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Shin-Woo Ha,1 Jin-Kyu Lee,2 George R Beck Jr1,3,4 1Division of Endocrinology, Department of Medicine, Emory University, Atlanta, GA, USA; 2Department of Chemistry, Seoul National University, Seoul, South Korea; 3The Atlanta Department of Veterans Affairs Medical Center, Decatur, 4The Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA Abstract: To date, delivery of light-emitting diode (LED)-activated compounds to cells and tissue remains a challenge. Silica-based materials possess good biocompatibility and have advantages of control of size and shape. Fluorescent silica nanoparticles (NPs) have been synthesized and used for applications such as cell tracking and tumor identification. Here, we report the synthesis and optimization of fluorescent silica NPs, which incorporate a naphthalimide dye with triethoxysilanes that are excited by the blue LED wavelength (LEDex NPs). The NPs can be imaged in the 420–470 nm wavelength, demonstrate a high quantum yield, are stable in a range of pH, and are taken into the cells. Therefore, these NPs represent a novel imaging technology for biomedical applications. Keywords: naphthalimide, imaging, bone marrow stromal cell migration, reduced toxicity

Jeong-A Lee,1,* Mi-Kyung Kim,1,* Hyoung-Mi Kim,2,* Jong Kwon Lee,3 Jayoung Jeong,4 Young-Rok Kim,5 Jae-Min Oh,2 Soo-Jin Choi1 1Department of Food Science and Technology, Seoul Women’s University, Seoul, Republic of Korea; 2Department of Chemistry and Medical Chemistry, College of Science and Technology, Yonsei University, Wonju, Republic of Korea; 3Hazard Substances Analysis Division, Gwangju Regional Food and Drug Administration, Ministry of Food and Drug Safety, Gwangju, Republic of Korea; 4Toxicological Research Division, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Chungcheongbuk-do, Republic of Korea; 5Department of Food Science and Biotechnology, Kyung Hee University, Yongin, Republic of Korea *These authors contributed equally to this work Background: Orally administered particles rapidly interact with biological fluids containing proteins, enzymes, electrolytes, and other biomolecules to eventually form particles covered by a corona, and this corona potentially affects particle uptake, fate, absorption, distribution, and elimination in vivo. This study explored relationships between the biological interactions of calcium carbonate particles and their biokinetics.Methods: We examined the effects of food grade calcium carbonates of different particle size (nano [N-Cal] and bulk [B-Cal]: specific surface areas of 15.8 and 0.83 m2/g, respectively) on biological interactions in in vitro simulated physiological fluids, ex vivo biofluids, and in vivo in gastrointestinal fluid. Moreover, absorption and tissue distribution of calcium carbonates were evaluated following a single dose oral administration to rats.Results: N-Cal interacted more with biomatrices than bulk materials in vitro and ex vivo, as evidenced by high fluorescence quenching ratios, but it did not interact more actively with biomatrices in vivo. Analysis of coronas revealed that immunoglobulin, apolipoprotein, thrombin, and fibrinogen, were the major corona proteins, regardless of particle size. A biokinetic study revealed that orally delivered N-Cal was more rapidly absorbed into the blood stream than B-Cal, but no significant differences were observed between the two in terms of absorption efficiencies or tissue distributions. Both calcium carbonates were primarily present as particulate forms in gastrointestinal fluids but enter the circulatory system in dissolved Ca2+, although both types showed partial phase transformation to dicalcium phosphate dihydrate. Relatively low dissolution (about 4%), no remarkable protein–particle interaction, and the major particulate fate of calcium carbonate in vivo gastrointestinal fluids can explain its low oral absorption (about 4%) regardless of particle size.Conclusion: We conclude that calcium carbonate nanoparticles can act more actively with biological matrices in vitro and ex vivo, but that in vivo, their biological interactions and biokinetics are not affected by particle size. Keywords: biological interaction, oral absorption, biokinetics, size effect, protein corona

Jae-Kwan Lee,1,4 Dong-Soon Choi,2,4 Insan Jang,2,4 Won-Youl Choi3,4 1Department of Periodontology, 2Department of Orthodontics, College of Dentistry, 3Department of Metal and Materials Engineering, 4Research Institute for Dental Engineering, Gangneung-Wonju National University, Gangneung, South Korea Abstract: TiO2 nanotube arrays on the surface of dental implants were fabricated by two-step anodic oxidation. Their effects on bone-implant contact were researched by a pilot in vivo study. The implants were classified into four groups. An implant group with TiO2 nanotube arrays and recombinant human bone morphogenetic protein-2 (rhBMP-2) was compared with various surface implants, including machined surface, sandblasted large-grit and acid-etched surface, and TiO2 nanotube array surface groups. The diameter of the TiO2 nanotube window and TiO2 nanotube were ~70 nm and ~110 nm, respectively. The rhBMP-2 was loaded into TiO2 nanotube arrays and elution was detected by an interferometric biosensing method. A change in optical thickness of ~75 nm was measured by flow cell testing for 9 days, indicating elution of rhBMP-2 from the TiO2 nanotube arrays. For the in vivo study, the four groups of implants were placed into the proximal tibia of New Zealand white rabbits. In the implant group with TiO2 nanotube arrays and rhBMP-2, the bone-to-implant contact ratio was 29.5% and the bone volume ratio was 77.3%. Bone remodeling was observed not only in the periosteum but also in the interface between the bone and implant threads. These values were higher than in the machined surface, sandblasted large-grit and acid-etched surface, and TiO2 nanotube array surface groups. Our results suggest that TiO2 nanotube arrays could potentially be used as a reservoir for rhBMP-2 to reinforce osseointegration on the surface of dental implants. Keywords: TiO2 nanotube arrays, drug reservoir, dental implant, bone morphogenetic protein

Jeong-A Lee,1 Mi-Kyung Kim,1 Hee-Jeong Paek,1 Yu-Ri Kim,2 Meyoung-Kon Kim,2 Jong-Kwon Lee,3 Jayoung Jeong,3 Soo-Jin Choi1 1Department of Food Science and Technology, Seoul Women’s University, Seoul, Republic of Korea; 2Department of Biochemistry and Molecular Biology, Korea University Medical School and College, Seoul, Republic of Korea; 3Toxicological Research Division, National Institute of Food and Drug Safety Evaluation, Chungchungbuk–do, Republic of Korea Purpose: The effects of particle size on the tissue distribution and excretion kinetics of silica nanoparticles and their biological fates were investigated following a single oral administration to male and female rats. Methods: Silica nanoparticles of two different sizes (20 nm and 100 nm) were orally administered to male and female rats, respectively. Tissue distribution kinetics, excretion profiles, and fates in tissues were analyzed using elemental analysis and transmission electron microscopy. Results: The differently sized silica nanoparticles mainly distributed to kidneys and liver for 3 days post-administration and, to some extent, to lungs and spleen for 2 days post-administration, regardless of particle size or sex. Transmission electron microscopy and energy dispersive spectroscopy studies in tissues demonstrated almost intact particles in liver, but partially decomposed particles with an irregular morphology were found in kidneys, especially in rats that had been administered 20 nm nanoparticles. Size-dependent excretion kinetics were apparent and the smaller 20 nm particles were found to be more rapidly eliminated than the larger 100 nm particles. Elimination profiles showed 7%–8% of silica nanoparticles were excreted via urine, but most nanoparticles were excreted via feces, regardless of particle size or sex. Conclusion: The kidneys, liver, lungs, and spleen were found to be the target organs of orally-administered silica nanoparticles in rats, and this organ distribution was not affected by particle size or animal sex. In vivo, silica nanoparticles were found to retain their particulate form, although more decomposition was observed in kidneys, especially for 20 nm particles. Urinary and fecal excretion pathways were determined to play roles in the elimination of silica nanoparticles, but 20 nm particles were secreted more rapidly, presumably because they are more easily decomposed. These findings will be of interest to those seeking to predict potential toxicological effects of silica nanoparticles on target organs. Keywords: biological fate, size effect, target organ

Jee Young Kwon,1,* Hye Lim Kim,1,* Jong Yun Lee,2 Yo Han Ju,2 Ji Soo Kim,2 Seung Hun Kang,1 Yu-Ri Kim,3 Jong-Kwon Lee,4 Jayoung Jeong,4 Meyoung-Kon Kim,3 Eun Ho Maeng,2 Young Rok Seo1 1Department of Life Science, Institute of Environmental Medicine, Dongguk University, Seoul, 2Korea Testing and Research Institute, 3Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, 4Toxicological Research Division, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Chungcheongbuk-do, Republic of Korea *These authors contributed equally to this work and should be considered co-first authors Background: Silica dioxide (SiO2) has been used in various industrial products, including paints and coatings, plastics, synthetic rubbers, and adhesives. Several studies have investigated the genotoxic effects of SiO2; however, the results remain controversial due to variations in the evaluation methods applied in determining its physicochemical properties. Thus, well characterized chemicals and standardized methods are needed for better assessment of the genotoxicity of nanoparticles.Methods: The genotoxicity of SiO2 was evaluated using two types of well characterized SiO2, ie, 20 nm (-) charge (SiO2EN20(-)) and 100 nm (-) charge (SiO2EN100(-)). Four end point genotoxicity tests, ie, the bacterial mutation assay, in vitro chromosomal aberration test, in vivo comet assay, and in vivo micronucleus test, were conducted following the test guidelines of the Organization for Economic Cooperation and Development (OECD) with application of Good Laboratory Practice.Results: No statistically significant differences were found in the bacterial mutation assay, in vitro chromosomal aberration test, in vivo comet assay, and in vivo micronucleus test when tested for induction of genotoxicity in both two types of SiO2 nanoparticles.Conclusion: These results suggest that SiO2 nanoparticles, in particular SiO2EN20(-) and SiO2EN100(-), are not genotoxic in both in vitro and in vivo systems under OECD guidelines. Further, the results were generated in accordance with OECD test guidelines, and Good Laboratory Practice application; it can be accepted as reliable information regarding SiO2-induced genotoxicity. Keywords: genotoxicity test, Organization for Economic Cooperation and Development test guideline, Good Laboratory Practice, silica dioxide

Kyoung-Min Kim,1 Hye Min Kim,1 Won-Jae Lee,2 Chang-Woo Lee,3 Tae-il Kim,4 Jong-Kwon Lee,5 Jayoung Jeong,5 Seung-Min Paek,2 Jae-Min Oh1 1Department of Chemistry and Medical Chemistry, College of Science and Technology, Yonsei University, Gangwon-do, Republic of Korea; 2Department of Chemistry, Kyungpook National University, Taegu, Republic of Korea; 3Battelle-Korea Laboratory, International Center for Converging Technology, Korea University, Seoul, Republic of Korea; 4Department of Biosystems and Biomaterials Science and Engineering, College of Agriculture and Life Sciences, Seoul National University, Seoul, Republic of Korea; 5Toxicological Research Division, National Institute of Food and Drug Safety Evaluation, Chungchungbuk-do, Republic of Korea Abstract: An attempt was made to control the surface charge of colloidal silica nanoparticles with 20 nm and 100 nm diameters. Untreated silica nanoparticles were determined to be highly negatively charged and have stable hydrodynamic sizes in a wide pH range. To change the surface to a positively charged form, various coating agents, such as amine containing molecules, multivalent metal cation, or amino acids, were used to treat the colloidal silica nanoparticles. Molecules with chelating amine sites were determined to have high affinity with the silica surface to make agglomerations or gel-like networks. Amino acid coatings resulted in relatively stable silica colloids with a modified surface charge. Three amino acid moiety coatings (L-serine, L-histidine, and L-arginine) exhibited surface charge modifying efficacy of L-histidine > L-arginine > L-serine and hydrodynamic size preservation efficacy of L-serine > L-arginine > L-histidine. The time dependent change in L-arginine coated colloidal silica was investigated by measuring the pattern of the backscattered light in a Turbiscan™. The results indicated that both the 20 nm and 100 nm L-arginine coated silica samples were fairly stable in terms of colloidal homogeneity, showing only slight coalescence and sedimentation. Keywords: silica, nanoparticles, surface charge, colloidal stability, turbidity, amino acids

Yu-Ri Kim,1,* Sung Ha Park,2,* Jong-Kwon Lee,3 Jayoung Jeong,3 Ja Hei Kim,4 Eun-Ho Meang,5 Tae Hyun Yoon,6 Seok Tae Lim,7 Jae-Min Oh,8 Seong Soo A An,9 Meyoung-Kon Kim1 1Department of Biochemistry and Molecular Biology, Korea University Medical School and College, Seoul, South Korea; 2Department of Biochemistry, University of Bath, Bath, UK; 3Toxicological Research Division, National Institute of Food and Drug Safety Evaluation, Chungchungbuk-do, 4Consumers Korea, Chongro-ku, 5General toxicology team, Korea Testing and Research Institute, 6Laboratory of Nanoscale Characterization and Environmental Chemistry, Department of Chemistry, College of Natural Sciences, Hanyang University, Seoul, 7Department of Nuclear Medicine, Chonbuk National University Medical School, Jeonju, Jellabuk-Do, 8Department of Chemistry and Medical Chemistry, College of Science and Technology, Yonsei University, Gangwon-do, 9Department of Bionanotechnology, Gachon Medical Research Institute, Gachon University, Seongnam, South Korea *Authors contributed equally to this work Abstract: Currently, products made with nanomaterials are used widely, especially in biology, biotechnologies, and medical areas. However, limited investigations on potential toxicities of nanomaterials are available. Hence, diverse and systemic toxicological data with new methods for nanomaterials are needed. In order to investigate the nanotoxicology of nanoparticles (NPs), the Research Team for Nano-Associated Safety Assessment (RT-NASA) was organized in three parts and launched. Each part focused on different contents of research directions: investigators in part I were responsible for the efficient management and international cooperation on nano-safety studies; investigators in part II performed the toxicity evaluations on target organs such as assessment of genotoxicity, immunotoxicity, or skin penetration; and investigators in part III evaluated the toxicokinetics of NPs with newly developed techniques for toxicokinetic analyses and methods for estimating nanotoxicity. The RT-NASA study was carried out in six steps: need assessment, physicochemical property, toxicity evaluation, toxicokinetics, peer review, and risk communication. During the need assessment step, consumer responses were analyzed based on sex, age, education level, and household income. Different sizes of zinc oxide and silica NPs were purchased and coated with citrate, L-serine, and L-arginine in order to modify surface charges (eight different NPs), and each of the NPs were characterized by various techniques, for example, zeta potentials, scanning electron microscopy, and transmission electron microscopy. Evaluation of the “no observed adverse effect level” and systemic toxicities of all NPs were performed by thorough evaluation steps and the toxicokinetics step, which included in vivo studies with zinc oxide and silica NPs. A peer review committee was organized to evaluate and verify the reliability of toxicity tests, and the risk communication step was also needed to convey the current findings to academia, industry, and consumers. Several limitations were encountered in the RT-NASA project, and they are discussed for consideration for improvements in future studies. Keywords: nanomaterials, nanotoxicity, toxicokinetics, physicochemical property, peer review

Hark-Soo Park,1 Sung-Sup Shin,1 Eun Ho Meang,1 Jeong-sup Hong,1 Jong-Il Park,1 Su-Hyon Kim,1 Sang-Bum Koh,1 Seung-Young Lee,1 Dong-Hyouk Jang,1 Jong-Yun Lee,1 Yle-Shik Sun,1 Jin Seok Kang,2 Yu-Ri Kim,3 Meyoung-Kon Kim,3 Jayoung Jeong,4 Jong-Kwon Lee,4 Woo-Chan Son,5 Jae-Hak Park6 1General Toxicology Team, Korea Testing and Research Institute, Seoul, Korea; 2Department of Biomedical Laboratory Science, Namseoul University, Cheonan, Korea; 3Department of Biochemistry and Molecular Biology, Korea University Medical School and College, Seoul, Korea; 4National Institute of Food and Drug Safety Evaluation, Seoul, Korea; 5Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea; 6Laboratory Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul, Korea Purpose: The widespread use of nanoparticles (NPs) in industrial and biomedical applications has prompted growing concern regarding their potential toxicity and impact on human health. This study therefore investigated the subchronic, systemic oral toxicity and no-observed-adverse-effect level (NOAEL) of 20 nm, negatively charged zinc oxide (ZnOSM20(-)) NPs in Sprague Dawley rats for 90 days.Methods: The high-dose NP level was set at 500 mg/kg of bodyweight, and the mid- and low-dose levels were set at 250 and 125 mg/kg, respectively. The rats were observed during a 14-day recovery period after the last NP administration for the persistence or reduction of any adverse effects. Toxicokinetic and distribution studies were also conducted to determine the systemic distribution of the NPs.Results: No rats died during the test period. However, ZnOSM20(-) NPs (500 mg/kg) induced changes in the levels of anemia-related factors, prompted acinar cell apoptosis and ductular hyperplasia, stimulated periductular lymphoid cell infiltration and excessive salivation, and increased the numbers of regenerative acinar cells in the pancreas. In addition, stomach lesions were seen at 125, 250, and 500 mg/kg, and retinal atrophy was observed at 250 and 500 mg/kg. The Zn concentration was dose-dependently increased in the liver, kidney, intestines, and plasma, but not in other organs investigated. Conclusion: A ZnOSM20(-) NP NOAEL could not be established from the current results, but the lowest-observed-adverse-effect level was 125 mg/kg. Furthermore, the NPs were associated with a number of undesirable systemic actions. Thus, their use in humans must be approached with caution. Keywords: negative charge, oral toxicity study, rat, ZnO

Hark-Soo Park,1 Seon-Ju Kim,1 Taek-Jin Lee,1 Geon-Yong Kim,1 EunHo Meang,1 Jeong-Sup Hong,1 Su-Hyon Kim,1 Sang-Bum Koh,1 Seung-Guk Hong,1 Yle-Shik Sun,1 Jin Seok Kang,2 Yu-Ri Kim,3 Meyoung-Kon Kim,3 Jayoung Jeong,4 Jong-Kwon Lee,4 Woo-Chan Son,5 Jae-Hak Park61General Toxicology Team, Korea Testing and Research Institute, Seoul, 2Department of Biomedical Laboratory Science, Namseoul University, Cheonan, 3Department of Biochemistry and Molecular Biology, Korea University Medical School and College, Seoul, 4National Institute of Food and Drug Safety Evaluation, Seoul, 5Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 6Laboratory Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul, KoreaPurpose: The study reported here was conducted to determine the systemic oral toxicity and to find the no-observed-adverse-effect level of 20 nm positively charged zinc oxide (ZnOSM,20(+)) nanoparticles in Sprague Dawley rats for 90 days.Methods: For the 90-day toxicity study, the high dose was set as 500 mg per kg of body weight (mg/kg) and the middle and low dose were set to 250 mg/kg and 125 mg/kg, respectively. The rats were held for a 14-day recovery period after the last administration, to observe for the persistence or reduction of any toxic effects. A distributional study was also carried out for the systemic distribution of ZnOSM,20(+) NPs.Results: No rats died during the test period. There were no significant clinical changes due to the test article during the experimental period in functional assessment, body weight, food and water consumption, ophthalmological testing, urine analysis, necropsy findings, or organ weights, but salivation was observed immediately after administration in both sexes. The total red blood cell count was increased, and hematocrit, albumin, mean cell volume, mean cell hemoglobin, and mean cell hemoglobin concentration were decreased significantly compared with control in both 500 mg/kg groups. Total protein and albumin levels were decreased significantly in both sexes in the 250 and 500 mg/kg groups. Histopathological studies revealed acinar cell apoptosis in the pancreas, inflammation and edema in stomach mucosa, and retinal atrophy of the eye in the 500 mg/kg group.Conclusion: There were significant parameter changes in terms of anemia in the hematological and blood chemical analyses in the 250 and 500 mg/kg groups. The significant toxic change was observed to be below 125 mg/kg, so the no-observed-adverse-effect level was not determined, but the lowest-observed-adverse-effect level was considered to be 125 mg/kg in both sexes and the target organs were found to be the pancreas, eye, and stomach.Keywords: positive charge, oral-toxicity study, no-observed-adverse-effect level, ZnO

Kyoung-Min Kim,1 Mun-Hyoung Choi,2 Jong-Kwon Lee,3 Jayoung Jeong,3 Yu-Ri Kim,4 Meyoung-Kon Kim,4 Seung-Min Paek,2 Jae-Min Oh1 1Department of Chemistry and Medical Chemistry, College of Science and Technology, Yonsei University, Gangwon-do, 2Department of Chemistry, Kyungpook National University, Taegu, 3Toxicological Research Division, National Institute of Food and Drug Safety Evaluation, Chungchungbuk-do, 4Department of Biochemistry and Molecular Biology, Korea University Medical School and College, Seoul, South Korea Abstract: In this study, four types of standardized ZnO nanoparticles were prepared for assessment of their potential biological risk. Powder-phased ZnO nanoparticles with different particle sizes (20 nm and 100 nm) were coated with citrate or L-serine to induce a negative or positive surface charge, respectively. The four types of coated ZnO nanoparticles were subjected to physicochemical evaluation according to the guidelines published by the Organisation for Economic Cooperation and Development. All four samples had a well crystallized Wurtzite phase, with particle sizes of ~30 nm and ~70 nm after coating with organic molecules. The coating agents were determined to have attached to the ZnO surfaces through either electrostatic interaction or partial coordination bonding. Electrokinetic measurements showed that the surface charges of the ZnO nanoparticles were successfully modified to be negative (about −40 mV) or positive (about +25 mV). Although all the four types of ZnO nanoparticles showed some agglomeration when suspended in water according to dynamic light scattering analysis, they had clearly distinguishable particle size and surface charge parameters and well defined physicochemical properties. Keywords: ZnO nanoparticles, surface coating, surface charge, particle size, physicochemical properties

Chang-Moon Lee,1–4,* Hwan-Jeong Jeong,1–4,* Kuk-No Yun,1–3 Dong Wook Kim,1–4 Myung-Hee Sohn,1–4 Jong Kwon Lee,5 Jayoung Jeong,5 Seok Tae Lim1–4 *These authors contributed equally to this work.1Department of Nuclear Medicine; 2Cyclotron Research Center; 3Research Institute of Clinical Medicine; 4Institute for Medical Sciences, Chonbuk National University Medical School and Hospital, Jeonju, Jeollabuk-Do, Republic of Korea; 5Toxicological Research Division, National Institute of Food and Drug Safety Evaluation, Osong-Eup, Chungchungbuk-Do, Republic of KoreaBackground: Understanding how nanomaterials are distributed in the body after exposure is important for assessing whether they are safe. In this study, we investigated the behavior and accumulation of nanoscaled and submicron-scaled zinc oxide (ZnO) particles in the body using optical imaging following oral exposure.Methods: To trace these nanoparticles in the body, ZnO nanoparticles were conjugated with a monoreactive hydroxysuccinimide ester of Cy5.5 (Cy5.5-NHS), and the conjugation-stabilizing effect of Cy5.5 on the nanoparticles was evaluated in simulated gastric fluid (pH 1.2) for 7 hours. To compare the distribution of Cy5.5-NHS and Cy5.5-conjugated ZnO nanoparticles, Cy5.5-NHS 0.5 mg/kg and Cy5.5-conjugated ZnO nanoparticles 250 mg/kg were administered orally to healthy rats. We collected blood from the rats at predesignated time points for 7 hours after administration, and optical imaging studies were performed at 1, 2, 3, 5, and 7 hours after dosing. To investigate the extent of nanoparticle accumulation in the organs and tissues, the mice were sacrificed at 23 hours after administration, and the organs were removed and imaged.Results: Cy5.5-conjugated ZnO nanoparticles were stable in simulated gastric fluid for 7 hours. The signal intensity of Cy5.5-NHS in blood was highest 3 hours after oral administration, and Cy5.5-conjugated ZnO nanoparticles showed the highest signal intensity in blood 5–7 hours after administration. In vivo optical images indicated that Cy5.5-NHS showed optical signals in the lung, liver, and gastrointestinal tract after oral administration, whereas Cy5.5-conjugated ZnO nanoparticles were seen only in the gastrointestinal tract. Seven hours following administration, biodistribution studies demonstrated that Cy5.5-NHS accumulated in the lung and liver, and Cy5.5-conjugated ZnO nanoparticles resulted in a strong signal in the kidney and liver. Different-sized ZnO nanoparticles showed dissimilar patterns of biodistribution in ex vivo optical images.Conclusion: ZnO nanoparticles are absorbed into the tissues following oral exposure and their behavior can be monitored and evaluated using optical imaging.Keywords: zinc oxide nanoparticles, biodistribution, optical imaging, oral administration

Miri Baek,1,* Hae-Eun Chung,1,* Jin Yu,1,* Jung-A Lee,1 Tae-Hyun Kim,2 Jae-Min Oh,2 Won-Jae Lee,3 Seung-Min Paek,3 Jong Kwon Lee,4 Jayoung Jeong, 4 Jin-Ho Choy,5 Soo-Jin Choi1 1Department of Food Science and Technology, Seoul Women's University, Seoul, 2Department of Chemistry and Medical Chemistry, College of Science and Technology, Yonsei University, Wonju, Gangwondo; 3Department of Chemistry and Green-Nano Materials Research Center, Kyungpook National University, Taegu, 4Toxicological Research Division, National Institute of Food and Drug Safety Evaluation, Chungchungbuk-do, 5Center for Intelligent Nano-Bio Materials, Department of Bioinspired Science and Department of Chemistry and Nano Science, Ewha Womans University, Seoul, Republic of Korea*These authors contributed equally to this workBackground: This study explored the pharmacokinetics, tissue distribution, and excretion profile of zinc oxide (ZnO) nanoparticles with respect to their particle size in rats.Methods: Two ZnO nanoparticles of different size (20 nm and 70 nm) were orally administered to male and female rats, respectively. The area under the plasma concentration-time curve, tissue distribution, excretion, and the fate of the nanoparticles in organs were analyzed.Results: The plasma zinc concentration of both sizes of ZnO nanoparticles increased during the 24 hours after administration in a dose-dependent manner. They were mainly distributed to organs such as the liver, lung, and kidney within 72 hours without any significant difference being found according to particle size or rat gender. Elimination kinetics showed that a small amount of ZnO nanoparticles was excreted via the urine, while most of nanoparticles were excreted via the feces. Transmission electron microscopy and x-ray absorption spectroscopy studies in the tissues showed no noticeable ZnO nanoparticles, while new Zn-S bonds were observed in tissues.Conclusion: ZnO nanoparticles of different size were not easily absorbed into the bloodstream via the gastrointestinal tract after a single oral dose. The liver, lung, and kidney could be possible target organs for accumulation and toxicity of ZnO nanoparticles was independent of particle size or gender. ZnO nanoparticles appear to be absorbed in the organs in an ionic form rather than in a particulate form due to newly formed Zn-S bonds. The nanoparticles were mainly excreted via the feces, and smaller particles were cleared more rapidly than the larger ones. ZnO nanoparticles at a concentration below 300 mg/kg were distributed in tissues and excreted within 24 hours. These findings provide crucial information on possible acute and chronic toxicity of ZnO nanoparticles in potential target organs.Keywords: ZnO nanoparticles, pharmacokinetics, tissue distribution, excretion, fate

Kwon JY, Kim HL, Lee JY, et al. Int J Nanomedicine. 2014;9(Suppl 2):173–181.The title of the paper “Undetactable levels of genotoxicity of SiO2 nanoparticles in in vitro and in vivo tests” should read “Undetectable levels of genotoxicity of SiO2 nanoparticles in in vitro and in vivo tests”.Read the original article

This study investigated the potential adverse effects of zinc oxide nanoparticles (ZnO(SM20[-]) NPs; negatively charged, 20 nm) on pregnant dams and embryo-fetal development after maternal exposure over the period of gestational days 5-19 with Sprague Dawley rats. ZnO(SM20(-)) NPs were administered to pregnant rats by gavage at 0 mg/kg/day, 100 mg/kg/day, 200 mg/kg/day, and 400 mg/kg/day. All dams were subjected to caesarean section on gestational day 20, and all the fetuses were examined for external, visceral, and skeletal alterations. Toxicity in the dams manifested as significantly decreased body weight at 400 mg/kg/day and decreased liver weight, and increased adrenal glands weight at 200 mg/kg/day and 400 mg/kg/day. However, no treatment-related difference in the number of corpora lutea, the number of implantation sites, the implantation rate (%), resorption, dead fetuses, litter size, fetal deaths, fetal and placental weights, and sex ratio were observed between the groups. Morphological examinations of the fetuses demonstrated no significant difference in the incidences of abnormalities between the groups. No significant difference was found in the Zn content of fetal tissue between the control and high-dose groups. These results showed that a 15-day repeated oral dose of ZnO(SM20(-)) was minimally maternotoxic at dose of 200 mg/kg/day and 400 mg/kg/day.