Nanoparticles and the brain: cause for concern?

Abstract

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 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.

Figure 1

Lung lavage neutrophils and protein response in PTFE-fume adapted and non-adapted F-344 rats. Adapted rats were exposed for 3 days for 5 min. each day to PTFE fumes, followed on Day 4 by a 15-min. exposure. Non-adapted rats were sham-exposed on 3 days for 5 min. and PTFE-fume exposed for 15 min. on day 4. Control rats were sham-exposed on all days for the same duration. Mean particle size was ~20 nm at concentration of 5×10⁵ part/cm³ (~50 μg/m³).

Figure 2

Predicted deposition fraction of inhaled particles by region in the human respiratory tract during nasal breathing. Diffusion is the main mechanism by which nano-sized particles (<0.1 μm) deposit. Based on ICRP (1994)

Figure 3

Outline of human nasal cavity indicating olfactory and trigeminal nerve supply of nasal olfactory region and turbinates. (Modified from Illum, 2000).

Figure 4

Sensory nerves in the respiratory tract, consisting of dense networks in the upper respiratory tract and tracheobronchial region and some in the alveolar region.

Figure 5

From respiratory tract to brain: Potential translocation pathways of nanoparticles after deposition in the upper and lower respiratory tract.

Figure 6

Nanogold (¹⁹⁸Au) activity of cerebrospinal fluid (CSF) collected at different locations of the brain surface one or two hours after nasal olfactory submucosal injection in rabbits. (based on results of Czerniawska, 1970).

Figure 7

“Direct Transport Percentage” to CNS regions and Cerebrospinal Fluid (CSF) of drug loaded into co-polymer nanoparticles () or as solution () during 6 hrs following intranasal instillation in rats. (redrawn from results by Zhang et al., 2006).

Figure 8

Inhalation of ultrafine (~30 nm) Mn-oxide particles in rats with right nostril occluded. Accumulation of Mn in right and left olfactory bulb 24 hours after a 6- hr. exposure to ultrafine Mn-oxide particles (n=3-5, mean ± SD). Green = left olfactory bulb; red = right olfactory bulb. Eleven percent of nano-Mn-oxide depositing on the olfactory mucosa was estimated to have translocated to the olfactory bulb. (Elder et al., 2006).

Figure 9

Mn concentration in lung and brain regions of rats following 12 days of ultrafine Mn-oxide exposure (mean ± SD; *significant increases vs. control). (465 μg/m³; 17×10⁶ part./cm³; CMD: 31 nm; GSD: 1.77). (Elder et al., 2006).

Figure 10

Changes of TNF alpha expression in brain regions after 12 day exposure (as specified in Fig. 9) to ultrafine Mn-oxide in rats (fold increase over control).

Figure 11

Microarray analysis of rat olfactory bulb tissue after PTFE fume exposure (4 hrs. after a 15 min. exposure at 2.6×10⁶ particles/cm³, ~20 nm).

Figure 12

Nanoparticle translocation to olfactory bulb 24 hrs. after left intranasal instillation in rats. Percent of total instilled dose of nanogold particles (10 μg) of different sizes coated with rat serum albumin (RSA), and Cd-Se quantum dots (5 μg Cd) with different surface modification measured in the olfactory bulb. Intranasally instilled nano-Mn-oxide (10 μg) (see Fig. 9) is shown for comparison.

Figure 13

Concept of differential adsorption for NP (corona formation) stating that physicochemical properties of NPs and the milieu at the portal-of-entry alter NP surface properties and determine their fate with respect to translocation to secondary organs and cell entry. (Modified from Müller and Heinemann, 1989 as referenced in Müller and Keck, 2004).

Figure 14

In vitro studies of NPs incubated with human β2 microglobulin resulting in protein corona formation on particles (Linse et al., 2007). This nanoparticle-protein association led to nucleation and acceleration of protein fibrillation (unfolding) by the nanoparticles. (shown here for Co-polymer NP; was also observed by the authors with QDs, Ceria, CNTs).

Figure 15a and b

Concept: Portal-of-entry and nanoparticle coating affect NP biokinetics. Depicted is a simplified scheme with only the brain and liver as target organs following dosing of the respiratory tract or the blood compartment with pegylated or albumin-coated gold NPs. Thickness of the arrows reflect approximate amount of translocation.

Figure 16

Exposure and biokinetics of nano-sized particles, emphasizing known elimination pathways (thick red arrows) or unknowns (?) (modified from Oberdörster et al., 2005).