Dextran-based nanodrugs with mitochondrial targeting/glutathione depleting synergy for enhanced photodynamic therapy

The efficacy of photodynamic therapy (PDT) for malignant tumors is significantly impeded by the short diffusion distance of reactive oxygen species (ROS) and the ROS-consuming glutathione (GSH) overexpressed in tumor cells. Therefore, enhanced PDT can be achieved by the construction of biomacromolecule-based nanodrugs that can specifically target ROS-sensitive mitochondria and deplete intracellular GSH. Herein, we synthesized the dextran-based nano-assemblies by a Graft copolymerization Induced Self-Assembly (GISA) method, in which methyl acrylate and diallyl disulfide (DADS) were copolymerized from a mixed dextran/amino dextran backbone in an aqueous medium. Notably, the disulfide bond-containing DADS served as both GSH-depleting agent and GSH-responsive crosslinker. In order to develop a nanodrug with mitochondrial targeting/GSH depleting synergy, we further conjugated a mitochondria-targeting ligand onto the amino dextran corona, and developed a "loading-post-assembly" strategy to load a hydrophobic photosensitizer protoporphyrin IX or even multi-drugs into the hydrophobic core of the nano-assemblies. Cell and animal studies illustrated that the nanodrug could accumulate in the mitochondria of tumor cells to generate ROS in situ and thus eliminate tumors. Taken together, our work presents the dextran-based nanodrug as an efficient platform to achieve mitochondria-targeting PDT with an enhanced efficiency by simultaneously depleting intracellular GSH.