Abstract 4143957: Assessing blood-nerve barrier permeability to nanoparticles over the course of experimental autoimmune neuritis

The acute inflammatory demyelinating polyneuropathy (AIDP) subtype of Guillain–Barré syndrome (GBS) is a debilitating autoimmune peripheral neuropathy. Treatment options are limited to nonspecific immunomodulation and are often ineffective. Systemic or local delivery of several candidate therapeutics have been demonstrated to attenuate the severity of experimental autoimmune neuritis (EAN), an established rat model of AIDP. However, advancement of these findings has been limited due to high doses or impractical routes of administration that are not clinically translatable. While the blood nerve barrier (BNB) normally restricts access of circulating molecules to the endoneurium, during the acute inflammation associated with some peripheral neuropathies, including AIDP, the BNB exhibits increased vascular permeability and enables immune cell infiltration. These pathological changes contribute to disease, but they may also offer a unique opportunity to access the otherwise restricted peripheral nerve microenvironment for therapeutic delivery. In other fields, it is established that circulating particles with favorable size and morphology will passively accumulate in sites with fenestrated vasculature through an enhanced permeation and retention process. In this work, we tested the hypothesis that nanoparticles (NPs) with surfaces modified for prolonged circulation will accumulate in affected nerves in rats with EAN through a similar process. We assessed BNB permeability to intravenously administered small molecules (Evan’s Blue Dye) and spectrally defined NPs (58 and 134 nm polystyrene) over the length of the nerve and the course of EAN. NPs were obtained as commercially available, carboxylated Fluospheres to which we covalently attached poly(ethylene) glycol (PEG) amine using carbodiimide coupling. We also quantified immune cells present in nerve cross sections and compared our findings to naïve rats to determine the correlation between immune cell infiltration, BNB permeability, and NP accumulation. Results demonstrate increased BNB permeability to small molecules at disease onset and permeability to NPs up to 138 nm in size during the intermediate to peak stages of the disease. NP permeability coincides with CD68+ macrophage infiltration.