title: Visualization and Quantitative Assessment of the Brain Distribution of Insulin through Nose-to-Brain Delivery Based on the Cell-Penetrating Peptide Noncovalent Strategy.
abstract: Our recent work suggested that intranasal coadministration with the cell-penetrating peptide (CPP) penetratin increased the brain distribution of the peptide drug insulin. The present study aimed to distinctly certify the ability of penetratin to facilitate the nose-to-brain delivery of insulin by quantitatively evaluating the distribution characteristics in brain using radioactive (64)Cu-NODAGA-insulin. Autoradiography and analysis using a gamma counter of brain areas demonstrated that the accumulation of radioactivity was greatest in the olfactory bulb, the anterior part of the brain closest to the administration site, at 15 min after intranasal administration of (64)Cu-NODAGA-insulin with l- or d-penetratin. The brain accumulation of (64)Cu-NODAGA-insulin with penetratin was confirmed by ELISA using unlabeled insulin in which intact insulin was delivered to the brain after intranasal coadministration with l- or d-penetratin. By contrast, quantification of cerebrospinal fluid (CSF) samples showed increased insulin concentration in only the anterior portion of the CSF at 15 min after intranasal coadministration with l-penetratin. This study gives the first concrete proof that penetratin can accelerate the direct transport of insulin from the nasal cavity to the brain parenchyma. Further optimization of intranasal administration with CPP may increase the efficacy of delivery of biopharmaceuticals to the brain while reducing the risk of systemic drug exposure.
authors.affiliation: Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University , 1-1-3 Minatojima, Chuo-ku, Kobe, Hyogo 650-8586, Japan.
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Kamei
authors.affiliation: RIKEN Center for Life Science Technologies , 6-7-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Tomotaka
authors.initials: T
authors.lastname: Shingaki
authors.affiliation: RIKEN Center for Life Science Technologies , 6-7-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Yousuke
authors.initials: Y
authors.lastname: Kanayama
authors.affiliation: Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University , 1-1-3 Minatojima, Chuo-ku, Kobe, Hyogo 650-8586, Japan.
authors.forename: Misa
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: RIKEN Center for Life Science Technologies , 6-7-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Riyo
authors.initials: R
authors.lastname: Zochi
authors.affiliation: Department of Pathology and Experimental Medicine, Graduate School of Medical Sciences, Kumamoto University , 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
authors.forename: Koki
authors.initials: K
authors.lastname: Hasegawa
authors.affiliation: RIKEN Center for Life Science Technologies , 6-7-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University , 1-1-3 Minatojima, Chuo-ku, Kobe, Hyogo 650-8586, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Takeda-Morishita
mesh_terms: D000085:Acetates / Q000737:chemistry*; D000281:Administration, Intranasal; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000378:metabolism*; D003301:Copper Radioisotopes / Q000032:analysis*; D016503:Drug Delivery Systems; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007328:Insulin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D008297:Male; D009297:Nasal Mucosa / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: C572723:1-(1,3-carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclononane; D000085:Acetates; D003301:Copper Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D007004:Hypoglycemic Agents; D007328:Insulin
keywords: biopharmaceuticals; brain delivery; cell-penetrating peptides; insulin; intranasal administration