International Journal of Nanomedicine (Aug 2018)
Low-molecular-weight sulfonated chitosan as template for anticoagulant nanoparticles
Abstract
Katja Heise,1,2 Mathias Hobisch,3,4 Liviu Sacarescu,5 Uros Maver,6 Josefine Hobisch,3 Tobias Reichelt,7 Marija Sega,6 Steffen Fischer,1 Stefan Spirk3,4 Members of EPNOE and NAWI Graz 1Institute of Plant and Wood Chemistry, Technische Universität Dresden, Tharandt, Germany; 2Department of Bioproducts and Biosystems, Aalto University, Espoo, Finland; 3Institute for Chemistry and Technology of Materials, Graz University of Technology, Graz, Austria; 4Institute for Paper, Pulp and Fiber Technology, Graz University of Technology, Graz, Austria; 5“Petru Poni” Institute of Macromolecular Chemistry, Romanian Academy, Iasi, Romania; 6Faculty of Medicine, University of Maribor, Maribor, Slovenia; 7Zentrum für Bucherhaltung GmbH, Leipzig, Germany Purpose: In this work, low-molecular-weight sulfoethyl chitosan (SECS) was used as a model template for the generation of silver core-shell nanoparticles with high potential as anticoagulants for medical applications. Materials and methods: SECS were synthesized by two reaction pathways, namely Michael addition and a nucleophilic substitution with sodium vinylsulfonate or sodium 2-bromoethanesulfonate (NaBES). Subsequently, these derivatives were used as reducing and capping agents for silver nanoparticles in a microwave-assisted reaction. The formed silver-chitosan core-shell particles were further surveyed in terms of their anticoagulant action by different coagulation assays focusing on the inhibition of either thrombin or cofactor Xa. Results: In-depth characterization revealed a sulfoalkylation of chitosan mainly on its sterically favored O6-position. Moreover, comparably high average degrees of substitution with sulfoethyl groups (DSSE) of up to 1.05 were realized in reactions with NaBES. The harsh reaction conditions led to significant chain degradation and consequently, SECS exhibits masses of <50 kDa. Throughout the following microwave reaction, stable nanoparticles were obtained only from highly substituted products because they provide a sufficient charge density that prevented particles from aggregation. High-resolution transmission electron microscopy images reveal that the silver core (diameter ~8 nm) is surrounded by a 1–2 nm thick SECS layer. These core-shell particles and the SECS itself exhibit an inhibiting activity, especially on cofactor Xa. Conclusion: This interesting model system enabled the investigation of structure–property correlations in the course of nanoparticle formation and anticoagulant activity of SECS and may lead to completely new anticoagulants on the basis of chitosan-capped nanoparticles. Keywords: chitosan ethylsulfonate, silver nanoparticles, antithrombotic activity, cofactor Xa
