title: Galactose-PEG dual conjugation of beta-(1-->3)-D-glucan schizophyllan for antisense oligonucleotides delivery to enhance the cellular uptake.
abstract: Antisense oligonucleotides (AS ODNs) are applied to silence a particular gene, and this approach is one of the potential gene therapies. However, naked oligonucleotides are easy to be degraded or absorbed in biological condition. Therefore, we need a carrier to deliver AS ODNs. This paper presents galactose moieties that were conjugated to the side chain of SPG to enhance cellular ingestion through endocytosis mediated by asialoglycoprotein receptor specifically located on parenchymal liver cells. We introduced galactose with two types of chemical bonds; amide and amine, and the amine connection showed lower ingestion and more toxicity than the amide one. Since PEG was known to induce endocytosis escape, we combined PEG and galactose aiming to provide both cellular up-take and subsequent endocytosis escape. We designed lactose or galactose moieties to attach to the end of the PEG chain that connects to the SPG side chain. When the PEG had the molecular weight of 5000-6000, the antisense effect reached the maximum. We believe that this new type of galactose and PEG dual conjugation broaden the horizon in antisense delivery.
authors.affiliation: Department of Chemical Process and Environments, The University of Kitakyushu, 1-1, Hibikino, Wakamatu-ku, Kitakyushu, Fukuoka 808-0135, Japan.
authors.forename: Ryouji
authors.initials: R
authors.lastname: Karinaga
authors.forename: Takahisa
authors.initials: T
authors.lastname: Anada
authors.forename: Jusaku
authors.initials: J
authors.lastname: Minari
authors.forename: Masami
authors.initials: M
authors.lastname: Mizu
authors.forename: Kazuya
authors.initials: K
authors.lastname: Koumoto
authors.forename: Junji
authors.initials: J
authors.lastname: Fukuda
authors.forename: Kohji
authors.initials: K
authors.lastname: Nakazawa
authors.forename: Teruaki
authors.initials: T
authors.lastname: Hasegawa
authors.forename: Munenori
authors.initials: M
authors.lastname: Numata
authors.forename: Seiji
authors.initials: S
authors.lastname: Shinkai
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sakurai
mesh_terms: D001672:Biocompatible Materials; D002460:Cell Line; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D005690:Galactose; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000378:metabolism*; D011092:Polyethylene Glycols; D012566:Sizofiran / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D047071:beta-Glucans / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D001672:Biocompatible Materials; D016376:Oligonucleotides, Antisense; D047071:beta-Glucans; D011092:Polyethylene Glycols; D012566:Sizofiran; C033363:beta-1,3-glucan; D005690:Galactose