Mitochondria-targeted photosensitizer based nanoplatform loading glutathione inhibitor for enhanced breast cancer photodynamic therapy

Photodynamic therapy (PDT) is an approved photoactivated technique that has been widely used for anti-tumor therapy through the generation of excessive ROS. However, the poor water solubility and targeting ability of photosensitizer and ROS depleting by high concentrations of glutathione (GSH) in the tumor microenvironment will limit the efficiency of PDT and synergistic therapy. Herein, we report a mitochondria targeted heterodimeric photosensitizer (TPP-TK-PPa) that can form co-delivery nanoplatform together with DSPE-PEG2000 and GSH-depleting agent DEM through the self-assembly. The TPP-TK-PPa/DEM NPs reveals excellent mitochondrial targeting ability and can efficiently deliver the therapeutic agents to tumor cells and release them into the mitochondria in an ROS-responsive manner. Additionally, The TPP-TK-PPa/DEM NPs can induce in situ production of ROS during PDT and reduce ROS consumption by decreasing intracellular GSH levels, which is attributed to the progressive release of DEM after cellular internalization. In addition, generation of ROS during PDT leads to distinct changes in mitochondrial membrane potential and morphology, which ultimately leads to apoptosis. More importantly, the in vitro antitumor activity results demonstrate that TPP-TK-PPa/DEM NPs showed remarkable phototoxicity and the IC50 values of TPP-TK-PPa/DEM NPs in MDA-MB-231 breast cancer cells was as low as 250 nM after PDT. This work provides a strategy for the development of photosensitizers with specific organelle targeting ability, which is of great importance for precise and effective PDT.