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

Mária Mészáros, Gergő Porkoláb, L. Kiss, Ana Maria Pilbat, Zoltán Kóta, Zoltán Kupihár, Albert Kéri, G. Galbács, L. Siklós, András Tóth, L. Fülöp, M. Csete, Áron Sipos, Petra Hülper, Péter Sipos, T. Páli, G. Rákhely, P. Szabó-Révész, Mária A. Deli, S. Veszelka

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 (67 kDa), 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.

Original languageEnglish
Pages (from-to)228-240
Number of pages13
JournalEuropean Journal of Pharmaceutical Sciences
Volume123
DOIs
Publication statusPublished - Oct 15 2018

Fingerprint

Blood-Brain Barrier
Liposomes
Ligands
Brain
Endothelial Cells
Nanoparticles
Glutathione
Filipin
Cell Membrane
Neutral Amino Acids
Glycocalyx
Cytochalasin D
Evans Blue
Membrane Fluidity
Hexoses
Neuraminidase
Coculture Techniques
Endocytosis
Microvessels
Serum Albumin

Keywords

  • Blood-brain barrier
  • Brain endothelial cell
  • Drug targeting
  • Dual-ligand
  • Nanoparticle
  • Niosome
  • Solute carriers

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Niosomes decorated with dual ligands targeting brain endothelial transporters increase cargo penetration across the blood-brain barrier. / Mészáros, Mária; Porkoláb, Gergő; Kiss, L.; Pilbat, Ana Maria; Kóta, Zoltán; Kupihár, Zoltán; Kéri, Albert; Galbács, G.; Siklós, L.; Tóth, András; Fülöp, L.; Csete, M.; Sipos, Áron; Hülper, Petra; Sipos, Péter; Páli, T.; Rákhely, G.; Szabó-Révész, P.; Deli, Mária A.; Veszelka, S.

In: European Journal of Pharmaceutical Sciences, Vol. 123, 15.10.2018, p. 228-240.

Research output: Contribution to journalArticle

Mészáros, Mária ; Porkoláb, Gergő ; Kiss, L. ; Pilbat, Ana Maria ; Kóta, Zoltán ; Kupihár, Zoltán ; Kéri, Albert ; Galbács, G. ; Siklós, L. ; Tóth, András ; Fülöp, L. ; Csete, M. ; Sipos, Áron ; Hülper, Petra ; Sipos, Péter ; Páli, T. ; Rákhely, G. ; Szabó-Révész, P. ; Deli, Mária A. ; Veszelka, S. / Niosomes decorated with dual ligands targeting brain endothelial transporters increase cargo penetration across the blood-brain barrier. In: European Journal of Pharmaceutical Sciences. 2018 ; Vol. 123. pp. 228-240.
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