title: Potential of surfactant-coated nanoparticles to improve brain delivery of arylsulfatase A.
abstract: The lysosomal storage disorder (LSD) metachromatic leukodystrophy (MLD) is caused by a deficiency of the soluble, lysosomal hydrolase arylsulfatase A (ASA). The disease is characterized by accumulation of 3-O-sulfogalactosylceramide (sulfatide), progressive demyelination of the nervous system and premature death. Enzyme replacement therapy (ERT), based on regular intravenous injections of recombinant functional enzyme, is in clinical use for several LSDs. For MLD and other LSDs with central nervous system (CNS) involvement, however, ERT is limited by the blood-brain barrier (BBB) restricting transport of therapeutic enzymes from the blood to the brain. In the present study, the potential of different types of surfactant-coated biodegradable nanoparticles to increase brain delivery of ASA was evaluated. Three different strategies to bind ASA to nanoparticle surfaces were compared: (1) adsorption, (2) high-affinity binding via the streptavidin-biotin system, and (3) covalent binding. Adsorption allowed binding of high amounts of active ASA. However, in presence of phosphate-buffered saline or serum rapid and complete desorption occurred, rendering this strategy ineffective for in vivo applications. In contrast, stable immobilization with negligible dissociation was achieved by high-affinity and covalent binding. Consequently, we analyzed the brain targeting of two stably nanoparticle-bound ASA formulations in ASA-/-mice, an animal model of MLD. Compared to free ASA, injected as a control, the biodistribution of nanoparticle-bound ASA was altered in peripheral organs, but no increase of brain levels was detectable. The failure to improve brain delivery suggests that the ASA glycoprotein interferes with processes required to target surfactant-coated nanoparticles to brain capillary endothelial cells.
authors.affiliation: Institute of Biochemistry and Molecular Biology, Rheinische Friedrich-Wilhelms Universität Bonn, Nussallee 11, D-53115 Bonn, Germany. Electronic address: tilman_schuster@gmx.de.
authors.forename: Tilman
authors.initials: T
authors.lastname: Schuster
authors.affiliation: Institute of Pharmaceutical Technology, Johann Wolfgang Goethe Universität Frankfurt am Main, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Mühlstein
authors.affiliation: Institute of Biochemistry and Molecular Biology, Rheinische Friedrich-Wilhelms Universität Bonn, Nussallee 11, D-53115 Bonn, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Yaghootfam
authors.affiliation: Nanosystem Ltd., Moscow, Russia.
authors.forename: Olga
authors.initials: O
authors.lastname: Maksimenko
authors.affiliation: Nanosystem Ltd., Moscow, Russia.
authors.forename: Elena
authors.initials: E
authors.lastname: Shipulo
authors.affiliation: Nanosystem Ltd., Moscow, Russia.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Gelperina
authors.affiliation: Institute of Pharmaceutical Technology, Johann Wolfgang Goethe Universität Frankfurt am Main, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Kreuter
authors.affiliation: Institute of Biochemistry and Molecular Biology, Rheinische Friedrich-Wilhelms Universität Bonn, Nussallee 11, D-53115 Bonn, Germany.
authors.forename: Volkmar
authors.initials: V
authors.lastname: Gieselmann
authors.affiliation: Institute of Biochemistry and Molecular Biology, Rheinische Friedrich-Wilhelms Universität Bonn, Nussallee 11, D-53115 Bonn, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Matzner
mesh_terms: D000818:Animals; D001360:Avidin / Q000737:chemistry; D019921:Biotinylation; D001921:Brain / Q000378:metabolism*; D002553:Cerebroside-Sulfatase / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics / Q000493:pharmacokinetics; D005260:Female; D019344:Lactic Acid / Q000737:chemistry; D007966:Leukodystrophy, Metachromatic / Q000188:drug therapy / Q000378:metabolism; D018345:Mice, Knockout; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D020442:Poloxamer / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D011091:Polyesters / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011136:Polysorbates / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D000075462:Serum Albumin, Human / Q000737:chemistry; D013501:Surface-Active Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D011091:Polyesters; D011136:Polysorbates; D013501:Surface-Active Agents; C093483:neutravidin; D020442:Poloxamer; D001360:Avidin; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C033616:poly(lactide); D002553:Cerebroside-Sulfatase; D000075462:Serum Albumin, Human
keywords: Blood-brain barrier; Enzyme replacement therapy; Lysosomal storage disease; Metachromatic leukodystrophy; Polymeric nanoparticles; Surfactant coating