Seamlessly Overcoming Biological Barriers with a Small Photosensitizer to Treat Metastatic Tumors with Photodynamic Therapy

Abstract A breakthrough in the treatment of solid tumors requires primary tumor ablation and remission of metastasis. Photodynamic therapy (PDT) may meet these requirements, but current photosensitizers poorly infiltrate dense tumors and insufficiently stimulate the immune system. We introduce LUZ51, a small bacteriochlorin that features strong near‐infrared absorption, high photostability, moderate lipophilicity, amphiphilicity, and appropriate singlet oxygen quantum yield. LUZ51 has a fast cellular uptake via passive diffusion and EC50s of 5–15 nM range for a light dose of 1 J/cm 2 . It seamlessly crosses biological barriers and accumulates in tumors. Mice with CT26 tumors cured in one treatment (0.15 mg/kg and 20 J/cm 2 ) resisted tumor rechallenge. Treatment of mice with 5 mm orthotopic 4T1 tumors enabled cures, with the associated inhibition of metastasis. The blood half‐life is 82 min and no skin photosensitivity was detected. Small‐size LUZ51 enables tissue‐agnostic PDT, with strong local and systemic effects.