The Cell-Penetrating Peptide Tat Facilitates Effective Internalization of PSD-95 Inhibitors Into Blood–Brain Barrier Endothelial Cells but less Efficient Permeation Across the Blood–Brain Barrier In Vitro and In Vivo

Inhibition of the interaction between scaffolding protein PSD-95 and NMDA receptor has been shown to obstruct ischemic stroke-triggered excitotoxic reactions, leading neuronal death. The peptides NR2B9c N -dimer are inhibitors this interaction. Delivery brain is challenging due general low blood–brain barrier (BBB) permeability. have therefore conjugated cell-penetrating peptide (CPP) Tat, facilitate permeation. However, BBB permeation Tat-NR2B9c Tat- not fully elucidated. We recently demonstrated that in vitro vivo was lowered upon conjugation or N- dimer Tat. In present study, we aimed further understand impact cargo Tat with respect across . were labeled fluorophore TAMRA (T) efficient Tat-mediated uptake into endothelial cells but differed their degree plasma membrane embedding (T-Tat-NR2B9c = T-Tat > T-Tat- -dimer) as well chemical stability (T-Tat- T-Tat-NR2B9c). conjugates all displayed a similar self-association and/or adsorption. T-Tat-NR2B9c affected integrity paracellular marker C 14 -mannitol. less an model representing healthy BBB, when compared T-Tat, rats.