title: Dual function MITO-Porter, a nano carrier integrating both efficient cytoplasmic delivery and mitochondrial macromolecule delivery.
abstract: Mitochondrial dysfunction is associated with a variety of human diseases including inherited mitochondrial diseases, neurodegenerative disorders, diabetes mellitus, and cancer. Effective medical therapies for mitochondrial diseases will ultimately require an optimal drug delivery system, which will likely be achieved through innovations in the nanotechnology of intracellular trafficking. To achieve efficient mitochondrial drug delivery, two independent processes, i.e., "cytoplasmic delivery through the cell membrane" and "mitochondrial delivery through the mitochondrial membrane" are required. In previous studies, we developed an octaarginine (R8) modified nano carrier for efficient cytoplasmic delivery, showing that R8-modified liposomes were internalized into cells efficiently. On the other hand, we also constructed MITO-Porter for the mitochondrial delivery of macromolecules, a liposome-based carrier that delivers cargos to mitochondria via membrane fusion. Here, we report the development of a dual function MITO-Porter (DF-MITO-Porter), based on the concept of integrating both R8-modified liposomes and MITO-Porter. We show that the DF-MITO-Porter effectively delivers exogenous macro-biomolecules into the mitochondrial matrix, and provide a demonstration of its potential use in therapies aimed at mitochondrial DNA.
authors.affiliation: Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo, Japan.
authors.forename: Yuma
authors.initials: Y
authors.lastname: Yamada
authors.forename: Ryo
authors.initials: R
authors.lastname: Furukawa
authors.forename: Yukari
authors.initials: Y
authors.lastname: Yasuzaki
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Harashima
mesh_terms: D001692:Biological Transport; D003593:Cytoplasm / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D003850:Deoxyribonuclease I / Q000378:metabolism*; D016503:Drug Delivery Systems; D006801:Humans; D008081:Liposomes / Q000378:metabolism; D046911:Macromolecular Substances / Q000378:metabolism; D008561:Membrane Fusion; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D049329:Nanostructures; D009842:Oligopeptides; D021381:Protein Transport
chemical_list: D004272:DNA, Mitochondrial; D008081:Liposomes; D046911:Macromolecular Substances; D009842:Oligopeptides; C448619:octaarginine; D003850:Deoxyribonuclease I