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Tuning the surface coating of IONs toward efficient sonochemical tethering and sustained liberation of topoisomerase II poisons

Authors Michalkova H, Strmiska V, Kudr J, Skubalova Z, Tesarova B, Svec P, Richtera L, Zitka O, Adam V, Heger Z

Received 14 March 2019

Accepted for publication 29 July 2019

Published 17 September 2019 Volume 2019:14 Pages 7609—7624


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Anderson Oliveira Lobo

Hana Michalkova,1 Vladislav Strmiska,1 Jiri Kudr,1,2 Zuzana Skubalova,1 Barbora Tesarova,1 Pavel Svec,1 Lukas Richtera,1,2 Ondrej Zitka,1,2 Vojtech Adam,1,2 Zbynek Heger1,2

1Department of Chemistry and Biochemistry, Mendel University in Brno, Brno CZ-613 00, Czech Republic; 2Smart Nanodevices Research Group, Central European Institute of Technology, Brno University of Technology, Brno CZ-621 00, Czech Republic

Correspondence: Zbynek Heger
Department of Chemistry and Biochemistry, Mendel University in Brno, Zemedelska 1, Brno CZ-613 00, Czech Republic
Tel +420 54 513 3350
Fax +420 54 521 2044

Background: Iron oxide nanoparticles (IONs) have been increasingly utilized in a wide spectrum of biomedical applications. Surface coatings of IONs can bestow a number of exceptional properties, including enhanced stability of IONs, increased loading of drugs or their controlled release.
Methods: Using two-step sonochemical protocol, IONs were surface-coated with polyoxyethylene stearate, polyvinylpyrrolidone or chitosan for a loading of two distinct topo II poisons (doxorubicin and ellipticine). The cytotoxic behavior was tested in vitro against breast cancer (MDA-MB-231) and healthy epithelial cells (HEK-293 and HBL-100). In addition, biocompatibility studies (hemotoxicity, protein corona formation, binding of third complement component) were performed.
Results: Notably, despite surface-coated IONs exhibited only negligible cytotoxicity, upon tethering with topo II poisons, synergistic or additional enhancement of cytotoxicity was found in MDA-MB-231 cells. Pronounced anti-migratory activity, DNA fragmentation, decrease in expression of procaspase-3 and enhancement of p53 expression were further identified upon exposure to surface-coated IONs with tethered doxorubicin and ellipticine. Moreover, surface-coated IONs nanoformulations of topo II poisons exhibited exceptional stability in human plasma with no protein corona and complement 3 binding, and only a mild induction of hemolysis in human red blood cells.
Conclusion: The results imply a high potential of an efficient ultrasound-mediated surface functionalization of IONs as delivery vehicles to improve therapeutic efficiency of topo II poisons.

Keywords: doxorubicin, ellipticine, iron oxide, nanoparticles, release kinetics

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