Redox-Activated Porphyrin-Based Liposome Remote-Loaded with IDO Inhibitor for Synergistic Photoimmunotherapy through Induction of Immunogenic Cell Death and Blockage of IDO Pathway.

Abstract

Immunotherapy through stimulating host immune system has emerged as a powerful therapeutic strategy for various malignant and metastatic tumors in clinic. However, harnessing the immune system for cancer treatment often fails to obtain a durable response rate due to the poor immunogenicity and the strong immunosuppressive milieu in tumor site. Herein, a redox-activated liposomes was developed from the self-assembly of porphyrin-phospholipid conjugate and co-encapsulation of IDO inhibitor into interior lumen via remote-loading for simultaneous induction of immunogenic cell death (ICD) and reversing of suppressive tumor microenvironment. The nanoparticle exhibited prolonged blood circulation and enhanced tumor accumulation in 4T1 tumor bearing mice after intravenous injection. The nanovesicle could render exponential activation of fluorescence signal and PDT activity (>100-fold) in response to high level of intracellular GSH after endocytosed by tumor cells, thereby achieving effective inhibition of tumor growth and reduced phototoxicity to normal tissues owing to the activatable design of nanoparticle. More importantly, redox-activated PDT induced intratumoral infiltration of cytotoxic T lymphocytes by induction of ICD of tumor cells. After combination with IDO inhibitor, the systemic antitumor immune response was further augmented. Hence, we believe that the present nanovesicle strategy has the potential for the synergistic immunotherapy of the metastatic cancers. KEYWORDS: redox-activatable liposome, immunotherapy, photodynamic therapy, immunogenic cell death, synergistic effect.