Mitochondria-Targeted Icaritin Nanoparticles Induce Immunogenic Cell Death in Hepatocellular Carcinoma
Siyu Chen, Yiyang Sun, Yangla Xie, Yanpeng Liu, Haitao Hu, Chang Xie, Shengjun Xu, Z. G. Zhang, Jing Zhang, Youqing Shen, Xiao Xu, Nasha Qiu
Abstract
Hepatocellular carcinoma (HCC) is a highly malignant tumor that is resistant to chemotherapy and immunotherapy. Icaritin (ICT), a traditional Chinese medicine, has been reported as an immunoregulatory agent for treating advanced unresectable HCC. ICT induces mitophagy to cause immunogenic cell death (ICD); however, the poor bioavailability of ICT limits its therapeutic efficacy and clinical use. Therefore, this study aimed to assess the effect of using the poly(2-( N -oxide- N, N -diethylamino) ethyl methacrylate)- b -poly(ε-caprolactone) copolymer (OPDEA-PCL) to encapsulate ICT into nanoparticles (ICT NPs). OPDEA-PCL/ICT NPs colocalized with the mitochondria, promoting the ICD induction effect of ICT in mouse HCC H22 cells. In the H22 subcutaneous tumor model, intravenously injected OPDEA-PCL/ICT NPs quickly accumulated in the tumor and efficiently activated systemic anticancer immunogenicity through their effects on mitophagy. The resulting tumor suppression rate was 60%, which was significantly higher than that of free ICT and poly(ethylene glycol) (PEG)-PCL/ICT NPs. Furthermore, mouse survival was also prolonged by nearly 2-fold with OPDEA-PCL/ICT NPs compared with PBS. In summary, this approach provides valuable insights into improving the immunotherapeutic efficacy of ICT for HCC.