title: [Development of an efficient short interference RNA (siRNA) delivery system with a new pH-sensitive cationic lipid].
abstract: The development of a carrier for the delivery of siRNA is a factor in the realization of RNA interference (RNAi) therapeutics. Modification of siRNA carriers with polyethylene glycol, i.e., PEGylation, is a general strategy for stabilizing a particle in the blood stream and delivering it to tissue or cells. However, it is well-known that, when a carrier is modified by PEGylation, it results in a significant inhibition of both cellular uptake and the endosomal escape process. In a previous study, we reported on the development of a multifunctional envelope-type nano device (MEND) for delivering siRNA and peptide-based functional devices for overcoming the effects conferred by PEGylation and succeeded in the delivery of siRNA to tumor tissue. In this study, we noticed that the pH-sensitive property, changing from neutral to cationic in response to a decrease in pH, could avoid the inhibition caused by PEGylation and succeeded in synthesizing a pH-sensitive cationic lipid, YSK05. The YSK05-MEND had a higher fusogenicity and potency for endosomal escape than other MENDs containing conventional cationic lipids. The PEGylated YSK05-MEND induced efficient gene silencing and avoided the inhibition of endosomal escape caused by PEGylation followed by optimization of the lipid composition. Furthermore, the intratumoral injection of the PEGylated YSK05-MEND resulted in a more efficient gene silencing compared with MENDs containing conventional cationic lipids. Thus, the YSK05-MEND is a promising siRNA carrier for avoiding the inhibition in intracellular trafficking caused by PEGylation both in vitro and in vivo.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan. yukke_overture@mail.sci.hokudai.ac.jp
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sato
authors.forename: Hiroto
authors.initials: H
authors.lastname: Hatakeyama
authors.forename: Mamoru
authors.initials: M
authors.lastname: Hyodo
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Akita
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Harashima
mesh_terms: D000818:Animals; D002412:Cations; D016503:Drug Delivery Systems; D055808:Drug Discovery; D011992:Endosomes / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015552:Injections, Intralesional; D008055:Lipids / Q000008:administration & dosage; D049329:Nanostructures / Q000008:administration & dosage; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D010880:Piperidines / Q000008:administration & dosage; D011092:Polyethylene Glycols; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000378:metabolism
chemical_list: D002412:Cations; D008055:Lipids; D010880:Piperidines; D034741:RNA, Small Interfering; C580570:YSK05; D011092:Polyethylene Glycols