98 Inhaled nanoparticle’s access, biodistribution, elimination and effects in the brain: a story of exogeneous countered by endogenous nanoparticles

Abstract Details on biodistribution of airborne “invader” exogenous nanoparticles (NP) are essential to understand hypothesized oxidative stress-induced effects involving neurodegeneration. Our analysis of NP in different brain regions selected two nose-to-brain neuronal pathways: (1) The rostral olfactory pathway from the olfactory bulb to deeper cerebral regions and (2) the caudal pathway to the trigeminal ganglion to the cerebellum. High-resolution imaging of human autopsied brain tissues and lab-particle-exposed mice brains shows exogenous-NP are typically located and bioprocessed next to NP-damaged neurons that have extensive demyelination. These pro-inflammatory NP are habitually surrounded by anti-inflammatory endogenous “ferritin”-NP, indicating a redox-protective mechanism by ferritin’s electron pumping capacity. Exogenous NP in different brain regions are diverse metals/metal-oxides, carbons (soot and nanotubes), and plastic/polymeric fragments. High-resolution analytical imaging (down to atomic scale) coupled with immunohistochemical (IHC) labelling shows NPs together with debris-collecting (eg myelin fragments) and inflammation and age-related corpora amylacea. Cerebral and cerebellar biodistribution occurs via axonal transport which—due to its particle size limitation of < 250 nm—cannot explain our findings of larger micro-sized NP in the cerebellum or other regions. Additional entry routes to the brain include blood-borne exogenous-NP that had entered the pulmonary interstitial compartment from deposits in the alveolar region. The brain’s capillaries through their tight junctions present an effective protection however, with age and increasing inflammatory conditions, these tight junctions become leaky, affording blood-borne NP-access. Discoveries of hypothesized further access portals of airborne NP reaching the brain, eg via the choroid plexus, optic nerve, or nervus terminalis, are future goals.