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Open AccessArticle

Conjugation of Therapeutic PSD-95 Inhibitors to the Cell-Penetrating Peptide Tat Affects Blood–Brain Barrier Adherence, Uptake, and Permeation

1
Department of Pharmacy, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark
2
Department of Neuroscience and Pharmacology, University of Copenhagen, DK-2200 Copenhagen N, Denmark
3
Department of Drug Design and Pharmacology, University of Copenhagen, DK-2100 Copenhagen Ø, Denmark
4
Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark
*
Author to whom correspondence should be addressed.
Pharmaceutics 2020, 12(7), 661; https://doi.org/10.3390/pharmaceutics12070661
Received: 11 June 2020 / Revised: 6 July 2020 / Accepted: 10 July 2020 / Published: 14 July 2020
(This article belongs to the Special Issue New Drug Delivery across the Blood–Brain Barrier)
Novel stroke therapies are needed. Inhibition of the interaction between the postsynaptic density-95 (PSD-95)/disc large/ZO-1 (PDZ) domains of PSD-95 and the N-methyl-D-aspartate (NMDA) receptor has been suggested as a strategy for relieving neuronal damage. The peptides NR2B9c and N-dimer have been designed to hinder this interaction; they are conjugated to the cell-penetrating peptide Tat to facilitate blood–brain barrier (BBB) permeation and neuronal uptake. Tat-N-dimer exhibits 1000-fold better target affinity than Tat-NR2B9c, but the same magnitude of improvement is not observed in terms of therapeutic effect. Differences in BBB permeation by Tat-NR2B9c and Tat-N-dimer may explain this difference, but studies providing a direct comparison of Tat-NR2B9c and Tat-N-dimer are lacking. The aim of the present study was therefore to compare the BBB uptake and permeation of Tat-NR2B9c and Tat-N-dimer. The peptides were conjugated to the fluorophore TAMRA and their chemical stability assessed. Endothelial membrane association and cell uptake, and transendothelial permeation were estimated using co-cultures of primary bovine brain capillary endothelial cells and rat astrocytes. In vivo BBB permeation was demonstrated in mice using two-photon microscopy imaging. Tissue distribution was evaluated in mice demonstrating brain accumulation of TAMRA-Tat (0.4% ID/g), TAMRA-Tat-NR2B9c (0.3% ID/g), and TAMRA-Tat-N-dimer (0.25% ID/g). In conclusion, we demonstrate that attachment of NR2B9c or N-dimer to Tat affects both the chemical stability and the ability of the resulting construct to interact with and permeate the BBB. View Full-Text
Keywords: brain peptide-drug delivery; blood–brain barrier; cell-penetrating peptide; Tat; stroke treatment brain peptide-drug delivery; blood–brain barrier; cell-penetrating peptide; Tat; stroke treatment
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Kristensen, M.; Kucharz, K.; Felipe Alves Fernandes, E.; Strømgaard, K.; Schallburg Nielsen, M.; Cederberg Helms, H.C.; Bach, A.; Ulrikkaholm Tofte-Hansen, M.; Irene Aldana Garcia, B.; Lauritzen, M.; Brodin, B. Conjugation of Therapeutic PSD-95 Inhibitors to the Cell-Penetrating Peptide Tat Affects Blood–Brain Barrier Adherence, Uptake, and Permeation. Pharmaceutics 2020, 12, 661.

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