Glycolysis inhibition can effectively block the energy supply and interrupt tumorigenesis in many types of cancers.However,when glycolysis is inhibited,tumor cells will break down glutamine as the raw material for the...Glycolysis inhibition can effectively block the energy supply and interrupt tumorigenesis in many types of cancers.However,when glycolysis is inhibited,tumor cells will break down glutamine as the raw material for the replenishment pathway to maintain the tricarboxylic acid cycle ensuring energy supply,therefore inducing ineffective interruption of metabolic.Herein,we designed glutamine transporter antagonist L-γ-glutamyl-p-nitroanilide(GPNA)loaded and 4T1 cancer cell membrane coated iridium oxide nanoparticles(IrO_(2)-GPNA@CCM)to realize a comprehensive inhibition of tumor energy supply which synergistically mediated by glycolysis and glutamine cycle.IrO_(2)NPs were used to catalyze the O_(2)generation by facilitating the decomposition of endogenous H_(2)O_(2)in tumor cells,which further downregulated the expression of HIF-1αand PI3K/pAKT to interrupt the generation of lactate.Meanwhile,the loaded GPNA was released under NIR irradiation to bind to alanine-serine-cysteine transporter(ASCT2)for glutamine uptake suppression,therefore realizing the comprehensive dysfunction of cell metabolism.Moreover,both in vitro and in vivo results convinced the thorough energy inhibition effect based on Ir O_(2)-GPNA@CCM NPs,which provided an inspiring strategy for future construction of tumor therapeutic regimen.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82273873,31971106,81372124)National Key Research and Development Program of China(Nos.2020YFC1512304,2020YFC1512301)+2 种基金the Applied Basic Research Project of Tianjin(No.21JCYBJC00660)the Young Elite Scientists Sponsorship Program by Tianjin(No.0701320001)the Major Special Projects of Tianjin(No.0402080005)。
文摘Glycolysis inhibition can effectively block the energy supply and interrupt tumorigenesis in many types of cancers.However,when glycolysis is inhibited,tumor cells will break down glutamine as the raw material for the replenishment pathway to maintain the tricarboxylic acid cycle ensuring energy supply,therefore inducing ineffective interruption of metabolic.Herein,we designed glutamine transporter antagonist L-γ-glutamyl-p-nitroanilide(GPNA)loaded and 4T1 cancer cell membrane coated iridium oxide nanoparticles(IrO_(2)-GPNA@CCM)to realize a comprehensive inhibition of tumor energy supply which synergistically mediated by glycolysis and glutamine cycle.IrO_(2)NPs were used to catalyze the O_(2)generation by facilitating the decomposition of endogenous H_(2)O_(2)in tumor cells,which further downregulated the expression of HIF-1αand PI3K/pAKT to interrupt the generation of lactate.Meanwhile,the loaded GPNA was released under NIR irradiation to bind to alanine-serine-cysteine transporter(ASCT2)for glutamine uptake suppression,therefore realizing the comprehensive dysfunction of cell metabolism.Moreover,both in vitro and in vivo results convinced the thorough energy inhibition effect based on Ir O_(2)-GPNA@CCM NPs,which provided an inspiring strategy for future construction of tumor therapeutic regimen.
