Development of EpCAM aptamer-siRNAs for Therapeutic Gene Silencing in Orthotopic Pancreatic Tumor Mouse Model

用于原位胰腺肿瘤小鼠模型中治疗性基因沉默的 EpCAM 适体-siRNA 的开发

• 批准号: 405039945
• 负责人: Dr. Dian-Jang Lee
• 金额: --
• 依托单位: Immune Disease Institute (aufgelöst)
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/405039945?language=en
• 关键词: Development; EpCAM; aptamer; siRNAs; Therapeutic

Pancreatic cancer is among the most lethal cancers, with 5-year survival rates averaging less than 5%, and currently there is still no satisfactory treatment for this malignancy. Small interfering RNA (siRNA)-based therapeutics have been developed with considerable promise as a new therapeutic tool in cancer treatments. Notably, epithelial cell adhesion molecule (EpCAM) is over-expressed in pancreatic cancer tissues, which distributed along the cell membrane. In contrast, in normal epithelia, EpCAM is only weakly expressed on non-druggable basolateral gap junctions. To facilitate tumor-specific uptake, in this study, antitumoral siRNA will be linked with an RNA aptamer that binds to EpCAM to generate EpCAM aptamer-siRNA. Moreover, it has been reported that approximately half of pancreatic cancer tissues are folate receptor (FR)-Alpha-positive, and noted that metastatic pancreatic carcinoma significantly express FR-Alpha. Thus, a valuable strategy would be ligand-based tumor targeting for FR. For this purpose, we will formulate EpCAM aptamer-siRNA with folate-conjugated targeted lipopolyplexes (TLPs), which may facilitate pharmacokinetic profile and tumoral retention of siRNA. To evaluate the therapeutic efficacy in similar tumor microenvironment as the primary tumor, we will establish orthotopic pancreatic tumor mouse model and monitor the antitumoral effect of EpCAM aptamer-siRNA TLPs. Taken together, we hope that the design of such siRNA delivery system with dual targeting strategy (EpCAM and FR) may represent a novel approach for translating RNAi-based cancer therapeutics to the clinics.

胰腺癌是最致命的癌症之一，5年生存率平均低于5%，目前仍然没有令人满意的治疗方法。基于小干扰RNA（siRNA）的治疗剂已经被开发为具有相当大的希望作为癌症治疗中的新治疗工具。值得注意的是，上皮细胞粘附分子（EpCAM）在胰腺癌组织中过表达，其沿细胞膜分布沿着。相比之下，在正常上皮中，EpCAM仅在不可药物化的基底外侧间隙连接上弱表达。为了促进肿瘤特异性摄取，在本研究中，将抗肿瘤siRNA与结合EpCAM的RNA适体连接以产生EpCAM适体-siRNA。此外，据报道，大约一半的胰腺癌组织是叶酸受体（FR）-α阳性的，并且注意到转移性胰腺癌显著表达FR-α。因此，一个有价值的策略将是基于配体的肿瘤靶向FR。为此，我们将制定EpCAM适体-siRNA与叶酸结合的靶向脂质复合物（TLPs），这可能有助于药代动力学和肿瘤保留的siRNA。为了评估在与原发性肿瘤相似的肿瘤微环境中的治疗效果，我们将建立原位胰腺肿瘤小鼠模型并监测EpCAM适体-siRNA TLPs的抗肿瘤效果。综上所述，我们希望这种具有双重靶向策略（EpCAM和FR）的siRNA递送系统的设计可以代表将基于RNAi的癌症治疗转化为临床的新方法。