Mitochondria-targeting near-infrared light-triggered thermosensitive liposomes for localized photothermal and photodynamic ablation of tumors combined with chemotherapy

Abstract

Lonidamine, an anticancer drug that acts on mitochondria, has poor water solubility. Mitochondria are the primary source of cellular reactive oxygen species (ROS), which are necessary for photodynamic therapy. Hence, a mitochondria-targeting drug delivery system loaded with Lonidamine and a ROS-produced photosensitizer could improve the bioavailability of Lonidamine and maximize photodynamic therapeutic efficiency. Here we report, for the first time, new IR-780 and Lonidamine encapsulated mitochondria-targeting thermosensitive liposomes (IL-TTSL). DSPE-PEG2000-NH₂ was coupled with triphenylphosphine to form DSPE-PEG_2K-TPP. The liposomes (IL-TTSL) were self-assembled from DPPC, DSPC, DSPE-PEG_2K-TPP, cholesterol, IR-780 and Lonidamine. Coupled linker modified triphenylphosphine (TPP) is cationic and can selectively accumulate several hundred-fold within mitochondria. Once the liposomes are located inside mitochondria, 808 nm laser irradiation could trigger photosensitizer IR-780 to elevate the local temperature, which could be utilized in photothermal therapy and induce the release of Lonidamine from the thermosensitive liposomes. Meanwhile, IR-780 could release ROS for photodynamic therapy in mitochondria and increase photodynamic therapeutic efficiency. Our results showed that the surface modification of the liposomes with triphenylphosphine cations had good mitochondria-targeting ability. The liposomes exhibited good biocompatibility and all components of the empty liposomes were safe to be used in humans. Few reports were related to IR-780 being used in photodynamic therapy and we proved this function of IR-780. Overall, the stealth liposomes provide a promising new strategy to realize mitochondria-targeting thermosensitive chemo-, photodynamic and photothermal combination therapy with a single light source for lung cancer.