Engineered nanoparticles (NPs) are in the same size category as atmospheric ultrafine particles, <100 nm. Per given volume, both have high numbers and surface areas compared to larger particles. The high proportion of surface atoms/molecules can give rise to a greater chemical as well as biological activity, for example the induction of reactive oxygen species in cell-free medium as well as in cells. When inhaled as singlet particles, NPs of different sizes deposit efficiently in all regions of the respiratory tract by diffusion. A major difference to larger size particles is the propensity of NPs to translocate across cell barriers from the portal of entry (e.g., the respiratory tract) to secondary organs and to enter cells by various mechanisms and associate with subcellular structures. This makes NPs uniquely suitable for therapeutic and diagnostic uses, but it also leaves target organs such as the central nervous system (CNS) vulnerable to potential adverse effects (e.g., oxidative stress). Neuronal transport of NPs has been described, involving retrograde and anterograde movement in axons and dendrites as well as perineural translocation. This is of importance for access of inhaled NPs to the central nervous system (CNS) via sensory nerves existing in the nasopharyngeal and tracheobronchial regions of the respiratory tract. The neuronal pathway circumvents the very tight blood brain barrier. In general, translocation rates of NP from the portal of entry into the blood compartment or the CNS are very low. Important modifiers of translocation are the physicochemical characteristics of NPs, most notably their size and surface properties, particularly surface chemistry. Primary surface coating (when NPs are manufactured) and secondary surface coating (adsorption of lipids/proteins occurring at the portal of entry and during subsequent translocation) can significantly alter NP biokinetics and their effects. Implications of species differences in respiratory tract anatomy, breathing pattern and brain anatomy for extrapolation to humans of NP effects observed in rodents need to be considered. Although there are anecdotal data indicating a causal relationship between long-term ultrafine particle exposures in ambient air (e.g., traffic related) or at the workplace (e.g., metal fumes) and resultant neurotoxic effects in humans, more studies are needed to test the hypothesis that inhaled nanoparticles cause neurodegenerative effects. Some, but probably not the majority of NPs, will have a significant toxicity (hazard) potential, and this will pose a significant risk if there is a sufficient exposure. The challenge is to identify such hazardous NPs and take appropriate measures to prevent exposure.

Dendrimers offer significant potential as nanocarriers for targeted delivery of drugs and imaging agents. The objectives of this study were to evaluate the transplacental transport, kinetics and biodistribution of PAMAM dendrimers ex-vivo across the human placenta in comparison with antipyrine, a freely diffusible molecule, using dually perfused re-circulating term human placental lobules. The purpose of this study is to determine if dendrimers as drug carriers can be used to design drug delivery systems directed at selectively treating either the mother or the fetus. The transplacental transfers of fluorescently (Alexa 488) tagged PAMAM dendrimer (16 kDa) and antipyrine (188 Da) from maternal to fetal circulation were measured using HPLC/dual UV and fluorescent detector (sensitivity of 10 ng / mL for dendrimer and 100 ng /mL for antipyrine respectively). C max for the dendrimer-Alexa (DA) in maternal perfusate (T max = 15min) was 18 times higher than in the fetal perfusate and never equilibrated with the maternal perfusate during 5.5 hours of perfusion (n=4). DA exhibited a significant but low transplacental transport of ~2.26 ± 0.12 μg / mL during 5.5 hours, where the mean transplacental transfer was 0.84 ±0.11 % of the total maternal concentration and the feto-maternal ratio as percent was 0.073% ± 0.02. The biochemical and physiological analysis of the placentae perfused with DA demonstrated normal function throughout the perfusion. The immunofluorescence histochemistry confirmed that the biodistribution of DA in perfused placenta was sparsely dispersed, and when noted was principally seen in the inter-villous spaces and outer rim of the villous branches. In a few cases, DA was found internalized and localized in nuclei and cytoplasm of syncytiotrophoblast and inside the villous core; however, DA was mostly absent from the villous capillaries. In conclusion, the PAMAM dendrimers exhibited a low rate of transfer from maternal to the fetal side across the perfused human placenta, which is similar to other investigations of large macromolecules, eg., IgG. These overall findings suggest that entry of drugs conjugated to polymers, i.e., dendrimers, would be limited in their transfer across the human placenta when compared to smaller drug © 2010 Elsevier B.V. All rights reserved. * Corresponding author: Rangaramanujam M. Kannan, Department of Chemical Engineering and Material Science, Wayne State University, Detroit, Michigan 48202; rkannan.wsu@gmail.com. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscr...

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Excessive exposure to manganese (Mn) by inhalation can induce psychosis and Parkinsonism. The clinical manifestations of Mn neurotoxicity have been related to numerous physiological and cellular processes, most notably dopamine depletion. However, few studies have explored the molecular events that are triggered in response to exposure to Mn by inhalation. In this current study, the transcriptional patterns of genes related to oxidative stress or inflammation were examined in the brain rats of exposed to inhaled Mn during either gestation or early adulthood. The expression of genes encoding for proteins critical to an inflammatory response and/or possessing pro-oxidant properties, including TGFb and nNOS, were slightly depressed by prenatal exposure, whereas inhalation exposure to Mn during adulthood markedly down-regulated their transcription. However, when exposures to manganese occurred during gestation, the extent of altered gene expression induced by subsequent exposure to Mn in adulthood was reduced. This suggests that prior exposure to Mn may have attenuated the effects of inhalation exposure to Mn in adulthood, in which the expression of inflammation-related genes were suppressed. #