Abstract

In recent years, using pharmacological ascorbic acid has emerged as a promising therapeutic approach in cancer treatment, owing to its capacity to induce extracellular hydrogen peroxide (H2O 2) production in solid tumors. The H2 O 2 is then converted into cytotoxic hydroxyl free radicals (HO•) by redox-active Fe2+ inside cells. However, the high dosage of ascorbic acid required for efficacy is hampered by adverse effects such as kidney stone formation. In a recent study, we demonstrated the efficient catalytic conver- sion of H2 O2 to HO• by wüstite (Fe 1−xO) nanoparticles (WNPs) through a heterogenous Fenton reaction. Here, we explore whether WNPs can enhance the therapeutic potential of ascorbic acid, thus mitigating its dose-related limitations. Our findings reveal distinct pH dependencies for WNPs and ascorbic acid in the Fenton reaction and H 2O 2 generation, respectively. Importantly, WNPs exhibit the capability to either impede or enhance the cytotoxic effect of ascorbic acid, depending on the spatial segregation of the two reagents by cellular compartments. Furthermore, our study demonstrates that treatment with ascorbic acid promotes the polarization of WNP-loaded macrophages toward a pro-inflammatory M1 phenotype, significantly suppressing the growth of 4T1 breast cancer cells. This study highlights the importance of orchestrating the interplay between ascorbic acid and nanozymes in cancer therapy and presents a novel macrophage-based cell therapy approach.

Document Type

Article

Publication Date

7-15-2024

Notes/Citation Information

This journal is © The Royal Society of Chemistry 2024

This article is licensed under aCreative Commons Attribution-NonCommercial 3.0 Unported Licence.

Digital Object Identifier (DOI)

https://doi.org/10.1039/d4nr01208a

Funding Information

This work was partly supported by the NIH/NIBIB funding (R01EB026893 to ST) and by the NIAMS funding (R21AR078447 to ST). The authors would like to thank the U. K. Electron Microscopy Center supported by the National Science Foundation (NNCI-2025075) and the U.K. Flow Cytometry & Immune Monitoring core facility supported by an NCI Center Core Support Grant (P30 CA177558).

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