Fluorination of Aza-BODIPY for Cancer Cell Plasma Membrane-Targeted Imaging and Therapy

Photodynamic therapy (PDT) holds great potential in cancer treatment, leveraging photosensitizers (PSs) to deliver targeted therapy. Fluorination can optimize the physicochemical and biological properties of PSs for better PDT performance. Here, we report some high-performance multifunctional PSs specifically designed for cancer PDT by fluorinating aza-BODIPY with perfluoro-tert-butoxymethyl (PFBM) groups. Fluorination plays several roles, including enhancing selective cancer cell uptake, plasma membrane (PM) targeting, and inducing pyroptosis. It also enables fluorescence imaging (FLI) and fluorine-19 magnetic resonance imaging (19F MRI) as well as facilitates oxygen delivery and oxygen partial pressure (pO2) measurements. Comparative physicochemical and biological studies, along with molecular dynamics simulations, reveal that fluorinated PSs selectively eradicate cancer cells by oxidizing PM phospholipids with singlet oxygen (1O2) and inducing pyroptosis, which enables effectively suppressed tumor growth by self-oxygenated 19F MRI-FLI-guided PDT in mice. This study demonstrates a fluorination strategy for tailoring high-performance multifunctional cancer PM-targeting materials for cancer therapy and beyond.