Nabeshi et al. Nanoscale Research Letters 2011, 6:93 http://www.nanoscalereslett.com/content/6/1/93 N A N O E X P R E S S Open Access Effect of surface properties of silica nanoparticles on their cytotoxicity and cellular distribution in murine macrophages Hiromi Nabeshi1,2, Tomoaki Yoshikawa1,2*, Akihiro Arimori1,2, Tokuyuki Yoshida1,2, Saeko Tochigi1,2, Toshiro Hirai1,2, Takanori Akase1,2, Kazuya Nagano2, Yasuhiro Abe2, Haruhiko Kamada2,3, Shin-ichi Tsunoda2,4, Norio Itoh1, Yasuo Yoshioka2,3, Yasuo Tsutsumi1,2,3* Abstract Surface properties are often hypothesized to be important factors in the development of safer forms of nanomaterials (NMs). However, the results obtained from studying the cellular responses to NMs are often contradictory. Hence, the aim of this study was to investigate the relationship between the surface properties of silica nanoparticles and their cytotoxicity against a murine macrophage cell line (RAW264.7). The surface of the silica nanoparticles was either unmodified (nSP70) or modified with amine (nSP70-N) or carboxyl groups (nSP70-C). First, the properties of the silica nanoparticles were characterized. RAW264.7 cells were then exposed to nSP70, nSP70-N, or nSP70-C, and any cytotoxic effects were monitored by analyzing DNA synthesis. The results of this study show that nSP70-N and nSP70-C have a smaller effect on DNA synthesis activity by comparison to unmodified nSP70. Analysis of the intracellular localization of the silica nanoparticles revealed that nSP70 had penetrated into the nucleus, whereas nSP70-N and nSP70-C showed no nuclear localization. These results suggest that intracellular localization is a critical factor underlying the cytotoxicity of these silica nanoparticles. Thus, the surface properties of silica nanoparticles play an important role in determining their safety. Our results suggest that optimization of the surface characteristics of silica nanoparticles will contribute to the development of safer forms of NMs. Introduction Recently, a range of nanomaterials (NMs) have been designed and used in a number of different industrial applications, such as medicine, cosmetics, and foods. The application of NMs is driven by the belief that they will offer improved performance and deliver new func- tionalities, including improved thermal and electrical conductivity, harder and stronger materials, improved catalytic activity, and advanced optical properties. For example, current estimates indicate that the global mar- ket for cosmetics using NMs will grow by 16.6% per year, reaching US$ 155.8 million in 2012 [1]. Hence, human exposure to NMs is already occurring and will inevitably increase in the future. * Correspondence: tomoaki@phs.osaka-u.ac.jp; ytsutsumi@phs.osaka-u.ac.jp 1Department of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565- 0871, Japan Full list of author information is available at the end of the article A NM is defined as a substance that has at least one dimension of <100 nm in size. NMs can assume many different forms, such as tubes, rods, wires, spheres, or particles. However, their small size can also be proble- matic in terms of eliciting a toxicological effect. For example, exposure of cells or animals to carbon nano- tubes, titanium dioxide particles, or silver nanoparticles can induce cytotoxicity and inflammation [2-14]. We have previously shown that silica nanoparticles display a different intracellular localization compared with submi- cron- and micro-sized silica particles, and induce a greater cytotoxic response [15]. However, analyses of the toxicological responses to NMs are often inconsis- tent. Given the uncertainty concerning the safety of NMs, it is critically important to analyze their potential toxicological hazards and devise means of minimizing the impact of exposure to such substances. These stu- dies will assist in driving forward the nanotechnology © 2011 Nabeshi et al; licensee Springer. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.