Unmodified cadmium telluride quantum dots induce reactive oxygen species formation leading to multiple organelle damage and cell death.

Quantum dots (QDs) are luminescent nanoparticles with unique optical properties that have been exploited for single-cell and whole-animal imaging. When coated with proteins or biocompatible polymers, QDs are not deleterious to cells and organisms. However, when QDs are retained in cells or accumulated in the body for a long period of time, their coatings may be degraded, yielding "naked" QDs. Here, we show that "naked" QDs induce damage to the plasma membrane, mitochondrion, and nucleus, leading to cell death. Reactive oxygen species (ROS) are important players in mediating QD-induced cellular damage. QD-induced cytotoxicity can be reduced or even eliminated without covalent binding of protective agents to the QD surface. Results from these studies suggest the critical role of several subcellular compartments in QD-induced cytotoxicity and point toward multiple molecular targets in nonclassical apoptosis.

[1]  A. Halestrap,et al.  Role of critical thiol groups on the matrix surface of the adenine nucleotide translocase in the mechanism of the mitochondrial permeability transition pore. , 2002, The Biochemical journal.

[2]  W. Webb,et al.  Water-Soluble Quantum Dots for Multiphoton Fluorescence Imaging in Vivo , 2003, Science.

[3]  S. Kelley,et al.  Oxidative DNA strand scission induced by peptides. , 2005, Chemistry & biology.

[4]  M. Howarth,et al.  Targeting quantum dots to surface proteins in living cells with biotin ligase. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[5]  R. Youle,et al.  Dynamics of mitochondrial morphology in healthy cells and during apoptosis , 2003, Cell Death and Differentiation.

[6]  A. Porter Protein translocation in apoptosis. , 1999, Trends in cell biology.

[7]  T. Tsuruo,et al.  Mitochondrial aggregation precedes cytochrome c release from mitochondria during apoptosis , 2003, Oncogene.

[8]  Zhivko Zhelev,et al.  Quantum dots as photosensitizers? , 2004, Nature Biotechnology.

[9]  N. Holbrook,et al.  Oxidants, oxidative stress and the biology of ageing , 2000, Nature.

[10]  Vladimir P Torchilin,et al.  Quantum dots spectrally distinguish multiple species within the tumor milieu in vivo , 2005, Nature Medicine.

[11]  Nikolai Gaponik,et al.  THIOL-CAPPING OF CDTE NANOCRYSTALS: AN ALTERNATIVE TO ORGANOMETALLIC SYNTHETIC ROUTES , 2002 .

[12]  Igor L. Medintz,et al.  Quantum dot bioconjugates for imaging, labelling and sensing , 2005, Nature materials.

[13]  Amane Shiohara,et al.  On the Cyto‐Toxicity Caused by Quantum Dots , 2004, Microbiology and immunology.

[14]  Xiaobo Chen,et al.  Semiconductor quantum dots for photodynamic therapy. , 2003, Journal of the American Chemical Society.

[15]  D. Newmeyer,et al.  Mitochondria Releasing Power for Life and Unleashing the Machineries of Death , 2003, Cell.

[16]  S. Srinivasula,et al.  Cytochrome c and dATP-Dependent Formation of Apaf-1/Caspase-9 Complex Initiates an Apoptotic Protease Cascade , 1997, Cell.

[17]  Erkki Ruoslahti,et al.  Nanocrystal targeting in vivo , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[18]  J. Post,et al.  Quantum dot ligands provide new insights into erbB/HER receptor–mediated signal transduction , 2004, Nature Biotechnology.

[19]  S. Nie,et al.  In vivo cancer targeting and imaging with semiconductor quantum dots , 2004, Nature Biotechnology.

[20]  Hedi Mattoussi,et al.  Tracking metastatic tumor cell extravasation with quantum dot nanocrystals and fluorescence emission-scanning microscopy , 2004, Nature Medicine.

[21]  Philippe Rostaing,et al.  Diffusion Dynamics of Glycine Receptors Revealed by Single-Quantum Dot Tracking , 2003, Science.

[22]  T. Murphy,et al.  Rapid Communication: Oxidative Stress Induces Apoptosis in Embryonic Cortical Neurons , 1994, Journal of neurochemistry.

[23]  L Manzo,et al.  Neuronal cell death: a demise with different shapes. , 1999, Trends in pharmacological sciences.

[24]  S. Korsmeyer,et al.  Proapoptotic BAX and BAK: A Requisite Gateway to Mitochondrial Dysfunction and Death , 2001, Science.

[25]  Marcel Leist,et al.  Four deaths and a funeral: from caspases to alternative mechanisms , 2001, Nature Reviews Molecular Cell Biology.

[26]  Byron Ballou,et al.  Noninvasive imaging of quantum dots in mice. , 2004, Bioconjugate chemistry.

[27]  M. Bruchez,et al.  Immunofluorescent labeling of cancer marker Her2 and other cellular targets with semiconductor quantum dots , 2003, Nature Biotechnology.

[28]  Vincent Noireaux,et al.  In Vivo Imaging of Quantum Dots Encapsulated in Phospholipid Micelles , 2002, Science.

[29]  G. Kroemer,et al.  Organelle-specific initiation of cell death pathways , 2001, Nature Cell Biology.

[30]  K. Yagi,et al.  Loss of molecular interaction between cytochrome c and cardiolipin due to lipid peroxidation. , 1999, Biochemical and biophysical research communications.

[31]  B. Kristal,et al.  Multiple roles of glutathione in the central nervous system. , 1997, Biological chemistry.

[32]  M. Madesh,et al.  VDAC-dependent permeabilization of the outer mitochondrial membrane by superoxide induces rapid and massive cytochrome c release , 2001, The Journal of cell biology.

[33]  Alan G. Porter,et al.  Caspase-3 Is Required for DNA Fragmentation and Morphological Changes Associated with Apoptosis* , 1998, The Journal of Biological Chemistry.

[34]  E. Oberdörster Manufactured Nanomaterials (Fullerenes, C60) Induce Oxidative Stress in the Brain of Juvenile Largemouth Bass , 2004, Environmental health perspectives.

[35]  Tim Liedl,et al.  Cytotoxicity of colloidal CdSe and CdSe/ZnS nanoparticles. , 2005, Nano letters.

[36]  Mark Green,et al.  Semiconductor quantum dots and free radical induced DNA nicking. , 2005, Chemical communications.

[37]  Raymond P. Molloy,et al.  In vivo multiphoton microscopy of deep brain tissue. , 2004, Journal of neurophysiology.

[38]  K. Schulze-Osthoff,et al.  Multiple kinetics of mitochondrial cytochrome c release in drug-induced apoptosis. , 2001, Molecular pharmacology.

[39]  Yigong Shi,et al.  Molecular mechanisms of caspase regulation during apoptosis , 2004, Nature Reviews Molecular Cell Biology.

[40]  Igor L. Medintz,et al.  Fluorescence resonance energy transfer between quantum dot donors and dye-labeled protein acceptors. , 2003, Journal of the American Chemical Society.

[41]  J M Land,et al.  Nitric oxide, mitochondria and neurological disease. , 1999, Biochimica et biophysica acta.

[42]  Igor L. Medintz,et al.  Reversible modulation of quantum dot photoluminescence using a protein- bound photochromic fluorescence resonance energy transfer acceptor. , 2004, Journal of the American Chemical Society.

[43]  J. Matthew Mauro,et al.  Long-term multiple color imaging of live cells using quantum dot bioconjugates , 2003, Nature Biotechnology.

[44]  S. Bhatia,et al.  Probing the Cytotoxicity Of Semiconductor Quantum Dots. , 2004, Nano letters.

[45]  Xiaogang Peng,et al.  Photochemical instability of CdSe nanocrystals coated by hydrophilic thiols. , 2001, Journal of the American Chemical Society.

[46]  Chaohua Yan,et al.  Apoptosis in the absence of caspase 3 , 2001, Oncogene.

[47]  T. Mihaljevic,et al.  Near-infrared fluorescent type II quantum dots for sentinel lymph node mapping , 2004, Nature Biotechnology.

[48]  S. Gambhir,et al.  Quantum Dots for Live Cells, in Vivo Imaging, and Diagnostics , 2005, Science.

[49]  W. Fiers,et al.  Dual Signaling of the Fas Receptor: Initiation of Both Apoptotic and Necrotic Cell Death Pathways , 1998, The Journal of experimental medicine.

[50]  C. Borner,et al.  Apoptosis without caspases: an inefficient molecular guillotine? , 1999, Cell Death and Differentiation.

[51]  I. Cotgreave,et al.  N-acetylcysteine: pharmacological considerations and experimental and clinical applications. , 1997, Advances in pharmacology.

[52]  Xiaogang Peng,et al.  Size-dependent dissociation pH of thiolate ligands from cadmium chalcogenide nanocrystals. , 2005, Journal of the American Chemical Society.

[53]  Hassan S. Bazzi,et al.  Differences in subcellular distribution and toxicity of green and red emitting CdTe quantum dots , 2005, Journal of Molecular Medicine.

[54]  Masato Yasuhara,et al.  Physicochemical Properties and Cellular Toxicity of Nanocrystal Quantum Dots Depend on Their Surface Modification , 2004 .