Dual functional BAFF receptor aptamers inhibit ligand-induced proliferation and deliver siRNAs to NHL cells

作者：Zhou Jiehua; Tiemann Katrin; Chomchan Pritsana; Alluin Jessica; Swiderski Piotr; Burnett John; Zhang Xizhe; Forman Stephen; Chen Robert; Rossi John^*

来源：Nucleic Acids Research, 2013, 41(7): 4266-4283.

DOI：10.1093/nar/gkt125

The B-cell-activating factor (BAFF)-receptor (BAFF-R) is restrictedly expressed on B-cells and is often overexpressed in B-cell malignancies, such as non-Hodgkin's lymphoma. On binding to its ligand BAFF, proliferation and cell survival are increased, enabling cancer cells to proliferate faster than normal B-cells. Nucleic acid aptamers can bind to target ligands with high specificity and affinity and may offer therapeutic advantages over antibody-based approaches. In this study, we isolated several 2'-F-modified RNA aptamers targeting the B-cell-specific BAFF-R with nanomolar affinity using in vitro SELEX technology. The aptamers efficiently bound to BAFF-R on the surface of B-cells, blocked BAFF-mediated B-cell proliferation and were internalized into B-cells. Furthermore, chimeric molecules between the BAFF-R aptamer and small interfering RNAs (siRNAs) were specifically delivered to BAFF-R expressing cells with a similar efficiency as the aptamer alone. We demonstrate that a signal transducer and activator of transcription 3 (STAT3) siRNA delivered by the BAFF-R aptamer was processed by Dicer and efficiently reduced levels of target mRNA and protein in Jeko-1 and Z138 human B-cell lines. Collectively, our results demonstrate that the dual-functional BAFF-R aptamer-siRNA conjugates are able to deliver siRNAs and block ligand mediated processes, suggesting it might be a promising combinatorial therapeutic agent for B-cell malignancies.

• 出版日期2013-4