title: A Universal Aptamer Chimera for the Delivery of Functional microRNA-126.
abstract: microRNAs (miRs) regulate vascular diseases such as atherosclerosis and cancer. miR-126 is important for endothelial cell signaling and promotes angiogenesis, protects against atherosclerosis, and reduces breast cancer cell growth and metastasis. The overexpression of miR-126, therefore, may be an attractive therapeutic strategy for the treatment of cardiovascular disease or cancer. Here we report a novel strategy to deliver miR-126 to endothelial and breast cancer cells. We tested three different strategies to deliver miR-126 by linking the miR to an aptamer for the ubiquitously expressed transferrin receptor (transferrin receptor aptamer, TRA). Linking the precursor of miR-126 (pre-miR-126) to the TRA by annealing of a complementary stick led to efficient uptake and processing of miR-126, resulting in the delivery of 1.6×10(6)±0.3×10(6) copies miR-126-3p per ng RNA in human endothelial cells and 7.4×10(5)±2×10(5) copies miR-126-3p per ng in MCF7 breast cancer cells. The functionality of the active TRA-miR-126 chimera was further demonstrated by showing that the chimera represses the known miR-126 target VCAM-1 and improved endothelial cell sprouting in a spheroid assay. Moreover, the TRA-miR-126 chimera reduced proliferation and paracrine endothelial cell recruitment of breast cancer cells to a similar extent as miR-126-3p mimics introduced by conventional liposome-based transfection. Together, this data demonstrates that pre-miR-126 can be delivered by a non-specific aptamer to exert biological functions in two different cell models. The use of the TRA-miR-126 chimera or the combination of the delivery strategy with other endothelial or tumor specific aptamers may provide an interesting therapeutic option to treat vascular disease or cancers.
authors.affiliation: 1Institute for Cardiovascular Regeneration, Center of Molecular Medicine, Goethe University Frankfurt, Frankfurt, Germany.
authors.forename: Jan-H
authors.initials: JH
authors.lastname: Rohde
authors.affiliation: 2Department of Biology, Technical University Darmstadt, Darmstadt, Germany.
authors.forename: Julia E
authors.initials: JE
authors.lastname: Weigand
authors.affiliation: 2Department of Biology, Technical University Darmstadt, Darmstadt, Germany.
authors.forename: Beatrix
authors.initials: B
authors.lastname: Suess
authors.affiliation: 1Institute for Cardiovascular Regeneration, Center of Molecular Medicine, Goethe University Frankfurt, Frankfurt, Germany.|3German Centre for Cardiovascular Research (DZHK), RheinMain, Frankfurt, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dimmeler
mesh_terms: D052157:Aptamers, Nucleotide / Q000737:chemistry*; D002678:Chimera; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D052157:Aptamers, Nucleotide; D035683:MicroRNAs