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WIREs Nanomed Nanobiotechnol
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Metal‐based nanoparticle interactions with the nervous system: the challenge of brain entry and the risk of retention in the organism

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This review of metal‐based nanoparticles focuses on factors influencing their distribution into the nervous system, evidence they enter brain parenchyma, and nervous system responses. Gold is emphasized as a model metal‐based nanoparticle and for risk assessment in the companion review. The anatomy and physiology of the nervous system, basics of colloid chemistry, and environmental factors that influence what cells see are reviewed to provide background on the biological, physical–chemical, and internal milieu factors that influence nervous system nanoparticle uptake. The results of literature searches reveal little nanoparticle research included the nervous system, which about equally involved in vitro and in vivo methods, and very few human studies. The routes of uptake into the nervous system and mechanisms of nanoparticle uptake by cells are presented with examples. Brain nanoparticle uptake inversely correlates with size. The influence of shape has not been reported. Surface charge has not been clearly shown to affect flux across the blood‐brain barrier. There is very little evidence for metal‐based nanoparticle distribution into brain parenchyma. Metal‐based nanoparticle disruption of the blood‐brain barrier and adverse brain changes have been shown, and are more pronounced for spheres than rods. Study concentrations need to be put in exposure contexts. Work with dorsal root ganglion cells and brain cells in vitro show the potential for metal‐based nanoparticles to produce toxicity. Interpretation of these results must consider the ability of nanoparticles to distribute across the barriers protecting the nervous system. Effects of the persistence of poorly soluble metal‐based nanoparticles are of particular concern. WIREs Nanomed Nanobiotechnol 2013, 5:346–373. doi: 10.1002/wnan.1202

Conflict of interest: The authors declare no conflict of interest.

Disclaimer: This manuscript has been reviewed by the National Health and Environmental Effects Research Laboratory of the U.S. Environmental Protection Agency and approved for publication. Approval does not signify that the contents reflect the views of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.

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Figure 1.

Interfacial double layers near colloidal particles. Collodial particle = gray sphere. Positive ions are shown in pink. Negative ions are shown in blue.

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Figure 2.

Results of SciFinder searches of (a) all publications of Nanoparticles (NPs) and those using in vitro and in vivo study platforms, (b) metal‐based NP nervous system publications by metal, and (c) metal‐based NP nervous system studies by research platform.

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Figure 3.

Global nanoparticle (NP) patent activity for all NPs and selected metal‐based NPs.

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Figure 4.

Nanoparticle (NP) distribution into the brain, expressed as a percentage of the dose and time after NP administration. Red: Unable to find the NP in the brain or reported that it was not in the brain. Black: Brain NP can be attributed to its presence in the brain's vascular compartment and the report provides no evidence of NP distribution into brain parenchyma. Blue: Brain NP is too high to be attributed to its presence in the brain's vascular compartment but the report provides no evidence of NP distribution into brain parenchyma, so the NP could have been associated with blood‐brain barrier (BBB) cells but did not enter brain parenchyma. Green: The report provides evidence of NP distribution into brain parenchyma.

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Figure 5.

Influence of nanoparticle (NP) size on brain uptake. (a)–(e) The percentage of gold NP dose in rat or mouse brain. (f) and (g) The percentage of the gold NP dose taken up into rat primary brain microvascular endothelial cells (BMECs) per mg protein. (h) The percentage of the gold NP dose that permeated through rat BMECs. Asterisks indicate NP sizes that were * not detectible, ** below control, or *** reported as 0. The ζ potential of the PEG‐coated gold NPs was approximately −2 to −11 mV. The dendrimers were an acetamide poly(amido amine) (PAMAM). Uptake in rat BMECs was conducted with primary cells. Rat brain permeation was through an endothelial and astrocyte cell coculture.

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James F. Leary

James F. Leary
has been contributing to nanomedical research and technologies throughout his career. Such contributions include the invention of high-speed flow cytometry, cell sorting techniques, and rare-event methods. Dr. Leary’s current research spans across three general areas in nanomedicine. The first is the development of high-throughput single-cell flow cytometry and cell sorting technologies. The second explores BioMEMS technologies. These include miniaturized cell sorters, portable devices for detection of microbial pathogens in food and water, and artificial human “organ-on-a-chip” technologies which consists of developing cell culture chips capable of simulating the activities and mechanics of entire organs and organ systems. His third area of research aims at developing smart nano-engineered systems for single-cell drug or gene delivery for nanomedicine. Dr. Leary currently holds nine issued U.S. Patents with four currently pending, and he has received NIH funding for over 25 years.

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