Biotin-Decorated Hollow Gold Nanoshell For Target NIR-Ⅱ Photothermal Synergy With Radiosensitizing Therapy In Breast Cancer

Radiotherapy(RT)is one of the main treatment methods of breast cancer.However,two major problems of insufficient deposition of X-rays at tumor sites and hypoxia-induced resistance to radiation resulted the limited therapeutic effect by single radiotherapy.Photothermal therapy(PTT),as a therapeutic method with high specificity and mild side effects,can effectively kill tumor cells.Meanwhile,the mild PTT can accelerate blood flow at the tumor sites to promote oxygenation and ameliorate the hypoxia in tumor microenvironment(TME).In addition,PTT also can effectively kill S-phase cells that are not sensitive to RT and inhibit the repair of DNA damage.Thus,it will achieve better antitumor effect by combining PTT with RT.Gold nanoshells(AuNS)are nanomaterials with good biocompatibility,which have the advantages of low toxicity,tunable size and morphology,and easy functionalization.Most importantly,the high Z element of Au and hypoxia alleviation by the photothermal effect of the AuNS will greatly improve the X-ray deposition in tumor site and promote the radiosensitization.Therefore,the combination of PTT synergy with radiosensitization therapy would greatly improve the therapeutic effect by using AuNS.In this thesis,we have constructed a biotin-decorated hollow gold nanoshell(HAuNS)for target NIR-Ⅱ photothermal synergy with radiosensitizing therapy in breast cancer.The main research contents are as follows:First,the dense and thick AuNS grew on the surface of metal organic framework(MOF)UiO-66-NH2 by one-step synthesis method to offer UiO-66-NH2@AuNS nanocomposites,and then NaHCO3 was used to etch UiO-66-NH2 to obtain HAuNS.The formed HAuNS was further modified with biotin-PEG-NH2 to give HAuNS@PEG-bio nanoplatform with the aim to improve its active tumor targeting.The successful synthesis of HAuNS@PEG-bio was characterized by UV-visible(UV-Vis)spectrum,dynamic light scattering(DLS),scanning electron microscope(SEM),transmission electron microscope(TEM)and powder X-ray diffraction(PXRD).We innovatively control the reducibility and acidity of the reaction solution by adjusting the ratio of formic acid/formaldehyde,so that the generated gold nanoshells have near infrared(NIR)Ⅱ region absorption.When the volume ratio of formic acid/formaldehyde is 0.6‰,UiO-66-NH2@AuNS has the best NIR Ⅱ region absorption capacity.It has excellent photothermal conversion efficiency(63%)irradiated by 1064 nm laser.Second,the performance of HAuNS@PEG-bio was studied at the cell level by using the 4T1 cells as a model.Cell uptake experiments showed that HAuNS@PEG-bio could be internalized by cells within 9 h and could enter into cells through biotin-mediated active targeting.MTT and apoptosis/necrosis assays showed that HAuNS@PEG-bio had prominent therapeutic effects of PTT combined with radiosensitizing therapy.The reactive oxygen species(ROS)generation,clone formation and DNA damage assays demonstrated that HAuNS@PEG-bio had a remarkable radiosensitization effect.Calreticulin(CRT),high mobility group box 1(HMGB1)and adenosine triphosphate(ATP)secretion experiments demonstrated that PTT combined with radiosensitizing therapy could effectively induce immunogenic cell death(ICD)to activate the immune response of body.Finally,in vivo fluorescence imaging experiments were conducted by using IR780-labeled HAuNS@PEG-bio through tumor-bearing mice model.The results demonstrated that HAuNS@PEG-bio nanoplatform can actively target to the tumor sites through biotin-mediated active targeting.In the treatment of mice,combining PTT with radiosensitizing therapy had the best antitumor effect.HAuNS@PEG-bio had excellent radiosensizitization effects because PTT could improve the hypoxic condition in tumor site and the gold nanoshell containing high Z element,which could increase the energy deposition of X-ray at the tumor sites.