Nano co-delivery of Plumbagin and Dihydrotanshinone I reverses immunosuppressive TME of liver cancer

• Published in: Journal of controlled release Vol. 348; pp. 250 - 263
• Main Authors: Han, Shulan, Bi, Shengnan, Guo, Tingting, Sun, Dandan, Zou, Yifang, Wang, Lingzhi, Song, Liu, Chu, Di, Liao, Anqi, Song, Xiaohuan, Yu, Zhuo, Guo, Jianfeng
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.08.2022
• Subjects: Biomimetic nanoformulation; cancer immunotherapy; Combination therapy; Hepatocellular carcinoma; Traditional herbal medicine; TAM; MDSC; DMSO; PFA; HMGB1; MTT; IFN-γ; RBC; GM-CSF; FBS; UPR; IC50; CLSM; DAMs; IL; MR; H&E; DAPI; DSPE-PEG-Man; HCC; ER; PVDF; ROS; RBCD; ATF6; NK; ELISA; NP; CRT; CTLs; PLB; Hepatocellular carcinoma; PERK; Combination therapy; DMEM; DCs; IRE1; TAAs; TGF-β; HPLC; CD; DIH; CI; Biomimetic nanoformulation; ICD; Traditional herbal medicine; TME; BMDCs; ECL; NAC; PLGA; cancer immunotherapy; LC; ATP
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2022.05.057

Hepatocellular carcinoma (HCC) is resistant to current immunotherapy. This poor outcome mainly results from the immunosuppressive characteristics of tumor microenvironment (TME). Accumulating evidence indicates that some chemotherapy agents trigger immunogenic cell death (ICD), providing a promising strategy to remodel the immunosuppressive TME. The role of Plumbagin (PLB, a naphthoquinone compound from Plumbago zeylanica L.) as the ICD inducer for HCC cells was confirmed in this study. Dihydrotanshinone I (DIH, a phenanthraquinone compound of Salvia miltiorrhiza) functioned as the ICD enhancer by generating the reactive oxygen species (ROS). A poly(D,L-lactic-co-glycolic acid) (PLGA)-based nanoparticle (NP) was used to co-encapsulate PLB, DIH and NH4HCO3 (a pH sensitive adjuvant). This NP was further coated with the mannose-inserted erythrocyte membrane to produce a nanoformulation. This nanoformulation significantly increased the half-life and tumor targeting of two drugs in orthotopic HCC mice, generating chemo-immunotherapeutic effects for reversal of immunosuppressive TME. Consequently, the biomimetic nanoformulation loaded with low doses of PLB and DIH achieved significantly longer survival of HCC mice, without causing toxic signs. Our study demonstrates a promising strategy for remodeling the immunosuppressive TME of liver cancer. Co-delivery of Plumbagin and Dihydrotanshinone I using biomimetic NPs for reversal of immunosuppressive TME in HCC. [Display omitted] •Plumbagin functions as an ICD inducer against HCC.•Dihydrotanshinone I generates ROS to enhance the ICD effects of PLB.•A biomimetic co-nanoformulation reverses the immunosuppressive tumor microenvironment of HCC.