A Triple Combination of Targeting Ligands Increases the Penetration of Nanoparticles across a Blood-Brain Barrier Culture Model

Abstract

Nanosized drug delivery systems targeting transporters of the blood-brain barrier (BBB) are promising carriers to enhance the penetration of therapeutics into the brain. The expression of solute carriers (SLC) is high and shows a specific pattern at the BBB. Here we show that targeting ligands ascorbic acid, leucine and glutathione on nanoparticles elevated the uptake of albumin cargo in cultured primary rat brain endothelial cells. Moreover, we demonstrated the ability of the triple-targeted nanovesicles to deliver their cargo into midbrain organoids after crossing the BBB model. The cellular uptake was temperature- and energy-dependent based on metabolic inhibition. The process was decreased by filipin and cytochalasin D, indicating that the cellular uptake of nanoparticles was partially mediated by endocytosis. The uptake of the cargo encapsulated in triple-targeted nanoparticles increased after modification of the negative zeta potential of endothelial cells by treatment with a cationic lipid or after cleaving the glycocalyx with an enzyme. We revealed that targeted nanoparticles elevated plasma membrane fluidity, indicating the fusion of nanovesicles with endothelial cell membranes. Our data indicate that labeling nanoparticles with three different ligands of multiple transporters of brain endothelial cells can promote the transfer and delivery of molecules across the BBB.

Galactomannan-graft-poly(methyl methacrylate) nanoparticles induce an anti-inflammatory phenotype in human macrophages

“…At 4 1C, all energy-dependent pathways are blocked, and the cell membrane fluidity and endocytosis are reduced. 38 Under this condition, NP uptake was negligible (Fig. 2A and Video S1D, ESI †).…”

From oncolytic peptides to oncolytic polymers: A new paradigm for oncotherapy

“…In fact, most of oncolytic peptides are lipophilic cationic compounds, which are theoretically prone to cross the BBB after certain structural design (e.g., surface charge regulation, targeting ligands modification, introduction of cell-penetrating peptides, etc.) [ [221] , [222] , [223] , [224] ]. Moreover, the cationic polymers such as poly- l -lysines and chitosan, have previously been observed to cross the BBB and used for brain-targeted drug delivery, thus suggesting the broad application prospects of positively-charged oncolytic polymers in the treatment of brain tumors [ 225 ].…”

Receptor-mediated transcytosis of macromolecules across the blood-brain barrier

“…Specificity-wise, the target's expression on the luminal membrane of BCEC would ideally be higher than that on blood cells and other endothelial and blood-facing epithelial cells of organs receiving most of the circulation. The targetor a combination of targets 97,98 -would ideally dominate the expression pattern, instead of being merely highly expressed on BCEC. For instance, I would argue that the use of basigin, identified as one of the promising RMT targets 34,99 , may be challenging in the long run for that reason alone, at least for those modalities whose payload delivery does not involve further intracellular processing steps that may differ between cell types, adding another layer of specificity.…”