Better in the Near Infrared: Sulfonamide Perfluorinated-Phenyl Photosensitizers for Improved Simultaneous Targeted...

Tetraphenyloporphyrin derivatives are a useful scaffold for developing new pharmaceuticals for photodynamic therapy (PDT) and the photodiagnosis (PD) of cancer. We synthesized new sulfonamide fluorinated porphyrin derivatives and investigated their potential as photosensitizers and real-time bioimaging agents for cancer. We found that 5,10,15,20-tetrakis-[2',3',5',6'-tetrafluoro-4'-methanesulfamidyl)phenyl]bacteriochlorin (F₄BMet) has intense absorption and fluorescence in the near-infrared, efficiently generates singlet oxygen and hydroxyl radicals, has low toxicity in the dark, and high phototoxicity. We increased its bioavailability with encapsulation in Pluronic-based micelles, which also improved the photodynamic effect. F₄BMet exhibits pH-dependent properties (lower pH promoted its aggregation), and a GlyGly buffer was used to effectively solubilize the compound. In vitro findings with 2D cell culture were complemented with human-induced pluripotent stem cell (hiPSC)-derived organoids. F₄BMet in P123 micelles showed enhanced efficacy compared to F₄BMet in the GlyGly formulation. F₄BMet was further evaluated in real-time bioimaging and PDT of BALB/c mice bearing CT26 tumors. After i.v. injection, the photosensitizer was visible in the tumor area 3 h after injection. The most successful therapeutic approach proved to be tumor-targeted PDT using P123-encapsulated F₄BMet illuminated 24 h after administration with a light dose of 42 J/cm², which led to a 30% long-term cure rate.