Binary prodrug nanoassemblies combining chemotherapy and ferroptosis activation for efficient triple-negative breast cancer therapy

Chemotherapy has been recommended as the standard protocol for triple-negative breast cancer （TNBC）at the advanced stage.However,the current treatment is unsatisfactory due to inefficient drug accumulation and rapid chemo-resistance.Thus,rational design of advanced drug delivery systems that can induce multiple cell death pathways is a promising strategy to combat TNBC.Ferroptosis is a powerful non-apoptotic cell death modality,showing potential in tumor inhibition.Herein,we propose a binary prodrug nanoassemblies that combines chemotherapy with ferroptosis for TNBC treatment.In this system,paclitaxel is linked with paracetamol （ferroptosis activator） by a disulfide linkage to construct self-assembly prodrug.Meanwhile,2-distearoyl-sn-glycerol-3-phosphoethanolamine-N-methyl（polyethylene glycol）-2000-tyrosine (DSPE-PEG2k-tyrosine) is applied for large neutral amino acid transporter 1 （LAT1） targeting,which is highly expressed in TNBC.The prodrug nanoassemblies exhibit good stability and a glutathione （GSH）-responsive release profile.Furthermore,the LAT1-targeted nanoassemblies show stronger cytotoxicity,higher cellular uptake,and more obvious ferroptosis activation than non-decorated ones.In a TNBC mice model,the prodrug nanoassemblies demonstrate strong anti-tumor efficacy.The application of ferroptosis-assisting chemotherapy may provide a promising strategy for TNBC therapy.