Tumor-targeted nanoparticle delivery of HuR siRNA inhibits lung tumor growth in vitro and in vivo by disrupting the oncogenic activity of the RNA-binding protein HuR

摘要

Selective downregulation of the human antigen R (HuR) protein by siRNA may provide a powerful approach for treating lung cancer. To this end, we investigated the efficacy of transferrin receptor-targeted liposomal nanoparticle-based HuR siRNA (HuR-TfNP) therapy and compared to control siRNA (C)-TfNP therapy both, in vitro and in vivo using lung cancer models.In vitro studies showed HuR-TfNP but not C-TfNP efficiently downregulated HuR and HuR-regulated proteins in A549, and HCC827 lung cancer cells resulting in reduced cell viability, inhibition of cell migration and invasion, and induction of G1 cell-cycle arrest culminating in apoptosis. However, HuR-TfNP activity in normal MRC-9 lung fibroblasts was negligible. In vivo biodistribution study demonstrated that fluorescently labeled HuR-siRNA or ICG dye loaded TfNP localized in tumor tissues. Efficacy studies showed intratumoral or intravenous administration of HuR-TfNP significantly inhibited A549 (>55% inhibition) and HCC827 (>45% inhibition) subcutaneous tumor growth compared to C-TfNP. Furthermore, HuR-TfNP treatment reduced HuR, Ki67, and CD31 expression and increased caspase-9 and PARP cleavage and TUNEL positive staining indicative of apoptotic cell death in tumor tissues compared to C-TfNP treatment. The antitumor activity of HuR-TfNP was also observed in an A549-luc lung metastatic model, as significantly fewer tumor nodules (9.5±3.1; p<0.001; 88% inhibition) were observed in HuR-TfNP-treated group compared with the C-TfNP-treated group (77.7±20.1). Significant reduction in HuR, Ki67, and CD31 expression was also observed in the tumor tissues of HuR-TfNP-treatment compared to C-TfNP treatment.Our findings highlight HuR-TfNP as a promising nano-therapeutic system for lung cancer treatment.