Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, USA.
Center for RNA Nanobiotechnology and Nanomedicine, The Ohio State University, Columbus, OH, USA; College of Pharmacy, Division of Pharmaceutics and Pharmaceutical Chemistry, The Ohio State University, Columbus, OH, USA; College of Medicine, Dorothy M. Davis Heart and Lung Research Institute and James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
Redox Biol. 2019 Feb;21:101085. doi: 10.1016/j.redox.2018.101085. Epub 2018 Dec 18.
We have previously demonstrated that DGLA treatment along with Delta-5-Desaturase (D5D) siRNA in various types of cancer cells enhances the formation of 8-HOA from COX-2-catalyzed DGLA peroxidation, which in turn inhibits cancer cell growth and migration. However, delivery of naked siRNA remains a formidable challenge due to its "off-target" effect. In this study, we employed RNA nanotechnology for specific delivery of D5D-siRNA to xenograft colon tumors using 3WJ RNA nanoparticles. When a targeting module, i.e., the EpCAM aptamer, was incorporated, the 3WJ pRNA nanoparticles were able specifically deliver D5D siRNA to human colon cancer HCA-7 cells both in vitro and in vivo, resulting in significant downregulation of D5D expression. Co-treatment with DGLA in combination with 3WJ-EpCAM-siRNA induced a higher DGLA/AA ratio and enhanced formation of 8-HOA at a threshold level, and in HCA-7 tumor-bearing mice, induced significant tumor suppression. We further confirmed that 8-HOA formation, promoted by COX-2-catalyzed DGLA peroxidation, inhibited HDAC and consequently induced apoptosis in tumor cells. Therefore, the 3WJ RNA nanoparticle system holds great promise as a suitable therapeutic delivery platform for colon cancer therapy.
我们之前已经证明，在各种类型的癌细胞中，用 DGLA 处理并结合 Delta-5-Desaturase（D5D）siRNA 可以增强 COX-2 催化 DGLA 过氧化反应生成 8-HOA，从而抑制癌细胞生长和迁移。然而，由于其“脱靶”效应，裸 siRNA 的递送仍然是一个巨大的挑战。在这项研究中，我们使用 3WJ RNA 纳米颗粒的 RNA 纳米技术将 D5D-siRNA 特异性递送至异种移植结肠肿瘤。当整合靶向模块，即 EpCAM 适体时，3WJ pRNA 纳米颗粒能够在体外和体内特异性地将 D5D siRNA 递送至人结肠癌细胞 HCA-7，从而显著下调 D5D 表达。与 DGLA 联合治疗，同时使用 3WJ-EpCAM-siRNA，可诱导更高的 DGLA/AA 比值，并在阈值水平增强 8-HOA 的形成，在 HCA-7 荷瘤小鼠中，可显著抑制肿瘤。我们进一步证实，由 COX-2 催化的 DGLA 过氧化反应促进的 8-HOA 形成抑制了 HDAC，从而诱导肿瘤细胞凋亡。因此，3WJ RNA 纳米颗粒系统作为结肠癌治疗的合适治疗性递药平台具有巨大的应用前景。
Zotero 插件
