Iron overload by Superparamagnetic Iron Oxide Nanoparticles is a High Risk Factor in Cirrhosis by a Systems Toxicology Assessment

Abstract

Superparamagnetic iron oxide nanoparticles (SPIONs) as a contrast agent have been widely used in magnetic resonance imaging for tumor diagnosis and theranostics. However, there has been safety concern of SPIONs with cirrhosis related to excess iron-induced oxidative stress. In this study, the impact of iron overload by SPIONs was assessed on a mouse cirrhosis model. A single dose of SPION injection at 0.5 or 5 mg Fe/kg in the cirrhosis group induced a septic shock response at 24 h with elevated serum levels of liver and kidney function markers and extended impacts over 14 days including high levels of serum cholesterols and persistent low serum iron level. In contrast, full restoration of liver functions was found in the normal group with the same dosages over time. Analysis with PCR array of the toxicity pathways revealed the high dose of SPIONs induced significant expression changes of a distinct subset of genes in the cirrhosis liver. All these results suggested that excess iron of the high dose of SPIONs might be a risk factor for cirrhosis because of the marked impacts of elevated lipid metabolism, disruption of iron homeostasis and possibly, aggravated loss of liver functions.

Synergistic Amplification of Oxidative Stress–Mediated Antitumor Activity via Liposomal Dichloroacetic Acid and MOF‐Fe2+

“…Particularly, Fenton reaction is a biological reaction that converts H 2 O 2 , an important product of mitochondrial oxidation, into a highly toxic •OH by Fe, and serves as a new class of ROS‐mediated anticancer therapeutics . However, free Fe may induce severe systemic toxicity due to lack of tumor specificity, so new catalysts for improving biological applications of Fenton reaction are urgently needed.…”

Evaluation of non-targeting, C- or N-pH (low) insertion peptide modified superparamagnetic iron oxide nanoclusters for selective MRI of liver tumors and their potential toxicity in cirrhosis

“…To ensure the potential safety of N-pHLIP-SPION as an MRI contrast agent for liver tumors, the toxicity prole of the assembled SPION was determined in cirrhosis model at the same injection dose. This was because although the poly-Llysine assembled SPION at 5 mg Fe per kg injection dose had no toxicity impact in healthy mice, signicant risk potential was discovered in cirrhosis model with disrupted liver function, lipid metabolism and iron level due to the iron overload post SPION injection, 25 which indicated the safety prole in cirrhosis was a more better safety study model. 26 Thus, the serum liver function markers and lipid cholesterol levels including alkaline phosphatase (AKP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol, high-density lipid cholesterol (HDL) and low-density lipid cholesterol (LDL) were monitored in cirrhosis mice over 15 days post the intravenous injection of assembled SPION.…”

“…[14][15][16][17][18][19] On the other hand, the potential cytotoxicity of SPIO has recently been considered as a major safety concern, [19][20][21] especially in chronic liver diseases due to SPIO induced iron overload resulting in increased risks of steatohepatitis and cirrhosis progression and liver lesions in obesity. [22][23][24][25][26] One way to enhance the safety prole of SPIO was to utilize the target-specic delivery strategy such as cRGD ligand or pH (low) insertion peptide (pHLIP). [27][28][29][30] pHLIP has been successfully utilized to target tumor-specic acidic microenvironment due to its unique conformational change under acidic conditions to a-helical membrane insertion mode.…”

Facilitating Translational Nanomedicine via Predictive Safety Assessment

“…56 Thus, overload or recurrent administration of SPIONs in prolonged treatments can result in high accumulation of SPIONs in the RES, elevate lipid metabolism, disrupt iron homeostasis, and affect liver functions. 57 This adverse effect could be more severe in patients with liver chronic diseases such as cirrhosis. 57 Thus, despite applying surface coatings (e.g., silicon and dextran) could improve the biocompatibility of SPIONs, this would not address the issue of iron overload in the body tissues.…”

“…57 This adverse effect could be more severe in patients with liver chronic diseases such as cirrhosis. 57 Thus, despite applying surface coatings (e.g., silicon and dextran) could improve the biocompatibility of SPIONs, this would not address the issue of iron overload in the body tissues. As such, new designs that could facilitate the rapid body clearance of iron are imperative.…”