Abstract
Abstract MicroRNAs (miRNAs) are small (18-22 nucleotide long) non-coding RNAs that play important roles in biological processes through post-transcriptional regulation of gene expression. Their aberrant expression and functional significance are reported in several human malignancies, including pancreatic cancer (PC). Recently, we identified miR-150 as a novel tumor suppressor microRNA in PC and demonstrated that its overexpression inhibits growth and malignant behavior of PC cells suggesting that restoration of miR-150 could serve as an effective therapeutic approach for pancreatic cancer. In the present study, we have developed a nanoparticle-based miR-150 delivery system and tested its therapeutic efficacy by in vitro assays. Using double emulsion solvent evaporation method, we developed a poly (D, L-lactide-co-glycolide) (PLGA)-based nanformulation (NF) of miR-150 (miR-150-NF). Polyethyleneimine (a cationic polymer) was incorporated in PLGA matrix to increase the encapsulation of miR-150. Physical characterization of miR-150-NF demonstrated that miR-150-loaded nanoparticles were spherical in shape, had high encapsulation efficiency (>75%), were stable at room temperature and exhibited sustained release profile. miR-150-NF efficiently delivered miR-150 mimics to PC cells and led to the downregulation of its target gene (MUC4) expression. Downregulation of MUC4 correlated with a concomitant decrease in the expression of its interacting partner, HER2, and repression of its downstream signaling. Furthermore, treatment of PC cells with miR-NF suppressed their growth, clonogenicity, motility and invasion. Together, these findings suggest that PLGA-based nanovector platform could be a potential candidate for systemic delivery of miR-150 to the pancreatic tumor cells and can be a step forward in miRNA-based cancer therapeutics. Citation Format: Sumit Arora, Suresh K. Swaminathan, Sanjeev K. Srivastava, Seema Singh, Jayanth Panyam, Ajay P. Singh. Development of miRNA-loaded polymeric nanoformulation for pancreatic cancer therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1457. doi:10.1158/1538-7445.AM2014-1457
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