Sorafenib-loaded porphyrin-phospholipid liposomes for enhanced chemophototherapy in hepatocellular carcinoma.

Sorafenib (SF) remains a frontline chemotherapeutic agent for treating hepatocellular carcinoma (HCC). However, its clinical utility is severely hampered by systemic toxicity and the rapid emergence of drug resistance. To overcome these challenges, we developed a liposomal nanoplatform co-encapsulating SF and a porphyrin-phospholipid conjugate (2HPoP) for combined chemo-photodynamic therapy. The synthesized SF-loaded 2HPoP liposomes (2HPoP lip@SF) exhibited favorable physicochemical characteristics, including high encapsulation efficiency, colloidal stability, and prolonged storage stability. Upon 665 nm red-light laser irradiation, 2HPoP lip@SF demonstrated controlled drug release and robust reactive oxygen species (ROS) generation, enabling synergistic antitumor effects. In vitro, 2HPoP lip@SF combined with red-light laser irradiation significantly reduced the viability of liver cancer cells, demonstrating a superior eminent therapeutic effect compared to the free SF at equivalent concentrations. In addition, 2HPoP lip@SF with laser irradiation showed more effective tumor shrinkage than equivalent chemotherapy and PDT monotherapies in a mouse model of human HCCLM3 tumors. In summary, we present a facile yet effective strategy for co-delivering SF and a photosensitizer within a single liposomal system. The 2HPoP lip@SF formulation not only enhances therapeutic efficacy but also provides a clinically translatable approach for improving HCC treatment outcomes.