast, incubation of the LLC-PK1 cells with the InGaP QD resulted in a dramatic increase in MT-IA expression by 21- and 43-fold, at 8 and 24 h, respectively. The most remarkable finding was evidence of extensive autophagy in QD-treated cells, as determined by Lysotracker Red dye uptake, TEM, and LC3 immunobloting. Autophagy induction has also been described for other nanomaterials and may represent a common cellular response. These data suggest that QD cytotoxicity is dependent upon properties of the particle as a whole, and not exclusively the metal core materials.
authors.affiliation: Nanotechnology Characterization Laboratory, Advanced Technology Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland 21702, USA. sternstephan@mail.nih.gov
authors.forename: Stephan T
authors.initials: ST
authors.lastname: Stern
authors.forename: Banu S
authors.initials: BS
authors.lastname: Zolnik
authors.forename: Christopher B
authors.initials: CB
authors.lastname: McLeland
authors.forename: Jeffery
authors.initials: J
authors.lastname: Clogston
authors.forename: Jiwen
authors.initials: J
authors.lastname: Zheng
authors.forename: Scott E
authors.initials: SE
authors.lastname: McNeil
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D019187:Cadmium Compounds / Q000633:toxicity*; D053148:Caspase 3 / Q000378:metabolism; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects* / Q000648:ultrastructure; D005708:Gallium / Q000633:toxicity*; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000187:drug effects* / Q000648:ultrastructure; D018374:LLC-PK1 Cells; D008668:Metallothionein / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D000073718:Pancreatitis-Associated Proteins; D010720:Phosphines / Q000633:toxicity*; D045663:Quantum Dots; D018036:Selenium Compounds / Q000633:toxicity*; D013552:Swine; D013997:Time Factors
chemical_list: D019187:Cadmium Compounds; D000073718:Pancreatitis-Associated Proteins; D010720:Phosphines; C000612141:REG3A protein, human; D018036:Selenium Compounds; C485338:gallium phosphide; D008668:Metallothionein; C058667:cadmium selenide; D005708:Gallium; D053148:Caspase 3