Multifunctional photo-responsive liposomes for tumor imaging and phototherapy to enhance the antitumor efficacy and reduce the hepatotoxicity of methotrexate

Abstract Methotrexate (MTX) is a chemotherapy drug widely applied in clinical treatment for various tumors. However, side effects caused by MTX greatly affect the therapeutic efficacy. Hence, photo-triggered release liposomes were constructed by amphiphilic photosensitizers ZnPc(PEG)4 and phospholipid materials DPPC to load MTX for improved antitumor effect. It was demonstrated that ZnPc(PEG)4 integrated into lipid layers endowed final product ZnPc(PEG)4:MTX@LiPOs improved stability. ZnPc(PEG)4:MTX@LiPOs was verified to have excellent characteristics in terms of photo-triggered release, ROS generation and heat production. In particular, cellular experiments indicated that ZnPc(PEG)4:MTX@LiPOs had synergistic cytotoxicity of phototherapy and chemotherapy. The cell uptake assay demonstrated that the internalization of MTX into tumor cells was significantly increased by the encapsulation of ZnPc(PEG)4@LiPOs. ZnPc(PEG)4:MTX@LiPOs was confirmed to possess excellent tumor targeting reflected in faster accumulation, higher drug level and longer retention at tumor sites than free ZnPc(PEG)4. In addition, ZnPc(PEG)4:MTX@LiPOs had significantly enhanced tumor inhibition rate. What's more, liver histopathology and serum enzyme tests indicated that ZnPc(PEG)4:MTX@LiPOs had distinctly reduced hepatotoxicity than MTX. The constructed liposomes with photo-triggered release can be applied to deliver other chemotherapy drugs for synergistic antitumor ability and reduced side effect.