Iron oxide nanoparticles induce human microvascular endothelial cell permeability through reactive oxygen species production and microtubule remodeling

Patrick L Apopa,Xianglin Shi,Yong Qian,Daniel C Flynn,Dale Porter,Nancy Lan Guo,Val Vallyathan,Maricica Pacurari,Vincent Castranova,Diane Schwegler-Berry,Rong Shao

doi:10.1186/1743-8977-6-1

Abstract

BackgroundEngineered iron nanoparticles are being explored for the development of biomedical applications and many other industry purposes. However, to date little is known concerning the precise mechanisms of translocation of iron nanoparticles into targeted tissues and organs from blood circulation, as well as the underlying implications of potential harmful health effects in human.ResultsThe confocal microscopy imaging analysis demonstrates that exposure to engineered iron nanoparticles induces an increase in cell permeability in human microvascular endothelial cells. Our studies further reveal iron nanoparticles enhance the permeability through the production of reactive oxygen species (ROS) and the stabilization of microtubules. We also showed Akt/GSK-3β signaling pathways are involved in iron nanoparticle-induced cell permeability. The inhibition of ROS demonstrate ROS play a major role in regulating Akt/GSK-3β – mediated cell permeability upon iron nanoparticle exposure. These results provide new insights into the bioreactivity of engineered iron nanoparticles which can inform potential applications in medical imaging or drug delivery.ConclusionOur results indicate that exposure to iron nanoparticles induces an increase in endothelial cell permeability through ROS oxidative stress-modulated microtubule remodeling. The findings from this study provide new understandings on the effects of nanoparticles on vascular transport of macromolecules and drugs.

Highlights

Engineered iron nanoparticles are being explored for the development of biomedical applications and many other industry purposes
Size distribution of nanoparticle in cell culture medium and uptake of iron nanoparticles by human microvascular endothelial cells (HMVECs) Iron nanoparticles used in these experiments are ferrites of maghemite (Fe2O3), which are superparamagnetic nanoparticles
Since a Transmission electron microscopy (TEM) can only measure very limited number of particles in solution and the particles subjected to measurements are fixed and dried, it may not provide an accurate profile of the particles in the working solution

Summary

Introduction

Engineered iron nanoparticles are being explored for the development of biomedical applications and many other industry purposes. To date little is known concerning the precise mechanisms of translocation of iron nanoparticles into targeted tissues and organs from blood circulation, as well as the underlying implications of potential harmful health effects in human. Iron nanoparticles show great potential in human biomedical applications, such as labeling and magnetic separation of biological materials, imaging and diagnostic applications in human, site-directed drug delivery, and anticancer hyperthermia therapy [2]. Significant knowledge gaps currently exist on the precise mechanisms of translocation of iron nanoparticles into the targeted tissues, organs, and tumors, as well as the toxicological effect of iron nanoparticles, which would deter their broad applications. Alteration of permeability barrier integrity plays a major role in drug-based therapies, as well as the pathogenesis of cardiovascular diseases, inflammation, acute lung injury syndromes, and carcinogenesis [3,5,6]

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Conclusion