Redox-Sensitive Nanocarriers For Anticancer Drug Delivery

Drug delivery via nanocarriers is an important strategy to increase antitumor efficacy and reduce adverse effects.Nanocarriers have a significant effect in anticancer therapy,but the problems of uncontrolled cargo release and poor accumulation in solid tumors still need to be resolved.Nanosacle drug delivery can increase antitumor efficacy and reduce adverse effects.The aims of this project were to investigate into the effect of linker length on the drug release kinetics and in vitro and in vivo antitumor efficacy of redox-responsive polymer-drug conjugate micelles,and to study the role of ferroptosis in PDT using a redox-sensitive,all-active nanocarrier.Redox-responsive polymer-drug conjugate micelles were generated for self-immolative intracellular drug delivery.The micelles were obtained by the typical dialysis method.The antitumor potency of these micelles was determined in vitro at three different cell lines,as well as in vivo in 4T1 tumor xenograft mice.Experiments prove that,two types of polymer-Cur conjugate micelles were produced,and both displayed particle size less than 100 nm.Micelles R5 induced a higher cytotoxicity in three model cell lines(He La,PC3,and 4T1)in contrast to Micelles R4.Such phenomenon was also observed in He La tumor-bearing nude mice in vivo.Regarding the non-covalent drug loading in redox-responsive nanocarriers,tailored MOF was prepared with a surface coating of amphiphilic pluronic F127.The disulfide-bearing imidazole and zinc(Zn²⁺)were chosen as the organic ligand and the the coordination metal,respectively to manufacture redox-sensitive metal organic framework(MOF)nanocarrier.The model photosensitizer(Ce6)was physically loaded,and the antitumor performances was then determined in 4T1 cells and in 4T1 tumor xenograft mice.The MOF-induced glutathione(GSH)depletion and ferroptosis induction was analyzed by quantitative determination of GSH,GPX4 and tailored lipid peroxides.Experiments prove that,regardless of light irradiation,the drug-loaded redox-sensitive MOF nanocarrier caused the GSH depletion in 4T1 cells via the disulfide thiol exchange reaction.The GSH depletion further caused GPX4 inactivation and induce ferroptosis.In 4T1 tumor-bearing mice,Ce6@RMOF had been shown to inhibit tumor growth and improve survival rate in vivo.In summary,we successully prepared a series of tailored redox-responsicve antitumor nanocarriers.Two types of novel redox-responsicve antitumor nanocarriers were designed and these tailored nanocarriers could enhance antitumor drug delivery via modulating drug release kinetics and intracellular redox homeostasis.