title: A Dual-Ligand Liposomal System Composed of a Cell-Penetrating Peptide and a Mitochondrial RNA Aptamer Synergistically Facilitates Cellular Uptake and Mitochondrial Targeting.
abstract: It has been reported that the use of mitochondrial RNA aptamers including RNase P (RP) results in the selective mitochondrial delivery of endogenous and exogenous RNAs. The issue of whether these aptamers would be useful ligands for the mitochondrial targeting of a nanoparticle has not been demonstrated to date because nanocarriers modified with these RNA aptamers are insufficiently internalized by cells. We report here on the development of a dual-ligand liposomal system composed of octaarginine (R8), a device that enhances cellular uptake, and an RP aptamer for mitochondrial targeting to permit a nanocarrier to be efficiently delivered to mitochondria. Surprisingly, the cellular uptake of the R8-modified nanocarrier was facilitated by modification with an RP aptamer. The optimal composition of a nanocarrier needed for efficient cellular uptake and mitochondrial targeting was determined. In a confocal laser scanning microscopy analysis, the dual-ligand-modified nanocarrier was found to result in effective mitochondrial targeting through an ATP-dependent pathway and was much more effective than a single-ligand R8-modified nanocarrier. This is the first report of the regulation of intracellular trafficking by a mitochondrial RNA aptamer-modified nanocarrier system.
authors.affiliation: Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Yuma
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Furukawa
authors.affiliation: Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan. Electronic address: harasima@pharm.hokudai.ac.jp.
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Harashima
mesh_terms: D052157:Aptamers, Nucleotide / Q000008:administration & dosage / Q000378:metabolism*; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage / Q000378:metabolism*; D004337:Drug Carriers / Q000008:administration & dosage / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D004357:Drug Synergism; D006367:HeLa Cells; D006801:Humans; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism*; D008024:Ligands; D008081:Liposomes; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D012313:RNA / Q000008:administration & dosage / Q000378:metabolism*; D000077278:RNA, Mitochondrial
chemical_list: D052157:Aptamers, Nucleotide; D057846:Cell-Penetrating Peptides; D004337:Drug Carriers; D008024:Ligands; D008081:Liposomes; D000077278:RNA, Mitochondrial; D012313:RNA
keywords: aptamer; drug delivery systems; liposomes; nanotechnology; targeted drug delivery