Stimuli-Responsive Nanoparticles Combining Photodynamic Therapy and Mitochondria Disruption Suppressed Tumor Metastasis

Photodynamic therapy (PDT) is a kind of commonly used strategy for the treatment of cancer, but tumor hypoxia severely limits the efficiency of this oxygen (O-2)-dependent modality. Disrupting mitochondria may be a promising direction to reverse the tumor hypoxia. However, to date, very few studies utilize mitochondria inhibiting strategy to complement PDT, because low permeability of mitochondria impedes the entry of therapeutic agents. A stimuli-responsive nanoparticle system that combines PDT and mitochondria disruption strategy is reported here. The nanoparticle consists of a gelatin core that accommodates photosensitizer chlorin e6 (Ce6) and a polymeric shell that chemically attaches with mitochondria-targeted anticancer drugs (doxorubicin-glycyrrhetinic acid conjugates, Dox-GA). Specifically, Ce6 produces excessive reactive oxygen species to support Dox-GA in escaping from lysosome. Then, thanks to mitochondria targeting, Dox-GA contributes significantly to mitochondrial dysfunction and O-2 consumption depression in tumor cells, resulting in enhanced PDT. As a result, the integration of mitochondria-targeting drug delivery and PDT shows synergistic effects in apoptosis induction, tumor growth inhibition and anti-metastasis. The tumor metastasis is almost completely inhibited without any lung nodules observed in vivo, making it a promising strategy by integrating mitochondria-targeting drug and PDT for metastatic breast cancer treatment.