A Bioactive Photosensitizer for Hypoxia‐Tolerant Molecular Targeting‐Photo‐Immunotherapy of Malignant Tumor

Abstract

Photosensitizers (PSs) with effective reactive oxygen species generation ability against hypoxia are of great potential for clinical treatment of malignant tumors. However, complex tumor microenvironment, such as antioxidative responses and immunosuppression, would ineluctably limit the efficiency of photodynamic therapy (PDT). Herein, a molecular‐targeting photosensitizer QTANHOH is rationally designed for histone deacetylases (HDACs‐targeting photo‐immunotherapy application. The PS QTANHOH displays excellent type‐I/II PDT performance, exhibiting significant phototoxicity toward cancer cells with half maximal inhibitory concentration (IC50) less than 10 nm in both normoxia and hypoxia conditions under blue laser irradiation. Moreover, the bioactive compound could inhibit HDACs and activate the immune microenvironment to boost PDT efficacy on the immunocompetent BALB/c mice with breast cancer, leading to the eradication of solid tumor and inhibition of metastasis. Notably, the molecular‐targeting photosensitizer introduces an alternative strategy to achieve superior phototherapy for cancer therapy.

DNA-Targeting Bioactive Photosensitizer for Chemo-Photodynamic Therapy of Malignant Tumor

“…20 Our study demonstrated that it is feasible to combine photosensitizers with targeted bioactive pharmacophores to design bioactive photosensitizers that simultaneously exert photodynamic and chemotherapy effects. Based on the above discussion, as well as our previous work on quinoxalinone skeleton based photosensitizers that usually show good light harvesting and photosensitization efficiencies, 20,42,43 herein, we further propose a design strategy for DNA targeted bioactive photosensitizers, aiming at chemophotodynamic synergistic therapy via single-molecule integration of DNA-targeting chemotherapy drugs and photosensitizers. The main design concept involves (1) the incorporation of chlormethine as a DNA alkylating chemotherapeutic moiety to effectively target DNA and damage DNA through a cross-linking reaction; (2) the integration of dimethylamino into the molecule to further enhance the interaction between the photosensitizer and DNA (please see the binding free energy results in Table S1) and improve hydrophily (please see the oil−water partition coefficients (log P) in Table S1); (3) the introduction of the anthraquinone group with good redox properties, serving as electron acceptor to promote the electron transfer, 44,45 thereby facilitating the efficient production of type-I ROS (Figure 1A and B).…”