Translocating the blood-brain barrier using electrostatics

Abstract

Mammalian cell membranes regulate homeostasis, protein activity, and cell signaling. The charge at the membrane surface has been correlated with these key events. Although mammalian cells are known to be slightly anionic, quantitative information on the membrane charge and the importance of electrostatic interactions in pharmacokinetics and pharmacodynamics remain elusive. Recently, we reported for the first time that brain endothelial cells (EC) are more negatively charged than human umbilical cord cells, using zeta-potential measurements by dynamic light scattering. Here, we hypothesize that anionicity is a key feature of the blood-brain barrier (BBB) and contributes to select which compounds cross into the brain. For the sake of comparison, we also studied the membrane surface charge of blood components—red blood cells (RBC), platelets, and peripheral blood mononuclear cells (PBMC). To further quantitatively correlate the negative zeta-potential values with membrane charge density, model membranes with different percentages of anionic lipids were also evaluated. From all the cells tested, brain cell membranes are the most anionic and those having their lipids mostly exposed, which explains why lipophilic cationic compounds are more prone to cross the blood-brain barrier.

Nucleic acid delivery by cell penetrating peptides derived from dengue virus capsid protein: design and mechanism of action

“…2). This observation raises the hypothesis that some key elements of the cell membrane structure that diverge with cell type and affect bilayer properties [56] are important for CPP function. Primary cell cultures are usually difficult to transfect [12] and it is relevant that pepM and pepR are able to translocate the plasma membrane of astrocytes.…”

Toward a Unified Model of Passive Drug Permeation II: The Physiochemical Determinants of Unbound Tissue Distribution with Applications to the Design of Hepatoselective Glucokinase Activators

“…This may provide another explanation for common observations that the physiochemical properties of compounds that are known to traverse the blood-brain barrier tend to be relatively lipophilic basic compounds rather than acidic compounds. Furthermore, this may provide another basis underlying the design strategy of using the physiochemical properties of lipophilic cations for central nervous system penetration (Tamai et al, 1997;Tsuji, 2005;Ribeiro et al, 2012). Forward Predictions-In Vivo Kpuu.…”

Molecular-Scale Biophysical Modulation of an Endothelial Membrane by Oxidized Phospholipids

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