Gadolinium Oxide Nanoparticles Induce Toxicity in Human Endothelial HUVECs via Lipid Peroxidation, Mitochondrial Dysfunction and Autophagy Modulation.

Mohd Javed Akhtar,Hisham Alhadlaq,Maqusood Ahamed

doi:10.3390/nano10091675

Abstract

In spite of the potential preclinical advantage of Gd2O3 nanoparticles (designated here as GO NPs) over gadolinium-based compounds in MRI, recent concerns of gadolinium deposits in various tissues undergoing MRI demands a mechanistic investigation. Hence, we chose human to measure umbilical vein endothelial cells (HUVECs) that line the vasculature and relevant biomarkers due to GO NPs exposure in parallel with the NPs of ZnO as a positive control of toxicity. GO NPs, as measured by TEM, had an average length of 54.8 ± 29 nm and a diameter of 13.7 ± 6 nm suggesting a fiber-like appearance. With not as pronounced toxicity associated with a 24-h exposure, GO NPs induced a concentration-dependent cytotoxicity (IC50 = 304 ± 17 µg/mL) in HUVECs when exposed for 48 h. GO NPs emerged as significant inducer of lipid peroxidation (LPO), reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and autophagic vesicles in comparison to that caused by ZnO NPs at its IC50 for the same exposure time (48 h). While ZnO NPs clearly appeared to induce apoptosis, GO NPs revealed both apoptotic as well as necrotic potentials in HUVECs. Intriguingly, the exogenous antioxidant NAC (N-acetylcysteine) co-treatment significantly attenuated the oxidative imbalance due to NPs preventing cytotoxicity significantly.

Highlights

Advances in nanotechnology have yielded nanoparticles (NPs; defined as particles having size less than 100 nm, at least, in one dimension) that are under exploration in various applications ranging from catalysis, biosensing, imaging, cancer therapy, DNA, drug delivery and enzyme immobilization [1,2]
Transmission electron microscope (TEM) images measured a length of 60–110 nm and a diameter of 9–23 nm, suggesting an average aspect ratio of over 4
Irneltehaisses, tTuBdAy,RcSytaocttoivxiitcyityanidndBuOceDdIPbYy Gadolinium Oxide Nanoparticles (GO NPs) in Human umbilical vein endothelial cells (HUVECs) was highly correlated with membrane damage as demonstrated by Lactate dehydrogenase (LDH) release, TBARS activity and BODIPY fluorescence

Summary

Introduction

Advances in nanotechnology have yielded nanoparticles (NPs; defined as particles having size less than 100 nm, at least, in one dimension) that are under exploration in various applications ranging from catalysis, biosensing, imaging, cancer therapy, DNA, drug delivery and enzyme immobilization [1,2]. NPs with potential biomedical applications are most likely to interact with human posing potential health hazard. One such applications of NPs is in the diagnosis of diseases using magnetic resonance imaging (MRI). Most contrast agents in MRI are based on gadolinium element (or gadolinium compounds) [3,4,5]. In pursuit of improving detection capability in MRI, NPs based on gadolinium element are under research in preclinical models [6,7,8]. The gadolinium element has been reported to enter the circulation and to deposit in the liver, breast, kidney, lung and neural tissues [4]. Gadolinium deposition has reported in the periodontal ligament of mice, resulting in reduced renal function [15]

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