Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
PCFM Lab of Ministry of Education, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou, China.
Hepatology. 2016 Apr;63(4):1240-55. doi: 10.1002/hep.28409. Epub 2016 Feb 19.
Because the primary surgical treatment options for hepatocellular carcinoma (HCC)-including hepatic resection and liver transplantation-often fail due to recurrence and metastasis, identifying early prognostic biomarkers and therapeutic targets for HCC is of great importance. This study shows that transducin β-like protein 1-related protein (TBLR1) is a key HCC oncogene that plays important roles in HCC proliferation, antiapoptosis, and angiogenesis by regulating the Wnt/β-catenin pathway. The folate-targeted theranostic small interfering RNA (siRNA) nanomedicine Fa-PEG-g-PEI-SPION/psiRNA-TBLR1 effectively silences the TBLR1 gene in different human HCC cell lines in vitro and in human HCC samples in vivo, resulting in the simultaneous suppression of HCC cell proliferation, antiapoptosis, and angiogenesis. Because of its multi-anticancer functions against HCC, intravenous injection of the folate-targeted siRNA nanomedicine into nude mice bearing intrahepatic or subcutaneous xenografts of human HCC has a significant therapeutic effect. Tumor growth in those animals was almost completely inhibited by treatment with Fa-PEG-g-PEI-SPION/psiRNA-TBLR1. Moreover, the SPION-encapsulated polyplexes possess high magnetic resonance imaging (MRI) detection sensitivity, which makes tumor-targeted siRNA delivery easily trackable using the clinical MRI technique.
The theranostic siRNA nanomedicine examined here possesses great theranostic potential for combined gene therapy and MRI diagnosis of HCC.
由于原发性肝癌（HCC）的主要治疗选择，包括肝切除术和肝移植，往往由于复发和转移而失败，因此确定 HCC 的早期预后生物标志物和治疗靶点非常重要。本研究表明，转导素β样蛋白 1 相关蛋白（TBLR1）是 HCC 的关键癌基因，通过调节 Wnt/β-catenin 通路，在 HCC 增殖、抗凋亡和血管生成中发挥重要作用。叶酸靶向治疗性小干扰 RNA（siRNA）纳米药物 Fa-PEG-g-PEI-SPION/psiRNA-TBLR1 可有效沉默不同人 HCC 细胞系中的 TBLR1 基因，并在体内人 HCC 样本中沉默 TBLR1 基因，导致 HCC 细胞增殖、抗凋亡和血管生成同时受到抑制。由于其对 HCC 的多种抗癌作用，将叶酸靶向 siRNA 纳米药物静脉注射到荷有人 HCC 肝内或皮下异种移植瘤的裸鼠中具有显著的治疗效果。用 Fa-PEG-g-PEI-SPION/psiRNA-TBLR1 治疗可几乎完全抑制这些动物的肿瘤生长。此外，封装 SPION 的聚阳离子复合物具有高磁共振成像（MRI）检测灵敏度，使得使用临床 MRI 技术很容易追踪肿瘤靶向 siRNA 递送至肿瘤部位。
本文研究的治疗性 siRNA 纳米药物具有联合基因治疗和 HCC MRI 诊断的巨大治疗潜力。
