Abstract 1071: Mir-145 based magnetic nanoformulation for pancreatic cancer therapy

Abstract

Abstract Background: Pancreatic cancer (PanCa) is the fourth leading cause of cancer related deaths in the USA, with a 5-year survival rate of less than 5%. MicroRNAs have been identified as attractive targets for therapeutic intervention. The functional significance of lost microRNAs have been reported in several human malignancies, including PanCa. Therefore, restoring lost miRNA function can provide a potential therapeutic benefit. Prior work has identified microRNA-145 (miR-145) as a tumor suppressor miRNA in pancreatic cancer. The restoration of miR-145 downregulates a number of oncogenes including mucin MUC13, a glycoprotein that is aberrantly expressed in PanCa, and efficiently inhibits tumor growth in mice. The main challenge for successful translation of microRNAs into clinical practice remains an effective in vivo delivery system. The focus of this study was to develop and assess the efficacy of a miR-145 based nanoparticle formulation for PanCa treatment. Methods: Magnetic nanoparticle (MNP) based nanoformulation of miR-145 (miR-145-MNPF) was developed for the intracellular delivery and sustained release of miR-145. The positively charged polyethyleneimine molecules were used to increase the loading efficiency of miR-145. MUC13 expressing pancreatic ductal adenocarcinoma cell lines (HPAF-II and AsPC-1) were used for the study. Following transfection of miR-145-MNPF, Western blotting and immunofluorescence techniques were used to investigate the effects of miR-145 restoration on number of proteins including MUC13. Additionally, functional studies of the effects of miR-145 restitution using miR-145-MNPF included cell proliferation, colony formation, cell migration, and cell invasion assays. Results: miR-145 expression was progressively suppressed over the course of development from PanIN I-III to late stage poorly differentiated PDAC. Treatment of cells with miR-145-MNPF led to efficient intracellular delivery of miR-145 mimics as observed through prussian blue staining. This led to the simultaneous upregulation of miR-145 levels in cells as confirmed by qRT-PCR. miR-145 restitution resulted in significant downregulation of target oncogenes including MUC13, HER2, P-AKT and p53 as observed through Western blotting and immunofluorescence techniques. miR-145-MNPF inhibited cell proliferation, clonogenicity, migration, and invasion of PanCa cells. MNPF mediated restitution of miR-145 effectively sensitizes PanCa cells for paclitaxel and TRAIL therapy. Conclusions: 1) MNP based delivery systems can be efficiently used for microRNA replacement therapy in order to restore lost microRNAs in cancer. 2) miR-145-MNPF efficiently restores miR-145 in pancreatic cancer cells and inhibits growth and invasion of PanCa. 3) miR-145 restitution using miR-145-MNPF may offer a potential therapeutic strategy for pancreatic cancer treatment alone or in combination with other therapies. Citation Format: Saini Setua, Sheema Khan, Murali Mohan Yallapu, Mohammed Sikander, Stephen W. Behrman, Meena Jaggi, Subhash C. Chauhan. Mir-145 based magnetic nanoformulation for pancreatic cancer therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1071.