Biotransformation modulates the penetration of metallic nanomaterials across an artificial blood–brain barrier model

Abstract

Understanding the potential of nanomaterials (NMs) to cross the blood–brain barrier (BBB), as a function of their physicochemical properties and subsequent behavior, fate, and adverse effect beyond that point, is vital for evaluating the neurological effects arising from their unintentional entry into the brain, which is yet to be fully explored. This is not only due to the complex nature of the brain but also the existing analytical limitations for characterization and quantification of NMs in the complex brain environment. By using a fit-for-purpose analytical workflow and an in vitro BBB model, we show that the physiochemical properties of metallic NMs influence their biotransformation in biological matrices, which in turn modulates the transport form, efficiency, amounts, and pathways of NMs through the BBB and, consequently, their neurotoxicity. The data presented here will support in silico modeling and prediction of the neurotoxicity of NMs and facilitate the tailored design of safe NMs.

Passage of exogeneous fine particles from the lung into the brain in humans and animals

“…A robust induction of zonula occludens-1 (ZO-1) indicated the successful setup of the in vitro BBB model, and the decrease of the ZO-1 level after particle treatment implied damage of the tight junctions ( SI Appendix , Fig. S18 B ), analogous to previous reports ( 30 ). After exposure to particles, the medium in the basolateral chamber was collected for HR-TEM observation and inductively coupled plasma mass spectrometry (ICP-MS) analysis to quantify the particle transport.…”

“…Particles that pass through the olfactory bulb or through the cellular receptor system do not need to damage the BBB, a tight barrier comprising endothelial cells that prevents unnecessary substances from crossing into the CNS. In the lung to brain route, particles must circulate through the bloodstream, and they likely acquire a layer of absorbed proteins and other biomolecules, which is referred to as corona formation, as previous studies found for engineered NPs ( 27 , 51 – 53 ) and may cross from the bloodstream through the BBB without visibly damaging it for final localization in the ventricles of the brain ( 30 ). In line with this route, we further found exogenous particles, including malayaite and SiO 2 , in blood specimens from the patients ( Fig.…”

“…To elucidate the mechanisms underlying the particle translocation through the BBB, we established an in vitro model dependent on the coculture of mouse brain–derived endothelial (bEnd.3) cells with mouse primary astrocytes ( SI Appendix , Fig. S18 A ) as previously established ( 30 , 63 ). A robust induction of zonula occludens-1 (ZO-1) indicated the successful setup of the in vitro BBB model, and the decrease of the ZO-1 level after particle treatment implied damage of the tight junctions ( SI Appendix , Fig.…”

“…In fact, inhaled ambient fine particles or exogeneous engineered nanoparticles (NPs) have been observed in human serum ( 25 ), pleural effusion ( 25 ), heart tissue ( 26 ), vascular inflammation ( 27 ), and even the placenta ( 28 ). Unlike the liver, spleen, and other organs with defenseless large-volume blood circulation, the brain is naturally protected by a stringent defense line, namely the blood–brain barrier (BBB), which prevents the crossing of both soluble and particulate foreign entities or offenders ( 29 , 30 ). Under this premise, it is rather difficult for PMs to penetrate the BBB; however, crossing may occur when the integrity of the BBB is impaired or if the PMs per se damage the BBB ( 5 , 30 ).…”

“…Unlike the liver, spleen, and other organs with defenseless large-volume blood circulation, the brain is naturally protected by a stringent defense line, namely the blood–brain barrier (BBB), which prevents the crossing of both soluble and particulate foreign entities or offenders ( 29 , 30 ). Under this premise, it is rather difficult for PMs to penetrate the BBB; however, crossing may occur when the integrity of the BBB is impaired or if the PMs per se damage the BBB ( 5 , 30 ). To date, multiple pathways have been proposed for the direct intrusion of PMs into the brain ( 4 , 5 , 31 ).…”