title: Crossing the blood-brain barrier: Glutathione-conjugated poly(ethylene imine) for gene delivery.
abstract: The targeted drug delivery to the central nervous system represents one of the major challenges in pharmaceutical formulations since it is strictly limited through the highly selective blood-brain barrier (BBB). l-Glutathione (GSH), a tripeptide and well-known antioxidant, has been studied in the last years as potential candidate to facilitate the receptor-mediated transcytosis of nanocarriers. We thus tested whether GSH decoration of a positively charged polymer, poly(ethylene imine), with this vector enables the transport of genetic material and, simultaneously, the passage through the BBB. In this study, we report the synthesis of GSH conjugated cationic poly(ethylene imine)s via ecologically desirable thiol-ene photo-addition. The copolymers, containing 80% primary or secondary amine groups, respectively, were investigated concerning their bio- and hemocompatibility as well as their ability to cross a hCMEC/D3 endothelial cell layer mimicking the BBB within microfluidically perfused biochips. We demonstrate that BBB passage depends on the used amino-groups and on the GSH ratio. Thereby the copolymer containing secondary amines showed an enhanced performance. We thus conclude that GSH-coupling represents a feasible and promising approach for the functionalization of nanocarriers intended to cross the BBB for the delivery of drugs to the central nervous system.
authors: Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, Humboldtstrasse 10, 07743 Jena, Germany; Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743 Jena, Germany.
authors: Christoph
authors: C
authors: Englert
authors: Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, Humboldtstrasse 10, 07743 Jena, Germany; Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743 Jena, Germany.
authors: Anne-Kristin
authors: AK
authors: Trützschler
authors: Institute of Biochemistry II, Jena University Hospital, Nonnenplan 2-4, 07743 Jena, Germany; Center for Sepsis Control and Care, Jena University Hospital, Erlanger Allee 101, 07747 Jena, Germany.
authors: Martin
authors: M
authors: Raasch
authors: Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, Humboldtstrasse 10, 07743 Jena, Germany; Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743 Jena, Germany.
authors: Tanja
authors: T
authors: Bus
authors: Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, Humboldtstrasse 10, 07743 Jena, Germany; Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743 Jena, Germany.
authors: Philipp
authors: P
authors: Borchers
authors: Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743 Jena, Germany; Institute of Biochemistry II, Jena University Hospital, Nonnenplan 2-4, 07743 Jena, Germany; Center for Sepsis Control and Care, Jena University Hospital, Erlanger Allee 101, 07747 Jena, Germany. Electronic address: alexander.mosig@med.uni-jena.de.
authors: Alexander S
authors: AS
authors: Mosig
authors: Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, Humboldtstrasse 10, 07743 Jena, Germany; Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743 Jena, Germany. Electronic address: anja.traeger@uni-jena.de.
authors: Anja
authors: A
authors: Traeger
authors: Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, Humboldtstrasse 10, 07743 Jena, Germany; Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743 Jena, Germany. Electronic address: ulrich.schubert@uni-jena.de.
authors: Ulrich S
authors: US
authors: Schubert
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D042783:Endothelial Cells / Q000378:metabolism; D018014:Gene Transfer Techniques; D005978:Glutathione / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence; D011094:Polyethyleneimine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D001672:Biocompatible Materials; D004337:Drug Carriers; D011094:Polyethyleneimine; D005978:Glutathione
keywords: Blood-brain barrier; Microfluidic biochip; Non-viral gene delivery; Poly(ethylene imine); l-Glutathione