Nanoparticles for Therapy and Diagnosis of Neurodegenerative Diseases

Nanoparticles (NPs) are studied as a promising tool to efficiently deliver drugs across biological barriers, which can hinder effective pharmacological treatment for a variety of diseases. One of the key issues to evaluate is the corona, a layer of proteins attached to the surface, formed upon contact of NPs with biological fluids. It is well known that the corona affects bioavailability, toxicity and clearance of NPs. Though the corona is relatively well defined under various conditions, its evolution when it crosses biological barriers was unknown. In my research I utilized gold NPs and a transwell cellular model of the BBB (human brain endothelial cells - hCMEC/D3) to investigate this issue. The protein composition of the corona across the “brain” and “blood” compartments was qualitatively and semi-quantitatively analyzed using SDS-PAGE and MS. The protein corona changed dramatically following passage through the BBB, since many proteins were removed, and 15 out of 381 were enriched in the “brain” side compared to the “blood” side, including alpha-2-macroglobulin and fetuin A. This clearly indicates the dynamic nature of the corona, and the ability or inability of specific proteins bound to NPs to traverse the BBB. The research also established that NP corona in the basolateral side is actually an evolution of the one formed on the apical side ruling out that it is formed in situ by interaction with proteins arriving independently from the apical side. Once beyond the barrier, the corona was stable upon incubation with other proteins Proteins that were enriched upon passage were used to functionalize NPs, demonstrating their ability to boost passage through the BBB and suggesting that physiological proteins could help to more effectively deliver drugs to the central nervous system. Altogether, these results are particularly relevant when developing NPs that are required to traverse any biological barrier and may lead to the more successful design of therapeutic and/or diagnostic nanodevices.