title: Brain delivery of insulin boosted by intranasal coadministration with cell-penetrating peptides.
abstract: Intranasal administration is considered as an alternative route to enable effective drug delivery to the central nervous system (CNS) by bypassing the blood-brain barrier. Several reports have proved that macromolecules can be transferred directly from the nasal cavity to the brain. However, strategies to enhance the delivery of macromolecules from the nasal cavity to CNS are needed because of their low delivery efficiencies via this route in general. We hypothesized that the delivery of biopharmaceuticals to the brain parenchyma can be facilitated by increasing the uptake of drugs by the nasal epithelium including supporting and neuronal cells to maximize the potentiality of the intranasal pathway. To test this hypothesis, the CNS-related model peptide insulin was intranasally coadministered with the cell-penetrating peptide (CPP) penetratin to mice. As a result, insulin coadministered with l- or d-penetratin reached the distal regions of the brain from the nasal cavity, including the cerebral cortex, cerebellum, and brain stem. In particular, d-penetratin could intranasally deliver insulin to the brain with a reduced risk of systemic insulin exposure. Thus, the results obtained in this study suggested that CPPs are potential tools for the brain delivery of peptide- and protein-based pharmaceuticals via intranasal administration.
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: Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, Hyogo 650-8586, Japan. Electronic address: mmtakeda@pharm.kobegakuin.ac.jp.
authors.forename: Mariko
authors.initials: M
authors.lastname: Takeda-Morishita
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002352:Carrier Proteins / Q000008:administration & dosage* / Q000493:pharmacokinetics; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D007328:Insulin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D051379:Mice
chemical_list: D002352:Carrier Proteins; D057846:Cell-Penetrating Peptides; D007328:Insulin; C414409:penetratin
keywords: Brain delivery; Cell-penetrating peptide; Insulin; Intranasal route; Penetratin