Local Regulation of Mitochondrial Respiratory for Enhancing Photodynamic Therapy and Breaking Chemoresistance in Hypoxia

Abstract The hypoxic condition in solid tumors induces therapy resistance, limited therapeutic efficacy, and tumor recurrence, especially for chemotherapy and aerobic photodynamic therapy (PDT). To address this matter, an O 2 regulator ( SNP@Ato ) is designed for breaking chemoresistance and enhancing PDT, which is constructed by loading Atovaquone (Ato) through self‐assembly and host‐guest interaction between β ‐cyclodextrin functionalized tetraphenylporphyrin (TPP‐CD 4 ) and thioketal‐linked camptothecin/azobenzene (Azo‐TK‐CPT). Specifically, the porphyrin units in SNP@Ato are in “Off state” due to the photoinduced electron transfer (PET) effect between the porphyrin units and azobenzene. After encountering the hypoxic condition in solid tumors, SNP@Ato is dissociated by the cleaved azobenzene on account of over‐expressed azo‐reductase. Then the mitochondrial respiratory of cancer cells would be suppressed with the participation of Ato, generating a local hypoxia relief for sensitized chemotherapy and enhanced PDT. Accompanied by efficient PDT, the TK linker is broken by ROS, and the CPT is released from the prodrugs. Compared with the SNP group without oxygen‐regulator, SNP@Ato exhibits a remarkable improvement of the therapeutic effect against hypoxic tumors in vitro and in vivo. This work proposes a novel paradigm for overcoming hypoxia‐induced therapeutic resistance.