Application Of Metal Ions-mediated Self-assemblies In The Treatment Of Gastric Cancer

Gastric cancer is the second leading cause of death from malignant cancers worldwide.At present,the main treatments of gastric cancer are surgery,radiotherapy and chemotherapy.Due to the limitations of various therapies,there is an urgent need to develop more efficient treatment methods to improve the survival rate of patients with gastric cancer.In recent years,the development of nanotechnology has had a profound impact on the field of drug delivery.Self-assembled nanostructures generally have the characteristics of suitable size,high drug loading and reversible drug release,which are of great value in drug delivery and tumor therapy.Due to the high leakage of blood vessels in tumor site,nano self-assemblies can prolong the blood circulation time of drugs and increase the accumulation in tumor site through EPR effect.Based on this,we have designed and prepared a variety of self-assemblies with simple synthesis methods and high biocompatibility by metal ion-mediated self-assembly technology for the treatment of gastric cancer.1.Ca²⁺mediated gold nanoclusters and proteins into self-assemblies.It is difficult for macromolecular protein drugs to penetrate into the cytoplasm due to the low efficiency of membrane penetration.Based on this,a metal ion-mediated gold nanoclusters（GNCS）-protein modular self-assembly method was developed for protein delivery in gastric cancer cells.In physiological environment,GNCS,metal ions and proteins spontaneously assemble into monodisperse spherical nano-assemblies through electrostatic interactions.The assemblies are taken up by gastric cancer cells through endocytosis,then disassembled in the cells and released proteins into the cytoplasm.This method can be used to deliver a variety of proteins with different molecular weights and isoelectric points,including BSA,β-galactosidase and RNase A,showing higher delivering efficiency than the commercial reagent PULSin^TM.During the process of delivery,the biological activity of protein can be well maintained,which lays a good foundation for subsequent protein therapy.2.Gd³⁺mediated gold nanoclusters and epigenetic inhibitors into self-assemblies.Although radiotherapy is more likely to damage cancer cells,it also damages normal cells,causing local or systemic radiation reactions.Based on this,Gd³⁺mediated gold nanoclusters-epigenetic inhibitors self-assemblies were developed for the synergistic radiosensitization of gastric cancer.The assemblies can increase the content of GNCs into gastric cancer cells and enhance the sensitivity of cells to X-rays.Meanwhile,the epigenetic inhibitor Vorinostat（SAHA）can promote the acetylation of histone H3 and H4,which can lead to the loose structure of nucleosome and enhance the DNA damage by X-ray.In vitro experiments show that the self-assemblies can induce DNA damage,inhibit cell proliferation and induce cell death under X-ray irradiation.In vivo experiments show that the self-assemblies significantly inhibit tumor growth,and have good biological safety in vivo,and they are expected to be used in the radiosensitization therapy of gastric cancer or other tumors.3.Zn²⁺induced epigenetic inhibitors into nanofiber self-assemblies.Chemotherapy is one of the main methods of current tumor treatment,but small molecule drugs have problems such as poor stability and low specificity of action,and they are easy to cause systemic side effects.Based on this,Zn²⁺mediated the self-assembly of two epigenetic inhibitors with different mechanisms of action into nanofibers with excellent chemical stability,combined to deliver epigenetic regulation drugs for synergistic epigenetic treatment of gastric cancer.In this assembly,histone deacetylase（HDACs）inhibitor Vornostat（SAHA）,DNA methyltransferase（DNMTs）inhibitor 5-azacytidine（5-Aza）and Zn²⁺are the basic modules.Driven by coordination,self-assembled SAHA-Zn²⁺-5-Aza nanofibers were with uniform appearance.After entering the cell,the nanofibers quickly respond to the acidic and redox environment in the tumor,releasing SAHA and5-Aza.SAHA and 5-Aza inhibit the activity of HDACs or DNMTs,promote histone acetylation modification or reduce DNA methylation levels,and then reprogram the gene expression profiles of gastric cancer cells cooperatively,thereby inhibiting cell proliferation and inducing cell apoptosis.In vivo experiments have shown that nanofibers can enhance the circulation time of drugs in the blood and increase the accumulation of drugs in tumor sites,thereby exerting synergistic anti-tumor effects,which can be used for epigenetic therapy of gastric cancer.