title: Delivery of siRNA to the brain using a combination of nose-to-brain delivery and cell-penetrating peptide-modified nano-micelles.
abstract: The potential for RNA-based agents to serve as effective therapeutics for central nerve systems (CNS) disorders has been successfully demonstrated in vitro. However, the blood-brain barrier limits the distribution of systemically administered therapeutics to the CNS, posing a major challenge for drug development aimed at combatting CNS disorders. Therefore, the development of effective strategies to enhance siRNA delivery to the brain is of great interest in clinical and pharmaceutical fields. To improve the efficiency of small interfering RNA (siRNA) delivery to the brain, we developed a nose-to-brain delivery system combined with cell-penetrating peptide (CPP) modified nano-micelles comprising polyethylene glycol-polycaprolactone (PEG-PCL) copolymers conjugated with the CPP, Tat (MPEG-PCL-Tat). In this study, we describe intranasal brain delivery of siRNA or dextran (Mw: 10,000 Da) as a model siRNA, by using MPEG-PCL-Tat. Intranasal delivery of dextran with MPEG-PCL-Tat improved brain delivery compared to intravenous delivery of dextran either with or without MPEG-PCL-Tat. We also studied the intranasal transfer of MPEG-PCL-Tat to the brain via the olfactory and trigeminal nerves, the putative pathways to the brain from the nasal cavity. We found that MPEG-PCL-Tat accelerated transport along the olfactory and trigeminal nerve pathway because of its high permeation across the nasal mucosa.
authors.affiliation: Laboratory of Pharmaceutics and Drug Delivery, Department of Pharmaceutical Science, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. Electronic address: kanazawa@toyaku.ac.jp.
authors.forename: T
authors.initials: T
authors.lastname: Kanazawa
authors.forename: F
authors.initials: F
authors.lastname: Akiyama
authors.forename: S
authors.initials: S
authors.lastname: Kakizaki
authors.forename: Y
authors.initials: Y
authors.lastname: Takashima
authors.forename: Y
authors.initials: Y
authors.lastname: Seta
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D057846:Cell-Penetrating Peptides / Q000494:pharmacology*; D003911:Dextrans / Q000378:metabolism; D005453:Fluorescence; D018014:Gene Transfer Techniques; D008297:Male; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry*; D009297:Nasal Mucosa / Q000378:metabolism*; D009830:Olfactory Bulb / Q000378:metabolism; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014276:Trigeminal Nerve / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism
chemical_list: D057846:Cell-Penetrating Peptides; D003911:Dextrans; D008823:Micelles; D011091:Polyesters; D034741:RNA, Small Interfering; C439611:methoxy poly(ethylene glycol-co-epsilon-caprolactone); D054322:tat Gene Products, Human Immunodeficiency Virus; C016240:polycaprolactone; D011092:Polyethylene Glycols
keywords: Central nerve system; Nano-sized micelles; Nose-to-brain; Tat analog; siRNA