Abstract 15038: A Universal Aptamer Chimera for the Delivery of Functional MicroRNA-126
MicroRNAs (miRs) regulate many diseases including vascular diseases such as atherosclerosis and cancer. MiR-126 is important for endothelial cell (EC) signaling, protects against atherosclerosis but reduces tumor angiogenesis by interfering with the paracrine release of pro-angiogenic signals in breast cancer cells. The overexpression of miR-126 therefore would be an attractive therapeutic strategy for the treatment of cardiovascular disease or cancer. Here, we report a novel strategy to deliver miR-126 to cells. For that purpose, we used aptamers, which can specifically bind to surface receptors and can deliver siRNAs. We first tested two different aptamers and showed that particularly the transferrin receptor aptamer (TRA) is efficiently taken up by EC. Next, we tested three different linking strategies to attach the mature or the pre-miR-126 to the transferrin receptor aptamer (TRA) for delivery. Linking the precursor of miR-126 (pre-miR-126) to TRA by annealing of a complementary stick (Ch3) displayed the most efficient uptake and processing of miR-126 (Figure). Treatment resulted in the delivery of 1.6x106±0.27x106 copies of miR-126-3p per ng RNA . The functionality of Ch3 was further demonstrated by the repression of the pro-inflammatory miR-126-3p target VCAM-1 and improved VEGF-induced sprouting in a spheroid assay (+39±14%, p<0.02). In MCF7 breast cancer cells, the TRA-miR-126 chimera was internalized, efficiently processed and reduced tumor cell proliferation by 36±8% and paracrine human EC recruitment by 33±8% to a similar extend as transfection of a conventional miR-126-3p mimic. Together, this data demonstrates that miR-126 delivery by TRA exerts biological functions in two different cell models. The use of Ch3 chimera or the combination of the delivery strategy with other EC or tumor specific aptamers may provide an interesting therapeutic option to treat vascular disease or attenuate tumor angiogenesis.
Author Disclosures: J. Rohde: None. J. Weigand: None. B. Suess: None. S. Dimmeler: None.
- © 2014 by American Heart Association, Inc.