Highly cationic cell-penetrating peptides affect the barrier integrity and facilitates mannitol permeation in a human stem cell-based blood-brain barrier model
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Highly cationic cell-penetrating peptides affect the barrier integrity and facilitates mannitol permeation in a human stem cell-based blood-brain barrier model. / Frøslev, Patrick; Franzyk, Henrik; Ozgür, Burak; Larsen, Birger Brodin; Kristensen, Mie.
In: European Journal of Pharmaceutical Sciences, Vol. 168, 106054, 2022.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Highly cationic cell-penetrating peptides affect the barrier integrity and facilitates mannitol permeation in a human stem cell-based blood-brain barrier model
AU - Frøslev, Patrick
AU - Franzyk, Henrik
AU - Ozgür, Burak
AU - Larsen, Birger Brodin
AU - Kristensen, Mie
PY - 2022
Y1 - 2022
N2 - The blood-brain barrier (BBB) allows passive permeation of only a limited number of, primarily lipophilic, low-molecular weight drugs that obey the so-called “rule of CNS likeness”. Therefore, novel strategies to facilitate drug delivery across the BBB are needed. Cell-penetrating peptides (CPPs) enable delivery of various therapeutic cargoes into cells and may potentially serve as shuttles for delivery of brain-specific drugs across the BBB. The CPPs Tat47–57 and penetratin are prototypical cationic CPPs, whereas apidaecin and oncocin belong to the group of proline-rich cationic antimicrobial peptides displaying CPP-like properties.The aim of the present study was to investigate the potential of Tat47–57, penetratin, apidaecin, and oncocin for interaction with and permeation of the BBB in vitro. We also studied whether the CPPs facilitated permeation of the paracellular flux marker mannitol as well as the transcellular flux marker propranolol. The peptides were labelled with the fluorophore 6-TAMRA (T) for visualization and quantification purposes. CPP membrane-adherence, membrane-embedding, and cellular uptake as well as barrier-permeation were evaluated in murine brain capillary endothelial cells (bEND3) and human induced pluripotent stem cell-derived (Bioni-010c) brain capillary endothelial-like monolayers. The cationic and the proline-rich cationic CPPs were taken up into the Bioni-010c monolayers. T-Tat47–57, T-apidaecin, and T-oncocin also permeated Bioni-010c monolayers, whereas T-penetratin did not. However, both T-Tat47–57 and T-penetratin affected the barrier integrity to a degree that facilitated permeation of 14C-mannitol. These results may therefore pave the way for future CPP-mediated brain delivery of small drugs that do not obey the “rule of CNS likeness”.
AB - The blood-brain barrier (BBB) allows passive permeation of only a limited number of, primarily lipophilic, low-molecular weight drugs that obey the so-called “rule of CNS likeness”. Therefore, novel strategies to facilitate drug delivery across the BBB are needed. Cell-penetrating peptides (CPPs) enable delivery of various therapeutic cargoes into cells and may potentially serve as shuttles for delivery of brain-specific drugs across the BBB. The CPPs Tat47–57 and penetratin are prototypical cationic CPPs, whereas apidaecin and oncocin belong to the group of proline-rich cationic antimicrobial peptides displaying CPP-like properties.The aim of the present study was to investigate the potential of Tat47–57, penetratin, apidaecin, and oncocin for interaction with and permeation of the BBB in vitro. We also studied whether the CPPs facilitated permeation of the paracellular flux marker mannitol as well as the transcellular flux marker propranolol. The peptides were labelled with the fluorophore 6-TAMRA (T) for visualization and quantification purposes. CPP membrane-adherence, membrane-embedding, and cellular uptake as well as barrier-permeation were evaluated in murine brain capillary endothelial cells (bEND3) and human induced pluripotent stem cell-derived (Bioni-010c) brain capillary endothelial-like monolayers. The cationic and the proline-rich cationic CPPs were taken up into the Bioni-010c monolayers. T-Tat47–57, T-apidaecin, and T-oncocin also permeated Bioni-010c monolayers, whereas T-penetratin did not. However, both T-Tat47–57 and T-penetratin affected the barrier integrity to a degree that facilitated permeation of 14C-mannitol. These results may therefore pave the way for future CPP-mediated brain delivery of small drugs that do not obey the “rule of CNS likeness”.
U2 - 10.1016/j.ejps.2021.106054
DO - 10.1016/j.ejps.2021.106054
M3 - Journal article
C2 - 34728364
VL - 168
JO - Norvegica Pharmaceutica Acta
JF - Norvegica Pharmaceutica Acta
SN - 0928-0987
M1 - 106054
ER -
ID: 283126867