Iron oxide nanoparticles (IONPs) are frequently used in biomedical applications, yet their toxic potential is still a major concern. While most studies of biosafety focus on cellular responses after exposure to nanomaterials, little is reported to analyze reactions on the surface of nanoparticles as a source of cytotoxicity. Here we report that different intracellular microenvironment in which IONPs are located leads to contradictive outcomes in their abilities to produce free radicals. We first verified pH-dependent peroxidase-like and catalase-like activities of IONPs and investigated how they interact with hydrogen peroxide (H(2)O(2)) within cells. Results showed that IONPs had a concentration-dependent cytotoxicity on human glioma U251 cells, and they could enhance H(2)O(2)-induced cell damage dramatically. By conducting electron spin resonance spectroscopy experiments, we showed that both Fe(3)O(4) and γ-Fe(2)O(3) nanoparticles could catalyze H(2)O(2) to produce hydroxyl radicals in acidic lysosome mimic conditions, with relative potency Fe(3)O(4) > γ-Fe(2)O(3), which was consistent with their peroxidase-like activities. However, no hydroxyl radicals were observed in neutral cytosol mimic conditions with both nanoparticles. Instead, they decomposed H(2)O(2) into H(2)O and O(2) directly in this condition through catalase-like activities. Transmission electron micrographs revealed that IONPs located in lysosomes in cells, the acidic environment of which may contribute to hydroxyl radical production. This is the first study regarding cytotoxicity based on their enzyme-like activities. Since H(2)O(2) is continuously produced in cells, our data indicate that lysosome-escaped strategy for IONP delivery would be an efficient way to diminish long-term toxic potential.

The generation of reactive oxygen species (ROS) is an important mechanism of nanomaterial toxicity. We found that Prussian blue nanoparticles (PBNPs) can effectively scavenge ROS via multienzyme-like activity including peroxidase (POD), catalase (CAT), and superoxide dismutase (SOD) activity. Instead of producing hydroxyl radicals (•OH) through the Fenton reaction, PBNPs were shown to be POD mimetics that can inhibit •OH generation. We theorized for the first time that the multienzyme-like activities of PBNPs were likely caused by the abundant redox potentials of their different forms, making them efficient electron transporters. To study the ROS scavenging ability of PBNPs, a series of in vitro ROS-generating models was established using chemicals, UV irradiation, oxidized low-density lipoprotein, high glucose contents, and oxygen glucose deprivation and reperfusion. To demonstrate the ROS scavenging ability of PBNPs, an in vivo inflammation model was established using lipoproteins in Institute for Cancer Research (ICR) mice. The results indicated that PBNPs hold great potential for inhibiting or relieving injury induced by ROS in these pathological processes.

Co3O4 nanoparticles (Co3O4 NPs), synthesized by the coprecipitation method, showed intrinsic catalase-like, peroxidase-like, and SOD-like activity. The catalytic activity of Co3O4 NPs was much higher than analogous Fe3O4 NPs. Co3O4's mechanisms of catalytic activity were analyzed in detail using the electron spin resonance (ESR) method, which confirmed that Co3O4 NPs don't follow the classical Fenton reactions with hydrogen peroxide the way Fe3O4 NPs do. The high redox potential of Co(3+)/Co(2+) was supposed to be the leading cause of the differences in both activity and mechanism with Fe3O4. Based on the high, peroxidase-like activity, a new immunohistochemical assay was designed in which the avastin antibody was conjugated onto the surface of Co3O4 NPs. The conjugates obtained were used to detect vascular endothelial growth factor (VEGF) that was overexpressed in tumor tissue. When the experimental and control groups were stained, there were clear distinctions between them. This study showed that there are many opportunities to improve the enzyme-like activities of nanomaterials and also to improve their potential applications for biocatalysis and bioassays, especially in relatively harsh conditions.

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