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Though photodynamic therapy (PDT) has been widely used in the non-invasive destruction of solid tumors, the therapeutic efficacy of PDT is often limited by the hypoxic tumor environment. Herein, we report the innovative use of metformin, an oral hypoglycemic agent commonly used in the treatment of type II diabetes, to improve tumor oxygenation, and overcome tumor hypoxia-associated resistance to PDT. In our design, hydrophilic metformin and modified hydrophobic chlorin e6 (HCe6) are co-encapsulated within the inner cavity and outer membrane of liposomes, respectively. Due to the high uptake of liposome nanoparticles by tumors, and the sustained release of metformin, the intravenous administration of metformin (Met)-HCe6-Liposome nanoparticles greatly improves tumor oxygenation in several different tumor models, as revealed by in vivo photoacoustic imaging and ex vivo immunofluorescence staining. Systemic administration of Met-HCe6-Liposomes followed by in vivo PDT achieved significantly improved therapeutic effects compared to that of PDT without metformin. Hence, our study represents a new strategy for the improvement of PDT efficacy through the modulation of tumor oxygenation by clinically approved agents.
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