Napabucasin-loaded PLGA nanoparticles trigger anti-HCC immune responses by metabolic reprogramming of
Zhenwei Song1, Hongfei Chen2, Xueyao Wang1
1Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, China.
Background:
JAK/STAT3 is one of the critical signaling pathways involved in the occurrence and development of hepatocellular carcinoma (HCC). BBI608 (Napabucasin), as a novel small molecule inhibitor of STAT3, has shown previously excellent anti-HCC effects in vitro and in mouse models. However, low bioavailability, high cytotoxicity and other shortcomings limit its clinical application. In this study, PLGA was selected to prepare Napabucasin PLGA nanoparticles (NPs) by solvent evaporation method, overcoming these limitations and improving the passive targeting effect that nanoparticle mediated. Base on this, we systematically evaluated the anti-HCC effect of Napabucasin-PLGA NPs and explored the underlying mechanisms.
Methods:
Napabucasin-PLGA NPs were prepared by solvent evaporation method. CCK-8 assay, Annexin V/PI double staining, RT-qPCR, colony formation assay, and Western blotting were performed to evaluate the anti-HCC effect of Napabucasin-PLGA NPs in vitro. Proliferation assay and migration assay were used to detect the effects of Napabucasin-PLGA NPs-treated HCC-TAMs on tumor biological characteristics of HCC cells. Flow cytometry was used to detect anti-HCC immune responses induced by Napabucasin-PLGA NPs in vivo.
Results:
Our results demonstrated that Napabucasin-PLGA NPs could improve the bioavailability of Napabucasin and enhance Napabucasin-mediated the anti-HCC effects in vitro and in vivo with no significant drug toxicity. In addition to the direct inhibitory effects on the tumor biological characteristics of HCC cells, Napabucasin-PLGA NPs could promote the polarization of macrophages from tumor-promoting M2-type to anti-tumor M1-type, improving the tumor immune microenvironment and augmenting T cell-mediated anti-tumor responses. The underlining mechanisms showed Napabucasin-PLGA NPs suppressed the STAT3/FAO signaling axis in HCC-induced tumor-associated macrophages (TAMs).
Conclusions:
These findings demonstrated Napabucasin-PLGA NPs is a potential therapeutic candidate for HCC, and provided a new theoretical and experimental basis for further development and clinical application of Napabucasin.
