Au@MnS@ZnS-PEG Core/Shell/Shell Nanoparticles For Magnetic Resonance Imaging And Enhanced Cancer Radiation Therapy

Conventional radiation therapy(RT), although has been widely used in the clinic to treat cancer, often has limited therapeutic outcomes and severe toxic effects. There is still much need to develop theranostic agents with both imaging and RT enhancing functions, so as to improve the accuracy and efficiency of RT.Objective: In order to develop multifunctional theranostic agents which have the capability of enhancing RT, and in the meantime offer strong contrast in MR imaging, to realize imaging-guided enhanced RT, we synthesized the core/shell/shell Au@MnS@ZnS nanoparticles and explored the mechanism of radiation sensitivity.Methods: The Au@MnS@ZnS nanoparticles were prepared by a high temperature chemical synthesis method and modified by PEG-grafted poly(maleic anhydride-alt-1-octadecene)(C18PMH-PEG). The obtained Au@MnS@ZnS nanoparticles were then carefully characterized. Transmission electron microscopy(TEM) images, Energy-dispersive X-ray spectroscopy(EDX) elemental mapping, The powder X-ray diffraction(XRD) pattern and UV-vis-NIR spectrum of Au@MnS@ZnS were conducted. Relative cell viabilities were determined by the standard 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di- phenytetrazoliumromide(MTT) assay. For in vitro enhanced radiotherapy based on Au@MnS@ZnS-PEG nanoparticles, clonogenic assays and !-H2 AX immunoflourescence were carried out. To understand the radio-sensitizing mechanism, cell cycle and cell apoptosis of 4T1 cells treated with or without Au@MnS@ZnS-PEG were analyzed by flow cytometry. We then studied in vivo MR imaging guided enhanced radiotherapy using Au@MnS@ZnS-PEG as a theranostic agent. IBM SPSS 19.0 were used to make a statistical analysis.Results: Herein, we synthesized Au@MnS@ZnS core/shell/shell nanoparticles with polyethylene glycol(PEG) functionalization, yielding Au@MnS@ZnS-PEG nanoparticles with great stability in different physiological solutions and no significant cytotoxicity. It was found that Au@MnS@ZnS-PEG nanoparticles could enhance the cancer cell killing efficiency induced by RT, as evidenced by multiple in vitro assays. Owing to the existence of paramagnetic Mn2+ in the nanoparticle shell, Au@MnS@ZnS-PEG nanoparticles could be used as a contrast agent for T1-weighted magnetic resonance(MR) imaging. MRI revealed the efficient retention of nanoparticles in the tumor of mice after intravenous injection. Importantly, by exposing tumor-bearing mice injected with Au@MnS@ZnS-PEG to X-ray irradiation, the tumor growth could be remarkably inhibited, showing obviously better efficacy compared to RT alone.Conclusions: We designed a novel radio-sensitizer for in vivo MR imaging guided enhanced radiotherapy of tumors. The obtained Au@MnS@ZnS-PEG nanoparticles exhibited great stability in physiological solutions, showing high passive tumor accumulation and achieving desired MR imaging enhanced effect. Moreover, we further used Au@MnS@ZnS-PEG nanoparticles as a radio-sensitizer for enhanced RT treatment, and achieved remarkable tumor inhibition using X-ray irradiation at 6 Gy. No obvious cytotoxicity or side effect in vivo of our Au@MnS@ZnS-PEG nanoparticles was observed at our tested doses. Therefore, our work presented a new type of theranostic radiosensitizing agent, potential for imaging-guided enhanced RT treatment of cancer.