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

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Conjugation of Therapeutic PSD-95 Inhibitors to the Cell-Penetrating Peptide Tat Affects Blood-Brain Barrier Adherence, Uptake, and Permeation. / Kristensen, Mie; Kucharz, Krzysztof; Felipe Alves Fernandes, Eduardo; Strømgaard, Kristian; Schallburg Nielsen, Morten; Cederberg Helms, Hans Christian; Bach, Anders; Ulrikkaholm Tofte-Hansen, Malte; Irene Aldana Garcia, Blanca; Lauritzen, Martin; Brodin, Birger.

I: Pharmaceutics, Bind 12, Nr. 7, 661, 2020, s. 1-24.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

Harvard

Kristensen, M, Kucharz, K, Felipe Alves Fernandes, E, Strømgaard, K, Schallburg Nielsen, M, Cederberg Helms, HC, Bach, A, Ulrikkaholm Tofte-Hansen, M, Irene Aldana Garcia, B, Lauritzen, M & Brodin, B 2020, 'Conjugation of Therapeutic PSD-95 Inhibitors to the Cell-Penetrating Peptide Tat Affects Blood-Brain Barrier Adherence, Uptake, and Permeation', Pharmaceutics, bind 12, nr. 7, 661, s. 1-24. https://doi.org/10.3390/pharmaceutics12070661

APA

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. (2020). Conjugation of Therapeutic PSD-95 Inhibitors to the Cell-Penetrating Peptide Tat Affects Blood-Brain Barrier Adherence, Uptake, and Permeation. Pharmaceutics, 12(7), 1-24. [661]. https://doi.org/10.3390/pharmaceutics12070661

CBE

Kristensen M, Kucharz K, Felipe Alves Fernandes E, Strømgaard K, Schallburg Nielsen M, Cederberg Helms HC, Bach A, Ulrikkaholm Tofte-Hansen M, Irene Aldana Garcia B, Lauritzen M, Brodin B. 2020. Conjugation of Therapeutic PSD-95 Inhibitors to the Cell-Penetrating Peptide Tat Affects Blood-Brain Barrier Adherence, Uptake, and Permeation. Pharmaceutics. 12(7):1-24. https://doi.org/10.3390/pharmaceutics12070661

MLA

Vancouver

Author

Kristensen, Mie ; Kucharz, Krzysztof ; Felipe Alves Fernandes, Eduardo ; Strømgaard, Kristian ; Schallburg Nielsen, Morten ; Cederberg Helms, Hans Christian ; Bach, Anders ; Ulrikkaholm Tofte-Hansen, Malte ; Irene Aldana Garcia, Blanca ; Lauritzen, Martin ; Brodin, Birger. / Conjugation of Therapeutic PSD-95 Inhibitors to the Cell-Penetrating Peptide Tat Affects Blood-Brain Barrier Adherence, Uptake, and Permeation. I: Pharmaceutics. 2020 ; Bind 12, Nr. 7. s. 1-24.

Bibtex

@article{06167abdf4214df38c58372dba15b090,
title = "Conjugation of Therapeutic PSD-95 Inhibitors to the Cell-Penetrating Peptide Tat Affects Blood-Brain Barrier Adherence, Uptake, and Permeation",
abstract = "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.",
keywords = "Blood–brain barrier, Brain peptide-drug delivery, Cell-penetrating peptide, Stroke treatment, Tat",
author = "Mie Kristensen and Krzysztof Kucharz and {Felipe Alves Fernandes}, Eduardo and Kristian Str{\o}mgaard and {Schallburg Nielsen}, Morten and {Cederberg Helms}, {Hans Christian} and Anders Bach and {Ulrikkaholm Tofte-Hansen}, Malte and {Irene Aldana Garcia}, Blanca and Martin Lauritzen and Birger Brodin",
year = "2020",
doi = "10.3390/pharmaceutics12070661",
language = "English",
volume = "12",
pages = "1--24",
journal = "Pharmaceutics",
issn = "1999-4923",
publisher = "MDPI AG",
number = "7",

}

RIS

TY - JOUR

T1 - Conjugation of Therapeutic PSD-95 Inhibitors to the Cell-Penetrating Peptide Tat Affects Blood-Brain Barrier Adherence, Uptake, and Permeation

AU - Kristensen, Mie

AU - Kucharz, Krzysztof

AU - Felipe Alves Fernandes, Eduardo

AU - Strømgaard, Kristian

AU - Schallburg Nielsen, Morten

AU - Cederberg Helms, Hans Christian

AU - Bach, Anders

AU - Ulrikkaholm Tofte-Hansen, Malte

AU - Irene Aldana Garcia, Blanca

AU - Lauritzen, Martin

AU - Brodin, Birger

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - Blood–brain barrier

KW - Brain peptide-drug delivery

KW - Cell-penetrating peptide

KW - Stroke treatment

KW - Tat

UR - http://www.scopus.com/inward/record.url?scp=85087936552&partnerID=8YFLogxK

U2 - 10.3390/pharmaceutics12070661

DO - 10.3390/pharmaceutics12070661

M3 - Journal article

C2 - 32674358

VL - 12

SP - 1

EP - 24

JO - Pharmaceutics

JF - Pharmaceutics

SN - 1999-4923

IS - 7

M1 - 661

ER -