Nanoparticles at the neurovascular unit: In vitro and in vivo studies to assess the blood-brain barrier permeability and function

Objective: The dilemma of the protection from noxious substances from the blood and the delivery of vital metabolites has always to be faced when dealing with the brain. Endothelial cells, forming the blood-brain barrier (BBB) with other cell types, regulate its trafficking. It is known that many common drugs cannot cross the BBB in appreciable concentration, decreasing the rate of success of possible available treatments for many central nervous system (CNS) diseases. In the last decades, nanomedicine has played a pivotal role in developing strategies to deliver drugs to the CNS. In our previous studies we administered liposomes functionalized with phosphatide acid and an ApoE-derived peptide (mApoE-PA-LIP) as a potential treatment for Alzheimer's disease (AD): their administration reduced brain beta-amyloid burden and ameliorated impaired memory in AD mice. We also evaluated the adaptability of warm microemulsion process for ligand surface modification of solid lipid nanoparticles (SLN) with ApoE to target the brain. Our in vivo biodistribution experiments, performed to study the influence of three different administration routes on SLN-mApoE bioavailability, showed that pulmonary administration increases the DiR-loaded SLN-mApoE bioavaibility to the brain in comparison to the intraperitoneal and intravenous ones, at the same concentrations and time points. In our ongoing experiments, we decided to further investigate the activities of NPs able to cross the BBB, independently from their administration routes. The aim of this study is to evaluate the interaction of mApoE-PA-UP and SLN at the neurovascular unit. In light of our previous results we here assess their interactions with human cerebral microvascular cells (hCMEC/D3) as in vi(ro BBB model. Our in vitro experiments by means of both the electrophysiological approach and the simultaneous calcium imaging will disclose if any active modulation on neuronal activities does occur after ex vivo and in vivo NPs administration. The obtained results will help us to better define the safety profile and active properties of NPs specifically developed to cross the BBB and to delivery their payload to the CNS.