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Investigation of the Transport Pathways Associated with Enhanced Brain Delivery of Peptide Drugs by Intranasal Coadministration with Penetratin

We previously found that coadministering peptides and proteins with the cell-penetrating peptide L-penetratin intranasally significantly increased transport to the brain and enhanced pharmacological effects. The present study aimed to clarify the mechanisms of nose-to-brain drug delivery enhancement...

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Autores principales: Kamei, Noriyasu, Suwabe, Susumu, Arime, Kenji, Bando, Hidemi, Murata, Kaho, Yamaguchi, Maika, Yokoyama, Natsuki, Tanaka, Erina, Hashimoto, Ayaka, Kanazawa, Takanori, Ago, Yukio, Takeda-Morishita, Mariko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8618983/
https://www.ncbi.nlm.nih.gov/pubmed/34834159
http://dx.doi.org/10.3390/pharmaceutics13111745
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author Kamei, Noriyasu
Suwabe, Susumu
Arime, Kenji
Bando, Hidemi
Murata, Kaho
Yamaguchi, Maika
Yokoyama, Natsuki
Tanaka, Erina
Hashimoto, Ayaka
Kanazawa, Takanori
Ago, Yukio
Takeda-Morishita, Mariko
author_facet Kamei, Noriyasu
Suwabe, Susumu
Arime, Kenji
Bando, Hidemi
Murata, Kaho
Yamaguchi, Maika
Yokoyama, Natsuki
Tanaka, Erina
Hashimoto, Ayaka
Kanazawa, Takanori
Ago, Yukio
Takeda-Morishita, Mariko
author_sort Kamei, Noriyasu
collection PubMed
description We previously found that coadministering peptides and proteins with the cell-penetrating peptide L-penetratin intranasally significantly increased transport to the brain and enhanced pharmacological effects. The present study aimed to clarify the mechanisms of nose-to-brain drug delivery enhancement by L-penetratin coadministration. First, we compared the concentrations of Exendin-4 in plasma and brain after intranasal and subcutaneous administration and suggested that coadministration with L-penetratin facilitated the direct nose-to-brain transport of Exendin-4. Second, we demonstrated that L-penetratin did not stimulate the transport of Cy7-labeled Exendin-4 and insulin through the trigeminal nerves but shifted their distribution to the olfactory mucosal pathway. Third, we investigated the distribution of insulin into the deeper regions of the brain after delivery via the olfactory pathway and suggested that insulin had entered the olfactory bulb, bottom part of the brain, and perivascular space through the cerebrospinal fluid and had diffused throughout the brain. We further demonstrated that intranasally delivered insulin with L-penetratin specifically accumulated on the hippocampus neuronal cells. Thus, this study suggested that administrating peptide drugs intranasally with L-penetratin allows direct transport to the olfactory bulb, bottom part of the brain, and perivascular space of the cerebral artery. This technique also potentially allows targeting of specific brain areas.
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spelling pubmed-86189832021-11-27 Investigation of the Transport Pathways Associated with Enhanced Brain Delivery of Peptide Drugs by Intranasal Coadministration with Penetratin Kamei, Noriyasu Suwabe, Susumu Arime, Kenji Bando, Hidemi Murata, Kaho Yamaguchi, Maika Yokoyama, Natsuki Tanaka, Erina Hashimoto, Ayaka Kanazawa, Takanori Ago, Yukio Takeda-Morishita, Mariko Pharmaceutics Article We previously found that coadministering peptides and proteins with the cell-penetrating peptide L-penetratin intranasally significantly increased transport to the brain and enhanced pharmacological effects. The present study aimed to clarify the mechanisms of nose-to-brain drug delivery enhancement by L-penetratin coadministration. First, we compared the concentrations of Exendin-4 in plasma and brain after intranasal and subcutaneous administration and suggested that coadministration with L-penetratin facilitated the direct nose-to-brain transport of Exendin-4. Second, we demonstrated that L-penetratin did not stimulate the transport of Cy7-labeled Exendin-4 and insulin through the trigeminal nerves but shifted their distribution to the olfactory mucosal pathway. Third, we investigated the distribution of insulin into the deeper regions of the brain after delivery via the olfactory pathway and suggested that insulin had entered the olfactory bulb, bottom part of the brain, and perivascular space through the cerebrospinal fluid and had diffused throughout the brain. We further demonstrated that intranasally delivered insulin with L-penetratin specifically accumulated on the hippocampus neuronal cells. Thus, this study suggested that administrating peptide drugs intranasally with L-penetratin allows direct transport to the olfactory bulb, bottom part of the brain, and perivascular space of the cerebral artery. This technique also potentially allows targeting of specific brain areas. MDPI 2021-10-20 /pmc/articles/PMC8618983/ /pubmed/34834159 http://dx.doi.org/10.3390/pharmaceutics13111745 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kamei, Noriyasu
Suwabe, Susumu
Arime, Kenji
Bando, Hidemi
Murata, Kaho
Yamaguchi, Maika
Yokoyama, Natsuki
Tanaka, Erina
Hashimoto, Ayaka
Kanazawa, Takanori
Ago, Yukio
Takeda-Morishita, Mariko
Investigation of the Transport Pathways Associated with Enhanced Brain Delivery of Peptide Drugs by Intranasal Coadministration with Penetratin
title Investigation of the Transport Pathways Associated with Enhanced Brain Delivery of Peptide Drugs by Intranasal Coadministration with Penetratin
title_full Investigation of the Transport Pathways Associated with Enhanced Brain Delivery of Peptide Drugs by Intranasal Coadministration with Penetratin
title_fullStr Investigation of the Transport Pathways Associated with Enhanced Brain Delivery of Peptide Drugs by Intranasal Coadministration with Penetratin
title_full_unstemmed Investigation of the Transport Pathways Associated with Enhanced Brain Delivery of Peptide Drugs by Intranasal Coadministration with Penetratin
title_short Investigation of the Transport Pathways Associated with Enhanced Brain Delivery of Peptide Drugs by Intranasal Coadministration with Penetratin
title_sort investigation of the transport pathways associated with enhanced brain delivery of peptide drugs by intranasal coadministration with penetratin
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8618983/
https://www.ncbi.nlm.nih.gov/pubmed/34834159
http://dx.doi.org/10.3390/pharmaceutics13111745
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