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Stensberg et al. Page 13 prepared using appropriate surface chemistries, often through biophysical inter action with proteins or other biomolecular species. For instance, Ag NPs conjugated to ligands bearing cyano groups (C≡N) have been used to image membrane receptor clustering on Hela cells through protein-mediated NP aggregation [151]. Alkyne- and carborane-functionalized Ag NPs can also produce large SERS signals and provide characteristic Raman signatures for antibody-targeted cell imaging [152,153]. SERS is even useful for detecting low-molecular- weight species and has been used to monitor adrenergic signaling to cardiac myocyte cells, which control the contraction and subsequent beating of heart muscles [154]. This ability to track molecular signatures may prove useful for cellular toxicology studies involving Ag NPs, by correlating their presence with nearby s tress-induced metabolites or biomarkers. Ag NPs as contrast agents in biomedical imaging Near-infrared-resonant Ag nanostructures, such as Ag nanoshells, have been investigated as optical contrast agents for photoacoustic imaging and other clinically relevant imaging modalities. Emelianov and coworkers proved the concept by injecting submicron Ag nanoshells with silica cores into porcine pancreas, with detection by multimodal ultrasound and photoacoustic imaging [155]. The Ag nanoshells not only increased photoacoustic contrast, but also enabled greater imaging depth into the tissue (Figure 10a & 10b). Colloidal Ag NPs have also been examined as contrast agents for computed tomography, based on their large x-ray absorption coefficients. Dendrimer-stabilized Ag NPs (16 nm) were injected subcutaneously under mouse skin tissue and determined to attenuate x-ray transmission at levels comparable to iodine-based x-ray contrast agents used in clinical settings [156]. Ag NPs (12 nm) have also been functionalized with the radiotracer 125I, followed by systemic administration in Balb/c mice for pharmacokinetic studies (Figure 10C & 10D) [157]. The in vivo biodistribution of these Ag NPs were evaluated by single-photon emission computerized tomography imaging, which indicated the spleen and liver as the primary organs of NP uptake 24 h after injection (41.5 and 24.5% ID/g, respectively). This study provides useful information about the near-term in vivo accumulation of Ag NPs, complementary to toxicity studies discussed earlier. Conclusion It is expected that the number of applications for Ag NPs will continue to grow, but there is still much that needs to be understood with respect to their fate and accumulation in the environment and their potential long-term effects on humans and other organisms. Recent studies have shown that the release of Ag NPs into the environment is increasing, yet there are large gaps in our understanding of how these particles are transported through ecosystems and migrate into the food chain and their consequences on human health. At the cellular level, a variety of mechanisms of Ag NP toxicity have been reported, including ROS generation, DNA damage and cytokine induction during in vitro studies. The few in vivo studies that have been conducted so far indicate the potential for adverse effects at the organismic level, with vulnerabilities in the circulatory, respiratory, central nervous, hepatic and dermal systems. Many more studies are needed to determine the biodistribution and subsequent toxicity of Ag NPs using in vivo systems. These future studies should include modeling of the toxicological impact of Ag NPs leached from textiles, a major source of anthropogenic silver. The physicochemical properties of Ag NPs are also important factors and should be monitored during the course of a toxicological study to assess the effects of any physical changes on NP uptake and bioavailability. While Ag NPs present some challenges for traditional toxicological assays, they also have unique qualities that enable entirely new approaches to examine their toxicological impact Nanomedicine (Lond). Author manuscript; available in PMC 2012 May 24. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptPDF Image | Toxicological studies on silver nanoparticles
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