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.

Stimuli-activated targeted delivery systems for highly accurate treatment of tumors have received considerable attention in recent years. Herein, we reveal a light-activable cancer-targeting strategy that uses a complementary DNA sequence to hybridize and mask sgc8 aptamers conjugated onto photothermal agents such as gold nanorods or single-walled carbon nanotubes (SWNTs). Upon exposure to near-infrared (NIR) laser, localized photothermal heating of the surface of those nano-agents results in dehybridization of the double-stranded DNA and uncaging of the aptamer sequence to allow specific cancer-cell targeting. Utilizing doxorubicin-loaded SWNTs as a model system, targeted drug delivery to cancer cells activated by NIR light was achieved. This work demonstrates the concept of NIR-activable tumor-targeting delivery systems with controllable cancer-cell binding to potentially enable highly specific and efficient cancer therapy.