Glutathione-responsive Manganese Cluster Nanoparticles For Electric Field-Amplified Chemodynamic Therapy In Vivo

Tumor microenvironment(TME),a complex integrated system,which plays a vital role in the process of tumor initiation,growth and metastasis.A wide range of therapy strategies have been developed by regulating the redox homeostasis of TME to improve therapeutic efficacy and reduce side effects.At present,the common strategy to improve the redox balance is to elevate the level of reactive oxygen species in tumor site and eliminate glutathione.Thereofore,it is urgently necessary to develop the novel anti-tumor materials that could respond to the tumor environment.Herein,we constructed heparin-conjugated manganese cluster nanoparticles nanoparticle(Mn₁₂-heparin)as a cascade bioreactor,its core is dodecanuclear manganese^III/IV cluster compound(Mn₁₂-Ac)with acetic acid as the ligand.In our design,the excellent stability and biocompatibility ROS-regulating agent was prepared ligand exchange between carboxylic acid ligands of heparin and acetic acid groups of Mn₁₂-Ac cluster.The high mixed valence manganese in Mn₁₂-heparin exhibits strong oxidability and can react with reducing substances(such as glutathione)to release Mn²⁺.When Mn₁₂-heparin was endocytosed by MCF-7 cells,the multivalent metal elements(Mn^3+/4+)in Mn₁₂-heparin are easily reduced by endogenous glutathione(GSH)in tumor.The released Mn²⁺could react with the intracellular hydrogen peroxide through Fenton-like reaction and produce hydroxyl radicals(·OH).With the introduce of electric field,the level of intracellular·OH was further increased and induced apoptosis and ferroptosis.Additionally,the GSH-induced and electric-facilitated inactivation of glutathione peroxidase 4(GPX4)leads to lipid peroxidation and ferroptosis.The treatments in vivo indicate that the tumors were completely eliminated after 14 days of treatments and no other side effects were observed with the combination of Mn₁₂-heparin and electric field.The immunofluorescence section analysis of tumor tissues proved that the up-regulation of intracellular·OH levels,the decrease of GPX4 activity and the decrease of glutathione level after treatments.Meanwhile,through triggering cell apoptosis and ferroptosis realize effective anti-tumor therapy effect.