Photodynamic therapy (PDT) is a promising targeted tumor treatment strategy, and developing high-performance photosensitizers is crucial for its advancement. As excellent macrocyclic photosensitive dyes, subphthalocyanines (SubPcs) show great application potential in tumor PDT. In this study, four low-symmetry SubPc derivatives with gradient fluoro-chloro substitution (SubPc 4-7) were prepared via a one-pot method. Combined with theoretical calculations, the regulatory effects of halogen substitution on their photophysical and antitumor properties were systematically investigated. The results showed that increasing chlorine substitution ratio led to progressive redshifts in both absorption and fluorescence emission wavelengths. Fluorescence quantum yield was negatively correlated with singlet oxygen quantum yield, and the cumulative heavy-atom effect of multiple chlorine atoms effectively promoted intersystem crossing, thereby enhancing photosensitization capability. These derivatives exhibited good optical stability in aqueous environments and could target lysosomes of tumor cells to generate reactive oxygen species. In vitro experiments confirmed that SubPc 4 achieved a tumor cell killing rate of 82%. In vivo mouse models and tissue section analysis further verified its potent antitumor efficacy in PDT. This study provides an important experimental basis for the application of SubPc derivatives in targeted photodynamic antitumor therapy.

Key words: Photodynamic Therapy, Subphthalocyanine, Halogen substitution, Singlet oxygen, Lysosome targeting