Inhibition of NADPH Oxidase-ROS Signal using Hyaluronic Acid Nanoparticles for Overcoming Radioresistance in Cancer Therapy

• Published in: ACS nano Vol. 16; no. 11; pp. 18708 - 18728
• Main Authors: Zhu, Lei, Zhao, Yi, Liu, Tongrui, Chen, Minglong, Qian, Wei Ping, Jiang, Binghua, Barwick, Benjamin G., Zhang, Lumeng, Styblo, Toncred M, Li, Xiaoxian, Yang, Lily
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 22.11.2022
• Subjects: Animals; Breast Neoplasms - drug therapy; Breast Neoplasms - radiotherapy; Female; Humans; Hyaluronic Acid - therapeutic use; Mice; Mice, Nude; NADPH Oxidases - genetics; NADPH Oxidases - metabolism; Nanoparticles; Radiation Tolerance; Reactive Oxygen Species - metabolism; hyaluronic acid nanoparticle (HANP); targeted cancer therapy; NADPH oxidases; reactive oxygen species; radiotherapy resistance; GKT831; Redox imbalance
• ISSN: 1936-0851; 1936-086X; 1936-086X
• DOI: 10.1021/acsnano.2c07440

Upregulation of NADPH oxidases (NOXs) in cancer cells leads to chronic increase in intracellular reactive oxygen species (ROS) and adaptation to a high ROS level for cell survival and, thereby, low sensitivity to radiotherapy. To overcome resistance to radiotherapy, we have developed a bioactive and CD44 targeted hyaluronic acid nanoparticle encapsulated with an NOX inhibitor, GKT831 (HANP/GKT831). We found that HANP/GKT831 had stronger inhibitory effects on ROS generation and cell proliferation than that of GKT831 alone in cancer cells. Systemic delivery of HANP/GKT831 led to the targeted accumulation in breast cancer patient derived xenograft (PDX) tumors in nude mice. Importantly, the combination of systemic delivery of HANP/GKT831 with a low dose of local radiotherapy significantly enhanced tumor growth inhibition in breast cancer PDX models. Our results showed that HANP/GKT831 primed tumor cells to radiation-induced DNA damage and cell death by downregulation of DNA repair function and oncogenic signal pathways.