Magnetic Nanoparticle and Exosomal Therapeutic (M-NEXT) Effects on HIV-Associated Neurotoxicity.

Abstract

The human immunodeficiency virus (HIV) envelope glycoprotein protein 120 (gp120) induces neurotoxicity associated with HIV-associated neurocognitive disorders (HAND). Mechanism of Gp120-mediated neurotoxicity is primarily apoptosis. Currently, there are no therapeutics that address gp120 neurotoxicity. A biocompatible, efficacious therapeutic that easily crosses the blood-brain barrier (BBB) is needed to treat neuronal toxicity observed in HIV-infected individuals. Magnetic nanoparticles (MNPs) have successfully delivered anti-HIV agents across in vitro BBB transwell model. However, MNPs at high doses may damage cells. Exosomal extracellular vesicles (xEVs) are endogenous nanocarriers capable of crossing the BBB. Unlike MNPs, xEVs interact with cells in a paracrine or juxtracrine manner, lacking long-range site specificity. Here we investigated the efficacy of an MNP and xEV-coupled therapeutic (M-NEXT) as a nanocarrier for targeted delivery of anti-HIV fusion agent across the BBB to inhibit HIV-gp120 associated neuropathology. M-NEXT consisting of MNPs encapsulated within xEV carrying T20 peptide on the surface was synthesized and characterized via zeta potential, dynamic light scattering, and TEM imaging. Preliminary efficacy studies using SH-SY5Y cocultured with the in vitro BBB model showed that the M-NEXT-T20-fusion peptide protected neurons from HIV gp120-mediated neurotoxicity. Additionally, BBB integrity and permeability assessed via trans-endothelial resistance (TEER) and a Dextran-FITC transport assay was unaffected. SH-SY5Y viability measured by XTT assay was not significantly modulated by M-NEXT. In summary, preliminary findings support M-NEXT as effective nanocarriers for delivery of anti-HIV gp120 associated neurotoxicity agents.