New strategy for precise cancer therapy: tumor-specific delivery of mitochondria-targeting photodynamic therapy agents and in situ O2-generation in hypoxic tumors

Abstract

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 O₂-producing nanoparticles to achieve highly selective and efficient PDT and self-sufficiency of O₂ 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 α_vβ₃ integrin-rich tumor cells, intracellular H₂O₂ easily penetrated the lipophilic shells into the aqueous cores of BDPP NPs, and it was catalyzed by catalase to quickly generate O₂ gas, causing the rupture of the NPs to release the photosensitizer. Therefore in vivo tumor cell mitochondria targeting by BDPP can be realized together with the favorable hypoxia relief. In vitro and in vivo experiments demonstrate that the therapeutic efficiency was significantly improved by the mitochondria-specific feature and H₂O₂-controllable generation of ¹O₂. More importantly, BDPP NPs continuously generate O₂ 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 selective in vivo PDT via targeting subcellular organelles and realize oxygen therapy in O₂-deprived tumors.