title: An oral oligonucleotide delivery system based on a thiolated polymer: Development and in vitro evaluation.
abstract: The purpose of this study was to develop and evaluate an oral oligonucleotide delivery system based on a thiolated polymer/reduced glutathione (GSH) system providing a protective effect toward nucleases and permeation enhancement. A polycarbophil-cysteine conjugate (PCP-Cys) was synthesized. Enzymatic degradation of a model oligonucleotide by DNase I and within freshly collected intestinal fluid was investigated in the absence and presence of PCP-Cys. Permeation studies with PCP-Cys/GSH versus control were performed in vitro on Caco-2 cell monolayers and ex vivo on rat intestinal mucosa. PCP-Cys displayed 223 ± 13.8 μmol thiol groups per gram polymer. After 4h, 61% of the free oligonucleotides were degraded by DNase I and 80% within intestinal fluid. In contrast, less than 41% (DNase I) and 60% (intestinal fluid) were degraded in the presence of 0.02% (m/v) PCP-Cys. Permeation studies revealed an 8-fold (Caco-2) and 10-fold (intestinal mucosa) increase in apparent permeability compared to buffer control. Hence, this PCP-Cys/GSH system might be a promising tool for the oral administration of oligonucleotides as it allows a significant protection toward degrading enzymes and facilitates their transport across intestinal membranes.
authors.affiliation: Department of Pharmaceutical Technology, Gadjah Mada University, Yogyakarta, Indonesia.
authors.forename: Ronny
authors.initials: R
authors.lastname: Martien
authors.forename: Herbert
authors.initials: H
authors.lastname: Hoyer
authors.forename: Glen
authors.initials: G
authors.lastname: Perera
authors.forename: Andreas Bernkop
authors.initials: AB
authors.lastname: Schnürch
mesh_terms: D000180:Acrylic Resins / Q000032:analysis / Q000737:chemistry*; D000284:Administration, Oral; D000818:Animals; D001826:Body Fluids / Q000737:chemistry / Q000378:metabolism; D018938:Caco-2 Cells; D003545:Cysteine / Q000032:analysis / Q000737:chemistry*; D003850:Deoxyribonuclease I / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry; D004339:Drug Compounding; D016503:Drug Delivery Systems; D004355:Drug Stability; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D009841:Oligonucleotides / Q000008:administration & dosage / Q000737:chemistry*; D010539:Permeability; D011108:Polymers / Q000737:chemistry*; D051381:Rats; D013438:Sulfhydryl Compounds / Q000032:analysis / Q000737:chemistry*; D013552:Swine
chemical_list: D000180:Acrylic Resins; D004337:Drug Carriers; D009841:Oligonucleotides; D011108:Polymers; D013438:Sulfhydryl Compounds; C030312:calcium polycarbophil; D003850:Deoxyribonuclease I; D003545:Cysteine