Niosomes decorated with dual ligands targeting brain endothelial transporters increase cargo penetration across the blood-brain barrier

Mészáros, Mária and Porkolab, Gergő and Kiss, Lóránd and Pilbat, Ana Maria and Kóta, Zoltán and Kéri, Albert and Galbács, Gábor and Siklós, László and Tóth, András and Sipos, Áron and Páli, Tibor and Rákhely, Gábor and Deli, Mária Anna and Veszelka, Szilvia (2018) Niosomes decorated with dual ligands targeting brain endothelial transporters increase cargo penetration across the blood-brain barrier. EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, 123. pp. 228-240. ISSN 0928-0987

Text Niosomes (Eur J Pharm Sci).pdf Restricted to Repository staff only Download (2MB) | Request a copy

Abstract

Nanoparticles targeting transporters of the blood-brain barrier (BBB) are promising candidates to increase the brain penetration of biopharmacons. Solute carriers (SLC) are expressed at high levels in brain endothelial cells and show a specific pattern at the BBB. The aim of our study was to test glutathione and ligands of SLC transporters as single or dual BBB targeting molecules for nanovesicles. High mRNA expression levels for hexose and neutral amino acid transporting SLCs were found in isolated rat brain microvessels and our rat primary cell based co-culture BBB model. Niosomes were derivatized with glutathione and SLC ligands glucopyranose and alanine. Serum albumin complexed with Evans blue (67kDa), which has a very low BBB penetration, was selected as a cargo. The presence of targeting ligands on niosomes, especially dual labeling, increased the uptake of the cargo molecule in cultured brain endothelial cells. This cellular uptake was temperature dependent and could be decreased with a metabolic inhibitor and endocytosis blockers filipin and cytochalasin D. Making the negative surface charge of brain endothelial cells more positive with a cationic lipid or digesting the glycocalyx with neuraminidase elevated the uptake of the cargo after treatment with targeted nanocarriers. Treatment with niosomes increased plasma membrane fluidity, suggesting the fusion of nanovesicles with endothelial cell membranes. Targeting ligands elevated the permeability of the cargo across the BBB in the culture model and in mice, and dual-ligand decoration of niosomes was more effective than single ligand labeling. Our data indicate that dual labeling with ligands of multiple SLC transporters can potentially be exploited for BBB targeting of nanoparticles.

Actions (login required)

Edit Item