The Radiosensitizing Effect of Zinc Oxide Nanoparticles in Sub-Cytotoxic Dosing Is Associated with Oxidative Stress In Vitro.

Till Jasper Meyer,Helena Moratin,Bülent Polat,Gisela Wohlleben,Julian Killisperger,Agmal Scherzad,Stephan Hackenberg,Norbert Kleinsasser,Thomas Eckert Gehrke,Rudolf Hagen,Sofia Dembski

doi:10.3390/ma12244062

Abstract

Radioresistance is an important cause of head and neck cancer therapy failure. Zinc oxide nanoparticles (ZnO-NP) mediate tumor-selective toxic effects. The aim of this study was to evaluate the potential for radiosensitization of ZnO-NP. The dose-dependent cytotoxicity of ZnO-NP20 nm and ZnO-NP100 nm was investigated in FaDu and primary fibroblasts (FB) by an MTT assay. The clonogenic survival assay was used to evaluate the effects of ZnO-NP alone and in combination with irradiation on FB and FaDu. A formamidopyrimidine-DNA glycosylase (FPG)-modified single-cell microgel electrophoresis (comet) assay was applied to detect oxidative DNA damage in FB as a function of ZnO-NP and irradiation exposure. A significantly increased cytotoxicity after FaDu exposure to ZnO-NP20 nm or ZnO-NP100 nm was observed in a concentration of 10 µg/mL or 1 µg/mL respectively in 30 µg/mL of ZnO-NP20 nm or 20 µg/mL of ZnO-NP100 nm in FB. The addition of 1, 5, or 10 µg/mL ZnO-NP20 nm or ZnO-NP100 nm significantly reduced the clonogenic survival of FaDu after irradiation. The sub-cytotoxic dosage of ZnO-NP100 nm increased the oxidative DNA damage compared to the irradiated control. This effect was not significant for ZnO-NP20 nm. ZnO-NP showed radiosensitizing properties in the sub-cytotoxic dosage. At least for the ZnO-NP100 nm, an increased level of oxidative stress is a possible mechanism of the radiosensitizing effect.

Highlights

With an estimated 65,000 new cases in 2019, head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer in the United States [1]
Zinc oxide (ZnO)-NP100 nm showed a mean diameter of 45–55 nm in TEM
Selective tumor-cell death mediated by Zinc oxide nanoparticles (ZnO-NP) is discussed as a promising characteristic of Selective tumor-cell death mediated by ZnO-NP is discussed as a promising characteristic of

Summary

Introduction

With an estimated 65,000 new cases in 2019, head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer in the United States [1]. In order to increase the antitumor effect of the radiation and to focus the effect of the radiation on the tumor volume, radiosensitizing agents such as cisplatin-chemotherapy are used in special clinical risk situations like primary radiation therapy, close or positive tumor margins, perineural invasion, or extranodal lymph node spread [4,5]. Nanoparticles (NP) are defined by a particle size of less than 100 nm Due to their ratio of surface area to particle mass, NP have special physico-chemical properties [6]. Zinc oxide (ZnO)-NP is moving into the focus of medical research due to its potential to trigger tumor-selective cell death [7] and as a cancer-inhibiting drug carrier [8]. Different groups could show a biological distribution characterized by greater accumulation of ZnO-NP in tumors as compared to healthy tissue [9]

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