Abstract
The blood-brain barrier (BBB) regulates the traffic of molecules into the central nervous system (CNS) and also limits the drug delivery. Due to their flexible properties, liposomes are an attractive tool to deliver drugs across the BBB. We previously characterized gH625, a peptide derived from Herpes simplex virus 1. The present study investigates the efficiency of liposomes functionalized on their surface with gH625 to promote the brain uptake of neuroprotective peptide PACAP (pituitary adenylate cyclase-activating polypeptide). Using a rat in vitro BBB model, we showed that the liposomes preparations were non-toxic for the endothelial cells, as assessed by analysis of tight junction protein ZO1 organization and barrier integrity. Next, we found that gH625 improves the transfer of liposomes across endothelial cell monolayers, resulting in both low cellular uptake and increased transport of PACAP. Finally, in vivo results demonstrated that gH625 ameliorates the efficiency of liposomes to deliver PACAP to the mouse brain after intravenous administration. gH625-liposomes improve both PACAP reaching and crossing the BBB, as showed by the higher number of brain cells labelled with PACAP. gH625-liposomes represent a promising strategy to deliver therapeutic agents to CNS and to provide an effective imaging and diagnostic tool for the brain.
Highlights
The high blood-brain barrier (BBB) impermeability and selectivity prevent the transport of many therapeutic molecules into the brain and makes ineffective their administration for the treatment of neurological disorders[1,2]
Liposomes were loaded with pituitary adenylate cyclase-activating polypeptide (PACAP), a neurotrophic and neuroprotective peptide proposed for treatment of central nervous system (CNS) injuries, stroke, and neurodegenerative diseases[41,42]
We developed liposomes loaded with PACAP27, that we fuctionalized on their surface with gH625 and we characterized by dynamic light scattering (DLS)
Summary
The high blood-brain barrier (BBB) impermeability and selectivity prevent the transport of many therapeutic molecules into the brain and makes ineffective their administration for the treatment of neurological disorders[1,2]. Liposomes are able to incorporate and deliver hydrophilic, lipophilic, and hydrophobic molecules, having lipid and water compartments They show excellent biocompatibility and biodegradability, low toxicity, and controlled drug release[7,12,13,14,15,16,17,18,19]. We recently showed that gH625 promotes the fusion of giant unilamellar vesicles and multivalency is key for internalization[40] Based on this background, we evaluated the efficacy of liposomes functionalized with gH625 to transport a therapeutic molecule in vitro across a rat BBB model and in vivo in mice. After mice tail intravenous administration, we evaluated the efficacy of the functionalized liposomes in vivo, by analysing PACAP brain distribution with light sheet fluorescence microscopy
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