Study Of Enhancement Of ¹³¹I Nuclide Efficacy By Nanomaterials In The Treatment Of Pancreatic Cancer

BackgroundThe incidence of pancreatic cancer is rising annually,yet there has been no breakthrough progress in the treatment of pancreatic cancer.Even though combining multiple strategies,the survival rate of pancreatic cancer does not improve,making the search for,accurate and efficient treatment methods are an urgent clinical priority.In recent years,with advancements in multidisciplinary integration,nanomaterials have gradually been applied for biological applications and have yielded promising achievements in clinical transformation.At present,the research on the combination of nuclide and nanomaterials has made some significant progress in the treatment of pancreatic cancer,yet the full potential of nuclide remains untapped.Iodine-131(131I),as powerful electron donors,serves as the foundation of therapy.It is highly meaningful to explore how to cleverly combine the electrons produced by the decay of nuclides with nanomaterials to maximize the therapeutic effect,and make it a sharp tool to inhibit the progression of tumors.This subject focuses on the background mentioned above,combining 131I nuclide and nanomaterials cleverly to construct a novel composite system of 131I nuclide and nanomaterials.By taking advantage of powerful electron donor 131I,it has achieved an effective treatment for pancreatic cancer.Two kinds of 131I-nanomaterial systems have been successfully constructed in this project.The specific research contents are as follows:Main research contents and results1.131I-mBTOK NPs Mediated Reductive Stress for Enhancing Pancreatic Cancer Immuno-therapy(1)Material preparation:The mBTO nanoparticles(NPs)with a particle size of about 90 nm cube structure(mBTO NPs)were successfully synthesized.BTO NPs formed porous mBTO NPs after etching with ammonia water,and the surface of mBTO had a uniform etching layer of about 1.45 nm,forming a Ba-O microchannel.The 131I nuclide was connected through the amino grafted tyrosine residue in the pore,and the high-energyβ rays(β-electron flow)generated by the decay of nuclide collided with the BaO layer of the plateau number of the pore wall.Reduce the kinetic energy of electrons and convert it into potential energy,so that the surface of the material is rich in high potential energy electrons and become a reducing material.(2)In vitro experiments and mechanism:131I-mBTO NPs nanomaterials rich in high-potential electrons achieved endoplasmic reticulum targeting by binding to KDEL peptides,and leaded to endoplasmic reticulum stress by electron interference with disulfide bond formation during protein folding in endoplasmic reticulum.For tumor cells,under the action of high dose of 131I-mBTOK NPs,ER stress signaling pathway promoted apoptosis of tumor cells,enhanced immunogenicity of tumor cells,and promoted activation of dendritic cell(DC)in tumor microenvironment(TME),and then enhanced the adaptive immunity of the body.For tumor-associated macrophages(TAM),the polarization of TAM to M1 macrophages was achieved by associating ER stress signaling with nuclear factor kappa-B(NF-κB)at a low dose of 131I-mBTOK NPs.Through the dual effects on tumor cells and TAM,the immune enhancement effect was achieved,and finally the highly efficient tumor therapy was achieved.(3)In vivo experiments:The results showed that 131I-mBTOK NPs had an immune-enhancing effect and could effectively inhibit tumor growth.Based on this,we proposed a new tumor treatment strategy of "reducing stress to enhance immune f-unction",and summarized the specific mechanism of 131I-mBTOK NPs as shown in the Figure 1 below:2.131I-A-M NPs Mediated Tubulin Degradation for Promoting Pancreatic Cancer Cell Death(1)Material preparation and characterization:A-M NPs with Au(Ⅲ)as the bulk were successfully synthesized at 140 nm.According to the results of Au high resolution X-Ray photoelectron spectra(XPS),the Au in the synthesized A-M was Au(Ⅲ).The 131I nuclide was successfully labeled by the traditional Iodogen method.A large number of electrons produced in the decay process of 131I were accepted by Au(Ⅲ)to form Au(I).The XPS results of 131I-A-M NPs showed that the material was successfully reduced from the original Au(Ⅲ)to Au(I),and the valence state of Au was changed.Then they gradually shed from the main body to form gold nanoclusters(AuNCs).(2)In vitro experiments and mechanism:Phagocytosis of 131I-A-M NPs would form AuNCs in situ inside cells,in which Au atoms bond with-SH of Tubulin to form covalent bonds.This covalent binding caused changes in the conformation of Tubulin,prompting Tubulin to be degraded by the proteasome system,and thereby affecting the formation of the spindle,caused cell cycle arrest,and finally activated cell apoptosis mechanism..(3)In vivo experiments and results:In vivo,131I-A-M NPs demonstrated significant tumor inhibition effect.The innovation of this study lied in the ingelious use of 131I as a powerful electron donor to realize the transformation of Au valence states and generate AuNCs in cells.Through molecular dynamic experiments(MD)analyzed the mechanism of action of Au6NCs formed by dissociation of 131I-A-M and Tubulinβ,and found and proved the degradation mechanism of Tubulin covalently bound by Au6NCs and its cellular effects.The specific action mechanism was summarized in Figure 2:Discussion and analysisAs a long-half-life nuclide,131I plays a certain role in the treatment of tumor therapy,especially in the treatment of thyroid cancer.However,the clinical application of 131I is limited by its scarce of targeting to common solid tumors and limited range of radiation action.But 131I nuclides have not been well used as powerful electron donors.In recent years,due to the rapid development of biological applications of nanomaterials,it is possible to exploit the additional functions of 131I nuclide.Exploring how to realize the efficient therapeutic function of nuclide with advantages of nanomaterials has become the direction of research.In this research,a preliminary study was conducted in order to maximize the advantages of 131I in tumor therapy.Our research group is dedicated to improve the efficiency of tumor treatment through the research and development of efficient nano-medicine.Two kinds of nanomaterials were cleverly designed by utilizing high-energy electrons produced by the decay of 131I nuclides.The pore effect and valence transition characteristics of nanomaterials were utilized in different ways.The mechanism of action was deeply discussed.and the killing effect of the two nanomaterials on pancreatic cancer cells was successfully demonstrated through different characterization methods.In summary,this project used 131I nuclide as a powerful electron donor,cleverly used high-energy electrons generated in the decay process,and improves the therapeutic effect of tumor with the advantage of nanomaterials.The design of this project broadened the application nuclide and provided a new idea and strategy for tumor therapy with nuclide.