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:	Noriyasu Kamei, Susumu Suwabe, Kenji Arime, Hidemi Bando, Kaho Murata, Maika Yamaguchi, Natsuki Yokoyama, Erina Tanaka, Ayaka Hashimoto, Takanori Kanazawa, Yukio Ago, Mariko Takeda-Morishita
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	nose-to-brain delivery exendin-4 insulin cell-penetrating peptide olfactory mucosa hippocampus Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/4e4196d487eb4e11a23e1a988f1f6ee1
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spelling	oai:doaj.org-article:4e4196d487eb4e11a23e1a988f1f6ee12021-11-25T18:40:19ZInvestigation of the Transport Pathways Associated with Enhanced Brain Delivery of Peptide Drugs by Intranasal Coadministration with Penetratin10.3390/pharmaceutics131117451999-4923https://doaj.org/article/4e4196d487eb4e11a23e1a988f1f6ee12021-10-01T00:00:00Zhttps://www.mdpi.com/1999-4923/13/11/1745https://doaj.org/toc/1999-4923We 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.Noriyasu KameiSusumu SuwabeKenji ArimeHidemi BandoKaho MurataMaika YamaguchiNatsuki YokoyamaErina TanakaAyaka HashimotoTakanori KanazawaYukio AgoMariko Takeda-MorishitaMDPI AGarticlenose-to-brain deliveryexendin-4insulincell-penetrating peptideolfactory mucosahippocampusPharmacy and materia medicaRS1-441ENPharmaceutics, Vol 13, Iss 1745, p 1745 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	nose-to-brain delivery exendin-4 insulin cell-penetrating peptide olfactory mucosa hippocampus Pharmacy and materia medica RS1-441
spellingShingle	nose-to-brain delivery exendin-4 insulin cell-penetrating peptide olfactory mucosa hippocampus Pharmacy and materia medica RS1-441 Noriyasu Kamei Susumu Suwabe Kenji Arime Hidemi Bando Kaho Murata Maika Yamaguchi Natsuki Yokoyama Erina Tanaka Ayaka Hashimoto Takanori Kanazawa Yukio Ago Mariko Takeda-Morishita Investigation of the Transport Pathways Associated with Enhanced Brain Delivery of Peptide Drugs by Intranasal Coadministration with Penetratin
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.
format	article
author	Noriyasu Kamei Susumu Suwabe Kenji Arime Hidemi Bando Kaho Murata Maika Yamaguchi Natsuki Yokoyama Erina Tanaka Ayaka Hashimoto Takanori Kanazawa Yukio Ago Mariko Takeda-Morishita
author_facet	Noriyasu Kamei Susumu Suwabe Kenji Arime Hidemi Bando Kaho Murata Maika Yamaguchi Natsuki Yokoyama Erina Tanaka Ayaka Hashimoto Takanori Kanazawa Yukio Ago Mariko Takeda-Morishita
author_sort	Noriyasu Kamei
title	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_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_sort	investigation of the transport pathways associated with enhanced brain delivery of peptide drugs by intranasal coadministration with penetratin
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/4e4196d487eb4e11a23e1a988f1f6ee1
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Investigation of the Transport Pathways Associated with Enhanced Brain Delivery of Peptide Drugs by Intranasal Coadministration with Penetratin

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