Antitumor Combination Therapy Of Selenium-containing Assemblies

Immunotherapy harnesses the body’s own immune system to target and destroy tumor cells,with the potential to enhance therapeutic efficacy and reduce harmful side effects.Natural killer(NK)cells are the first immune barrier of the human body against virus-infected and transformed cells,possessing a range of effector functions.Selenium is an essential trace element with significant potential for cancer prevention and treatment.Selenium-containing compounds have shown remarkable sensitivity to reactive oxygen species(ROS),making them an attractive option for targeted delivery and controlled release of chemotherapeutic drugs.In addition,selenium-containing small molecules demonstrate both anticancer activity and immune activation ability.In this thesis,we generated organic seleninic acid in situ by expoiting the differential ROS concentration and gene expression between cancer cells and normal cells.We investigated the anticancer activity of seleninic acid and its mechanism of action on NK cell immune activation,thereby achieving a novel combination therapy of NK cell-based immunotherapy and other means of cancer treatment modalities.This paper presents the following two main achievements:1.A series of ROS-responsive selenium-containing assemblies were constructed by combining pemetrexed and β-seleno ester structures through triple hydrogen bonding,realizing the synergistic effect of NK cell immunotherapy and pemetrexed chemotherapy.The assembly can improve the enrichment of pemetrexed in the tumor area and enhance its chemotherapeutic effect by producing seleninic acid via the oxidation of β-seleno ester.Furthermore,seleninic acid can inhibit the expression of the NK cell inhibitory receptor ligand human leukocyte antigen E(HLA-E),thereby activating the immune activity of NK cells.In vitro and in vivo experiments revealed the potential chemoenhancement and immune activation mechanisms of seleninic acid,highlighting the promising potential of this strategy in enhancing chemoimmunotherapy.2.A selenium-containing assembly consisting of Cetuximab,a diselenide compound,and the inhibitor LY345899 was developed to realize synergistic enhancement of NK cell immune activity by seleninic acid and Cetuximab.Cetuximab can target the epidermal growth factor receptor(EGFR)on the surface of cancer cells and inhibit the phosphorylation of downstream pathways,induce the downregulation of methylenetetrahydrofolate dehydrogenase 2(MTHFD2),and synergize with LY345899 on MTHFD2 inhibition of the activity to produce excess ROS,and then oxidize the diselenide compound to generate seleninic acid.Moreover,seleninic acid synergistically activates NK cell immune activity by reducing the expression of HLA-E combined with cetuximab-mediated antibody-dependent cell-mediated cytotoxicity(ADCC)effect.This strategy can not only effectively inhibit the growth of xenograft tumors,but also significantly inhibit the growth of distant tumors via the abscopal effect.This work provides a new strategy for reversing NK cell exhaustion and has great application potential in the treatment of metastatic tumors.