New strategy for precise cancer therapy: tumor-specific delivery of mitochondria-targeting photodynamic therapy agents andin situO2-generation in hypoxic tumors

Besides tumor hypoxia and limitation of superficial lesions, the short lifetime of photoinduced reactive oxygen species (ROS) is another factor repressing photodynamic therapy (PDT) efficacy. To overcome these problems, this study developed newly designed mitochondria-specific, H2O2-activatable, and O-2-producing nanoparticles to achieve highly selective and efficient PDT and self-sufficiency of O(2)in hypoxic tumors. The newly designed nanoparticles (BDPP NPs) are composed of a mitochondria-targeting photosensitizer and catalase in the aqueous core and a black hole quencher and fluorescent tracker in the polymeric shell, and modified with the tumor-targeting cyclic pentapeptide c(RGDfK). Once taken up by alpha(v)beta(3)integrin-rich tumor cells, intracellular H(2)O(2)easily penetrated the lipophilic shells into the aqueous cores of BDPP NPs, and it was catalyzed by catalase to quickly generate O(2)gas, causing the rupture of the NPs to release the photosensitizer. Thereforein vivotumor cell mitochondria targeting by BDPP can be realized together with the favorable hypoxia relief.In vitroandin vivoexperiments demonstrate that the therapeutic efficiency was significantly improved by the mitochondria-specific feature and H2O2-controllable generation of(1)O(2). More importantly, BDPP NPs continuously generate O(2)in the PDT process, which can be helpful for resolving the overconsumption of oxygen in PDT and enhancing the PDT efficiency of cancer chemotherapy. We anticipate that this work may provide new insight into the design of smart PDT systems to achieve highly selectivein vivoPDTviatargeting subcellular organelles and realize oxygen therapy in O-2-deprived tumors.