title: Amphiphilic Copolymers Shuttle Drugs Across the Blood-Brain Barrier.
abstract: Medical treatment of diseases of the central nervous system requires transport of drugs across the blood-brain barrier (BBB). Here, it is extended previously in vitro experiments with a model compound to show that the non-water-soluble and brain-impermeable drug domperidone (DOM) itself can be enriched in the brain by use of an amphiphilic copolymer as a carrier. This carrier consists of poly(N-(2-hydroxypropyl)-methacrylamide), statistically copolymerized with 10 mol% hydrophobic lauryl methacrylate, into whose micellar aggregates DOM is noncovalently absorbed. As tested in a BBB model efficient transport of DOM across, the BBB is achievable over a wide range of formulations, containing 0.8 to 35.5 wt% domperidone per copolymer. In neither case, the polymer itself is translocated across the BBB model. In vivo experiments in mice show that already 10 min after intraperitoneal injection of the polymer/domperidone (PolyDOM) formulation, domperidone can be detected in blood and in the brain. Highest serum and brain levels of domperidone are detected 40 min after injection. At that time point serum domperidone is increased 48-fold. Most importantly, domperidone is exclusively detectable in high amounts in the brain of PolyDOM injected mice and not in mice injected with bare domperidone.
authors.affiliation: Institute for Organic Chemistry, Johannes Gutenberg-University Mainz, 55128, Mainz, Germany.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Clemens-Hemmelmann
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center Johannes Gutenberg-University Mainz, 55131, Mainz, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Kuffner
authors.affiliation: Institute of Pharmacy and Biochemistry - Therapeutical Life Sciences, Johannes Gutenberg-University Mainz, 55128, Mainz, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Metz
authors.affiliation: Institute for Organic Chemistry, Johannes Gutenberg-University Mainz, 55128, Mainz, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Kircher
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center Johannes Gutenberg-University Mainz, 55131, Mainz, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schmitt
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medical Center Johannes Gutenberg-University Mainz, 55131, Mainz, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Hiemke
authors.affiliation: Institute of Pharmacy and Biochemistry - Therapeutical Life Sciences, Johannes Gutenberg-University Mainz, 55128, Mainz, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Postina
authors.affiliation: Institute for Organic Chemistry, Johannes Gutenberg-University Mainz, 55128, Mainz, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Zentel
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D002493:Central Nervous System Diseases / Q000188:drug therapy*; D004294:Domperidone / Q000008:administration & dosage / Q000737:chemistry; D016503:Drug Delivery Systems; D006801:Humans; D008689:Methacrylates / Q000008:administration & dosage / Q000737:chemistry; D051379:Mice; D008823:Micelles; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry*
chemical_list: D008689:Methacrylates; D008823:Micelles; D011108:Polymers; C115846:dodecyl methacrylate; D004294:Domperidone
keywords: HPMA-based polymer; blood-brain barrier; central nervous system; domperidone; drug delivery; micelles