Impact of Surface Chemistry of Ultrasmall Superparamagnetic Iron Oxide Nanoparticles on Protein Corona Formation and Endothelial Cell Uptake, Toxicity, and Barrier Function

Daysi M Diaz-Diestra; Teresa Palacios-Hernandez; Yizhong Liu; Diane E Smith; Alexander K Nguyen; Todor Todorov; Patrick J Gray; Jiwen Zheng; Shelby A Skoog; Peter L Goering

doi:10.1093/toxsci/kfac058

Impact of Surface Chemistry of Ultrasmall Superparamagnetic Iron Oxide Nanoparticles on Protein Corona Formation and Endothelial Cell Uptake, Toxicity, and Barrier Function

Toxicol Sci. 2022 Jul 28;188(2):261-275. doi: 10.1093/toxsci/kfac058.

Affiliations

¹ Division of Biology, Chemistry, and Materials Science, Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland 20993, USA.
² The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland 20817, USA.
³ Division of Bioanalytical Chemistry, Office of Regulatory Science, Center for Food Safety and Applied Nutrition, US Food and Drug Administration, College Park, Maryland 20740, USA.

PMID: 35708658
DOI: 10.1093/toxsci/kfac058

Abstract

Ultrasmall superparamagnetic iron oxide nanoparticles (USPIONs) have been investigated for biomedical applications, including novel contrast agents, magnetic tracers for tumor imaging, targeted drug delivery vehicles, and magneto-mechanical actuators for hyperthermia and thrombolysis. Despite significant progress, recent clinical reports have raised concerns regarding USPION safety related to endothelial cell dysfunction; however, there is limited information on factors contributing to these clinical responses. The influence of USPION surface chemistry on nanoparticle interactions with proteins may impact endothelial cell function leading to adverse responses. Therefore, the goal of this study was to assess the effects of carboxyl-functionalized USPION (CU) or amine-functionalized USPION (AU) (approximately 30 nm diameter) on biological responses in human coronary artery endothelial cells. Increased protein adsorption was observed for AU compared with CU after exposure to serum proteins. Exposure to CU, but not AU, resulted in a concentration-dependent decrease in cell viability and perinuclear accumulation inside cytoplasmic vesicles. Internalization of CU was correlated with endothelial cell functional changes under non-cytotoxic conditions, as evidenced by a marked decreased expression of endothelial-specific adhesion proteins (eg, vascular endothelial-cadherin and platelet endothelial cell adhesion molecule-1) and increased endothelial permeability. Evaluation of downstream signaling indicated endothelial permeability is associated with actin cytoskeleton remodeling, possibly elicited by intracellular events involving reactive oxygen species, calcium ions, and the nanoparticle cellular uptake pathway. This study demonstrated that USPION surface chemistry significantly impacts protein adsorption and endothelial cell uptake, viability, and barrier function. This information will advance the current toxicological profile of USPION and improve development, safety assessment, and clinical outcomes of USPION-enabled medical products.

Keywords: cytotoxicity; endothelial cell; iron oxide; nanoparticles; protein corona.

Published by Oxford University Press on behalf of the Society of Toxicology 2022.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Endothelial Cells / metabolism
Ferric Compounds / metabolism
Humans
Magnetic Iron Oxide Nanoparticles
Nanoparticles*
Protein Corona* / metabolism

Substances

Ferric Compounds
Protein Corona

Grants and funding

FD/FDA HHS/United States