Cytotoxic and genotoxic characterization of titanium dioxide, gadolinium oxide, and poly(lactic-co-glycolic acid) nanoparticles in human fibroblasts.

Engineered nanomaterials have become prevalent in our everyday life. While the popularity of using nanomaterials in consumer products continues to rise, increasing awareness of nanotoxicology has also fuelled efforts to accelerate our understanding of the ill effects that different nanomaterials can bring to biological systems. In this study, we investigated the potential cytotoxicity and genotoxicity of three nanoparticles: titanium dioxide (TiO(2)), terbium-doped gadolinium oxide (Tb-Gd(2)O(3)), and poly(lactic-co-glycolic acid) (PLGA). To evaluate nanoparticle-induced genotoxicity more realistically, a human skin fibroblast cell line (BJ) with less mutated genotype compared with cancer cell line was used. The nanoparticles were first characterized by size, morphology, and surface charge. Cytotoxicity effects of the nanoparticles were then evaluated by monitoring the proliferation of treated BJ cells. Genotoxic influence was ascertained by profiling DNA damage via detection of γH2AX expression. Our results suggested that both TiO(2) and Tb-Gd(2)O(3) nanoparticles induced cytotoxicity in a dose dependent way on BJ cells. These two nanomaterials also promoted genotoxicity via DNA damage. On the contrary, PLGA nanoparticles did not induce significant cytotoxic or genotoxic effects on BJ cells.

[1]  O. Hammarsten,et al.  An optimized method for detecting gamma-H2AX in blood cells reveals a significant interindividual variation in the gamma-H2AX response among humans , 2007, Nucleic acids research.

[2]  D. Meek,et al.  The p53 response to DNA damage. , 2004, DNA repair.

[3]  G. Toney,et al.  Acute and Subacute Physiological and Histological Studies of the Central Nervous System After Intrathecal Gadolinium Injection in the Anesthetized Rat , 2001, Investigative radiology.

[4]  Ai-Ping Zhang,et al.  Photocatalytic killing effect of TiO2 nanoparticles on Ls-174-t human colon carcinoma cells. , 2004, World journal of gastroenterology.

[5]  Chun-jing Zhang,et al.  Adsorption/desorption behavior of protein on nanosized hydroxyapatite coatings: A quartz crystal microbalance study , 2009 .

[6]  C. Lehr,et al.  PLGA Nanoparticles Stabilized with Cationic Surfactant: Safety Studies and Application in Oral Delivery of Paclitaxel to Treat Chemical-Induced Breast Cancer in Rat , 2009, Pharmaceutical Research.

[7]  R. Agami,et al.  The tumor-suppressive functions of the human INK4A locus. , 2003, Cancer cell.

[8]  Xinbin Chen,et al.  p53 modulation of the DNA damage response , 2007, Journal of cellular biochemistry.

[9]  Q. Lu,et al.  Cytotoxicity of titanium dioxide nanoparticles in mouse fibroblast cells. , 2008, Chemical research in toxicology.

[10]  Jin Chang,et al.  PLGA/polymeric liposome for targeted drug and gene co-delivery. , 2010, Biomaterials.

[11]  Dietmar W Hutmacher,et al.  The challenge to measure cell proliferation in two and three dimensions. , 2005, Tissue engineering.

[12]  Kenneth A. Dawson,et al.  Protein–Nanoparticle Interactions , 2008, Nano-Enabled Medical Applications.

[13]  E. Dopp,et al.  Titanium dioxide nanoparticles induce oxidative stress and DNA-adduct formation but not DNA-breakage in human lung cells , 2009, Particle and Fibre Toxicology.

[14]  Kui Wang,et al.  La(3+), Gd(3+) and Yb(3+) induced changes in mitochondrial structure, membrane permeability, cytochrome c release and intracellular ROS level. , 2003, Chemico-biological interactions.

[15]  Wei Huang,et al.  PHBV microspheres--PLGA matrix composite scaffold for bone tissue engineering. , 2010, Biomaterials.

[16]  Bengt Fadeel,et al.  Nanotoxicology: no small matter. , 2010, Nanoscale.

[17]  P. Chumakov,et al.  The antioxidant function of the p53 tumor suppressor , 2005, Nature Medicine.

[18]  K. Jan,et al.  Ultrafine titanium dioxide particles in the absence of photoactivation can induce oxidative damage to human bronchial epithelial cells. , 2005, Toxicology.

[19]  Kui Wang,et al.  Gadolinium‐induced oxidative stress triggers endoplasmic reticulum stress in rat cortical neurons , 2011, Journal of neurochemistry.

[20]  J. Loo,et al.  Gadolinium oxide ultranarrow nanorods as multimodal contrast agents for optical and magnetic resonance imaging. , 2010, Langmuir : the ACS journal of surfaces and colloids.

[21]  K. Uvdal,et al.  Positive MRI contrast enhancement in THP-1 cells with Gd2O3 nanoparticles. , 2008, Contrast media & molecular imaging.

[22]  J. Loo,et al.  The role of the tumor suppressor p53 pathway in the cellular DNA damage response to zinc oxide nanoparticles. , 2011, Biomaterials.

[23]  Feng Xu,et al.  Cytotoxicity of titanium dioxide nanoparticles differs in four liver cells from human and rat , 2011 .

[24]  Jim E Riviere,et al.  Surface coatings determine cytotoxicity and irritation potential of quantum dot nanoparticles in epidermal keratinocytes. , 2007, The Journal of investigative dermatology.

[25]  G. Oberdörster,et al.  Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles , 2005, Environmental health perspectives.

[26]  J. Loo,et al.  Comparative cytotoxicity evaluation of lanthanide nanomaterials on mouse and human cell lines with metabolic and DNA-quantification assays , 2010, Biointerphases.

[27]  Lili He,et al.  In vitro evaluation of the genotoxicity of a family of novel MeO-PEG-poly(D,L-lactic-co-glycolic acid)-PEG-OMe triblock copolymer and PLGA nanoparticles , 2009, Nanotechnology.

[28]  Benjamin Gilbert,et al.  Comparison of the mechanism of toxicity of zinc oxide and cerium oxide nanoparticles based on dissolution and oxidative stress properties. , 2008, ACS nano.

[29]  James M. Anderson,et al.  In vitro cytotoxicity evaluation of biomedical nanoparticles and their extracts. , 2009, Journal of biomedical materials research. Part A.

[30]  Su Jin Kang,et al.  Titanium dioxide nanoparticles trigger p53‐mediated damage response in peripheral blood lymphocytes , 2008, Environmental and molecular mutagenesis.

[31]  A. Nakamura,et al.  Role of oxidatively induced DNA lesions in human pathogenesis. , 2010, Mutation research.

[32]  Dragan Uskoković,et al.  DNA damage and alterations in expression of DNA damage responsive genes induced by TiO2 nanoparticles in human hepatoma HepG2 cells , 2011, Nanotoxicology.

[33]  S. Elledge,et al.  DNA damage-induced activation of p53 by the checkpoint kinase Chk2. , 2000, Science.

[34]  H. Lindberg,et al.  Genotoxic effects of nanosized and fine TiO2 , 2009, Human & experimental toxicology.

[35]  J. Pedraza-Chaverri,et al.  Titanium dioxide nanoparticles impair lung mitochondrial function. , 2011, Toxicology letters.

[36]  J. Loo,et al.  Cellular uptake of Poly‐(D,L‐lactide‐co‐glycolide) (PLGA) nanoparticles synthesized through solvent emulsion evaporation and nanoprecipitation method , 2011, Biotechnology journal.

[37]  Ulrike Diebold,et al.  The surface science of titanium dioxide , 2003 .

[38]  M. Hussain,et al.  Continuing differentiation of human mesenchymal stem cells and induced chondrogenic and osteogenic lineages in electrospun PLGA nanofiber scaffold. , 2007, Biomaterials.

[39]  B. Ohtani,et al.  What is Degussa (Evonik) P25? Crystalline composition analysis, reconstruction from isolated pure particles and photocatalytic activity test , 2010 .

[40]  Jongheop Yi,et al.  Oxidative stress and apoptosis induced by titanium dioxide nanoparticles in cultured BEAS-2B cells. , 2008, Toxicology letters.

[41]  A. Seifalian,et al.  Properties Evaluation of a New MRI Contrast Agent Based on Gd-Loaded Nanoparticles , 2010, Biological Trace Element Research.

[42]  Wonyong Choi,et al.  Linear correlation between inactivation of E. coli and OH radical concentration in TiO2 photocatalytic disinfection. , 2004, Water research.

[43]  Anders Axelsson,et al.  The mechanisms of drug release in poly(lactic-co-glycolic acid)-based drug delivery systems--a review. , 2011, International journal of pharmaceutics.

[44]  Jeffrey I. Zink,et al.  Dispersion and stability optimization of TiO2 nanoparticles in cell culture media. , 2010, Environmental science & technology.

[45]  Sang-sik Kang,et al.  Investigation of the imaging characteristics of the Gd2O3:Eu nanophosphor for high-resolution digital X-ray imaging system , 2007 .

[46]  B. Halliwell,et al.  Damage to DNA by reactive oxygen and nitrogen species: role in inflammatory disease and progression to cancer. , 1996, The Biochemical journal.

[47]  P. Marckmann,et al.  Multiorgan gadolinium (Gd) deposition and fibrosis in a patient with nephrogenic systemic fibrosis--an autopsy-based review. , 2011, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[48]  Katsuhide Fujita,et al.  Protein adsorption of ultrafine metal oxide and its influence on cytotoxicity toward cultured cells. , 2009, Chemical research in toxicology.

[49]  M. Avena,et al.  Adsorption of Bovine Serum Albumin onto TiO2Particles , 1997 .

[50]  H. Swai,et al.  In vivo evaluation of the biodistribution and safety of PLGA nanoparticles as drug delivery systems. , 2010, Nanomedicine : nanotechnology, biology, and medicine.

[51]  J. Yi,et al.  Induction of chronic inflammation in mice treated with titanium dioxide nanoparticles by intratracheal instillation. , 2009, Toxicology.