Synergizing photodynamic therapy and ethanol ablation: Light‐activatable sustained‐exposure ethanol injection technology for enhanced tumor ablation

Chemical ablative therapies offer effective alternatives for tumor treatment, particularly when surgical resection or heat‐based ablation therapies are unsuitable due to the tumor's stage, location, or extent. Photodynamic therapy (PDT), which involves delivering light‐activated, tumor‐killing photosensitizers, and percutaneous ethanol injection (PEI), which involves the direct injection of pure ethanol into tumor nodules, are two non‐heat‐based chemical ablative methods that have been proven safe with low adverse effects for unresectable tumors. We have investigated combining these two treatments using a new formulation known as BPD‐EC‐EtOH. This formulation includes three components: (1) benzoporphyrin derivative, a commonly used photosensitizer for PDT; (2) ethyl cellulose (EC), an FDA‐approved polymer that forms a gel in the water phase and enhances drug retention; and (3) pure ethanol for PEI application. Here, we demonstrated the localization of BPD and confirmed that it retains its photochemical properties within the EC‐EtOH gel in tissue‐mimicking phantoms and in swine liver tissues. We also characterized EC's ability to act as a light‐scattering agent, which effectively extends light propagation distance in both in vitro models and ex vivo porcine liver tissues, potentially overcoming the limitations of light penetration in pigmented organs. We then investigated the therapeutic effects of BPD‐EC‐EtOH using two well‐established subcutaneous animal models of hepatocellular carcinoma and pancreatic ductal adenocarcinoma, both in single‐ and multi‐cycle combination treatments, showing tumor‐killing effects. These findings highlight the potential of BPD‐EC‐EtOH as a novel therapeutic approach, effective with either single or multi‐cycle treatment sessions.