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Int. J. Mol. Sci. 2017, 18(9), 1837; doi:10.3390/ijms18091837

Synthesis and Characterization of Tissue Plasminogen Activator—Functionalized Superparamagnetic Iron Oxide Nanoparticles for Targeted Fibrin Clot Dissolution

1
Department of Otorhinolaryngology—Head and Neck Surgery, Section of Experimental Oncology and Nanomedicine (SEON), Else Kröner-Fresenius-Stiftungsprofessur, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
2
Physikalisch-Technische Bundesanstalt, Braunschweig und Berlin, 10587 Berlin, Germany
3
Institute of Biomaterials, Department of Materials Science and Engineering, University Erlangen-Nuremberg, 91058 Erlangen, Germany
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 24 July 2017 / Revised: 10 August 2017 / Accepted: 18 August 2017 / Published: 24 August 2017
(This article belongs to the Special Issue Nanotechnology in Drug Delivery)
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Abstract

Superparamagnetic iron oxide nanoparticles (SPIONs) have attracted great attention in many biomedical fields and are used in preclinical/experimental drug delivery, hyperthermia and medical imaging. In this study, biocompatible magnetite drug carriers, stabilized by a dextran shell, were developed to carry tissue plasminogen activator (tPA) for targeted thrombolysis under an external magnetic field. Different concentrations of active tPA were immobilized on carboxylated nanoparticles through carbodiimide-mediated amide bond formation. Evidence for successful functionalization of SPIONs with carboxyl groups was shown by Fourier transform infrared spectroscopy. Surface properties after tPA immobilization were altered as demonstrated by dynamic light scattering and ζ potential measurements. The enzyme activity of SPION-bound tPA was determined by digestion of fibrin-containing agarose gels and corresponded to about 74% of free tPA activity. Particles were stored for three weeks before a slight decrease in activity was observed. tPA-loaded SPIONs were navigated into thrombus-mimicking gels by external magnets, proving effective drug targeting without losing the protein. Furthermore, all synthesized types of nanoparticles were well tolerated in cell culture experiments with human umbilical vein endothelial cells, indicating their potential utility for future therapeutic applications in thromboembolic diseases. View Full-Text
Keywords: protein binding; activated ester reaction; fibrinolysis; tissue plasminogen activator; superparamagnetic iron oxide nanoparticles; drug targeting protein binding; activated ester reaction; fibrinolysis; tissue plasminogen activator; superparamagnetic iron oxide nanoparticles; drug targeting
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Heid, S.; Unterweger, H.; Tietze, R.; Friedrich, R.P.; Weigel, B.; Cicha, I.; Eberbeck, D.; Boccaccini, A.R.; Alexiou, C.; Lyer, S. Synthesis and Characterization of Tissue Plasminogen Activator—Functionalized Superparamagnetic Iron Oxide Nanoparticles for Targeted Fibrin Clot Dissolution. Int. J. Mol. Sci. 2017, 18, 1837.

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