Synergistic Effect Of Thermo-radiotherapy Using Au@FeS Core-shell Nanoparticles As Multifunctiona Therapeutic Nanoagents

Cancer is one of the most serious diseases that threaten human health.Radiation therapy of malignant tumor is one of the main methods of cancer treatment.Radiation therapy uses radiation to kill cancer cells to achieve the purpose of tumor treatment,including external radiation(such as X-ray and electron beam irradiation)and radioisotope therapy(internal radiation)of tumor.Although tumor radiotherapy has been widely used in clinic,it easily causes damage to normal tissues of patients and causes lots of side effects;in addition,repeated radiotherapy radiation may cause drug resistance of cancer cells,resulting in unsatisfactory results.Therefore,the ways that improve the existing methods of radiotherapy,and integrate other tumor treatments,are expected to bring new opportunities for further development and optimization of the traditional therapy of tumor radiotherapy.Owing to its unique physical and chemical properties,functional nanomaterials have great application prospects in the field of cancer diagnosis and treatment.In this dissertation,we have prepared a multifunctional nano-probe with integration of diagnosis and treatment to achieve imaging guided combination of photothermal therapy and radiotherapy.More importantly,we have found that weak near infrared laser irradiation on tumors can increase their oxygen supply,and improve the tumor hypoxia microenvironment.Thus,it further enhances the radiosensitivity of tumor cells and increases the cure rate of tumors.Objective:To prepare a new type of core-shell Au@FeS nanomaterials,and to make appropriate surface modification to study their biological safety and stability.The synergistic effect of the functional nanomaterials based on the cellular level was studied.At the same time,we explored the effect of the functional nanomaterial on the 4T1 tumor model and the ability to improve the tumor microenvironment in vivo.On this basis,the use of specific properties of Au@FeS nanomaterials on the 4T1 tumor model for combined therapy has achieved very good tumor suppression effects.Methods:The core-shell Au@FeS nanoparticles were synthesized using a high-temperature chemical reaction,and then modified with PEG through a layer-by-layer(LBL)method,which exhibited good stability and biocompatibility.Au@FeS nanoparticles were characterized by X-ray powder diffraction,UV spectrophotometer,DLS,transmission electron microscopy and high resolution electron microscopy,etc.Moreover,magnetic resonance(MR)imaging and thermal imaging were also used to evaluate the performance of Au@FeS nanoparticles.In cell experiments,MTT was used to evaluate the cytotoxicity of Au@FeS nanoparticles.Cell clone,fluorescence immunoassay and immunohistochemistry were carried out to evaluate the therapeutic efficiency of enhanced radiotherapy using Au@FeS nanoparticles.In animal experiments,mice bearing 4T1 tumor models were intratumoral injected with Au@FeS-PEG nanoparticles for MR imaging and thermal imaging.The hypoxia microenvironment of local tumor was reduced by mild heating.Next,Au@FeS-PEG nanoparticles could be used as excellent therapeutic agent for combined therapy,achieving synergistic therapeutic outcomes.Results:1.We synthesized core-shell Au@FeS-PEG nanoparticles,obtaining uniform size of nanoparticles.2.TEM imaging showed that the obtained nanoparticles have obvious core-shell structure with the size about 100 nm.The hydrodynamic size of Au@FeS-PEG nanoparticles were measured to be 150-200 nm by DLS measurement.UV spectrum showed Au@FeS-PEG nanoparticles have obvious absorption at 300-1000 nm.XRD spectra and Mapping spectra further proved that the nanoparticles have FeS shell and Au core.3.Magnetic resonance imaging of mice showed that Au@FeS nanoparticles exhibited concentration-dependent darkening.4.Thermal imaging of mice showed that the tumor treated with Au@FeS nanoparticles and laser irradiation exhibited significant heating up.5.MTT experiments showed that Au@FeS-PEG had no obvious toxicity to 4T1 cancer cells.The sensitizing enhancement ratio of Au@FeS-PEG nanoparticles was measured to be 1.17.Au@FeS-PEG under X-ray irradiation could induce DNA strand damage.More important,we found that mild heating could reduce the hypoxia microenvironment,further accelerating the synergistic therapeutic effects based on Au@FeS-PEG nanoparticles.6.The potential toxicity of Au@FeS-PEG nanoparticles was investigated by blood routine,biochemical analysis.The results showed no obvious toxicity and side-effect to treated mice at our used dose.