A universal aptamer chimera for the delivery of functional microRNA-126

JH Rohde, JE Weigand, B Suess… - nucleic acid …, 2015 - liebertpub.com
nucleic acid therapeutics, 2015liebertpub.com
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 …
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 1.6×106±0.3×106 copies miR-126-3p per ng RNA in human endothelial cells and 7.4×105±2×105 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.
Mary Ann Liebert