Ultrasound-Enhanced Generation of Reactive Oxygen Species for MRI-Guided Tumor Therapy by the Fe@Fe₃O₄-Based Peroxidase-Mimicking Nanozyme

Abstract

Reactive oxygen species (ROS)-based tumor therapy is still challenging due to limited ROS-generating efficacy. Herein, we constructed heparin-conjugated Fe@Fe3O4 NPs (Fe@Fe3O4@heparin, denoted as MNPs) as a peroxidase-mimicking nanozyme to generate ROS for tumor therapy through the combination of the ultrasound-stimulated Fenton reaction and the increased concentration of H2O2 by β-lapachone (La) in a tumor. La was first intraperitoneally injected into mice and induced to generate a considerable quantity of H2O2 through a specific tumor reaction, which was catalyzed by MNPs to produce highly hydroxyl radicals (•OH). Furthermore, the therapy efficacy for malignant tumors could significantly be enhanced by an ultrasonic stimulation. With the help of the increased amount of H2O2 generated by La in the tumor and the enhanced peroxidase-mimicking activity of MNPs by ultrasound, MNPs manifest good therapeutic performance in a 4T1 xenograft model, which provides a strategy for enhanced nanozyme-mediated tumor therapy.

Density Functional Theory-Based Method to Predict the Activities of Nanomaterials as Peroxidase Mimics

“…However, this descriptor is obviously inapplicable to non-noble metals, which easily induce the dissociation of H 2 O 2 due to their strong reducibility but show no POD-like activities. For monometallic Fe 3 O 4 nanoparticles consisting of both trivalent Fe­(III) and divalent Fe­(II) ions, Chen et al found that the nanoparticles containing more Fe­(II) had stronger POD-like activities . However, this relationship between the Fe­(II) content and POD-like activity cannot be generalized to all iron oxides because ferrous oxide (FeO) nanoparticles consisting entirely of Fe­(II) have lower POD-like activities than Fe 3 O 4 .…”

Metal–Organic‐Framework‐Engineered Enzyme‐Mimetic Catalysts

“…Natural enzymes, one of the most potent biocatalysts with high catalytic activities and substrate specificity, play an essential role in industrial, medical, and biological fields. [1,2] However, the inherent deficiencies of natural enzymes, such as high cost of fabrication and purification, low operational stability, (e.g., pH value, [25] oxygen content, [26] and redox conditions [27,28] ) or external stimuli (e.g., light, [29][30][31][32][33] ultrasound, [34,35] and X-rays [36] ), which result in unsatisfactory catalytic performance and selectivity toward a particular catalytic reaction. Moreover, the size, crystal structure, elemental composition, and surface status of diverse Enz-Cats are of great significance in the adjustment of catalytic properties.…”

“…Although some developed Enz‐Cats have exhibited efficient in vitro activities, the catalytic performances and selectivity in diverse physiological environments are still vital considerations during the exploration of their further application in biomedical areas. [ 22–24 ] Furthermore, the inherent physicochemical characteristics of these Enz‐Cats may yield multiple catalytic reactions, such as generating or scavenging reactive oxygen species (ROS) under internal microenvironments (e.g., pH value, [ 25 ] oxygen content, [ 26 ] and redox conditions [ 27,28 ] ) or external stimuli (e.g., light, [ 29–33 ] ultrasound, [ 34,35 ] and X‐rays [ 36 ] ), which result in unsatisfactory catalytic performance and selectivity toward a particular catalytic reaction. Moreover, the size, crystal structure, elemental composition, and surface status of diverse Enz‐Cats are of great significance in the adjustment of catalytic properties.…”

Endogenous H2O2-Sensitive and Weak Acidic pH-Triggered Nitrogen-Doped Graphene Nanoparticles (N-GNMs) in the Tumor Microenvironment Serve as Peroxidase-Mimicking Nanozymes for Tumor-Specific Treatment

“…These peculiar features in the TME can thus be exploited as a strategy for tumor-specific treatment by introducing a peroxidase (POD)-mimicking nanozyme [ 5 ]. In the presence of a POD-mimicking nanozyme, H 2 O 2 can be decomposed into hydroxyl radicals (•OH) under acidic conditions [ 6 ]. The produced •OH is a highly toxic substance that can attack and oxidize most organic molecules (cell proteins, cell proteins, etc.)…”

“…In normal cells, glycolysis is inhibited and the pH is controlled at approximately 7.4 [ 10 , 11 ]. The catalytic performance of POD-mimicking nanozymes is acidic pH-triggered [ 6 ]. POD-like catalytic activities are activated in the acidic TME to generate highly toxic •OH and cause tumor cell death while this does not occur in the neutral pH environment of normal tissues, leaving the normal cells unharmed.…”