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Development of a novel DNA oligonucleotide targeting low-density lipoprotein receptor

Wang, T., Rahimizadeh, K. and Veedu, R.N. (2019) Development of a novel DNA oligonucleotide targeting low-density lipoprotein receptor. Molecular Therapy - Nucleic Acids, 19 . pp. 190-198.

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Low-density lipoprotein receptor (LDL-R) is a cell surface receptor protein expressed in a variety of solid cancers including lung, colon, breast, brain and liver, therefore opens up opportunities to deliver lysosome sensitive anti-cancer agents, especially synthetic nucleic acid-based therapeutic mole- cules. In this study, we focused on developing novel nucleic acid molecules specific to LDL-R. For this purpose, we performed in vitro selection procedure via SELEX methodologies using mammalian cell- expressed human recombinant LDL-R protein as a target. After ten rounds of selections, we identified a novel DNA oligonucleotide aptamer, RNV-L7, that can bind specifically to LDL-R protein with high affinity and specificity (Kd = 19.6 nM). Furthermore, flow cytometry and fluorescence imaging assays demonstrated efficient binding to LDL-R over-expressed human cancer cells including Huh-7 liver can- cer cells and MDA-MB-231 breast cancer cells with a binding affinity of ∼200 nM. Furthermore, we evaluated the functional potential of the developed LDL-R aptamer RNV-L7 by conjugating with a pre- viously reported miR-21 targeting DNAzyme for inhibiting miR-21 expression. The results showed that the miR-21 DNAzyme-RNV-L7 aptamer chimera efficiently reduced the expression of miR-21 in Huh- 7 liver cancer cells. As currently there are no reports on LDL-R aptamer development, we believe that RNV-L7 could be beneficial towards the development of targeted cancer therapeutics.

Item Type: Journal Article
Murdoch Affiliation(s): Centre for Molecular Medicine and Innovative Therapeutics (CMMIT)
Publisher: Elsevier
Copyright: © 2019 The Author(s).
United Nations SDGs: Goal 3: Good Health and Well-Being
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