title: Reducible Micelleplexes are Stable Systems for Anti-miRNA Delivery in Cerebrospinal Fluid.
abstract: Glioblastoma multiforme (GBM) and other central nervous system (CNS) cancers have poor long-term prognosis, and there is a significant need for improved treatments. GBM initiation and progression are mediated, in part, by microRNA (miRNA), which are endogenous posttranscriptional gene regulators. Misregulation of miRNAs is a potential target for therapeutic intervention in GBM. In this work, a micelle-like nanoparticle delivery system based upon the block copolymer poly(ethylene glycol-b-lactide-b-arginine) was designed with and without a reducible linkage between the lactide and RNA-binding peptide, R15, to assess the ability of the micelle-like particles to disassemble. Using confocal live cell imaging, intracellular dissociation was pronounced for the reducible micelleplexes. This dissociation was also supported by higher efficiency in a dual luciferase assay specific for the miRNA of interest, miR-21. Notably, micelleplexes were found to have significantly better stability and higher anti-miRNA activity in cerebrospinal fluid than in human plasma, suggesting an advantage for applying micelleplexes to CNS diseases and in vivo CNS therapeutics. The reducible delivery system was determined to be a promising delivery platform for the treatment of CNS diseases with miRNA therapy.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jason S
authors.initials: JS
authors.lastname: Buhrman
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Rayahin
authors.affiliation: Department of Bioengineering, University of Illinois , Chicago, Illinois 60607-7052, United States.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gemeinhart
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001120:Arginine / Q000008:administration & dosage; D001932:Brain Neoplasms / Q000188:drug therapy; D002555:Cerebrospinal Fluid / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods; D005909:Glioblastoma / Q000188:drug therapy; D006801:Humans; D008823:Micelles; D035683:MicroRNAs / Q000378:metabolism*; D053758:Nanoparticles / Q000008:administration & dosage; D011091:Polyesters / Q000008:administration & dosage; D011092:Polyethylene Glycols / Q000008:administration & dosage; D011108:Polymers / Q000008:administration & dosage
chemical_list: D000970:Antineoplastic Agents; D008823:Micelles; D035683:MicroRNAs; D011091:Polyesters; D011108:Polymers; D011092:Polyethylene Glycols; C083464:poly(ethyleneglycol-lactide); D001120:Arginine
keywords: anti-miRNAs; cell-penetrating peptide; glioblastoma; miRNA-21; miRNAs; micelleplexes; micelles