title: Oligoarginine-linked polymers as a new class of penetration enhancers.
abstract: Oligoarginines, which are known as cell-penetrating peptides, enhance the cellular uptake of poorly membrane-permeable bioactive molecules that are chemically conjugated to them. We designed a novel polymer: oligoarginine-linked poly(N-vinylacetamide-co-acrylic acid), with the expectation that the polymers will enhance the cellular uptake of the bioactive molecules that are physically mixed with them. Oligoarginines were grafted onto the polymer backbone through the chemical reaction with acrylic acid functional groups. The changes in the blood glucose concentration after nasal administration of insulin with and without the polymer were monitored in mice. The blood glucose concentration was slightly reduced when insulin was given solely at a dose of 10IU/kg. A D-octaarginine-linked poly(N-vinylacetamide-co-acrylic acid) with a grafting degree of 2% significantly enhanced the insulin-induced hypoglycemic effect. A similar enhancement was not observed when the polymer was substituted with intact D-octaarginine. The penetration-enhancing function of D-octaarginine-linked poly(N-vinylacetamide-co-acrylic acid) increased dramatically with an increase in the grafting degree of D-octaarginine. Substitution of D-octaarginine with the corresponding optical isomer and an increase in the number of arginine residues rather reduced the penetration-enhancing function. In vitro cell studies also indicated that a D-octaarginine-linked poly(N-vinylacetamide-co-acrylic acid) with a grafting degree of 17% enabled fluorescein isothiocyanate-dextran to effectively penetrate the cell membrane. Results demonstrated that our oligoarginine-linked polymer has a potential to provide a new class of penetration enhancers.
authors.affiliation: Faculty of Pharmaceutical Sciences, Setsunan University, 45-1, Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan. sakuma@pharm.setsunan.ac.jp
authors.forename: Shinji
authors.initials: S
authors.lastname: Sakuma
authors.forename: Masaya
authors.initials: M
authors.lastname: Suita
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Masaoka
authors.forename: Makoto
authors.initials: M
authors.lastname: Kataoka
authors.forename: Noriko
authors.initials: N
authors.lastname: Nakajima
authors.forename: Norihiro
authors.initials: N
authors.lastname: Shinkai
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yamauchi
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Hiwatari
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tachikawa
authors.forename: Ryoji
authors.initials: R
authors.lastname: Kimura
authors.forename: Shinji
authors.initials: S
authors.lastname: Yamashita
mesh_terms: D000081:Acetamides / Q000008:administration & dosage* / Q000737:chemistry; D000179:Acrylates / Q000008:administration & dosage* / Q000737:chemistry; D000281:Administration, Intranasal; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002626:Chemistry, Pharmaceutical; D004337:Drug Carriers; D004339:Drug Compounding; D000077270:Exenatide; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000737:chemistry; D007328:Insulin / Q000008:administration & dosage* / Q000737:chemistry; D051379:Mice; D009297:Nasal Mucosa / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000008:administration & dosage* / Q000737:chemistry; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry; D011145:Polyvinyls / Q000008:administration & dosage* / Q000737:chemistry; D013997:Time Factors; D014688:Venoms / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D000081:Acetamides; D000179:Acrylates; D001786:Blood Glucose; D004337:Drug Carriers; D007004:Hypoglycemic Agents; D007328:Insulin; D009842:Oligopeptides; D010455:Peptides; D011145:Polyvinyls; D014688:Venoms; C500307:octa-arginine peptide; C539745:poly(N-vinylacetamide); D000077270:Exenatide