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Potential of surfactant-coated nanoparticles to improve brain delivery of arylsulfatase A.

  • Schuster, Tilman1
  • Mühlstein, Astrid2
  • Yaghootfam, Claudia3
  • Maksimenko, Olga4
  • Shipulo, Elena4
  • Gelperina, Svetlana4
  • Kreuter, Jörg2
  • Gieselmann, Volkmar3
  • Matzner, Ulrich3
  • 1 Institute of Biochemistry and Molecular Biology, Rheinische Friedrich-Wilhelms Universität Bonn, Nussallee 11, D-53115 Bonn, Germany. Electronic address: [email protected] , (Germany)
  • 2 Institute of Pharmaceutical Technology, Johann Wolfgang Goethe Universität Frankfurt am Main, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany. , (Germany)
  • 3 Institute of Biochemistry and Molecular Biology, Rheinische Friedrich-Wilhelms Universität Bonn, Nussallee 11, D-53115 Bonn, Germany. , (Germany)
  • 4 Nanosystem Ltd., Moscow, Russia.
Published Article
Journal of controlled release : official journal of the Controlled Release Society
Publication Date
May 10, 2017
DOI: 10.1016/j.jconrel.2017.02.016
PMID: 28215668


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.

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