Glutathione conjugation dose-dependently increases brain-specific liposomal drug delivery in vitro and in vivo

Publication date: Available online 13 October 2016 Source:Drug Discovery Today: Technologies Author(s): David Maussang, Jaap Rip, Joan van Kregten, Angelique van den Heuvel, Susanne van der Pol, Burt van der Boom, Arie Reijerkerk, Linda Chen, Marco de Boer, Pieter Gaillard, Helga de Vries The blood–brain barrier (BBB) represents a major obstacle for the delivery and development of drugs curing brain pathologies. However, this biological barrier presents numerous endogenous specialized transport systems that can be exploited by engineered nanoparticles to enable drug delivery to the brain. In particular, conjugation of glutathione (GSH) onto PEGylated liposomes (G-Technology®) showed to safely enhance delivery of encapsulated drugs to the brain. Yet, understanding of the mechanism of action remains limited and full mechanistic understanding will aid in the further optimization of the technology. In order to elucidate the mechanism of brain targeting by GSH-PEG liposomes, we here demonstrate that the in vivo delivery of liposomal ribavirin is increased in brain extracellular fluid according to the extent of GSH conjugation onto the liposomes. In vitro, using the hCMEC/D3 human cerebral microvascular endothelial (CMEC) cell line, as well as primary bovine and porcine CMEC (and in contrast to non-brain derived endothelial and epithelial cells), we show that liposomal uptake occurs through the process of endocytosis and that the brain-specific uptake is also glutat...
Source: Drug Discovery Today: Technologies - Category: Drugs & Pharmacology Source Type: research