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

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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.