Demonstrating approaches to chemically modify the surface of Ag nanoparticles in order to influence their cytotoxicity and biodistribution after single dose acute intravenous administration

Abstract With the advance in material science and the need to diversify market applications, silver nanoparticles (AgNPs) are modified by different surface coatings. However, how these surface modifications influence the effects of AgNPs on human health is still largely unknown. We have evaluated the uptake, toxicity and pharmacokinetics of AgNPs coated with citrate, polyethylene glycol, polyvinyl pyrolidone and branched polyethyleneimine (Citrate AgNPs, PEG AgNPs, PVP AgNPs and BPEI AgNPs, respectively). Our results demonstrated that the toxicity of AgNPs depends on the intracellular localization that was highly dependent on the surface charge. BPEI AgNPs (ζ potential = +46.5 mV) induced the highest cytotoxicity and DNA fragmentation in Hepa1c1c7. In addition, it showed the highest damage to the nucleus of liver cells in the exposed mice, which is associated with a high accumulation in liver tissues. The PEG AgNPs (ζ potential = −16.2 mV) showed the cytotoxicity, a long blood circulation, as well as bioaccumulation in spleen (34.33 µg/g), which suggest better biocompatibility compared to the other chemically modified AgNPs. Moreover, the adsorption ability with bovine serum albumin revealed that the PEG surface of AgNPs has an optimal biological inertia and can effectively resist opsonization or non-specific binding to protein in mice. The overall results indicated that the biodistribution of AgNPs was significantly dependent on surface chemistry: BPEI AgNPs > Citrate AgNPs = PVP AgNPs > PEG AgNPs. This toxicological data could be useful in supporting the development of safe AgNPs for consumer products and drug delivery applications.

[1]  J. Jung,et al.  Twenty-Eight-Day Inhalation Toxicity Study of Silver Nanoparticles in Sprague-Dawley Rats , 2007, Inhalation toxicology.

[2]  P. Couvreur,et al.  Stealth® PEGylated polycyanoacrylate nanoparticles for intravenous administration and splenic targeting , 1999 .

[3]  Konrad Hungerbühler,et al.  A physiologically based pharmacokinetic model for ionic silver and silver nanoparticles , 2013, International journal of nanomedicine.

[4]  Tao Chen,et al.  Cytotoxicity and genotoxicity assessment of silver nanoparticles in mouse , 2014, Nanotoxicology.

[5]  Leaf Huang,et al.  Pharmacokinetics and biodistribution of nanoparticles. , 2008, Molecular pharmaceutics.

[6]  Chunying Chen,et al.  Fast intracellular dissolution and persistent cellular uptake of silver nanoparticles in CHO-K1 cells: implication for cytotoxicity , 2015, Nanotoxicology.

[7]  S. Boyce,et al.  Assessment of a silver-coated barrier dressing for potential use with skin grafts on excised burns. , 2003, Burns : journal of the International Society for Burn Injuries.

[8]  Ting Zhang,et al.  Acute toxic effects and gender‐related biokinetics of silver nanoparticles following an intravenous injection in mice , 2012, Journal of applied toxicology : JAT.

[9]  Jae Hyun Kim,et al.  The use of biodegradable PLGA nanoparticles to mediate SOX9 gene delivery in human mesenchymal stem cells (hMSCs) and induce chondrogenesis. , 2011, Biomaterials.

[10]  Yang Xu,et al.  Cytotoxicity and biological effects of functional nanomaterials delivered to various cell lines , 2010, Journal of applied toxicology : JAT.

[11]  Nicholas A Peppas,et al.  Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. , 2006, International journal of pharmaceutics.

[12]  Bengt Fadeel,et al.  Size-dependent cytotoxicity of silver nanoparticles in human lung cells: the role of cellular uptake, agglomeration and Ag release , 2014, Particle and Fibre Toxicology.

[13]  Chengfang Pang,et al.  Effects of sediment-associated copper to the deposit-feeding snail, Potamopyrgus antipodarum: a comparison of Cu added in aqueous form or as nano- and micro-CuO particles. , 2012, Aquatic toxicology.

[14]  Ying Liu,et al.  Quantitative biokinetics and systemic translocation of various gold nanostructures are highly dependent on their size and shape. , 2014, Journal of nanoscience and nanotechnology.

[15]  L. Unsworth,et al.  BSA Nanoparticles for siRNA Delivery: Coating Effects on Nanoparticle Properties, Plasma Protein Adsorption, and In Vitro siRNA Delivery , 2012, International journal of biomaterials.

[16]  Limin Wang,et al.  Multi-platform genotoxicity analysis of silver nanoparticles in the model cell line CHO-K1. , 2013, Toxicology letters.

[17]  Kai Yang,et al.  Biodistribution, pharmacokinetics and toxicology of Ag2S near-infrared quantum dots in mice. , 2013, Biomaterials.

[18]  Naomi Lubick,et al.  Nanosilver toxicity: ions, nanoparticles--or both? , 2008, Environmental science & technology.

[19]  Y. Ikada,et al.  Controlled release of growth factors based on biodegradation of gelatin hydrogel , 2001, Journal of biomaterials science. Polymer edition.

[20]  Herman Autrup,et al.  Global gene expression profiling of human lung epithelial cells after exposure to nanosilver. , 2012, Toxicological sciences : an official journal of the Society of Toxicology.

[21]  V. Trudeau,et al.  Nanosilver cytotoxicity in rainbow trout (Oncorhynchus mykiss) erythrocytes and hepatocytes. , 2014, Comparative biochemistry and physiology. Toxicology & pharmacology : CBP.

[22]  S. Alarifi,et al.  Evaluation of cytotoxic, oxidative stress, proinflammatory and genotoxic effect of silver nanoparticles in human lung epithelial cells , 2015, Environmental toxicology.

[23]  N. Chatterjee,et al.  Integrated mRNA and micro RNA profiling reveals epigenetic mechanism of differential sensitivity of Jurkat T cells to AgNPs and Ag ions. , 2014, Toxicology letters.

[24]  Feng Liu,et al.  Implications of pharmacokinetic behavior of lipoplex for its inflammatory toxicity. , 2005, Advanced drug delivery reviews.

[25]  T. Begley,et al.  Oral ingestion of silver nanoparticles induces genomic instability and DNA damage in multiple tissues , 2015, Nanotoxicology.

[26]  Fong-Yu Cheng,et al.  Cytotoxicity, oxidative stress, apoptosis and the autophagic effects of silver nanoparticles in mouse embryonic fibroblasts. , 2014, Biomaterials.

[27]  S. Hirota,et al.  Effect of liposomalization on the antitumor activity, side-effects and tissue distribution of CPT-11. , 1998, Cancer letters.

[28]  Jingyuan Li,et al.  Revealing the binding structure of the protein corona on gold nanorods using synchrotron radiation-based techniques: understanding the reduced damage in cell membranes. , 2013, Journal of the American Chemical Society.

[29]  Francesco Stellacci,et al.  Effect of surface properties on nanoparticle-cell interactions. , 2010, Small.

[30]  Ying Liu,et al.  Surface chemistry and aspect ratio mediated cellular uptake of Au nanorods. , 2010, Biomaterials.

[31]  I. Choi,et al.  Inflammasome formation and IL-1β release by human blood monocytes in response to silver nanoparticles. , 2012, Biomaterials.

[32]  Bruno F B Silva,et al.  Uptake and transfection efficiency of PEGylated cationic liposome-DNA complexes with and without RGD-tagging. , 2014, Biomaterials.

[33]  Andrew Emili,et al.  Protein corona fingerprinting predicts the cellular interaction of gold and silver nanoparticles. , 2014, ACS nano.

[34]  Jing-fu Liu,et al.  Quantification of the uptake of silver nanoparticles and ions to HepG2 cells. , 2013, Environmental science & technology.

[35]  Jing-fu Liu,et al.  Evaluating the sorption of organophosphate esters to different sourced humic acids and its effects on the toxicity to Daphnia magna , 2013, Environmental toxicology and chemistry.

[36]  John C Trefry,et al.  Silver nanoparticles inhibit vaccinia virus infection by preventing viral entry through a macropinocytosis-dependent mechanism. , 2013, Journal of biomedical nanotechnology.

[37]  W. D. de Jong,et al.  The kinetics of the tissue distribution of silver nanoparticles of different sizes. , 2010, Biomaterials.

[38]  J. S. Park,et al.  Poly(N-isopropylacrylamide-co-acrylic acid) nanogels for tracing and delivering genes to human mesenchymal stem cells. , 2013, Biomaterials.

[39]  Alaaldin M. Alkilany,et al.  Nanoparticle-protein interactions: a thermodynamic and kinetic study of the adsorption of bovine serum albumin to gold nanoparticle surfaces. , 2013, Langmuir : the ACS journal of surfaces and colloids.

[40]  Ha Ryong Kim,et al.  Genotoxic effects of silver nanoparticles stimulated by oxidative stress in human normal bronchial epithelial (BEAS-2B) cells. , 2011, Mutation research.

[41]  S. Ghosh,et al.  Silver Nanoparticles Impregnated Alginate–Chitosan‐Blended Nanocarrier Induces Apoptosis in Human Glioblastoma Cells , 2014, Advanced healthcare materials.

[42]  F. Stellacci,et al.  Effects of surface compositional and structural heterogeneity on nanoparticle-protein interactions: different protein configurations. , 2014, ACS nano.

[43]  R. Bai,et al.  Endoplasmic reticulum stress induced by zinc oxide nanoparticles is an earlier biomarker for nanotoxicological evaluation. , 2014, ACS nano.

[44]  U. Heinzmann,et al.  Pulmonary and systemic distribution of inhaled ultrafine silver particles in rats. , 2001, Environmental health perspectives.

[45]  Saura C Sahu,et al.  Comparative cytotoxicity of nanosilver in human liver HepG2 and colon Caco2 cells in culture , 2014, Journal of applied toxicology : JAT.

[46]  K. Tollefsen,et al.  Uptake and effects of manufactured silver nanoparticles in rainbow trout (Oncorhynchus mykiss) gill cells. , 2011, Aquatic toxicology.

[47]  R. Minchin,et al.  Cellular uptake of densely packed polymer coatings on gold nanoparticles. , 2010, ACS nano.

[48]  J. H. Kim,et al.  Non-viral gene delivery of DNA polyplexed with nanoparticles transfected into human mesenchymal stem cells. , 2010, Biomaterials.

[49]  Candace C. Fleischer,et al.  Nanoparticle–Cell Interactions: Molecular Structure of the Protein Corona and Cellular Outcomes , 2014, Accounts of chemical research.

[50]  G. Jiang,et al.  Silver nanoparticle exposure attenuates the viability of rat cerebellum granule cells through apoptosis coupled to oxidative stress. , 2013, Small.

[51]  I. Chen,et al.  The surface modification of silver nanoparticles by phosphoryl disulfides for improved biocompatibility and intracellular uptake. , 2008, Biomaterials.

[52]  Chengfang Pang,et al.  Bioaccumulation, toxicokinetics, and effects of copper from sediment spiked with aqueous Cu, nano‐CuO, or micro‐CuO in the deposit‐feeding snail, Potamopyrgus antipodarum , 2013, Environmental toxicology and chemistry.

[53]  Lennart Möller,et al.  Intracellular uptake and toxicity of Ag and CuO nanoparticles: a comparison between nanoparticles and their corresponding metal ions. , 2013, Small.

[54]  P. Ramarao,et al.  Cellular uptake, intracellular trafficking and cytotoxicity of silver nanoparticles. , 2012, Toxicology letters.

[55]  F. Dosio,et al.  Preparation, characterization and properties of sterically stabilized paclitaxel-containing liposomes. , 2000, Journal of controlled release : official journal of the Controlled Release Society.

[56]  W. Kreyling,et al.  Effects of silver nanoparticles on the liver and hepatocytes in vitro. , 2013, Toxicological sciences : an official journal of the Society of Toxicology.

[57]  G. Ulrich Nienhaus,et al.  Impact of protein modification on the protein corona on nanoparticles and nanoparticle-cell interactions. , 2014, ACS nano.

[58]  Kinam Park,et al.  Targeted drug delivery to tumors: myths, reality and possibility. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[59]  Linqi Shi,et al.  In vivo biodistribution of mixed shell micelles with tunable hydrophilic/hydrophobic surface. , 2013, Biomacromolecules.