Nanomedicine-mediated induction of immunogenic cell death and prevention of PD-L1 overexpression for enhanced hepatocellular carcinoma therapy

Abstract

Background: The present study aims to develop a nanoparticle encapsulating doxorubicin (DOX) and programmed death-ligand 1 (PD-L1) siRNA and evaluate its anti-tumor effects on hepatoma carcinoma (HCC). Methods: Nanoparticle encapsulating DOX and PD-L1 siRNA (NPDOX/siPD-L1) was characterized by dynamic light scattering and transmission electron microscopy. Flow cytometry was applied to analyze cell populations, NPDOX/siPD-L1 internalization, and cell apoptosis. Real-Time (RT)-quantitative reverse transcription (qPCR) and western blotting were used to determine the mRNA and protein levels, respectively. Released ATP was determined using ATP determination kit and cytokines were determined using specific ELISAs. A tumor-bearing animal model was established to evaluate the anti-tumor effects of NPDOX/siPD-L1. Results: Treatment of NPDOX/siPD-L1 induced immunogenic cell death (ICD) and PD-L1 overexpression in HCC. In vivo study demonstrated that intravenously injection of NPDOX/siPD-L1 significantly inhibited the tumor volume and PD-L1 expressions of tumor tissue in the H22 tumor-bearing animal model. Besides, the treatment of NPDOX/siPD-L1 also regulated the populations of matured dendritic cells and cytotoxic T cells and the productions of cytokines in the tumor tissues. Conclusion: Taken together, NPDOX/siPD-L1 showed significant anti-tumor effects on HCC by the induction of ICD and inhibition of PD-L1 overexpression.