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Cover image for Vol. 9 Issue 9‐10

Special Issue: Nanotoxicology

May 27, 2013

Volume 9, Issue 9-10

Pages 1413–1865

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      Carbon Nanotubes: Short Multiwall Carbon Nanotubes Promote Neuronal Differentiation of PC12 Cells via Up-Regulation of the Neurotrophin Signaling Pathway (Small 9–10/2013) (page 1413)

      Li Meng, Rui Chen, Aihua Jiang, Liming Wang, Peng Wang, Chen-zhong Li, Ru Bai, Yuliang Zhao, Herman Autrup and Chunying Chen

      Article first published online: 16 MAY 2013 | DOI: 10.1002/smll.201370052

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      The front cover image for this special issue was provided by C. Chen and co-workers. CNTs show good biocompatibility, and can be used to modulate neurite outgrowth in culture and in vivo. Positive effects such as promoting regeneration and differentiation can be initiated by up-regulating cellular uptake and exocytosis. On page 1786 it is shown that shorter carboxyl-terminated multiwall carbon nanotubes (MWCNTs) demonstrate higher cellular uptake by PC12 cells and more obvious exocytosis compared to longer ones. Incubation of PC12 cells with carboxylated MWCNTs does not affect cellular morphology or viability at lower concentrations.

  2. Inside Front Cover

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      Proteins: Biosafety and Bioapplication of Nanomaterials by Designing Protein–Nanoparticle Interactions (Small 9–10/2013) (page 1414)

      Sheng-Tao Yang, Ying Liu, Yan-Wen Wang and Aoneng Cao

      Article first published online: 16 MAY 2013 | DOI: 10.1002/smll.201370053

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      When nanomaterials (NMs) enter biosystems, they interact with various biomolecules, especially proteins, forming a protein corona on the surface. Understanding how nanoparticles (NPs) interact with proteins is crucial for bioapplications and for the biosafety of NMs. On page 1635, A. Cao and co-workers summarize the current understanding of protein–NP interactions. Guidelines for improving bioapplication performance and reducing the potential biosafety hazard of NMs by designing the protein–NP interactions are discussed, along with future directions and challenges in this exciting field.

  3. Back Cover

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      Nanotoxicity (Small 9-10/2013) (page 1868)

      Article first published online: 16 MAY 2013 | DOI: 10.1002/smll.201370054

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  4. Masthead

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      Masthead: (Small 9–10/2013)

      Article first published online: 16 MAY 2013 | DOI: 10.1002/smll.201370055

  5. Contents

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      Contents: (Small 9–10/2013) (pages 1415–1425)

      Article first published online: 16 MAY 2013 | DOI: 10.1002/smll.201370056

  6. Editorial

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  7. Essay

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    1. Implementation of a Multidisciplinary Approach to Solve Complex Nano EHS Problems by the UC Center for the Environmental Implications of Nanotechnology (pages 1428–1443)

      Tian Xia, Davin Malasarn, Sijie Lin, Zhaoxia Ji, Haiyuan Zhang, Robert J. Miller, Arturo A. Keller, Roger M. Nisbet, Barbara H. Harthorn, Hilary A. Godwin, Hunter S. Lenihan, Rong Liu, Jorge Gardea-Torresdey, Yoram Cohen, Lutz Mädler, Patricia A. Holden, Jeffrey I. Zink and Andre E. Nel

      Article first published online: 2 OCT 2012 | DOI: 10.1002/smll.201201700

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      The science in UC CEIN is integrated through four major thrusts: 1) Acquisition of engineered nanomaterial (ENM) libraries for high-throughput screening (HTS) and in silico analysis to establish structure–activity relationships (SARs); 2) Environmental modeling through environmental fate and transport as well as life cycle analyses; 3) Ecological impacts of materials on trophic life forms in terrestrial and aquatic ecosystems; 4) Education and outreach activities.

  8. Concepts

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    1. Cytophilic/Cytophobic Design of Nanomaterials at Biointerfaces (pages 1444–1448)

      Kang Sun, Hongliang Liu, Shutao Wang and Lei Jiang

      Article first published online: 18 FEB 2013 | DOI: 10.1002/smll.201201667

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      A general strategy for designing the surface chemistry of nanomaterials is proposed on the basis of cytophilic/cytophobic affinity. Based on the strategy, nanomaterials can be designed with controlled cell affinity, or new cytophilic/cytophobic moieties can be explored. Controlling the surface cytophilic/cytophobic properties of nanomaterials is crucial for their biomedical applications, such as therapy, tissue engineering, and biosensors.

  9. Frontispiece

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      Iron Oxide Nanoparticles: Chemical Design of Biocompatible Iron Oxide Nanoparticles for Medical Applications (Small 9–10/2013) (page 1449)

      Daishun Ling and Taeghwan Hyeon

      Article first published online: 16 MAY 2013 | DOI: 10.1002/smll.201370057

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      The strategies for the chemical design of biocompatible iron oxide nanoparticles for diverse biomedical applications are reviewed by D. Ling and T. Hyeon on page 1450. A review of the large-scale chemical synthetic methods is given first, and the chemical design strategies for biocompatible coatings are summarized. Finally, the toxicity of various kinds of iron oxide nanoparticles is reported.

  10. Reviews

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    1. Chemical Design of Biocompatible Iron Oxide Nanoparticles for Medical Applications (pages 1450–1466)

      Daishun Ling and Taeghwan Hyeon

      Article first published online: 11 DEC 2012 | DOI: 10.1002/smll.201202111

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      High-quality iron oxide nanoparticles, synthesized on a large scale via green chemistry and a chemically well-designed biocompatible shell, have great potential as a new iron-oxide-based nanomedicine.

    2. Colorimetric Detection of Mercury Ions Based on Plasmonic Nanoparticles (pages 1467–1481)

      Jianjun Du, Lin Jiang, Qi Shao, Xiaogang Liu, Robert S. Marks, Jan Ma and Xiaodong Chen

      Article first published online: 7 SEP 2012 | DOI: 10.1002/smll.201200811

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      Recent progress in the development of gold nanoparticle-based colorimetric assays for Hg2+ are summarized. The general design principle for nanoparticle-based colorimetric probes is highlighted, with a particular emphasis on the functionalization of nanoparticles with oligonucleotides, oligopeptides, and various functional molecules.

    3. Quantifying and Imaging Engineered Nanomaterials In Vivo: Challenges and Techniques (pages 1482–1491)

      Xiao He, Yuhui Ma, Meng Li, Peng Zhang, Yuanyuan Li and Zhiyong Zhang

      Article first published online: 2 OCT 2012 | DOI: 10.1002/smll.201201502

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      The trends and challenges in the in vivo quantification of engineered nanomaterials are presented, which demand improvements in quantitative analysis methods to obtain lower detection limits and higher spatial resolution. Some commonly used techniques for the in vivo quantification of engineered nanomaterials are reviewed, and the state of the art, limitations, and future prospects are addressed.

    4. Behavior and Toxicity of Graphene and Its Functionalized Derivatives in Biological Systems (pages 1492–1503)

      Kai Yang, Yingjie Li, Xiaofang Tan, Rui Peng and Zhuang Liu

      Article first published online: 17 SEP 2012 | DOI: 10.1002/smll.201201417

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      The toxicity and behavior of graphene in biological systems are systemically reviewed. Despite certain inconsistencies in several detailed experimental results and hypotheses of toxicity mechanisms, numerous reports agree that the physicochemical properties such as surface functional groups, charges, coatings, sizes, and structural defects of graphene materials would affect their in vitro/in vivo behavior as well as toxicity in biological systems.

    5. Emerging In Vitro Models for Safety Screening of High-Volume Production Nanomaterials under Environmentally Relevant Exposure Conditions (pages 1504–1520)

      Mustafa Hussain Kathawala, Sijing Xiong, Mark Richards, Kee Woei Ng, Saji George and Say Chye Joachim Loo

      Article first published online: 28 SEP 2012 | DOI: 10.1002/smll.201201452

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      In vivo assessment on the safety of nanomaterials, though the gold standard, is extremely resource intensive, thus rendering this approach economically unviable. Conventional in vitro models, though fast and highly economical, do not perfectly mimic real-life situations. This review delves into emerging in vitro techniques that could bridge the gap between in vivo and in vivo studies, thereby balancing between resource usage and relevance to real-life situations.

    6. Physicochemical Characteristics of Nanoparticles Affect Circulation, Biodistribution, Cellular Internalization, and Trafficking (pages 1521–1532)

      Xiaopin Duan and Yaping Li

      Article first published online: 28 SEP 2012 | DOI: 10.1002/smll.201201390

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      Multifunctional nanosystems that ensure not only long half-life, but also efficient internalization, are suitable for tumor-targeting delivery. Elongated particles coated with a hydrophilic polymer can selectively accumulate in tumors. After reaching tumor tissue, particles shift to spheres, and hydrophilic polymer is released to make particles hydrophobic, with ligand exposed on the surface facilitating internalization.

    7. Applications and Potential Toxicity of Magnetic Iron Oxide Nanoparticles (pages 1533–1545)

      Gang Liu, Jinhao Gao, Hua Ai and Xiaoyuan Chen

      Article first published online: 28 SEP 2012 | DOI: 10.1002/smll.201201531

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      Magnetic iron oxide nanoparticles have become a powerful platform in many diverse aspects of biomedicine, including magnetic resonance imaging, drug and gene delivery, biological sensing, and hyperthermia. However, the biomedical applications of magnetic iron oxide nanoparticles arouse serious concerns about their pharmacokinetics, metabolism and toxicity. This review presents a broad overview of the biomedical applications and available toxicity assessments of magnetic iron oxide nanoparticles.

    8. Interactions Between Proteins and Carbon-Based Nanoparticles: Exploring the Origin of Nanotoxicity at the Molecular Level (pages 1546–1556)

      Guanghong Zuo, Seung-gu Kang, Peng Xiu, Yuliang Zhao and Ruhong Zhou

      Article first published online: 5 OCT 2012 | DOI: 10.1002/smll.201201381

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      Two potential molecular mechanisms have been proposed for carbon nanotubes’ inhibition of protein functions, one by disruption of the protein active sites, and the other by competitive binding with incoming ligands. The driving force is revealed to be dominated by the π–π stacking interaction.

    9. Interactions of Engineered Nanoparticles with Organs Protected by Internal Biological Barriers (pages 1557–1572)

      Antonio Pietroiusti, Luisa Campagnolo and Bengt Fadeel

      Article first published online: 23 OCT 2012 | DOI: 10.1002/smll.201201463

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      Evidence derived from in vivo (animal) studies on the interactions of nanoparticles with critical internal barriers is discussed. Different physico-chemical properties of nanomaterials may determine their ability to breach biological barriers and the situation is further compounded by the formation of a so-called corona of biomolecules on the surfaces of nanoparticles, the composition of which may vary depending on the route of exposure and the translocation of nanoparticles from one biological compartment to another.

    10. Interfacing Engineered Nanoparticles with Biological Systems: Anticipating Adverse Nano–Bio Interactions (pages 1573–1584)

      Beatriz Pelaz, Gaëlle Charron, Christian Pfeiffer, Yuliang Zhao, Jesus M. de la Fuente, Xing-Jie Liang, Wolfgang J. Parak and Pablo del Pino

      Article first published online: 30 OCT 2012 | DOI: 10.1002/smll.201201229

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      The biological fate of engineered nanoparticles (NPs) in physiological media is discussed. The four color-labeled scenarios illustrate (green) potential adverse effects following protein adsorption, (orange) functionalization of NPs with cell-penetrating peptides (CPPs) and antibodies (active targeting), (yellow) the possibility of ‘passivating’ NPs with suitable coatings, (blue) and adverse effects such as ‘NP dissolution’ and reactive oxygen species generation.

    11. Temporal Techniques: Dynamic Tracking of Nanomaterials in Live Cells (pages 1585–1594)

      Wei Li, Ru Liu, Yaling Wang, Yuliang Zhao and Xueyun Gao

      Article first published online: 8 NOV 2012 | DOI: 10.1002/smll.201201508

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      The technique to track nanoparticles would provide rich information to well understand their behaviors in live cell, this because such techniques could disclose the nanoparticles in high spatial resolution in situ. This review highlights these techniques and their applications in monitoring the nanoparticles in live cells, and the biological properties of nanomaterials are summarized according the temporal techniques.

    12. NLRP3 Inflammasome Activation Induced by Engineered Nanomaterials (pages 1595–1607)

      Bingbing Sun, Xiang Wang, Zhaoxia Ji, Ruibin Li and Tian Xia

      Article first published online: 23 NOV 2012 | DOI: 10.1002/smll.201201962

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      Mechanisms of NLRP3 inflammasome activation induced by engineered nanomaterials (ENMs): the physicochemical properties of ENMs that can be linked to NLRP3 inflammasome activation are reviewed. The elucidation of mechanisms of ENM–NLRP3 inflammasome interaction will help to develop safer ENMs and a potential therapy for ENM-induced adverse health effects.

    13. Zebrafish: An In Vivo Model for Nano EHS Studies (pages 1608–1618)

      Sijie Lin, Yan Zhao, André E. Nel and Shuo Lin

      Article first published online: 3 DEC 2012 | DOI: 10.1002/smll.201202115

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      Zebrafish, an in vivo model, possesses great potential for facilitating nano EHS studies. With its high fecundity, embryo transparency, highly conserved cellular and metabolic activities etc., zebrafish offers higher biological relevance and complexities compared to in vitro cellular assays, while maintaining high throughput and high volume data generation capabilities.

    14. Understanding the Particokinetics of Engineered Nanomaterials for Safe and Effective Therapeutic Applications (pages 1619–1634)

      Motao Zhu, Sarah Perrett and Guangjun Nie

      Article first published online: 6 DEC 2012 | DOI: 10.1002/smll.201201630

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      The concept of “particokinetics” is introduced to address the dynamic biological behavior of engineered nanomaterials (ENMs) at the molecular, cellular, and whole-organism levels. Mathematical modeling methods and the impact of the physicochemical properties on the particokinetics of ENMs is discussed, in order to provide a quantitative description of the biological behavior of ENMs and to guide the design of safe and effective therapeutic applications.

    15. Biosafety and Bioapplication of Nanomaterials by Designing Protein–Nanoparticle Interactions (pages 1635–1653)

      Sheng-Tao Yang, Ying Liu, Yan-Wen Wang and Aoneng Cao

      Article first published online: 23 JAN 2013 | DOI: 10.1002/smll.201201492

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      Protein–nanoparticle (NP) interaction is the first step when nanomaterials (NMs) enter the human body, forming a protein corona. Understanding the protein–NP interaction is crucial for both the bioapplications and safety of NMs. The current understanding of these interactions is summarized and guidelines are proposed to improve bioapplication performances and to reduce potential biosafety hazards of NMs by designing the protein–NP interactions.

    16. Nanotoxicity: A Growing Need for Study in the Endocrine System (pages 1654–1671)

      Xuefei Lu, Ying Liu, Xiangjun Kong, Peter E. Lobie, Chunying Chen and Tao Zhu

      Article first published online: 11 FEB 2013 | DOI: 10.1002/smll.201201517

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      Emerging roles of nanomaterials as possible endocrine disruptors are highlighted in this review. Nanomaterials may impact the endocrine system to modulate both physiological and pathological functions. Current knowledge of nanomaterial-related endocrine toxicity is rudimentary. Further systematic in depth studying is thus warranted.

    17. Boron Nitride Nanotubes: Biocompatibility and Potential Spill-Over in Nanomedicine (pages 1672–1685)

      Gianni Ciofani, Serena Danti, Giada Graziana Genchi, Barbara Mazzolai and Virgilio Mattoli

      Article first published online: 19 FEB 2013 | DOI: 10.1002/smll.201201315

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      Potential applications of boron nitride nanotubes in biomedicine: the exploitation of their chemical and physical properties is reviewed.

  11. Communications

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    1. Graphene Oxide, But Not Fullerenes, Targets Immunoproteasomes and Suppresses Antigen Presentation by Dendritic Cells (pages 1686–1690)

      Alexey V. Tkach, Naveena Yanamala, Shyla Stanley, Michael R. Shurin, Galina V. Shurin, Elena R. Kisin, Ashley R. Murray, Samantha Pareso, Timur Khaliullin, Gregg P. Kotchey, Vincent Castranova, Sanjay Mathur, Bengt Fadeel, Alexander Star, Valerian E. Kagan and Anna A. Shvedova

      Article first published online: 13 AUG 2012 | DOI: 10.1002/smll.201201546

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      Graphene oxide (GO) and C60- or C60-TRIS fullerenes, internalized by murine dendritic cells (DCs), differently affect their abilities to present antigens to T-cells. While C60-fullerenes stimulate the ovalbumin-specific MHC class I-restricted T-cell response, GO impairs the stimulatory potential of DCs. In contrast to C60-fullerenes, GO decreases the intracellular levels of LMP7 immunoproteasome subunits required for processing of protein antigens. This is important for the development of DC-based vaccines.

    2. Carbon Nanotubes Enhance Metastatic Growth of Lung Carcinoma via Up-Regulation of Myeloid-Derived Suppressor Cells (pages 1691–1695)

      Anna A. Shvedova, Alexey V. Tkach, Elena R. Kisin, Timur Khaliullin, Shyla Stanley, Dmitriy W. Gutkin, Alexander Star, Yanan Chen, Galina V. Shurin, Valerian E. Kagan and Michael R. Shurin

      Article first published online: 20 SEP 2012 | DOI: 10.1002/smll.201201470

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      Metastatic establishment and growth of Lewis lung carcinoma is promoted by single-walled carbon nanotubes (SWCNT) in C57BL6/J mice. The effect is mediated by increased local and systemic accumulation of myeloid-derived suppressor cells (MDSC), as their depletion abrogated pro-tumor activity in vivo. These data are important for the design of novel theranostics platforms with modules capable of depleting or functionally suppressing MDSC to ensure effective immunosurveillance in the tumor microenvironment.

    3. Evaluation of Cell Function Upon Nanovector Internalization (pages 1696–1702)

      Jonathan O. Martinez, Alessandro Parodi, Xuewu Liu, Mikhail G. Kolonin, Mauro Ferrari and Ennio Tasciotti

      Article first published online: 20 NOV 2012 | DOI: 10.1002/smll.201202001

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      In vitro toxicity assays based on the evaluation and retention of advanced and specific cellular functions are proposed to investigate mesoporous silicon nanovectors. This approach provides greater insight compared to simple cellular viability and toxicity assays. Electron microscopy images demonstrate internalized nanovectors altering the curvature of the nuclear envelope with minimal effect on viability or biological function.

    4. Three-Dimensional Graphene Network Composites for Detection of Hydrogen Peroxide (pages 1703–1707)

      Xiehong Cao, Zhiyuan Zeng, Wenhui Shi, Peiru Yep, Qingyu Yan and Hua Zhang

      Article first published online: 30 AUG 2012 | DOI: 10.1002/smll.201200683

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      A three-dimensional graphene network (3DGN) prepared by CVD is used as a template to synthesize various composites. These composites are further used as electrodes for electrochemical sensors, which exhibit a low detection limit, quick response time, and wide linear range toward the detection of H2O2.

    5. Gold Nanoparticles Elevate Plasma Testosterone Levels in Male Mice without Affecting Fertility (pages 1708–1714)

      Wen-Qing Li, Feng Wang, Zhi-Min Liu, Yu-Cai Wang, Jun Wang and Fei Sun

      Article first published online: 22 AUG 2012 | DOI: 10.1002/smll.201201079

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      ω-Methoxy and ω-aminoethyl poly(ethylene glycol)-modified 14-nm gold nanoparticles can accumulate in mouse testes, pass through the blood–testis barrier, and enter germ cells. Furthermore, PEG–NH2@AuNP accumulate more easier in the testes and increase plasma T levels. However, these two gold nanoparticle types have no effect on male fertility, fetal survival, or fetal development.

    6. Silver Nanoparticles Decrease Body Weight and Locomotor Activity in Adult Male Rats (pages 1715–1720)

      Yongbin Zhang, Sherry A. Ferguson, Fumiya Watanabe, Yvonne Jones, Yang Xu, Alexandru S. Biris, Saber Hussain and Syed F. Ali

      Article first published online: 20 JAN 2013 | DOI: 10.1002/smll.201201548

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      Silver nanoparticles (Ag-NPs) are widely used in FDA regulated products. The physical-chemical properties of Ag-NPs are characterized using various instruments. The dose-dependent activity and body weight alterations are evaluated after rats were exposed to Ag nanoparticles, suggesting a major human health risk, given the wide application of silver nanomaterials.

  12. Frontispiece

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      Mesoporous Silicon: Short and Long Term, In Vitro and In Vivo Correlations of Cellular and Tissue Responses to Mesoporous Silicon Nanovectors (Small 9–10/2013) (page 1721)

      Jonathan O. Martinez, Christian Boada, Iman K. Yazdi, Michael Evangelopoulos, Brandon S. Brown, Xuewu Liu, Mauro Ferrari and Ennio Tasciotti

      Article first published online: 16 MAY 2013 | DOI: 10.1002/smll.201370058

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      Current assessment of the toxicity associated with nanocarriers provides poor insight into their true impact on cell function and cell fate. This pseudo-colored scanning electron microscopy image from E. Tasciotti and co-workers shows a nanoporous silicon particle in the process of being engulfed by murine macrophages. The particle induces a response in the macrophage, which triggers filopodic tentacles to extend and capture the nanocarrier to begin phagocytosis. Alternative methods are proposed on page 1722 to effectively study the influences of nanovectors on biological systems.

  13. Full Papers

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    1. Short and Long Term, In Vitro and In Vivo Correlations of Cellular and Tissue Responses to Mesoporous Silicon Nanovectors (pages 1722–1733)

      Jonathan O. Martinez, Christian Boada, Iman K. Yazdi, Michael Evangelopoulos, Brandon S. Brown, Xuewu Liu, Mauro Ferrari and Ennio Tasciotti

      Article first published online: 16 DEC 2012 | DOI: 10.1002/smll.201201939

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      The toxicities accompanying mesoporous silicon nanovectors are evaluated using established in vitro and in vivo analogous techniques aiming to provide corresponding information on cellular and systemic levels over prolonged periods. In vivo longitudinal imaging demonstrates substantial accumulation of particles within the liver and spleen, which produce negligible cytotoxic effects, supporting their use for biomedical applications.

    2. Evaluating the Toxicity of Hydroxyapatite Nanoparticles in Catfish Cells and Zebrafish Embryos (pages 1734–1741)

      Xinxin Zhao, Kimberly J. Ong, James D. Ede, James L. Stafford, Kee Woei Ng, Greg G. Goss and Say Chye Joachim Loo

      Article first published online: 9 AUG 2012 | DOI: 10.1002/smll.201200639

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      Hydroxyapatite nanoparticles (nHA) can delay zebrafish hatching. The hatching delay is related to particle concentration. nHA studied at the lowest concentration (3 μg mL−1) with hydrodynamic size of 394 nm causes the highest hatching inhibition at 72 hpf. Increased concentration induces microsize agglomeration, concomitant with low hatching inhibition.

    3. Susceptibility of Young and Adult Rats to the Oral Toxicity of Titanium Dioxide Nanoparticles (pages 1742–1752)

      Yun Wang, Zhangjian Chen, Te Ba, Ji Pu, Tian Chen, Yanshuang Song, Yongen Gu, Qin Qian, Yingying Xu, Kun Xiang, Haifang Wang and Guang Jia

      Article first published online: 4 SEP 2012 | DOI: 10.1002/smll.201201185

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      This work compares the oral toxicity of TiO2 nanoparticles across different ages of rats, finding that young rats are more susceptible to nanoparticle exposure than adult rats. These results suggest that it is necessary to consider age differences when we set up the recommended daily intake of TiO2 NPs in food.

    4. An Assessment of Fluorescence- and Absorbance-Based Assays to Study Metal-Oxide Nanoparticle ROS Production and Effects on Bacterial Membranes (pages 1753–1764)

      Allison M. Horst, Raja Vukanti, John H. Priester and Patricia A. Holden

      Article first published online: 10 SEP 2012 | DOI: 10.1002/smll.201201455

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      Five assays to study nanoparticle reactive oxygen species generation and effects on bacterial membrane integrity, membrane potential, and electron transport chain activity are assessed. A detailed quantitative assessment of nanoscale TiO2, CeO2, and ZnO interferences with assay reagents and function are included, in the context of a general scheme to test for nanoparticle interferences with fluorescence- and absorbance-based assays.

    5. Characterization and Preliminary Toxicity Assay of Nano-Titanium Dioxide Additive in Sugar-Coated Chewing Gum (pages 1765–1774)

      Xin-Xin Chen, Bin Cheng, Yi-Xin Yang, Aoneng Cao, Jia-Hui Liu, Li-Jing Du, Yuanfang Liu, Yuliang Zhao and Haifang Wang

      Article first published online: 15 OCT 2012 | DOI: 10.1002/smll.201201506

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      A facile method to separate nano-TiO2 particles from chewing gum to achieve comprehensive characterization is reported. Over 93% of TiO2 in gum is smaller than 200 nm, and around 95% would enter the body of a person chewing the gum. These nano-TiO2 particles are relatively safe for gastrointestinal cells.

  14. Frontispiece

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      Metal Oxides: Zebrafish High-Throughput Screening to Study the Impact of Dissolvable Metal Oxide Nanoparticles on the Hatching Enzyme, ZHE1 (Small 9–10/2013) (page 1775)

      Sijie Lin, Yan Zhao, Zhaoxia Ji, Jason Ear, Chong Hyun Chang, Haiyuan Zhang, Cecile Low-Kam, Kristin Yamada, Huan Meng, Xiang Wang, Rong Liu, Suman Pokhrel, Lutz Mädler, Robert Damoiseaux, Tian Xia, Hilary A. Godwin, Shuo Lin and André E. Nel

      Article first published online: 16 MAY 2013 | DOI: 10.1002/smll.201370059

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      Zebrafish is emerging as a model organism for the safety assessment and hazard ranking of engineered nanomaterials. On page 1776, A. E. Nel and co-workers showcase a highly automated high-throughput screening (HTS) platform using zebrafish embryos for the hazard assessment of 24 representative metal oxide nanoparticles. Through HTS analysis, four metal oxide nanoparticles are found to interfere with zebrafish embryo hatching. It is further demonstrated that hatching interference is a result of toxic metal ion shed from nanoparticles, compromising the zebrafish hatching enzyme 1 (ZHE1) activity. The structural and functional similarities of hatching enzymes across fish species suggest that the ZHE1 mechanistic paradigm could be used to predict the toxicity of a large number of engineered nanoparticles that may be hazardous to aquatic species.

  15. Full Papers

    1. Top of page
    2. Cover Picture
    3. Inside Front Cover
    4. Back Cover
    5. Masthead
    6. Contents
    7. Editorial
    8. Essay
    9. Concepts
    10. Frontispiece
    11. Reviews
    12. Communications
    13. Frontispiece
    14. Full Papers
    15. Frontispiece
    16. Full Papers
    1. Zebrafish High-Throughput Screening to Study the Impact of Dissolvable Metal Oxide Nanoparticles on the Hatching Enzyme, ZHE1 (pages 1776–1785)

      Sijie Lin, Yan Zhao, Zhaoxia Ji, Jason Ear, Chong Hyun Chang, Haiyuan Zhang, Cecile Low-Kam, Kristin Yamada, Huan Meng, Xiang Wang, Rong Liu, Suman Pokhrel, Lutz Mädler, Robert Damoiseaux, Tian Xia, Hilary A. Godwin, Shuo Lin and André E. Nel

      Article first published online: 23 NOV 2012 | DOI: 10.1002/smll.201202128

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      Automated high-throughput screening using zebrafish embryos is used for hazard assessment of 24 representative metal oxide nanoparticles. Four nanoparticles are found to interfere with zebrafish embryo hatching. Hatching interference is a result of toxic metal ion shedding from nanoparticles, compromising the zebrafish hatching enzyme 1 (ZHE1) activity. The structural and functional similarities of hatching enzymes across fish species suggest that the ZHE1 mechanistic paradigm could be used to predict the toxicity of a large number of engineered nanoparticles.

    2. Short Multiwall Carbon Nanotubes Promote Neuronal Differentiation of PC12 Cells via Up-Regulation of the Neurotrophin Signaling Pathway (pages 1786–1798)

      Li Meng, Rui Chen, Aihua Jiang, Liming Wang, Peng Wang, Chen-zhong Li, Ru Bai, Yuliang Zhao, Herman Autrup and Chunying Chen

      Article first published online: 7 NOV 2012 | DOI: 10.1002/smll.201201388

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      The roles of the length of multiwall carbon nanotubes (MWCNTs) on neuronal differentiation of PC12 cells are investigated. Incubation of PC12 cells with carboxylated MWCNTs does not affect cellular morphology and viability at lower concentrations. Shorter MWCNTs show higher cellular uptake and more obvious exocytosis compared to longer ones, which can result in a higher ability to promote PC12 cell differentiation. Pre-incubation of short MWCNTs can up-regulate the expression of neurotrophin signaling pathway-associated TrkA/p75 receptors and Pincher/Gap43/TH proteins, which might be the underlying mechanism for the improved neuronal differentiation in PC12 cells.

    3. Multistage Vectored siRNA Targeting Ataxia-Telangiectasia Mutated for Breast Cancer Therapy (pages 1799–1808)

      Rong Xu, Yi Huang, Junhua Mai, Guodong Zhang, Xiaojing Guo, Xiaojun Xia, Eugene J. Koay, Guoting Qin, Donald R. Erm, Qingpo Li, Xuewu Liu, Mauro Ferrari and Haifa Shen

      Article first published online: 6 JAN 2013 | DOI: 10.1002/smll.201201510

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      Delivery of ataxia-telangiectasia mutated (ATM) siRNA to breast cancer is mediated by a multistage vector (MSV) system. This system consists of a porous silicon microparticle loaded with siRNA nanoparticles. The MSV particles settle at the tumor vasculature where the siRNA nanoparticles are released into the tumor interstitium. Uptake of siRNA by tumor cells results in knockdown of ATM expression, and subsequently tumor growth inhibition.

    4. Internalization Pathways of Anisotropic Disc-Shaped Zeolite L Nanocrystals with Different Surface Properties in HeLa Cancer Cells (pages 1809–1820)

      Zhen Li, Jana Hüve, Christina Krampe, Gianluigi Luppi, Manuel Tsotsalas, Jürgen Klingauf, Luisa De Cola and Kristina Riehemann

      Article first published online: 18 JAN 2013 | DOI: 10.1002/smll.201201702

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      Interaction of zeolite L nanocontainers with cancer cells. By inhibition and colocalization experiments, the route of uptake and the intracellular fate of functionalized zeolite L nanoparticles in Hela cancer cells are described. According to their surface charge, zeolites are selectively engulfed and intracellularly targeted. The results show how the destiny of nanoparticles in cancer cells can be altered by surface functionalization.

    5. Biosensing Approaches for Rapid Genotoxicity and Cytotoxicity Assays upon Nanomaterial Exposure (pages 1821–1830)

      Xuena Zhu, Evangelia Hondroulis, Wenjun Liu and Chen-zhong Li

      Article first published online: 18 FEB 2013 | DOI: 10.1002/smll.201201593

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      Nanomaterials can enhance reactive oxygen species generation inside the human body, inducing oxidative stress, DNA damage, and unregulated cell signaling, and eventually leading to changes in cell motility, apoptosis, and even carcinogenesis. A novel lateral flow immunosensor is developed for rapid nanotoxicity assessment based on an oxidative DNA damage biomarker (8-hydroxy-2′-deoxyguanosine).

    6. Silver Nanoparticle Exposure Attenuates the Viability of Rat Cerebellum Granule Cells through Apoptosis Coupled to Oxidative Stress (pages 1831–1841)

      Nuoya Yin, Qian Liu, Jiyan Liu, Bin He, Lin Cui, Zhuona Li, Zhaojun Yun, Guangbo Qu, Sijin Liu, Qunfang Zhou and Guibin Jiang

      Article first published online: 20 FEB 2013 | DOI: 10.1002/smll.201202732

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      Silver nanoparticles (AgNPs) can induce significant cellular toxicity to cerebellum granule cells (CGCs). The apoptotic proportion of CGCs and caspase-3 activity increase in AgNP-treated groups compared to controls. AgNPs can also induce oxidative stress in CGCs. An in vivo test shows that AgNPs can provoke the destruction of the cerebellum granular layer with concomitant activation of caspase-3 after AgNP administration through intranasal instillation.

    7. Nano-SAR Development for Bioactivity of Nanoparticles with Considerations of Decision Boundaries (pages 1842–1852)

      Rong Liu, Robert Rallo, Ralph Weissleder, Carlos Tassa, Stanley Shaw and Yoram Cohen

      Article first published online: 19 FEB 2013 | DOI: 10.1002/smll.201201903

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      A classification nano-structure–activity relationships (nano-SARs) development process is presented for nanoparticle (NP) bioactivity, in which multiparametric high-throughput screening (HTS) bioactivity profiles are integrated to arrive at statistically meaningful nano-SAR endpoints (bioactive/inactive class definitions). The approach presents quantification of nano-SAR applicability domains and determination of nano-SAR decision boundaries for different acceptance levels of false negative to false positive predictions.

    8. Mapping the Biological Oxidative Damage of Engineered Nanomaterials (pages 1853–1865)

      Shu-Feng Hsieh, Dhimiter Bello, Daniel F. Schmidt, Anoop K. Pal, Aaron Stella, Jacqueline A. Isaacs and Eugene J. Rogers

      Article first published online: 19 FEB 2013 | DOI: 10.1002/smll.201201995

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      Biological oxidative damage (BOD) elicited by a range of nanomaterials demonstrate the influence of physicochemical characteristics on oxidative potential. Both within-class and between-class variations of BOD values are high. BOD values varied by different chemical compositions, and within the same chemical class BOD values are altered by particle size, surface area, and surface functionalization or treatment.

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