A tumor-pH-responsive phthalocyanine as activatable type I photosensitizer for improved photodynamic immunotherapy

The development of a simple drug formulation capable of achieving both activatable type I photoreaction and tumor-responsive release of immunomodulator is crucial for advancing photodynamic immunotherapy (PDIT). Herein, we present a nanostructured photosensitizer (NP5) that is activated by the acidic tumor microenvironment to produce type I reactive oxygen species (ROS) under light irradiation and release the immunomodulator demethylcantharidin (DMC) for PDIT. The NP5 is formed by self-assembly of a versatile phthalocyanine molecule which is composed of DMC and phthalocyanine linked via a pH-responsive amide bond. NP5 produces minimal ROS under light irradiation at the condition of pH 7.4. However, NP5 can release DMC at the condition of pH 6.5 and concurrently trigger type I photoreactions. The results of in vivo experiments indicate that NP5-mediated PDIT induce the increase of cytotoxic T lymphocytes and decrease of regulatory T lymphocytes, which can effectively inhibit the bilateral tumor growth. This work is anticipated to serve as a reference for the development of innovative agents for precise PDIT of hypoxic tumors.